04620nas a2201141 4500008004100000022001400041245011000055210006900165260000900234300001200243490000700255520126600262653002401528653001301552653002301565653001101588653001501599653002001614100001901634700002301653700002201676700002101698700002001719700002301739700002101762700002601783700001901809700002001828700001901848700002201867700002301889700002401912700001701936700002101953700001701974700001601991700002402007700002502031700002502056700002302081700002302104700002702127700002402154700001602178700002102194700002602215700002502241700002102266700002102287700001902308700003202327700002102359700002202380700002002402700001902422700002602441700001802467700001802485700002302503700002102526700001902547700001902566700002202585700001802607700001902625700001802644700002302662700001802685700002002703700001902723700003302742700002602775700002702801700002502828700002302853700001802876700002302894700001702917700002402934700001802958700002202976700002502998700002003023700002303043700002003066700002603086700002003112700001903132700002203151700002203173700002003195700002303215700002103238700001803259700002403277710003503301856014203336 2024 eng d a1664-322400aDrug-target identification in COVID-19 disease mechanisms using computational systems biology approaches.0 aDrugtarget identification in COVID19 disease mechanisms using co c2023 a12828590 v143 a

INTRODUCTION: The COVID-19 Disease Map project is a large-scale community effort uniting 277 scientists from 130 Institutions around the globe. We use high-quality, mechanistic content describing SARS-CoV-2-host interactions and develop interoperable bioinformatic pipelines for novel target identification and drug repurposing.

METHODS: Extensive community work allowed an impressive step forward in building interfaces between Systems Biology tools and platforms. Our framework can link biomolecules from omics data analysis and computational modelling to dysregulated pathways in a cell-, tissue- or patient-specific manner. Drug repurposing using text mining and AI-assisted analysis identified potential drugs, chemicals and microRNAs that could target the identified key factors.

RESULTS: Results revealed drugs already tested for anti-COVID-19 efficacy, providing a mechanistic context for their mode of action, and drugs already in clinical trials for treating other diseases, never tested against COVID-19.

DISCUSSION: The key advance is that the proposed framework is versatile and expandable, offering a significant upgrade in the arsenal for virus-host interactions and other complex pathologies.

10aComputer Simulation10aCOVID-1910adrug repositioning10aHumans10aSARS-CoV-210aSystems biology1 aNiarakis, Anna1 aOstaszewski, Marek1 aMazein, Alexander1 aKuperstein, Inna1 aKutmon, Martina1 aGillespie, Marc, E1 aFunahashi, Akira1 aAcencio, Marcio, Luis1 aHemedan, Ahmed1 aAichem, Michael1 aKlein, Karsten1 aCzauderna, Tobias1 aBurtscher, Felicia1 aYamada, Takahiro, G1 aHiki, Yusuke1 aHiroi, Noriko, F1 aHu, Finterly1 aPham, Nhung1 aEhrhart, Friederike1 aWillighagen, Egon, L1 aValdeolivas, Alberto1 aDugourd, Aurélien1 aMessina, Francesco1 aEsteban-Medina, Marina1 aPeña-Chilet, Maria1 aRian, Kinza1 aSoliman, Sylvain1 aAghamiri, Sara, Sadat1 aPuniya, Bhanwar, Lal1 aNaldi, Aurélien1 aHelikar, Tomáš1 aSingh, Vidisha1 aFernández, Marco, Fariñas1 aBermudez, Viviam1 aTsirvouli, Eirini1 aMontagud, Arnau1 aNoël, Vincent1 aPonce-de-Leon, Miguel1 aMaier, Dieter1 aBauch, Angela1 aGyori, Benjamin, M1 aBachman, John, A1 aLuna, Augustin1 aPiñero, Janet1 aFurlong, Laura, I1 aBalaur, Irina1 aRougny, Adrien1 aJarosz, Yohan1 aOverall, Rupert, W1 aPhair, Robert1 aPerfetto, Livia1 aMatthews, Lisa1 aRex, Devasahayam, Arokia Bal1 aOrlic-Milacic, Marija1 aGomez, Luis, Cristobal1 aDe Meulder, Bertrand1 aRavel, Jean, Marie1 aJassal, Bijay1 aSatagopam, Venkata1 aWu, Guanming1 aGolebiewski, Martin1 aGawron, Piotr1 aCalzone, Laurence1 aBeckmann, Jacques, S1 aEvelo, Chris, T1 aD'Eustachio, Peter1 aSchreiber, Falk1 aSaez-Rodriguez, Julio1 aDopazo, Joaquin1 aKuiper, Martin1 aValencia, Alfonso1 aWolkenhauer, Olaf1 aKitano, Hiroaki1 aBarillot, Emmanuel1 aAuffray, Charles1 aBalling, Rudi1 aSchneider, Reinhard1 aCOVID-19 Disease Map Community uhttp://clinbioinfosspa.es/content/drug-target-identification-covid-19-disease-mechanisms-using-computational-systems-biology-approaches-003598nas a2200277 4500008004100000022001400041245013400055210006900189260001600258300000800274490000700282520262900289653001202918653000902930653002502939653002402964100002702988700002003015700001603035700002003051700003103071700002003102700002003122700002403142856015403166 2024 eng d a1479-587600aThe mechanistic functional landscape of retinitis pigmentosa: a machine learning-driven approach to therapeutic target discovery.0 amechanistic functional landscape of retinitis pigmentosa a machi c2024 Feb 06 a1390 v223 a

BACKGROUND: Retinitis pigmentosa is the prevailing genetic cause of blindness in developed nations with no effective treatments. In the pursuit of unraveling the intricate dynamics underlying this complex disease, mechanistic models emerge as a tool of proven efficiency rooted in systems biology, to elucidate the interplay between RP genes and their mechanisms. The integration of mechanistic models and drug-target interactions under the umbrella of machine learning methodologies provides a multifaceted approach that can boost the discovery of novel therapeutic targets, facilitating further drug repurposing in RP.

METHODS: By mapping Retinitis Pigmentosa-related genes (obtained from Orphanet, OMIM and HPO databases) onto KEGG signaling pathways, a collection of signaling functional circuits encompassing Retinitis Pigmentosa molecular mechanisms was defined. Next, a mechanistic model of the so-defined disease map, where the effects of interventions can be simulated, was built. Then, an explainable multi-output random forest regressor was trained using normal tissue transcriptomic data to learn causal connections between targets of approved drugs from DrugBank and the functional circuits of the mechanistic disease map. Selected target genes involvement were validated on rd10 mice, a murine model of Retinitis Pigmentosa.

RESULTS: A mechanistic functional map of Retinitis Pigmentosa was constructed resulting in 226 functional circuits belonging to 40 KEGG signaling pathways. The method predicted 109 targets of approved drugs in use with a potential effect over circuits corresponding to nine hallmarks identified. Five of those targets were selected and experimentally validated in rd10 mice: Gabre, Gabra1 (GABARα1 protein), Slc12a5 (KCC2 protein), Grin1 (NR1 protein) and Glr2a. As a result, we provide a resource to evaluate the potential impact of drug target genes in Retinitis Pigmentosa.

CONCLUSIONS: The possibility of building actionable disease models in combination with machine learning algorithms to learn causal drug-disease interactions opens new avenues for boosting drug discovery. Such mechanistically-based hypotheses can guide and accelerate the experimental validations prioritizing drug target candidates. In this work, a mechanistic model describing the functional disease map of Retinitis Pigmentosa was developed, identifying five promising therapeutic candidates targeted by approved drug. Further experimental validation will demonstrate the efficiency of this approach for a systematic application to other rare diseases.

10aAnimals10aMice10aRetinitis pigmentosa10aSignal Transduction1 aEsteban-Medina, Marina1 aLoucera, Carlos1 aRian, Kinza1 aVelasco, Sheyla1 aOlivares-González, Lorena1 aRodrigo, Regina1 aDopazo, Joaquin1 aPeña-Chilet, Maria uhttp://clinbioinfosspa.es/content/mechanistic-functional-landscape-retinitis-pigmentosa-machine-learning-driven-approach-therapeutic-target-discovery01708nas a2200181 4500008004100000245013000041210006900171260000900240300001200249490000700261520105400268100001801322700003401340700003401374700002601408700003301434856005901467 2023 eng d00aCase report: Analysis of phage therapy failure in a patient with a Pseudomonas aeruginosa prosthetic vascular graft infection0 aCase report Analysis of phage therapy failure in a patient with  c2023 a11996570 v103 a

Clinical case of a patient with a multidrug-resistant prosthetic vascular graft infection which was treated with a cocktail of phages (PT07, 14/01, and PNM) in combination with ceftazidime-avibactam (CZA). After the application of the phage treatment and in absence of antimicrobial therapy, a new bloodstream infection (BSI) with a septic residual limb metastasis occurred, now involving a wild-type strain being susceptible to ß-lactams and quinolones. Clinical strains were analyzed by microbiology and whole genome sequencing techniques. In relation with phage administration, the clinical isolates of before phage therapy (HE2011471) and post phage therapy (HE2105886) showed a clonal relationship but with important genomic changes which could be involved in the resistance to this therapy. Finally, phenotypic studies showed a decrease in Minimum Inhibitory Concentration (MIC) to ß-lactams and quinolones as well as an increase of the biofilm production and phage resistant mutants in the clinical isolate of post phage therapy.

1 aBlasco, Lucia1 aLópez-Hernández, Inmaculada1 aRodríguez-Fernández, Miguel1 aPerez-Florido, Javier1 aCasimiro-Soriguer, Carlos, S uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10235614/00729nam a2200205 4500008004100000020002200041022001400063245010000077210006900177260003800246300001200284490001000296100002000306700002500326700003000351700003600381700002000417700002000437856006600457 2023 eng d a978-3-031-42696-4 a0302-974300aCell-Level Pathway Scoring Comparison with a Biologically Constrained Variational Autoencoder0 aCellLevel Pathway Scoring Comparison with a Biologically Constra aChambSpringer Nature Switzerland a62 - 770 v141371 aGundogdu, Pelin1 aPayá-Milans, Miriam1 aAlamo-Alvarez, Inmaculada1 aNepomuceno-Chamorro, Isabel, A.1 aDopazo, Joaquin1 aLoucera, Carlos uhttps://link.springer.com/chapter/10.1007/978-3-031-42697-1_502245nas a2200253 4500008004100000022001400041245013700055210006900192260001600261490000700277520134400284100002701628700002001655700002401675700002601699700001801725700001801743700002101761700001901782700002801801700002001829700002601849856011601875 2023 eng d a1999-492300aA Comprehensive Analysis of 21 Actionable Pharmacogenes in the Spanish Population: From Genetic Characterisation to Clinical Impact.0 aComprehensive Analysis of 21 Actionable Pharmacogenes in the Spa c2023 Apr 190 v153 a

The implementation of pharmacogenetics (PGx) is a main milestones of precision medicine nowadays in order to achieve safer and more effective therapies. Nevertheless, the implementation of PGx diagnostics is extremely slow and unequal worldwide, in part due to a lack of ethnic PGx information. We analysed genetic data from 3006 Spanish individuals obtained by different high-throughput (HT) techniques. Allele frequencies were determined in our population for the main 21 actionable PGx genes associated with therapeutical changes. We found that 98% of the Spanish population harbours at least one allele associated with a therapeutical change and, thus, there would be a need for a therapeutical change in a mean of 3.31 of the 64 associated drugs. We also identified 326 putative deleterious variants that were not previously related with PGx in 18 out of the 21 main PGx genes evaluated and a total of 7122 putative deleterious variants for the 1045 PGx genes described. Additionally, we performed a comparison of the main HT diagnostic techniques, revealing that after whole genome sequencing, genotyping with the PGx HT array is the most suitable solution for PGx diagnostics. Finally, all this information was integrated in the Collaborative Spanish Variant Server to be available to and updated by the scientific community.

1 aNúñez-Torres, Rocío1 aPita, Guillermo1 aPeña-Chilet, Maria1 aLópez-López, Daniel1 aZamora, Jorge1 aRoldán, Gema1 aHerráez, Belén1 aAlvarez, Nuria1 aAlonso, María, Rosario1 aDopazo, Joaquin1 aGonzález-Neira, Anna uhttp://clinbioinfosspa.es/content/comprehensive-analysis-21-actionable-pharmacogenes-spanish-population-genetic01707nas a2200169 4500008004100000022001400041245008500055210006900140260001600209490000700225520110800232100001801340700002001358700002401378700002001402856011501422 2023 eng d a1422-006700aCrosstalk between Metabolite Production and Signaling Activity in Breast Cancer.0 aCrosstalk between Metabolite Production and Signaling Activity i c2023 Apr 180 v243 a

The reprogramming of metabolism is a recognized cancer hallmark. It is well known that different signaling pathways regulate and orchestrate this reprogramming that contributes to cancer initiation and development. However, recent evidence is accumulating, suggesting that several metabolites could play a relevant role in regulating signaling pathways. To assess the potential role of metabolites in the regulation of signaling pathways, both metabolic and signaling pathway activities of Breast invasive Carcinoma (BRCA) have been modeled using mechanistic models. Gaussian Processes, powerful machine learning methods, were used in combination with SHapley Additive exPlanations (SHAP), a recent methodology that conveys causality, to obtain potential causal relationships between the production of metabolites and the regulation of signaling pathways. A total of 317 metabolites were found to have a strong impact on signaling circuits. The results presented here point to the existence of a complex crosstalk between signaling and metabolic pathways more complex than previously was thought.

1 aCubuk, Cankut1 aLoucera, Carlos1 aPeña-Chilet, Maria1 aDopazo, Joaquin uhttp://clinbioinfosspa.es/content/crosstalk-between-metabolite-production-and-signaling-activity-breast-cancer02663nas a2200301 4500008004100000022001400041245008600055210006900141260001600210300000700226490000700233520168700240100002601927700001801953700002901971700002302000700002102023700002102044700002602065700002202091700002002113700002702133700002602160700002402186700002002210710002902230856010202259 2023 eng d a1479-736400aA crowdsourcing database for the copy-number variation of the Spanish population.0 acrowdsourcing database for the copynumber variation of the Spani c2023 Mar 09 a200 v173 a

BACKGROUND: Despite being a very common type of genetic variation, the distribution of copy-number variations (CNVs) in the population is still poorly understood. The knowledge of the genetic variability, especially at the level of the local population, is a critical factor for distinguishing pathogenic from non-pathogenic variation in the discovery of new disease variants.

RESULTS: Here, we present the SPAnish Copy Number Alterations Collaborative Server (SPACNACS), which currently contains copy number variation profiles obtained from more than 400 genomes and exomes of unrelated Spanish individuals. By means of a collaborative crowdsourcing effort whole genome and whole exome sequencing data, produced by local genomic projects and for other purposes, is continuously collected. Once checked both, the Spanish ancestry and the lack of kinship with other individuals in the SPACNACS, the CNVs are inferred for these sequences and they are used to populate the database. A web interface allows querying the database with different filters that include ICD10 upper categories. This allows discarding samples from the disease under study and obtaining pseudo-control CNV profiles from the local population. We also show here additional studies on the local impact of CNVs in some phenotypes and on pharmacogenomic variants. SPACNACS can be accessed at: http://csvs.clinbioinfosspa.es/spacnacs/ .

CONCLUSION: SPACNACS facilitates disease gene discovery by providing detailed information of the local variability of the population and exemplifies how to reuse genomic data produced for other purposes to build a local reference database.

1 aLópez-López, Daniel1 aRoldán, Gema1 aFernandez-Rueda, Jose, L1 aBostelmann, Gerrit1 aCarmona, Rosario1 aAquino, Virginia1 aPerez-Florido, Javier1 aOrtuno, Francisco1 aPita, Guillermo1 aNúñez-Torres, Rocío1 aGonzález-Neira, Anna1 aPeña-Chilet, Maria1 aDopazo, Joaquin1 aCSVS Crowdsourcing Group uhttp://clinbioinfosspa.es/content/crowdsourcing-database-copy-number-variation-spanish-population02229nas a2200325 4500008004100000022001400041245014800055210006900203260001600272300001100288490000700299520106600306100002701372700003201399700002401431700001701455700002601472700001901498700002101517700001801538700002201556700001701578700001901595700002901614700002001643700002301663700002301686700002401709856017001733 2023 eng d a2211-124700aDefective extracellular matrix remodeling in brown adipose tissue is associated with fibro-inflammation and reduced diet-induced thermogenesis.0 aDefective extracellular matrix remodeling in brown adipose tissu c2023 Jun 13 a1126400 v423 a

The relevance of extracellular matrix (ECM) remodeling is reported in white adipose tissue (AT) and obesity-related dysfunctions, but little is known about the importance of ECM remodeling in brown AT (BAT) function. Here, we show that a time course of high-fat diet (HFD) feeding progressively impairs diet-induced thermogenesis concomitantly with the development of fibro-inflammation in BAT. Higher markers of fibro-inflammation are associated with lower cold-induced BAT activity in humans. Similarly, when mice are housed at thermoneutrality, inactivated BAT features fibro-inflammation. We validate the pathophysiological relevance of BAT ECM remodeling in response to temperature challenges and HFD using a model of a primary defect in the collagen turnover mediated by partial ablation of the Pepd prolidase. Pepd-heterozygous mice display exacerbated dysfunction and BAT fibro-inflammation at thermoneutrality and in HFD. Our findings show the relevance of ECM remodeling in BAT activation and provide a mechanism for BAT dysfunction in obesity.

1 aPellegrinelli, Vanessa1 aFigueroa-Juárez, Elizabeth1 aSamuelson, Isabella1 aU-Din, Mueez1 aRodriguez-Fdez, Sonia1 aVirtue, Samuel1 aLeggat, Jennifer1 aCubuk, Cankut1 aPeirce, Vivian, J1 aNiemi, Tarja1 aCampbell, Mark1 aRodriguez-Cuenca, Sergio1 aDopazo, Joaquin1 aCarobbio, Stefania1 aVirtanen, Kirsi, A1 aVidal-Puig, Antonio uhttp://clinbioinfosspa.es/content/defective-extracellular-matrix-remodeling-brown-adipose-tissue-associated-fibro-inflammation-and-reduced-diet-induced-thermogenesis02368nas a2200337 4500008004100000022001400041245017900055210006900234260001600303490000700319520115700326100002601483700003301509700002201542700002901564700001901593700001701612700002101629700003401650700002801684700002301712700002601735700002301761700002001784700001701804700002001821700002201841700002001863700001801883856012901901 2023 eng d a1422-006700aDetection of High Level of Co-Infection and the Emergence of Novel SARS CoV-2 Delta-Omicron and Omicron-Omicron Recombinants in the Epidemiological Surveillance of Andalusia.0 aDetection of High Level of CoInfection and the Emergence of Nove c2023 Jan 260 v243 a

Recombination is an evolutionary strategy to quickly acquire new viral properties inherited from the parental lineages. The systematic survey of the SARS-CoV-2 genome sequences of the Andalusian genomic surveillance strategy has allowed the detection of an unexpectedly high number of co-infections, which constitute the ideal scenario for the emergence of new recombinants. Whole genome sequence of SARS-CoV-2 has been carried out as part of the genomic surveillance programme. Sample sources included the main hospitals in the Andalusia region. In addition to the increase of co-infections and known recombinants, three novel SARS-CoV-2 delta-omicron and omicron-omicron recombinant variants with two break points have been detected. Our observations document an epidemiological scenario in which co-infection and recombination are detected more frequently. Finally, we describe a family case in which co-infection is followed by the detection of a recombinant made from the two co-infecting variants. This increased number of recombinants raises the risk of emergence of recombinant variants with increased transmissibility and pathogenicity.

1 aPerez-Florido, Javier1 aCasimiro-Soriguer, Carlos, S1 aOrtuno, Francisco1 aFernandez-Rueda, Jose, L1 aAguado, Andrea1 aLara, María1 aRiazzo, Cristina1 aRodriguez-Iglesias, Manuel, A1 aCamacho-Martinez, Pedro1 aMerino-Diaz, Laura1 aPupo-Ledo, Inmaculada1 ade Salazar, Adolfo1 aViñuela, Laura1 aFuentes, Ana1 aChueca, Natalia1 aGarcía, Federico1 aDopazo, Joaquin1 aLepe, Jose, A uhttp://clinbioinfosspa.es/content/detection-high-level-co-infection-and-emergence-novel-sars-cov-2-delta-omicron-and-omicron00614nas a2200169 4500008004100000022001400041245009200055210006900147260000900216300001200225490000700237100002200244700002000266700001900286700002000305856011900325 2023 eng d a1664-802100aEditorial: Critical assessment of massive data analysis (CAMDA) annual conference 2021.0 aEditorial Critical assessment of massive data analysis CAMDA ann c2023 a11543980 v141 aŁabaj, Paweł, P1 aDopazo, Joaquin1 aXiao, Wenzhong1 aKreil, David, P uhttp://clinbioinfosspa.es/content/editorial-critical-assessment-massive-data-analysis-camda-annual-conference-202102288nas a2200301 4500008004100000022001400041245015200055210006900207260001600276300000900292490000800301520121000309653001201519653001301531653002101544653001101565653004001576653001501616653003201631100002601663700002301689700001701712700002001729700002601749700002001775700002201795856016901817 2023 eng d a1469-440900aEvaluation of a combined detection of SARS-CoV-2 and its variants using real-time allele-specific PCR strategy: an advantage for clinical practice.0 aEvaluation of a combined detection of SARSCoV2 and its variants  c2023 Nov 24 ae2010 v1513 a

This study aimed to assess the ability of a real-time reverse transcription polymerase chain reaction (RT-PCR) with multiple targets to detect SARS-CoV-2 and its variants in a single test. Nasopharyngeal specimens were collected from patients in Granada, Spain, between January 2021 and December 2022. Five allele-specific RT-PCR kits were used sequentially, with each kit designed to detect a predominant variant at the time. When the Alpha variant was dominant, the kit included the HV69/70 deletion, E and N genes. When Delta replaced Alpha, the kit incorporated the L452R mutation in addition to E and N genes. When Omicron became dominant, L452R was replaced with the N679K mutation. Before incorporating each variant kit, a comparative analysis was carried out with SARS-CoV-2 whole genome sequencing (WGS). The results demonstrated that RT-PCR with multiple targets can provide rapid and effective detection of SARS-CoV-2 and its variants in a single test. A very high degree of agreement (96.2%) was obtained between the comparison of RT-PCR and WGS. Allele-specific RT-PCR assays make it easier to implement epidemiological surveillance systems for effective public health decision making.

10aAlleles10aCOVID-1910aCOVID-19 Testing10aHumans10aReal-Time Polymerase Chain Reaction10aSARS-CoV-210aSensitivity and Specificity1 aChaves-Blanco, Lucía1 ade Salazar, Adolfo1 aFuentes, Ana1 aViñuela, Laura1 aPerez-Florido, Javier1 aDopazo, Joaquin1 aGarcía, Federico uhttp://clinbioinfosspa.es/content/evaluation-combined-detection-sars-cov-2-and-its-variants-using-real-time-allele-specific-pcr-strategy-advantage-clinical-practice02624nas a2200205 4500008004100000022001400041245020600055210006900261260001600330520167600346100002002022700002102042700002302063700003102086700002102117700003202138700002002170700002002190856020802210 2023 eng d a1578-898900aEvidence of the association between increased use of direct oral anticoagulants and a reduction in the rate of atrial fibrillation-related stroke and major bleeding at the population level (2012-2019).0 aEvidence of the association between increased use of direct oral c2023 Nov 203 a

BACKGROUND: The introduction of direct-acting oral anticoagulants (DOACs) has shown to decrease atrial fibrillation (AF)-related stroke and bleeding rates in clinical studies, but there is no certain evidence about their effects at the population level. Our aim was to assess changes in AF-related stroke and major bleeding rates between 2012 and 2019 in Andalusia (Spain), and the association between DOACs use and events rates at the population level.

METHODS: All patients with an AF diagnosis from 2012 to 2019 were identified using the Andalusian Health Population Base, that provides clinical information on all Andalusian people. Annual ischemic and hemorrhagic stroke, major bleeding rates, and used antithrombotic treatments were determined. Marginal hazard ratios (HR) were calculated for each treatment.

RESULTS: A total of 95,085 patients with an AF diagnosis were identified. Mean age was 76.1±10.2 years (49.7% women). An increase in the use of DOACs was observed throughout the study period in both males and females (p<0.001). The annual rate of ischemic stroke decreased by one third, while that of hemorrhagic stroke and major bleeding decreased 2-3-fold from 2012 to 2019. Marginal HR was lower than 0.50 for DOACs compared to VKA for all ischemic or hemorrhagic events.

CONCLUSIONS: In this contemporary population-based study using clinical and administrative databases in Andalusia, a significant reduction in the incidence of AF-related ischemic and hemorrhagic stroke and major bleeding was observed between 2012 and 2019. The increased use of DOACs seems to be associated with this reduction.

1 aLoucera, Carlos1 aCarmona, Rosario1 aBostelmann, Gerrit1 aMuñoyerro-Muñiz, Dolores1 aVillegas, Román1 aGonzalez-Manzanares, Rafael1 aDopazo, Joaquin1 aAnguita, Manuel uhttp://clinbioinfosspa.es/content/evidence-association-between-increased-use-direct-oral-anticoagulants-and-reduction-rate-atrial-fibrillation-related-stroke-and-major-bleeding-population-level-2012-201902648nas a2200409 4500008004100000022001400041245014400055210006900199260001600268300000800284490000600292520117700298100002801475700003601503700002001539700001801559700003301577700002901610700003801639700003601677700002601713700003401739700003701773700002701810700002901837700001701866700001901883700002601902700002501928700002001953700001901973700002401992700002902016700003002045700003202075856013102107 2023 eng d a2399-364200aMetabolic reprogramming by Acly inhibition using SB-204990 alters glucoregulation and modulates molecular mechanisms associated with aging.0 aMetabolic reprogramming by Acly inhibition using SB204990 alters c2023 Mar 08 a2500 v63 a

ATP-citrate lyase is a central integrator of cellular metabolism in the interface of protein, carbohydrate, and lipid metabolism. The physiological consequences as well as the molecular mechanisms orchestrating the response to long-term pharmacologically induced Acly inhibition are unknown. We report here that the Acly inhibitor SB-204990 improves metabolic health and physical strength in wild-type mice when fed with a high-fat diet, while in mice fed with healthy diet results in metabolic imbalance and moderated insulin resistance. By applying a multiomic approach using untargeted metabolomics, transcriptomics, and proteomics, we determined that, in vivo, SB-204990 plays a role in the regulation of molecular mechanisms associated with aging, such as energy metabolism, mitochondrial function, mTOR signaling, and folate cycle, while global alterations on histone acetylation are absent. Our findings indicate a mechanism for regulating molecular pathways of aging that prevents the development of metabolic abnormalities associated with unhealthy dieting. This strategy might be explored for devising therapeutic approaches to prevent metabolic diseases.

1 aSola-García, Alejandro1 aCáliz-Molina, María, Ángeles1 aEspadas, Isabel1 aPetr, Michael1 aPanadero-Morón, Concepción1 aGonzález-Morán, Daniel1 aMartín-Vázquez, María, Eugenia1 aNarbona-Pérez, Álvaro, Jesús1 aLópez-Noriega, Livia1 aMartínez-Corrales, Guillermo1 aLópez-Fernández-Sobrino, Raúl1 aCarmona-Marin, Lina, M1 aMartínez-Force, Enrique1 aYanes, Oscar1 aVinaixa, Maria1 aLópez-López, Daniel1 aReyes, José, Carlos1 aDopazo, Joaquin1 aMartín, Franz1 aGauthier, Benoit, R1 aScheibye-Knudsen, Morten1 aCapilla-González, Vivian1 aMartín-Montalvo, Alejandro uhttp://clinbioinfosspa.es/content/metabolic-reprogramming-acly-inhibition-using-sb-204990-alters-glucoregulation-and-modulates02396nas a2200301 4500008004100000022001400041245012200055210006900177260001600246300001100262520135200273100002301625700002701648700002601675700001801701700002701719700001801746700002101764700002301785700002401808700003201832700002401864700002201888700002001910700001601930700002301946856012501969 2023 eng d a1474-972600amicroRNAs-mediated regulation of insulin signaling in white adipose tissue during aging: Role of caloric restriction.0 amicroRNAsmediated regulation of insulin signaling in white adipo c2023 Jul 04 ae139193 a

Caloric restriction is a non-pharmacological intervention known to ameliorate the metabolic defects associated with aging, including insulin resistance. The levels of miRNA expression may represent a predictive tool for aging-related alterations. In order to investigate the role of miRNAs underlying insulin resistance in adipose tissue during the early stages of aging, 3- and 12-month-old male animals fed ad libitum, and 12-month-old male animals fed with a 20% caloric restricted diet were used. In this work we demonstrate that specific miRNAs may contribute to the impaired insulin-stimulated glucose metabolism specifically in the subcutaneous white adipose tissue, through the regulation of target genes implicated in the insulin signaling cascade. Moreover, the expression of these miRNAs is modified by caloric restriction in middle-aged animals, in accordance with the improvement of the metabolic state. Overall, our work demonstrates that alterations in posttranscriptional gene expression because of miRNAs dysregulation might represent an endogenous mechanism by which insulin response in the subcutaneous fat depot is already affected at middle age. Importantly, caloric restriction could prevent this modulation, demonstrating that certain miRNAs could constitute potential biomarkers of age-related metabolic alterations.

1 aCorrales, Patricia1 aMartin-Taboada, Marina1 aVivas-García, Yurena1 aTorres, Lucia1 aRamirez-Jimenez, Laura1 aLopez, Yamila1 aHorrillo, Daniel1 aVila-Bedmar, Rocio1 aBarber-Cano, Eloisa1 aIzquierdo-Lahuerta, Adriana1 aPeña-Chilet, Maria1 aMartínez, Carmen1 aDopazo, Joaquin1 aRos, Manuel1 aMedina-Gomez, Gema uhttp://clinbioinfosspa.es/content/micrornas-mediated-regulation-insulin-signaling-white-adipose-tissue-during-aging-role02391nas a2200193 4500008004100000022001400041245017300055210006900228260001600297300001100313520159800324100002301922700003501945700001701980700002101997700002002018700003002038856012902068 2023 eng d a1873-642400aPolystyrene nanoplastics affect transcriptomic and epigenomic signatures of human fibroblasts and derived induced pluripotent stem cells: Implications for human health.0 aPolystyrene nanoplastics affect transcriptomic and epigenomic si c2022 Dec 09 a1208493 a

Plastic pollution is increasing at an alarming rate yet the impact of this pollution on human health is poorly understood. Because human induced pluripotent stem cells (hiPSC) are frequently derived from dermal fibroblasts, these cells offer a powerful platform for the identification of molecular biomarkers of environmental pollution in human cells. Here, we describe a novel proof-of-concept for deriving hiPSC from human dermal fibroblasts deliberately exposed to polystyrene (PS) nanoplastic particles; unexposed hiPSC served as controls. In parallel, unexposed hiPSC were exposed to low and high concentrations of PS nanoparticles. Transcriptomic and epigenomic signatures of all fibroblasts and hiPSCs were defined using RNA-seq and whole genome methyl-seq, respectively. Both PS-treated fibroblasts and derived hiPSC showed alterations in expression of ESRRB and HNF1A genes and circuits involved in the pluripotency of stem cells, as well as in pathways involved in cancer, inflammatory disorders, gluconeogenesis, carbohydrate metabolism, innate immunity, and dopaminergic synapse. Similarly, the expression levels of identified key transcriptional and DNA methylation changes (DNMT3A, ESSRB, FAM133CP, HNF1A, SEPTIN7P8, and TTC34) were significantly affected in both PS-exposed fibroblasts and hiPSC. This study illustrates the power of human cellular models of environmental pollution to narrow down and prioritize the list of candidate molecular biomarkers of environmental pollution. This knowledge will facilitate the deciphering of the origins of environmental diseases.

1 aStojkovic, Miodrag1 aGuzmán, Francisco, Manuel Ort1 aHan, Dongjun1 aStojkovic, Petra1 aDopazo, Joaquin1 aStankovic, Konstantina, M uhttp://clinbioinfosspa.es/content/polystyrene-nanoplastics-affect-transcriptomic-and-epigenomic-signatures-human-fibroblasts03351nas a2200265 4500008004100000022001400041245012500055210006900180260001600249300000800265490000600273520241900279100001802698700001902716700003602735700002902771700002702800700002002827700001802847700002002865700002002885700003102905700001902936856013002955 2023 eng d a2058-771600aRapid degeneration of iPSC-derived motor neurons lacking Gdap1 engages a mitochondrial-sustained innate immune response.0 aRapid degeneration of iPSCderived motor neurons lacking Gdap1 en c2023 Jul 01 a2170 v93 a

Charcot-Marie-Tooth disease is a chronic hereditary motor and sensory polyneuropathy targeting Schwann cells and/or motor neurons. Its multifactorial and polygenic origin portrays a complex clinical phenotype of the disease with a wide range of genetic inheritance patterns. The disease-associated gene GDAP1 encodes for a mitochondrial outer membrane protein. Mouse and insect models with mutations in Gdap1 have reproduced several traits of the human disease. However, the precise function in the cell types affected by the disease remains unknown. Here, we use induced-pluripotent stem cells derived from a Gdap1 knockout mouse model to better understand the molecular and cellular phenotypes of the disease caused by the loss-of-function of this gene. Gdap1-null motor neurons display a fragile cell phenotype prone to early degeneration showing (1) altered mitochondrial morphology, with an increase in the fragmentation of these organelles, (2) activation of autophagy and mitophagy, (3) abnormal metabolism, characterized by a downregulation of Hexokinase 2 and ATP5b proteins, (4) increased reactive oxygen species and elevated mitochondrial membrane potential, and (5) increased innate immune response and p38 MAP kinase activation. Our data reveals the existence of an underlying Redox-inflammatory axis fueled by altered mitochondrial metabolism in the absence of Gdap1. As this biochemical axis encompasses a wide variety of druggable targets, our results may have implications for developing therapies using combinatorial pharmacological approaches and improving therefore human welfare. A Redox-immune axis underlying motor neuron degeneration caused by the absence of Gdap1. Our results show that Gdap1 motor neurons have a fragile cellular phenotype that is prone to degeneration. Gdap1 iPSCs differentiated into motor neurons showed an altered metabolic state: decreased glycolysis and increased OXPHOS. These alterations may lead to hyperpolarization of mitochondria and increased ROS levels. Excessive amounts of ROS might be the cause of increased mitophagy, p38 activation and inflammation as a cellular response to oxidative stress. The p38 MAPK pathway and the immune response may, in turn, have feedback mechanisms, leading to the induction of apoptosis and senescence, respectively. CAC, citric acid cycle; ETC, electronic transport chain; Glc, glucose; Lac, lactate; Pyr, pyruvate.

1 aLeón, Marian1 aPrieto, Javier1 aMolina-Navarro, María, Micaela1 aGarcia-Garcia, Francisco1 aBarneo-Muñoz, Manuela1 aPonsoda, Xavier1 aSáez, Rosana1 aPalau, Francesc1 aDopazo, Joaquin1 aBelmonte, Juan, Carlos Izp1 aTorres, Josema uhttp://clinbioinfosspa.es/content/rapid-degeneration-ipsc-derived-motor-neurons-lacking-gdap1-engages-mitochondrial-sustained02334nas a2200229 4500008004100000022001400041245013100055210006900186260001600255300000800271490000700279520147800286100002001764700002101784700002701805700002301832700003101855700002101886700002401907700002001931856015301951 2023 eng d a1743-422X00aReal-world evidence with a retrospective cohort of 15,968 COVID-19 hospitalized patients suggests 21 new effective treatments.0 aRealworld evidence with a retrospective cohort of 15968 COVID19  c2023 Oct 06 a2260 v203 a

PURPOSE: Despite the extensive vaccination campaigns in many countries, COVID-19 is still a major worldwide health problem because of its associated morbidity and mortality. Therefore, finding efficient treatments as fast as possible is a pressing need. Drug repurposing constitutes a convenient alternative when the need for new drugs in an unexpected medical scenario is urgent, as is the case with COVID-19.

METHODS: Using data from a central registry of electronic health records (the Andalusian Population Health Database), the effect of prior consumption of drugs for other indications previous to the hospitalization with respect to patient outcomes, including survival and lymphocyte progression, was studied on a retrospective cohort of 15,968 individuals, comprising all COVID-19 patients hospitalized in Andalusia between January and November 2020.

RESULTS: Covariate-adjusted hazard ratios and analysis of lymphocyte progression curves support a significant association between consumption of 21 different drugs and better patient survival. Contrarily, one drug, furosemide, displayed a significant increase in patient mortality.

CONCLUSIONS: In this study we have taken advantage of the availability of a regional clinical database to study the effect of drugs, which patients were taking for other indications, on their survival. The large size of the database allowed us to control covariates effectively.

1 aLoucera, Carlos1 aCarmona, Rosario1 aEsteban-Medina, Marina1 aBostelmann, Gerrit1 aMuñoyerro-Muñiz, Dolores1 aVillegas, Román1 aPeña-Chilet, Maria1 aDopazo, Joaquin uhttp://clinbioinfosspa.es/content/real-world-evidence-retrospective-cohort-15968-covid-19-hospitalized-patients-suggests-21-new-effective-treatments00578nas a2200169 4500008004100000022001400041245007500055210006900130260001300199300001100212490000800223653001300231653001900244653001100263110003800274856009600312 2023 eng d a1476-468700aA second update on mapping the human genetic architecture of COVID-19.0 asecond update on mapping the human genetic architecture of COVID c2023 Sep aE7-E260 v62110aCOVID-1910aHuman Genetics10aHumans1 aCOVID-19 Host Genetics Initiative uhttp://clinbioinfosspa.es/content/second-update-mapping-human-genetic-architecture-covid-1902197nas a2200181 4500008004100000022001400041245011200055210006900167260001600236490000700252520151000259100002001769700002201789700003501811700002001846700002001866856012901886 2023 eng d a2079-773700aSigPrimedNet: A Signaling-Informed Neural Network for scRNA-seq Annotation of Known and Unknown Cell Types.0 aSigPrimedNet A SignalingInformed Neural Network for scRNAseq Ann c2023 Apr 100 v123 a

Single-cell RNA sequencing is increasing our understanding of the behavior of complex tissues or organs, by providing unprecedented details on the complex cell type landscape at the level of individual cells. Cell type definition and functional annotation are key steps to understanding the molecular processes behind the underlying cellular communication machinery. However, the exponential growth of scRNA-seq data has made the task of manually annotating cells unfeasible, due not only to an unparalleled resolution of the technology but to an ever-increasing heterogeneity of the data. Many supervised and unsupervised methods have been proposed to automatically annotate cells. Supervised approaches for cell-type annotation outperform unsupervised methods except when new (unknown) cell types are present. Here, we introduce SigPrimedNet an artificial neural network approach that leverages (i) efficient training by means of a sparsity-inducing signaling circuits-informed layer, (ii) feature representation learning through supervised training, and (iii) unknown cell-type identification by fitting an anomaly detection method on the learned representation. We show that SigPrimedNet can efficiently annotate known cell types while keeping a low false-positive rate for unseen cells across a set of publicly available datasets. In addition, the learned representation acts as a proxy for signaling circuit activity measurements, which provide useful estimations of the cell functionalities.

1 aGundogdu, Pelin1 aAlamo, Inmaculada1 aNepomuceno-Chamorro, Isabel, A1 aDopazo, Joaquin1 aLoucera, Carlos uhttp://clinbioinfosspa.es/content/sigprimednet-signaling-informed-neural-network-scrna-seq-annotation-known-and-unknown-cell03070nas a2200325 4500008004100000022001400041245009700055210006900152260000900221300001200230490000600242520201700248100001802265700001802283700001902301700002402320700002702344700003202371700002202403700001502425700002202440700002202462700002202484700002602506700002402532700002002556700002202576700002302598856012302621 2023 eng d a2673-764700aVisualization of automatically combined disease maps and pathway diagrams for rare diseases.0 aVisualization of automatically combined disease maps and pathway c2023 a11015050 v33 a

Investigation of molecular mechanisms of human disorders, especially rare diseases, require exploration of various knowledge repositories for building precise hypotheses and complex data interpretation. Recently, increasingly more resources offer diagrammatic representation of such mechanisms, including disease-dedicated schematics in pathway databases and disease maps. However, collection of knowledge across them is challenging, especially for research projects with limited manpower. In this article we present an automated workflow for construction of maps of molecular mechanisms for rare diseases. The workflow requires a standardized definition of a disease using Orphanet or HPO identifiers to collect relevant genes and variants, and to assemble a functional, visual repository of related mechanisms, including data overlays. The diagrams composing the final map are unified to a common systems biology format from CellDesigner SBML, GPML and SBML+layout+render. The constructed resource contains disease-relevant genes and variants as data overlays for immediate visual exploration, including embedded genetic variant browser and protein structure viewer. We demonstrate the functionality of our workflow on two examples of rare diseases: Kawasaki disease and retinitis pigmentosa. Two maps are constructed based on their corresponding identifiers. Moreover, for the retinitis pigmentosa use-case, we include a list of differentially expressed genes to demonstrate how to tailor the workflow using omics datasets. In summary, our work allows for an ad-hoc construction of molecular diagrams combined from different sources, preserving their layout and graphical style, but integrating them into a single resource. This allows to reduce time consuming tasks of prototyping of a molecular disease map, enabling visual exploration, hypothesis building, data visualization and further refinement. The code of the workflow is open and accessible at https://gitlab.lcsb.uni.lu/minerva/automap/.

1 aGawron, Piotr1 aHoksza, David1 aPiñero, Janet1 aPeña-Chilet, Maria1 aEsteban-Medina, Marina1 aFernandez-Rueda, Jose, Luis1 aColonna, Vincenza1 aSmula, Ewa1 aHeirendt, Laurent1 aAncien, François1 aGrouès, Valentin1 aSatagopam, Venkata, P1 aSchneider, Reinhard1 aDopazo, Joaquin1 aFurlong, Laura, I1 aOstaszewski, Marek uhttp://clinbioinfosspa.es/content/visualization-automatically-combined-disease-maps-and-pathway-diagrams-rare-diseases02570nas a2200457 4500008004100000022001400041245008300055210006900138260001600207490000700223520116500230653001301395653001801408653001101426653001301437653001401450653001401464653001501478100002001493700002601513700003301539700002501572700002101597700002301618700003201641700003101673700002101704700002901725700002601754700002001780700002501800700002701825700002801852700002301880700002301903700002001926700001801946700002201964700002001986856010602006 2022 eng d a1999-491500aAssessing the Impact of SARS-CoV-2 Lineages and Mutations on Patient Survival.0 aAssessing the Impact of SARSCoV2 Lineages and Mutations on Patie c2022 Aug 270 v143 a

OBJECTIVES: More than two years into the COVID-19 pandemic, SARS-CoV-2 still remains a global public health problem. Successive waves of infection have produced new SARS-CoV-2 variants with new mutations for which the impact on COVID-19 severity and patient survival is uncertain.

METHODS: A total of 764 SARS-CoV-2 genomes, sequenced from COVID-19 patients, hospitalized from 19th February 2020 to 30 April 2021, along with their clinical data, were used for survival analysis.

RESULTS: A significant association of B.1.1.7, the alpha lineage, with patient mortality (log hazard ratio (LHR) = 0.51, C.I. = [0.14,0.88]) was found upon adjustment by all the covariates known to affect COVID-19 prognosis. Moreover, survival analysis of mutations in the SARS-CoV-2 genome revealed 27 of them were significantly associated with higher mortality of patients. Most of these mutations were located in the genes coding for the S, ORF8, and N proteins.

CONCLUSIONS: This study illustrates how a combination of genomic and clinical data can provide solid evidence for the impact of viral lineage on patient survival.

10aCOVID-1910aGenome, Viral10aHumans10amutation10aPandemics10aPhylogeny10aSARS-CoV-21 aLoucera, Carlos1 aPerez-Florido, Javier1 aCasimiro-Soriguer, Carlos, S1 aOrtuno, Francisco, M1 aCarmona, Rosario1 aBostelmann, Gerrit1 aMartínez-González, Javier1 aMuñoyerro-Muñiz, Dolores1 aVillegas, Román1 aRodríguez-Baño, Jesús1 aRomero-Gómez, Manuel1 aLorusso, Nicola1 aGarcia-León, Javier1 aNavarro-Marí, Jose, M1 aCamacho-Martinez, Pedro1 aMerino-Diaz, Laura1 ade Salazar, Adolfo1 aViñuela, Laura1 aLepe, Jose, A1 aGarcía, Federico1 aDopazo, Joaquin uhttp://clinbioinfosspa.es/content/assessing-impact-sars-cov-2-lineages-and-mutations-patient-survival02674nas a2200337 4500008004100000022001400041245011500055210006900170260001600239520155800255100001601813700001901829700002001848700001901868700003101887700002201918700002501940700001701965700001701982700001901999700002102018700002702039700002002066700002202086700002202108700001902130700002002149700002102169710002002190856012602210 2022 eng d a1399-000400aCIBERER: Spanish National Network for Research on Rare Diseases: a highly productive collaborative initiative.0 aCIBERER Spanish National Network for Research on Rare Diseases a c2022 Jan 203 a

CIBER (Center for Biomedical Network Research; Centro de Investigación Biomédica En Red) is a public national consortium created in 2006 under the umbrella of the Spanish National Institute of Health Carlos III (ISCIII). This innovative research structure comprises 11 different specific areas dedicated to the main public health priorities in the National Health System. CIBERER, the thematic area of CIBER focused on Rare Diseases currently consists of 75 research groups belonging to universities, research centers and hospitals of the entire country. CIBERER's mission is to be a center prioritizing and favoring collaboration and cooperation between biomedical and clinical research groups, with special emphasis on the aspects of genetic, molecular, biochemical and cellular research of rare diseases. This research is the basis for providing new tools for the diagnosis and therapy of low-prevalence diseases, in line with the International Rare Diseases Research Consortium (IRDiRC) objectives, thus favoring translational research between the scientific environment of the laboratory and the clinical setting of health centers. In this paper, we intend to review CIBERER's 15-year journey and summarize the main results obtained in terms of internationalization, scientific production, contributions towards the discovery of new therapies and novel genes associated to diseases, cooperation with patients' associations and many other topics related to rare disease research. This article is protected by copyright. All rights reserved.

1 aLuque, Juan1 aMendes, Ingrid1 aGómez, Beatriz1 aMorte, Beatriz1 ade Heredia, Miguel, López1 aHerreras, Enrique1 aCorrochano, Virginia1 aBueren, Juan1 aGallano, Pia1 aArtuch, Rafael1 aFillat, Cristina1 aPérez-Jurado, Luis, A1 aMontoliu, Lluis1 aCarracedo, Ángel1 aMillán, José, M1 aWebb, Susan, M1 aPalau, Francesc1 aLapunzina, Pablo1 aCIBERER Network uhttp://clinbioinfosspa.es/content/ciberer-spanish-national-network-research-rare-diseases-highly-productive-collaborative01965nas a2200157 4500008004100000022001400041245015200055210006900207260001600276520129100292100003001583700002001613700002401633700002001657856013001677 2022 eng d a1460-208300aDiscovering potential interactions between rare diseases and COVID-19 by combining mechanistic models of viral infection with statistical modeling.0 aDiscovering potential interactions between rare diseases and COV c2022 Jan 123 a

Recent studies have demonstrated a relevant role of the host genetics in the COVID-19 prognosis. Most of the 7000 rare diseases described to date have a genetic component, typically highly penetrant. However, this vast spectrum of genetic variability remains yet unexplored with respect to possible interactions with COVID-19. Here, a mathematical mechanistic model of the COVID-19 molecular disease mechanism has been used to detect potential interactions between rare disease genes and the COVID-19 infection process and downstream consequences. Out of the 2518 disease genes analyzed, causative of 3854 rare diseases, a total of 254 genes have a direct effect on the COVID-19 molecular disease mechanism and 207 have an indirect effect revealed by a significant strong correlation. This remarkable potential of interaction occurs for more than 300 rare diseases. Mechanistic modeling of COVID-19 disease map has allowed a holistic systematic analysis of the potential interactions between the loss of function in known rare disease genes and the pathological consequences of COVID-19 infection. The results identify links between disease genes and COVID-19 hallmarks and demonstrate the usefulness of the proposed approach for future preventive measures in some rare diseases.

1 aLópez-Sánchez, Macarena1 aLoucera, Carlos1 aPeña-Chilet, Maria1 aDopazo, Joaquin uhttp://clinbioinfosspa.es/content/discovering-potential-interactions-between-rare-diseases-and-covid-19-combining-mechanistic02967nas a2200445 4500008004100000022001400041245010400055210006900159260001600228490000700244520152100251653001901772653001301791653001101804653003201815653001501847653002901862653001901891653002401910100002601934700002201960700002801982700003002010700002802040700002702068700002702095700003002122700002802152700002202180700002002202700001602222700001902238700002802257700002202285700001602307700002402323700002402347700002202371856012802393 2022 eng d a1422-006700aEndoglin and MMP14 Contribute to Ewing Sarcoma Spreading by Modulation of Cell-Matrix Interactions.0 aEndoglin and MMP14 Contribute to Ewing Sarcoma Spreading by Modu c2022 Aug 040 v233 a

Endoglin (ENG) is a mesenchymal stem cell (MSC) marker typically expressed by active endothelium. This transmembrane glycoprotein is shed by matrix metalloproteinase 14 (MMP14). Our previous work demonstrated potent preclinical activity of first-in-class anti-ENG antibody-drug conjugates as a nascent strategy to eradicate Ewing sarcoma (ES), a devastating rare bone/soft tissue cancer with a putative MSC origin. We also defined a correlation between ENG and MMP14 expression in ES. Herein, we show that ENG expression is significantly associated with a dismal prognosis in a large cohort of ES patients. Moreover, both ENG/MMP14 are frequently expressed in primary ES tumors and metastasis. To deepen in their functional relevance in ES, we conducted transcriptomic and proteomic profiling of in vitro ES models that unveiled a key role of ENG and MMP14 in cell mechano-transduction. Migration and adhesion assays confirmed that loss of ENG disrupts actin filament assembly and filopodia formation, with a concomitant effect on cell spreading. Furthermore, we observed that ENG regulates cell-matrix interaction through activation of focal adhesion signaling and protein kinase C expression. In turn, loss of MMP14 contributed to a more adhesive phenotype of ES cells by modulating the transcriptional extracellular matrix dynamics. Overall, these results suggest that ENG and MMP14 exert a significant role in mediating correct spreading machinery of ES cells, impacting the aggressiveness of the disease.

10aBone Neoplasms10aEndoglin10aHumans10aMatrix Metalloproteinase 1410aProteomics10aReceptors, Growth Factor10aSarcoma, Ewing10aSignal Transduction1 aPuerto-Camacho, Pilar1 aDiaz-Martin, Juan1 aOlmedo-Pelayo, Joaquín1 aBolado-Carrancio, Alfonso1 aSalguero-Aranda, Carmen1 aJordán-Pérez, Carmen1 aEsteban-Medina, Marina1 aAlamo-Alvarez, Inmaculada1 aDelgado-Bellido, Daniel1 aLobo-Selma, Laura1 aDopazo, Joaquin1 aSastre, Ana1 aAlonso, Javier1 aGrünewald, Thomas, G P1 aBernabeu, Carmelo1 aByron, Adam1 aBrunton, Valerie, G1 aAmaral, Ana, Teresa1 ade Alava, Enrique uhttp://clinbioinfosspa.es/content/endoglin-and-mmp14-contribute-ewing-sarcoma-spreading-modulation-cell-matrix-interactions03518nas a2200553 4500008004100000022001400041245007400055210006900129260001300198300001000211490000700221520170300228100002701931700002001958700003101978700002802009700003002037700002502067700001702092700002702109700003202136700002602168700002602194700003502220700003102255700001702286700003102303700003002334700003302364700003302397700003502430700003302465700002502498700003102523700002602554700002502580700002002605700002302625700002302648700002102671700002902692700003102721700002002752700002002772700002102792700002702813710002202840856010202862 2022 eng d a1579-212900aIncidence and Prevalence of Children's Diffuse Lung Disease in Spain.0 aIncidence and Prevalence of Childrens Diffuse Lung Disease in Sp c2022 Jan a22-290 v583 a

BACKGROUND: Children's diffuse lung disease, also known as children's Interstitial Lung Diseases (chILD), are a heterogeneous group of rare diseases with relevant morbidity and mortality, which diagnosis and classification are very complex. Epidemiological data are scarce. The aim of this study was to analyse incidence and prevalence of chILD in Spain.

METHODS: Multicentre observational prospective study in patients from 0 to 18 years of age with chILD to analyse its incidence and prevalence in Spain, based on data reported in 2018 and 2019.

RESULTS: A total of 381 cases with chILD were notified from 51 paediatric pulmonology units all over Spain, covering the 91.7% of the paediatric population. The average incidence of chILD was 8.18 (CI 95% 6.28-10.48) new cases/million of children per year. The average prevalence of chILD was 46.53 (CI 95% 41.81-51.62) cases/million of children. The age group with the highest prevalence were children under 1 year of age. Different types of disorders were seen in children 2-18 years of age compared with children 0-2 years of age. Most frequent cases were: primary pulmonary interstitial glycogenosis in neonates (17/65), neuroendocrine cell hyperplasia of infancy in infants from 1 to 12 months (44/144), idiopathic pulmonary haemosiderosis in children from 1 to 5 years old (13/74), hypersensitivity pneumonitis in children from 5 to 10 years old (9/51), and scleroderma in older than 10 years old (8/47).

CONCLUSIONS: We found a higher incidence and prevalence of chILD than previously described probably due to greater understanding and increased clinician awareness of these rare diseases.

1 aTorrent-Vernetta, Alba1 aGaboli, Mirella1 aCastillo-Corullón, Silvia1 aMondéjar-López, Pedro1 aSantiago, Verónica, Sanz1 aCosta-Colomer, Jordi1 aOsona, Borja1 aTorres-Borrego, Javier1 ade la Serna-Blázquez, Olga1 aAlonso, Sara, Bellón1 aAguilera, Pilar, Caro1 ade Atauri, Álvaro, Gimeno-Dí1 aSoria, Alfredo, Valenzuela1 aAyats, Roser1 ade Vicente, Carlos, Martin1 aGonzález, Valle, Velasco1 aGonzález, José, Domingo Mo1 aCalderín, Elisa, María Can1 aPastor-Vivero, María, Dolores1 aÁlvarez, María, Ángeles V1 aRovira-Amigo, Sandra1 aSerrano, Ignacio, Iglesias1 aIzquierdo, Ana, Díez1 aMessa, Inés, de Mir1 aGartner, Silvia1 aNavarro, Alexandra1 aBaz-Redón, Noelia1 aCarmona, Rosario1 aCamats-Tarruella, Núria1 aFernández-Cancio, Mónica1 aRapp, Christina1 aDopazo, Joaquin1 aGriese, Matthias1 aMoreno-Galdó, Antonio1 aChILD-Spain Group uhttp://clinbioinfosspa.es/content/incidence-and-prevalence-childrens-diffuse-lung-disease-spain-003231nas a2200193 4500008004100000022001400041245011800055210006900173260001600242300000600258490000700264520252200271100002002793700002002813700003002833700002002863700002302883856013102906 2022 eng d a1756-038100aIntegrating pathway knowledge with deep neural networks to reduce the dimensionality in single-cell RNA-seq data.0 aIntegrating pathway knowledge with deep neural networks to reduc c2022 Jan 03 a10 v153 a

BACKGROUND: Single-cell RNA sequencing (scRNA-seq) data provide valuable insights into cellular heterogeneity which is significantly improving the current knowledge on biology and human disease. One of the main applications of scRNA-seq data analysis is the identification of new cell types and cell states. Deep neural networks (DNNs) are among the best methods to address this problem. However, this performance comes with the trade-off for a lack of interpretability in the results. In this work we propose an intelligible pathway-driven neural network to correctly solve cell-type related problems at single-cell resolution while providing a biologically meaningful representation of the data.

RESULTS: In this study, we explored the deep neural networks constrained by several types of prior biological information, e.g. signaling pathway information, as a way to reduce the dimensionality of the scRNA-seq data. We have tested the proposed biologically-based architectures on thousands of cells of human and mouse origin across a collection of public datasets in order to check the performance of the model. Specifically, we tested the architecture across different validation scenarios that try to mimic how unknown cell types are clustered by the DNN and how it correctly annotates cell types by querying a database in a retrieval problem. Moreover, our approach demonstrated to be comparable to other less interpretable DNN approaches constrained by using protein-protein interactions gene regulation data. Finally, we show how the latent structure learned by the network could be used to visualize and to interpret the composition of human single cell datasets.

CONCLUSIONS: Here we demonstrate how the integration of pathways, which convey fundamental information on functional relationships between genes, with DNNs, that provide an excellent classification framework, results in an excellent alternative to learn a biologically meaningful representation of scRNA-seq data. In addition, the introduction of prior biological knowledge in the DNN reduces the size of the network architecture. Comparative results demonstrate a superior performance of this approach with respect to other similar approaches. As an additional advantage, the use of pathways within the DNN structure enables easy interpretability of the results by connecting features to cell functionalities by means of the pathway nodes, as demonstrated with an example with human melanoma tumor cells.

1 aGundogdu, Pelin1 aLoucera, Carlos1 aAlamo-Alvarez, Inmaculada1 aDopazo, Joaquin1 aNepomuceno, Isabel uhttp://clinbioinfosspa.es/content/integrating-pathway-knowledge-deep-neural-networks-reduce-dimensionality-single-cell-rna-seq08208nas a2202125 4500008004100000022001400041245005800055210005600113260001600169520175300185100001701938700002901955700002801984700002002012700002702032700002002059700003002079700003402109700002902143700002702172700003102199700002002230700002502250700002002275700002802295700002302323700002102346700001902367700002902386700002302415700001802438700002202456700002402478700002902502700002902531700002902560700002102589700002502610700002302635700001802658700002002676700002002696700002602716700002402742700001802766700002202784700002402806700003102830700002802861700001802889700002102907700003202928700002502960700003102985700003003016700002403046700001903070700003303089700002903122700002903151700003403180700002803214700002503242700002503267700003303292700003203325700002903357700003303386700002703419700003003446700002903476700002803505700002503533700002903558700002003587700002803607700002103635700002603656700002603682700003303708700002703741700002303768700003103791700001903822700002703841700002403868700002603892700002203918700002003940700002203960700002103982700002804003700002004031700002504051700002004076700002904096700002604125700003004151700001804181700002604199700002104225700002704246700002804273700003304301700003104334700002804365700002704393700001604420700002504436700002404461700002004485700002704505700003704532700002104569700002504590700002004615700002504635700002104660700001704681700002204698700002004720700002304740700003004763700002404793700001804817700002204835700001904857700002204876700002804898700001904926700001904945700001704964700002004981700002605001700001905027700002005046700002205066700001905088700003105107700002205138700002205160700002105182700001805203700002105221700002605242700002605268700003005294700002105324700002305345700002405368700002005392700002305412700001605435700002005451700003205471700002005503700001805523700002005541700001805561700001705579700002005596700001805616700001805634700001805652700001905670700002205689700002305711700003005734700001805764700002605782700002205808700002805830700001905858700002105877700002205898710002505920710002505945710002405970856008805994 2022 eng d a1460-208300aNovel genes and sex differences in COVID-19 severity.0 aNovel genes and sex differences in COVID19 severity c2022 Jun 163 a

Here we describe the results of a genome-wide study conducted in 11 939 COVID-19 positive cases with an extensive clinical information that were recruited from 34 hospitals across Spain (SCOURGE consortium). In sex-disaggregated genome-wide association studies for COVID-19 hospitalization, genome-wide significance (p < 5x10-8) was crossed for variants in 3p21.31 and 21q22.11 loci only among males (p = 1.3x10-22 and p = 8.1x10-12, respectively), and for variants in 9q21.32 near TLE1 only among females (p = 4.4x10-8). In a second phase, results were combined with an independent Spanish cohort (1598 COVID-19 cases and 1068 population controls), revealing in the overall analysis two novel risk loci in 9p13.3 and 19q13.12, with fine-mapping prioritized variants functionally associated with AQP3 (p = 2.7x10-8) and ARHGAP33 (p = 1.3x10-8), respectively. The meta-analysis of both phases with four European studies stratified by sex from the Host Genetics Initiative confirmed the association of the 3p21.31 and 21q22.11 loci predominantly in males and replicated a recently reported variant in 11p13 (ELF5, p = 4.1x10-8). Six of the COVID-19 HGI discovered loci were replicated and an HGI-based genetic risk score predicted the severity strata in SCOURGE. We also found more SNP-heritability and larger heritability differences by age (<60 or ≥ 60 years) among males than among females. Parallel genome-wide screening of inbreeding depression in SCOURGE also showed an effect of homozygosity in COVID-19 hospitalization and severity and this effect was stronger among older males. In summary, new candidate genes for COVID-19 severity and evidence supporting genetic disparities among sexes are provided.

1 aCruz, Raquel1 ade Almeida, Silvia, Diz-1 aHeredia, Miguel, López1 aQuintela, Inés1 aCeballos, Francisco, C1 aPita, Guillermo1 aLorenzo-Salazar, José, M1 aGonzález-Montelongo, Rafaela1 aGago-Domínguez, Manuela1 aPorras, Marta, Sevilla1 aCastaño, Jair, Antonio Te1 aNevado, Julián1 aAguado, Jose, María1 aAguilar, Carlos1 aAguilera-Albesa, Sergio1 aAlmadana, Virginia1 aAlmoguera, Berta1 aAlvarez, Nuria1 aAndreu-Bernabeu, Álvaro1 aArana-Arri, Eunate1 aArango, Celso1 aArranz, María, J1 aArtiga, Maria-Jesus1 aBaptista-Rosas, Raúl, C1 aBarreda-Sánchez, María1 aBelhassen-Garcia, Moncef1 aBezerra, Joao, F1 aBezerra, Marcos, A C1 aBoix-Palop, Lucía1 aBrión, Maria1 aBrugada, Ramón1 aBustos, Matilde1 aCalderón, Enrique, J1 aCarbonell, Cristina1 aCastano, Luis1 aCastelao, Jose, E1 aConde-Vicente, Rosa1 aCordero-Lorenzana, Lourdes1 aCortes-Sanchez, Jose, L1 aCorton, Marta1 aDarnaude, Teresa1 aDe Martino-Rodríguez, Alba1 aCampo-Pérez, Victor1 aBustamante, Aranzazu, Diaz1 aDomínguez-Garrido, Elena1 aLuchessi, André, D1 aEirós, Rocío1 aSanabria, Gladys, Mercedes E1 aFariñas, María, Carmen1 aFernández-Robelo, Uxía1 aFernández-Rodríguez, Amanda1 aFernández-Villa, Tania1 aGil-Fournier, Belén1 aGómez-Arrue, Javier1 aÁlvarez, Beatriz, González1 aQuirós, Fernan, Gonzalez B1 aGonzález-Peñas, Javier1 aGutiérrez-Bautista, Juan, F1 aHerrero, María, José1 aHerrero-Gonzalez, Antonio1 aJimenez-Sousa, María, A1 aLattig, María, Claudia1 aBorja, Anabel, Liger1 aLopez-Rodriguez, Rosario1 aMancebo, Esther1 aMartín-López, Caridad1 aMartín, Vicente1 aMartinez-Nieto, Oscar1 aMartinez-Lopez, Iciar1 aMartinez-Resendez, Michel, F1 aMartinez-Perez, Ángel1 aMazzeu, Juliana, A1 aMacías, Eleuterio, Merayo1 aMinguez, Pablo1 aCuerda, Victor, Moreno1 aSilbiger, Vivian, N1 aOliveira, Silviene, F1 aOrtega-Paino, Eva1 aParellada, Mara1 aPaz-Artal, Estela1 aSantos, Ney, P C1 aPérez-Matute, Patricia1 aPerez, Patricia1 aPérez-Tomás, Elena1 aPerucho, Teresa1 aPinsach-Abuin, Mel, Lina1 aPompa-Mera, Ericka, N1 aPorras-Hurtado, Gloria, L1 aPujol, Aurora1 aLeón, Soraya, Ramiro1 aResino, Salvador1 aFernandes, Marianne, R1 aRodríguez-Ruiz, Emilio1 aRodriguez-Artalejo, Fernando1 aRodriguez-Garcia, José, A1 aRuiz-Cabello, Francisco1 aRuiz-Hornillos, Javier1 aRyan, Pablo1 aSoria, José, Manuel1 aSouto, Juan, Carlos1 aTamayo, Eduardo1 aTamayo-Velasco, Alvaro1 aTaracido-Fernandez, Juan, Carlos1 aTeper, Alejandro1 aTorres-Tobar, Lilian1 aUrioste, Miguel1 aValencia-Ramos, Juan1 aYáñez, Zuleima1 aZarate, Ruth1 aNakanishi, Tomoko1 aPigazzini, Sara1 aDegenhardt, Frauke1 aButler-Laporte, Guillaume1 aMaya-Miles, Douglas1 aBujanda, Luis1 aBouysran, Youssef1 aPalom, Adriana1 aEllinghaus, David1 aMartínez-Bueno, Manuel1 aRolker, Selina1 aAmitrano, Sara1 aRoade, Luisa1 aFava, Francesca1 aSpinner, Christoph, D1 aPrati, Daniele1 aBernardo, David1 aGarcía, Federico1 aDarcis, Gilles1 aFernández-Cadenas, Israel1 aHolter, Jan, Cato1 aBanales, Jesus, M1 aFrithiof, Robert1 aDuga, Stefano1 aAsselta, Rosanna1 aPereira, Alexandre, C1 aRomero-Gómez, Manuel1 aNafría-Jiménez, Beatriz1 aHov, Johannes, R1 aMigeotte, Isabelle1 aRenieri, Alessandra1 aPlanas, Anna, M1 aLudwig, Kerstin, U1 aButi, Maria1 aRahmouni, Souad1 aAlarcón-Riquelme, Marta, E1 aSchulte, Eva, C1 aFranke, Andre1 aKarlsen, Tom, H1 aValenti, Luca1 aZeberg, Hugo1 aRichards, Brent1 aGanna, Andrea1 aBoada, Mercè1 aRojas, Itziar1 aRuiz, Agustín1 aSánchez, Pascual1 aReal, Luis, Miguel1 aGuillén-Navarro, Encarna1 aAyuso, Carmen1 aGonzález-Neira, Anna1 aRiancho, José, A1 aRojas-Martinez, Augusto1 aFlores, Carlos1 aLapunzina, Pablo1 aCarracedo, Ángel1 aSCOURGE Cohort Group1 aHOSTAGE Cohort Group1 aGRA@CE Cohort Group uhttp://clinbioinfosspa.es/content/novel-genes-and-sex-differences-covid-19-severity03086nas a2200241 4500008004100000022001400041245013700055210006900192260001600261300001000277490000700287520215900294100002402453700003202477700003202509700002102541700002102562700002602583700004102609700002002650700004302670856013102713 2022 eng d a2045-232200aProtein and functional isoform levels and genetic variants of the BAFF and APRIL pathway components in systemic lupus erythematosus.0 aProtein and functional isoform levels and genetic variants of th c2022 Jul 02 a112190 v123 a

Systemic lupus erythematosus (SLE) is the prototype of an autoimmune disease. Belimumab, a monoclonal antibody targets BAFF, is the only biologic approved for SLE and active lupus nephritis. BAFF is a cytokine with a key-regulatory role in the B cell homeostasis, which acts by binding to three receptors: BAFF-R, TACI and BCMA. TACI and BCMA also bind APRIL. Many studies reported elevated soluble BAFF and APRIL levels in the sera of SLE patients, but other questions about the role of this system in the disease remain open. The study aimed to investigate the utility of the cytokine levels in serum and urine as biomarkers, the role of non-functional isoforms, and the association of gene variants with the disease. This case-control study includes a cohort (women, 18-60 years old) of 100 patients (48% with nephritis) and 100 healthy controls. We used ELISA assays to measure the cytokine concentrations in serum (sBAFF and sAPRIL) and urine (uBAFF and uAPRIL); TaqMan Gene Expression Assays to quantify the relative mRNA expression of ΔBAFF, βAPRIL, and εAPRIL, and next-generation sequencing to genotype the cytokine (TNFSF13 and TNFSF13B) and receptor (TNFRSF13B, TNFRSF17 and TNFRSF13C) genes. The statistical tests used were: Kruskal-Wallis (qualitative variables), the Spearman Rho coefficient (correlations), the Chi-square and SKAT (association of common and rare genetic variants, respectively). As expected, sBAFF and sAPRIL levels were higher in patients than in controls (p ≤ 0.001) but found differences between patient subgroups. sBAFF and sAPRIL significantly correlated only in patients with nephritis (r = 0.67, p ≤ 0.001) and βAPRIL levels were lower in patients with nephritis (p = 0.04), and ΔBAFF levels were lower in patients with dsDNA antibodies (p = 0.04). Rare variants of TNFSF13 and TNFRSF13B and TNFSF13 p.Gly67Arg and TNFRSF13B p.Val220Ala were associated with SLE. Our study supports differences among SLE patient subgroups with diverse clinical features in the BAFF/APRIL pathway. In addition, it suggests the involvement of genetic variants in the susceptibility to the disease.

1 aOrtiz-Aljaro, Pilar1 aMontes-Cano, Marco, Antonio1 aGarcía-Lozano, José-Raúl1 aAquino, Virginia1 aCarmona, Rosario1 aPerez-Florido, Javier1 aGarcía-Hernández, Francisco, José1 aDopazo, Joaquin1 aGonzález-Escribano, María, Francisca uhttp://clinbioinfosspa.es/content/protein-and-functional-isoform-levels-and-genetic-variants-baff-and-april-pathway-components02438nas a2200241 4500008004100000022001400041245012800055210006900183260001600252490000700268520156100275100003101836700002001867700001901887700002701906700001901933700002001952700002901972700002402001700002402025700002002049856012702069 2022 eng d a2076-392100aAn SPM-Enriched Marine Oil Supplement Shifted Microglia Polarization toward M2, Ameliorating Retinal Degeneration in Mice.0 aSPMEnriched Marine Oil Supplement Shifted Microglia Polarization c2022 Dec 300 v123 a

Retinitis pigmentosa (RP) is the most common inherited retinal dystrophy causing progressive vision loss. It is accompanied by chronic and sustained inflammation, including M1 microglia activation. This study evaluated the effect of an essential fatty acid (EFA) supplement containing specialized pro-resolving mediators (SPMs), on retinal degeneration and microglia activation in mice, a model of RP, as well as on LPS-stimulated BV2 cells. The EFA supplement was orally administered to mice from postnatal day (P)9 to P18. At P18, the electrical activity of the retina was examined by electroretinography (ERG) and innate behavior in response to light were measured. Retinal degeneration was studied via histology including the TUNEL assay and microglia immunolabeling. Microglia polarization (M1/M2) was assessed by flow cytometry, qPCR, ELISA and histology. Redox status was analyzed by measuring antioxidant enzymes and markers of oxidative damage. Interestingly, the EFA supplement ameliorated retinal dysfunction and degeneration by improving ERG recording and sensitivity to light, and reducing photoreceptor cell loss. The EFA supplement reduced inflammation and microglia activation attenuating M1 markers as well as inducing a shift to the M2 phenotype in mouse retinas and LPS-stimulated BV2 cells. It also reduced oxidative stress markers of lipid peroxidation and carbonylation. These findings could open up new therapeutic opportunities based on resolving inflammation with oral supplementation with SPMs such as the EFA supplement.

1 aOlivares-González, Lorena1 aVelasco, Sheyla1 aGallego, Idoia1 aEsteban-Medina, Marina1 aPuras, Gustavo1 aLoucera, Carlos1 aMartínez-Romero, Alicia1 aPeña-Chilet, Maria1 aPedraz, José, Luis1 aRodrigo, Regina uhttp://clinbioinfosspa.es/content/spm-enriched-marine-oil-supplement-shifted-microglia-polarization-toward-m2-ameliorating02048nas a2200181 4500008004100000022001400041245013200055210006900187260001600256300000800272490000700280520135300287100003301640700002001673700002401693700002001717856012901737 2022 eng d a2045-232200aTowards a metagenomics machine learning interpretable model for understanding the transition from adenoma to colorectal cancer.0 aTowards a metagenomics machine learning interpretable model for  c2022 Jan 10 a4500 v123 a

Gut microbiome is gaining interest because of its links with several diseases, including colorectal cancer (CRC), as well as the possibility of being used to obtain non-intrusive predictive disease biomarkers. Here we performed a meta-analysis of 1042 fecal metagenomic samples from seven publicly available studies. We used an interpretable machine learning approach based on functional profiles, instead of the conventional taxonomic profiles, to produce a highly accurate predictor of CRC with better precision than those of previous proposals. Moreover, this approach is also able to discriminate samples with adenoma, which makes this approach very promising for CRC prevention by detecting early stages in which intervention is easier and more effective. In addition, interpretable machine learning methods allow extracting features relevant for the classification, which reveals basic molecular mechanisms accounting for the changes undergone by the microbiome functional landscape in the transition from healthy gut to adenoma and CRC conditions. Functional profiles have demonstrated superior accuracy in predicting CRC and adenoma conditions than taxonomic profiles and additionally, in a context of explainable machine learning, provide useful hints on the molecular mechanisms operating in the microbiota behind these conditions.

1 aCasimiro-Soriguer, Carlos, S1 aLoucera, Carlos1 aPeña-Chilet, Maria1 aDopazo, Joaquin uhttp://clinbioinfosspa.es/content/towards-metagenomics-machine-learning-interpretable-model-understanding-transition-adenoma02333nas a2200373 4500008004100000022001400041245009100055210006900146260001600215300000800231490000700239520108200246653002401328653002601352653002301378653001101401100003001412700002901442700002801471700002801499700003701527700002401564700003101588700001801619700002701637700002501664700003101689700002401720700002001744700002601764700003201790700002501822856011201847 2021 eng d a1471-210500aA comprehensive database for integrated analysis of omics data in autoimmune diseases.0 acomprehensive database for integrated analysis of omics data in  c2021 Jun 24 a3430 v223 a

BACKGROUND: Autoimmune diseases are heterogeneous pathologies with difficult diagnosis and few therapeutic options. In the last decade, several omics studies have provided significant insights into the molecular mechanisms of these diseases. Nevertheless, data from different cohorts and pathologies are stored independently in public repositories and a unified resource is imperative to assist researchers in this field.

RESULTS: Here, we present Autoimmune Diseases Explorer ( https://adex.genyo.es ), a database that integrates 82 curated transcriptomics and methylation studies covering 5609 samples for some of the most common autoimmune diseases. The database provides, in an easy-to-use environment, advanced data analysis and statistical methods for exploring omics datasets, including meta-analysis, differential expression or pathway analysis.

CONCLUSIONS: This is the first omics database focused on autoimmune diseases. This resource incorporates homogeneously processed data to facilitate integrative analyses among studies.

10aAutoimmune Diseases10aComputational Biology10aDatabases, Factual10aHumans1 aMartorell-Marugán, Jordi1 aLópez-Domínguez, Raúl1 aGarcía-Moreno, Adrián1 aToro-Domínguez, Daniel1 aVillatoro-García, Juan, Antonio1 aBarturen, Guillermo1 aMartín-Gómez, Adoración1 aTroule, Kevin1 aGómez-López, Gonzalo1 aAl-Shahrour, Fátima1 aGonzález-Rumayor, Víctor1 aPeña-Chilet, Maria1 aDopazo, Joaquin1 aSaez-Rodriguez, Julio1 aAlarcón-Riquelme, Marta, E1 aCarmona-Sáez, Pedro uhttp://clinbioinfosspa.es/content/comprehensive-database-integrated-analysis-omics-data-autoimmune-diseases07188nas a2202077 4500008004100000022001400041245010000055210006900155260001200224300001100236490000700247520130900254653002101563653002601584653002201610653001301632653001401645653001601659653002301675653003101698653003201729653001101761653002301772653002201795653002101817653001601838653003601854653001801890653003201908653001501940653002401955653001301979653002601992653001902018100002302037700001902060700002202079700002102101700001802122700002702140700001902167700002602186700002602212700001802238700001902256700001702275700002202292700002102314700001902335700002902354700001802383700001602401700002902417700001802446700002302464700002202487700002002509700002002529700002702549700002102576700001702597700001802614700002402632700002102656700001602677700002102693700001902714700002302733700002302756700002002779700001702799700001902816700002402835700002102859700002402880700001702904700002302921700002402944700001902968700002002987700001903007700001903026700002903045700002303074700002003097700001703117700001803134700002403152700003303176700002003209700002003229700001603249700001503265700001803280700001903298700002603317700002703343700002003370700002403390700001803414700002403432700002203456700002203478700001903500700002003519700002103539700001803560700001503578700002203593700002303615700001703638700001903655700002403674700001703698700001803715700001703733700002303750700001803773700001803791700002303809700002103832700001703853700002203870700002003892700001803912700001803930700002303948700002103971700002503992700001804017700002004035700001704055700001904072700001704091700002104108700002504129700002704154700002404181700001604205700002104221700002504242700001704267700002004284700001804304700002504322700002404347700002304371700002104394700001904415700002204434700001804456700001604474700002204490700002004512700001804532700002504550700001904575700002204594700002404616700002304640700002004663700002304683700002204706700002304728700002304751700002604774700002004800700002204820700002004842700002304862700002104885700001804906700002404924710003504948856012704983 2021 eng d a1744-429200aCOVID19 Disease Map, a computational knowledge repository of virus-host interaction mechanisms.0 aCOVID19 Disease Map a computational knowledge repository of viru c2021 10 ae103870 v173 a

We need to effectively combine the knowledge from surging literature with complex datasets to propose mechanistic models of SARS-CoV-2 infection, improving data interpretation and predicting key targets of intervention. Here, we describe a large-scale community effort to build an open access, interoperable and computable repository of COVID-19 molecular mechanisms. The COVID-19 Disease Map (C19DMap) is a graphical, interactive representation of disease-relevant molecular mechanisms linking many knowledge sources. Notably, it is a computational resource for graph-based analyses and disease modelling. To this end, we established a framework of tools, platforms and guidelines necessary for a multifaceted community of biocurators, domain experts, bioinformaticians and computational biologists. The diagrams of the C19DMap, curated from the literature, are integrated with relevant interaction and text mining databases. We demonstrate the application of network analysis and modelling approaches by concrete examples to highlight new testable hypotheses. This framework helps to find signatures of SARS-CoV-2 predisposition, treatment response or prioritisation of drug candidates. Such an approach may help deal with new waves of COVID-19 or similar pandemics in the long-term perspective.

10aAntiviral Agents10aComputational Biology10aComputer Graphics10aCOVID-1910aCytokines10aData Mining10aDatabases, Factual10aGene Expression Regulation10aHost Microbial Interactions10aHumans10aImmunity, Cellular10aImmunity, Humoral10aImmunity, Innate10aLymphocytes10aMetabolic Networks and Pathways10aMyeloid Cells10aProtein Interaction Mapping10aSARS-CoV-210aSignal Transduction10aSoftware10aTranscription Factors10aViral Proteins1 aOstaszewski, Marek1 aNiarakis, Anna1 aMazein, Alexander1 aKuperstein, Inna1 aPhair, Robert1 aOrta-Resendiz, Aurelio1 aSingh, Vidisha1 aAghamiri, Sara, Sadat1 aAcencio, Marcio, Luis1 aGlaab, Enrico1 aRuepp, Andreas1 aFobo, Gisela1 aMontrone, Corinna1 aBrauner, Barbara1 aFrishman, Goar1 aGómez, Luis, Cristóbal1 aSomers, Julia1 aHoch, Matti1 aGupta, Shailendra, Kumar1 aScheel, Julia1 aBorlinghaus, Hanna1 aCzauderna, Tobias1 aSchreiber, Falk1 aMontagud, Arnau1 ade Leon, Miguel, Ponce1 aFunahashi, Akira1 aHiki, Yusuke1 aHiroi, Noriko1 aYamada, Takahiro, G1 aDräger, Andreas1 aRenz, Alina1 aNaveez, Muhammad1 aBocskei, Zsolt1 aMessina, Francesco1 aBörnigen, Daniela1 aFergusson, Liam1 aConti, Marta1 aRameil, Marius1 aNakonecnij, Vanessa1 aVanhoefer, Jakob1 aSchmiester, Leonard1 aWang, Muying1 aAckerman, Emily, E1 aShoemaker, Jason, E1 aZucker, Jeremy1 aOxford, Kristie1 aTeuton, Jeremy1 aKocakaya, Ebru1 aSummak, Gökçe, Yağmur1 aHanspers, Kristina1 aKutmon, Martina1 aCoort, Susan1 aEijssen, Lars1 aEhrhart, Friederike1 aRex, Devasahayam, Arokia Bal1 aSlenter, Denise1 aMartens, Marvin1 aPham, Nhung1 aHaw, Robin1 aJassal, Bijay1 aMatthews, Lisa1 aOrlic-Milacic, Marija1 aRibeiro, Andrea, Senff1 aRothfels, Karen1 aShamovsky, Veronica1 aStephan, Ralf1 aSevilla, Cristoffer1 aVarusai, Thawfeek1 aRavel, Jean-Marie1 aFraser, Rupsha1 aOrtseifen, Vera1 aMarchesi, Silvia1 aGawron, Piotr1 aSmula, Ewa1 aHeirendt, Laurent1 aSatagopam, Venkata1 aWu, Guanming1 aRiutta, Anders1 aGolebiewski, Martin1 aOwen, Stuart1 aGoble, Carole1 aHu, Xiaoming1 aOverall, Rupert, W1 aMaier, Dieter1 aBauch, Angela1 aGyori, Benjamin, M1 aBachman, John, A1 aVega, Carlos1 aGrouès, Valentin1 aVazquez, Miguel1 aPorras, Pablo1 aLicata, Luana1 aIannuccelli, Marta1 aSacco, Francesca1 aNesterova, Anastasia1 aYuryev, Anton1 ade Waard, Anita1 aTurei, Denes1 aLuna, Augustin1 aBabur, Ozgun1 aSoliman, Sylvain1 aValdeolivas, Alberto1 aEsteban-Medina, Marina1 aPeña-Chilet, Maria1 aRian, Kinza1 aHelikar, Tomáš1 aPuniya, Bhanwar, Lal1 aModos, Dezso1 aTreveil, Agatha1 aOlbei, Marton1 aDe Meulder, Bertrand1 aBallereau, Stephane1 aDugourd, Aurélien1 aNaldi, Aurélien1 aNoël, Vincent1 aCalzone, Laurence1 aSander, Chris1 aDemir, Emek1 aKorcsmaros, Tamas1 aFreeman, Tom, C1 aAugé, Franck1 aBeckmann, Jacques, S1 aHasenauer, Jan1 aWolkenhauer, Olaf1 aWilighagen, Egon, L1 aPico, Alexander, R1 aEvelo, Chris, T1 aGillespie, Marc, E1 aStein, Lincoln, D1 aHermjakob, Henning1 aD'Eustachio, Peter1 aSaez-Rodriguez, Julio1 aDopazo, Joaquin1 aValencia, Alfonso1 aKitano, Hiroaki1 aBarillot, Emmanuel1 aAuffray, Charles1 aBalling, Rudi1 aSchneider, Reinhard1 aCOVID-19 Disease Map Community uhttp://clinbioinfosspa.es/content/covid19-disease-map-computational-knowledge-repository-virus-host-interaction-mechanisms03503nas a2200709 4500008004100000022001400041245008200055210006900137260001500206300001600221490000700237520139500244653001201639653002301651653001801674653002301692653001001715653001901725653002201744653002501766653001801791653001301809653001101822653001301833653002301846653001301869653001001882100002401892700001801916700002601934700002501960700002101985700002102006700002602027700002002053700002902073700002302102700002902125700002602154700002002180700002702200700002702227700001802254700001902272700003002291700001802321700003402339700001902373700002902392700002702421700001902448700002502467700001702492700002802509700002802537700001902565700002202584700001902606700002002625710004302645856010502688 2021 eng d a1362-496200aCSVS, a crowdsourcing database of the Spanish population genetic variability.0 aCSVS a crowdsourcing database of the Spanish population genetic  c2021 01 08 aD1130-D11370 v493 a

The knowledge of the genetic variability of the local population is of utmost importance in personalized medicine and has been revealed as a critical factor for the discovery of new disease variants. Here, we present the Collaborative Spanish Variability Server (CSVS), which currently contains more than 2000 genomes and exomes of unrelated Spanish individuals. This database has been generated in a collaborative crowdsourcing effort collecting sequencing data produced by local genomic projects and for other purposes. Sequences have been grouped by ICD10 upper categories. A web interface allows querying the database removing one or more ICD10 categories. In this way, aggregated counts of allele frequencies of the pseudo-control Spanish population can be obtained for diseases belonging to the category removed. Interestingly, in addition to pseudo-control studies, some population studies can be made, as, for example, prevalence of pharmacogenomic variants, etc. In addition, this genomic data has been used to define the first Spanish Genome Reference Panel (SGRP1.0) for imputation. This is the first local repository of variability entirely produced by a crowdsourcing effort and constitutes an example for future initiatives to characterize local variability worldwide. CSVS is also part of the GA4GH Beacon network. CSVS can be accessed at: http://csvs.babelomics.org/.

10aAlleles10aChromosome Mapping10aCrowdsourcing10aDatabases, Genetic10aExome10aGene Frequency10aGenetic Variation10aGenetics, Population10aGenome, Human10aGenomics10aHumans10aInternet10aPrecision Medicine10aSoftware10aSpain1 aPeña-Chilet, Maria1 aRoldán, Gema1 aPerez-Florido, Javier1 aOrtuno, Francisco, M1 aCarmona, Rosario1 aAquino, Virginia1 aLópez-López, Daniel1 aLoucera, Carlos1 aFernandez-Rueda, Jose, L1 aGallego, Asunción1 aGarcia-Garcia, Francisco1 aGonzález-Neira, Anna1 aPita, Guillermo1 aNúñez-Torres, Rocío1 aSantoyo-López, Javier1 aAyuso, Carmen1 aMinguez, Pablo1 aAvila-Fernandez, Almudena1 aCorton, Marta1 aMoreno-Pelayo, Miguel, Ángel1 aMorin, Matías1 aGallego-Martinez, Alvaro1 aLopez-Escamez, Jose, A1 aBorrego, Salud1 aAntiňolo, Guillermo1 aAmigo, Jorge1 aSalgado-Garrido, Josefa1 aPasalodos-Sanchez, Sara1 aMorte, Beatriz1 aCarracedo, Ángel1 aAlonso, Ángel1 aDopazo, Joaquin1 aSpanish Exome Crowdsourcing Consortium uhttp://clinbioinfosspa.es/content/csvs-crowdsourcing-database-spanish-population-genetic-variability03228nas a2200613 4500008004100000022001400041245014900055210006900204260001200273300001200285490000800297520129600305653002101601653002601622653001301648653001001661653003101671653003201702653001101734653000901745653003301754653002101787653001901808653002201827653001301849653002601862653003401888653002701922100003001949700002701979700002802006700001702034700001902051700001902070700002102089700002902110700002202139700001902161700002402180700002202204700002102226700001902247700002102266700002202287700001702309700001902326700002002345700002602365700003002391700001902421700002602440700001902466856012902485 2021 eng d a1552-483300aDe novo small deletion affecting transcription start site of short isoform of AUTS2 gene in a patient with syndromic neurodevelopmental defects.0 aDe novo small deletion affecting transcription start site of sho c2021 03 a877-8830 v1853 a

Disruption of the autism susceptibility candidate 2 (AUTS2) gene through genomic rearrangements, copy number variations (CNVs), and intragenic deletions and mutations, has been recurrently involved in syndromic forms of developmental delay and intellectual disability, known as AUTS2 syndrome. The AUTS2 gene plays an important role in regulation of neuronal migration, and when altered, associates with a variable phenotype from severely to mildly affected patients. The more severe phenotypes significantly correlate with the presence of defects affecting the C-terminus part of the gene. This article reports a new patient with a syndromic neurodevelopmental disorder, who presents a deletion of 30 nucleotides in the exon 9 of the AUTS2 gene. Importantly, this deletion includes the transcription start site for the AUTS2 short transcript isoform, which has an important role in brain development. Gene expression analysis of AUTS2 full-length and short isoforms revealed that the deletion found in this patient causes a remarkable reduction in the expression level, not only of the short isoform, but also of the full AUTS2 transcripts. This report adds more evidence for the role of mutated AUTS2 short transcripts in the development of a severe phenotype in the AUTS2 syndrome.

10aChild, Preschool10aCytoskeletal Proteins10aDwarfism10aExons10aGene Expression Regulation10aGenetic Association Studies10aHumans10aMale10aNeurodevelopmental Disorders10aProtein Isoforms10aRNA, Messenger10aSequence Deletion10aSyndrome10aTranscription Factors10aTranscription Initiation Site10aTranscription, Genetic1 aMartinez-Delgado, Beatriz1 aLopez-Martin, Estrella1 aLara-Herguedas, Julián1 aMonzon, Sara1 aCuesta, Isabel1 aJuliá, Miguel1 aAquino, Virginia1 aRodriguez-Martin, Carlos1 aDamian, Alejandra1 aGonzalo, Irene1 aGomez-Mariano, Gema1 aBaladron, Beatriz1 aCazorla, Rosario1 aIglesias, Gema1 aRoman, Enriqueta1 aRos, Purificacion1 aTutor, Pablo1 aMellor, Susana1 aJimenez, Carlos1 aCabrejas, Maria, Jose1 aGonzalez-Vioque, Emiliano1 aAlonso, Javier1 aBermejo-Sánchez, Eva1 aPosada, Manuel uhttp://clinbioinfosspa.es/content/de-novo-small-deletion-affecting-transcription-start-site-short-isoform-auts2-gene-patient00616nas a2200157 4500008004100000245013100041210006900172260001600241300000900257490000600266100003100272700002800303700001800331700002000349856008900369 2021 eng d00aDeciphering Genomic Heterogeneity and the Internal Composition of Tumour Activities through a Hierarchical Factorisation Model0 aDeciphering Genomic Heterogeneity and the Internal Composition o cJan-11-2021 a28330 v91 aCarbonell-Caballero, José1 aLópez-Quílez, Antonio1 aConesa, David1 aDopazo, Joaquin uhttps://www.mdpi.com/2227-7390/9/21/2833https://www.mdpi.com/2227-7390/9/21/2833/pdf03078nas a2200493 4500008004100000022001400041245014600055210006900201260001200270300001400282490000700296520140800303100002001711700002401731700002901755700002801784700002501812700002501837700001801862700002401880700002901904700003101933700003501964700002101999700003102020700002102051700001902072700002802091700001802119700003102137700002802168700001702196700003902213700001702252700002502269700002202294700002002316700002302336700001802359700002202377700002902399700002502428856013102453 2021 eng d a1878-026100aA DNA damage repair gene-associated signature predicts responses of patients with advanced soft-tissue sarcoma to treatment with trabectedin.0 aDNA damage repair geneassociated signature predicts responses of c2021 12 a3691-37050 v153 a

Predictive biomarkers of trabectedin represent an unmet need in advanced soft-tissue sarcomas (STS). DNA damage repair (DDR) genes, involved in homologous recombination or nucleotide excision repair, had been previously described as biomarkers of trabectedin resistance or sensitivity, respectively. The majority of these studies only focused on specific factors (ERCC1, ERCC5, and BRCA1) and did not evaluate several other DDR-related genes that could have a relevant role for trabectedin efficacy. In this retrospective translational study, 118 genes involved in DDR were evaluated to determine, by transcriptomics, a predictive gene signature of trabectedin efficacy. A six-gene predictive signature of trabectedin efficacy was built in a series of 139 tumor samples from patients with advanced STS. Patients in the high-risk gene signature group showed a significantly worse progression-free survival compared with patients in the low-risk group (2.1 vs 6.0 months, respectively). Differential gene expression analysis defined new potential predictive biomarkers of trabectedin sensitivity (PARP3 and CCNH) or resistance (DNAJB11 and PARP1). Our study identified a new gene signature that significantly predicts patients with higher probability to respond to treatment with trabectedin. Targeting some genes of this signature emerges as a potential strategy to enhance trabectedin efficacy.

1 aMoura, David, S1 aPeña-Chilet, Maria1 aVarela, Juan, Antonio Co1 aAlvarez-Alegret, Ramiro1 aAgra-Pujol, Carolina1 aIzquierdo, Francisco1 aRamos, Rafael1 aOrtega-Medina, Luis1 aMartin-Davila, Francisco1 aCastilla-Ramirez, Carolina1 aHernandez-Leon, Carmen, Nieves1 aRomagosa, Cleofe1 aSalgado, Maria, Angeles Va1 aLavernia, Javier1 aBagué, Silvia1 aMayodormo-Aranda, Empar1 aVicioso, Luis1 aBarceló, Jose, Emilio Her1 aRubio-Casadevall, Jordi1 ade Juan, Ana1 aFiaño-Valverde, Maria, Concepcion1 aHindi, Nadia1 aLopez-Alvarez, Maria1 aLacerenza, Serena1 aDopazo, Joaquin1 aGutierrez, Antonio1 aAlvarez, Rosa1 aValverde, Claudia1 aMartinez-Trufero, Javier1 aMartin-Broto, Javier uhttp://clinbioinfosspa.es/content/dna-damage-repair-gene-associated-signature-predicts-responses-patients-advanced-soft-tissue01023nas a2200313 4500008004100000022001400041245008100055210006900136260001200205300001400217490000700231653001500238653002600253653002400279653001100303653002300314653002000337653003200357100001500389700002000404700002600424700001700450700002400467700002100491700002600512700002500538710004000563856010600603 2021 eng d a1548-710500aDOME: recommendations for supervised machine learning validation in biology.0 aDOME recommendations for supervised machine learning validation  c2021 10 a1122-11270 v1810aAlgorithms10aComputational Biology10aGuidelines as Topic10aHumans10aModels, Biological10aResearch Design10aSupervised Machine Learning1 aWalsh, Ian1 aFishman, Dmytro1 aGarcia-Gasulla, Dario1 aTitma, Tiina1 aPollastri, Gianluca1 aHarrow, Jennifer1 aPsomopoulos, Fotis, E1 aTosatto, Silvio, C E1 aELIXIR Machine Learning Focus Group uhttp://clinbioinfosspa.es/content/dome-recommendations-supervised-machine-learning-validation-biology00806nas a2200229 4500008004100000022001300041245014700054210006900201260001600270300001600286490000700302100001600309700002300325700001800348700002200366700002000388700002700408700003000435700002400465700002000489856006700509 2021 eng d a2001037000aGenome-scale mechanistic modeling of signaling pathways made easy: A bioconductor/cytoscape/web server framework for the analysis of omic data0 aGenomescale mechanistic modeling of signaling pathways made easy cJan-01-2021 a2968 - 29780 v191 aRian, Kinza1 aHidalgo, Marta, R.1 aCubuk, Cankut1 aFalco, Matias, M.1 aLoucera, Carlos1 aEsteban-Medina, Marina1 aAlamo-Alvarez, Inmaculada1 aPeña-Chilet, Maria1 aDopazo, Joaquin uhttps://linkinghub.elsevier.com/retrieve/pii/S200103702100203800926nas a2200229 4500008004100000022001400041245021100055210006900266260001600335490000700351100002900358700002600387700002000413700003400433700002300467700003100490700003300521700002500554700002000579700001900599856007800618 2021 eng d a1868-707500aGenome-wide analysis of DNA methylation in Hirschsprung enteric precursor cells: unraveling the epigenetic landscape of enteric nervous system developmentAbstractBackgroundResultsConclusionsGraphic abstract0 aGenomewide analysis of DNA methylation in Hirschsprung enteric p cJan-12-20210 v131 aVillalba-Benito, Leticia1 aLópez-López, Daniel1 aTorroglosa, Ana1 aCasimiro-Soriguer, Carlos, S.1 aLuzón-Toro, Berta1 aFernández, Raquel, María1 aMoya-Jiménez, María, José1 aAntiňolo, Guillermo1 aDopazo, Joaquin1 aBorrego, Salud uhttp://link.springer.com/article/10.1186/s13148-021-01040-6/fulltext.html02548nas a2200301 4500008004100000022001400041245009700055210006900152260001500221490000700236520154600243653001801789653001401807653001501821653002801836100002501864700002001889700003301909700001801942700002901960700002401989700002302013700002002036700002202056700002602078700002002104856012202124 2021 eng d a2047-217X00aHighly accurate whole-genome imputation of SARS-CoV-2 from partial or low-quality sequences.0 aHighly accurate wholegenome imputation of SARSCoV2 from partial  c2021 12 020 v103 a

BACKGROUND: The current SARS-CoV-2 pandemic has emphasized the utility of viral whole-genome sequencing in the surveillance and control of the pathogen. An unprecedented ongoing global initiative is producing hundreds of thousands of sequences worldwide. However, the complex circumstances in which viruses are sequenced, along with the demand of urgent results, causes a high rate of incomplete and, therefore, useless sequences. Viral sequences evolve in the context of a complex phylogeny and different positions along the genome are in linkage disequilibrium. Therefore, an imputation method would be able to predict missing positions from the available sequencing data.

RESULTS: We have developed the impuSARS application, which takes advantage of the enormous number of SARS-CoV-2 genomes available, using a reference panel containing 239,301 sequences, to produce missing data imputation in viral genomes. ImpuSARS was tested in a wide range of conditions (continuous fragments, amplicons or sparse individual positions missing), showing great fidelity when reconstructing the original sequences, recovering the lineage with a 100% precision for almost all the lineages, even in very poorly covered genomes (<20%).

CONCLUSIONS: Imputation can improve the pace of SARS-CoV-2 sequencing production by recovering many incomplete or low-quality sequences that would be otherwise discarded. ImpuSARS can be incorporated in any primary data processing pipeline for SARS-CoV-2 whole-genome sequencing.

10aGenome, Viral10aPhylogeny10aSARS-CoV-210aWhole Genome Sequencing1 aOrtuno, Francisco, M1 aLoucera, Carlos1 aCasimiro-Soriguer, Carlos, S1 aLepe, Jose, A1 aMartinez, Pedro, Camacho1 aDiaz, Laura, Merino1 ade Salazar, Adolfo1 aChueca, Natalia1 aGarcía, Federico1 aPerez-Florido, Javier1 aDopazo, Joaquin uhttp://clinbioinfosspa.es/content/highly-accurate-whole-genome-imputation-sars-cov-2-partial-or-low-quality-sequences02196nas a2200325 4500008004100000022001400041245010300055210006900158260001300227300001400240490000700254520111400261653001201375653002201387653003501409653002801444653001301472653001101485653001801496653001801514653001901532100003501551700002501586700002901611700002301640700002901663700002401692700002601716856012801742 2021 eng d a1432-085100aImmunotherapy in nonsmall-cell lung cancer: current status and future prospects for liquid biopsy.0 aImmunotherapy in nonsmallcell lung cancer current status and fut c2021 May a1177-11880 v703 a

Immunotherapy has been one of the great advances in the recent years for the treatment of advanced tumors, with nonsmall-cell lung cancer (NSCLC) being one of the cancers that has benefited most from this approach. Currently, the only validated companion diagnostic test for first-line immunotherapy in metastatic NSCLC patients is testing for programmed death ligand 1 (PD-L1) expression in tumor tissues. However, not all patients experience an effective response with the established selection criteria and immune checkpoint inhibitors (ICIs). Liquid biopsy offers a noninvasive opportunity to monitor disease in patients with cancer and identify those who would benefit the most from immunotherapy. This review focuses on the use of liquid biopsy in immunotherapy treatment of NSCLC patients. Circulating tumor cells (CTCs), cell-free DNA (cfDNA) and exosomes are promising tools for developing new biomarkers. We discuss the current application and future implementation of these parameters to improve therapeutic decision-making and identify the patients who will benefit most from immunotherapy.

10aAnimals10aBiomarkers, Tumor10aCarcinoma, Non-Small-Cell Lung10aCell-Free Nucleic Acids10aExosomes10aHumans10aImmunotherapy10aLiquid Biopsy10aLung Neoplasms1 aBrozos-Vázquez, Elena, María1 aDíaz-Peña, Roberto1 aGarcía-González, Jorge1 aLeón-Mateos, Luis1 aMondelo-Macía, Patricia1 aPeña-Chilet, Maria1 aLópez-López, Rafael uhttp://clinbioinfosspa.es/content/immunotherapy-nonsmall-cell-lung-cancer-current-status-and-future-prospects-liquid-biopsy02741nas a2200253 4500008004100000022001400041245011600055210006900171260001600240490000700256520183900263100002002102700002402122700002202146700002002168700002802188700002702216700002602243700002902269700002002298700001802318700002602336856012502362 2021 eng d a2075-442600aImplementing Personalized Medicine in COVID-19 in Andalusia: An Opportunity to Transform the Healthcare System.0 aImplementing Personalized Medicine in COVID19 in Andalusia An Op c2021 May 260 v113 a

The COVID-19 pandemic represents an unprecedented opportunity to exploit the advantages of personalized medicine for the prevention, diagnosis, treatment, surveillance and management of a new challenge in public health. COVID-19 infection is highly variable, ranging from asymptomatic infections to severe, life-threatening manifestations. Personalized medicine can play a key role in elucidating individual susceptibility to the infection as well as inter-individual variability in clinical course, prognosis and response to treatment. Integrating personalized medicine into clinical practice can also transform health care by enabling the design of preventive and therapeutic strategies tailored to individual profiles, improving the detection of outbreaks or defining transmission patterns at an increasingly local level. SARS-CoV2 genome sequencing, together with the assessment of specific patient genetic variants, will support clinical decision-makers and ultimately better ways to fight this disease. Additionally, it would facilitate a better stratification and selection of patients for clinical trials, thus increasing the likelihood of obtaining positive results. Lastly, defining a national strategy to implement in clinical practice all available tools of personalized medicine in COVID-19 could be challenging but linked to a positive transformation of the health care system. In this review, we provide an update of the achievements, promises, and challenges of personalized medicine in the fight against COVID-19 from susceptibility to natural history and response to therapy, as well as from surveillance to control measures and vaccination. We also discuss strategies to facilitate the adoption of this new paradigm for medical and public health measures during and after the pandemic in health care systems.

1 aDopazo, Joaquin1 aMaya-Miles, Douglas1 aGarcía, Federico1 aLorusso, Nicola1 aCalleja, Miguel, Ángel1 aPareja, María, Jesús1 aLópez-Miranda, José1 aRodríguez-Baño, Jesús1 aPadillo, Javier1 aTúnez, Isaac1 aRomero-Gómez, Manuel uhttp://clinbioinfosspa.es/content/implementing-personalized-medicine-covid-19-andalusia-opportunity-transform-healthcare02137nas a2200145 4500008004100000022001400041245005600055210005400111260001300165300001200178490000800190520167300198110003801871856008201909 2021 eng d a1476-468700aMapping the human genetic architecture of COVID-19.0 aMapping the human genetic architecture of COVID19 c2021 Dec a472-4770 v6003 a

The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-19, host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases. They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.

1 aCOVID-19 Host Genetics Initiative uhttp://clinbioinfosspa.es/content/mapping-human-genetic-architecture-covid-1901572nas a2200253 4500008004100000022001400041245005600055210005300111260001600164300000600180490000700186520083300193100001601026700002701042700002201069700001801091700002101109700002001130700001901150700002301169700002401192700002001216856008201236 2021 eng d a1756-038100aMechanistic modeling of the SARS-CoV-2 disease map.0 aMechanistic modeling of the SARSCoV2 disease map c2021 Jan 21 a50 v143 a

Here we present a web interface that implements a comprehensive mechanistic model of the SARS-CoV-2 disease map. In this framework, the detailed activity of the human signaling circuits related to the viral infection, covering from the entry and replication mechanisms to the downstream consequences as inflammation and antigenic response, can be inferred from gene expression experiments. Moreover, the effect of potential interventions, such as knock-downs, or drug effects (currently the system models the effect of more than 8000 DrugBank drugs) can be studied. This freely available tool not only provides an unprecedentedly detailed view of the mechanisms of viral invasion and the consequences in the cell but has also the potential of becoming an invaluable asset in the search for efficient antiviral treatments.

1 aRian, Kinza1 aEsteban-Medina, Marina1 aHidalgo, Marta, R1 aCubuk, Cankut1 aFalco, Matias, M1 aLoucera, Carlos1 aGunyel, Devrim1 aOstaszewski, Marek1 aPeña-Chilet, Maria1 aDopazo, Joaquin uhttp://clinbioinfosspa.es/content/mechanistic-modeling-sars-cov-2-disease-map01933nas a2200277 4500008004100000022001400041245011400055210006900169260001600238490000700254520095600261100002701217700002401244700002601268700003001294700001901324700001901343700003401362700003601396700002001432700002001452700001801472700001701490700002001507856012801527 2021 eng d a2072-669400aMutational Characterization of Cutaneous Melanoma Supports Divergent Pathways Model for Melanoma Development.0 aMutational Characterization of Cutaneous Melanoma Supports Diver c2021 Oct 180 v133 a

According to the divergent pathway model, cutaneous melanoma comprises a nevogenic group with a propensity to melanocyte proliferation and another one associated with cumulative solar damage (CSD). While characterized clinically and epidemiologically, the differences in the molecular profiles between the groups have remained primarily uninvestigated. This study has used a custom gene panel and bioinformatics tools to investigate the potential molecular differences in a thoroughly characterized cohort of 119 melanoma patients belonging to nevogenic and CSD groups. We found that the nevogenic melanomas had a restricted set of mutations, with the prominently mutated gene being . The CSD melanomas, in contrast, showed mutations in a diverse group of genes that included , , , and . We thus provide evidence that nevogenic and CSD melanomas constitute different biological entities and highlight the need to explore new targeted therapies.

1 aMillán-Esteban, David1 aPeña-Chilet, Maria1 aGarcía-Casado, Zaida1 aManrique-Silva, Esperanza1 aRequena, Celia1 aBañuls, José1 aLopez-Guerrero, Jose, Antonio1 aRodríguez-Hernández, Aranzazu1 aTraves, Víctor1 aDopazo, Joaquin1 aVirós, Amaya1 aKumar, Rajiv1 aNagore, Eduardo uhttp://clinbioinfosspa.es/content/mutational-characterization-cutaneous-melanoma-supports-divergent-pathways-model-melanoma03248nas a2201189 4500008004100000022001400041245003300055210002900088260001600117100002300133700002200156700001900178700001500197700002500212700001700237700001900254700001700273700002900290700001800319700001600337700002200353700001300375700001700388700002000405700001800425700002500443700002500468700002800493700001800521700001900539700001900558700002300577700002600600700002400626700002500650700002600675700001700701700001400718700002400732700001600756700002100772700002100793700001500814700001900829700002100848700002100869700002400890700001700914700002600931700001900957700001700976700002100993700002501014700002301039700001601062700002301078700001901101700002101120700001901141700002401160700002701184700002001211700002101231700002101252700002201273700002001295700002101315700002001336700001901356700001801375700001901393700002501412700002201437700002401459700001901483700002101502700001901523700001901542700001701561700002601578700002401604700001601628700001801644700002201662700001701684700001801701700001401719700002501733700001701758700002301775700001701798700001801815700002401833700002801857700001801885700001801903700001901921700001701940700002201957700002501979856005402004 2021 eng d a1061-403600aThe NCI Genomic Data Commons0 aNCI Genomic Data Commons cOct-02-20221 aHeath, Allison, P.1 aFerretti, Vincent1 aAgrawal, Stuti1 aAn, Maksim1 aAngelakos, James, C.1 aArya, Renuka1 aBajari, Rosita1 aBaqar, Bilal1 aBarnowski, Justin, H. B.1 aBurt, Jeffrey1 aCatton, Ann1 aChan, Brandon, F.1 aChu, Fay1 aCullion, Kim1 aDavidsen, Tanja1 aDo, Phuong-My1 aDompierre, Christian1 aFerguson, Martin, L.1 aFitzsimons, Michael, S.1 aFord, Michael1 aFukuma, Miyuki1 aGaheen, Sharon1 aGanji, Gajanan, L.1 aGarcia, Tzintzuni, I.1 aGeorge, Sameera, S.1 aGerhard, Daniela, S.1 aGerthoffert, Francois1 aGomez, Fauzi1 aHan, Kang1 aHernandez, Kyle, M.1 aIssac, Biju1 aJackson, Richard1 aJensen, Mark, A.1 aJoshi, Sid1 aKadam, Ajinkya1 aKhurana, Aishmit1 aKim, Kyle, M. J.1 aKraft, Victoria, E.1 aLi, Shenglai1 aLichtenberg, Tara, M.1 aLodato, Janice1 aLolla, Laxmi1 aMartinov, Plamen1 aMazzone, Jeffrey, A.1 aMiller, Daniel, P.1 aMiller, Ian1 aMiller, Joshua, S.1 aMiyauchi, Koji1 aMurphy, Mark, W.1 aNullet, Thomas1 aOgwara, Rowland, O.1 aOrtuño, Francisco, M.1 aPedrosa, Jesús1 aPham, Phuong, L.1 aPopov, Maxim, Y.1 aPorter, James, J.1 aPowell, Raymond1 aRademacher, Karl1 aReid, Colin, P.1 aRich, Samantha1 aRogel, Bessie1 aSahni, Himanso1 aSavage, Jeremiah, H.1 aSchmitt, Kyle, A.1 aSimmons, Trevar, J.1 aSislow, Joseph1 aSpring, Jonathan1 aStein, Lincoln1 aSullivan, Sean1 aTang, Yajing1 aThiagarajan, Mathangi1 aTroyer, Heather, D.1 aWang, Chang1 aWang, Zhining1 aWest, Bedford, L.1 aWilmer, Alex1 aWilson, Shane1 aWu, Kaman1 aWysocki, William, P.1 aXiang, Linda1 aYamada, Joseph, T.1 aYang, Liming1 aYu, Christine1 aYung, Christina, K.1 aZenklusen, Jean, Claude1 aZhang, Junjun1 aZhang, Zhenyu1 aZhao, Yuanheng1 aZubair, Ariz1 aStaudt, Louis, M.1 aGrossman, Robert, L. uhttp://www.nature.com/articles/s41588-021-00791-502212nas a2200349 4500008004100000022001400041245009500055210006900150260001500219300000900234490000700243520109300250100002301343700001801366700001901384700002201403700002301425700001601448700002701464700001901491700001501510700001601525700001801541700001901559700001301578700001501591700001801606700001701624700002601641710007101667856012401738 2021 eng d a2041-172300aOrchestrating and sharing large multimodal data for transparent and reproducible research.0 aOrchestrating and sharing large multimodal data for transparent  c2021 10 04 a57970 v123 a

Reproducibility is essential to open science, as there is limited relevance for findings that can not be reproduced by independent research groups, regardless of its validity. It is therefore crucial for scientists to describe their experiments in sufficient detail so they can be reproduced, scrutinized, challenged, and built upon. However, the intrinsic complexity and continuous growth of biomedical data makes it increasingly difficult to process, analyze, and share with the community in a FAIR (findable, accessible, interoperable, and reusable) manner. To overcome these issues, we created a cloud-based platform called ORCESTRA ( orcestra.ca ), which provides a flexible framework for the reproducible processing of multimodal biomedical data. It enables processing of clinical, genomic and perturbation profiles of cancer samples through automated processing pipelines that are user-customizable. ORCESTRA creates integrated and fully documented data objects with persistent identifiers (DOI) and manages multiple dataset versions, which can be shared for future studies.

1 aMammoliti, Anthony1 aSmirnov, Petr1 aNakano, Minoru1 aSafikhani, Zhaleh1 aEeles, Christopher1 aSeo, Heewon1 aNair, Sisira, Kadambat1 aMer, Arvind, S1 aSmith, Ian1 aHo, Chantal1 aBeri, Gangesh1 aKusko, Rebecca1 aLin, Eva1 aYu, Yihong1 aMartin, Scott1 aHafner, Marc1 aHaibe-Kains, Benjamin1 aMassive Analysis Quality Control (MAQC) Society Board of Directors uhttp://clinbioinfosspa.es/content/orchestrating-and-sharing-large-multimodal-data-transparent-and-reproducible-research00782nas a2200229 4500008004100000245009000041210006900131260001600200300000800216490000700224100003400231700002600265700003000291700002600321700002700347700002000374700003600394700002800430700002000458700002900478856004500507 2021 eng d00aPhylogenetic Analysis of the 2020 West Nile Virus (WNV) Outbreak in Andalusia (Spain)0 aPhylogenetic Analysis of the 2020 West Nile Virus WNV Outbreak i cJan-05-2021 a8360 v131 aCasimiro-Soriguer, Carlos, S.1 aPerez-Florido, Javier1 aFernandez-Rueda, Jose, L.1 aPedrosa-Corral, Irene1 aGuillot-Sulay, Vicente1 aLorusso, Nicola1 aMartinez-Gonzalez, Luis, Javier1 aNavarro-Marí, Jose, M.1 aDopazo, Joaquin1 aSanbonmatsu-Gámez, Sara uhttps://www.mdpi.com/1999-4915/13/5/836 02564nas a2200253 4500008004100000022001400041245008300055210006900138260000900207300001100216490000700227520173400234100003601968700002502004700002902029700001802058700002102076700001902097700002602116700002202142700002002164710002002184856010602204 2021 eng d a1662-509900aPresenilin-1 Mutations Are a Cause of Primary Lateral Sclerosis-Like Syndrome.0 aPresenilin1 Mutations Are a Cause of Primary Lateral SclerosisLi c2021 a7210470 v143 a

Background and Purpose: Primary lateral sclerosis (PLS) is a progressive upper motor neuron (UMN) disorder. It is debated whether PLS is part of the amyotrophic lateral sclerosis (ALS) spectrum, or a syndrome encompassing different neurodegenerative diseases. Recently, new diagnostic criteria for PLS have been proposed. We describe four patients of two pedigrees, meeting definite PLS criteria and harboring two different mutations in presenilin 1 ().

Methods: Patients underwent neurological and neuropsychological examination, MRI, 18F-fluorodeoxyglucose positron emission tomography (FDG-PET), amyloid-related biomarkers, and next-generation sequencing (NGS) testing.

Results: Four patients, aged 25-45 years old, presented with a progressive UMN syndrome meeting clinical criteria of definite PLS. Cognitive symptoms and signs were mild or absent during the first year of the disease but appeared or progressed later in the disease course. Brain MRI showed microbleeds in two siblings, but iron-related hypointensities in the motor cortex were absent. Brain FDG-PET showed variable areas of hypometabolism, including the motor cortex and frontotemporal lobes. Amyloid deposition was confirmed with either cerebrospinal fluid (CSF) or imaging biomarkers. Two heterozygous likely pathogenic mutations in (p.Pro88Leu and p.Leu166Pro) were found in the NGS testing.

Conclusion: Clinically defined PLS is a syndrome encompassing different neurodegenerative diseases. The NGS testing should be part of the diagnostic workup in patients with PLS, at least in those with red flags, such as early-onset, cognitive impairment, and/or family history of neurodegenerative diseases.

1 aVázquez-Costa, Juan, Francisco1 aPayá-Montes, María1 aMartínez-Molina, Marina1 aJaijo, Teresa1 aSzymanski, Jazek1 aMazón, Miguel1 aSopena-Novales, Pablo1 aPérez-Tur, Jordi1 aSevilla, Teresa1 aENoD Consortium uhttp://clinbioinfosspa.es/content/presenilin-1-mutations-are-cause-primary-lateral-sclerosis-syndrome02756nas a2200385 4500008004100000022001400041245015900055210006900214260001500283300001000298490000700308520150900315653001601824653001301840653001101853653001101864653002601875653000901901653002601910653001001936653002201946653001401968100002001982700002402002700002702026700003102053700002102084700002602105700002902131700001802160700002002178700002002198700002802218856012402246 2021 eng d a2045-232200aReal world evidence of calcifediol or vitamin D prescription and mortality rate of COVID-19 in a retrospective cohort of hospitalized Andalusian patients.0 aReal world evidence of calcifediol or vitamin D prescription and c2021 12 03 a233800 v113 a

COVID-19 is a major worldwide health problem because of acute respiratory distress syndrome, and mortality. Several lines of evidence have suggested a relationship between the vitamin D endocrine system and severity of COVID-19. We present a survival study on a retrospective cohort of 15,968 patients, comprising all COVID-19 patients hospitalized in Andalusia between January and November 2020. Based on a central registry of electronic health records (the Andalusian Population Health Database, BPS), prescription of vitamin D or its metabolites within 15-30 days before hospitalization were recorded. The effect of prescription of vitamin D (metabolites) for other indication previous to the hospitalization was studied with respect to patient survival. Kaplan-Meier survival curves and hazard ratios support an association between prescription of these metabolites and patient survival. Such association was stronger for calcifediol (Hazard Ratio, HR = 0.67, with 95% confidence interval, CI, of [0.50-0.91]) than for cholecalciferol (HR = 0.75, with 95% CI of [0.61-0.91]), when prescribed 15 days prior hospitalization. Although the relation is maintained, there is a general decrease of this effect when a longer period of 30 days prior hospitalization is considered (calcifediol HR = 0.73, with 95% CI [0.57-0.95] and cholecalciferol HR = 0.88, with 95% CI [0.75, 1.03]), suggesting that association was stronger when the prescription was closer to the hospitalization.

10aCalcifediol10aCOVID-1910aFemale10aHumans10aKaplan-Meier Estimate10aMale10aRetrospective Studies10aSpain10aSurvival Analysis10aVitamin D1 aLoucera, Carlos1 aPeña-Chilet, Maria1 aEsteban-Medina, Marina1 aMuñoyerro-Muñiz, Dolores1 aVillegas, Román1 aLópez-Miranda, José1 aRodríguez-Baño, Jesús1 aTúnez, Isaac1 aBouillon, Roger1 aDopazo, Joaquin1 aGomez, Jose, Manuel Que uhttp://clinbioinfosspa.es/content/real-world-evidence-calcifediol-or-vitamin-d-prescription-and-mortality-rate-covid-1905404nas a2201477 4500008004100000022001400041245007800055210006900133260001200202300001400214490000700228520122900235653002601464653001401490653001101504653001501515653003501530653002001565653003801585100001901623700001901642700001801661700002301679700002401702700002301726700002101749700002801770700001801798700002501816700002401841700002701865700001801892700002301910700002001933700001501953700002201968700002001990700002702010700002102037700002202058700001802080700001902098700002702117700002002144700001902164700002002183700002102203700001702224700002102241700002302262700002002285700002202305700002002327700001802347700002302365700001802388700002102406700002602427700001902453700001702472700001802489700002402507700001902531700001602550700001702566700001602583700002102599700002102620700002102641700002102662700002202683700002202705700002102727700001602748700001702764700001502781700002102796700001702817700002402834700002202858700002002880700002402900700001802924700001602942700002302958700002102981700002403002700001703026700002603043700002403069700002503093700002403118700002203142700002103164700001703185700001903202700001803221700001803239700001303257700001703270700001603287700001903303700002703322700002003349700001703369700002203386700001903408700001903427700002603446700001903472700002903491700002103520700001603541700002203557700001603579700002003595700002403615700001903639700002403658700002203682700002003704700001803724710003303742710004903775856010203824 2021 eng d a1546-170X00aReporting guidelines for human microbiome research: the STORMS checklist.0 aReporting guidelines for human microbiome research the STORMS ch c2021 11 a1885-18920 v273 a

The particularly interdisciplinary nature of human microbiome research makes the organization and reporting of results spanning epidemiology, biology, bioinformatics, translational medicine and statistics a challenge. Commonly used reporting guidelines for observational or genetic epidemiology studies lack key features specific to microbiome studies. Therefore, a multidisciplinary group of microbiome epidemiology researchers adapted guidelines for observational and genetic studies to culture-independent human microbiome studies, and also developed new reporting elements for laboratory, bioinformatics and statistical analyses tailored to microbiome studies. The resulting tool, called 'Strengthening The Organization and Reporting of Microbiome Studies' (STORMS), is composed of a 17-item checklist organized into six sections that correspond to the typical sections of a scientific publication, presented as an editable table for inclusion in supplementary materials. The STORMS checklist provides guidance for concise and complete reporting of microbiome studies that will facilitate manuscript preparation, peer review, and reader comprehension of publications and comparative analysis of published results.

10aComputational Biology10aDysbiosis10aHumans10aMicrobiota10aObservational Studies as Topic10aResearch Design10aTranslational Science, Biomedical1 aMirzayi, Chloe1 aRenson, Audrey1 aZohra, Fatima1 aElsafoury, Shaimaa1 aGeistlinger, Ludwig1 aKasselman, Lora, J1 aEckenrode, Kelly1 avan de Wijgert, Janneke1 aLoughman, Amy1 aMarques, Francine, Z1 aMacIntyre, David, A1 aArumugam, Manimozhiyan1 aAzhar, Rimsha1 aBeghini, Francesco1 aBergstrom, Kirk1 aBhatt, Ami1 aBisanz, Jordan, E1 aBraun, Jonathan1 aBravo, Hector, Corrada1 aBuck, Gregory, A1 aBushman, Frederic1 aCasero, David1 aClarke, Gerard1 aCollado, Maria, Carmen1 aCotter, Paul, D1 aCryan, John, F1 aDemmer, Ryan, T1 aDevkota, Suzanne1 aElinav, Eran1 aEscobar, Juan, S1 aFettweis, Jennifer1 aFinn, Robert, D1 aFodor, Anthony, A1 aForslund, Sofia1 aFranke, Andre1 aFurlanello, Cesare1 aGilbert, Jack1 aGrice, Elizabeth1 aHaibe-Kains, Benjamin1 aHandley, Scott1 aHerd, Pamela1 aHolmes, Susan1 aJacobs, Jonathan, P1 aKarstens, Lisa1 aKnight, Rob1 aKnights, Dan1 aKoren, Omry1 aKwon, Douglas, S1 aLangille, Morgan1 aLindsay, Brianna1 aMcGovern, Dermot1 aMcHardy, Alice, C1 aMcWeeney, Shannon1 aMueller, Noel, T1 aNezi, Luigi1 aOlm, Matthew1 aPalm, Noah1 aPasolli, Edoardo1 aRaes, Jeroen1 aRedinbo, Matthew, R1 aRühlemann, Malte1 aSartor, Balfour1 aSchloss, Patrick, D1 aSchriml, Lynn1 aSegal, Eran1 aShardell, Michelle1 aSharpton, Thomas1 aSmirnova, Ekaterina1 aSokol, Harry1 aSonnenburg, Justin, L1 aSrinivasan, Sujatha1 aThingholm, Louise, B1 aTurnbaugh, Peter, J1 aUpadhyay, Vaibhav1 aWalls, Ramona, L1 aWilmes, Paul1 aYamada, Takuji1 aZeller, Georg1 aZhang, Mingyu1 aZhao, Ni1 aZhao, Liping1 aBao, Wenjun1 aCulhane, Aedin1 aDevanarayan, Viswanath1 aDopazo, Joaquin1 aFan, Xiaohui1 aFischer, Matthias1 aJones, Wendell1 aKusko, Rebecca1 aMason, Christopher, E1 aMercer, Tim, R1 aSansone, Susanna-Assunta1 aScherer, Andreas1 aShi, Leming1 aThakkar, Shraddha1 aTong, Weida1 aWolfinger, Russ1 aHunter, Christopher1 aSegata, Nicola1 aHuttenhower, Curtis1 aDowd, Jennifer, B1 aJones, Heidi, E1 aWaldron, Levi1 aGenomic Standards Consortium1 aMassive Analysis and Quality Control Society uhttp://clinbioinfosspa.es/content/reporting-guidelines-human-microbiome-research-storms-checklist01585nas a2200505 4500008004100000245010600041210007100147260001600218300000800234490000700242100002700249700001900276700002000295700002800315700002900343700002700372700002800399700002500427700002000452700001700472700001900489700001900508700002000527700002100547700002900568700002600597700002700623700002200650700002700672700001800699700002200717700001500739700001800754700002100772700001900793700002100812700001800833700001800851700002400869700002200893700002100915710003200936710002400968856008700992 2021 eng d00aSchuurs–Hoeijmakers Syndrome (PACS1 Neurodevelopmental Disorder): Seven Novel Patients and a Review0 aSchuurs–Hoeijmakers Syndrome PACS1 Neurodevelopmental Disorder S cJan-05-2021 a7380 v121 aTenorio-Castaño, Jair1 aMorte, Beatriz1 aNevado, Julián1 aMartínez-Glez, Víctor1 aSantos-Simarro, Fernando1 aGarcía-Miñaur, Sixto1 aPalomares-Bralo, María1 aPacio-Míguez, Marta1 aGómez, Beatriz1 aArias, Pedro1 aAlcochea, Alba1 aCarrión, Juan1 aArias, Patricia1 aAlmoguera, Berta1 aLópez-Grondona, Fermina1 aLorda-Sanchez, Isabel1 aGalán-Gómez, Enrique1 aValenzuela, Irene1 aPerez, María, Méndez1 aCuscó, Ivón1 aBarros, Francisco1 aPié, Juan1 aRamos, Sergio1 aRamos, Feliciano1 aKuechler, Alma1 aTizzano, Eduardo1 aAyuso, Carmen1 aKaiser, Frank1 aPérez-Jurado, Luis1 aCarracedo, Ángel1 aLapunzina, Pablo1 aThe ENoD-CIBERER Consortium1 aThe SIDE Consortium uhttps://www.mdpi.com/2073-4425/12/5/738https://www.mdpi.com/2073-4425/12/5/738/pdf03596nas a2200505 4500008004100000022001400041245013900055210006900194260001500263300000700278490000700285520188200292653001702174653002602191653001402217653003202231653000902263653001102272653001502283653001702298653003202315653002902347653001402376100003502390700003102425700003302456700002002489700001802509700002802527700003202555700002902587700003002616700002602646700001902672700003602691700002202727700002902749700002802778700003102806700002602837700002602863700003302889700004002922856012802962 2021 eng d a1528-365800aTaxonomic variations in the gut microbiome of gout patients with and without tophi might have a functional impact on urate metabolism.0 aTaxonomic variations in the gut microbiome of gout patients with c2021 05 24 a500 v273 a

OBJECTIVE: To evaluate the taxonomic composition of the gut microbiome in gout patients with and without tophi formation, and predict bacterial functions that might have an impact on urate metabolism.

METHODS: Hypervariable V3-V4 regions of the bacterial 16S rRNA gene from fecal samples of gout patients with and without tophi (n = 33 and n = 25, respectively) were sequenced and compared to fecal samples from 53 healthy controls. We explored predictive functional profiles using bioinformatics in order to identify differences in taxonomy and metabolic pathways.

RESULTS: We identified a microbiome characterized by the lowest richness and a higher abundance of Phascolarctobacterium, Bacteroides, Akkermansia, and Ruminococcus_gnavus_group genera in patients with gout without tophi when compared to controls. The Proteobacteria phylum and the Escherichia-Shigella genus were more abundant in patients with tophaceous gout than in controls. Fold change analysis detected nine genera enriched in healthy controls compared to gout groups (Bifidobacterium, Butyricicoccus, Oscillobacter, Ruminococcaceae_UCG_010, Lachnospiraceae_ND2007_group, Haemophilus, Ruminococcus_1, Clostridium_sensu_stricto_1, and Ruminococcaceae_UGC_013). We found that the core microbiota of both gout groups shared Bacteroides caccae, Bacteroides stercoris ATCC 43183, and Bacteroides coprocola DSM 17136. These bacteria might perform functions linked to one-carbon metabolism, nucleotide binding, amino acid biosynthesis, and purine biosynthesis. Finally, we observed differences in key bacterial enzymes involved in urate synthesis, degradation, and elimination.

CONCLUSION: Our findings revealed that taxonomic variations in the gut microbiome of gout patients with and without tophi might have a functional impact on urate metabolism.

10aBiodiversity10aComputational Biology10aDysbiosis10aGastrointestinal Microbiome10aGout10aHumans10aMetagenome10ametagenomics10aProtein Interaction Mapping10aProtein Interaction Maps10aUric Acid1 aMéndez-Salazar, Eder, Orlando1 aVázquez-Mellado, Janitzia1 aCasimiro-Soriguer, Carlos, S1 aDopazo, Joaquin1 aCubuk, Cankut1 aZamudio-Cuevas, Yessica1 aFrancisco-Balderas, Adriana1 aMartínez-Flores, Karina1 aFernández-Torres, Javier1 aLozada-Pérez, Carlos1 aPineda, Carlos1 aSánchez-González, Austreberto1 aSilveira, Luis, H1 aBurguete-García, Ana, I1 aOrbe-Orihuela, Citlalli1 aLagunas-Martínez, Alfredo1 aVazquez-Gomez, Alonso1 aLópez-Reyes, Alberto1 aPalacios-González, Berenice1 aMartínez-Nava, Gabriela, Angélica uhttp://clinbioinfosspa.es/content/taxonomic-variations-gut-microbiome-gout-patients-and-without-tophi-might-have-functional00678nas a2200217 4500008004100000245007400041210006900115260001600184490000700200100001800207700002000225700002100245700001700266700001600283700001900299700002200318700002200340700001900362700002500381856005400406 2021 eng d00aUniform genomic data analysis in the NCI Genomic Data CommonsAbstract0 aUniform genomic data analysis in the NCI Genomic Data CommonsAbs cJan-12-20210 v121 aZhang, Zhenyu1 aHernandez, Kyle1 aSavage, Jeremiah1 aLi, Shenglai1 aMiller, Dan1 aAgrawal, Stuti1 aOrtuno, Francisco1 aStaudt, Louis, M.1 aHeath, Allison1 aGrossman, Robert, L. uhttp://www.nature.com/articles/s41467-021-21254-902115nas a2200409 4500008004100000022001400041245012500055210006900180260001200249300001300261490000700274520080500281653001501086653002101101653002601122653002301148653003001171653001301201653004201214653001101256653002401267653001301291653001201304653002401316653001301340653001801353653002701371653001301398100003101411700002601442700002501468700002401493700002001517700002201537700002001559856012601579 2021 eng d a1553-735800aA versatile workflow to integrate RNA-seq genomic and transcriptomic data into mechanistic models of signaling pathways.0 aversatile workflow to integrate RNAseq genomic and transcriptomi c2021 02 ae10087480 v173 a

MIGNON is a workflow for the analysis of RNA-Seq experiments, which not only efficiently manages the estimation of gene expression levels from raw sequencing reads, but also calls genomic variants present in the transcripts analyzed. Moreover, this is the first workflow that provides a framework for the integration of transcriptomic and genomic data based on a mechanistic model of signaling pathway activities that allows a detailed biological interpretation of the results, including a comprehensive functional profiling of cell activity. MIGNON covers the whole process, from reads to signaling circuit activity estimations, using state-of-the-art tools, it is easy to use and it is deployable in different computational environments, allowing an optimized use of the resources available.

10aAlgorithms10aCell Line, Tumor10aComputational Biology10aDatabases, Factual10aGene Expression Profiling10aGenomics10aHigh-Throughput Nucleotide Sequencing10aHumans10aModels, Theoretical10amutation10aRNA-seq10aSignal Transduction10aSoftware10aTranscriptome10awhole exome sequencing10aWorkflow1 aGarrido-Rodriguez, Martín1 aLópez-López, Daniel1 aOrtuno, Francisco, M1 aPeña-Chilet, Maria1 aMuñoz, Eduardo1 aCalzado, Marco, A1 aDopazo, Joaquin uhttp://clinbioinfosspa.es/content/versatile-workflow-integrate-rna-seq-genomic-and-transcriptomic-data-mechanistic-models01344nas a2200181 4500008004100000022001400041245014700055210006900202260001600271300001000287520063300297100002500930700002100955700001800976700002600994710000901020856013301029 2020 eng d a1878-507700a10th Anniversary of the European Association for Predictive, Preventive and Personalised (3P) Medicine - EPMA World Congress Supplement 2020.0 a10th Anniversary of the European Association for Predictive Prev c2020 Aug 19 a1-1333 a

In 2019, the EPMA celebrated its 10th anniversary at the 5th World Congress in Pilsen, Czech Republic. The history of the International Professional Network dedicated to Predictive, Preventive and Personalised Medicine (PPPM / 3PM) is rich in achievements. Facing the coronavirus COVID-19 pandemic it is getting evident globally that the predictive approach, targeted prevention and personalisation of medical services is the optimal paradigm in healthcare demonstrating the high potential to save lives and to benefit the society as a whole. The EPMA World Congress Supplement 2020 highlights advances in 3P medicine.

1 aGolubnitschaja, Olga1 aTopolcan, Ondrej1 aKucera, Radek1 aCostigliola, Vincenzo1 aEPMA uhttp://clinbioinfosspa.es/content/10th-anniversary-european-association-predictive-preventive-and-personalised-3p-medicine%C2%A003640nas a2200565 4500008004100000022001400041245014000055210006900195260001300264300001200277490000700289520189600296653004202192653003102234653001502265653001902280653002002299653002402319653001902343653003002362653003202392653001502424653001902439653002802458653001002486653001102496653001602507653004402523653001402567653003602581653002702617100002102644700003102665700001502696700001402711700001502725700002202740700001602762700001202778700002302790700001402813700001302827700001902840700002402859700001502883700001402898700001902912700001502931856012802946 2020 eng d a1469-069100aAssociation of a single nucleotide polymorphism in the ubxn6 gene with long-term non-progression phenotype in HIV-positive individuals.0 aAssociation of a single nucleotide polymorphism in the ubxn6 gen c2020 Jan a107-1140 v263 a

OBJECTIVES: The long-term non-progressors (LTNPs) are a heterogeneous group of HIV-positive individuals characterized by their ability to maintain high CD4 T-cell counts and partially control viral replication for years in the absence of antiretroviral therapy. The present study aims to identify host single nucleotide polymorphisms (SNPs) associated with non-progression in a cohort of 352 individuals.

METHODS: DNA microarrays and exome sequencing were used for genotyping about 240 000 functional polymorphisms throughout more than 20 000 human genes. The allele frequencies of 85 LTNPs were compared with a control population. SNPs associated with LTNPs were confirmed in a population of typical progressors. Functional analyses in the affected gene were carried out through knockdown experiments in HeLa-P4, macrophages and dendritic cells.

RESULTS: Several SNPs located within the major histocompatibility complex region previously related to LTNPs were confirmed in this new cohort. The SNP rs1127888 (UBXN6) surpassed the statistical significance of these markers after Bonferroni correction (q = 2.11 × 10). An uncommon allelic frequency of rs1127888 among LTNPs was confirmed by comparison with typical progressors and other publicly available populations. UBXN6 knockdown experiments caused an increase in CAV1 expression and its accumulation in the plasma membrane. In vitro infection of different cell types with HIV-1 replication-competent recombinant viruses caused a reduction of the viral replication capacity compared with their corresponding wild-type cells expressing UBXN6.

CONCLUSIONS: A higher prevalence of Ala31Thr in UBXN6 was found among LTNPs within its N-terminal region, which is crucial for UBXN6/VCP protein complex formation. UBXN6 knockdown affected CAV1 turnover and HIV-1 replication capacity.

10aAdaptor Proteins, Vesicular Transport10aAutophagy-Related Proteins10aCaveolin 110aCohort Studies10aDendritic Cells10aDisease Progression10aGene Frequency10aGene Knockdown Techniques10aGenetic Association Studies10aHeLa Cells10aHIV Infections10aHIV Long-Term Survivors10aHIV-110aHumans10aMacrophages10aOligonucleotide Array Sequence Analysis10aPhenotype10aPolymorphism, Single Nucleotide10awhole exome sequencing1 aDíez-Fuertes, F1 aDe La Torre-Tarazona, H, E1 aCalonge, E1 aPernas, M1 aBermejo, M1 aGarcía-Pérez, J1 aÁlvarez, A1 aCapa, L1 aGarcía-García, F1 aSaumoy, M1 aRiera, M1 aBoland-Auge, A1 aLópez-Galíndez, C1 aLathrop, M1 aDopazo, J1 aSakuntabhai, A1 aAlcamí, J uhttp://clinbioinfosspa.es/content/association-single-nucleotide-polymorphism-ubxn6-gene-long-term-non-progression-phenotype02932nas a2200613 4500008004100000022001400041245012600055210006900181260001500250300001500265490000700280520120500287653001801492653001101510653001301521653001101534653002101545653000901566653001401575653002001589653001301609653001501622653001801637100001301655700002401668700001201692700001701704700001601721700001701737700001601754700001601770700001201786700001401798700001601812700001501828700002101843700002101864700002201885700001501907700002301922700002101945700002101966700001601987700001602003700002102019700002502040700001902065700001702084700001402101700001802115700002602133710003102159856012802190 2020 eng d a2405-472000aCommunity Assessment of the Predictability of Cancer Protein and Phosphoprotein Levels from Genomics and Transcriptomics.0 aCommunity Assessment of the Predictability of Cancer Protein and c2020 08 26 a186-195.e90 v113 a

Cancer is driven by genomic alterations, but the processes causing this disease are largely performed by proteins. However, proteins are harder and more expensive to measure than genes and transcripts. To catalyze developments of methods to infer protein levels from other omics measurements, we leveraged crowdsourcing via the NCI-CPTAC DREAM proteogenomic challenge. We asked for methods to predict protein and phosphorylation levels from genomic and transcriptomic data in cancer patients. The best performance was achieved by an ensemble of models, including as predictors transcript level of the corresponding genes, interaction between genes, conservation across tumor types, and phosphosite proximity for phosphorylation prediction. Proteins from metabolic pathways and complexes were the best and worst predicted, respectively. The performance of even the best-performing model was modest, suggesting that many proteins are strongly regulated through translational control and degradation. Our results set a reference for the limitations of computational inference in proteogenomics. A record of this paper's transparent peer review process is included in the Supplemental Information.

10aCrowdsourcing10aFemale10aGenomics10aHumans10aMachine Learning10aMale10aNeoplasms10aPhosphoproteins10aProteins10aProteomics10aTranscriptome1 aYang, Mi1 aPetralia, Francesca1 aLi, Zhi1 aLi, Hongyang1 aMa, Weiping1 aSong, Xiaoyu1 aKim, Sunkyu1 aLee, Heewon1 aYu, Han1 aLee, Bora1 aBae, Seohui1 aHeo, Eunji1 aKaczmarczyk, Jan1 aStępniak, Piotr1 aWarchoł, Michał1 aYu, Thomas1 aCalinawan, Anna, P1 aBoutros, Paul, C1 aPayne, Samuel, H1 aReva, Boris1 aBoja, Emily1 aRodriguez, Henry1 aStolovitzky, Gustavo1 aGuan, Yuanfang1 aKang, Jaewoo1 aWang, Pei1 aFenyö, David1 aSaez-Rodriguez, Julio1 aNCI-CPTAC-DREAM Consortium uhttp://clinbioinfosspa.es/content/community-assessment-predictability-cancer-protein-and-phosphoprotein-levels-genomics-and01793nas a2200577 4500008004100000022001400041245011100055210006900166260001500235300000800250490000600258653002000264653002600284653002700310653001300337653002300350653003200373653003100405653001100436653003000447653002300477653001400500653002100514653001500535100002300550700002200573700002300595700002100618700001900639700002300658700002300681700002500704700002000729700001900749700002000768700002100788700001600809700002200825700002200847700002300869700002000892700002700912700002300939700002200962700002100984700002001005700002101025700001801046700002401064856012701088 2020 eng d a2052-446300aCOVID-19 Disease Map, building a computational repository of SARS-CoV-2 virus-host interaction mechanisms.0 aCOVID19 Disease Map building a computational repository of SARSC c2020 05 05 a1360 v710aBetacoronavirus10aComputational Biology10aCoronavirus Infections10aCOVID-1910aDatabases, Factual10aHost Microbial Interactions10aHost-Pathogen Interactions10aHumans10aInternational Cooperation10aModels, Biological10aPandemics10aPneumonia, Viral10aSARS-CoV-21 aOstaszewski, Marek1 aMazein, Alexander1 aGillespie, Marc, E1 aKuperstein, Inna1 aNiarakis, Anna1 aHermjakob, Henning1 aPico, Alexander, R1 aWillighagen, Egon, L1 aEvelo, Chris, T1 aHasenauer, Jan1 aSchreiber, Falk1 aDräger, Andreas1 aDemir, Emek1 aWolkenhauer, Olaf1 aFurlong, Laura, I1 aBarillot, Emmanuel1 aDopazo, Joaquin1 aOrta-Resendiz, Aurelio1 aMessina, Francesco1 aValencia, Alfonso1 aFunahashi, Akira1 aKitano, Hiroaki1 aAuffray, Charles1 aBalling, Rudi1 aSchneider, Reinhard uhttp://clinbioinfosspa.es/content/covid-19-disease-map-building-computational-repository-sars-cov-2-virus-host-interaction01082nas a2200313 4500008004100000022001400041245014500055210006900200260001500269300000800284490000600292653002800298653001300326653002300339653001100362653002100373653003300394653003100427653001300458653001500471653002400486100002000510700002700530700001600557700002100573700002000594700002400614856013000638 2020 eng d a2059-363500aDrug repurposing for COVID-19 using machine learning and mechanistic models of signal transduction circuits related to SARS-CoV-2 infection.0 aDrug repurposing for COVID19 using machine learning and mechanis c2020 12 11 a2900 v510aComputational Chemistry10aCOVID-1910adrug repositioning10aHumans10aMachine Learning10aMolecular Docking Simulation10aMolecular Targeted Therapy10aProteins10aSARS-CoV-210aSignal Transduction1 aLoucera, Carlos1 aEsteban-Medina, Marina1 aRian, Kinza1 aFalco, Matias, M1 aDopazo, Joaquin1 aPeña-Chilet, Maria uhttp://clinbioinfosspa.es/content/drug-repurposing-covid-19-using-machine-learning-and-mechanistic-models-signal-transduction03120nas a2200673 4500008004100000022001400041245010800055210006900163260000900232490000600241520108900247653002601336653003101362653004201393653001101435100001901446700002101465700002001486700001901506700003301525700002701558700003501585700002001620700002201640700001201662700001801674700002201692700001301714700002101727700002001748700002101768700001801789700001801807700002601825700001801851700001601869700002401885700001801909700002101927700001701948700002701965700001801992700002302010700001902033700002702052700001402079700002302093700001702116700001902133700001502152700002202167700002102189700002202210700001702232700003202249700001802281700002402299856012302323 2020 eng d a2046-140200aThe ELIXIR Human Copy Number Variations Community: building bioinformatics infrastructure for research.0 aELIXIR Human Copy Number Variations Community building bioinform c20200 v93 a

Copy number variations (CNVs) are major causative contributors both in the genesis of genetic diseases and human neoplasias. While "High-Throughput" sequencing technologies are increasingly becoming the primary choice for genomic screening analysis, their ability to efficiently detect CNVs is still heterogeneous and remains to be developed. The aim of this white paper is to provide a guiding framework for the future contributions of ELIXIR's recently established with implications beyond human disease diagnostics and population genomics. This white paper is the direct result of a strategy meeting that took place in September 2018 in Hinxton (UK) and involved representatives of 11 ELIXIR Nodes. The meeting led to the definition of priority objectives and tasks, to address a wide range of CNV-related challenges ranging from detection and interpretation to sharing and training. Here, we provide suggestions on how to align these tasks within the ELIXIR Platforms strategy, and on how to frame the activities of this new ELIXIR Community in the international context.

10aComputational Biology10aDNA Copy Number Variations10aHigh-Throughput Nucleotide Sequencing10aHumans1 aSalgado, David1 aArmean, Irina, M1 aBaudis, Michael1 aBeltran, Sergi1 aCapella-Gutíerrez, Salvador1 aCarvalho-Silva, Denise1 aDel Angel, Victoria, Dominguez1 aDopazo, Joaquin1 aFurlong, Laura, I1 aGao, Bo1 aGarcia, Leyla1 aGerloff, Dietlind1 aGut, Ivo1 aGyenesei, Attila1 aHabermann, Nina1 aHancock, John, M1 aHanauer, Marc1 aHovig, Eivind1 aJohansson, Lennart, F1 aKeane, Thomas1 aKorbel, Jan1 aLauer, Katharina, B1 aLaurie, Steve1 aLeskošek, Brane1 aLloyd, David1 aMarqués-Bonet, Tomás1 aMei, Hailiang1 aMonostory, Katalin1 aPiñero, Janet1 aPoterlowicz, Krzysztof1 aRath, Ana1 aSamarakoon, Pubudu1 aSanz, Ferran1 aSaunders, Gary1 aSie, Daoud1 aSwertz, Morris, A1 aTsukanov, Kirill1 aValencia, Alfonso1 aVidak, Marko1 aGonzález, Cristina, Yenyxe1 aYlstra, Bauke1 aBéroud, Christophe uhttp://clinbioinfosspa.es/content/elixir-human-copy-number-variations-community-building-bioinformatics-infrastructure02417nas a2200481 4500008004100000022001400041245004700055210004600102260001600148300001100164490000700175520106100182100001901243700002701262700001901289700002001308700002201328700002101350700002001371700001901391700002401410700001501434700002501449700002301474700002401497700002001521700002701541700002401568700002001592700002101612700002201633700002201655700002901677700001801706700001301724700001701737700001601754700002001770700002501790700001901815700002601834856007501860 2020 eng d a2589-004200aImmune Cell Associations with Cancer Risk.0 aImmune Cell Associations with Cancer Risk c2020 Jul 24 a1012960 v233 a

Proper immune system function hinders cancer development, but little is known about whether genetic variants linked to cancer risk alter immune cells. Here, we report 57 cancer risk loci associated with differences in immune and/or stromal cell contents in the corresponding tissue. Predicted target genes show expression and regulatory associations with immune features. Polygenic risk scores also reveal associations with immune and/or stromal cell contents, and breast cancer scores show consistent results in normal and tumor tissue. SH2B3 links peripheral alterations of several immune cell types to the risk of this malignancy. Pleiotropic SH2B3 variants are associated with breast cancer risk in BRCA1/2 mutation carriers. A retrospective case-cohort study indicates a positive association between blood counts of basophils, leukocytes, and monocytes and age at breast cancer diagnosis. These findings broaden our knowledge of the role of the immune system in cancer and highlight promising prevention strategies for individuals at high risk.

1 aPalomero, Luis1 aGalván-Femenía, Ivan1 ade Cid, Rafael1 aEspín, Roderic1 aBarnes, Daniel, R1 aBlommaert, Eline1 aGil-Gil, Miguel1 aFalo, Catalina1 aStradella, Agostina1 aOuchi, Dan1 aRoso-Llorach, Albert1 aViolan, Concepció1 aPeña-Chilet, Maria1 aDopazo, Joaquin1 aExtremera, Ana, Isabel1 aGarcía-Valero, Mar1 aHerranz, Carmen1 aMateo, Francesca1 aMereu, Elisabetta1 aBeesley, Jonathan1 aChenevix-Trench, Georgia1 aRoux, Cecilia1 aMak, Tak1 aBrunet, Joan1 aHakem, Razq1 aGorrini, Chiara1 aAntoniou, Antonis, C1 aLázaro, Conxi1 aPujana, Miquel, Angel uhttp://clinbioinfosspa.es/content/immune-cell-associations-cancer-risk01455nas a2200217 4500008004100000022001400041245006500055210006200120260001900182300001200201490000700213520073900220653002200959653001100981100003700992700002901029700003801058700003101096700002001127856009001147 2020 spa d a1578-128300a[Impact assessment on data protection in research projects].0 aImpact assessment on data protection in research projects c2020 Sep - Oct a521-5230 v343 a

Recent changes in European regulations for personal data protection still allow the use of health data for research purposes, but they have set the Impact Assessment on Data Protection as an instrument for reflection and risk analysis in the process of data processing. The publication of a guide for facilitates this impact assessment, although it is not directly applicable to research projects. Experience in a specific project is detailed, showing how the context of the treatment becomes relevant with respect to the data characteristics. Carrying out an impact assessment is an opportunity to ensure compliance with the principles of data protection in an increasingly complex environment with greater ethical challenges.

10aComputer Security10aHumans1 aGarcía-León, Francisco, Javier1 aVillegas-Portero, Román1 aGoicoechea-Salazar, Juan, Antonio1 aMuñoyerro-Muñiz, Dolores1 aDopazo, Joaquin uhttp://clinbioinfosspa.es/content/impact-assessment-data-protection-research-projects00750nas a2200157 4500008004100000245011500041210006900156260001600225490000600241100002100247700002400268700002000292700002200312700002000334856023800354 2020 eng d00aMechanistic models of signaling pathways deconvolute the glioblastoma single-cell functional landscapeAbstract0 aMechanistic models of signaling pathways deconvolute the gliobla cJan-06-20200 v21 aFalco, Matias, M1 aPeña-Chilet, Maria1 aLoucera, Carlos1 aHidalgo, Marta, R1 aDopazo, Joaquin uhttps://academic.oup.com/narcancer/article/doi/10.1093/narcan/zcaa011/5862620http://academic.oup.com/narcancer/article-pdf/2/2/zcaa011/33428092/zcaa011.pdfhttp://academic.oup.com/narcancer/article-pdf/2/2/zcaa011/33428092/zcaa011.pdf02316nas a2200241 4500008004100000022001400041245014100055210006900196260001500265490000600280520146700286653001101753653004301764653001101807653000901818653001401827653002401841100001801865700001801883700002401901700002001925856012901945 2020 eng d a2073-440900aMechanistic Models of Signaling Pathways Reveal the Drug Action Mechanisms behind Gender-Specific Gene Expression for Cancer Treatments.0 aMechanistic Models of Signaling Pathways Reveal the Drug Action  c2020 06 290 v93 a

Despite the existence of differences in gene expression across numerous genes between males and females having been known for a long time, these have been mostly ignored in many studies, including drug development and its therapeutic use. In fact, the consequences of such differences over the disease mechanisms or the drug action mechanisms are completely unknown. Here we applied mechanistic mathematical models of signaling activity to reveal the ultimate functional consequences that gender-specific gene expression activities have over cell functionality and fate. Moreover, we also used the mechanistic modeling framework to simulate the drug interventions and unravel how drug action mechanisms are affected by gender-specific differential gene expression. Interestingly, some cancers have many biological processes significantly affected by these gender-specific differences (e.g., bladder or head and neck carcinomas), while others (e.g., glioblastoma or rectum cancer) are almost insensitive to them. We found that many of these gender-specific differences affect cancer-specific pathways or in physiological signaling pathways, also involved in cancer origin and development. Finally, mechanistic models have the potential to be used for finding alternative therapeutic interventions on the pathways targeted by the drug, which lead to similar results compensating the downstream consequences of gender-specific differences in gene expression.

10aFemale10aGene Expression Regulation, Neoplastic10aHumans10aMale10aNeoplasms10aSignal Transduction1 aCubuk, Cankut1 aCan, Fatma, E1 aPeña-Chilet, Maria1 aDopazo, Joaquin uhttp://clinbioinfosspa.es/content/mechanistic-models-signaling-pathways-reveal-drug-action-mechanisms-behind-gender-specific03270nas a2200493 4500008004100000022001400041245012000055210006900175260001200244490000600256520175600262653001002018653000902028653004102037653001102078653001102089653000902100653001602109653001402125653001202139653001402151653001602165100002502181700001702206700002302223700002902246700002002275700002202295700002402317700002502341700002402366700002302390700002502413700002802438700002202466700001902488700002402507700002002531700002702551700002502578700002002603700002602623856012702649 2020 eng d a2051-142600aNivolumab and sunitinib combination in advanced soft tissue sarcomas: a multicenter, single-arm, phase Ib/II trial.0 aNivolumab and sunitinib combination in advanced soft tissue sarc c2020 110 v83 a

BACKGROUND: Sarcomas exhibit low expression of factors related to immune response, which could explain the modest activity of PD-1 inhibitors. A potential strategy to convert a cold into an inflamed microenvironment lies on a combination therapy. As tumor angiogenesis promotes immunosuppression, we designed a phase Ib/II trial to test the double inhibition of angiogenesis (sunitinib) and PD-1/PD-L1 axis (nivolumab).

METHODS: This single-arm, phase Ib/II trial enrolled adult patients with selected subtypes of sarcoma. Phase Ib established two dose levels: level 0 with sunitinib 37.5 mg daily from day 1, plus nivolumab 3 mg/kg intravenously on day 15, and then every 2 weeks; and level -1 with sunitinib 37.5 mg on the first 14 days (induction) and then 25 mg per day plus nivolumab on the same schedule. The primary endpoint was to determine the recommended dose for phase II (phase I) and the 6-month progression-free survival rate, according to Response Evaluation Criteria in Solid Tumors 1.1 (phase II).

RESULTS: From May 2017 to April 2019, 68 patients were enrolled: 16 in phase Ib and 52 in phase II. The recommended dose of sunitinib for phase II was 37.5 mg as induction and then 25 mg in combination with nivolumab. After a median follow-up of 17 months (4-26), the 6-month progression-free survival rate was 48% (95% CI 41% to 55%). The most common grade 3-4 adverse events included transaminitis (17.3%) and neutropenia (11.5%).

CONCLUSIONS: Sunitinib plus nivolumab is an active scheme with manageable toxicity in the treatment of selected patients with advanced soft tissue sarcoma, with almost half of patients free of progression at 6 months. NCT03277924.

10aAdult10aAged10aAntineoplastic Agents, Immunological10aFemale10aHumans10aMale10aMiddle Aged10aNivolumab10aSarcoma10aSunitinib10aYoung Adult1 aMartin-Broto, Javier1 aHindi, Nadia1 aGrignani, Giovanni1 aMartinez-Trufero, Javier1 aRedondo, Andres1 aValverde, Claudia1 aStacchiotti, Silvia1 aLopez-Pousa, Antonio1 aD'Ambrosio, Lorenzo1 aGutierrez, Antonio1 aPerez-Vega, Herminia1 aEncinas-Tobajas, Victor1 ade Alava, Enrique1 aCollini, Paola1 aPeña-Chilet, Maria1 aDopazo, Joaquin1 aCarrasco-Garcia, Irene1 aLopez-Alvarez, Maria1 aMoura, David, S1 aLopez-Martin, Jose, A uhttp://clinbioinfosspa.es/content/nivolumab-and-sunitinib-combination-advanced-soft-tissue-sarcomas-multicenter-single-arm05175nas a2201117 4500008004100000022001400041245011300055210006900168260001200237300001200249490000700261520174900268653001402017653003102031653001502062653002502077653001902102653005102121653001102172653002902183653003802212653001102250653000902261653002302270653003602293653002702329100002202356700001702378700002402395700002802419700003302447700002702480700001502507700002402522700002902546700002602575700002802601700001702629700002002646700002102666700001902687700002702706700001902733700002002752700002402772700003002796700001902826700002602845700002902871700001802900700002102918700002202939700003202961700002002993700002603013700002903039700002103068700002203089700002103111700001903132700002703151700002403178700002903202700003203231700002003263700001803283700003103301700002803332700001603360700002503376700003103401700003303432700002903465700002203494700002103516700002403537700001903561700002503580700001703605700001703622700001803639700002303657700002003680700001603700700002203716700002503738700001803763700002303781700002003804700002003824700002103844700003303865700001703898700002103915856012103936 2020 eng d a1468-624400aOptimised molecular genetic diagnostics of Fanconi anaemia by whole exome sequencing and functional studies.0 aOptimised molecular genetic diagnostics of Fanconi anaemia by wh c2020 04 a258-2680 v573 a

PURPOSE: Patients with Fanconi anaemia (FA), a rare DNA repair genetic disease, exhibit chromosome fragility, bone marrow failure, malformations and cancer susceptibility. FA molecular diagnosis is challenging since FA is caused by point mutations and large deletions in 22 genes following three heritability patterns. To optimise FA patients' characterisation, we developed a simplified but effective methodology based on whole exome sequencing (WES) and functional studies.

METHODS: 68 patients with FA were analysed by commercial WES services. Copy number variations were evaluated by sequencing data analysis with RStudio. To test missense variants, wt FANCA cDNA was cloned and variants were introduced by site-directed mutagenesis. Vectors were then tested for their ability to complement DNA repair defects of a FANCA-KO human cell line generated by TALEN technologies.

RESULTS: We identified 93.3% of mutated alleles including large deletions. We determined the pathogenicity of three FANCA missense variants and demonstrated that two variants reported in mutations databases as 'affecting functions' are SNPs. Deep analysis of sequencing data revealed patients' true mutations, highlighting the importance of functional analysis. In one patient, no pathogenic variant could be identified in any of the 22 known FA genes, and in seven patients, only one deleterious variant could be identified (three patients each with FANCA and FANCD2 and one patient with FANCE mutations) CONCLUSION: WES and proper bioinformatics analysis are sufficient to effectively characterise patients with FA regardless of the rarity of their complementation group, type of mutations, mosaic condition and DNA source.

10aCell Line10aDNA Copy Number Variations10aDNA Repair10aDNA-Binding Proteins10aFanconi Anemia10aFanconi Anemia Complementation Group A Protein10aFemale10aGene Knockout Techniques10aGenetic Predisposition to Disease10aHumans10aMale10aMutation, Missense10aPolymorphism, Single Nucleotide10awhole exome sequencing1 aBogliolo, Massimo1 aPujol, Roser1 aAza-Carmona, Miriam1 aMuñoz-Subirana, Núria1 aRodriguez-Santiago, Benjamin1 aCasado, José, Antonio1 aRio, Paula1 aBauser, Christopher1 aReina-Castillón, Judith1 aLopez-Sanchez, Marcos1 aGonzalez-Quereda, Lidia1 aGallano, Pia1 aCatalá, Albert1 aRuiz-Llobet, Ana1 aBadell, Isabel1 aDiaz-Heredia, Cristina1 aHladun, Raquel1 aSenent, Leonort1 aArgiles, Bienvenida1 aBurgues, Juan, Miguel Ber1 aBañez, Fatima1 aArrizabalaga, Beatriz1 aAlmaraz, Ricardo, López1 aLopez, Monica1 aFiguera, Ángela1 aMolinés, Antonio1 ade Soto, Inmaculada, Pérez1 aHernando, Inés1 aMuñoz, Juan, Antonio1 aMarin, Maria, Del Rosari1 aBalmaña, Judith1 aStjepanovic, Neda1 aCarrasco, Estela1 aCuesta, Isabel1 aCosuelo, José, Miguel1 aRegueiro, Alexandra1 aJimenez, José, Moraleda1 aGalera-Miñarro, Ana, Maria1 aRosiñol, Laura1 aCarrió, Anna1 aBeléndez-Bieler, Cristina1 aSoto, Antonio, Escudero1 aCela, Elena1 ade la Mata, Gregorio1 aFernández-Delgado, Rafael1 aGarcia-Pardos, Maria, Carmen1 aSáez-Villaverde, Raquel1 aBarragaño, Marta1 aPortugal, Raquel1 aLendinez, Francisco1 aHernadez, Ines1 aVagace, José, Manue1 aTapia, Maria1 aNieto, José1 aGarcia, Marta1 aGonzalez, Macarena1 aVicho, Cristina1 aGalvez, Eva1 aValiente, Alberto1 aAntelo, Maria, Luisa1 aAncliff, Phil1 aGarcía, Francisco1 aDopazo, Joaquin1 aSevilla, Julian1 aPaprotka, Tobias1 aPérez-Jurado, Luis, Alberto1 aBueren, Juan1 aSurralles, Jordi uhttp://clinbioinfosspa.es/content/optimised-molecular-genetic-diagnostics-fanconi-anaemia-whole-exome-sequencing-and04656nas a2200625 4500008004100000022001400041245010700055210006900162260001200231300001200243490000700255520277400262653000903036653001103045653002203056653001103078653001403089653000903103653001603112653002403128653001403152653002403166653003003190653001603220653004903236653002803285653001703313653001803330100002503348700001903373700001903392700001903411700001703430700001603447700002003463700002103483700002203504700003403526700002003560700002403580700002303604700001903627700002003646700002003666700002503686700002303711700002203734700002003756700002903776700003203805700002103837700002003858700002403878856012803902 2020 eng d a1474-548800aPazopanib for treatment of typical solitary fibrous tumours: a multicentre, single-arm, phase 2 trial.0 aPazopanib for treatment of typical solitary fibrous tumours a mu c2020 03 a456-4660 v213 a

BACKGROUND: Solitary fibrous tumour is an ultra-rare sarcoma, which encompasses different clinicopathological subgroups. The dedifferentiated subgroup shows an aggressive course with resistance to pazopanib, whereas in the malignant subgroup, pazopanib shows higher activity than in previous studies with chemotherapy. We designed a trial to test pazopanib activity in two different cohorts of solitary fibrous tumour: the malignant-dedifferentiated cohort, which was previously published, and the typical cohort, which is presented here.

METHODS: In this single-arm, phase 2 trial, adult patients (aged ≥18 years) diagnosed with confirmed metastatic or unresectable typical solitary fibrous tumour of any location, who had progressed in the previous 6 months (by Choi criteria or Response Evaluation Criteria in Solid Tumors [RECIST]) and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 were enrolled at 11 tertiary hospitals in Italy, France, and Spain. Patients received pazopanib 800 mg once daily, taken orally, until progression, unacceptable toxicity, withdrawal of consent, non-compliance, or a delay in pazopanib administration of longer than 3 weeks. The primary endpoint was proportion of patients achieving an overall response measured by Choi criteria in patients who received at least 1 month of treatment with at least one radiological assessment. All patients who received at least one dose of the study drug were included in the safety analyses. This study is registered in ClinicalTrials.gov, NCT02066285, and with the European Clinical Trials Database, EudraCT 2013-005456-15.

FINDINGS: From June 26, 2014, to Dec 13, 2018, of 40 patients who were assessed, 34 patients were enrolled and 31 patients were included in the response analysis. Median follow-up was 18 months (IQR 14-34), and 18 (58%) of 31 patients had a partial response, 12 (39%) had stable disease, and one (3%) showed progressive disease according to Choi criteria and central review. The proportion of overall response based on Choi criteria was 58% (95% CI 34-69). There were no deaths caused by toxicity, and the most frequent adverse events were diarrhoea (18 [53%] of 34 patients), fatigue (17 [50%]), and hypertension (17 [50%]).

INTERPRETATION: To our knowledge, this is the first prospective trial of pazopanib for advanced typical solitary fibrous tumour. The manageable toxicity and activity shown by pazopanib in this cohort suggest that this drug could be considered as first-line treatment for advanced typical solitary fibrous tumour.

FUNDING: Spanish Group for Research on Sarcomas (GEIS), Italian Sarcoma Group (ISG), French Sarcoma Group (FSG), GlaxoSmithKline, and Novartis.

10aAged10aFemale10aFollow-Up Studies10aHumans10aIndazoles10aMale10aMiddle Aged10aNeoplasm Metastasis10aPrognosis10aProspective Studies10aProtein Kinase Inhibitors10aPyrimidines10aResponse Evaluation Criteria in Solid Tumors10aSolitary Fibrous Tumors10aSulfonamides10aSurvival Rate1 aMartin-Broto, Javier1 aCruz, Josefina1 aPenel, Nicolas1 aLe Cesne, Axel1 aHindi, Nadia1 aLuna, Pablo1 aMoura, David, S1 aBernabeu, Daniel1 ade Alava, Enrique1 aLopez-Guerrero, Jose, Antonio1 aDopazo, Joaquin1 aPeña-Chilet, Maria1 aGutierrez, Antonio1 aCollini, Paola1 aKaranian, Marie1 aRedondo, Andres1 aLopez-Pousa, Antonio1 aGrignani, Giovanni1 aDiaz-Martin, Juan1 aMarcilla, David1 aFernandez-Serra, Antonio1 aGonzalez-Aguilera, Cristina1 aCasali, Paolo, G1 aBlay, Jean-Yves1 aStacchiotti, Silvia uhttp://clinbioinfosspa.es/content/pazopanib-treatment-typical-solitary-fibrous-tumours-multicentre-single-arm-phase-2-trial02753nas a2200373 4500008004100000022001400041245009300055210006900148260001500217300001400232490000700246520158800253653002801841653001101869653003501880653002401915653001801939653001301957653001701970653001801987653002202005100001702027700002102044700002102065700002002086700002902106700002002135700002202155700002002177700001902197700001702216700002302233856012302256 2020 eng d a1549-491800aPlatform to study intracellular polystyrene nanoplastic pollution and clinical outcomes.0 aPlatform to study intracellular polystyrene nanoplastic pollutio c2020 10 01 a1321-13250 v383 a

Increased pollution by plastics has become a serious global environmental problem, but the concerns for human health have been raised after reported presence of microplastics (MPs) and nanoplastics (NPs) in food and beverages. Unfortunately, few studies have investigate the potentially harmful effects of MPs/NPs on early human development and human health. Therefore, we used a new platform to study possible effects of polystyrene NPs (PSNPs) on the transcription profile of preimplantation human embryos and human induced pluripotent stem cells (hiPSCs). Two pluripotency genes, LEFTY1 and LEFTY2, which encode secreted ligands of the transforming growth factor-beta, were downregulated, while CA4 and OCLM, which are related to eye development, were upregulated in both samples. The gene set enrichment analysis showed that the development of atrioventricular heart valves and the dysfunction of cellular components, including extracellular matrix, were significantly affected after exposure of hiPSCs to PSNPs. Finally, using the HiPathia method, which uncovers disease mechanisms and predicts clinical outcomes, we determined the APOC3 circuit, which is responsible for increased risk for ischemic cardiovascular disease. These results clearly demonstrate that better understanding of NPs bioactivities and its implications for human health is of extreme importance. Thus, the presented platform opens further aspects to study interactions between different environmental and intracellular pollutions with the aim to decipher the mechanism and origin of human diseases.

10aEnvironmental Pollution10aHumans10aInduced Pluripotent Stem Cells10aIntracellular Space10aNanoparticles10aPlastics10aPolystyrenes10aTranscriptome10aTreatment Outcome1 aBojic, Sanja1 aFalco, Matias, M1 aStojkovic, Petra1 aLjujic, Biljana1 aJankovic, Marina, Gazdic1 aArmstrong, Lyle1 aMarkovic, Nebojsa1 aDopazo, Joaquin1 aLako, Majlinda1 aBauer, Roman1 aStojkovic, Miodrag uhttp://clinbioinfosspa.es/content/platform-study-intracellular-polystyrene-nanoplastic-pollution-and-clinical-outcomes02123nas a2200325 4500008004100000022001400041245008900055210006900144260001200213300001400225490000700239520106200246653001801308653003101326653004201357653001101399653003101410653001301441653003901454100002601493700002001519700002101539700002101560700002001581700002001601700002001621700001901641700002001660856011701680 2020 eng d a1098-100400aSMN1 copy-number and sequence variant analysis from next-generation sequencing data.0 aSMN1 copynumber and sequence variant analysis from nextgeneratio c2020 12 a2073-20770 v413 a

Spinal muscular atrophy (SMA) is a severe neuromuscular autosomal recessive disorder affecting 1/10,000 live births. Most SMA patients present homozygous deletion of SMN1, while the vast majority of SMA carriers present only a single SMN1 copy. The sequence similarity between SMN1 and SMN2, and the complexity of the SMN locus makes the estimation of the SMN1 copy-number by next-generation sequencing (NGS) very difficult. Here, we present SMAca, the first python tool to detect SMA carriers and estimate the absolute SMN1 copy-number using NGS data. Moreover, SMAca takes advantage of the knowledge of certain variants specific to SMN1 duplication to also identify silent carriers. This tool has been validated with a cohort of 326 samples from the Navarra 1000 Genomes Project (NAGEN1000). SMAca was developed with a focus on execution speed and easy installation. This combination makes it especially suitable to be integrated into production NGS pipelines. Source code and documentation are available at https://www.github.com/babelomics/SMAca.

10aBase Sequence10aDNA Copy Number Variations10aHigh-Throughput Nucleotide Sequencing10aHumans10aReproducibility of Results10aSoftware10aSurvival of Motor Neuron 1 Protein1 aLópez-López, Daniel1 aLoucera, Carlos1 aCarmona, Rosario1 aAquino, Virginia1 aSalgado, Josefa1 aPasalodos, Sara1 aMiranda, María1 aAlonso, Ángel1 aDopazo, Joaquin uhttp://clinbioinfosspa.es/content/smn1-copy-number-and-sequence-variant-analysis-next-generation-sequencing-data02695nas a2200325 4500008004100000022001400041245009200055210006900147260001200216300001400228490000700242520165100249653002201900653002601922653003301948653003001981653001102011653002102022653001202043653001902055100002002074700002902094700002102123700002102144700001802165700002002183700002502203700001902228856012202247 2020 eng d a2168-220800aTowards Improving Skin Cancer Diagnosis by Integrating Microarray and RNA-Seq Datasets.0 aTowards Improving Skin Cancer Diagnosis by Integrating Microarra c2020 07 a2119-21300 v243 a

Many clinical studies have revealed the high biological similarities existing among different skin pathological states. These similarities create difficulties in the efficient diagnosis of skin cancer, and encourage to study and design new intelligent clinical decision support systems. In this sense, gene expression analysis can help find differentially expressed genes (DEGs) simultaneously discerning multiple skin pathological states in a single test. The integration of multiple heterogeneous transcriptomic datasets requires different pipeline stages to be properly designed: from suitable batch merging and efficient biomarker selection to automated classification assessment. This article presents a novel approach addressing all these technical issues, with the intention of providing new sights about skin cancer diagnosis. Although new future efforts will have to be made in the search for better biomarkers recognizing specific skin pathological states, our study found a panel of 8 highly relevant multiclass DEGs for discerning up to 10 skin pathological states: 2 healthy skin conditions a priori, 2 cataloged precancerous skin diseases and 6 cancerous skin states. Their power of diagnosis over new samples was widely tested by previously well-trained classification models. Robust performance metrics such as overall and mean multiclass F1-score outperformed recognition rates of 94% and 80%, respectively. Clinicians should give special attention to highlighted multiclass DEGs that have high gene expression changes present among them, and understand their biological relationship to different skin pathological states.

10aBiomarkers, Tumor10aComputational Biology10aDiagnosis, Computer-Assisted10aGene Expression Profiling10aHumans10aMachine Learning10aRNA-seq10aSkin Neoplasms1 aGalvez, Juan, M1 aCastillo-Secilla, Daniel1 aHerrera, Luis, J1 aValenzuela, Olga1 aCaba, Octavio1 aPrados, Jose, C1 aOrtuno, Francisco, M1 aRojas, Ignacio uhttp://clinbioinfosspa.es/content/towards-improving-skin-cancer-diagnosis-integrating-microarray-and-rna-seq-datasets03110nas a2200493 4500008004100000022001400041245014400055210006900199260001500268490000700283520148700290653001201777653003601789653003001825653003101855653001801886653001101904653003601915653000901951653001501960653002401975653003401999653003302033653002402066653000902090653002502099653001502124653001702139653002302156653001802179653003402197653001802231100001802249700002902267700001702296700002402313700002102337700003102358700002002389700002102409700002602430700003402456856012602490 2020 eng d a2073-442500aTranscriptomic Analysis of a Diabetic Skin-Humanized Mouse Model Dissects Molecular Pathways Underlying the Delayed Wound Healing Response.0 aTranscriptomic Analysis of a Diabetic SkinHumanized Mouse Model  c2020 12 310 v123 a

Defective healing leading to cutaneous ulcer formation is one of the most feared complications of diabetes due to its consequences on patients' quality of life and on the healthcare system. A more in-depth analysis of the underlying molecular pathophysiology is required to develop effective healing-promoting therapies for those patients. Major architectural and functional differences with human epidermis limit extrapolation of results coming from rodents and other small mammal-healing models. Therefore, the search for reliable humanized models has become mandatory. Previously, we developed a diabetes-induced delayed humanized wound healing model that faithfully recapitulated the major histological features of such skin repair-deficient condition. Herein, we present the results of a transcriptomic and functional enrichment analysis followed by a mechanistic analysis performed in such humanized wound healing model. The deregulation of genes implicated in functions such as angiogenesis, apoptosis, and inflammatory signaling processes were evidenced, confirming published data in diabetic patients that in fact might also underlie some of the histological features previously reported in the delayed skin-humanized healing model. Altogether, these molecular findings support the utility of such preclinical model as a valuable tool to gain insight into the molecular basis of the delayed diabetic healing with potential impact in the translational medicine field.

10aAnimals10aDiabetes Mellitus, Experimental10aGene Expression Profiling10aGene Expression Regulation10aGene ontology10aHumans10aMetabolic Networks and Pathways10aMice10aMice, Nude10aMicroarray Analysis10aMolecular Sequence Annotation10aPrincipal Component Analysis10aSignal Transduction10aSkin10aSkin Transplantation10aSkin Ulcer10aStreptozocin10aTissue Engineering10aTranscriptome10aTransplantation, Heterologous10aWound Healing1 aLeón, Carlos1 aGarcia-Garcia, Francisco1 aLlames, Sara1 aGarcía-Pérez, Eva1 aCarretero, Marta1 aArriba, María, Del Carmen1 aDopazo, Joaquin1 aDel Rio, Marcela1 aEscamez, Maria, José1 aMartínez-Santamaría, Lucía uhttp://clinbioinfosspa.es/content/transcriptomic-analysis-diabetic-skin-humanized-mouse-model-dissects-molecular-pathways01358nas a2200433 4500008004100000022001400041245006500055210006400120260001200184300001200196490000800208653001500216653002800231653003100259100002600290700002800316700001700344700002600361700001800387700001300405700002000418700002100438700002000459700002100479700002200500700002400522700002100546700002200567700002000589700001800609700001900627700002300646700001900669700002500688700002200713700002300735710007100758856009500829 2020 eng d a1476-468700aTransparency and reproducibility in artificial intelligence.0 aTransparency and reproducibility in artificial intelligence c2020 10 aE14-E160 v58610aAlgorithms10aArtificial Intelligence10aReproducibility of Results1 aHaibe-Kains, Benjamin1 aAdam, George, Alexandru1 aHosny, Ahmed1 aKhodakarami, Farnoosh1 aWaldron, Levi1 aWang, Bo1 aMcIntosh, Chris1 aGoldenberg, Anna1 aKundaje, Anshul1 aGreene, Casey, S1 aBroderick, Tamara1 aHoffman, Michael, M1 aLeek, Jeffrey, T1 aKorthauer, Keegan1 aHuber, Wolfgang1 aBrazma, Alvis1 aPineau, Joelle1 aTibshirani, Robert1 aHastie, Trevor1 aIoannidis, John, P A1 aQuackenbush, John1 aAerts, Hugo, J W L1 aMassive Analysis Quality Control (MAQC) Society Board of Directors uhttp://clinbioinfosspa.es/content/transparency-and-reproducibility-artificial-intelligence02330nas a2200289 4500008004100000022001400041245008800055210006900143260001500212300001400227490000700241520142800248653001201676653002701688653002601715653001101741653002401752653001301776100002801789700001701817700002501834700001701859700001501876700002401891700001501915856011001930 2020 eng d a1367-481100aUsing AnABlast for intergenic sORF prediction in the Caenorhabditis elegans genome.0 aUsing AnABlast for intergenic sORF prediction in the Caenorhabdi c2020 12 08 a4827-48320 v363 a

MOTIVATION: Short bioactive peptides encoded by small open reading frames (sORFs) play important roles in eukaryotes. Bioinformatics prediction of ORFs is an early step in a genome sequence analysis, but sORFs encoding short peptides, often using non-AUG initiation codons, are not easily discriminated from false ORFs occurring by chance.

RESULTS: AnABlast is a computational tool designed to highlight putative protein-coding regions in genomic DNA sequences. This protein-coding finder is independent of ORF length and reading frame shifts, thus making of AnABlast a potentially useful tool to predict sORFs. Using this algorithm, here, we report the identification of 82 putative new intergenic sORFs in the Caenorhabditis elegans genome. Sequence similarity, motif presence, expression data and RNA interference experiments support that the underlined sORFs likely encode functional peptides, encouraging the use of AnABlast as a new approach for the accurate prediction of intergenic sORFs in annotated eukaryotic genomes.

AVAILABILITY AND IMPLEMENTATION: AnABlast is freely available at http://www.bioinfocabd.upo.es/ab/. The C.elegans genome browser with AnABlast results, annotated genes and all data used in this study is available at http://www.bioinfocabd.upo.es/celegans.

SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

10aAnimals10aCaenorhabditis elegans10aComputational Biology10aGenome10aOpen Reading Frames10aSoftware1 aCasimiro-Soriguer, C, S1 aRigual, M, M1 aBrokate-Llanos, A, M1 aMuñoz, M, J1 aGarzón, A1 aPérez-Pulido, A, J1 aJimenez, J uhttp://clinbioinfosspa.es/content/using-anablast-intergenic-sorf-prediction-caenorhabditis-elegans-genome02121nas a2200289 4500008004100000022001400041245015000055210006900205260001500274300000700289490000700296520113800303653001501441653001101456653003101467653002101498653001501519653001501534653001701549653001501566100003301581700002001614700002701634700002601661700002001687856012401707 2019 eng d a1745-615000aAntibiotic resistance and metabolic profiles as functional biomarkers that accurately predict the geographic origin of city metagenomics samples.0 aAntibiotic resistance and metabolic profiles as functional bioma c2019 08 20 a150 v143 a

BACKGROUND: The availability of hundreds of city microbiome profiles allows the development of increasingly accurate predictors of the origin of a sample based on its microbiota composition. Typical microbiome studies involve the analysis of bacterial abundance profiles.

RESULTS: Here we use a transformation of the conventional bacterial strain or gene abundance profiles to functional profiles that account for bacterial metabolism and other cell functionalities. These profiles are used as features for city classification in a machine learning algorithm that allows the extraction of the most relevant features for the classification.

CONCLUSIONS: We demonstrate here that the use of functional profiles not only predict accurately the most likely origin of a sample but also to provide an interesting functional point of view of the biogeography of the microbiota. Interestingly, we show how cities can be classified based on the observed profile of antibiotic resistances.

REVIEWERS: Open peer review: Reviewed by Jin Zhuang Dou, Jing Zhou, Torsten Semmler and Eran Elhaik.

10abiomarkers10aCities10aDrug Resistance, Microbial10aMachine Learning10aMetabolome10aMetagenome10ametagenomics10aMicrobiota1 aCasimiro-Soriguer, Carlos, S1 aLoucera, Carlos1 aFlorido, Javier, Perez1 aLópez-López, Daniel1 aDopazo, Joaquin uhttp://clinbioinfosspa.es/content/antibiotic-resistance-and-metabolic-profiles-functional-biomarkers-accurately-predict03264nas a2200685 4500008004100000022001400041245011800055210006900173260001500242300000900257490000700266520115400273653001901427653005101446653001701497653002201514653002101536653002601557653002201583653002001605653003001625653001901655653001301674653001101687653003101698653001301729653001401742653002101756653003501777653004101812653002201853100002301875700001701898700001901915700001801934700002301952700001901975700001501994700001702009700001602026700002002042700001602062700002402078700001902102700001802121700002402139700001802163700002502181700001702206700001902223700002302242700002702265700002002292700002502312700002002337700002102357700002602378710005702404856011702461 2019 eng d a2041-172300aCommunity assessment to advance computational prediction of cancer drug combinations in a pharmacogenomic screen.0 aCommunity assessment to advance computational prediction of canc c2019 06 17 a26740 v103 a

The effectiveness of most cancer targeted therapies is short-lived. Tumors often develop resistance that might be overcome with drug combinations. However, the number of possible combinations is vast, necessitating data-driven approaches to find optimal patient-specific treatments. Here we report AstraZeneca's large drug combination dataset, consisting of 11,576 experiments from 910 combinations across 85 molecularly characterized cancer cell lines, and results of a DREAM Challenge to evaluate computational strategies for predicting synergistic drug pairs and biomarkers. 160 teams participated to provide a comprehensive methodological development and benchmarking. Winning methods incorporate prior knowledge of drug-target interactions. Synergy is predicted with an accuracy matching biological replicates for >60% of combinations. However, 20% of drug combinations are poorly predicted by all methods. Genomic rationale for synergy predictions are identified, including ADAM17 inhibitor antagonism when combined with PIK3CB/D inhibition contrasting to synergy when combined with other PI3K-pathway inhibitors in PIK3CA mutant cells.

10aADAM17 Protein10aAntineoplastic Combined Chemotherapy Protocols10aBenchmarking10aBiomarkers, Tumor10aCell Line, Tumor10aComputational Biology10aDatasets as Topic10aDrug Antagonism10aDrug Resistance, Neoplasm10aDrug Synergism10aGenomics10aHumans10aMolecular Targeted Therapy10amutation10aNeoplasms10apharmacogenetics10aPhosphatidylinositol 3-Kinases10aPhosphoinositide-3 Kinase Inhibitors10aTreatment Outcome1 aMenden, Michael, P1 aWang, Dennis1 aMason, Mike, J1 aSzalai, Bence1 aBulusu, Krishna, C1 aGuan, Yuanfang1 aYu, Thomas1 aKang, Jaewoo1 aJeon, Minji1 aWolfinger, Russ1 aNguyen, Tin1 aZaslavskiy, Mikhail1 aJang, In, Sock1 aGhazoui, Zara1 aAhsen, Mehmet, Eren1 aVogel, Robert1 aNeto, Elias, Chaibub1 aNorman, Thea1 aK Y Tang, Eric1 aGarnett, Mathew, J1 aDi Veroli, Giovanni, Y1 aFawell, Stephen1 aStolovitzky, Gustavo1 aGuinney, Justin1 aDry, Jonathan, R1 aSaez-Rodriguez, Julio1 aAstraZeneca-Sanger Drug Combination DREAM Consortium uhttp://clinbioinfosspa.es/content/community-assessment-advance-computational-prediction-cancer-drug-combinations01813nas a2200265 4500008004100000022001400041245007700055210006900132260001500201300001400216490000700230520098400237653001501221653001101236653002301247653002401270653002001294653001801314100001901332700002201351700001801373700003101391700002001422856010501442 2019 eng d a1477-405400aA comparison of mechanistic signaling pathway activity analysis methods.0 acomparison of mechanistic signaling pathway activity analysis me c2019 09 27 a1655-16680 v203 a

Understanding the aspects of cell functionality that account for disease mechanisms or drug modes of action is a main challenge for precision medicine. Classical gene-based approaches ignore the modular nature of most human traits, whereas conventional pathway enrichment approaches produce only illustrative results of limited practical utility. Recently, a family of new methods has emerged that change the focus from the whole pathways to the definition of elementary subpathways within them that have any mechanistic significance and to the study of their activities. Thus, mechanistic pathway activity (MPA) methods constitute a new paradigm that allows recoding poorly informative genomic measurements into cell activity quantitative values and relate them to phenotypes. Here we provide a review on the MPA methods available and explain their contribution to systems medicine approaches for addressing challenges in the diagnostic and treatment of complex diseases.

10aAlgorithms10aHumans10aPostmortem Changes10aSignal Transduction10aSystems biology10aTranscriptome1 aAmadoz, Alicia1 aHidalgo, Marta, R1 aCubuk, Cankut1 aCarbonell-Caballero, José1 aDopazo, Joaquin uhttp://clinbioinfosspa.es/content/comparison-mechanistic-signaling-pathway-activity-analysis-methods02819nas a2200397 4500008004100000022001400041245011600055210006900171260000900240300000600249490000600255520157600261653002601837653002401863653001901887653002901906653001101935653001301946653003601959653002301995653001402018653001402032653001302046653001802059100001802077700002202095700001902117700001602136700002402152700002202176700002102198700002002219700003102239700002002270856013102290 2019 eng d a2056-718900aDifferential metabolic activity and discovery of therapeutic targets using summarized metabolic pathway models.0 aDifferential metabolic activity and discovery of therapeutic tar c2019 a70 v53 a

In spite of the increasing availability of genomic and transcriptomic data, there is still a gap between the detection of perturbations in gene expression and the understanding of their contribution to the molecular mechanisms that ultimately account for the phenotype studied. Alterations in the metabolism are behind the initiation and progression of many diseases, including cancer. The wealth of available knowledge on metabolic processes can therefore be used to derive mechanistic models that link gene expression perturbations to changes in metabolic activity that provide relevant clues on molecular mechanisms of disease and drug modes of action (MoA). In particular, pathway modules, which recapitulate the main aspects of metabolism, are especially suitable for this type of modeling. We present Metabolizer, a web-based application that offers an intuitive, easy-to-use interactive interface to analyze differences in pathway metabolic module activities that can also be used for class prediction and in silico prediction of knock-out (KO) effects. Moreover, Metabolizer can automatically predict the optimal KO intervention for restoring a diseased phenotype. We provide different types of validations of some of the predictions made by Metabolizer. Metabolizer is a web tool that allows understanding molecular mechanisms of disease or the MoA of drugs within the context of the metabolism by using gene expression measurements. In addition, this tool automatically suggests potential therapeutic targets for individualized therapeutic interventions.

10aComputational Biology10aComputer Simulation10aDrug discovery10aGene Regulatory Networks10aHumans10aInternet10aMetabolic Networks and Pathways10aModels, Biological10aNeoplasms10aPhenotype10aSoftware10aTranscriptome1 aCubuk, Cankut1 aHidalgo, Marta, R1 aAmadoz, Alicia1 aRian, Kinza1 aSalavert, Francisco1 aPujana, Miguel, A1 aMateo, Francesca1 aHerranz, Carmen1 aCarbonell-Caballero, José1 aDopazo, Joaquin uhttp://clinbioinfosspa.es/content/differential-metabolic-activity-and-discovery-therapeutic-targets-using-summarized-metabolic01957nas a2200277 4500008004100000022001400041245011500055210006900170260001600239300000800255490000700263520105900270653002301329653001901352653001301371653001101384653002101395653001401416653001301430653002401443100002701467700002401494700002001518700002001538856012101558 2019 eng d a1471-210500aExploring the druggable space around the Fanconi anemia pathway using machine learning and mechanistic models.0 aExploring the druggable space around the Fanconi anemia pathway  c2019 Jul 02 a3700 v203 a

BACKGROUND: In spite of the abundance of genomic data, predictive models that describe phenotypes as a function of gene expression or mutations are difficult to obtain because they are affected by the curse of dimensionality, given the disbalance between samples and candidate genes. And this is especially dramatic in scenarios in which the availability of samples is difficult, such as the case of rare diseases.

RESULTS: The application of multi-output regression machine learning methodologies to predict the potential effect of external proteins over the signaling circuits that trigger Fanconi anemia related cell functionalities, inferred with a mechanistic model, allowed us to detect over 20 potential therapeutic targets.

CONCLUSIONS: The use of artificial intelligence methods for the prediction of potentially causal relationships between proteins of interest and cell activities related with disease-related phenotypes opens promising avenues for the systematic search of new targets in rare diseases.

10aDatabases, Factual10aFanconi Anemia10aGenomics10aHumans10aMachine Learning10aPhenotype10aProteins10aSignal Transduction1 aEsteban-Medina, Marina1 aPeña-Chilet, Maria1 aLoucera, Carlos1 aDopazo, Joaquin uhttp://clinbioinfosspa.es/content/exploring-druggable-space-around-fanconi-anemia-pathway-using-machine-learning-and05141nas a2200745 4500008004100000022001400041245013000055210006900185260001200254300001200266490000800278520304400286653001503330653001003345653001103355653001203366653002503378653002003403653001003423653002103433653002603454653003803480653002503518653003403543653001103577653001603588653001303604653003103617653002303648653001103671653001103682653002003693653000903713653001603722653001303738653002503751653003103776653002503807653001203832653000903844653002603853653001603879100002203895700001303917700001303930700002303943700001503966700001903981700002404000700001604024700001604040700002904056700001404085700001504099700002704114700002404141700001404165700001204179700001604191700001504207700001504222700001404237700001504251856012904266 2019 eng d a1365-213300aFibroblast activation and abnormal extracellular matrix remodelling as common hallmarks in three cancer-prone genodermatoses.0 aFibroblast activation and abnormal extracellular matrix remodell c2019 09 a512-5220 v1813 a

BACKGROUND: Recessive dystrophic epidermolysis bullosa (RDEB), Kindler syndrome (KS) and xeroderma pigmentosum complementation group C (XPC) are three cancer-prone genodermatoses whose causal genetic mutations cannot fully explain, on their own, the array of associated phenotypic manifestations. Recent evidence highlights the role of the stromal microenvironment in the pathology of these disorders.

OBJECTIVES: To investigate, by means of comparative gene expression analysis, the role played by dermal fibroblasts in the pathogenesis of RDEB, KS and XPC.

METHODS: We conducted RNA-Seq analysis, which included a thorough examination of the differentially expressed genes, a functional enrichment analysis and a description of affected signalling circuits. Transcriptomic data were validated at the protein level in cell cultures, serum samples and skin biopsies.

RESULTS: Interdisease comparisons against control fibroblasts revealed a unifying signature of 186 differentially expressed genes and four signalling pathways in the three genodermatoses. Remarkably, some of the uncovered expression changes suggest a synthetic fibroblast phenotype characterized by the aberrant expression of extracellular matrix (ECM) proteins. Western blot and immunofluorescence in situ analyses validated the RNA-Seq data. In addition, enzyme-linked immunosorbent assay revealed increased circulating levels of periostin in patients with RDEB.

CONCLUSIONS: Our results suggest that the different causal genetic defects converge into common changes in gene expression, possibly due to injury-sensitive events. These, in turn, trigger a cascade of reactions involving abnormal ECM deposition and underexpression of antioxidant enzymes. The elucidated expression signature provides new potential biomarkers and common therapeutic targets in RDEB, XPC and KS. What's already known about this topic? Recessive dystrophic epidermolysis bullosa (RDEB), Kindler syndrome (KS) and xeroderma pigmentosum complementation group C (XPC) are three genodermatoses with high predisposition to cancer development. Although their causal genetic mutations mainly affect epithelia, the dermal microenvironment likely contributes to the physiopathology of these disorders. What does this study add? We disclose a large overlapping transcription profile between XPC, KS and RDEB fibroblasts that points towards an activated phenotype with high matrix-synthetic capacity. This common signature seems to be independent of the primary causal deficiency, but reflects an underlying derangement of the extracellular matrix via transforming growth factor-β signalling activation and oxidative state imbalance. What is the translational message? This study broadens the current knowledge about the pathology of these diseases and highlights new targets and biomarkers for effective therapeutic intervention. It is suggested that high levels of circulating periostin could represent a potential biomarker in RDEB.

10aAdolescent10aAdult10aBiopsy10aBlister10aCase-Control Studies10aCells, Cultured10aChild10aChild, Preschool10aEpidermolysis Bullosa10aEpidermolysis Bullosa Dystrophica10aExtracellular Matrix10aExtracellular Matrix Proteins10aFemale10aFibroblasts10aFibrosis10aGene Expression Regulation10aHealthy Volunteers10aHumans10aInfant10aInfant, Newborn10aMale10aMiddle Aged10amutation10aPeriodontal Diseases10aPhotosensitivity Disorders10aPrimary Cell Culture10aRNA-seq10aSkin10aXeroderma Pigmentosum10aYoung Adult1 aChacón-Solano, E1 aLeón, C1 aDíaz, F1 aGarcía-García, F1 aGarcía, M1 aEscámez, M, J1 aGuerrero-Aspizua, S1 aConti, C, J1 aMencía, Á1 aMartínez-Santamaría, L1 aLlames, S1 aPévida, M1 aCarbonell-Caballero, J1 aPuig-Butillé, J, A1 aMaseda, R1 aPuig, S1 ade Lucas, R1 aBaselga, E1 aLarcher, F1 aDopazo, J1 aDel Rio, M uhttp://clinbioinfosspa.es/content/fibroblast-activation-and-abnormal-extracellular-matrix-remodelling-common-hallmarks-three05181nas a2200661 4500008004100000022001400041245013800055210006900193260001200262300001200274490000700286520316900293653001003462653000903472653002803481653002603509653001103535653001103546653001403557653000903571653001603580653002603596653001603622653004903638653002603687653002803713653001703741653002203758100002503780700002403805700002503829700002003854700002103874700002203895700002103917700002203938700002303960700002003983700002404003700002204027700002204049700001804071700001904089700003004108700002904138700002304167700001804190700002904208700002404237700001704261700001504278700002004293700002704313700001804340700002004358700001904378856012204397 2019 eng d a1474-548800aPazopanib for treatment of advanced malignant and dedifferentiated solitary fibrous tumour: a multicentre, single-arm, phase 2 trial.0 aPazopanib for treatment of advanced malignant and dedifferentiat c2019 01 a134-1440 v203 a

BACKGROUND: A solitary fibrous tumour is a rare soft-tissue tumour with three clinicopathological variants: typical, malignant, and dedifferentiated. Preclinical experiments and retrospective studies have shown different sensitivities of solitary fibrous tumour to chemotherapy and antiangiogenics. We therefore designed a trial to assess the activity of pazopanib in a cohort of patients with malignant or dedifferentiated solitary fibrous tumour. The clinical and translational results are presented here.

METHODS: In this single-arm, phase 2 trial, adult patients (aged ≥ 18 years) with histologically confirmed metastatic or unresectable malignant or dedifferentiated solitary fibrous tumour at any location, who had progressed (by RECIST and Choi criteria) in the previous 6 months and had an ECOG performance status of 0-2, were enrolled at 16 third-level hospitals with expertise in sarcoma care in Spain, Italy, and France. Patients received pazopanib 800 mg once daily, taken orally without food, at least 1 h before or 2 h after a meal, until progression or intolerance. The primary endpoint of the study was overall response measured by Choi criteria in the subset of the intention-to-treat population (patients who received at least 1 month of treatment with at least one radiological assessment). All patients who received at least one dose of the study drug were included in the safety analyses. This study is registered with ClinicalTrials.gov, number NCT02066285, and with the European Clinical Trials Database, EudraCT number 2013-005456-15.

FINDINGS: From June 26, 2014, to Nov 24, 2016, of 40 patients assessed, 36 were enrolled (34 with malignant solitary fibrous tumour and two with dedifferentiated solitary fibrous tumour). Median follow-up was 27 months (IQR 16-31). Based on central radiology review, 18 (51%) of 35 evaluable patients had partial responses, nine (26%) had stable disease, and eight (23%) had progressive disease according to Choi criteria. Further enrolment of patients with dedifferentiated solitary fibrous tumour was stopped after detection of early and fast progressions in a planned interim analysis. 51% (95% CI 34-69) of 35 patients achieved an overall response according to Choi criteria. Ten (29%) of 35 patients died. There were no deaths related to adverse events and the most frequent grade 3 or higher adverse events were hypertension (11 [31%] of 36 patients), neutropenia (four [11%]), increased concentrations of alanine aminotransferase (four [11%]), and increased concentrations of bilirubin (three [8%]).

INTERPRETATION: To our knowledge, this is the first trial of pazopanib for treatment of malignant solitary fibrous tumour showing activity in this patient group. The manageable toxicity profile and the activity shown by pazopanib suggests that this drug could be an option for systemic treatment of advanced malignant solitary fibrous tumour, and provides a benchmark for future trials.

FUNDING: Spanish Group for Research on Sarcomas (GEIS), Italian Sarcoma Group (ISG), French Sarcoma Group (FSG), GlaxoSmithKline, and Novartis.

10aAdult10aAged10aAngiogenesis Inhibitors10aAntineoplastic Agents10aFemale10aHumans10aIndazoles10aMale10aMiddle Aged10aMultivariate Analysis10aPyrimidines10aResponse Evaluation Criteria in Solid Tumors10aSoft Tissue Neoplasms10aSolitary Fibrous Tumors10aSulfonamides10aSurvival Analysis1 aMartin-Broto, Javier1 aStacchiotti, Silvia1 aLopez-Pousa, Antonio1 aRedondo, Andres1 aBernabeu, Daniel1 ade Alava, Enrique1 aCasali, Paolo, G1 aItaliano, Antoine1 aGutierrez, Antonio1 aMoura, David, S1 aPeña-Chilet, Maria1 aDiaz-Martin, Juan1 aBiscuola, Michele1 aTaron, Miguel1 aCollini, Paola1 aRanchere-Vince, Dominique1 aDel Muro, Xavier, Garcia1 aGrignani, Giovanni1 aDumont, Sarah1 aMartinez-Trufero, Javier1 aPalmerini, Emanuela1 aHindi, Nadia1 aSebio, Ana1 aDopazo, Joaquin1 aTos, Angelo, Paolo Dei1 aLeCesne, Axel1 aBlay, Jean-Yves1 aCruz, Josefina uhttp://clinbioinfosspa.es/content/pazopanib-treatment-advanced-malignant-and-dedifferentiated-solitary-fibrous-tumour02189nas a2200241 4500008004100000022001400041245006800055210006700123260001500190300001200205490000700217520142700224653001901651653002601670653001101696653002301707100002701730700002001757700002201777700002201799700002501821856010101846 2019 eng d a1477-405400aPrecision medicine needs pioneering clinical bioinformaticians.0 aPrecision medicine needs pioneering clinical bioinformaticians c2019 05 21 a752-7660 v203 a

Success in precision medicine depends on accessing high-quality genetic and molecular data from large, well-annotated patient cohorts that couple biological samples to comprehensive clinical data, which in conjunction can lead to effective therapies. From such a scenario emerges the need for a new professional profile, an expert bioinformatician with training in clinical areas who can make sense of multi-omics data to improve therapeutic interventions in patients, and the design of optimized basket trials. In this review, we first describe the main policies and international initiatives that focus on precision medicine. Secondly, we review the currently ongoing clinical trials in precision medicine, introducing the concept of 'precision bioinformatics', and we describe current pioneering bioinformatics efforts aimed at implementing tools and computational infrastructures for precision medicine in health institutions around the world. Thirdly, we discuss the challenges related to the clinical training of bioinformaticians, and the urgent need for computational specialists capable of assimilating medical terminologies and protocols to address real clinical questions. We also propose some skills required to carry out common tasks in clinical bioinformatics and some tips for emergent groups. Finally, we explore the future perspectives and the challenges faced by precision medicine bioinformatics.

10aCohort Studies10aComputational Biology10aHumans10aPrecision Medicine1 aGómez-López, Gonzalo1 aDopazo, Joaquin1 aCigudosa, Juan, C1 aValencia, Alfonso1 aAl-Shahrour, Fátima uhttp://clinbioinfosspa.es/content/precision-medicine-needs-pioneering-clinical-bioinformaticians02565nas a2200253 4500008004100000022001400041245011000055210006900165260001600234300000800250490000700258520169900265653002601964653002301990653001302013653002802026100002202054700002402076700002002100700002402120700002002144700002002164856012702184 2019 eng d a1471-210500aPyCellBase, an efficient python package for easy retrieval of biological data from heterogeneous sources.0 aPyCellBase an efficient python package for easy retrieval of bio c2019 Mar 28 a1590 v203 a

BACKGROUND: Biological databases and repositories are incrementing in diversity and complexity over the years. This rapid expansion of current and new sources of biological knowledge raises serious problems of data accessibility and integration. To handle the growing necessity of unification, CellBase was created as an integrative solution. CellBase provides a centralized NoSQL database containing biological information from different and heterogeneous sources. Access to this information is done through a RESTful web service API, which provides an efficient interface to the data.

RESULTS: In this work we present PyCellBase, a Python package that provides programmatic access to the rich RESTful web service API offered by CellBase. This package offers a fast and user-friendly access to biological information without the need of installing any local database. In addition, a series of command-line tools are provided to perform common bioinformatic tasks, such as variant annotation. CellBase data is always available by a high-availability cluster and queries have been tuned to ensure a real-time performance.

CONCLUSION: PyCellBase is an open-source Python package that provides an efficient access to heterogeneous biological information. It allows to perform tasks that require a comprehensive set of knowledge resources, as for example variant annotation. Queries can be easily fine-tuned to retrieve the desired information of particular biological features. PyCellBase offers the convenience of an object-oriented scripting language and provides the ability to integrate the obtained results into other Python applications and pipelines.

10aComputational Biology10aDatabases, Factual10aSoftware10aUser-Computer Interface1 aPerez-Gil, Daniel1 aLopez, Francisco, J1 aDopazo, Joaquin1 aMarin-Garcia, Pablo1 aRendon, Augusto1 aMedina, Ignacio uhttp://clinbioinfosspa.es/content/pycellbase-efficient-python-package-easy-retrieval-biological-data-heterogeneous-sources00765nas a2200181 4500008004100000245009000041210006900131260001600200490000600216100002400222700002700246700002200273700001600295700002300311700002000334700002000354856020900374 2019 eng d00aUsing mechanistic models for the clinical interpretation of complex genomic variation0 aUsing mechanistic models for the clinical interpretation of comp cJan-12-20190 v91 aPeña-Chilet, Maria1 aEsteban-Medina, Marina1 aFalco, Matias, M.1 aRian, Kinza1 aHidalgo, Marta, R.1 aLoucera, Carlos1 aDopazo, Joaquin uhttp://www.nature.com/articles/s41598-019-55454-7http://www.nature.com/articles/s41598-019-55454-7.pdfhttp://www.nature.com/articles/s41598-019-55454-7.pdfhttp://www.nature.com/articles/s41598-019-55454-701484nas a2200421 4500008004100000245011900041210006900160260001600229490000600245110005300251700001800304700001800322700002300340700002500363700001600388700001900404700001500423700001800438700001900456700002400475700001900499700002200518700001600540700003100556700001800587700001800605700001800623700001900641700002200660700002300682700002700705700002700732700001900759700002400778700002500802700002600827856020900853 2018 eng d00aA crowdsourced analysis to identify ab initio molecular signatures predictive of susceptibility to viral infection0 acrowdsourced analysis to identify ab initio molecular signatures cJan-12-20180 v91 aThe Respiratory Viral DREAM Challenge Consortium1 aFourati, Slim1 aTalla, Aarthi1 aMahmoudian, Mehrad1 aBurkhart, Joshua, G.1 aKlén, Riku1 aHenao, Ricardo1 aYu, Thomas1 aAydın, Zafer1 aYeung, Ka, Yee1 aAhsen, Mehmet, Eren1 aAlmugbel, Reem1 aJahandideh, Samad1 aLiang, Xiao1 aNordling, Torbjörn, E. M.1 aShiga, Motoki1 aStanescu, Ana1 aVogel, Robert1 aPandey, Gaurav1 aChiu, Christopher1 aMcClain, Micah, T.1 aWoods, Christopher, W.1 aGinsburg, Geoffrey, S.1 aElo, Laura, L.1 aTsalik, Ephraim, L.1 aMangravite, Lara, M.1 aSieberts, Solveig, K. uhttp://www.nature.com/articles/s41467-018-06735-8http://www.nature.com/articles/s41467-018-06735-8.pdfhttp://www.nature.com/articles/s41467-018-06735-8.pdfhttp://www.nature.com/articles/s41467-018-06735-802572nas a2200529 4500008004100000022001400041245008700055210006900142260001500211300000800226490000600234520103000240653001001270653001801280653001001298653001101308653002001319653001101339653002301350653002301373653001901396653002501415653001801440100002301458700002701481700002101508700002501529700001601554700001901570700001701589700002201606700002401628700003101652700002101683700002401704700001901728700002401747700001801771700001801789700002101807700002001828700002001848700002101868700002301889700002001912856011001932 2018 eng d a2041-172300aThe effects of death and post-mortem cold ischemia on human tissue transcriptomes.0 aeffects of death and postmortem cold ischemia on human tissue tr c2018 02 13 a4900 v93 a

Post-mortem tissues samples are a key resource for investigating patterns of gene expression. However, the processes triggered by death and the post-mortem interval (PMI) can significantly alter physiologically normal RNA levels. We investigate the impact of PMI on gene expression using data from multiple tissues of post-mortem donors obtained from the GTEx project. We find that many genes change expression over relatively short PMIs in a tissue-specific manner, but this potentially confounding effect in a biological analysis can be minimized by taking into account appropriate covariates. By comparing ante- and post-mortem blood samples, we identify the cascade of transcriptional events triggered by death of the organism. These events do not appear to simply reflect stochastic variation resulting from mRNA degradation, but active and ongoing regulation of transcription. Finally, we develop a model to predict the time since death from the analysis of the transcriptome of a few readily accessible tissues.

10aBlood10aCold Ischemia10aDeath10aFemale10agene expression10aHumans10aModels, Biological10aPostmortem Changes10aRNA, Messenger10aStochastic Processes10aTranscriptome1 aFerreira, Pedro, G1 aMuñoz-Aguirre, Manuel1 aReverter, Ferran1 aGodinho, Caio, P Sá1 aSousa, Abel1 aAmadoz, Alicia1 aSodaei, Reza1 aHidalgo, Marta, R1 aPervouchine, Dmitri1 aCarbonell-Caballero, José1 aNurtdinov, Ramil1 aBreschi, Alessandra1 aAmador, Raziel1 aOliveira, Patrícia1 aCubuk, Cankut1 aCurado, João1 aAguet, François1 aOliveira, Carla1 aDopazo, Joaquin1 aSammeth, Michael1 aArdlie, Kristin, G1 aGuigó, Roderic uhttp://clinbioinfosspa.es/content/effects-death-and-post-mortem-cold-ischemia-human-tissue-transcriptomes02672nas a2200373 4500008004100000022001400041245014700055210006900202260001500271300000900286490000600295520150800301653002801809653002901837653001901866653002001885653001101905653001301916653001901929653002601948100001401974700001301988700001802001700001402019700002602033700001502059700002502074700002702099700001202126700001502138700001102153700001302164856012102177 2018 eng d a2045-232200aEvolution of the Quorum network and the mobilome (plasmids and bacteriophages) in clinical strains of Acinetobacter baumannii during a decade.0 aEvolution of the Quorum network and the mobilome plasmids and ba c2018 02 06 a25230 v83 a

In this study, we compared eighteen clinical strains of A. baumannii belonging to the ST-2 clone and isolated from patients in the same intensive care unit (ICU) in 2000 (9 strains referred to collectively as Ab_GEIH-2000) and 2010 (9 strains referred to collectively as Ab_GEIH-2010), during the GEIH-REIPI project (Umbrella BioProject PRJNA422585). We observed two main molecular differences between the Ab_GEIH-2010 and the Ab_GEIH-2000 collections, acquired over the course of the decade long sampling interval and involving the mobilome: i) a plasmid harbouring genes for bla ß-lactamase and abKA/abkB proteins of a toxin-antitoxin system; and ii) two temperate bacteriophages, Ab105-1ϕ (63 proteins) and Ab105-2ϕ (93 proteins), containing important viral defence proteins. Moreover, all Ab_GEIH-2010 strains contained a Quorum functional network of Quorum Sensing (QS) and Quorum Quenching (QQ) mechanisms, including a new QQ enzyme, AidA, which acts as a bacterial defence mechanism against the exogenous 3-oxo-C12-HSL. Interestingly, the infective capacity of the bacteriophages isolated in this study (Ab105-1ϕ and Ab105-2ϕ) was higher in the Ab_GEIH-2010 strains (carrying a functional Quorum network) than in the Ab_GEIH-2000 strains (carrying a deficient Quorum network), in which the bacteriophages showed little or no infectivity. This is the first study about the evolution of the Quorum network and the mobilome in clinical strains of Acinetobacter baumannii during a decade.

10aAcinetobacter baumannii10aAcinetobacter Infections10aBacteriophages10aCross Infection10aHumans10aPlasmids10aQuorum Sensing10aRetrospective Studies1 aLópez, M1 aRueda, A1 aFlorido, J, P1 aBlasco, L1 aFernández-García, L1 aTrastoy, R1 aFernández-Cuenca, F1 aMartínez-Martínez, L1 aVila, J1 aPascual, A1 aBou, G1 aTomas, M uhttp://clinbioinfosspa.es/content/evolution-quorum-network-and-mobilome-plasmids-and-bacteriophages-clinical-strains02782nas a2200349 4500008004100000022001400041245008700055210006900142260001200211490000600223520171300229653001201942653003001954653001101984653002201995653001302017653001102030653000902041653001002050653002702060100003302087700002902120700002002149700003002169700002102199700001902220700002002239700001902259700001902278700002202297856011302319 2018 eng d a2057-585800aThe first complete genomic structure of Butyrivibrio fibrisolvens and its chromid.0 afirst complete genomic structure of Butyrivibrio fibrisolvens an c2018 100 v43 a

Butyrivibrio fibrisolvens forms part of the gastrointestinal microbiome of ruminants and other mammals, including humans. Indeed, it is one of the most common bacteria found in the rumen and plays an important role in ruminal fermentation of polysaccharides, yet, to date, there is no closed reference genome published for this species in any ruminant animal. We successfully assembled the nearly complete genome sequence of B. fibrisolvens strain INBov1 isolated from cow rumen using Illumina paired-end reads, 454 Roche single-end and mate pair sequencing technology. Additionally, we constructed an optical restriction map of this strain to aid in scaffold ordering and positioning, and completed the first genomic structure of this species. Moreover, we identified and assembled the first chromid of this species (pINBov266). The INBov1 genome encodes a large set of genes involved in the cellulolytic process but lacks key genes. This seems to indicate that B. fibrisolvens plays an important role in ruminal cellulolytic processes, but does not have autonomous cellulolytic capacity. When searching for genes involved in the biohydrogenation of unsaturated fatty acids, no linoleate isomerase gene was found in this strain. INBov1 does encode oleate hydratase genes known to participate in the hydrogenation of oleic acids. Furthermore, INBov1 contains an enolase gene, which has been recently determined to participate in the synthesis of conjugated linoleic acids. This work confirms the presence of a novel chromid in B. fibrisolvens and provides a new potential reference genome sequence for this species, providing new insight into its role in biohydrogenation and carbohydrate degradation.

10aAnimals10aButyrivibrio fibrisolvens10aCattle10aGenome, Bacterial10aGenomics10aHumans10aMilk10aRumen10aSequence Analysis, DNA1 aHernáez, Javier, Rodríguez1 aCucchi, Maria, Esperanza1 aCravero, Silvio1 aMartinez, Maria, Carolina1 aGonzalez, Sergio1 aPuebla, Andrea1 aDopazo, Joaquin1 aFarber, Marisa1 aPaniego, Norma1 aRivarola, Máximo uhttp://clinbioinfosspa.es/content/first-complete-genomic-structure-butyrivibrio-fibrisolvens-and-its-chromid02945nas a2200445 4500008004100000022001400041245009500055210006900150260001500219300001400234490000700248520156700255653002101822653002101843653002401864653003001888653004301918653002901961653001101990653002602001653001502027653001302042653001402055653001402069653001402083653001402097653002702111653002702138653001802165653002202183100001802205700002202223700001902245700002202264700002102286700002002307700003102327700002002358856012102378 2018 eng d a1538-744500aGene Expression Integration into Pathway Modules Reveals a Pan-Cancer Metabolic Landscape.0 aGene Expression Integration into Pathway Modules Reveals a PanCa c2018 11 01 a6059-60720 v783 a

Metabolic reprogramming plays an important role in cancer development and progression and is a well-established hallmark of cancer. Despite its inherent complexity, cellular metabolism can be decomposed into functional modules that represent fundamental metabolic processes. Here, we performed a pan-cancer study involving 9,428 samples from 25 cancer types to reveal metabolic modules whose individual or coordinated activity predict cancer type and outcome, in turn highlighting novel therapeutic opportunities. Integration of gene expression levels into metabolic modules suggests that the activity of specific modules differs between cancers and the corresponding tissues of origin. Some modules may cooperate, as indicated by the positive correlation of their activity across a range of tumors. The activity of many metabolic modules was significantly associated with prognosis at a stronger magnitude than any of their constituent genes. Thus, modules may be classified as tumor suppressors and oncomodules according to their potential impact on cancer progression. Using this modeling framework, we also propose novel potential therapeutic targets that constitute alternative ways of treating cancer by inhibiting their reprogrammed metabolism. Collectively, this study provides an extensive resource of predicted cancer metabolic profiles and dependencies. Combining gene expression with metabolic modules identifies molecular mechanisms of cancer undetected on an individual gene level and allows discovery of new potential therapeutic targets. .

10aCell Line, Tumor10aCluster Analysis10aDisease Progression10aGene Expression Profiling10aGene Expression Regulation, Neoplastic10aGene Regulatory Networks10aHumans10aKaplan-Meier Estimate10aMetabolome10amutation10aNeoplasms10aOncogenes10aPhenotype10aPrognosis10aRNA, Small Interfering10aSequence Analysis, RNA10aTranscriptome10aTreatment Outcome1 aCubuk, Cankut1 aHidalgo, Marta, R1 aAmadoz, Alicia1 aPujana, Miguel, A1 aMateo, Francesca1 aHerranz, Carmen1 aCarbonell-Caballero, José1 aDopazo, Joaquin uhttp://clinbioinfosspa.es/content/gene-expression-integration-pathway-modules-reveals-pan-cancer-metabolic-landscape02576nas a2200517 4500008004100000022001400041245005200055210005100107260001500158300001200173490000800185520112500193653002301318653001701341653001101358653002001369653002501389653002301414653001801437653001301455653001501468653001701483653002101500653002001521653002701541653001401568100002401582700001801606700002201624700002801646700002601674700002101700700002001721700002401741700003101765700002001796700001701816700001801833700002401851700002101875700002001896700002601916700002301942700001801965856007501983 2018 eng d a1476-468700aGenomics of the origin and evolution of Citrus.0 aGenomics of the origin and evolution of Citrus c2018 02 15 a311-3160 v5543 a

The genus Citrus, comprising some of the most widely cultivated fruit crops worldwide, includes an uncertain number of species. Here we describe ten natural citrus species, using genomic, phylogenetic and biogeographic analyses of 60 accessions representing diverse citrus germ plasms, and propose that citrus diversified during the late Miocene epoch through a rapid southeast Asian radiation that correlates with a marked weakening of the monsoons. A second radiation enabled by migration across the Wallace line gave rise to the Australian limes in the early Pliocene epoch. Further identification and analyses of hybrids and admixed genomes provides insights into the genealogy of major commercial cultivars of citrus. Among mandarins and sweet orange, we find an extensive network of relatedness that illuminates the domestication of these groups. Widespread pummelo admixture among these mandarins and its correlation with fruit size and acidity suggests a plausible role of pummelo introgression in the selection of palatable mandarins. This work provides a new evolutionary framework for the genus Citrus.

10aAsia, Southeastern10aBiodiversity10acitrus10aCrop Production10aEvolution, Molecular10aGenetic Speciation10aGenome, Plant10aGenomics10aHaplotypes10aHeterozygote10aHistory, Ancient10aHuman Migration10aHybridization, Genetic10aPhylogeny1 aWu, Guohong, Albert1 aTerol, Javier1 aIbañez, Victoria1 aLópez-García, Antonio1 aPérez-Román, Estela1 aBorredá, Carles1 aDomingo, Concha1 aTadeo, Francisco, R1 aCarbonell-Caballero, José1 aAlonso, Roberto1 aCurk, Franck1 aDu, Dongliang1 aOllitrault, Patrick1 aRoose, Mikeal, L1 aDopazo, Joaquin1 aGmitter, Frederick, G1 aRokhsar, Daniel, S1 aTalon, Manuel uhttp://clinbioinfosspa.es/content/genomics-origin-and-evolution-citrus03412nas a2200793 4500008004100000022001400041245009300055210006900148260001500217300000900232490000600241520096600247653001201213653001401225653002301239653001801262653003601280653003001316653001101346653003101357653001101388653002401399653002101423653001201444653002801456653002501484653004101509653001601550653000901566653000901575653002301584653001501607653003901622653001701661653003001678653003401708100002801742700002201770700003201792700002901824700002601853700002601879700003101905700003301936700002201969700003101991700001902022700002002041700002002061700002202081700002002103700002302123700001602146700002302162700002302185700002302208700001902231700002502250700002902275700002102304700002502325700003202350700001602382700001802398700003802416700001702454700002402471856012302495 2018 eng d a2041-172300aLRH-1 agonism favours an immune-islet dialogue which protects against diabetes mellitus.0 aLRH1 agonism favours an immuneislet dialogue which protects agai c2018 04 16 a14880 v93 a

Type 1 diabetes mellitus (T1DM) is due to the selective destruction of islet beta cells by immune cells. Current therapies focused on repressing the immune attack or stimulating beta cell regeneration still have limited clinical efficacy. Therefore, it is timely to identify innovative targets to dampen the immune process, while promoting beta cell survival and function. Liver receptor homologue-1 (LRH-1) is a nuclear receptor that represses inflammation in digestive organs, and protects pancreatic islets against apoptosis. Here, we show that BL001, a small LRH-1 agonist, impedes hyperglycemia progression and the immune-dependent inflammation of pancreas in murine models of T1DM, and beta cell apoptosis in islets of type 2 diabetic patients, while increasing beta cell mass and insulin secretion. Thus, we suggest that LRH-1 agonism favors a dialogue between immune and islet cells, which could be druggable to protect against diabetes mellitus.

10aAnimals10aApoptosis10aCell Communication10aCell Survival10aDiabetes Mellitus, Experimental10aDiabetes Mellitus, Type 210aFemale10aGene Expression Regulation10aHumans10aHypoglycemic Agents10aImmunity, Innate10ainsulin10aInsulin-Secreting Cells10aIslets of Langerhans10aIslets of Langerhans Transplantation10aMacrophages10aMale10aMice10aMice, Inbred C57BL10aPhenalenes10aReceptors, Cytoplasmic and Nuclear10aStreptozocin10aT-Lymphocytes, Regulatory10aTransplantation, Heterologous1 aCobo-Vuilleumier, Nadia1 aLorenzo, Petra, I1 aRodríguez, Noelia, García1 aGómez, Irene, de Gracia1 aFuente-Martin, Esther1 aLópez-Noriega, Livia1 aMellado-Gil, José, Manuel1 aRomero-Zerbo, Silvana-Yanina1 aBaquié, Mathurin1 aLachaud, Christian, Claude1 aStifter, Katja1 aPerdomo, German1 aBugliani, Marco1 aDe Tata, Vincenzo1 aBosco, Domenico1 aParnaud, Geraldine1 aPozo, David1 aHmadcha, Abdelkrim1 aFlorido, Javier, P1 aToscano, Miguel, G1 ade Haan, Peter1 aSchoonjans, Kristina1 aPalazón, Luis, Sánchez1 aMarchetti, Piero1 aSchirmbeck, Reinhold1 aMartín-Montalvo, Alejandro1 aMeda, Paolo1 aSoria, Bernat1 aBermúdez-Silva, Francisco-Javier1 aSt-Onge, Luc1 aGauthier, Benoit, R uhttp://clinbioinfosspa.es/content/lrh-1-agonism-favours-immune-islet-dialogue-which-protects-against-diabetes-mellitus02234nas a2200277 4500008004100000022001400041245011400055210006900169260001500238300000700253490000700260520126600267653002601533653004301559653001101602653004201613653002401655653001801679653002401697100002201721700001901743700001801762700003101780700002001811856012501831 2018 eng d a1745-615000aModels of cell signaling uncover molecular mechanisms of high-risk neuroblastoma and predict disease outcome.0 aModels of cell signaling uncover molecular mechanisms of highris c2018 08 22 a160 v133 a

BACKGROUND: Despite the progress in neuroblastoma therapies the mortality of high-risk patients is still high (40-50%) and the molecular basis of the disease remains poorly known. Recently, a mathematical model was used to demonstrate that the network regulating stress signaling by the c-Jun N-terminal kinase pathway played a crucial role in survival of patients with neuroblastoma irrespective of their MYCN amplification status. This demonstrates the enormous potential of computational models of biological modules for the discovery of underlying molecular mechanisms of diseases.

RESULTS: Since signaling is known to be highly relevant in cancer, we have used a computational model of the whole cell signaling network to understand the molecular determinants of bad prognostic in neuroblastoma. Our model produced a comprehensive view of the molecular mechanisms of neuroblastoma tumorigenesis and progression.

CONCLUSION: We have also shown how the activity of signaling circuits can be considered a reliable model-based prognostic biomarker.

REVIEWERS: This article was reviewed by Tim Beissbarth, Wenzhong Xiao and Joanna Polanska. For the full reviews, please go to the Reviewers' comments section.

10aComputational Biology10aGene Expression Regulation, Neoplastic10aHumans10aJNK Mitogen-Activated Protein Kinases10aModels, Theoretical10aNeuroblastoma10aSignal Transduction1 aHidalgo, Marta, R1 aAmadoz, Alicia1 aCubuk, Cankut1 aCarbonell-Caballero, José1 aDopazo, Joaquin uhttp://clinbioinfosspa.es/content/models-cell-signaling-uncover-molecular-mechanisms-high-risk-neuroblastoma-and-predict02949nas a2200541 4500008004100000022001400041245008900055210006900144260000900213300001300222490000700235520138200242653001001624653000901634653001801643653001101661653002901672653003201701653002601733653001101759653001401770653002901784653000901813653001601822653001301838653002201851653001801873653001401891653002701905100002101932700003101953700002001984700002402004700002402028700002602052700001602078700001902094700001902113700002502132700002002157700001902177700002002196700002002216700002402236700002002260700001902280856010802299 2018 eng d a1932-620300aThe modular network structure of the mutational landscape of Acute Myeloid Leukemia.0 amodular network structure of the mutational landscape of Acute M c2018 ae02029260 v133 a

Acute myeloid leukemia (AML) is associated with the sequential accumulation of acquired genetic alterations. Although at diagnosis cytogenetic alterations are frequent in AML, roughly 50% of patients present an apparently normal karyotype (NK), leading to a highly heterogeneous prognosis. Due to this significant heterogeneity, it has been suggested that different molecular mechanisms may trigger the disease with diverse prognostic implications. We performed whole-exome sequencing (WES) of tumor-normal matched samples of de novo AML-NK patients lacking mutations in NPM1, CEBPA or FLT3-ITD to identify new gene mutations with potential prognostic and therapeutic relevance to patients with AML. Novel candidate-genes, together with others previously described, were targeted resequenced in an independent cohort of 100 de novo AML patients classified in the cytogenetic intermediate-risk (IR) category. A mean of 4.89 mutations per sample were detected in 73 genes, 35 of which were mutated in more than one patient. After a network enrichment analysis, we defined a single in silico model and established a set of seed-genes that may trigger leukemogenesis in patients with normal karyotype. The high heterogeneity of gene mutations observed in AML patients suggested that a specific alteration could not be as essential as the interaction of deregulated pathways.

10aAdult10aAged10aCytodiagnosis10aFemale10aGene Regulatory Networks10aGenetic Association Studies10aGenetic Heterogeneity10aHumans10aKaryotype10aLeukemia, Myeloid, Acute10aMale10aMiddle Aged10amutation10aNeoplasm Proteins10aNucleophosmin10aPrognosis10awhole exome sequencing1 aIbáñez, Mariam1 aCarbonell-Caballero, José1 aSuch, Esperanza1 aGarcía-Alonso, Luz1 aLiquori, Alessandro1 aLópez-Pavía, María1 aLLop, Marta1 aAlonso, Carmen1 aBarragán, Eva1 aGómez-Seguí, Inés1 aNeef, Alexander1 aHervás, David1 aMontesinos, Pau1 aSanz, Guillermo1 aSanz, Miguel, Angel1 aDopazo, Joaquin1 aCervera, José uhttp://clinbioinfosspa.es/content/modular-network-structure-mutational-landscape-acute-myeloid-leukemia02375nas a2200313 4500008004100000022001400041245011300055210006900168260001600237300000800253490000700261520133500268653001201603653002301615653003001638653004201668653001301710653002701723653001801750653002801768100002101796700002201817700002201839700002101861700002101882700002001903700001901923856011901942 2017 eng d a1471-210500aATGC transcriptomics: a web-based application to integrate, explore and analyze de novo transcriptomic data.0 aATGC transcriptomics a webbased application to integrate explore c2017 Feb 22 a1210 v183 a

BACKGROUND: In the last years, applications based on massively parallelized RNA sequencing (RNA-seq) have become valuable approaches for studying non-model species, e.g., without a fully sequenced genome. RNA-seq is a useful tool for detecting novel transcripts and genetic variations and for evaluating differential gene expression by digital measurements. The large and complex datasets resulting from functional genomic experiments represent a challenge in data processing, management, and analysis. This problem is especially significant for small research groups working with non-model species.

RESULTS: We developed a web-based application, called ATGC transcriptomics, with a flexible and adaptable interface that allows users to work with new generation sequencing (NGS) transcriptomic analysis results using an ontology-driven database. This new application simplifies data exploration, visualization, and integration for a better comprehension of the results.

CONCLUSIONS: ATGC transcriptomics provides access to non-expert computer users and small research groups to a scalable storage option and simple data integration, including database administration and management. The software is freely available under the terms of GNU public license at http://atgcinta.sourceforge.net .

10aAnimals10aDatabases, Genetic10aGene Expression Profiling10aHigh-Throughput Nucleotide Sequencing10aInternet10aSequence Analysis, RNA10aTranscriptome10aUser-Computer Interface1 aGonzalez, Sergio1 aClavijo, Bernardo1 aRivarola, Máximo1 aMoreno, Patricio1 aFernandez, Paula1 aDopazo, Joaquin1 aPaniego, Norma uhttp://clinbioinfosspa.es/content/atgc-transcriptomics-web-based-application-integrate-explore-and-analyze-de-novo02800nas a2200445 4500008004100000022001400041245015700055210006900212260001600281300001600297490000600313520134500319653001001664653002501674653002601699653002001725653003801745653001301783653001501796653001101811653001801822653001601840653001601856653001401872653003501886100003001921700002401951700002201975700002601997700002902023700002202052700002602074700002502100700002402125700002102149700002002170700001802190700001702208856012902225 2017 eng d a1949-255300aGenomic expression differences between cutaneous cells from red hair color individuals and black hair color individuals based on bioinformatic analysis.0 aGenomic expression differences between cutaneous cells from red  c2017 Feb 14 a11589-115990 v83 a

The MC1R gene plays a crucial role in pigmentation synthesis. Loss-of-function MC1R variants, which impair protein function, are associated with red hair color (RHC) phenotype and increased skin cancer risk. Cultured cutaneous cells bearing loss-of-function MC1R variants show a distinct gene expression profile compared to wild-type MC1R cultured cutaneous cells. We analysed the gene signature associated with RHC co-cultured melanocytes and keratinocytes by Protein-Protein interaction (PPI) network analysis to identify genes related with non-functional MC1R variants. From two detected networks, we selected 23 nodes as hub genes based on topological parameters. Differential expression of hub genes was then evaluated in healthy skin biopsies from RHC and black hair color (BHC) individuals. We also compared gene expression in melanoma tumors from individuals with RHC versus BHC. Gene expression in normal skin from RHC cutaneous cells showed dysregulation in 8 out of 23 hub genes (CLN3, ATG10, WIPI2, SNX2, GABARAPL2, YWHA, PCNA and GBAS). Hub genes did not differ between melanoma tumors in RHC versus BHC individuals. The study suggests that healthy skin cells from RHC individuals present a constitutive genomic deregulation associated with the red hair phenotype and identify novel genes involved in melanocyte biology.

10aAdult10aCoculture Techniques10aComputational Biology10agene expression10aGenetic Predisposition to Disease10aGenomics10aHair Color10aHumans10aKeratinocytes10aMelanocytes10aMiddle Aged10aPhenotype10aReceptor, Melanocortin, Type 11 aPuig-Butille, Joan, Anton1 aGimenez-Xavier, Pol1 aVisconti, Alessia1 aNsengimana, Jérémie1 aGarcia-Garcia, Francisco1 aTell-Marti, Gemma1 aEscamez, Maria, José1 aNewton-Bishop, Julia1 aBataille, Veronique1 aDel Rio, Marcela1 aDopazo, Joaquin1 aFalchi, Mario1 aPuig, Susana uhttp://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path%5B%5D=14140&path%5B%5D=4509401430nas a2200481 4500008004100000022001400041245007200055210006900127260001500196300001400211490000800225653000900233653002400242653003700266653003400303653001900337653001000356653002900366653001100395653002200406653002800428653001100456653001600467653001300483100002100496700002100517700002800538700002700566700002600593700002000619700002000639700002000659700002900679700002000708700002600728700002800754700002200782700002400804700002000828700002100848700002500869856005400894 2017 eng d a1533-440600aGGPS1 Mutation and Atypical Femoral Fractures with Bisphosphonates.0 aGGPS1 Mutation and Atypical Femoral Fractures with Bisphosphonat c2017 05 04 a1794-17950 v37610aAged10aAmino Acid Sequence10aBone Density Conservation Agents10aDimethylallyltranstransferase10aDiphosphonates10aExome10aFarnesyltranstransferase10aFemale10aFemoral Fractures10aGeranyltranstransferase10aHumans10aMiddle Aged10amutation1 aRoca-Ayats, Neus1 aBalcells, Susana1 aGarcia-Giralt, Natàlia1 aFalcó-Mascaró, Maite1 aMartínez-Gil, Núria1 aAbril, Josep, F1 aUrreizti, Roser1 aDopazo, Joaquin1 aQuesada-Gómez, José, M1 aNogués, Xavier1 aMellibovsky, Leonardo1 aPrieto-Alhambra, Daniel1 aDunford, James, E1 aJavaid, Muhammad, K1 aRussell, Graham1 aGrinberg, Daniel1 aDíez-Pérez, Adolfo uhttp://www.nejm.org/doi/full/10.1056/NEJMc161280402580nas a2200349 4500008004100000022001400041245014600055210006900201260001500270300001200285490000700297520142200304653001201726653001501738653002001753653002001773653003501793653003001828653002101858653002401879653002301903653001201926653001601938653001801954653002101972100002301993700002902016700002002045700001702065700001902082856012902101 2017 eng d a1460-219900aGlobal Transcriptome Analysis of Primary Cerebrocortical Cells: Identification of Genes Regulated by Triiodothyronine in Specific Cell Types.0 aGlobal Transcriptome Analysis of Primary Cerebrocortical Cells I c2017 01 01 a706-7170 v273 a

Thyroid hormones, thyroxine, and triiodothyronine (T3) are crucial for cerebral cortex development acting through regulation of gene expression. To define the transcriptional program under T3 regulation, we have performed RNA-Seq of T3-treated and untreated primary mouse cerebrocortical cells. The expression of 1145 genes or 7.7% of expressed genes was changed upon T3 addition, of which 371 responded to T3 in the presence of cycloheximide indicating direct transcriptional regulation. The results were compared with available transcriptomic datasets of defined cellular types. In this way, we could identify targets of T3 within genes enriched in astrocytes and neurons, in specific layers including the subplate, and in specific neurons such as prepronociceptin, cholecystokinin, or cortistatin neurons. The subplate and the prepronociceptin neurons appear as potentially major targets of T3 action. T3 upregulates mostly genes related to cell membrane events, such as G-protein signaling, neurotransmission, and ion transport and downregulates genes involved in nuclear events associated with the M phase of cell cycle, such as chromosome organization and segregation. Remarkably, the transcriptomic changes induced by T3 sustain the transition from fetal to adult patterns of gene expression. The results allow defining in molecular terms the elusive role of thyroid hormones on neocortical development.

10aAnimals10aAstrocytes10aCells, Cultured10aCerebral Cortex10aFluorescent Antibody Technique10aGene Expression Profiling10aMice, 129 Strain10aMice, Inbred BALB C10aMice, Inbred C57BL10aNeurons10aPiperazines10aTranscriptome10aTriiodothyronine1 aGil-Ibañez, Pilar1 aGarcia-Garcia, Francisco1 aDopazo, Joaquin1 aBernal, Juan1 aMorte, Beatriz uhttp://clinbioinfosspa.es/content/global-transcriptome-analysis-primary-cerebrocortical-cells-identification-genes-regulated03363nas a2200241 4500008004100000022001400041245008900055210006900144260001600213300000800229490000700237520258700244653002102831653001102852653002902863653002802892653001102920653002402931653001302955100002002968700001702988856011603005 2017 eng d a1752-050900aGraph-theoretical comparison of normal and tumor networks in identifying BRCA genes.0 aGraphtheoretical comparison of normal and tumor networks in iden c2017 Nov 22 a1100 v113 a

BACKGROUND: Identification of driver genes related to certain types of cancer is an important research topic. Several systems biology approaches have been suggested, in particular for the identification of breast cancer (BRCA) related genes. Such approaches usually rely on differential gene expression and/or mutational landscape data. In some cases interaction network data is also integrated to identify cancer-related modules computationally.

RESULTS: We provide a framework for the comparative graph-theoretical analysis of networks integrating the relevant gene expression, mutations, and potein-protein interaction network data. The comparisons involve a graph-theoretical analysis of normal and tumor network pairs across all instances of a given set of breast cancer samples. The network measures under consideration are based on appropriate formulations of various centrality measures: betweenness, clustering coefficients, degree centrality, random walk distances, graph-theoretical distances, and Jaccard index centrality.

CONCLUSIONS: Among all the studied centrality-based graph-theoretical properties, we show that a betweenness-based measure differentiates BRCA genes across all normal versus tumor network pairs, than the rest of the popular centrality-based measures. The AUROC and AUPR values of the gene lists ordered with respect to the measures under study as compared to NCBI BioSystems pathway and the COSMIC database of cancer genes are the largest with the betweenness-based differentiation, followed by the measure based on degree centrality. In order to test the robustness of the suggested measures in prioritizing cancer genes, we further tested the two most promising measures, those based on betweenness and degree centralities, on randomly rewired networks. We show that both measures are quite resilient to noise in the input interaction network. We also compared the same measures against a state-of-the-art alternative disease gene prioritization method, MUFFFINN. We show that both our graph-theoretical measures outperform MUFFINN prioritizations in terms of ROC and precions/recall analysis. Finally, we filter the ordered list of the best measure, the betweenness-based differentiation, via a maximum-weight independent set formulation and investigate the top 50 genes in regards to literature verification. We show that almost all genes in the list are verified by the breast cancer literature and three genes are presented as novel genes that may potentialy be BRCA-related but missing in literature.

10aBreast Neoplasms10aFemale10aGene Regulatory Networks10aGenes, Tumor Suppressor10aHumans10aModels, Theoretical10amutation1 aDopazo, Joaquin1 aErten, Cesim uhttp://clinbioinfosspa.es/content/graph-theoretical-comparison-normal-and-tumor-networks-identifying-brca-genes00523nas a2200121 4500008004100000245008800041210006900129260001600198490000700214100002000221700001700241856014300258 2017 eng d00aGraph-theoretical comparison of normal and tumor networks in identifying BRCA genes0 aGraphtheoretical comparison of normal and tumor networks in iden cJan-12-20170 v111 aDopazo, Joaquin1 aErten, Cesim uhttps://bmcsystbiol.biomedcentral.com/articles/10.1186/s12918-017-0495-0http://link.springer.com/content/pdf/10.1186/s12918-017-0495-0.pdf02298nas a2200361 4500008004100000022001400041245004600055210004400101260001500145300001400160490000700174520132500181653002201506653001801528653001101546653001301557653001301570653002801583100001801611700001701629700002101646700002301667700002301690700002201713700001601735700001701751700001901768700001801787700002001805700002001825700002001845856007101865 2017 eng d a1362-496200aHGVA: the Human Genome Variation Archive.0 aHGVA the Human Genome Variation Archive c2017 07 03 aW189-W1940 v453 a

High-profile genomic variation projects like the 1000 Genomes project or the Exome Aggregation Consortium, are generating a wealth of human genomic variation knowledge which can be used as an essential reference for identifying disease-causing genotypes. However, accessing these data, contrasting the various studies and integrating those data in downstream analyses remains cumbersome. The Human Genome Variation Archive (HGVA) tackles these challenges and facilitates access to genomic data for key reference projects in a clean, fast and integrated fashion. HGVA provides an efficient and intuitive web-interface for easy data mining, a comprehensive RESTful API and client libraries in Python, Java and JavaScript for fast programmatic access to its knowledge base. HGVA calculates population frequencies for these projects and enriches their data with variant annotation provided by CellBase, a rich and fast annotation solution. HGVA serves as a proof-of-concept of the genome analysis developments being carried out by the University of Cambridge together with UK's 100 000 genomes project and the National Institute for Health Research BioResource Rare-Diseases, in particular, deploying open-source for Computational Biology (OpenCB) software platform for storing and analyzing massive genomic datasets.

10aGenetic Variation10aGenome, Human10aHumans10aInternet10aSoftware10aUser-Computer Interface1 aLopez, Javier1 aColl, Jacobo1 aHaimel, Matthias1 aKandasamy, Swaathi1 aTárraga, Joaquín1 aFurio-Tari, Pedro1 aBari, Wasim1 aBleda, Marta1 aRueda, Antonio1 aGräf, Stefan1 aRendon, Augusto1 aDopazo, Joaquin1 aMedina, Ignacio uhttps://academic.oup.com/nar/article-lookup/doi/10.1093/nar/gkx44502043nas a2200313 4500008004100000022001400041245012900055210006900184260001600253300001400269490000600283520099600289653002601285653002001311653002901331653001101360653001301371653001401384653002301398653002701421653002401448100002201472700001801494700001901512700002401531700003101555700002001586856012301606 2017 eng d a1949-255300aHigh throughput estimation of functional cell activities reveals disease mechanisms and predicts relevant clinical outcomes.0 aHigh throughput estimation of functional cell activities reveals c2017 Jan 17 a5160-51780 v83 a

Understanding the aspects of the cell functionality that account for disease or drug action mechanisms is a main challenge for precision medicine. Here we propose a new method that models cell signaling using biological knowledge on signal transduction. The method recodes individual gene expression values (and/or gene mutations) into accurate measurements of changes in the activity of signaling circuits, which ultimately constitute high-throughput estimations of cell functionalities caused by gene activity within the pathway. Moreover, such estimations can be obtained either at cohort-level, in case/control comparisons, or personalized for individual patients. The accuracy of the method is demonstrated in an extensive analysis involving 5640 patients from 12 different cancer types. Circuit activity measurements not only have a high diagnostic value but also can be related to relevant disease outcomes such as survival, and can be used to assess therapeutic interventions.

10aComputational Biology10agene expression10aGene Regulatory Networks10aHumans10amutation10aNeoplasms10aPrecision Medicine10aSequence Analysis, RNA10aSignal Transduction1 aHidalgo, Marta, R1 aCubuk, Cankut1 aAmadoz, Alicia1 aSalavert, Francisco1 aCarbonell-Caballero, José1 aDopazo, Joaquin uhttp://clinbioinfosspa.es/content/high-throughput-estimation-functional-cell-activities-reveals-disease-mechanisms-and03008nas a2200433 4500008004100000022001400041245016000055210006900215260001300284300001200297490000700309520160000316653001601916653003801932653001501970653001701985653001902002653002702021653001502048653002602063653002602089653001002115100002402125700002402149700001902173700002002192700002202212700002102234700002202255700002902277700002002306700001802326700002002344700002402364700001902388700002102407700001902428856012702447 2017 eng d a1573-502800aIntegration of transcriptomic and metabolic data reveals hub transcription factors involved in drought stress response in sunflower (Helianthus annuus L.).0 aIntegration of transcriptomic and metabolic data reveals hub tra c2017 Jul a549-5640 v943 a

By integration of transcriptional and metabolic profiles we identified pathways and hubs transcription factors regulated during drought conditions in sunflower, useful for applications in molecular and/or biotechnological breeding. Drought is one of the most important environmental stresses that effects crop productivity in many agricultural regions. Sunflower is tolerant to drought conditions but the mechanisms involved in this tolerance remain unclear at the molecular level. The aim of this study was to characterize and integrate transcriptional and metabolic pathways related to drought stress in sunflower plants, by using a system biology approach. Our results showed a delay in plant senescence with an increase in the expression level of photosynthesis related genes as well as higher levels of sugars, osmoprotectant amino acids and ionic nutrients under drought conditions. In addition, we identified transcription factors that were upregulated during drought conditions and that may act as hubs in the transcriptional network. Many of these transcription factors belong to families implicated in the drought response in model species. The integration of transcriptomic and metabolomic data in this study, together with physiological measurements, has improved our understanding of the biological responses during droughts and contributes to elucidate the molecular mechanisms involved under this environmental condition. These findings will provide useful biotechnological tools to improve stress tolerance while maintaining crop yield under restricted water availability.

10aChlorophyll10aGene Expression Regulation, Plant10aHelianthus10aPlant Leaves10aPlant Proteins10aProtein Array Analysis10aRNA, Plant10aStress, Physiological10aTranscription Factors10aWater1 aMoschen, Sebastián1 aDi Rienzo, Julio, A1 aHiggins, Janet1 aTohge, Takayuki1 aWatanabe, Mutsumi1 aGonzalez, Sergio1 aRivarola, Máximo1 aGarcia-Garcia, Francisco1 aDopazo, Joaquin1 aHopp, Esteban1 aHoefgen, Rainer1 aFernie, Alisdair, R1 aPaniego, Norma1 aFernandez, Paula1 aHeinz, Ruth, A uhttp://clinbioinfosspa.es/content/integration-transcriptomic-and-metabolic-data-reveals-hub-transcription-factors-involved02560nas a2200541 4500008004100000022001400041245008600055210006900141260001200210300001200222490000700234520094000241653002801181653001201209653002801221653001001249653004201259653001301301653001101314653003101325653000901356653001301365653001401378653003301392653002801425100002201453700001701475700002501492700003201517700002201549700001801571700002101589700002001610700002401630700003401654700001901688700002001707700002901727700002501756700001901781700002001800700001901820700001801839700001701857700001901874700001901893856010601912 2017 eng d a1098-100400aMutations in TRAPPC11 are associated with a congenital disorder of glycosylation.0 aMutations in TRAPPC11 are associated with a congenital disorder  c2017 02 a148-1510 v383 a

Congenital disorders of glycosylation (CDG) are a heterogeneous and rapidly growing group of diseases caused by abnormal glycosylation of proteins and/or lipids. Mutations in genes involved in the homeostasis of the endoplasmic reticulum (ER), the Golgi apparatus (GA), and the vesicular trafficking from the ER to the ER-Golgi intermediate compartment (ERGIC) have been found to be associated with CDG. Here, we report a patient with defects in both N- and O-glycosylation combined with a delayed vesicular transport in the GA due to mutations in TRAPPC11, a subunit of the TRAPPIII complex. TRAPPIII is implicated in the anterograde transport from the ER to the ERGIC as well as in the vesicle export from the GA. This report expands the spectrum of genetic alterations associated with CDG, providing new insights for the diagnosis and the understanding of the physiopathological mechanisms underlying glycosylation disorders.

10aAbnormalities, Multiple10aAlleles10aAmino Acid Substitution10aBrain10aCongenital Disorders of Glycosylation10aGenotype10aHumans10aMagnetic Resonance Imaging10aMale10amutation10aPhenotype10aVesicular Transport Proteins10aWhole Genome Sequencing1 aMatalonga, Leslie1 aBravo, Miren1 aSerra-Peinado, Carla1 aGarcía-Pelegrí, Elisabeth1 aUgarteburu, Olatz1 aVidal, Silvia1 aLlambrich, Maria1 aQuintana, Ester1 aFuster-Jorge, Pedro1 aGonzalez-Bravo, Maria, Nieves1 aBeltran, Sergi1 aDopazo, Joaquin1 aGarcia-Garcia, Francisco1 aFoulquier, François1 aMatthijs, Gert1 aMills, Philippa1 aRibes, Antonia1 aEgea, Gustavo1 aBriones, Paz1 aTort, Frederic1 aGirós, Marisa uhttp://clinbioinfosspa.es/content/mutations-trappc11-are-associated-congenital-disorder-glycosylation01755nas a2200217 4500008004100000022001400041245008100055210006900136260001600205300000800221490000700229520109100236653001501327653000801342100002001350700002001370700002101390700002301411700002101434856008201455 2017 eng d a1471-210500aA new parallel pipeline for DNA methylation analysis of long reads datasets.0 anew parallel pipeline for DNA methylation analysis of long reads c2017 Mar 09 a1610 v183 aBACKGROUND: DNA methylation is an important mechanism of epigenetic regulation in development and disease. New generation sequencers allow genome-wide measurements of the methylation status by reading short stretches of the DNA sequence (Methyl-seq). Several software tools for methylation analysis have been proposed over recent years. However, the current trend is that the new sequencers and the ones expected for an upcoming future yield sequences of increasing length, making these software tools inefficient and obsolete. RESULTS: In this paper, we propose a new software based on a strategy for methylation analysis of Methyl-seq sequencing data that requires much shorter execution times while yielding a better level of sensitivity, particularly for datasets composed of long reads. This strategy can be exported to other methylation, DNA and RNA analysis tools. CONCLUSIONS: The developed software tool achieves execution times one order of magnitude shorter than the existing tools, while yielding equal sensitivity for short reads and even better sensitivity for long reads.10aMethyl-Seq10aNGS1 aOlanda, Ricardo1 aPérez, Mariano1 aOrduña, Juan, M1 aTárraga, Joaquín1 aDopazo, Joaquín uhttp://bmcbioinformatics.biomedcentral.com/articles/10.1186/s12859-017-1574-302685nas a2200349 4500008004100000022001400041245011500055210006900170260001600239300001400255490000700269520162000276653001201896653002201908653001101930653001301941653001301954653001101967653002401978653002002002653003102022653001302053100003102066700001902097700002002116700002202136700001802158700001802176700002802194700002002222856009302242 2017 eng d a1367-481100aReference genome assessment from a population scale perspective: an accurate profile of variability and noise.0 aReference genome assessment from a population scale perspective  c2017 Nov 15 a3511-35170 v333 a

Motivation: Current plant and animal genomic studies are often based on newly assembled genomes that have not been properly consolidated. In this scenario, misassembled regions can easily lead to false-positive findings. Despite quality control scores are included within genotyping protocols, they are usually employed to evaluate individual sample quality rather than reference sequence reliability. We propose a statistical model that combines quality control scores across samples in order to detect incongruent patterns at every genomic region. Our model is inherently robust since common artifact signals are expected to be shared between independent samples over misassembled regions of the genome.

Results: The reliability of our protocol has been extensively tested through different experiments and organisms with accurate results, improving state-of-the-art methods. Our analysis demonstrates synergistic relations between quality control scores and allelic variability estimators, that improve the detection of misassembled regions, and is able to find strong artifact signals even within the human reference assembly. Furthermore, we demonstrated how our model can be trained to properly rank the confidence of a set of candidate variants obtained from new independent samples.

Availability and implementation: This tool is freely available at http://gitlab.com/carbonell/ces.

Contact: jcarbonell.cipf@gmail.com or joaquin.dopazo@juntadeandalucia.es.

Supplementary information: Supplementary data are available at Bioinformatics online.

10aAnimals10aGenetic Variation10aGenome10aGenomics10aGenotype10aHumans10aModels, Statistical10aQuality Control10aReproducibility of Results10aSoftware1 aCarbonell-Caballero, José1 aAmadoz, Alicia1 aAlonso, Roberto1 aHidalgo, Marta, R1 aCubuk, Cankut1 aConesa, David1 aLópez-Quílez, Antonio1 aDopazo, Joaquin uhttps://academic.oup.com/bioinformatics/article-lookup/doi/10.1093/bioinformatics/btx48201955nas a2200325 4500008004100000022001400041245009200055210006900147260001600216300000800232490000700240520091900247653001801166653002001184653002001204653004201224653001101266653001301277653002801290653002201318100002101340700002301361700002301384700002201407700002401429700002001453700001901473700002001492856011701512 2017 eng d a1471-210500aVISMapper: ultra-fast exhaustive cartography of viral insertion sites for gene therapy.0 aVISMapper ultrafast exhaustive cartography of viral insertion si c2017 Sep 20 a4210 v183 a

BACKGROUND: The possibility of integrating viral vectors to become a persistent part of the host genome makes them a crucial element of clinical gene therapy. However, viral integration has associated risks, such as the unintentional activation of oncogenes that can result in cancer. Therefore, the analysis of integration sites of retroviral vectors is a crucial step in developing safer vectors for therapeutic use.

RESULTS: Here we present VISMapper, a vector integration site analysis web server, to analyze next-generation sequencing data for retroviral vector integration sites. VISMapper can be found at: http://vismapper.babelomics.org .

CONCLUSIONS: Because it uses novel mapping algorithms VISMapper is remarkably faster than previous available programs. It also provides a useful graphical interface to analyze the integration sites found in the genomic context.

10aBase Sequence10aGenetic Therapy10aGenetic Vectors10aHigh-Throughput Nucleotide Sequencing10aHumans10aInternet10aUser-Computer Interface10aVirus Integration1 aJuanes, José, M1 aGallego, Asunción1 aTárraga, Joaquín1 aChaves, Felipe, J1 aMarin-Garcia, Pablo1 aMedina, Ignacio1 aArnau, Vicente1 aDopazo, Joaquin uhttp://clinbioinfosspa.es/content/vismapper-ultra-fast-exhaustive-cartography-viral-insertion-sites-gene-therapy01877nas a2200577 4500008004100000245010800041210006900149260001600218490000700234100001900241700002000260700002300280700002600303700002500329700002200354700001700376700002200393700002700415700002000442700002300462700002000485700002300505700001900528700001800547700001800565700002400583700002300607700001800630700002200648700001600670700002600686700001800712700002300730700001700753700002200770700002300792700003500815700002900850700002400879700003100903700002800934700001800962700001900980700002500999700002601024700002301050700002101073700003401094700002701128856014401155 2017 eng d00aWhole exome sequencing coupled with unbiased functional analysis reveals new Hirschsprung disease genes0 aWhole exome sequencing coupled with unbiased functional analysis cJan-12-20170 v181 aGui, Hongsheng1 aSchriemer, Duco1 aCheng, William, W.1 aChauhan, Rajendra, K.1 aAntiňolo, Guillermo1 aBerrios, Courtney1 aBleda, Marta1 aBrooks, Alice, S.1 aBrouwer, Rutger, W. W.1 aBurns, Alan, J.1 aCherny, Stacey, S.1 aDopazo, Joaquin1 aEggen, Bart, J. L.1 aGriseri, Paola1 aJalloh, Binta1 aLe, Thuy-Linh1 aLui, Vincent, C. H.1 aLuzón-Toro, Berta1 aMatera, Ivana1 aNgan, Elly, S. W.1 aPelet, Anna1 aRuiz-Ferrer, Macarena1 aSham, Pak, C.1 aShepherd, Iain, T.1 aSo, Man-Ting1 aSribudiani, Yunia1 aTang, Clara, S. M.1 avan den Hout, Mirjam, C. G. N.1 avan der Linde, Herma, C.1 avan Ham, Tjakko, J.1 avan IJcken, Wilfred, F. J.1 aVerheij, Joke, B. G. M.1 aAmiel, Jeanne1 aBorrego, Salud1 aCeccherini, Isabella1 aChakravarti, Aravinda1 aLyonnet, Stanislas1 aTam, Paul, K. H.1 aGarcia-Barceló, Maria-Mercè1 aHofstra, Robert, M. W. uhttp://genomebiology.biomedcentral.com/articles/10.1186/s13059-017-1174-6http://link.springer.com/content/pdf/10.1186/s13059-017-1174-6.pdf03542nas a2200649 4500008004100000022001400041245010900055210006900164260001600233300000700249490000700256520162800263653001601891653001701907653000801924100001901932700002001951700002201971700002501993700002502018700002202043700001702065700002102082700002502103700001902128700002202147700002002169700002102189700001902210700001802229700001802247700002202265700002302287700001802310700002002328700001602348700002602364700001702390700002202407700001702429700002202446700002102468700003202489700002802521700002302549700002902572700002502601700001802626700001902644700002502663700002602688700002302714700001902737700003402756700002402790856007802814 2017 eng d a1474-760X00aWhole exome sequencing coupled with unbiased functional analysis reveals new Hirschsprung disease genes.0 aWhole exome sequencing coupled with unbiased functional analysis c2017 Mar 08 a480 v183 aBACKGROUND: Hirschsprung disease (HSCR), which is congenital obstruction of the bowel, results from a failure of enteric nervous system (ENS) progenitors to migrate, proliferate, differentiate, or survive within the distal intestine. Previous studies that have searched for genes underlying HSCR have focused on ENS-related pathways and genes not fitting the current knowledge have thus often been ignored. We identify and validate novel HSCR genes using whole exome sequencing (WES), burden tests, in silico prediction, unbiased in vivo analyses of the mutated genes in zebrafish, and expression analyses in zebrafish, mouse, and human. RESULTS: We performed de novo mutation (DNM) screening on 24 HSCR trios. We identify 28 DNMs in 21 different genes. Eight of the DNMs we identified occur in RET, the main HSCR gene, and the remaining 20 DNMs reside in genes not reported in the ENS. Knockdown of all 12 genes with missense or loss-of-function DNMs showed that the orthologs of four genes (DENND3, NCLN, NUP98, and TBATA) are indispensable for ENS development in zebrafish, and these results were confirmed by CRISPR knockout. These genes are also expressed in human and mouse gut and/or ENS progenitors. Importantly, the encoded proteins are linked to neuronal processes shared by the central nervous system and the ENS. CONCLUSIONS: Our data open new fields of investigation into HSCR pathology and provide novel insights into the development of the ENS. Moreover, the study demonstrates that functional analyses of genes carrying DNMs are warranted to delineate the full genetic architecture of rare complex diseases.10aHirschprung10aRare Disease10aWES1 aGui, Hongsheng1 aSchriemer, Duco1 aCheng, William, W1 aChauhan, Rajendra, K1 aAntiňolo, Guillermo1 aBerrios, Courtney1 aBleda, Marta1 aBrooks, Alice, S1 aBrouwer, Rutger, W W1 aBurns, Alan, J1 aCherny, Stacey, S1 aDopazo, Joaquin1 aEggen, Bart, J L1 aGriseri, Paola1 aJalloh, Binta1 aLe, Thuy-Linh1 aLui, Vincent, C H1 aLuzón-Toro, Berta1 aMatera, Ivana1 aNgan, Elly, S W1 aPelet, Anna1 aRuiz-Ferrer, Macarena1 aSham, Pak, C1 aShepherd, Iain, T1 aSo, Man-Ting1 aSribudiani, Yunia1 aTang, Clara, S M1 avan den Hout, Mirjam, C G N1 avan der Linde, Herma, C1 avan Ham, Tjakko, J1 avan IJcken, Wilfred, F J1 aVerheij, Joke, B G M1 aAmiel, Jeanne1 aBorrego, Salud1 aCeccherini, Isabella1 aChakravarti, Aravinda1 aLyonnet, Stanislas1 aTam, Paul, K H1 aGarcia-Barceló, Maria-Mercè1 aHofstra, Robert, Mw uhttp://genomebiology.biomedcentral.com/articles/10.1186/s13059-017-1174-603274nas a2200469 4500008004100000022001400041245010000055210006900155260001600224520184400240653001202084653000802096653001802104653002402122653001902146653000802165100002102173700001902194700001702213700002402230700002302254700002902277700002302306700002302329700002102352700001902373700002202392700003302414700002302447700001602470700002602486700002802512700002002540700002002560700002702580700002002607700002702627700001902654700002702673700002502700856007902725 2016 eng d a1537-171900a267 Spanish exomes reveal population-specific differences in disease-related genetic variation.0 a267 Spanish exomes reveal populationspecific differences in dise c2016 Jan 133 aRecent results from large-scale genomic projects suggest that allele frequencies, which are highly relevant for medical purposes, differ considerably across different populations. The need for a detailed catalogue of local variability motivated the whole exome sequencing of 267 unrelated individuals, representative of the healthy Spanish population. Like in other studies, a considerable number of rare variants were found (almost one third of the described variants). There were also relevant differences in allelic frequencies in polymorphic variants, including about 10,000 polymorphisms private to the Spanish population. The allelic frequencies of variants conferring susceptibility to complex diseases (including cancer, schizophrenia, Alzheimer disease, type 2 diabetes and other pathologies) were overall similar to those of other populations. However, the trend is the opposite for variants linked to Mendelian and rare diseases (including several retinal degenerative dystrophies and cardiomyopathies) that show marked frequency differences between populations. Interestingly, a correspondence between differences in allelic frequencies and disease prevalence was found, highlighting the relevance of frequency differences in disease risk. These differences are also observed in variants that disrupt known drug binding sites, suggesting an important role for local variability in population-specific drug resistances or adverse effects. We have made the Spanish population variant server web page that contains population frequency information for the complete list of 170,888 variant positions we found publicly available (http://spv.babelomics.org/), We show that it if fundamental to determine population-specific variant frequencies in order to distinguish real disease associations from population-specific polymorphisms.10adisease10aNGS10apolymorphisms10aPopulation genomics10aprioritization10aSNP1 aDopazo, Joaquín1 aAmadoz, Alicia1 aBleda, Marta1 aGarcía-Alonso, Luz1 aAlemán, Alejandro1 aGarcia-Garcia, Francisco1 aRodriguez, Juan, A1 aDaub, Josephine, T1 aMuntané, Gerard1 aRueda, Antonio1 aVela-Boza, Alicia1 aLópez-Domingo, Francisco, J1 aFlorido, Javier, P1 aArce, Pablo1 aRuiz-Ferrer, Macarena1 aMéndez-Vidal, Cristina1 aArnold, Todd, E1 aSpleiss, Olivia1 aAlvarez-Tejado, Miguel1 aNavarro, Arcadi1 aBhattacharya, Shomi, S1 aBorrego, Salud1 aSantoyo-López, Javier1 aAntiňolo, Guillermo uhttps://mbe.oxfordjournals.org/content/early/2016/02/17/molbev.msw005.full01971nas a2200301 4500008004100000022001400041245010200055210006900157260001500226520100600241653002101247653002201268653002601290653001901316653002101335653002601356653001501382653002401397100002401421700002101445700001901466700001801485700002001503700001901523700003101542700002101573856007501594 2016 eng d a1362-496200aActionable pathways: interactive discovery of therapeutic targets using signaling pathway models.0 aActionable pathways interactive discovery of therapeutic targets c2016 May 23 aThe discovery of actionable targets is crucial for targeted therapies and is also a constituent part of the drug discovery process. The success of an intervention over a target depends critically on its contribution, within the complex network of gene interactions, to the cellular processes responsible for disease progression or therapeutic response. Here we present PathAct, a web server that predicts the effect that interventions over genes (inhibitions or activations that simulate knock-outs, drug treatments or over-expressions) can have over signal transmission within signaling pathways and, ultimately, over the cell functionalities triggered by them. PathAct implements an advanced graphical interface that provides a unique interactive working environment in which the suitability of potentially actionable genes, that could eventually become drug targets for personalized or individualized therapies, can be easily tested. The PathAct tool can be found at: http://pathact.babelomics.org.10aactionable genes10aDisease mechanism10adrug action mechanism10aDrug discovery10apathway analysis10apersonalized medicine10asignalling10atherapeutic targets1 aSalavert, Francisco1 aHidago, Marta, R1 aAmadoz, Alicia1 aCubuk, Cankut1 aMedina, Ignacio1 aCrespo, Daniel1 aCarbonell-Caballero, José1 aDopazo, Joaquín uhttp://nar.oxfordjournals.org/content/early/2016/05/02/nar.gkw369.full02635nas a2200361 4500008004100000022001400041245014600055210006900201260001500270520148500285653002401770653000801794653001501802653000801817653001101825653001801836653002601854100001901880700002901899700001801928700002001946700002401966700002401990700002102014700001902035700002102054700003102075700003202106700002302138700002002161700002102181856007102202 2016 eng d a1943-781100aAssessment of Targeted Next-Generation Sequencing as a Tool for the Diagnosis of Charcot-Marie-Tooth Disease and Hereditary Motor Neuropathy.0 aAssessment of Targeted NextGeneration Sequencing as a Tool for t c2016 Jan 23 aCharcot-Marie-Tooth disease is characterized by broad genetic heterogeneity with >50 known disease-associated genes. Mutations in some of these genes can cause a pure motor form of hereditary motor neuropathy, the genetics of which are poorly characterized. We designed a panel comprising 56 genes associated with Charcot-Marie-Tooth disease/hereditary motor neuropathy. We validated this diagnostic tool by first testing 11 patients with pathological mutations. A cohort of 33 affected subjects was selected for this study. The DNAJB2 c.352+1G>A mutation was detected in two cases; novel changes and/or variants with low frequency (<1%) were found in 12 cases. There were no candidate variants in 18 cases, and amplification failed for one sample. The DNAJB2 c.352+1G>A mutation was also detected in three additional families. On haplotype analysis, all of the patients from these five families shared the same haplotype; therefore, the DNAJB2 c.352+1G>A mutation may be a founder event. Our gene panel allowed us to perform a very rapid and cost-effective screening of genes involved in Charcot-Marie-Tooth disease/hereditary motor neuropathy. Our diagnostic strategy was robust in terms of both coverage and read depth for all of the genes and patient samples. These findings demonstrate the difficulty in achieving a definitive molecular diagnosis because of the complexity of interpreting new variants and the genetic heterogeneity that is associated with these neuropathies.10aCharcot-Marie-Tooth10aCMT10aDiagnostic10aNGS10aPanels10arare diseases10aTargeted resequencing1 aLupo, Vincenzo1 aGarcia-Garcia, Francisco1 aSancho, Paula1 aTello, Cristina1 aGarcía-Romero, Mar1 aVillarreal, Liliana1 aAlberti, Antonia1 aSivera, Rafael1 aDopazo, Joaquín1 aPascual-Pascual, Samuel, I1 aMárquez-Infante, Celedonio1 aCasasnovas, Carlos1 aSevilla, Teresa1 aEspinós, Carmen uhttp://www.sciencedirect.com/science/article/pii/S152515781500261502634nas a2200289 4500008004100000022001400041245015800055210006900213260001500282300000900297520167800306653001901984653001202003653000902015653000902024653002302033653001202056653002102068100002302089700001802112700003002130700002302160700002002183700002402203700002902227856008802256 2016 eng d a1607-888800aChronic subordination stress selectively downregulates the insulin signaling pathway in liver and skeletal muscle but not in adipose tissue of male mice.0 aChronic subordination stress selectively downregulates the insul c2016 Mar 7 a1-113 aChronic stress has been associated with obesity, glucose intolerance, and insulin resistance. We developed a model of chronic psychosocial stress (CPS) in which subordinate mice are vulnerable to obesity and the metabolic-like syndrome while dominant mice exhibit a healthy metabolic phenotype. Here we tested the hypothesis that the metabolic difference between subordinate and dominant mice is associated with changes in functional pathways relevant for insulin sensitivity, glucose and lipid homeostasis. Male mice were exposed to CPS for four weeks and fed either a standard diet or a high-fat diet (HFD). We first measured, by real-time PCR candidate genes, in the liver, skeletal muscle, and the perigonadal white adipose tissue (pWAT). Subsequently, we used a probabilistic analysis approach to analyze different ways in which signals can be transmitted across the pathways in each tissue. Results showed that subordinate mice displayed a drastic downregulation of the insulin pathway in liver and muscle, indicative of insulin resistance, already on standard diet. Conversely, pWAT showed molecular changes suggestive of facilitated fat deposition in an otherwise insulin-sensitive tissue. The molecular changes in subordinate mice fed a standard diet were greater compared to HFD-fed controls. Finally, dominant mice maintained a substantially normal metabolic and molecular phenotype even when fed a HFD. Overall, our data demonstrate that subordination stress is a potent stimulus for the downregulation of the insulin signaling pathway in liver and muscle and a major risk factor for the development of obesity, insulin resistance, and type 2 diabetes mellitus.10aAdipose tissue10ainsulin10aIRS110aIRS210ametabolic syndrome10aobesity10apathway analysis1 aSanghez, Valentina1 aCubuk, Cankut1 aSebastián-Leon, Patricia1 aCarobbio, Stefania1 aDopazo, Joaquin1 aVidal-Puig, Antonio1 aBartolomucci, Alessandro uhttp://www.tandfonline.com/doi/abs/10.3109/10253890.2016.1151491?journalCode=ists2002237nas a2200409 4500008004100000022001400041245006800055210006700123260001300190300001400203490000700217520102100224653001201245653002701257653002701284653001501311653001301326653003001339653000901369653002701378653001201405653002601417653002701443653002601470100001901496700001801515700002001533700002901553700001601582700001501598700002701613700002001640700002001660700002701680700001901707856010101726 2016 eng d a1551-400500aDysfunctional mitochondrial fission impairs cell reprogramming.0 aDysfunctional mitochondrial fission impairs cell reprogramming c2016 Dec a3240-32500 v153 a

We have recently shown that mitochondrial fission is induced early in reprogramming in a Drp1-dependent manner; however, the identity of the factors controlling Drp1 recruitment to mitochondria was unexplored. To investigate this, we used a panel of RNAi targeting factors involved in the regulation of mitochondrial dynamics and we observed that MiD51, Gdap1 and, to a lesser extent, Mff were found to play key roles in this process. Cells derived from Gdap1-null mice were used to further explore the role of this factor in cell reprogramming. Microarray data revealed a prominent down-regulation of cell cycle pathways in Gdap1-null cells early in reprogramming and cell cycle profiling uncovered a G2/M growth arrest in Gdap1-null cells undergoing reprogramming. High-Content analysis showed that this growth arrest was DNA damage-independent. We propose that lack of efficient mitochondrial fission impairs cell reprogramming by interfering with cell cycle progression in a DNA damage-independent manner.

10aAnimals10aCell Cycle Checkpoints10aCellular Reprogramming10aDNA Damage10aG2 Phase10aGene Knockdown Techniques10aMice10aMitochondrial Dynamics10aMitosis10aNerve Tissue Proteins10aPluripotent Stem Cells10aTranscription Factors1 aPrieto, Javier1 aLeón, Marian1 aPonsoda, Xavier1 aGarcia-Garcia, Francisco1 aBort, Roque1 aSerna, Eva1 aBarneo-Muñoz, Manuela1 aPalau, Francesc1 aDopazo, Joaquin1 aLópez-García, Carlos1 aTorres, Josema uhttp://clinbioinfosspa.es/content/dysfunctional-mitochondrial-fission-impairs-cell-reprogramming02094nas a2200349 4500008004100000022001400041245011200055210006900167260000900236300001000245490000600255520101800261100002001279700003401299700002701333700002701360700002201387700002301409700002401432700002101456700001901477700002001496700002301516700002201539700001901561700003301580700002001613700002301633700002001656700002101676856004701697 2016 eng d a2041-172300aExtension of human lncRNA transcripts by RACE coupled with long-read high-throughput sequencing (RACE-Seq).0 aExtension of human lncRNA transcripts by RACE coupled with longr c2016 a123390 v73 aLong non-coding RNAs (lncRNAs) constitute a large, yet mostly uncharacterized fraction of the mammalian transcriptome. Such characterization requires a comprehensive, high-quality annotation of their gene structure and boundaries, which is currently lacking. Here we describe RACE-Seq, an experimental workflow designed to address this based on RACE (rapid amplification of cDNA ends) and long-read RNA sequencing. We apply RACE-Seq to 398 human lncRNA genes in seven tissues, leading to the discovery of 2,556 on-target, novel transcripts. About 60% of the targeted loci are extended in either 5’ or 3’, often reaching genomic hallmarks of gene boundaries. Analysis of the novel transcripts suggests that lncRNAs are as long, have as many exons and undergo as much alternative splicing as protein-coding genes, contrary to current assumptions. Overall, we show that RACE-Seq is an effective tool to annotate an organism’s deep transcriptome, and compares favourably to other targeted sequencing techniques.1 aLagarde, Julien1 aUszczynska-Ratajczak, Barbara1 aSantoyo-López, Javier1 aGonzalez, Jose, Manuel1 aTapanari, Electra1 aMudge, Jonathan, M1 aSteward, Charles, A1 aWilming, Laurens1 aTanzer, Andrea1 aHowald, Cédric1 aChrast, Jacqueline1 aVela-Boza, Alicia1 aRueda, Antonio1 aLópez-Domingo, Francisco, J1 aDopazo, Joaquin1 aReymond, Alexandre1 aGuigó, Roderic1 aHarrow, Jennifer uhttp://www.nature.com/articles/ncomms1233901158nas a2200313 4500008004100000245011100041210006900152260001600221490000600237100002000243700003400263700002700297700002700324700002200351700002400373700002500397700002100422700001900443700002000462700002300482700002200505700001900527700003300546700002000579700002300599700002000622700002100642856018100663 2016 eng d00aExtension of human lncRNA transcripts by RACE coupled with long-read high-throughput sequencing (RACE-Seq)0 aExtension of human lncRNA transcripts by RACE coupled with longr cJan-11-20160 v71 aLagarde, Julien1 aUszczynska-Ratajczak, Barbara1 aSantoyo-López, Javier1 aGonzalez, Jose, Manuel1 aTapanari, Electra1 aMudge, Jonathan, M.1 aSteward, Charles, A.1 aWilming, Laurens1 aTanzer, Andrea1 aHowald, Cédric1 aChrast, Jacqueline1 aVela-Boza, Alicia1 aRueda, Antonio1 aLopez-Domingo, Francisco, J.1 aDopazo, Joaquin1 aReymond, Alexandre1 aGuigó, Roderic1 aHarrow, Jennifer uhttp://www.nature.com/articles/ncomms12339http://www.nature.com/articles/ncomms12339.pdfhttp://www.nature.com/articles/ncomms12339.pdfhttp://www.nature.com/articles/ncomms1233901693nas a2200337 4500008004100000022001400041245007000055210006800125260001300193300001100206490000700217520067800224653001300902653004200915653001100957653003200968653002701000653001801027100001401045700001601059700001701075700001801092700001901110700001601129700002301145700002301168700002601191700002501217700001401242856009901256 2016 eng d a1756-166300aHighly sensitive and ultrafast read mapping for RNA-seq analysis.0 aHighly sensitive and ultrafast read mapping for RNAseq analysis c2016 Apr a93-1000 v233 a

As sequencing technologies progress, the amount of data produced grows exponentially, shifting the bottleneck of discovery towards the data analysis phase. In particular, currently available mapping solutions for RNA-seq leave room for improvement in terms of sensitivity and performance, hindering an efficient analysis of transcriptomes by massive sequencing. Here, we present an innovative approach that combines re-engineering, optimization and parallelization. This solution results in a significant increase of mapping sensitivity over a wide range of read lengths and substantial shorter runtimes when compared with current RNA-seq mapping methods available.

10aGenomics10aHigh-Throughput Nucleotide Sequencing10aHumans10aSensitivity and Specificity10aSequence Analysis, RNA10aTranscriptome1 aMedina, I1 aTárraga, J1 aMartínez, H1 aBarrachina, S1 aCastillo, M, I1 aPaschall, J1 aSalavert-Torres, J1 aBlanquer-Espert, I1 aHernández-García, V1 aQuintana-Ortí, E, S1 aDopazo, J uhttp://clinbioinfosspa.es/content/highly-sensitive-and-ultrafast-read-mapping-rna-seq-analysis01901nas a2200241 4500008004100000022001400041245008000055210006900135260000900204300000800213490000700221520123600228653001101464653000801475653001301483653000801496100002301504700002301527700001901550700002001569700002001589856005001609 2016 eng d a1471-210500aHPG pore: an efficient and scalable framework for nanopore sequencing data.0 aHPG pore an efficient and scalable framework for nanopore sequen c2016 a1070 v173 aBACKGROUND: The use of nanopore technologies is expected to spread in the future because they are portable and can sequence long fragments of DNA molecules without prior amplification. The first nanopore sequencer available, the MinION™ from Oxford Nanopore Technologies, is a USB-connected, portable device that allows real-time DNA analysis. In addition, other new instruments are expected to be released soon, which promise to outperform the current short-read technologies in terms of throughput. Despite the flood of data expected from this technology, the data analysis solutions currently available are only designed to manage small projects and are not scalable. RESULTS: Here we present HPG Pore, a toolkit for exploring and analysing nanopore sequencing data. HPG Pore can run on both individual computers and in the Hadoop distributed computing framework, which allows easy scale-up to manage the large amounts of data expected to result from extensive use of nanopore technologies in the future. CONCLUSIONS: HPG Pore allows for virtually unlimited sequencing data scalability, thus guaranteeing its continued management in near future scenarios. HPG Pore is available in GitHub at http://github.com/opencb/hpg-pore .10ahadoop10aHPC10ananopore10aNGS1 aTárraga, Joaquín1 aGallego, Asunción1 aArnau, Vicente1 aMedina, Ignacio1 aDopazo, Joaquin uhttp://www.biomedcentral.com/1471-2105/17/10700587nas a2200157 4500008004100000245007900041210006900120260001600189490000700205100002300212700002300235700001900258700002000277700002000297856011200317 2016 eng d00aHPG pore: an efficient and scalable framework for nanopore sequencing data0 aHPG pore an efficient and scalable framework for nanopore sequen cJan-12-20160 v171 aTárraga, Joaquín1 aGallego, Asunción1 aArnau, Vicente1 aMedina, Ignacio1 aDopazo, Joaquin uhttp://www.biomedcentral.com/1471-2105/17/107http://link.springer.com/content/pdf/10.1186/s12859-016-0966-002494nas a2200505 4500008004100000022001400041245008800055210006900143260001600212300000900228490000600237520111400243653001001357653000901367653002201376653002001398653001601418653001101434653001101445653000901456653001601465653003101481653002201512653002601534100002201560700001201582700001301594700001301607700001401620700002301634700001801657700001701675700002301692700002001715700002001735700001401755700001401769700001301783700001601796700001201812700001401824700001601838700001601854856011801870 2016 eng d a2158-318800aHuman DNA methylomes of neurodegenerative diseases show common epigenomic patterns.0 aHuman DNA methylomes of neurodegenerative diseases show common e c2016 Jan 19 ae7180 v63 a

Different neurodegenerative disorders often show similar lesions, such as the presence of amyloid plaques, TAU-neurotangles and synuclein inclusions. The genetically inherited forms are rare, so we wondered whether shared epigenetic aberrations, such as those affecting DNA methylation, might also exist. The studied samples were gray matter samples from the prefrontal cortex of control and neurodegenerative disease-associated cases. We performed the DNA methylation analyses of Alzheimer's disease, dementia with Lewy bodies, Parkinson's disease and Alzheimer-like neurodegenerative profile associated with Down's syndrome samples. The DNA methylation landscapes obtained show that neurodegenerative diseases share similar aberrant CpG methylation shifts targeting a defined gene set. Our findings suggest that neurodegenerative disorders might have similar pathogenetic mechanisms that subsequently evolve into different clinical entities. The identified aberrant DNA methylation changes can be used as biomarkers of the disorders and as potential new targets for the development of new therapies.

10aAdult10aAged10aAged, 80 and over10aDNA Methylation10aEpigenomics10aFemale10aHumans10aMale10aMiddle Aged10aneurodegenerative diseases10aPrefrontal Cortex10aTissue Array Analysis1 aSanchez-Mut, J, V1 aHeyn, H1 aVidal, E1 aMoran, S1 aSayols, S1 aDelgado-Morales, R1 aSchultz, M, D1 aAnsoleaga, B1 aGarcia-Esparcia, P1 aPons-Espinal, M1 ade Lagran, M, M1 aDopazo, J1 aRabano, A1 aAvila, J1 aDierssen, M1 aLott, I1 aFerrer, I1 aEcker, J, R1 aEsteller, M uhttp://clinbioinfosspa.es/content/human-dna-methylomes-neurodegenerative-diseases-show-common-epigenomic-patterns03221nas a2200697 4500008004100000022001400041245013600055210006900191260001500260300001000275490000600285520117300291653000901464653001201473653002601485653002001511653001901531653003801550653001801588653002801606653001001634653001701644653001101661653003101672653002101703653002501724653001501749653001101764653000901775653000901784653001601793653003601809653003201845653001101877653002401888653003601912653002501948653001001973653002101983653002602004100001402030700002402044700001602068700001602084700001702100700002402117700002702141700002402168700002102192700001302213700002302226700001402249700002702263700002002290700002302310700001402333700002402347700001402371700001302385856012502398 2016 eng d a2045-232200aIdentification of the Photoreceptor Transcriptional Co-Repressor SAMD11 as Novel Cause of Autosomal Recessive Retinitis Pigmentosa.0 aIdentification of the Photoreceptor Transcriptional CoRepressor  c2016 10 13 a353700 v63 a

Retinitis pigmentosa (RP), the most frequent form of inherited retinal dystrophy is characterized by progressive photoreceptor degeneration. Many genes have been implicated in RP development, but several others remain to be identified. Using a combination of homozygosity mapping, whole-exome and targeted next-generation sequencing, we found a novel homozygous nonsense mutation in SAMD11 in five individuals diagnosed with adult-onset RP from two unrelated consanguineous Spanish families. SAMD11 is ortholog to the mouse major retinal SAM domain (mr-s) protein that is implicated in CRX-mediated transcriptional regulation in the retina. Accordingly, protein-protein network analysis revealed a significant interaction of SAMD11 with CRX. Immunoblotting analysis confirmed strong expression of SAMD11 in human retina. Immunolocalization studies revealed SAMD11 was detected in the three nuclear layers of the human retina and interestingly differential expression between cone and rod photoreceptors was observed. Our study strongly implicates SAMD11 as novel cause of RP playing an important role in the pathogenesis of human degeneration of photoreceptors.

10aAged10aAnimals10aCo-Repressor Proteins10aCodon, Nonsense10aCohort Studies10aComparative Genomic Hybridization10aConsanguinity10aDNA Mutational Analysis10aExome10aEye Proteins10aFemale10aGene Expression Regulation10aGenes, Recessive10aHomeodomain Proteins10aHomozygote10aHumans10aMale10aMice10aMiddle Aged10aPolymorphism, Single Nucleotide10aProtein Interaction Mapping10aRetina10aRetinal Dystrophies10aRetinal Rod Photoreceptor Cells10aRetinitis pigmentosa10aSpain10aTrans-Activators10aTranscription Factors1 aCorton, M1 aAvila-Fernández, A1 aCampello, L1 aSánchez, M1 aBenavides, B1 aLópez-Molina, M, I1 aFernández-Sánchez, L1 aSánchez-Alcudia, R1 ada Silva, L, R J1 aReyes, N1 aMartín-Garrido, E1 aZurita, O1 aSan José, Fernández-1 aPérez-Carro, R1 aGarcía-García, F1 aDopazo, J1 aGarcía-Sandoval, B1 aCuenca, N1 aAyuso, C uhttp://clinbioinfosspa.es/content/identification-photoreceptor-transcriptional-co-repressor-samd11-novel-cause-autosomal02756nas a2200397 4500008004100000022001400041245012200055210006900177260001600246300001000262490000600272520143100278653001201709653002401721653003101745653002801776653001701804653001701821653003201838653002601870653002001896653004201916653001101958653001301969653001401982653002401996100002302020700002802043700002502071700003302096700003602129700002002165700001902185700002502204856012902229 2016 eng d a2045-232200aImproving the management of Inherited Retinal Dystrophies by targeted sequencing of a population-specific gene panel.0 aImproving the management of Inherited Retinal Dystrophies by tar c2016 Apr 01 a239100 v63 a

Next-generation sequencing (NGS) has overcome important limitations to the molecular diagnosis of Inherited Retinal Dystrophies (IRD) such as the high clinical and genetic heterogeneity and the overlapping phenotypes. The purpose of this study was the identification of the genetic defect in 32 Spanish families with different forms of IRD. With that aim, we implemented a custom NGS panel comprising 64 IRD-associated genes in our population, and three disease-associated intronic regions. A total of 37 pathogenic mutations (14 novels) were found in 73% of IRD patients ranging from 50% for autosomal dominant cases, 75% for syndromic cases, 83% for autosomal recessive cases, and 100% for X-linked cases. Additionally, unexpected phenotype-genotype correlations were found in 6 probands, which led to the refinement of their clinical diagnoses. Furthermore, intra- and interfamilial phenotypic variability was observed in two cases. Moreover, two cases unsuccessfully analysed by exome sequencing were resolved by applying this panel. Our results demonstrate that this hypothesis-free approach based on frequently mutated, population-specific loci is highly cost-efficient for the routine diagnosis of this heterogeneous condition and allows the unbiased analysis of a miscellaneous cohort. The molecular information found here has aid clinical diagnosis and has improved genetic counselling and patient management.

10aAlleles10aComputer Simulation10aDNA Copy Number Variations10aDNA Mutational Analysis10aEye Proteins10aGene Library10aGenetic Association Studies10aGenetic Heterogeneity10aGenetic Therapy10aHigh-Throughput Nucleotide Sequencing10aHumans10amutation10aPhenotype10aRetinal Dystrophies1 aBravo-Gil, Nereida1 aMéndez-Vidal, Cristina1 aRomero-Pérez, Laura1 adel Pozo, María, González-1 ade la Rúa, Enrique, Rodríguez1 aDopazo, Joaquin1 aBorrego, Salud1 aAntiňolo, Guillermo uhttp://clinbioinfosspa.es/content/improving-management-inherited-retinal-dystrophies-targeted-sequencing-population-specific02429nas a2200289 4500008004100000022001400041245005500055210005400110260001500164300001200179490000700191520155100198653002601749653003001775653001801805653002901823653004201852653001101894653001401905653001401919653003101933100002901964700002201993700002002015700002002035856008402055 2016 eng d a1367-481100aIntegrated gene set analysis for microRNA studies.0 aIntegrated gene set analysis for microRNA studies c2016 09 15 a2809-160 v323 a

MOTIVATION: Functional interpretation of miRNA expression data is currently done in a three step procedure: select differentially expressed miRNAs, find their target genes, and carry out gene set overrepresentation analysis Nevertheless, major limitations of this approach have already been described at the gene level, while some newer arise in the miRNA scenario.Here, we propose an enhanced methodology that builds on the well-established gene set analysis paradigm. Evidence for differential expression at the miRNA level is transferred to a gene differential inhibition score which is easily interpretable in terms of gene sets or pathways. Such transferred indexes account for the additive effect of several miRNAs targeting the same gene, and also incorporate cancellation effects between cases and controls. Together, these two desirable characteristics allow for more accurate modeling of regulatory processes.

RESULTS: We analyze high-throughput sequencing data from 20 different cancer types and provide exhaustive reports of gene and Gene Ontology-term deregulation by miRNA action.

AVAILABILITY AND IMPLEMENTATION: The proposed methodology was implemented in the Bioconductor library mdgsa http://bioconductor.org/packages/mdgsa For the purpose of reproducibility all of the scripts are available at https://github.com/dmontaner-papers/gsa4mirna

CONTACT: : david.montaner@gmail.com

SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

10aComputational Biology10aGene Expression Profiling10aGene ontology10aGene Regulatory Networks10aHigh-Throughput Nucleotide Sequencing10aHumans10aMicroRNAs10aNeoplasms10aReproducibility of Results1 aGarcia-Garcia, Francisco1 aPanadero, Joaquin1 aDopazo, Joaquin1 aMontaner, David uhttp://clinbioinfosspa.es/content/integrated-gene-set-analysis-microrna-studies03249nas a2200493 4500008004100000022001400041245010800055210006900163260001300232300001100245490000700256520165600263653004101919653003001960653003801990653001802028653001702046653001502063653000902078653001702087653004402104653001702148653003302165653001902198653002602217100002402243700002602267700002402293700002802317700002002345700002202365700002102387700002102408700002202429700002902451700002002480700002702500700002002527700002402547700001902571700002102590700001902611856012502630 2016 eng d a1467-765200aIntegrating transcriptomic and metabolomic analysis to understand natural leaf senescence in sunflower.0 aIntegrating transcriptomic and metabolomic analysis to understan c2016 Feb a719-340 v143 a

Leaf senescence is a complex process, which has dramatic consequences on crop yield. In sunflower, gap between potential and actual yields reveals the economic impact of senescence. Indeed, sunflower plants are incapable of maintaining their green leaf area over sustained periods. This study characterizes the leaf senescence process in sunflower through a systems biology approach integrating transcriptomic and metabolomic analyses: plants being grown under both glasshouse and field conditions. Our results revealed a correspondence between profile changes detected at the molecular, biochemical and physiological level throughout the progression of leaf senescence measured at different plant developmental stages. Early metabolic changes were detected prior to anthesis and before the onset of the first senescence symptoms, with more pronounced changes observed when physiological and molecular variables were assessed under field conditions. During leaf development, photosynthetic activity and cell growth processes decreased, whereas sucrose, fatty acid, nucleotide and amino acid metabolisms increased. Pathways related to nutrient recycling processes were also up-regulated. Members of the NAC, AP2-EREBP, HB, bZIP and MYB transcription factor families showed high expression levels, and their expression level was highly correlated, suggesting their involvement in sunflower senescence. The results of this study thus contribute to the elucidation of the molecular mechanisms involved in the onset and progression of leaf senescence in sunflower leaves as well as to the identification of candidate genes involved in this process.

10aGas Chromatography-Mass Spectrometry10aGene Expression Profiling10aGene Expression Regulation, Plant10aGene ontology10aGenes, Plant10aHelianthus10aIons10ametabolomics10aOligonucleotide Array Sequence Analysis10aPlant Leaves10aPrincipal Component Analysis10aRNA, Messenger10aTranscription Factors1 aMoschen, Sebastián1 aLuoni, Sofía, Bengoa1 aDi Rienzo, Julio, A1 aCaro, María, Del Pilar1 aTohge, Takayuki1 aWatanabe, Mutsumi1 aHollmann, Julien1 aGonzalez, Sergio1 aRivarola, Máximo1 aGarcia-Garcia, Francisco1 aDopazo, Joaquin1 aHopp, Horacio, Esteban1 aHoefgen, Rainer1 aFernie, Alisdair, R1 aPaniego, Norma1 aFernandez, Paula1 aHeinz, Ruth, A uhttp://clinbioinfosspa.es/content/integrating-transcriptomic-and-metabolomic-analysis-understand-natural-leaf-senescence02859nas a2200433 4500008004100000022001400041245013500055210006900190260000900259300001300268490000700281520145800288653001001746653002901756653001801785653001101803653001901814653003501833653001301868653001801881653003601899653003101935100002101966700003101987700002402018700002002042700002902062700001902091700001902110700002602129700001602155700001902171700002502190700002002215700002002235700002002255700001902275856013102294 2016 eng d a1932-620300aThe Mutational Landscape of Acute Promyelocytic Leukemia Reveals an Interacting Network of Co-Occurrences and Recurrent Mutations.0 aMutational Landscape of Acute Promyelocytic Leukemia Reveals an  c2016 ae01483460 v113 a

Preliminary Acute Promyelocytic Leukemia (APL) whole exome sequencing (WES) studies have identified a huge number of somatic mutations affecting more than a hundred different genes mainly in a non-recurrent manner, suggesting that APL is a heterogeneous disease with secondary relevant changes not yet defined. To extend our knowledge of subtle genetic alterations involved in APL that might cooperate with PML/RARA in the leukemogenic process, we performed a comprehensive analysis of somatic mutations in APL combining WES with sequencing of a custom panel of targeted genes by next-generation sequencing. To select a reduced subset of high confidence candidate driver genes, further in silico analysis were carried out. After prioritization and network analysis we found recurrent deleterious mutations in 8 individual genes (STAG2, U2AF1, SMC1A, USP9X, IKZF1, LYN, MYCBP2 and PTPN11) with a strong potential of being involved in APL pathogenesis. Our network analysis of multiple mutations provides a reliable approach to prioritize genes for additional analysis, improving our knowledge of the leukemogenesis interactome. Additionally, we have defined a functional module in the interactome of APL. The hypothesis is that the number, or the specific combinations, of mutations harbored in each patient might not be as important as the disturbance caused in biological key functions, triggered by several not necessarily recurrent mutations.

10aExome10aGene Regulatory Networks10aGenome, Human10aHumans10aINDEL Mutation10aLeukemia, Promyelocytic, Acute10amutation10aMutation Rate10aPolymorphism, Single Nucleotide10aReproducibility of Results1 aIbáñez, Mariam1 aCarbonell-Caballero, José1 aGarcía-Alonso, Luz1 aSuch, Esperanza1 aJiménez-Almazán, Jorge1 aVidal, Enrique1 aBarragán, Eva1 aLópez-Pavía, María1 aLLop, Marta1 aMartín, Iván1 aGómez-Seguí, Inés1 aMontesinos, Pau1 aSanz, Miguel, A1 aDopazo, Joaquin1 aCervera, José uhttp://clinbioinfosspa.es/content/mutational-landscape-acute-promyelocytic-leukemia-reveals-interacting-network-co-occurrences03502nas a2200517 4500008004100000022001400041245007400055210006900129260001300198300001000211490000800221520209300229653001002322653000902332653001202341653001002353653003202363653001102395653002002406653001102426653001102437653000902448653000902457653001602466653001302482653001302495653001402508653001802522653001602540653002602556653001602582100002002598700001902618700002902637700001802666700001902684700002502703700002402728700003102752700001802783700002002801700002202821700002002843700002102863856010002884 2016 eng d a1460-215600aMutations in the MORC2 gene cause axonal Charcot-Marie-Tooth disease.0 aMutations in the MORC2 gene cause axonal CharcotMarieTooth disea c2016 Jan a62-720 v1393 a

Charcot-Marie-Tooth disease (CMT) is a complex disorder with wide genetic heterogeneity. Here we present a new axonal Charcot-Marie-Tooth disease form, associated with the gene microrchidia family CW-type zinc finger 2 (MORC2). Whole-exome sequencing in a family with autosomal dominant segregation identified the novel MORC2 p.R190W change in four patients. Further mutational screening in our axonal Charcot-Marie-Tooth disease clinical series detected two additional sporadic cases, one patient who also carried the same MORC2 p.R190W mutation and another patient that harboured a MORC2 p.S25L mutation. Genetic and in silico studies strongly supported the pathogenicity of these sequence variants. The phenotype was variable and included patients with congenital or infantile onset, as well as others whose symptoms started in the second decade. The patients with early onset developed a spinal muscular atrophy-like picture, whereas in the later onset cases, the initial symptoms were cramps, distal weakness and sensory impairment. Weakness and atrophy progressed in a random and asymmetric fashion and involved limb girdle muscles, leading to a severe incapacity in adulthood. Sensory loss was always prominent and proportional to disease severity. Electrophysiological studies were consistent with an asymmetric axonal motor and sensory neuropathy, while fasciculations and myokymia were recorded rather frequently by needle electromyography. Sural nerve biopsy revealed pronounced multifocal depletion of myelinated fibres with some regenerative clusters and occasional small onion bulbs. Morc2 is expressed in both axons and Schwann cells of mouse peripheral nerve. Different roles in biological processes have been described for MORC2. As the silencing of Charcot-Marie-Tooth disease genes have been associated with DNA damage response, it is tempting to speculate that a deregulation of this pathway may be linked to the axonal degeneration observed in MORC2 neuropathy, thus adding a new pathogenic mechanism to the long list of causes of Charcot-Marie-Tooth disease.

10aAdult10aAged10aAnimals10aAxons10aCharcot-Marie-Tooth Disease10aFemale10agene expression10aHumans10aInfant10aMale10aMice10aMiddle Aged10amutation10aPedigree10aPhenotype10aSciatic Nerve10aSural Nerve10aTranscription Factors10aYoung Adult1 aSevilla, Teresa1 aLupo, Vincenzo1 aMartínez-Rubio, Dolores1 aSancho, Paula1 aSivera, Rafael1 aChumillas, María, J1 aGarcía-Romero, Mar1 aPascual-Pascual, Samuel, I1 aMuelas, Nuria1 aDopazo, Joaquin1 aVílchez, Juan, J1 aPalau, Francesc1 aEspinós, Carmen uhttp://clinbioinfosspa.es/content/mutations-morc2-gene-cause-axonal-charcot-marie-tooth-disease00573nas a2200145 4500008004100000245005300041210004800094260001600142490000600158100002200164700001700186700003100203700002000234856017300254 2016 eng d00aThe pan-cancer pathological regulatory landscape0 apancancer pathological regulatory landscape cJan-12-20160 v61 aFalco, Matias, M.1 aBleda, Marta1 aCarbonell-Caballero, José1 aDopazo, Joaquin uhttp://www.nature.com/articles/srep39709http://www.nature.com/articles/srep39709.pdfhttp://www.nature.com/articles/srep39709.pdfhttp://www.nature.com/articles/srep3970901876nas a2200181 4500008004100000022001400041245005400055210004800109260001600157300001000173490000600183520137000189100002101559700001701580700003101597700002101628856004501649 2016 eng d a2045-232200aThe pan-cancer pathological regulatory landscape.0 apancancer pathological regulatory landscape c2016 Dec 21 a397090 v63 aDysregulation of the normal gene expression program is the cause of a broad range of diseases, including cancer. Detecting the specific perturbed regulators that have an effect on the generation and the development of the disease is crucial for understanding the disease mechanism and for taking decisions on efficient preventive and curative therapies. Moreover, detecting such perturbations at the patient level is even more important from the perspective of personalized medicine. We applied the Transcription Factor Target Enrichment Analysis, a method that detects the activity of transcription factors based on the quantification of the collective transcriptional activation of their targets, to a large collection of 5607 cancer samples covering eleven cancer types. We produced for the first time a comprehensive catalogue of altered transcription factor activities in cancer, a considerable number of them significantly associated to patient’s survival. Moreover, we described several interesting TFs whose activity do not change substantially in the cancer with respect to the normal tissue but ultimately play an important role in patient prognostic determination, which suggest they might be promising therapeutic targets. An additional advantage of this method is that it allows obtaining personalized TF activity estimations for individual patients.1 aFalco, Matias, M1 aBleda, Marta1 aCarbonell-Caballero, José1 aDopazo, Joaquín uhttp://www.nature.com/articles/srep3970902421nas a2200325 4500008004100000022001400041245006600055210006400121260001300185300001000198490000700208520140200215653002501617653003401642653003701676653001101713653002201724653002101746653003601767653002301803100002101826700001701847700002001864700002201884700003201906700001901938700002201957700002101979856009502000 2016 eng d a2363-891500aProgress in pharmacogenetics: consortiums and new strategies.0 aProgress in pharmacogenetics consortiums and new strategies c2016 Mar a17-230 v313 a

Pharmacogenetics (PGx), as a field dedicated to achieving the goal of personalized medicine (PM), is devoted to the study of genes involved in inter-individual response to drugs. Due to its nature, PGx requires access to large samples; therefore, in order to progress, the formation of collaborative consortia seems to be crucial. Some examples of this collective effort are the European Society of Pharmacogenomics and personalized Therapy and the Ibero-American network of Pharmacogenetics. As an emerging field, one of the major challenges that PGx faces is translating their discoveries from research bench to bedside. The development of genomic high-throughput technologies is generating a revolution and offers the possibility of producing vast amounts of genome-wide single nucleotide polymorphisms for each patient. Moreover, there is a need of identifying and replicating associations of new biomarkers, and, in addition, a greater effort must be invested in developing regulatory organizations to accomplish a correct standardization. In this review, we outline the current progress in PGx using examples to highlight both the importance of polymorphisms and the research strategies for their detection. These concepts need to be applied together with a proper dissemination of knowledge to improve clinician and patient understanding, in a multidisciplinary team-based approach.

10aCooperative Behavior10aGenome-Wide Association Study10aHigh-Throughput Screening Assays10aHumans10aPatient Care Team10apharmacogenetics10aPolymorphism, Single Nucleotide10aPrecision Medicine1 aMaroñas, Olalla1 aLatorre, Ana1 aDopazo, Joaquin1 aPirmohamed, Munir1 aRodríguez-Antona, Cristina1 aSiest, Gérard1 aCarracedo, Ángel1 aLLerena, Adrián uhttp://clinbioinfosspa.es/content/progress-pharmacogenetics-consortiums-and-new-strategies02956nas a2200505 4500008004100000022001400041245008800055210006900143260001300212300001000225490000900235520151700244653001501761653001701776653001001793653002101803653002101824653001001845653001101855653004201866653001101908653001101919653002801930653000901958653001301967653001301980653001401993653001402007653002302021100002002044700002102064700001902085700002902104700002302133700002202156700002202178700001902200700001902219700002002238700001702258700002302275700002102298700002102319856011002340 2016 eng d a1552-483300aScreening of CD96 and ASXL1 in 11 patients with Opitz C or Bohring-Opitz syndromes.0 aScreening of CD96 and ASXL1 in 11 patients with Opitz C or Bohri c2016 Jan a24-310 v170A3 a

Opitz C trigonocephaly (or Opitz C syndrome, OTCS) and Bohring-Opitz syndrome (BOS or C-like syndrome) are two rare genetic disorders with phenotypic overlap. The genetic causes of these diseases are not understood. However, two genes have been associated with OTCS or BOS with dominantly inherited de novo mutations. Whereas CD96 has been related to OTCS (one case) and to BOS (one case), ASXL1 has been related to BOS only (several cases). In this study we analyze CD96 and ASXL1 in a group of 11 affected individuals, including 2 sibs, 10 of them were diagnosed with OTCS, and one had a BOS phenotype. Exome sequences were available on six patients with OTCS and three parent pairs. Thus, we could analyze the CD96 and ASXL1 sequences in these patients bioinformatically. Sanger sequencing of all exons of CD96 and ASXL1 was carried out in the remaining patients. Detailed scrutiny of the sequences and assessment of variants allowed us to exclude putative pathogenic and private mutations in all but one of the patients. In this patient (with BOS) we identified a de novo mutation in ASXL1 (c.2100dupT). By nature and location within the gene, this mutation resembles those previously described in other BOS patients and we conclude that it may be responsible for the condition. Our results indicate that in 10 of 11, the disease (OTCS or BOS) cannot be explained by small changes in CD96 or ASXL1. However, the cohort is too small to make generalizations about the genetic etiology of these diseases.

10aAdolescent10aAntigens, CD10aChild10aChild, Preschool10aCraniosynostoses10aExome10aFemale10aHigh-Throughput Nucleotide Sequencing10aHumans10aInfant10aIntellectual Disability10aMale10amutation10aPedigree10aPhenotype10aPrognosis10aRepressor Proteins1 aUrreizti, Roser1 aRoca-Ayats, Neus1 aTrepat, Judith1 aGarcia-Garcia, Francisco1 aAlemán, Alejandro1 aOrteschi, Daniela1 aMarangi, Giuseppe1 aNeri, Giovanni1 aOpitz, John, M1 aDopazo, Joaquin1 aCormand, Bru1 aVilageliu, Lluïsa1 aBalcells, Susana1 aGrinberg, Daniel uhttp://clinbioinfosspa.es/content/screening-cd96-and-asxl1-11-patients-opitz-c-or-bohring-opitz-syndromes02605nas a2200397 4500008004100000022001400041245017300055210006900228260001600297300001300313490000600326520129300332653001001625653000901635653002201644653003501666653002401701653001101725653001101736653001901747653000901766653001701775653001601792653004301808100003001851700002801881700002501909700002901934700001501963700002101978700001601999700002002015700001802035700002702053856012702080 2016 eng d a1949-255300aSerum metabolomic profiling facilitates the non-invasive identification of metabolic biomarkers associated with the onset and progression of non-small cell lung cancer.0 aSerum metabolomic profiling facilitates the noninvasive identifi c2016 Mar 15 a12904-160 v73 a

Lung cancer (LC) is responsible for most cancer deaths. One of the main factors contributing to the lethality of this disease is the fact that a large proportion of patients are diagnosed at advanced stages when a clinical intervention is unlikely to succeed. In this study, we evaluated the potential of metabolomics by 1H-NMR to facilitate the identification of accurate and reliable biomarkers to support the early diagnosis and prognosis of non-small cell lung cancer (NSCLC).We found that the metabolic profile of NSCLC patients, compared with healthy individuals, is characterized by statistically significant changes in the concentration of 18 metabolites representing different amino acids, organic acids and alcohols, as well as different lipids and molecules involved in lipid metabolism. Furthermore, the analysis of the differences between the metabolic profiles of NSCLC patients at different stages of the disease revealed the existence of 17 metabolites involved in metabolic changes associated with disease progression.Our results underscore the potential of metabolomics profiling to uncover pathophysiological mechanisms that could be useful to objectively discriminate NSCLC patients from healthy individuals, as well as between different stages of the disease.

10aAdult10aAged10aBiomarkers, Tumor10aCarcinoma, Non-Small-Cell Lung10aDisease Progression10aFemale10aHumans10aLung Neoplasms10aMale10ametabolomics10aMiddle Aged10aProton Magnetic Resonance Spectroscopy1 aPuchades-Carrasco, Leonor1 aJantus-Lewintre, Eloisa1 aPérez-Rambla, Clara1 aGarcia-Garcia, Francisco1 aLucas, Rut1 aCalabuig, Silvia1 aBlasco, Ana1 aDopazo, Joaquin1 aCamps, Carlos1 aPineda-Lucena, Antonio uhttp://clinbioinfosspa.es/content/serum-metabolomic-profiling-facilitates-non-invasive-identification-metabolic-biomarkers03441nas a2200277 4500008004100000022001400041245011600055210006900171260001300240300001000253490000600263520251800269100001902787700002102806700002002827700002202847700001802869700001902887700001702906700002202923700002002945700002402965700001902989700002903008856012603037 2016 eng d a2212-877800aStress-induced activation of brown adipose tissue prevents obesity in conditions of low adaptive thermogenesis.0 aStressinduced activation of brown adipose tissue prevents obesit c2016 Jan a19-330 v53 a

BACKGROUND: Stress-associated conditions such as psychoemotional reactivity and depression have been paradoxically linked to either weight gain or weight loss. This bi-directional effect of stress is not understood at the functional level. Here we tested the hypothesis that pre-stress level of adaptive thermogenesis and brown adipose tissue (BAT) functions explain the vulnerability or resilience to stress-induced obesity.

METHODS: We used wt and triple β1,β2,β3-Adrenergic Receptors knockout (β-less) mice exposed to a model of chronic subordination stress (CSS) at either room temperature (22 °C) or murine thermoneutrality (30 °C). A combined behavioral, physiological, molecular, and immunohistochemical analysis was conducted to determine stress-induced modulation of energy balance and BAT structure and function. Immortalized brown adipocytes were used for in vitro assays.

RESULTS: Departing from our initial observation that βARs are dispensable for cold-induced BAT browning, we demonstrated that under physiological conditions promoting low adaptive thermogenesis and BAT activity (e.g. thermoneutrality or genetic deletion of the βARs), exposure to CSS acted as a stimulus for BAT activation and thermogenesis, resulting in resistance to diet-induced obesity despite the presence of hyperphagia. Conversely, in wt mice acclimatized to room temperature, and therefore characterized by sustained BAT function, exposure to CSS increased vulnerability to obesity. Exposure to CSS enhanced the sympathetic innervation of BAT in wt acclimatized to thermoneutrality and in β-less mice. Despite increased sympathetic innervation suggesting adrenergic-mediated browning, norepinephrine did not promote browning in βARs knockout brown adipocytes, which led us to identify an alternative sympathetic/brown adipocytes purinergic pathway in the BAT. This pathway is downregulated under conditions of low adaptive thermogenesis requirements, is induced by stress, and elicits activation of UCP1 in wt and β-less brown adipocytes. Importantly, this purinergic pathway is conserved in human BAT.

CONCLUSION: Our findings demonstrate that thermogenesis and BAT function are determinant of the resilience or vulnerability to stress-induced obesity. Our data support a model in which adrenergic and purinergic pathways exert complementary/synergistic functions in BAT, thus suggesting an alternative to βARs agonists for the activation of human BAT.

1 aRazzoli, Maria1 aFrontini, Andrea1 aGurney, Allison1 aMondini, Eleonora1 aCubuk, Cankut1 aKatz, Liora, S1 aCero, Cheryl1 aBolan, Patrick, J1 aDopazo, Joaquin1 aVidal-Puig, Antonio1 aCinti, Saverio1 aBartolomucci, Alessandro uhttp://clinbioinfosspa.es/content/stress-induced-activation-brown-adipose-tissue-prevents-obesity-conditions-low-adaptive02266nas a2200253 4500008004100000022001400041245007800055210006900133260001500202300001000217490000600227520146300233653001601696653001201712653003001724653003101754653001401785100001901799700002901818700002001847700002101867700002301888856010101911 2016 eng d a2045-232200aThe transcriptomics of an experimentally evolved plant-virus interaction.0 atranscriptomics of an experimentally evolved plantvirus interact c2016 04 26 a249010 v63 a

Models of plant-virus interaction assume that the ability of a virus to infect a host genotype depends on the matching between virulence and resistance genes. Recently, we evolved tobacco etch potyvirus (TEV) lineages on different ecotypes of Arabidopsis thaliana, and found that some ecotypes selected for specialist viruses whereas others selected for generalists. Here we sought to evaluate the transcriptomic basis of such relationships. We have characterized the transcriptomic responses of five ecotypes infected with the ancestral and evolved viruses. Genes and functional categories differentially expressed by plants infected with local TEV isolates were identified, showing heterogeneous responses among ecotypes, although significant parallelism existed among lineages evolved in the same ecotype. Although genes involved in immune responses were altered upon infection, other functional groups were also pervasively over-represented, suggesting that plant resistance genes were not the only drivers of viral adaptation. Finally, the transcriptomic consequences of infection with the generalist and specialist lineages were compared. Whilst the generalist induced very similar perturbations in the transcriptomes of the different ecotypes, the perturbations induced by the specialist were divergent. Plant defense mechanisms were activated when the infecting virus was specialist but they were down-regulated when infecting with generalist.

10aArabidopsis10aEcotype10aGene Expression Profiling10aHost-Pathogen Interactions10aPotyvirus1 aHillung, Julia1 aGarcia-Garcia, Francisco1 aDopazo, Joaquin1 aCuevas, José, M1 aElena, Santiago, F uhttp://clinbioinfosspa.es/content/transcriptomics-experimentally-evolved-plant-virus-interaction01573nas a2200253 4500008004100000022001400041245006500055210006300120260001500183300001100198490000700209520080700216653002601023653001301049653001301062100002401075700002401099700002101123700002001144700001701164700002001181700002001201856009801221 2016 eng d a1367-481100aWeb-based network analysis and visualization using CellMaps.0 aWebbased network analysis and visualization using CellMaps c2016 10 01 a3041-30 v323 a

UNLABELLED: : CellMaps is an HTML5 open-source web tool that allows displaying, editing, exploring and analyzing biological networks as well as integrating metadata into them. Computations and analyses are remotely executed in high-end servers, and all the functionalities are available through RESTful web services. CellMaps can easily be integrated in any web page by using an available JavaScript API.

AVAILABILITY AND IMPLEMENTATION: The application is available at: http://cellmaps.babelomics.org/ and the code can be found in: https://github.com/opencb/cell-maps The client is implemented in JavaScript and the server in C and Java.

CONTACT: jdopazo@cipf.es

SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

10aBiochemical Phenomena10aInternet10aSoftware1 aSalavert, Francisco1 aGarcía-Alonso, Luz1 aSánchez, Rubén1 aAlonso, Roberto1 aBleda, Marta1 aMedina, Ignacio1 aDopazo, Joaquin uhttp://clinbioinfosspa.es/content/web-based-network-analysis-and-visualization-using-cellmaps02962nas a2200529 4500008004100000022001400041245011800055210006900173260001200242300001400254490000800268520135400276653001501630653001001645653001201655653002701667653002101694653002401715653001001739653002101749653002801770653001001798653001101808653003501819653002201854653004201876653001101918653003301929653001301962653002601975653003702001653002502038653001802063100002202081700001902103700001802122700001902140700001502159700001802174700001902192700001902211700002002230700001802250700002202268700002002290856012202310 2016 eng d a1432-120300aWhole exome sequencing of Rett syndrome-like patients reveals the mutational diversity of the clinical phenotype.0 aWhole exome sequencing of Rett syndromelike patients reveals the c2016 12 a1343-13540 v1353 a

Classical Rett syndrome (RTT) is a neurodevelopmental disorder where most of cases carry MECP2 mutations. Atypical RTT variants involve mutations in CDKL5 and FOXG1. However, a subset of RTT patients remains that do not carry any mutation in the described genes. Whole exome sequencing was carried out in a cohort of 21 female probands with clinical features overlapping with those of RTT, but without mutations in the customarily studied genes. Candidates were functionally validated by assessing the appearance of a neurological phenotype in Caenorhabditis elegans upon disruption of the corresponding ortholog gene. We detected pathogenic variants that accounted for the RTT-like phenotype in 14 (66.6 %) patients. Five patients were carriers of mutations in genes already known to be associated with other syndromic neurodevelopmental disorders. We determined that the other patients harbored mutations in genes that have not previously been linked to RTT or other neurodevelopmental syndromes, such as the ankyrin repeat containing protein ANKRD31 or the neuronal acetylcholine receptor subunit alpha-5 (CHRNA5). Furthermore, worm assays demonstrated that mutations in the studied candidate genes caused locomotion defects. Our findings indicate that mutations in a variety of genes contribute to the development of RTT-like phenotypes.

10aAdolescent10aAdult10aAnimals10aCaenorhabditis elegans10aCarrier Proteins10aCell Cycle Proteins10aChild10aChild, Preschool10aDNA Mutational Analysis10aExome10aFemale10aForkhead Transcription Factors10aGenetic Variation10aHigh-Throughput Nucleotide Sequencing10aHumans10aMethyl-CpG-Binding Protein 210amutation10aNerve Tissue Proteins10aProtein Serine-Threonine Kinases10aReceptors, Nicotinic10aRett Syndrome1 aLucariello, Mario1 aVidal, Enrique1 aVidal, Silvia1 aSaez, Mauricio1 aRoa, Laura1 aHuertas, Dori1 aPineda, Mercè1 aDalfó, Esther1 aDopazo, Joaquin1 aJurado, Paola1 aArmstrong, Judith1 aEsteller, Manel uhttp://clinbioinfosspa.es/content/whole-exome-sequencing-rett-syndrome-patients-reveals-mutational-diversity-clinical01932nas a2200253 4500008004100000022001400041245011000055210006900165260001600234300001400250490000700264520114400271653000801415653001301423653001501436653002001451100003601471700002401507700003001531700002301561700002001584700002101604856005301625 2015 eng d a1362-496200aAssessing the impact of mutations found in next generation sequencing data over human signaling pathways.0 aAssessing the impact of mutations found in next generation seque c2015 Apr 16 aW270-W2750 v433 aModern sequencing technologies produce increasingly detailed data on genomic variation. However, conventional methods for relating either individual variants or mutated genes to phenotypes present known limitations given the complex, multigenic nature of many diseases or traits. Here we present PATHiVar, a web-based tool that integrates genomic variation data with gene expression tissue information. PATHiVar constitutes a new generation of genomic data analysis methods that allow studying variants found in next generation sequencing experiment in the context of signaling pathways. Simple Boolean models of pathways provide detailed descriptions of the impact of mutations in cell functionality so as, recurrences in functionality failures can easily be related to diseases, even if they are produced by mutations in different genes. Patterns of changes in signal transmission circuits, often unpredictable from individual genes mutated, correspond to patterns of affected functionalities that can be related to complex traits such as disease progression, drug response, etc. PATHiVar is available at: http://pathivar.babelomics.org.10aNGS10apathways10asignalling10aSystems biology1 aHernansaiz-Ballesteros, Rosa, D1 aSalavert, Francisco1 aSebastián-Leon, Patricia1 aAlemán, Alejandro1 aMedina, Ignacio1 aDopazo, Joaquín uhttp://nar.oxfordjournals.org/content/43/W1/W27002445nas a2200469 4500008004100000022001400041245008300055210006900138260001600207300001400223490000700237520108700244653001501331653002101346653002201367653001601389653002101405653000801426653001201434653002001446653002001466100002001486700002401506700002901530700003101559700001701590700002401607700002301631700002201654700002401676700002101700700001801721700002201739700001901761700003601780700002301816700002301839700002001862700002001882700002001902856005301922 2015 eng d a1362-496200aBabelomics 5.0: functional interpretation for new generations of genomic data.0 aBabelomics 50 functional interpretation for new generations of g c2015 Apr 20 aW117-W1210 v433 aBabelomics has been running for more than one decade offering a user-friendly interface for the functional analysis of gene expression and genomic data. Here we present its fifth release, which includes support for Next Generation Sequencing data including gene expression (RNA-seq), exome or genome resequencing. Babelomics has simplified its interface, being now more intuitive. Improved visualization options, such as a genome viewer as well as an interactive network viewer, have been implemented. New technical enhancements at both, client and server sides, makes the user experience faster and more dynamic. Babelomics offers user-friendly access to a full range of methods that cover: (i) primary data analysis, (ii) a variety of tests for different experimental designs and (iii) different enrichment and network analysis algorithms for the interpretation of the results of such tests in the proper functional context. In addition to the public server, local copies of Babelomics can be downloaded and installed. Babelomics is freely available at: http://www.babelomics.org.10ababelomics10adata integration10agene set analysis10ainteractome10anetwork analysis10aNGS10aRNA-seq10aSystems biology10atranscriptomics1 aAlonso, Roberto1 aSalavert, Francisco1 aGarcia-Garcia, Francisco1 aCarbonell-Caballero, José1 aBleda, Marta1 aGarcía-Alonso, Luz1 aSanchis-Juan, Alba1 aPerez-Gil, Daniel1 aMarin-Garcia, Pablo1 aSánchez, Rubén1 aCubuk, Cankut1 aHidalgo, Marta, R1 aAmadoz, Alicia1 aHernansaiz-Ballesteros, Rosa, D1 aAlemán, Alejandro1 aTárraga, Joaquín1 aMontaner, David1 aMedina, Ignacio1 aDopazo, Joaquin uhttp://nar.oxfordjournals.org/content/43/W1/W11702810nas a2200277 4500008004100000022001400041245006700055210006600122260000900188300000800197490000700205520198700212100001902199700002902218700002602247700002802273700002902301700001702330700002202347700002202369700002102391700002502412700002202437700002302459856005002482 2015 eng d a1471-240700aBRCA1 Alternative splicing landscape in breast tissue samples.0 aBRCA1 Alternative splicing landscape in breast tissue samples c2015 a2190 v153 aBACKGROUND: BRCA1 is a key protein in cell network, involved in DNA repair pathways and cell cycle. Recently, the ENIGMA consortium has reported a high number of alternative splicing (AS) events at this locus in blood-derived samples. However, BRCA1 splicing pattern in breast tissue samples is unknown. Here, we provide an accurate description of BRCA1 splicing events distribution in breast tissue samples. METHODS: BRCA1 splicing events were scanned in 70 breast tumor samples, 4 breast samples from healthy individuals and in 72 blood-derived samples by capillary electrophoresis (capillary EP). Molecular subtype was identified in all tumor samples. Splicing events were considered predominant if their relative expression level was at least the 10% of the full-length reference signal. RESULTS: 54 BRCA1 AS events were identified, 27 of them were annotated as predominant in at least one sample. Δ5q, Δ13, Δ9, Δ5 and ▼1aA were significantly more frequently annotated as predominant in breast tumor samples than in blood-derived samples. Predominant splicing events were, on average, more frequent in tumor samples than in normal breast tissue samples (P = 0.010). Similarly, likely inactivating splicing events (PTC-NMDs, Non-Coding, Δ5 and Δ18) were more frequently annotated as predominant in tumor than in normal breast samples (P = 0.020), whereas there were no significant differences for other splicing events (No-Fs) frequency distribution between tumor and normal breast samples (P = 0.689). CONCLUSIONS: Our results complement recent findings by the ENIGMA consortium, demonstrating that BRCA1 AS, despite its tremendous complexity, is similar in breast and blood samples, with no evidences for tissue specific AS events. Further on, we conclude that somatic inactivation of BRCA1 through spliciogenic mutations is, at best, a rare mechanism in breast carcinogenesis, albeit our data detects an excess of likely inactivating AS events in breast tumor samples.1 aRomero, Atocha1 aGarcia-Garcia, Francisco1 aLópez-Perolio, Irene1 ade Garibay, Gorka, Ruiz1 aGarcía-Sáenz, José, A1 aGarre, Pilar1 aAyllón, Patricia1 aBenito, Esperanza1 aDopazo, Joaquín1 aDíaz-Rubio, Eduardo1 aCaldés, Trinidad1 ade la Hoya, Miguel uhttp://www.biomedcentral.com/1471-2407/15/21903376nas a2200793 4500008004100000022001400041245011500055210006900170260001600239520112300255653001101378653000801389653002001397100001901417700002601436700001201462700001801474700002201492700002701514700002201541700002201563700001901585700002901604700002301633700002001656700002001676700002301696700002501719700002201744700002201766700002101788700004001809700001201849700001701861700001201878700001601890700001901906700001801925700002101943700001601964700002001980700002402000700002002024700001802044700001302062700001702075700001802092700002102110700002402131700002002155700002102175700001702196700002102213700002502234700002102259700001902280700001902299700002102318700001602339700001402355700001702369700001502386700001302401700003102414700002102445700002102466700002002487856007502507 2015 eng d a1548-710500aCombining tumor genome simulation with crowdsourcing to benchmark somatic single-nucleotide-variant detection.0 aCombining tumor genome simulation with crowdsourcing to benchmar c2015 May 183 aThe detection of somatic mutations from cancer genome sequences is key to understanding the genetic basis of disease progression, patient survival and response to therapy. Benchmarking is needed for tool assessment and improvement but is complicated by a lack of gold standards, by extensive resource requirements and by difficulties in sharing personal genomic information. To resolve these issues, we launched the ICGC-TCGA DREAM Somatic Mutation Calling Challenge, a crowdsourced benchmark of somatic mutation detection algorithms. Here we report the BAMSurgeon tool for simulating cancer genomes and the results of 248 analyses of three in silico tumors created with it. Different algorithms exhibit characteristic error profiles, and, intriguingly, false positives show a trinucleotide profile very similar to one found in human tumors. Although the three simulated tumors differ in sequence contamination (deviation from normal cell sequence) and in subclonality, an ensemble of pipelines outperforms the best individual pipeline in all cases. BAMSurgeon is available at https://github.com/adamewing/bamsurgeon/.10acancer10aNGS10avariant calling1 aEwing, Adam, D1 aHoulahan, Kathleen, E1 aHu, Yin1 aEllrott, Kyle1 aCaloian, Cristian1 aYamaguchi, Takafumi, N1 aBare, Christopher1 aP’ng, Christine1 aWaggott, Daryl1 aSabelnykova, Veronica, Y1 aKellen, Michael, R1 aNorman, Thea, C1 aHaussler, David1 aFriend, Stephen, H1 aStolovitzky, Gustavo1 aMargolin, Adam, A1 aStuart, Joshua, M1 aBoutros, Paul, C1 aparticipants, ICGC-TCGA, DREAM Soma1 aXi, Liu1 aDewal, Ninad1 aFan, Yu1 aWang, Wenyi1 aWheeler, David1 aWilm, Andreas1 aTing, Grace, Hui1 aLi, Chenhao1 aBertrand, Denis1 aNagarajan, Niranjan1 aChen, Qing-Rong1 aHsu, Chih-Hao1 aHu, Ying1 aYan, Chunhua1 aKibbe, Warren1 aMeerzaman, Daoud1 aCibulskis, Kristian1 aRosenberg, Mara1 aBergelson, Louis1 aKiezun, Adam1 aRadenbaugh, Amie1 aSertier, Anne-Sophie1 aFerrari, Anthony1 aTonton, Laurie1 aBhutani, Kunal1 aHansen, Nancy, F1 aWang, Difei1 aSong, Lei1 aLai, Zhongwu1 aLiao, Yang1 aShi, Wei1 aCarbonell-Caballero, José1 aDopazo, Joaquín1 aLau, Cheryl, C K1 aGuinney, Justin uhttp://www.nature.com/nmeth/journal/vaop/ncurrent/full/nmeth.3407.html02945nas a2200217 4500008004100000022001400041245012100055210006900176260001500245520217400260100003602434700003402470700002102504700002702525700002002552700002202572700002102594700002502615700001602640856007102656 2015 eng d a1878-589100aComparative gene expression study of the vestibular organ of the Igf1 deficient mouse using whole-transcript arrays.0 aComparative gene expression study of the vestibular organ of the c2015 Sep 13 aThe auditory and vestibular organs form the inner ear and have a common developmental origin. Insulin like growth factor 1 (IGF-1) has a central role in the development of the cochlea and maintenance of hearing. Its deficiency causes sensorineural hearing loss in man and mice. During chicken early development, IGF-1 modulates neurogenesis of the cochleovestibular ganglion but no further studies have been conducted to explore the potential role of IGF-1 in the vestibular system. In this study we have compared the whole transcriptome of the vestibular organ from wild type and Igf1(-/-) mice at different developmental and postnatal times. RNA was prepared from E18.5, P15 and P90 vestibular organs of Igf1(-/-) and Igf1(+/+) mice and the transcriptome analysed in triplicates using Affymetrix® Mouse Gene 1.1 ST Array Plates. These plates are whole-transcript arrays that include probes to measure both messenger (mRNA) and long intergenic non-coding RNA transcripts (lincRNA), with a coverage of over 28 thousand coding transcripts and over 7 thousands non-coding transcripts. Given the complexity of the data we used two different methods VSN-RMA and mmBGX to analyse and compare the data. This is to better evaluate the number of false positives and to quantify uncertainty of low signals. We identified a number of differentially expressed genes that we described using functional analysis and validated using RT-qPCR. The morphology of the vestibular organ did not show differences between genotypes and no evident alterations were observed in the vestibular sensory areas of the null mice. However, well-defined cellular alterations were found in the vestibular neurons with respect their number and size. Although these mice did not show a dramatic vestibular phenotype, we conducted a functional analysis on differentially expressed genes between genotypes and across time. This was with the aim to identify new pathways that are involved in the development of the vestibular organ as well as pathways that maybe affected by the lack of IGF-1 and be associated to the morphological changes of the vestibular neurons that we observed in the Igf1(-/-) mice.1 ade la Rosa, Lourdes, Rodríguez1 aSánchez-Calderón, Hortensia1 aContreras, Julio1 aMurillo-Cuesta, Silvia1 aFalagan, Sandra1 aAvendaño, Carlos1 aDopazo, Joaquín1 aVarela-Nieto, Isabel1 aMilo, Marta uhttp://www.sciencedirect.com/science/article/pii/S037859551500183501828nas a2200253 4500008004100000022001400041245007200055210006900127260001700196300001300213490000700226520106800233653000801301653000801309653002301317100002101340700002301361700002001384700002301404700002201427700002001449700003001469856007501499 2015 eng d a1557-996400aConcurrent and Accurate Short Read Mapping on Multicore Processors.0 aConcurrent and Accurate Short Read Mapping on Multicore Processo c2015 Sep-Oct a995-10070 v123 aWe introduce a parallel aligner with a work-flow organization for fast and accurate mapping of RNA sequences on servers equipped with multicore processors. Our software, [Formula: see text] ([Formula: see text] is an open-source application. The software is available at http://www.opencb.org, exploits a suffix array to rapidly map a large fraction of the RNA fragments (reads), as well as leverages the accuracy of the Smith-Waterman algorithm to deal with conflictive reads. The aligner is enhanced with a careful strategy to detect splice junctions based on an adaptive division of RNA reads into small segments (or seeds), which are then mapped onto a number of candidate alignment locations, providing crucial information for the successful alignment of the complete reads. The experimental results on a platform with Intel multicore technology report the parallel performance of [Formula: see text], on RNA reads of 100-400 nucleotides, which excels in execution time/sensitivity to state-of-the-art aligners such as TopHat 2+Bowtie 2, MapSplice, and STAR.10aHPC10aNGS10ashort real mapping1 aMartinez, Hector1 aTárraga, Joaquín1 aMedina, Ignacio1 aBarrachina, Sergio1 aCastillo, Maribel1 aDopazo, Joaquin1 aQuintana-Orti, Enrique, S uhttp://ieeexplore.ieee.org/xpl/articleDetails.jsp?tp=&arnumber=701000503277nas a2200445 4500008004100000022001400041245015900055210006900214260001600283300000900299490000800308520183200316653001002148653000902158653001102167653004102178653002302219653003002242653004602272653001802318653003402336653001702370653001102387653001602398653002002414653001302434653004402447653001202491653003402503653002402537100002302561700002502584700001602609700002302625700001302648700001402661700001602675700001302691856012702704 2015 eng d a1879-003800aDeregulation of key signaling pathways involved in oocyte maturation in FMR1 premutation carriers with Fragile X-associated primary ovarian insufficiency.0 aDeregulation of key signaling pathways involved in oocyte matura c2015 Oct 15 a52-70 v5713 a

FMR1 premutation female carriers are at risk for Fragile X-associated primary ovarian insufficiency (FXPOI). Insights from knock-in mouse model have recently demonstrated that FXPOI is due to an increased rate of follicle depletion or an impaired development of the growing follicles. Molecular mechanisms responsible for this reduced viability are still unknown. In an attempt to provide new data on the mechanisms that lead to FXPOI, we report the first investigation involving transcription profiling of total blood from FMR1 premutation female carriers with and without FXPOI. A total of 16 unrelated female individuals (6 FMR1 premutated females with FXPOI; 6 FMR1 premutated females without FXPOI; and 4 no-FXPOI females) were studied by whole human genome oligonucleotide microarray (Agilent Technologies). Fold change analysis did not show any genes with significant differential gene expression. However, functional profiling by gene set analysis showed large number of statistically significant deregulated GO annotations as well as numerous KEGG pathways in FXPOI females. These results suggest that the impairment of fertility in these females might be due to a generalized deregulation of key signaling pathways involved in oocyte maturation. In particular, the vasoendotelial growth factor signaling, the inositol phosphate metabolism, the cell cycle, and the MAPK signaling pathways were found to be down-regulated in FXPOI females. Furthermore, a high statistical enrichment of biological processes involved in cell death and survival were found deregulated among FXPOI females. Our results provide new strategic approaches to further investigate the molecular mechanisms and potential therapeutic targets for FXPOI not focused in a single gene but rather in the set of genes involved in these pathways.

10aAdult10aAged10aFemale10aFragile X Mental Retardation Protein10aFragile X Syndrome10aGene Expression Profiling10aGene Expression Regulation, Developmental10aGene ontology10aGenome-Wide Association Study10aHeterozygote10aHumans10aMiddle Aged10aModels, Genetic10amutation10aOligonucleotide Array Sequence Analysis10aOocytes10aPrimary Ovarian Insufficiency10aSignal Transduction1 aAlvarez-Mora, M, I1 aRodriguez-Revenga, L1 aMadrigal, I1 aGarcía-García, F1 aDuran, M1 aDopazo, J1 aEstivill, X1 aMilà, M uhttp://clinbioinfosspa.es/content/deregulation-key-signaling-pathways-involved-oocyte-maturation-fmr1-premutation-carriers02346nas a2200229 4500008004100000022001400041245014200055210006900197260001600266520153800282100001701820700002401837700001401861700001401875700001501889700002301904700001401927700001801941700001501959700001501974856012701989 2015 eng d a1523-174700aDifferential Features Between Chronic Skin Inflammatory Diseases Revealed in Skin-Humanized Psoriasis and Atopic Dermatitis Mouse Models.0 aDifferential Features Between Chronic Skin Inflammatory Diseases c2015 Sep 233 a

Psoriasis (PS) and atopic dermatitis (AD) are chronic and relapsing inflammatory diseases of the skin affecting a large number of patients worldwide. Psoriasis is characterized by a Th1/Th17 immunological response whereas acute AD lesions exhibit Th2-dominant inflammation. Current single gene and signaling pathways-based models of inflammatory skin diseases are incomplete. Previous work allowed us to model psoriasis in skin-humanized mice through proper combinations of inflammatory cell components and disruption of barrier function. Herein we describe and characterize an animal model for AD using similar bioengineered-based approaches, by intradermal injection of human Th2 lymphocytes in regenerated human skin after partial removal of stratum corneum. In the present work we have extensively compared this model with the previous and an improved version of the PS model, in which Th17/Th1 lymphocytes replace exogenous cytokines. Comparative expression analyses revealed marked differences in specific epidermal proliferation and differentiation markers and immune-related molecules including antimicrobial peptides. Likewise, the composition of the dermal inflammatory infiltrate presented important differences. Availability of accurate and reliable animal models for these diseases will contribute to the understanding of the pathogenesis and provide valuable tools for drug development and testing.Journal of Investigative Dermatology accepted article preview online, 23 September 2015. doi:10.1038/jid.2015.362.

1 aCarretero, M1 aGuerrero-Aspizua, S1 aIllera, N1 aGalvez, V1 aNavarro, M1 aGarcía-García, F1 aDopazo, J1 aJorcano, J, L1 aLarcher, F1 aDel Rio, M uhttp://clinbioinfosspa.es/content/differential-features-between-chronic-skin-inflammatory-diseases-revealed-skin-humanized02461nas a2200445 4500008004100000022001400041245006900055210006200124260001300186300001200199490000700211520128200218653001001500653000901510653002201519653001001541653003201551653003601583653001001619653001101629653001101640653000901651653001601660653001301676653001301689653001401702653003001716653001601746100001501762700001401777700002301791700001201814700002001826700001501846700001401861700001901875700001301894700001601907856009201923 2015 eng d a1468-133100aThe EGR2 gene is involved in axonal Charcot-Marie-Tooth disease.0 aEGR2 gene is involved in axonal CharcotMarieTooth disease c2015 Dec a1548-550 v223 a

BACKGROUND AND PURPOSE: A three-generation family affected by axonal Charcot-Marie-Tooth disease (CMT) was investigated with the aim of discovering genetic defects and to further characterize the phenotype.

METHODS: The clinical, nerve conduction studies and muscle magnetic resonance images of the patients were reviewed. A whole exome sequencing was performed and the changes were investigated by genetic studies, in silico analysis and luciferase reporter assays.

RESULTS: A novel c.1226G>A change (p.R409Q) in the EGR2 gene was identified. Patients presented with a typical, late-onset axonal CMT phenotype with variable severity that was confirmed in the ancillary tests. The in silico studies showed that the residue R409 is an evolutionary conserved amino acid. The p.R409Q mutation, which is predicted as probably damaging, would alter the conformation of the protein slightly and would cause a decrease of gene expression.

CONCLUSIONS: This is the first report of an EGR2 mutation presenting as an axonal CMT phenotype with variable severity. This study broadens the phenotype of the EGR2-related neuropathies and suggests that the genetic testing of patients suffering from axonal CMT should include the EGR2 gene.

10aAdult10aAged10aAged, 80 and over10aAxons10aCharcot-Marie-Tooth Disease10aEarly Growth Response Protein 210aExome10aFemale10aHumans10aMale10aMiddle Aged10amutation10aPedigree10aPhenotype10aSeverity of Illness Index10aYoung Adult1 aSevilla, T1 aSivera, R1 aMartínez-Rubio, D1 aLupo, V1 aChumillas, M, J1 aCalpena, E1 aDopazo, J1 aVílchez, J, J1 aPalau, F1 aEspinós, C uhttp://clinbioinfosspa.es/content/egr2-gene-involved-axonal-charcot-marie-tooth-disease02548nas a2200373 4500008004100000022001400041245009200055210006900147260000900216300001000225490000600235520144500241653001501686653001601701653000801717653001901725100002301744700001901767700002601786700002501812700002601837700002001863700002001883700002601903700002601929700002201955700001701977700003601994700002102030700002502051700003402076700001902110856004502129 2015 eng d a2045-232200aExome sequencing reveals a high genetic heterogeneity on familial Hirschsprung disease.0 aExome sequencing reveals a high genetic heterogeneity on familia c2015 a164730 v53 aHirschsprung disease (HSCR; OMIM 142623) is a developmental disorder characterized by aganglionosis along variable lengths of the distal gastrointestinal tract, which results in intestinal obstruction. Interactions among known HSCR genes and/or unknown disease susceptibility loci lead to variable severity of phenotype. Neither linkage nor genome-wide association studies have efficiently contributed to completely dissect the genetic pathways underlying this complex genetic disorder. We have performed whole exome sequencing of 16 HSCR patients from 8 unrelated families with SOLID platform. Variants shared by affected relatives were validated by Sanger sequencing. We searched for genes recurrently mutated across families. Only variations in the FAT3 gene were significantly enriched in five families. Within-family analysis identified compound heterozygotes for AHNAK and several genes (N = 23) with heterozygous variants that co-segregated with the phenotype. Network and pathway analyses facilitated the discovery of polygenic inheritance involving FAT3, HSCR known genes and their gene partners. Altogether, our approach has facilitated the detection of more than one damaging variant in biologically plausible genes that could jointly contribute to the phenotype. Our data may contribute to the understanding of the complex interactions that occur during enteric nervous system development and the etiopathology of familial HSCR.10ababelomics10aHirschprung10aNGS10aprioritization1 aLuzón-Toro, Berta1 aGui, Hongsheng1 aRuiz-Ferrer, Macarena1 aTang, Clara, Sze-Man1 aFernández, Raquel, M1 aSham, Pak-Chung1 aTorroglosa, Ana1 aTam, Paul, Kwong-Hang1 aEspino-Paisán, Laura1 aCherny, Stacey, S1 aBleda, Marta1 aEnguix-Riego, María, Del Valle1 aDopazo, Joaquín1 aAntiňolo, Guillermo1 aGarcia-Barceló, Maria-Mercè1 aBorrego, Salud uhttp://www.nature.com/articles/srep1647301072nas a2200289 4500008004100000245009100041210006900132260001600201490000600217100002300223700001900246700002600265700002500291700002700316700002000343700002000363700002600383700002600409700002300435700001700458700003600475700002000511700002500531700003400556700001900590856017300609 2015 eng d00aExome sequencing reveals a high genetic heterogeneity on familial Hirschsprung disease0 aExome sequencing reveals a high genetic heterogeneity on familia cJan-12-20150 v51 aLuzón-Toro, Berta1 aGui, Hongsheng1 aRuiz-Ferrer, Macarena1 aTang, Clara, Sze-Man1 aFernández, Raquel, M.1 aSham, Pak-Chung1 aTorroglosa, Ana1 aTam, Paul, Kwong-Hang1 aEspino-Paisán, Laura1 aCherny, Stacey, S.1 aBleda, Marta1 aEnguix-Riego, María, Del Valle1 aDopazo, Joaquin1 aAntiňolo, Guillermo1 aGarcia-Barceló, Maria-Mercè1 aBorrego, Salud uhttp://www.nature.com/articles/srep16473http://www.nature.com/articles/srep16473.pdfhttp://www.nature.com/articles/srep16473.pdfhttp://www.nature.com/articles/srep1647302220nas a2200265 4500008004100000022001400041245012800055210006900183260001300252300001200265490000800277520128900285100002301574700002801597700002501625700002001650700002001670700001901690700002501709700002301734700002501757700002501782700002101807856012601828 2015 eng d a1600-072200aFamily-based genome-wide association study in Patagonia confirms the association of the DMD locus and cleft lip and palate.0 aFamilybased genomewide association study in Patagonia confirms t c2015 Oct a381-3840 v1233 a

The etiology of cleft lip with or without cleft palate (CL±P) is complex and heterogeneous, and multiple genetic and environmental factors are involved. Some candidate genes reported to be associated with oral clefts are located on the X chromosome. At least three genes causing X-linked syndromes [midline 1 (MID1), oral-facial-digital syndrome 1 (OFD1), and dystrophin (DMD)] were previously found to be associated with isolated CL±P. We attempted to confirm the role of X-linked genes in the etiology of isolated CL±P in a South American population through a family-based genome-wide scan. We studied 27 affected children and their mothers, from 26 families, in a Patagonian population with a high prevalence of CL±P. We conducted an exploratory analysis of the X chromosome to identify candidate regions associated with CL±P. Four genomic segments were identified, two of which showed a statistically significant association with CL±P. One is an 11-kb region of Xp21.1 containing the DMD gene, and the other is an intergenic region (8.7 kb; Xp11.4). Our results are consistent with recent data on the involvement of the DMD gene in the etiology of CL±P. The MID1 and OFD1 genes were not included in the four potential CL±P-associated X-chromosome genomic segments.

1 aFonseca, Renata, F1 ade Carvalho, Flávia, M1 aPoletta, Fernando, A1 aMontaner, David1 aDopazo, Joaquin1 aMereb, Juan, C1 aMoreira, Miguel, A M1 aSeuanez, Hector, N1 aVieira, Alexandre, R1 aCastilla, Eduardo, E1 aOrioli, Iêda, M uhttp://clinbioinfosspa.es/content/family-based-genome-wide-association-study-patagonia-confirms-association-dmd-locus-and02551nas a2200301 4500008004100000022001400041245008500055210006900140260001600209300000700225490000700232520160800239653001501847653001801862653001301880653004201893653001101935653002301946653002701969653001301996100002002009700002002029700002302049700002002072700002002092700002202112856011502134 2015 eng d a1471-210500aFast inexact mapping using advanced tree exploration on backward search methods.0 aFast inexact mapping using advanced tree exploration on backward c2015 Jan 28 a180 v163 a

BACKGROUND: Short sequence mapping methods for Next Generation Sequencing consist on a combination of seeding techniques followed by local alignment based on dynamic programming approaches. Most seeding algorithms are based on backward search alignment, using the Burrows Wheeler Transform, the Ferragina and Manzini Index or Suffix Arrays. All these backward search algorithms have excellent performance, but their computational cost highly increases when allowing errors. In this paper, we discuss an inexact mapping algorithm based on pruning strategies for search tree exploration over genomic data.

RESULTS: The proposed algorithm achieves a 13x speed-up over similar algorithms when allowing 6 base errors, including insertions, deletions and mismatches. This algorithm can deal with 400 bps reads with up to 9 errors in a high quality Illumina dataset. In this example, the algorithm works as a preprocessor that reduces by 55% the number of reads to be aligned. Depending on the aligner the overall execution time is reduced between 20-40%.

CONCLUSIONS: Although not intended as a complete sequence mapping tool, the proposed algorithm could be used as a preprocessing step to modern sequence mappers. This step significantly reduces the number reads to be aligned, accelerating overall alignment time. Furthermore, this algorithm could be used for accelerating the seeding step of already available sequence mappers. In addition, an out-of-core index has been implemented for working with large genomes on systems without expensive memory configurations.

10aAlgorithms10aGenome, Human10aGenomics10aHigh-Throughput Nucleotide Sequencing10aHumans10aSequence Alignment10aSequence Analysis, DNA10aSoftware1 aSalavert, José1 aTomás, Andrés1 aTárraga, Joaquín1 aMedina, Ignacio1 aDopazo, Joaquin1 aBlanquer, Ignacio uhttp://clinbioinfosspa.es/content/fast-inexact-mapping-using-advanced-tree-exploration-backward-search-methods01498nas a2200289 4500008004100000022001400041245014900055210006900204260000800273300000700281490000600288520057300294100002300867700001700890700001900907700002400926700002600950700002000976700002800996700002701024700002701051700002001078700002501098700002001123700001901143856004601162 2015 eng d a1755-879400aIdentification of epistatic interactions through genome-wide association studies in sporadic medullary and juvenile papillary thyroid carcinomas0 aIdentification of epistatic interactions through genomewide asso cDec a830 v83 aThe molecular mechanisms leading to sporadic medullary thyroid carcinoma (sMTC) and juvenile papillary thyroid carcinoma (PTC), two rare tumours of the thyroid gland, remain poorly understood. Genetic studies on thyroid carcinomas have been conducted, although just a few loci have been systematically associated. Given the difficulties to obtain single-loci associations, this work expands its scope to the study of epistatic interactions that could help to understand the genetic architecture of complex diseases and explain new heritable components of genetic risk.1 aLuzón-Toro, Berta1 aBleda, Marta1 aNavarro, Elena1 aGarcía-Alonso, Luz1 aRuiz-Ferrer, Macarena1 aMedina, Ignacio1 aMartín-Sánchez, Marta1 aGonzalez, Cristina, Y.1 aFernández, Raquel, M.1 aTorroglosa, Ana1 aAntiňolo, Guillermo1 aDopazo, Joaquin1 aBorrego, Salud uhttps://doi.org/10.1186/s12920-015-0160-702478nas a2200325 4500008004100000022001400041245015000055210006900205260000900274300000700283490000600290520144200296653001401738653000901752653001901761100002301780700001701803700001901820700002401839700002601863700002001889700002801909700002601937700002601963700002001989700002502009700002002034700001902054856007902073 2015 eng d a1755-879400aIdentification of epistatic interactions through genome-wide association studies in sporadic medullary and juvenile papillary thyroid carcinomas.0 aIdentification of epistatic interactions through genomewide asso c2015 a830 v83 aBACKGROUND: The molecular mechanisms leading to sporadic medullary thyroid carcinoma (sMTC) and juvenile papillary thyroid carcinoma (PTC), two rare tumours of the thyroid gland, remain poorly understood. Genetic studies on thyroid carcinomas have been conducted, although just a few loci have been systematically associated. Given the difficulties to obtain single-loci associations, this work expands its scope to the study of epistatic interactions that could help to understand the genetic architecture of complex diseases and explain new heritable components of genetic risk. METHODS: We carried out the first screening for epistasis by Multifactor-Dimensionality Reduction (MDR) in genome-wide association study (GWAS) on sMTC and juvenile PTC, to identify the potential simultaneous involvement of pairs of variants in the disease. RESULTS: We have identified two significant epistatic gene interactions in sMTC (CHFR-AC016582.2 and C8orf37-RNU1-55P) and three in juvenile PTC (RP11-648k4.2-DIO1, RP11-648k4.2-DMGDH and RP11-648k4.2-LOXL1). Interestingly, each interacting gene pair included a non-coding RNA, providing thus support to the relevance that these elements are increasingly gaining to explain carcinoma development and progression. CONCLUSIONS: Overall, this study contributes to the understanding of the genetic basis of thyroid carcinoma susceptibility in two different case scenarios such as sMTC and juvenile PTC.10aepistasis10aGWAS10aThyroid cancer1 aLuzón-Toro, Berta1 aBleda, Marta1 aNavarro, Elena1 aGarcía-Alonso, Luz1 aRuiz-Ferrer, Macarena1 aMedina, Ignacio1 aMartín-Sánchez, Marta1 aGonzalez, Cristina, Y1 aFernández, Raquel, M1 aTorroglosa, Ana1 aAntiňolo, Guillermo1 aDopazo, Joaquin1 aBorrego, Salud uhttp://bmcmedgenomics.biomedcentral.com/articles/10.1186/s12920-015-0160-702538nas a2200241 4500008004100000022001400041245015600055210006900211260001600280300000700296490000700303520174800310100001802058700002202076700002102098700002002119700002602139700002702165700001602192700002102208700001802229856004902247 2015 eng d a1471-216400aInvolvement of a citrus meiotic recombination TTC-repeat motif in the formation of gross deletions generated by ionizing radiation and MULE activation.0 aInvolvement of a citrus meiotic recombination TTCrepeat motif in c2015 Feb 13 a690 v163 aBACKGROUND: Transposable-element mediated chromosomal rearrangements require the involvement of two transposons and two double-strand breaks (DSB) located in close proximity. In radiobiology, DSB proximity is also a major factor contributing to rearrangements. However, the whole issue of DSB proximity remains virtually unexplored. RESULTS: Based on DNA sequencing analysis we show that the genomes of 2 derived mutations, Arrufatina (sport) and Nero (irradiation), share a similar 2 Mb deletion of chromosome 3. A 7 kb Mutator-like element found in Clemenules was present in Arrufatina in inverted orientation flanking the 5’ end of the deletion. The Arrufatina Mule displayed "dissimilar" 9-bp target site duplications separated by 2 Mb. Fine-scale single nucleotide variant analyses of the deleted fragments identified a TTC-repeat sequence motif located in the center of the deletion responsible of a meiotic crossover detected in the citrus reference genome. CONCLUSIONS: Taken together, this information is compatible with the proposal that in both mutants, the TTC-repeat motif formed a triplex DNA structure generating a loop that brought in close proximity the originally distinct reactive ends. In Arrufatina, the loop brought the Mule ends nearby the 2 distinct insertion target sites and the inverted insertion of the transposable element between these target sites provoked the release of the in-between fragment. This proposal requires the involvement of a unique transposon and sheds light on the unresolved question of how two distinct sites become located in close proximity. These observations confer a crucial role to the TTC-repeats in fundamental plant processes as meiotic recombination and chromosomal rearrangements.1 aTerol, Javier1 aIbañez, Victoria1 aCarbonell, José1 aAlonso, Roberto1 aEstornell, Leandro, H1 aLicciardello, Concetta1 aGut, Ivo, G1 aDopazo, Joaquín1 aTalon, Manuel uhttp://www.biomedcentral.com/1471-2164/16/6901104nas a2200241 4500008004100000022001400041245015500055210006900210260000800279300000700287490000700294520032500301100001800626700002200644700002100666700002000687700002700707700002700734700001700761700002000778700001800798856004600816 2015 eng d a1471-216400aInvolvement of a citrus meiotic recombination TTC-repeat motif in the formation of gross deletions generated by ionizing radiation and MULE activation0 aInvolvement of a citrus meiotic recombination TTCrepeat motif in cFeb a690 v163 aTransposable-element mediated chromosomal rearrangements require the involvement of two transposons and two double-strand breaks (DSB) located in close proximity. In radiobiology, DSB proximity is also a major factor contributing to rearrangements. However, the whole issue of DSB proximity remains virtually unexplored.1 aTerol, Javier1 aIbañez, Victoria1 aCarbonell, José1 aAlonso, Roberto1 aEstornell, Leandro, H.1 aLicciardello, Concetta1 aGut, Ivo, G.1 aDopazo, Joaquin1 aTalon, Manuel uhttps://doi.org/10.1186/s12864-015-1280-302385nas a2200397 4500008004100000022001400041245007600055210006900131260001300200300001300213490000700226520116000233653001201393653001801405653002201423653002201445653002301467653002401490653002801514653003801542653001101580653002001591653002801611653001301639653002201652653001401674653003601688653003201724653002401756100002401780700002401804700001801828700002001846700001701866856010401883 2015 eng d a1553-735800aA Pan-Cancer Catalogue of Cancer Driver Protein Interaction Interfaces.0 aPanCancer Catalogue of Cancer Driver Protein Interaction Interfa c2015 Oct ae10045180 v113 a

Despite their importance in maintaining the integrity of all cellular pathways, the role of mutations on protein-protein interaction (PPI) interfaces as cancer drivers has not been systematically studied. Here we analyzed the mutation patterns of the PPI interfaces from 10,028 proteins in a pan-cancer cohort of 5,989 tumors from 23 projects of The Cancer Genome Atlas (TCGA) to find interfaces enriched in somatic missense mutations. To that end we use e-Driver, an algorithm to analyze the mutation distribution of specific protein functional regions. We identified 103 PPI interfaces enriched in somatic cancer mutations. 32 of these interfaces are found in proteins coded by known cancer driver genes. The remaining 71 interfaces are found in proteins that have not been previously identified as cancer drivers even that, in most cases, there is an extensive literature suggesting they play an important role in cancer. Finally, we integrate these findings with clinical information to show how tumors apparently driven by the same gene have different behaviors, including patient outcomes, depending on which specific interfaces are mutated.

10aAnimals10aBase Sequence10aBiomarkers, Tumor10aCatalogs as Topic10aChromosome Mapping10aComputer Simulation10aDNA Mutational Analysis10aGenetic Predisposition to Disease10aHumans10aModels, Genetic10aMolecular Sequence Data10amutation10aNeoplasm Proteins10aNeoplasms10aPolymorphism, Single Nucleotide10aProtein Interaction Mapping10aSignal Transduction1 aPorta-Pardo, Eduard1 aGarcía-Alonso, Luz1 aHrabe, Thomas1 aDopazo, Joaquin1 aGodzik, Adam uhttp://clinbioinfosspa.es/content/pan-cancer-catalogue-cancer-driver-protein-interaction-interfaces02283nas a2200253 4500008004100000022001400041245009200055210006900147260001600216300001400232490000700246520154200253653001101795653000801806653001601814653000801830100002301838700002001861700002101881700001701902700002001919700002101939856006901960 2015 eng d a1367-481100aA Parallel and Sensitive Software Tool for Methylation Analysis on Multicore Platforms.0 aParallel and Sensitive Software Tool for Methylation Analysis on c2015 Jun 10 a3130-31380 v313 aMOTIVATION: DNA methylation analysis suffers from very long processing time, since the advent of Next-Generation Sequencers (NGS) has shifted the bottleneck of genomic studies from the sequencers that obtain the DNA samples to the software that performs the analysis of these samples. The existing software for methylation analysis does not seem to scale efficiently neither with the size of the dataset nor with the length of the reads to be analyzed. Since it is expected that the sequencers will provide longer and longer reads in the near future, efficient and scalable methylation software should be developed. RESULTS: We present a new software tool, called HPG-Methyl, which efficiently maps bisulfite sequencing reads on DNA, analyzing DNA methylation. The strategy used by this software consists of leveraging the speed of the Burrows-Wheeler Transform to map a large number of DNA fragments (reads) rapidly, as well as the accuracy of the Smith-Waterman algorithm, which is exclusively employed to deal with the most ambiguous and shortest reads. Experimental results on platforms with Intel multicore processors show that HPGMethyl significantly outperforms in both execution time and sensitivity state-of-the-art software such as Bismark, BS-Seeker or BSMAP, particularly for long bisulfite reads. AVAILABILITY: Software in the form of C libraries and functions, together with instructions to compile and execute this software. Available by sftp to anonymous@clariano.uv.es (password "anonymous"). CONTACT: Juan.Orduna@uv.es.10aBS-seq10aHPC10amethylation10aNGS1 aTárraga, Joaquín1 aPérez, Mariano1 aOrduña, Juan, M1 aDuato, José1 aMedina, Ignacio1 aDopazo, Joaquín uhttp://bioinformatics.oxfordjournals.org/content/31/19/3130.long02086nas a2200253 4500008004100000022001400041245014200055210006900197260001600266300001400282490000700296520127300303653001601576653001101592653001401603653000801617100003101625700002001656700002201676700001801698700001801716700002001734856007801754 2015 eng d a1537-171900aA phylogenetic analysis of 34 chloroplast genomes elucidates the relationships between wild and domestic species within the genus Citrus.0 aphylogenetic analysis of 34 chloroplast genomes elucidates the r c2015 Apr 14 a2015-20350 v323 aCitrus genus includes some of the most important cultivated fruit trees worldwide. Despite being extensively studied because of its commercial relevance, the origin of cultivated citrus species and the history of its domestication still remain an open question. Here we present a phylogenetic analysis of the chloroplast genomes of 34 citrus genotypes which constitutes the most comprehensive and detailed study to date on the evolution and variability of the genus Citrus. A statistical model was used to estimate divergence times between the major citrus groups. Additionally, a complete map of the variability across the genome of different citrus species was produced, including single nucleotide variants, heteroplasmic positions, indels and large structural variants. The distribution of all these variants provided further independent support to the phylogeny obtained. An unexpected finding was the high level of heteroplasmy found in several of the analysed genomes. The use of the complete chloroplast DNA not only paves the way for a better understanding of the phylogenetic relationships within the Citrus genus, but also provides original insights into other elusive evolutionary processes such as chloroplast inheritance, heteroplasmy and gene selection.10achloroplast10acitrus10aPhylogeny10aWGS1 aCarbonell-Caballero, José1 aAlonso, Roberto1 aIbañez, Victoria1 aTerol, Javier1 aTalon, Manuel1 aDopazo, Joaquin uhttp://mbe.oxfordjournals.org/content/early/2015/04/27/molbev.msv082.full02147nas a2200301 4500008004100000022001400041245009600055210006900151260001600220520124900236100002101485700002401506700001401530700001401544700002201558700001701580700001701597700001701614700002301631700001701654700001801671700001501689700001901704700001801723700001501741700001801756856007101774 2015 eng d a1546-169600aPrediction of human population responses to toxic compounds by a collaborative competition.0 aPrediction of human population responses to toxic compounds by a c2015 Aug 103 aThe ability to computationally predict the effects of toxic compounds on humans could help address the deficiencies of current chemical safety testing. Here, we report the results from a community-based DREAM challenge to predict toxicities of environmental compounds with potential adverse health effects for human populations. We measured the cytotoxicity of 156 compounds in 884 lymphoblastoid cell lines for which genotype and transcriptional data are available as part of the Tox21 1000 Genomes Project. The challenge participants developed algorithms to predict interindividual variability of toxic response from genomic profiles and population-level cytotoxicity data from structural attributes of the compounds. 179 submitted predictions were evaluated against an experimental data set to which participants were blinded. Individual cytotoxicity predictions were better than random, with modest correlations (Pearson’s r < 0.28), consistent with complex trait genomic prediction. In contrast, predictions of population-level response to different compounds were higher (r < 0.66). The results highlight the possibility of predicting health risks associated with unknown compounds, although risk estimation accuracy remains suboptimal.1 aEduati, Federica1 aMangravite, Lara, M1 aWang, Tao1 aTang, Hao1 aBare, Christopher1 aHuang, Ruili1 aNorman, Thea1 aKellen, Mike1 aMenden, Michael, P1 aYang, Jichen1 aZhan, Xiaowei1 aZhong, Rui1 aXiao, Guanghua1 aXia, Menghang1 aAbdo, Nour1 aKosyk, Oksana uhttp://www.nature.com/nbt/journal/vaop/ncurrent/full/nbt.3299.html02325nas a2200265 4500008004100000022001400041245012000055210006900175260001300244300001300257490000700270520140800277653002301685653001301708653003201721653004301753100001901796700001901815700001601834700002401850700002001874700002401894700001501918856012601933 2015 eng d a1362-496200aPTMcode v2: a resource for functional associations of post-translational modifications within and between proteins.0 aPTMcode v2 a resource for functional associations of posttransla c2015 Jan aD494-5020 v433 a

The post-translational regulation of proteins is mainly driven by two molecular events, their modification by several types of moieties and their interaction with other proteins. These two processes are interdependent and together are responsible for the function of the protein in a particular cell state. Several databases focus on the prediction and compilation of protein-protein interactions (PPIs) and no less on the collection and analysis of protein post-translational modifications (PTMs), however, there are no resources that concentrate on describing the regulatory role of PTMs in PPIs. We developed several methods based on residue co-evolution and proximity to predict the functional associations of pairs of PTMs that we apply to modifications in the same protein and between two interacting proteins. In order to make data available for understudied organisms, PTMcode v2 (http://ptmcode.embl.de) includes a new strategy to propagate PTMs from validated modified sites through orthologous proteins. The second release of PTMcode covers 19 eukaryotic species from which we collected more than 300,000 experimentally verified PTMs (>1,300,000 propagated) of 69 types extracting the post-translational regulation of >100,000 proteins and >100,000 interactions. In total, we report 8 million associations of PTMs regulating single proteins and over 9.4 million interplays tuning PPIs.

10aDatabases, Protein10aInternet10aProtein Interaction Mapping10aProtein Processing, Post-Translational1 aMinguez, Pablo1 aLetunic, Ivica1 aParca, Luca1 aGarcía-Alonso, Luz1 aDopazo, Joaquin1 aHuerta-Cepas, Jaime1 aBork, Peer uhttp://clinbioinfosspa.es/content/ptmcode-v2-resource-functional-associations-post-translational-modifications-within-and02531nas a2200361 4500008004100000022001400041245008000055210006900135260001300204300001300217490000800230520137100238653001801609653004901627653003401676653001701710653001101727653002801738653002301766653001301789653002501802653002701827653001001854100003301864700002301897700002801920700003301948700002201981700002002003700001902023700002502042856010202067 2015 eng d a1552-483300aRe-evaluation casts doubt on the pathogenicity of homozygous USH2A p.C759F.0 aReevaluation casts doubt on the pathogenicity of homozygous USH2 c2015 Jul a1597-6000 v1673 a

Mutations in USH2A are a common cause of Retinitis Pigmentosa (RP). Among the most frequently reported USH2A variants, c.2276G>T (p.C759F) has been found in both affected and healthy individuals. The pathogenicity of this variant remains controversial since it was detected in homozygosity in two healthy siblings of a Spanish family (S23), eleven years ago. The fact that these individuals remain asymptomatic today, prompted us to study the presence of other pathogenic variants in this family using targeted resequencing of 26 retinal genes in one of the affected individuals. This approach allowed us to identify one novel pathogenic homozygous mutation in exon 13 of PDE6B (c.1678C>T; p.R560C). This variant cosegregated with the disease and was absent in 200 control individuals. Remarkably, the identified variant in PDE6B corresponds to the mutation responsible of the retinal degeneration in the naturally occurring rd10 mutant mice. To our knowledge, this is the first report of the identification of the rd10 mice mutation in a RP family. These findings, together with a review of the literature, support the hypothesis that homozygous p.C759F mutations are not pathogenic and led us to exclude the implication of p.C759F in the RP of family S23. Our results indicate the need of re-evaluating all families genetically diagnosed with this mutation.

10aBase Sequence10aCyclic Nucleotide Phosphodiesterases, Type 610aExtracellular Matrix Proteins10aGene Library10aHumans10aMolecular Sequence Data10aMutation, Missense10aPedigree10aRetinitis pigmentosa10aSequence Analysis, DNA10aSpain1 aDel Pozo, María, González-1 aBravo-Gil, Nereida1 aMéndez-Vidal, Cristina1 aMontero-de-Espinosa, Ignacio1 aMillán, José, M1 aDopazo, Joaquin1 aBorrego, Salud1 aAntiňolo, Guillermo uhttp://clinbioinfosspa.es/content/re-evaluation-casts-doubt-pathogenicity-homozygous-ush2a-pc759f02545nas a2200253 4500008004100000022001400041245011200055210006900167260001300236300001100249490000700260520175500267100001902022700002002041700001702061700002002078700001702098700002102115700002302136700002202159700001802181700002102199856007102220 2015 eng d a1872-914200aTherapeutic targets for olive pollen allergy defined by gene markers modulated by Ole e 1-derived peptides.0 aTherapeutic targets for olive pollen allergy defined by gene mar c2015 Apr a252-610 v643 aTwo regions of Ole e 1, the major olive-pollen allergen, have been characterized as T-cell epitopes, one as immunodominant region (aa91-130) and the other, as mainly recognized by non-allergic subjects (aa10-31). This report tries to characterize the specific relevance of these epitopes in the allergic response to olive pollen by analyzing the secreted cytokines and the gene expression profiles induced after specific stimulation of peripheral blood mononuclear cells (PBMCs). PBMCs from olive pollen-allergic and non-allergic control subjects were stimulated with olive-pollen extract and Ole e 1 dodecapeptides containing relevant T-cell epitopes. Levels of cytokines were measured in cellular supernatants and gene expression was determined by microarrays, on the RNAs extracted from PBMCs. One hundred eighty-nine differential genes (fold change >2 or <-2, P<0.05) were validated by qRT-PCR in a large population. It was not possible to define a pattern of response according the overall cytokine results but interesting differences were observed, mainly in the regulatory cytokines. Principal component (PCA) gene-expression analysis defined clusters that correlated with the experimental conditions in the group of allergic subjects. Gene expression and functional analyses revealed differential genes and pathways among the experimental conditions. A set of 51 genes (many essential to T-cell tolerance and homeostasis) correlated with the response to aa10-31 of Ole e 1. In conclusion, two peptides derived from Ole e 1 could regulate the immune response in allergic patients, by gene-expression modification of several regulation-related genes. These results open new research ways to the regulation of allergy by Oleaceae family members.1 aCalzada, David1 aAguerri, Miriam1 aBaos, Selene1 aMontaner, David1 aMata, Manuel1 aDopazo, Joaquín1 aQuiralte, Joaquín1 aFlorido, Fernando1 aLahoz, Carlos1 aCárdaba, Blanca uhttp://www.sciencedirect.com/science/article/pii/S016158901400335601866nas a2200337 4500008004100000022001400041245010900055210006900164260001600233300001000249490000600259520081400265653001501079653002601094653001501120653002101135653001801156653002001174653001101194653001901205653001401224653002001238653001301258653002401271100001901295700003001314700001901344700002401363700002001387856012101407 2015 eng d a2045-232200aUsing activation status of signaling pathways as mechanism-based biomarkers to predict drug sensitivity.0 aUsing activation status of signaling pathways as mechanismbased  c2015 Dec 18 a184940 v53 a

Many complex traits, as drug response, are associated with changes in biological pathways rather than being caused by single gene alterations. Here, a predictive framework is presented in which gene expression data are recoded into activity statuses of signal transduction circuits (sub-pathways within signaling pathways that connect receptor proteins to final effector proteins that trigger cell actions). Such activity values are used as features by a prediction algorithm which can efficiently predict a continuous variable such as the IC50 value. The main advantage of this prediction method is that the features selected by the predictor, the signaling circuits, are themselves rich-informative, mechanism-based biomarkers which provide insight into or drug molecular mechanisms of action (MoA).

10aAlgorithms10aAntineoplastic Agents10abiomarkers10aCell Line, Tumor10aCell Survival10agene expression10aHumans10aLethal Dose 5010aNeoplasms10aPhosphorylation10aProteins10aSignal Transduction1 aAmadoz, Alicia1 aSebastián-Leon, Patricia1 aVidal, Enrique1 aSalavert, Francisco1 aDopazo, Joaquin uhttp://clinbioinfosspa.es/content/using-activation-status-signaling-pathways-mechanism-based-biomarkers-predict-drug02872nas a2200373 4500008004100000022001400041245013900055210006900194260001600263300001400279490000700293520162700300100003001927700002401957700001801981700003201999700002002031700001802051700002802069700002202097700003402119700002602153700003302179700002802212700002702240700001802267700002902285700002002314700002802334700001902362700002002381700001802401856007902419 2015 eng d a1460-208300aWhole Exome Sequencing Reveals ZNF408 as a New Gene Associated With Autosomal Recessive Retinitis Pigmentosa with Vitreal Alterations.0 aWhole Exome Sequencing Reveals ZNF408 as a New Gene Associated W c2015 Apr 16 a4037-40480 v243 aRetinitis Pigmentosa (RP) is a group of progressive inherited retinal dystrophies that cause visual impairment as a result of photoreceptor cell death. RP is heterogeneous, both clinically and genetically making difficult to establish precise genotype-phenotype correlations. In a Spanish family with autosomal recessive RP (arRP), homozygosity mapping and whole exome sequencing led to the identification of a homozygous mutation (c.358_359delGT; p.Ala122Leufs*2) in the ZNF408 gene. A screening performed in 217 additional unrelated families revealed another homozygous mutation (c.1621C>T; p.Arg541Cys) in an isolated RP case. ZNF408 encodes a transcription factor that harbors ten predicted C2H2-type fingers thought to be implicated in DNA binding. To elucidate the ZNF408 role in the retina and the pathogenesis of these mutations we have performed different functional studies. By immunohistochemical analysis in healthy human retina, we identified that ZNF408 is expressed in both cone and rod photoreceptors, in a specific type of amacrine and ganglion cells, and in retinal blood vessels. ZNF408 revealed a cytoplasmic localization and a nuclear distribution in areas corresponding with the euchromatin fraction. Immunolocalization studies showed a partial mislocalization of the p.Arg541Cys mutant protein retaining part of the WT protein in the cytoplasm. Our study demonstrates that ZNF408, previously associated with Familial Exudative Vitreoretinopathy (FEVR), is a new gene causing arRP with vitreous condensations supporting the evidence that this protein plays additional functions into the human retina.1 aAvila-Fernandez, Almudena1 aPerez-Carro, Raquel1 aCorton, Marta1 aLopez-Molina, Maria, Isabel1 aCampello, Laura1 aGaranto, Alex1 aFernadez-Sanchez, Laura1 aDuijkers, Lonneke1 aLopez-Martinez, Miguel, Angel1 aRiveiro-Alvarez, Rosa1 ada Silva, Luciana, Rodrigues1 aSanchez-Alcudia, Rocío1 aMartin-Garrido, Esther1 aReyes, Noelia1 aGarcia-Garcia, Francisco1 aDopazo, Joaquin1 aGarcia-Sandoval, Blanca1 aCollin, Rob, W1 aCuenca, Nicolas1 aAyuso, Carmen uhttp://hmg.oxfordjournals.org/content/early/2015/04/16/hmg.ddv140.abstract03593nas a2200601 4500008004100000022001400041245013900055210006900194260001600263300001200279490000700291520163400298653002401932653001201956653002501968653002301993653001402016653002502030653001002055653003402065653004202099653001502141653001102156653002802167653002002195653001302215653001102228653003702239653003602276653002502312653002602337100003002363700002402393700001802417700003202435700002002467700002302487700002902510700002202539700003402561700002602595700003302621700002802654700002702682700001802709700002902727700002002756700002802776700002102804700002002825700001802845856012802863 2015 eng d a1460-208300aWhole-exome sequencing reveals ZNF408 as a new gene associated with autosomal recessive retinitis pigmentosa with vitreal alterations.0 aWholeexome sequencing reveals ZNF408 as a new gene associated wi c2015 Jul 15 a4037-480 v243 a

Retinitis pigmentosa (RP) is a group of progressive inherited retinal dystrophies that cause visual impairment as a result of photoreceptor cell death. RP is heterogeneous, both clinically and genetically making difficult to establish precise genotype-phenotype correlations. In a Spanish family with autosomal recessive RP (arRP), homozygosity mapping and whole-exome sequencing led to the identification of a homozygous mutation (c.358_359delGT; p.Ala122Leufs*2) in the ZNF408 gene. A screening performed in 217 additional unrelated families revealed another homozygous mutation (c.1621C>T; p.Arg541Cys) in an isolated RP case. ZNF408 encodes a transcription factor that harbors 10 predicted C2H2-type fingers thought to be implicated in DNA binding. To elucidate the ZNF408 role in the retina and the pathogenesis of these mutations we have performed different functional studies. By immunohistochemical analysis in healthy human retina, we identified that ZNF408 is expressed in both cone and rod photoreceptors, in a specific type of amacrine and ganglion cells, and in retinal blood vessels. ZNF408 revealed a cytoplasmic localization and a nuclear distribution in areas corresponding with the euchromatin fraction. Immunolocalization studies showed a partial mislocalization of the p.Arg541Cys mutant protein retaining part of the WT protein in the cytoplasm. Our study demonstrates that ZNF408, previously associated with Familial Exudative Vitreoretinopathy (FEVR), is a new gene causing arRP with vitreous condensations supporting the evidence that this protein plays additional functions into the human retina.

10aAmino Acid Sequence10aAnimals10aChlorocebus aethiops10aChromosome Mapping10aCOS Cells10aDNA-Binding Proteins10aExome10aGenome-Wide Association Study10aHigh-Throughput Nucleotide Sequencing10aHomozygote10aHumans10aMolecular Sequence Data10aMutant Proteins10aPedigree10aRetina10aRetinal Cone Photoreceptor Cells10aRetinal Rod Photoreceptor Cells10aRetinitis pigmentosa10aTranscription Factors1 aAvila-Fernandez, Almudena1 aPerez-Carro, Raquel1 aCorton, Marta1 aLopez-Molina, Maria, Isabel1 aCampello, Laura1 aGaranto, Alejandro1 aFernandez-Sanchez, Laura1 aDuijkers, Lonneke1 aLopez-Martinez, Miguel, Angel1 aRiveiro-Alvarez, Rosa1 ada Silva, Luciana, Rodrigues1 aSanchez-Alcudia, Rocío1 aMartin-Garrido, Esther1 aReyes, Noelia1 aGarcia-Garcia, Francisco1 aDopazo, Joaquin1 aGarcia-Sandoval, Blanca1 aCollin, Rob, W J1 aCuenca, Nicolas1 aAyuso, Carmen uhttp://clinbioinfosspa.es/content/whole-exome-sequencing-reveals-znf408-new-gene-associated-autosomal-recessive-retinitis-001441nas a2200265 4500008004100000022001400041245009700055210006900152260001600221300001400237490000700251520057300258653000800831653004300839100002300882700001900905700002100924700001700945700001900962700002700981700002901008700002101037700002001058856009701078 2014 eng d a1367-481100aAcceleration of short and long DNA read mapping without loss of accuracy using suffix array.0 aAcceleration of short and long DNA read mapping without loss of  c2014 Aug 20 a3396-33980 v303 aHPG Aligner applies suffix arrays for DNA read mapping. This implementation produces a highly sensitive and extremely fast mapping of DNA reads that scales up almost linearly with read length. The approach presented here is faster (over 20x for long reads) and more sensitive (over 98% in a wide range of read lengths) than the current, state-of-the-art mappers. HPG Aligner is not only an optimal alternative for current sequencers but also the only solution available to cope with longer reads and growing throughputs produced by forthcoming sequencing technologies.10aNGS10ashort read mapping. HPC. suffix arrays1 aTárraga, Joaquín1 aArnau, Vicente1 aMartinez, Hector1 aMoreno, Raul1 aCazorla, Diego1 aSalavert-Torres, José1 aBlanquer-Espert, Ignacio1 aDopazo, Joaquín1 aMedina, Ignacio uhttp://bioinformatics.oxfordjournals.org/content/early/2014/08/19/bioinformatics.btu553.long02163nas a2200289 4500008004100000022001400041245017000055210006900225260000900294300000800303490000600311520111200317100002701429700001601456700002901472700002601501700002901527700001901556700002101575700002901596700002701625700002001652700002401672700002401696700002601720856012701746 2014 eng d a2234-943X00aThe Activation of the Sox2 RR2 Pluripotency Transcriptional Reporter in Human Breast Cancer Cell Lines is Dynamic and Labels Cells with Higher Tumorigenic Potential.0 aActivation of the Sox2 RR2 Pluripotency Transcriptional Reporter c2014 a3080 v43 a

The striking similarity displayed at the mechanistic level between tumorigenesis and the generation of induced pluripotent stem cells and the fact that genes and pathways relevant for embryonic development are reactivated during tumor progression highlights the link between pluripotency and cancer. Based on these observations, we tested whether it is possible to use a pluripotency-associated transcriptional reporter, whose activation is driven by the SRR2 enhancer from the Sox2 gene promoter (named S4+ reporter), to isolate cancer stem cells (CSCs) from breast cancer cell lines. The S4+ pluripotency transcriptional reporter allows the isolation of cells with enhanced tumorigenic potential and its activation was switched on and off in the cell lines studied, reflecting a plastic cellular process. Microarray analysis comparing the populations in which the reporter construct is active versus inactive showed that positive cells expressed higher mRNA levels of cytokines (IL-8, IL-6, TNF) and genes (such as ATF3, SNAI2, and KLF6) previously related with the CSC phenotype in breast cancer.

1 aIglesias, Juan, Manuel1 aLeis, Olatz1 aRuiz, Estíbaliz, Pérez1 aBarrie, Juan, Gumuzio1 aGarcia-Garcia, Francisco1 aAduriz, Ariane1 aBeloqui, Izaskun1 aHernandez-Garcia, Susana1 aLopez-Mato, Maria, Paz1 aDopazo, Joaquin1 aPandiella, Atanasio1 aMenendez, Javier, A1 aMartin, Angel, Garcia uhttp://clinbioinfosspa.es/content/activation-sox2-rr2-pluripotency-transcriptional-reporter-human-breast-cancer-cell-lines02676nas a2200541 4500008004100000022001400041245013100055210006900186260000900255300000900264490000600273520115300279653001201432100002001444700002001464700001601484700001701500700002501517700001601542700002001558700001801578700002101596700001801617700002001635700002001655700002101675700001401696700001501710700001801725700001901743700002601762700002701788700002701815700001601842700001301858700002101871700002601892700001801918700001601936700001801952700001501970700001501985700001302000700001502013700001302028700001602041856007702057 2014 eng d a2041-172300aAssessing technical performance in differential gene expression experiments with external spike-in RNA control ratio mixtures.0 aAssessing technical performance in differential gene expression  c2014 a51250 v53 aThere is a critical need for standard approaches to assess, report and compare the technical performance of genome-scale differential gene expression experiments. Here we assess technical performance with a proposed standard ’dashboard’ of metrics derived from analysis of external spike-in RNA control ratio mixtures. These control ratio mixtures with defined abundance ratios enable assessment of diagnostic performance of differentially expressed transcript lists, limit of detection of ratio (LODR) estimates and expression ratio variability and measurement bias. The performance metrics suite is applicable to analysis of a typical experiment, and here we also apply these metrics to evaluate technical performance among laboratories. An interlaboratory study using identical samples shared among 12 laboratories with three different measurement processes demonstrates generally consistent diagnostic power across 11 laboratories. Ratio measurement variability and bias are also comparable among laboratories for the same measurement process. We observe different biases for measurement processes using different mRNA-enrichment protocols.10aRNA-seq1 aMunro, Sarah, A1 aLund, Steven, P1 aPine, Scott1 aBinder, Hans1 aClevert, Djork-Arné1 aConesa, Ana1 aDopazo, Joaquin1 aFasold, Mario1 aHochreiter, Sepp1 aHong, Huixiao1 aJafari, Nadereh1 aKreil, David, P1 aLabaj, Paweł, P1 aLi, Sheng1 aLiao, Yang1 aLin, Simon, M1 aMeehan, Joseph1 aMason, Christopher, E1 aSantoyo-López, Javier1 aSetterquist, Robert, A1 aShi, Leming1 aShi, Wei1 aSmyth, Gordon, K1 aStralis-Pavese, Nancy1 aSu, Zhenqiang1 aTong, Weida1 aWang, Charles1 aWang, Jian1 aXu, Joshua1 aYe, Zhan1 aYang, Yong1 aYu, Ying1 aSalit, Marc uhttp://www.nature.com/ncomms/2014/140925/ncomms6125/full/ncomms6125.html02750nas a2200217 4500008004100000022001400041245011000055210006900165260000900234300001100243490000600254520206500260100002702325700002002352700002402372700001602396700002102412700001902433700002802452856005202480 2014 eng d a1932-620300aCombined genetic and high-throughput strategies for molecular diagnosis of inherited retinal dystrophies.0 aCombined genetic and highthroughput strategies for molecular dia c2014 ae884100 v93 aMost diagnostic laboratories are confronted with the increasing demand for molecular diagnosis from patients and families and the ever-increasing genetic heterogeneity of visual disorders. Concerning Retinal Dystrophies (RD), almost 200 causative genes have been reported to date, and most families carry private mutations. We aimed to approach RD genetic diagnosis using all the available genetic information to prioritize candidates for mutational screening, and then restrict the number of cases to be analyzed by massive sequencing. We constructed and optimized a comprehensive cosegregation RD-chip based on SNP genotyping and haplotype analysis. The RD-chip allows to genotype 768 selected SNPs (closely linked to 100 RD causative genes) in a single cost-, time-effective step. Full diagnosis was attained in 17/36 Spanish pedigrees, yielding 12 new and 12 previously reported mutations in 9 RD genes. The most frequently mutated genes were USH2A and CRB1. Notably, RD3-up to now only associated to Leber Congenital Amaurosis- was identified as causative of Retinitis Pigmentosa. The main assets of the RD-chip are: i) the robustness of the genetic information that underscores the most probable candidates, ii) the invaluable clues in cases of shared haplotypes, which are indicative of a common founder effect, and iii) the detection of extended haplotypes over closely mapping genes, which substantiates cosegregation, although the assumptions in which the genetic analysis is based could exceptionally lead astray. The combination of the genetic approach with whole exome sequencing (WES) greatly increases the diagnosis efficiency, and revealed novel mutations in USH2A and GUCY2D. Overall, the RD-chip diagnosis efficiency ranges from 16% in dominant, to 80% in consanguineous recessive pedigrees, with an average of 47%, well within the upper range of massive sequencing approaches, highlighting the validity of this time- and cost-effective approach whilst high-throughput methodologies become amenable for routine diagnosis in medium sized labs.1 ade Castro-Miró, Marta1 aPomares, Esther1 aLorés-Motta, Laura1 aTonda, Raul1 aDopazo, Joaquín1 aMarfany, Gemma1 aGonzàlez-Duarte, Roser uhttp://dx.plos.org/10.1371/journal.pone.008841001916nas a2200253 4500008004100000022001400041245013800055210006900193260001600262300001400278490000700292520118400299653000801483653001201491653000901503100001101512700001601523700000501539700001501544700000501559700001601564700001101580856007101591 2014 eng d a1546-169600aA comprehensive assessment of RNA-seq accuracy, reproducibility and information content by the Sequencing Quality Control Consortium.0 acomprehensive assessment of RNAseq accuracy reproducibility and  c2014 Aug 24 a903–9140 v323 aWe present primary results from the Sequencing Quality Control (SEQC) project, coordinated by the US Food and Drug Administration. Examining Illumina HiSeq, Life Technologies SOLiD and Roche 454 platforms at multiple laboratory sites using reference RNA samples with built-in controls, we assess RNA sequencing (RNA-seq) performance for junction discovery and differential expression profiling and compare it to microarray and quantitative PCR (qPCR) data using complementary metrics. At all sequencing depths, we discover unannotated exon-exon junctions, with >80% validated by qPCR. We find that measurements of relative expression are accurate and reproducible across sites and platforms if specific filters are used. In contrast, RNA-seq and microarrays do not provide accurate absolute measurements, and gene-specific biases are observed for all examined platforms, including qPCR. Measurement performance depends on the platform and data analysis pipeline, and variation is large for transcript-level profiling. The complete SEQC data sets, comprising >100 billion reads (10Tb), provide unique resources for evaluating RNA-seq analyses for clinical and regulatory settings.10aNGS10aRNA-seq10aSEQC1 aSu, Z.1 aLabaj, P.P.1 a1 aDopazo, J.1 a1 aMason, C.E.1 aShi, L uhttp://www.nature.com/nbt/journal/vaop/ncurrent/full/nbt.2957.html02423nas a2200433 4500008004100000022001400041245008500055210006900140260001500209300001400224490000700238520117700245653001501422653001601437653003101453100002001484700002201504700001901526700001901545700001701564700002201581700001901603700002601622700001801648700002301666700002201689700002101711700002001732700001801752700002001770700003001790700002301820700002501843700002001868700002001888700001301908700002001921856004801941 2014 eng d a1538-744500aA Comprehensive DNA Methylation Profile of Epithelial-to-Mesenchymal Transition.0 aComprehensive DNA Methylation Profile of EpithelialtoMesenchymal c2014 Aug 8 a5608–190 v743 aEpithelial-to-mesenchymal transition (EMT) is a plastic process in which fully differentiated epithelial cells are converted into poorly differentiated, migratory and invasive mesenchymal cells and it has been related to the metastasis potential of tumors. This is a reversible process and cells can also eventually undergo mesenchymal-to-epithelial transition (MET). The existence of a dynamic EMT process suggests the involvement of epigenetic shifts in the phenotype. Herein, we obtained the DNA methylomes at single-base resolution of MDCK cells undergoing epithelial-to-mesenchymal transition (EMT) and translated the identified differentially methylated regions (DMRs) to human breast cancer cells undergoing a gain of migratory and invasive capabilities associated with the EMT phenotype. We noticed dynamic and reversible changes of DNA methylation, both on promoter sequences and gene-bodies in association with transcription regulation of EMT-related genes. Most importantly, the identified DNA methylation markers of EMT were present in primary mammary tumors in association with the epithelial or the mesenchymal phenotype of the studied breast cancer samples.10aMethyl-Seq10aMethylomics10aNext Generation Sequencing1 aCarmona, Javier1 aDavalos, Veronica1 aVidal, Enrique1 aGomez, Antonio1 aHeyn, Holger1 aHashimoto, Yutaka1 aVizoso, Miguel1 aMartinez-Cardus, Anna1 aSayols, Sergi1 aFerreira, Humberto1 aSanchez-Mut, Jose1 aMoran, Sebastian1 aMargeli, Mireia1 aCastella, Eva1 aBerdasco, Maria1 aStefansson, Olafur, Andri1 aEyfjord, Jorunn, E1 aGonzalez-Suarez, Eva1 aDopazo, Joaquin1 aOrozco, Modesto1 aGut, Ivo1 aEsteller, Manel uhttp://www.ncbi.nlm.nih.gov/pubmed/2510642702250nas a2200241 4500008004100000245010000041210006900141300001200210490000600222520144700228100003301675700002801708700002701736700002201763700002301785700001901808700002401827700003201851700002101883700001901904700002501923856006001948 2014 eng d00aDeciphering intrafamilial phenotypic variability by exome sequencing in a Bardet–Biedl family0 aDeciphering intrafamilial phenotypic variability by exome sequen a124-1330 v23 aBardet–Biedl syndrome (BBS) is a model ciliopathy characterized by a wide range of clinical variability. The heterogeneity of this condition is reflected in the number of underlying gene defects and the epistatic interactions between the proteins encoded. BBS is generally inherited in an autosomal recessive trait. However, in some families, mutations across different loci interact to modulate the expressivity of the phenotype. In order to investigate the magnitude of epistasis in one BBS family with remarkable intrafamilial phenotypic variability, we designed an exome sequencing–based approach using SOLID 5500xl platform. This strategy allowed the reliable detection of the primary causal mutations in our family consisting of two novel compound heterozygous mutations in McKusick–Kaufman syndrome (MKKS) gene (p.D90G and p.V396F). Additionally, exome sequencing enabled the detection of one novel heterozygous NPHP4 variant which is predicted to activate a cryptic acceptor splice site and is only present in the most severely affected patient. Here, we provide an exome sequencing analysis of a BBS family and show the potential utility of this tool, in combination with network analysis, to detect disease-causing mutations and second-site modifiers. Our data demonstrate how next-generation sequencing (NGS) can facilitate the dissection of epistatic phenomena, and shed light on the genetic basis of phenotypic variability.1 adel Pozo, María, González-1 aMéndez-Vidal, Cristina1 aSantoyo-López, Javier1 aVela-Boza, Alicia1 aBravo-Gil, Nereida1 aRueda, Antonio1 aGarcía-Alonso, Luz1 aVázquez-Marouschek, Carmen1 aDopazo, Joaquín1 aBorrego, Salud1 aAntiňolo, Guillermo uhttp://onlinelibrary.wiley.com/doi/10.1002/mgg3.50/full02364nas a2200265 4500008004100000022001400041245009900055210006900154260001300223300001100236490000600247520144900253100003301702700002801735700002701763700002201790700002301812700001901835700002401854700003201878700002001910700001901930700002501949856012401974 2014 eng d a2324-926900aDeciphering intrafamilial phenotypic variability by exome sequencing in a Bardet-Biedl family.0 aDeciphering intrafamilial phenotypic variability by exome sequen c2014 Mar a124-330 v23 a

Bardet-Biedl syndrome (BBS) is a model ciliopathy characterized by a wide range of clinical variability. The heterogeneity of this condition is reflected in the number of underlying gene defects and the epistatic interactions between the proteins encoded. BBS is generally inherited in an autosomal recessive trait. However, in some families, mutations across different loci interact to modulate the expressivity of the phenotype. In order to investigate the magnitude of epistasis in one BBS family with remarkable intrafamilial phenotypic variability, we designed an exome sequencing-based approach using SOLID 5500xl platform. This strategy allowed the reliable detection of the primary causal mutations in our family consisting of two novel compound heterozygous mutations in McKusick-Kaufman syndrome (MKKS) gene (p.D90G and p.V396F). Additionally, exome sequencing enabled the detection of one novel heterozygous NPHP4 variant which is predicted to activate a cryptic acceptor splice site and is only present in the most severely affected patient. Here, we provide an exome sequencing analysis of a BBS family and show the potential utility of this tool, in combination with network analysis, to detect disease-causing mutations and second-site modifiers. Our data demonstrate how next-generation sequencing (NGS) can facilitate the dissection of epistatic phenomena, and shed light on the genetic basis of phenotypic variability.

1 adel Pozo, María, González-1 aMéndez-Vidal, Cristina1 aSantoyo-López, Javier1 aVela-Boza, Alicia1 aBravo-Gil, Nereida1 aRueda, Antonio1 aGarcía-Alonso, Luz1 aVázquez-Marouschek, Carmen1 aDopazo, Joaquin1 aBorrego, Salud1 aAntiňolo, Guillermo uhttp://clinbioinfosspa.es/content/deciphering-intrafamilial-phenotypic-variability-exome-sequencing-bardet-biedl-family02775nas a2200445 4500008004100000022001400041245012000055210006900175260000900244300001200253490000600265520144600271653001501717653001001732653002401742653001801766653001001784653002701794653002801821653001001849653001101859653001101870653001101881653002501892653000901917653001601926653002801942653001301970653001301983653002401996653001402020100003302034700002802067700002302095700002202118700002002140700001902160700002502179856012502204 2014 eng d a1932-620300aExome sequencing reveals novel and recurrent mutations with clinical significance in inherited retinal dystrophies.0 aExome sequencing reveals novel and recurrent mutations with clin c2014 ae1161760 v93 a

This study aimed to identify the underlying molecular genetic cause in four Spanish families clinically diagnosed of Retinitis Pigmentosa (RP), comprising one autosomal dominant RP (adRP), two autosomal recessive RP (arRP) and one with two possible modes of inheritance: arRP or X-Linked RP (XLRP). We performed whole exome sequencing (WES) using NimbleGen SeqCap EZ Exome V3 sample preparation kit and SOLID 5500xl platform. All variants passing filter criteria were validated by Sanger sequencing to confirm familial segregation and the absence in local control population. This strategy allowed the detection of: (i) one novel heterozygous splice-site deletion in RHO, c.937-2_944del, (ii) one rare homozygous mutation in C2orf71, c.1795T>C; p.Cys599Arg, not previously associated with the disease, (iii) two heterozygous null mutations in ABCA4, c.2041C>T; p.R681* and c.6088C>T; p.R2030*, and (iv) one mutation, c.2405-2406delAG; p.Glu802Glyfs*31 in the ORF15 of RPGR. The molecular findings for RHO and C2orf71 confirmed the initial diagnosis of adRP and arRP, respectively, while patients with the two ABCA4 mutations, both previously associated with Stargardt disease, presented symptoms of RP with early macular involvement. Finally, the X-Linked inheritance was confirmed for the family with the RPGR mutation. This latter finding allowed the inclusion of carrier sisters in our preimplantational genetic diagnosis program.

10aAdolescent10aAdult10aAmino Acid Sequence10aBase Sequence10aChild10aChromosome Segregation10aDNA Mutational Analysis10aExome10aFamily10aFemale10aHumans10aInheritance Patterns10aMale10aMiddle Aged10aMolecular Sequence Data10amutation10aPedigree10aRetinal Dystrophies10aRhodopsin1 adel Pozo, María, González-1 aMéndez-Vidal, Cristina1 aBravo-Gil, Nereida1 aVela-Boza, Alicia1 aDopazo, Joaquin1 aBorrego, Salud1 aAntiňolo, Guillermo uhttp://clinbioinfosspa.es/content/exome-sequencing-reveals-novel-and-recurrent-mutations-clinical-significance-inherited01427nas a2200229 4500008004100000022001400041245005200055210005100107260001600158300001100174490000700185520080300192653002000995653001901015653002301034653001701057653001301074653002101087653002101108100002001129856004801149 2014 eng d a1878-583200aGenomics and transcriptomics in drug discovery.0 aGenomics and transcriptomics in drug discovery c2013 Jun 14 a126-320 v193 aThe popularization of genomic high-throughput technologies is causing a revolution in biomedical research and, particularly, is transforming the field of drug discovery. Systems biology offers a framework to understand the extensive human genetic heterogeneity revealed by genomic sequencing in the context of the network of functional, regulatory and physical protein-drug interactions. Thus, approaches to find biomarkers and therapeutic targets will have to take into account the complex system nature of the relationships of the proteins with the disease. Pharmaceutical companies will have to reorient their drug discovery strategies considering the human genetic heterogeneity. Consequently, modeling and computational data analysis will have an increasingly important role in drug discovery.10aadverse effects10aDrug discovery10adrug repositioning10ametagenomics10amodeling10anetwork analysis10apathway analysis1 aDopazo, Joaquin uhttp://www.ncbi.nlm.nih.gov/pubmed/2377386001989nas a2200181 4500008004100000245008700041210006900128300001400197490000800211520142000219100001901639700001801658700001801676700001501694700001501709700001701724856006601741 2014 eng d00aMolecular interactions between sugar beet and Polymyxa betae during its life cycle0 aMolecular interactions between sugar beet and Polymyxa betae dur a244–2560 v1643 aPolymyxa betae is a biotrophic obligate sugar beet parasite that belongs to plasmodiophorids. The infection of sugar beet roots by this parasite is asymptomatic, except when it transmits Beet necrotic yellow vein virus (BNYVV), the causal agent of rhizomania. To date, there has been little work on P. betae–sugar beet molecular interactions, mainly because of the obligate nature of the parasite and also because research on rhizomania has tended to focus on the virus. In this study, we investigated these interactions through differential transcript analysis, using suppressive subtractive hybridization. The analysis included 76 P. betae and 120 sugar beet expressed sequence tags (ESTs). The expression of selected ESTs from both organisms was monitored during the protist life cycle, revealing a potential role of two P. betae proteins, profilin and a Von Willebrand factor domain-containing protein, in the early phase of infection. This study also revealed an over-expression of some sugar beet genes involved in defence, such as those encoding PR proteins, stress resistance proteins or lectins, especially during the plasmodial stage of the P. betae life cycle. In addition to providing new information on the molecular aspects of P. betae–sugar beet interactions, this study also enabled previously unknown ESTs of P. betae to be sequenced, thus enhancing our knowledge of the genome of this protist.1 aDesoignies, N.1 aCarbonell, J.1 aMoreau, J.-S.1 aConesa, A.1 aDopazo, J.1 aLegrève, A. uhttp://onlinelibrary.wiley.com/doi/10.1111/aab.12095/abstract02492nas a2200577 4500008004100000022001400041245006100055210005800116260001500174300001600189490000700205520082400212653000801036653001901044653001701063100001801080700002101098700002101119700002801140700002301168700001701191700002201208700002201230700003001252700001601282700002001298700002601318700002901344700002201373700002201395700002001417700002901437700002701466700002101493700001701514700002201531700002101553700002401574700002201598700002901620700002701649700002001676700002001696700002501716700002101741700002001762700001601782700002801798700002101826856006701847 2014 eng d a1098-100400aA New Overgrowth Syndrome is Due to Mutations in RNF125.0 aNew Overgrowth Syndrome is Due to Mutations in RNF125 c2014 Sep 5 a1436–14410 v353 aOvergrowth syndromes (OGS) are a group of disorders in which all parameters of growth and physical development are above the mean for age and sex. We evaluated a series of 270 families from the Spanish Overgrowth Syndrome Registry with no known overgrowth syndrome. We identified one de novo deletion and three missense mutations in RNF125 in six patients from 4 families with overgrowth, macrocephaly, intellectual disability, mild hydrocephaly, hypoglycaemia and inflammatory diseases resembling Sjögren syndrome. RNF125 encodes an E3 ubiquitin ligase and is a novel gene of OGS. Our studies of the RNF125 pathway point to upregulation of RIG-I-IPS1-MDA5 and/or disruption of the PI3K-AKT and interferon signaling pathways as the putative final effectors. This article is protected by copyright. All rights reserved.10aNGS10aprioritization10aRare Disease1 aTenorio, Jair1 aMansilla, Alicia1 aValencia, María1 aMartínez-Glez, Víctor1 aRomanelli, Valeria1 aArias, Pedro1 aCastrejón, Nerea1 aPoletta, Fernando1 aGuillén-Navarro, Encarna1 aGordo, Gema1 aMansilla, Elena1 aGarcía-Santiago, Fé1 aGonzález-Casado, Isabel1 aVallespín, Elena1 aPalomares, María1 aMori, María, A1 aSantos-Simarro, Fernando1 aGarcía-Miñaur, Sixto1 aFernández, Luis1 aMena, Rocío1 aBenito-Sanz, Sara1 aDel Pozo, Angela1 aSilla, Juan, Carlos1 aIbañez, Kristina1 aLópez-Granados, Eduardo1 aMartín-Trujillo, Alex1 aMontaner, David1 aHeath, Karen, E1 aCampos-Barros, Angel1 aDopazo, Joaquín1 aNevado, Julián1 aMonk, David1 aRuiz-Pérez, Víctor, L1 aLapunzina, Pablo uhttp://onlinelibrary.wiley.com/doi/10.1002/humu.22689/abstract01909nas a2200265 4500008004100000022001400041245007900055210006900134260001600203300001100219490000700230520106400237653001001301653001801311653004201329653001101371653002701382653001301409100003301422700002301455700001901478700002001497700002701517856009901544 2014 eng d a1367-481100angsCAT: a tool to assess the efficiency of targeted enrichment sequencing.0 angsCAT a tool to assess the efficiency of targeted enrichment se c2014 Jun 15 a1767-80 v303 a

MOTIVATION: Targeted enrichment sequencing by next-generation sequencing is a common approach to interrogate specific loci or the whole exome in the human genome. The efficiency and the lack of bias in the enrichment process need to be assessed as a quality control step before performing downstream analysis of the sequence data. Tools that can report on the sensitivity, specificity, uniformity and other enrichment-specific features are needed.

RESULTS: We have implemented the next-generation sequencing data Capture Assessment Tool (ngsCAT), a tool that takes the information of the mapped reads and the coordinates of the targeted regions as input files, and generates a report with metrics and figures that allows the evaluation of the efficiency of the enrichment process. The tool can also take as input the information of two samples allowing the comparison of two different experiments.

AVAILABILITY AND IMPLEMENTATION: Documentation and downloads for ngsCAT can be found at http://www.bioinfomgp.org/ngscat.

10aExome10aGenome, Human10aHigh-Throughput Nucleotide Sequencing10aHumans10aSequence Analysis, DNA10aSoftware1 aLópez-Domingo, Francisco, J1 aFlorido, Javier, P1 aRueda, Antonio1 aDopazo, Joaquin1 aSantoyo-López, Javier uhttp://clinbioinfosspa.es/content/ngscat-tool-assess-efficiency-targeted-enrichment-sequencing01770nas a2200229 4500008004100000022001400041245007700055210006900132260001500201300001000216490000700226520109900233100001501332700002301347700001201370700002501382700001701407700001501424700001301439700001601452856007201468 2014 eng d a1873-236400aA novel locus for a hereditary recurrent neuropathy on chromosome 21q21.0 anovel locus for a hereditary recurrent neuropathy on chromosome  c2014 May 9 a660-50 v243 aHereditary recurrent neuropathies are uncommon. Disorders with a known molecular basis falling within this group include hereditary neuropathy with liability to pressure palsies (HNPP) due to the deletion of the PMP22 gene or to mutations in this same gene, and hereditary neuralgic amyotrophy (HNA) caused by mutations in the SEPT9 gene. We report a three-generation family presenting a hereditary recurrent neuropathy without pathological changes in either PMP22 or SEPT9 genes. We performed a genome-wide mapping, which yielded a locus of 12.4Mb on chromosome 21q21. The constructed haplotype fully segregated with the disease and we found significant evidence of linkage. After mutational screening of genes located within this locus, encoding for proteins and microRNAs, as well as analysis of large deletions/insertions, we identified 71 benign polymorphisms. Our findings suggest a novel genetic locus for a recurrent hereditary neuropathy of which the molecular defect remains elusive. Our results further underscore the clinical and genetic heterogeneity of this group of neuropathies.1 aCalpena, E1 aMartínez-Rubio, D1 aArpa, J1 aGarcía-Peñas, J, J1 aMontaner, D.1 aDopazo, J.1 aPalau, F1 aEspinós, C uhttp://www.sciencedirect.com/science/article/pii/S0960896614001060#03760nas a2200397 4500008004100000022001400041245013500055210006900190260001600259300000800275490000700283520244800290653002602738653001802764653002502782653002802807653001702835653002102852653003202873653001102905653002702916653003602943653002302979653001303002653001403015653001103029653002503040100002803065700002303093700003303116700002203149700002003171700001903191700002503210856012703235 2014 eng d a1471-215600aNovel RP1 mutations and a recurrent BBS1 variant explain the co-existence of two distinct retinal phenotypes in the same pedigree.0 aNovel RP1 mutations and a recurrent BBS1 variant explain the coe c2014 Dec 14 a1430 v153 a

BACKGROUND: Molecular diagnosis of Inherited Retinal Dystrophies (IRD) has long been challenging due to the extensive clinical and genetic heterogeneity present in this group of disorders. Here, we describe the clinical application of an integrated next-generation sequencing approach to determine the underlying genetic defects in a Spanish family with a provisional clinical diagnosis of autosomal recessive Retinitis Pigmentosa (arRP).

RESULTS: Exome sequencing of the index patient resulted in the identification of the homozygous BBS1 p.M390R mutation. Sanger sequencing of additional members of the family showed lack of co-segregation of the p.M390R variant in some individuals. Clinical reanalysis indicated co-ocurrence of two different phenotypes in the same family: Bardet-Biedl syndrome in the individual harboring the BBS1 mutation and non-syndromic arRP in extended family members. To identify possible causative mutations underlying arRP, we conducted disease-targeted gene sequencing using a panel of 26 IRD genes. The in-house custom panel was validated using 18 DNA samples known to harbor mutations in relevant genes. All variants were redetected, indicating a high mutation detection rate. This approach allowed the identification of two novel heterozygous null mutations in RP1 (c.4582_4585delATCA; p.I1528Vfs*10 and c.5962dupA; p.I1988Nfs*3) which co-segregated with the disease in arRP patients. Additionally, a mutational screening in 96 patients of our cohort with genetically unresolved IRD revealed the presence of the c.5962dupA mutation in one unrelated family.

CONCLUSIONS: The combination of molecular findings for RP1 and BBS1 genes through exome and gene panel sequencing enabled us to explain the co-existence of two different retinal phenotypes in a family. The identification of two novel variants in RP1 suggests that the use of panels containing the prevalent genes of a particular population, together with an optimized data analysis pipeline, is an efficient and cost-effective approach that can be reliably implemented into the routine diagnostic process of diverse inherited retinal disorders. Moreover, the identification of these novel variants in two unrelated families supports the relatively high prevalence of RP1 mutations in Spanish population and the role of private mutations for commonly mutated genes, while extending the mutational spectrum of RP1.

10aBardet-Biedl Syndrome10aBase Sequence10aCase-Control Studies10aDNA Mutational Analysis10aEye Proteins10aGenes, Recessive10aGenetic Association Studies10aHumans10aMicrosatellite Repeats10aMicrotubule-Associated Proteins10aMutation, Missense10aPedigree10aPhenotype10aRetina10aRetinitis pigmentosa1 aMéndez-Vidal, Cristina1 aBravo-Gil, Nereida1 adel Pozo, María, González-1 aVela-Boza, Alicia1 aDopazo, Joaquin1 aBorrego, Salud1 aAntiňolo, Guillermo uhttp://clinbioinfosspa.es/content/novel-rp1-mutations-and-recurrent-bbs1-variant-explain-co-existence-two-distinct-retinal03070nas a2200385 4500008004100000022001400041245005700055210005600112260000900168300000700177490001400184520197500198653002202173653001502195653002002210653003002230653002902260653002002289653001502309653003002324653001602354653001202370653002902382653002002411653001402431100002102445700001802466700002002484700001802504700002002522700002102542700002002563700001602583856008502599 2014 eng d a1752-050900aPathway network inference from gene expression data.0 aPathway network inference from gene expression data c2014 aS70 v8 Suppl 23 a

BACKGROUND: The development of high-throughput omics technologies enabled genome-wide measurements of the activity of cellular elements and provides the analytical resources for the progress of the Systems Biology discipline. Analysis and interpretation of gene expression data has evolved from the gene to the pathway and interaction level, i.e. from the detection of differentially expressed genes, to the establishment of gene interaction networks and the identification of enriched functional categories. Still, the understanding of biological systems requires a further level of analysis that addresses the characterization of the interaction between functional modules.

RESULTS: We present a novel computational methodology to study the functional interconnections among the molecular elements of a biological system. The PANA approach uses high-throughput genomics measurements and a functional annotation scheme to extract an activity profile from each functional block -or pathway- followed by machine-learning methods to infer the relationships between these functional profiles. The result is a global, interconnected network of pathways that represents the functional cross-talk within the molecular system. We have applied this approach to describe the functional transcriptional connections during the yeast cell cycle and to identify pathways that change their connectivity in a disease condition using an Alzheimer example.

CONCLUSIONS: PANA is a useful tool to deepen in our understanding of the functional interdependences that operate within complex biological systems. We show the approach is algorithmically consistent and the inferred network is well supported by the available functional data. The method allows the dissection of the molecular basis of the functional connections and we describe the different regulatory mechanisms that explain the network's topology obtained for the yeast cell cycle data.

10aAlzheimer Disease10aCell Cycle10aDNA Replication10aGene Expression Profiling10aGene Regulatory Networks10aGluconeogenesis10aGlycolysis10aOxidative Phosphorylation10aProteolysis10aPurines10aSaccharomyces cerevisiae10aSystems biology10aUbiquitin1 aPonzoni, Ignacio1 aNueda, María1 aTarazona, Sonia1 aGötz, Stefan1 aMontaner, David1 aDussaut, Julieta1 aDopazo, Joaquin1 aConesa, Ana uhttp://clinbioinfosspa.es/content/pathway-network-inference-gene-expression-data02515nas a2200445 4500008004100000022001400041245009400055210006900149260000900218300001200227490000600239520119500245653001201440653001501452653001901467653001601486653002701502653002101529653001101550653002901561653001601590653001001606653003001616653001501646653001301661653001401674653001201688653001501700100001801715700002801733700003301761700002001794700002901814700001801843700002401861700002001885700002301905700002201928856011901950 2014 eng d a1932-620300aPermanent cardiac sarcomere changes in a rabbit model of intrauterine growth restriction.0 aPermanent cardiac sarcomere changes in a rabbit model of intraut c2014 ae1130670 v93 a

BACKGROUND: Intrauterine growth restriction (IUGR) induces fetal cardiac remodelling and dysfunction, which persists postnatally and may explain the link between low birth weight and increased cardiovascular mortality in adulthood. However, the cellular and molecular bases for these changes are still not well understood. We tested the hypothesis that IUGR is associated with structural and functional gene expression changes in the fetal sarcomere cytoarchitecture, which remain present in adulthood.

METHODS AND RESULTS: IUGR was induced in New Zealand pregnant rabbits by selective ligation of the utero-placental vessels. Fetal echocardiography demonstrated more globular hearts and signs of cardiac dysfunction in IUGR. Second harmonic generation microscopy (SHGM) showed shorter sarcomere length and shorter A-band and thick-thin filament interaction lengths, that were already present in utero and persisted at 70 postnatal days (adulthood). Sarcomeric M-band (GO: 0031430) functional term was over-represented in IUGR fetal hearts.

CONCLUSION: The results suggest that IUGR induces cardiac dysfunction and permanent changes on the sarcomere.

10aAnimals10abiomarkers10aBlood Pressure10aBody Weight10aDisease Models, Animal10aEchocardiography10aFemale10aFetal Growth Retardation10aFetal Heart10aFetus10aGene Expression Profiling10aOrgan Size10aPlacenta10aPregnancy10aRabbits10aSarcomeres1 aTorre, Iratxe1 aGonzález-Tendero, Anna1 aGarcía-Cañadilla, Patricia1 aCrispi, Fátima1 aGarcia-Garcia, Francisco1 aBijnens, Bart1 aIruretagoyena, Igor1 aDopazo, Joaquin1 aAmat-Roldán, Ivan1 aGratacós, Eduard uhttp://clinbioinfosspa.es/content/permanent-cardiac-sarcomere-changes-rabbit-model-intrauterine-growth-restriction02479nas a2200205 4500008004100000022001400041245013400055210006900189260001600258520174200274100002202016700002902038700002902067700001802096700001902114700002302133700002002156700002202176856007502198 2014 eng d a1460-243100aProgrammed cell death activated by Rose Bengal in Arabidopsis thaliana cell suspension cultures requires functional chloroplasts.0 aProgrammed cell death activated by Rose Bengal in Arabidopsis th c2014 Apr 103 aLight-grown Arabidopsis thaliana cell suspension culture (ACSC) were subjected to mild photooxidative damage with Rose Bengal (RB) with the aim of gaining a better understanding of singlet oxygen-mediated defence responses in plants. Additionally, ACSC were treated with H2O2 at concentrations that induced comparable levels of protein oxidation damage. Under low to medium light conditions, both RB and H2O2 treatments activated transcriptional defence responses and inhibited photosynthetic activity, but they differed in that programmed cell death (PCD) was only observed in cells treated with RB. When dark-grown ACSC were subjected to RB in the light, PCD was suppressed, indicating that the singlet oxygen-mediated signalling pathway in ACSC requires functional chloroplasts. Analysis of up-regulated transcripts in light-grown ACSC, treated with RB in the light, showed that both singlet oxygen-responsive transcripts and transcripts with a key role in hormone-activated PCD (i.e. ethylene and jasmonic acid) were present. A co-regulation analysis proved that ACSC treated with RB exhibited higher correlation with the conditional fluorescence (flu) mutant than with other singlet oxygen-producing mutants or wild-type plants subjected to high light. However, there was no evidence for the up-regulation of EDS1, suggesting that activation of PCD was not associated with the EXECUTER- and EDS1-dependent signalling pathway described in the flu mutant. Indigo Carmine and Methylene Violet, two photosensitizers unable to enter chloroplasts, did not activate transcriptional defence responses in ACSC; however, whether this was due to their location or to their inherently low singlet oxygen quantum efficiencies was not determined.1 aGutiérrez, Jorge1 aGonzález-Pérez, Sergio1 aGarcia-Garcia, Francisco1 aDaly, Cara, T1 aLorenzo, Oscar1 aRevuelta, José, L1 aMcCabe, Paul, F1 aArellano, Juan, B uhttp://jxb.oxfordjournals.org/content/early/2014/04/09/jxb.eru151.long02932nas a2200397 4500008004100000022001400041245010000055210006900155260001600224300000800240490000700248520172500255653001201980653001001992653001702002653002202019653002502041653001802066653001302084653001102097653002002108653001302128653001402141653002502155653002902180653002702209653001102236100002402247700002902271700003102300700002202331700002702353700002502380700002002405856010902425 2014 eng d a1744-429200aThe role of the interactome in the maintenance of deleterious variability in human populations.0 arole of the interactome in the maintenance of deleterious variab c2014 Sep 26 a7520 v103 a

Recent genomic projects have revealed the existence of an unexpectedly large amount of deleterious variability in the human genome. Several hypotheses have been proposed to explain such an apparently high mutational load. However, the mechanisms by which deleterious mutations in some genes cause a pathological effect but are apparently innocuous in other genes remain largely unknown. This study searched for deleterious variants in the 1,000 genomes populations, as well as in a newly sequenced population of 252 healthy Spanish individuals. In addition, variants causative of monogenic diseases and somatic variants from 41 chronic lymphocytic leukaemia patients were analysed. The deleterious variants found were analysed in the context of the interactome to understand the role of network topology in the maintenance of the observed mutational load. Our results suggest that one of the mechanisms whereby the effect of these deleterious variants on the phenotype is suppressed could be related to the configuration of the protein interaction network. Most of the deleterious variants observed in healthy individuals are concentrated in peripheral regions of the interactome, in combinations that preserve their connectivity, and have a marginal effect on interactome integrity. On the contrary, likely pathogenic cancer somatic deleterious variants tend to occur in internal regions of the interactome, often with associated structural consequences. Finally, variants causative of monogenic diseases seem to occupy an intermediate position. Our observations suggest that the real pathological potential of a variant might be more a systems property rather than an intrinsic property of individual proteins.

10aAlleles10aExome10aGene Library10aGenetic Variation10aGenetics, Population10aGenome, Human10aGenomics10aHumans10aModels, Genetic10amutation10aPhenotype10aProtein Conformation10aProtein Interaction Maps10aSequence Analysis, DNA10aWhites1 aGarcía-Alonso, Luz1 aJiménez-Almazán, Jorge1 aCarbonell-Caballero, José1 aVela-Boza, Alicia1 aSantoyo-López, Javier1 aAntiňolo, Guillermo1 aDopazo, Joaquin uhttp://clinbioinfosspa.es/content/role-interactome-maintenance-deleterious-variability-human-populations02920nas a2200409 4500008004100000022001400041245011400055210006900169260001300238300001000251490000700261520165700268653001201925653001501937653001101952653003901963653001802002653001902020653001202039653003102051653001302082653000902095653001402104653001602118653002702134653002402161653001802185100002102203700002502224700003102249700001602280700002002296700001802316700002502334700003202359856011902391 2014 eng d a1096-093700aSequencing and functional analysis of the genome of a nematode egg-parasitic fungus, Pochonia chlamydosporia.0 aSequencing and functional analysis of the genome of a nematode e c2014 Apr a69-800 v653 a

Pochonia chlamydosporia is a worldwide-distributed soil fungus with a great capacity to infect and destroy the eggs and kill females of plant-parasitic nematodes. Additionally, it has the ability to colonize endophytically roots of economically-important crop plants, thereby promoting their growth and eliciting plant defenses. This multitrophic behavior makes P. chlamydosporia a potentially useful tool for sustainable agriculture approaches. We sequenced and assembled ∼41 Mb of P. chlamydosporia genomic DNA and predicted 12,122 gene models, of which many were homologous to genes of fungal pathogens of invertebrates and fungal plant pathogens. Predicted genes (65%) were functionally annotated according to Gene Ontology, and 16% of them found to share homology with genes in the Pathogen Host Interactions (PHI) database. The genome of this fungus is highly enriched in genes encoding hydrolytic enzymes, such as proteases, glycoside hydrolases and carbohydrate esterases. We used RNA-Seq technology in order to identify the genes expressed during endophytic behavior of P. chlamydosporia when colonizing barley roots. Functional annotation of these genes showed that hydrolytic enzymes and transporters are expressed during endophytism. This structural and functional analysis of the P. chlamydosporia genome provides a starting point for understanding the molecular mechanisms involved in the multitrophic lifestyle of this fungus. The genomic information provided here should also prove useful for enhancing the capabilities of this fungus as a biocontrol agent of plant-parasitic nematodes and as a plant growth-promoting organism.

10aAnimals10aAscomycota10aFemale10aGene Expression Regulation, Fungal10aGene ontology10aGenome, Fungal10aHordeum10aHost-Pathogen Interactions10aNematoda10aOvum10aPhylogeny10aPlant Roots10aSequence Analysis, DNA10aSignal Transduction10aTranscriptome1 aLarriba, Eduardo1 aJaime, María, D L A1 aCarbonell-Caballero, José1 aConesa, Ana1 aDopazo, Joaquin1 aNislow, Corey1 aMartín-Nieto, José1 aLopez-Llorca, Luis, Vicente uhttp://clinbioinfosspa.es/content/sequencing-and-functional-analysis-genome-nematode-egg-parasitic-fungus-pochonia03195nas a2200517 4500008004100000022001400041245017300055210006900228260001300297300001000310490000700320520152000327653003201847653003101879653001601910653001101926653000901937653002301946653002801969653001501997653002002012100002802032700002302060700001602083700002402099700002502123700002102148700001902169700002202188700002102210700002002231700002002251700002202271700001902293700002102312700002802333700002202361700002002383700001702403700002702420700002602447700002102473700002402494700002802518856013102546 2014 eng d a1098-100400aTwo novel mutations in the BCKDK (branched-chain keto-acid dehydrogenase kinase) gene are responsible for a neurobehavioral deficit in two pediatric unrelated patients.0 aTwo novel mutations in the BCKDK branchedchain ketoacid dehydrog c2014 Apr a470-70 v353 a

Inactivating mutations in the BCKDK gene, which codes for the kinase responsible for the negative regulation of the branched-chain α-keto acid dehydrogenase complex (BCKD), have recently been associated with a form of autism in three families. In this work, two novel exonic BCKDK mutations, c.520C>G/p.R174G and c.1166T>C/p.L389P, were identified at the homozygous state in two unrelated children with persistently reduced body fluid levels of branched-chain amino acids (BCAAs), developmental delay, microcephaly, and neurobehavioral abnormalities. Functional analysis of the mutations confirmed the missense character of the c.1166T>C change and showed a splicing defect r.[520c>g;521_543del]/p.R174Gfs1*, for c.520C>G due to the presence of a new donor splice site. Mutation p.L389P showed total loss of kinase activity. Moreover, patient-derived fibroblasts showed undetectable (p.R174Gfs1*) or barely detectable (p.L389P) levels of BCKDK protein and its phosphorylated substrate (phospho-E1α), resulting in increased BCKD activity and the very rapid BCAA catabolism manifested by the patients' clinical phenotype. Based on these results, a protein-rich diet plus oral BCAA supplementation was implemented in the patient homozygous for p.R174Gfs1*. This treatment normalized plasma BCAA levels and improved growth, developmental and behavioral variables. Our results demonstrate that BCKDK mutations can result in neurobehavioral deficits in humans and support the rationale for dietary intervention.

10aAmino Acids, Branched-Chain10aDevelopmental Disabilities10aFibroblasts10aHumans10aMale10aMutation, Missense10aNervous System Diseases10aPediatrics10aProtein Kinases1 aGarcía-Cazorla, Angels1 aOyarzabal, Alfonso1 aFort, Joana1 aRobles, Concepción1 aCastejón, Esperanza1 aRuiz-Sala, Pedro1 aBodoy, Susanna1 aMerinero, Begoña1 aLopez-Sala, Anna1 aDopazo, Joaquin1 aNunes, Virginia1 aUgarte, Magdalena1 aArtuch, Rafael1 aPalacín, Manuel1 aRodríguez-Pombo, Pilar1 aAlcaide, Patricia1 aNavarrete, Rosa1 aSanz, Paloma1 aFont-Llitjós, Mariona1 aVilaseca, Ma, Antonia1 aOrmaizabal, Aida1 aPristoupilova, Anna1 aAgulló, Sergi, Beltran uhttp://clinbioinfosspa.es/content/two-novel-mutations-bckdk-branched-chain-keto-acid-dehydrogenase-kinase-gene-are-responsible02611nas a2200313 4500008004100000022001400041245017200055210006900227260001600296300001000312490000700322520157100329100002801900700002301928700001601951700002401967700002501991700002102016700001902037700002202056700002102078700002102099700002002120700002202140700001902162700002102181700002802202856006702230 2014 eng d a1098-100400aTwo Novel Mutations in the BCKDK Gene (Branched-Chain Keto-Acid Dehydrogenase Kinase) are Responsible of a Neurobehavioral Deficit in two Pediatric Unrelated Patients.0 aTwo Novel Mutations in the BCKDK Gene BranchedChain KetoAcid Deh c2014 Jan 21 a470-70 v353 aInactivating mutations in the BCKDK gene, which codes for the kinase responsible for the negative regulation of the branched-chain keto-acid dehydrogenase complex (BCKD), have recently been associated with a form of autism in three families. In this work, two novel exonic BCKDK mutations, c.520C>G/p.R174G and c.1166T>C/p.L389P, were identified at the homozygous state in two unrelated children with persistently reduced body fluid levels of branched-chain amino acids (BCAAs), developmental delay, microcephaly and neurobehavioral abnormalities. Functional analysis of the mutations confirmed the missense character of the c.1166T>C change and showed a splicing defect r.[520c>g;521_543del]/p.R174Gfs1*, for c.520C>G due to the presence of a new donor splice site. Mutation p.L389P showed total loss of kinase activity. Moreover, patient-derived fibroblasts showed undetectable (p.R174Gfs1*) or barely detectable (p.L389P) levels of BCKDK protein and its phosphorylated substrate (phospho-E1α), resulting in increased BCKD activity and the very rapid BCAA catabolism manifested by the patients’ clinical phenotype. Based on these results, a protein-rich diet plus oral BCAA supplementation was implemented in the patient homozygous for p.R174Gfs1*. This treatment normalized plasma BCAA levels and improved growth, developmental and behavioral variables. Our results demonstrate that BCKDK mutations can result in neurobehavioral deficits in humans and support the rationale for dietary intervention. This article is protected by copyright. All rights reserved.1 aGarcía-Cazorla, Angels1 aOyarzabal, Alfonso1 aFort, Joana1 aRobles, Concepción1 aCastejón, Esperanza1 aRuiz-Sala, Pedro1 aBodoy, Susanna1 aMerinero, Begoña1 aLopez-Sala, Anna1 aDopazo, Joaquín1 aNunes, Virginia1 aUgarte, Magdalena1 aArtuch, Rafael1 aPalacín, Manuel1 aRodríguez-Pombo, Pilar uhttp://onlinelibrary.wiley.com/doi/10.1002/humu.22513/abstract00801nas a2200241 4500008004100000245008100041210006900122260000700191300000800198490000600206100003000212700001900242700001900261700001600280700002000296700001900316700001900335700003200354700002400386700002000410700002000430856010900450 2014 eng d00aUnderstanding disease mechanisms with models of signaling pathway activities0 aUnderstanding disease mechanisms with models of signaling pathwa c10 a1210 v81 aSebastián-Leon, Patricia1 aVidal, Enrique1 aMinguez, Pablo1 aConesa, Ana1 aTarazona, Sonia1 aAmadoz, Alicia1 aArmero, Carmen1 aTorres, Francisco, Salavert1 aVidal-Puig, Antonio1 aMontaner, David1 aDopazo, Joaquin uhttp://clinbioinfosspa.es/content/understanding-disease-mechanisms-models-signaling-pathway-activities-102249nas a2200313 4500008004100000022001400041245008200055210006900137260001600206300000800222490000600230520134100236653002201577653001201599653001501611653002001626100003001646700001901676700001901695700001601714700002001730700001901750700001901769700002401788700002401812700002001836700002101856856005801877 2014 eng d a1752-050900aUnderstanding disease mechanisms with models of signaling pathway activities.0 aUnderstanding disease mechanisms with models of signaling pathwa c2014 Oct 25 a1210 v83 aBackgroundUnderstanding the aspects of the cell functionality that account for disease or drug action mechanisms is one of the main challenges in the analysis of genomic data and is on the basis of the future implementation of precision medicine.ResultsHere we propose a simple probabilistic model in which signaling pathways are separated into elementary sub-pathways or signal transmission circuits (which ultimately trigger cell functions) and then transforms gene expression measurements into probabilities of activation of such signal transmission circuits. Using this model, differential activation of such circuits between biological conditions can be estimated. Thus, circuit activation statuses can be interpreted as biomarkers that discriminate among the compared conditions. This type of mechanism-based biomarkers accounts for cell functional activities and can easily be associated to disease or drug action mechanisms. The accuracy of the proposed model is demonstrated with simulations and real datasets.ConclusionsThe proposed model provides detailed information that enables the interpretation disease mechanisms as a consequence of the complex combinations of altered gene expression values. Moreover, it offers a framework for suggesting possible ways of therapeutic intervention in a pathologically perturbed system.10aDisease mechanism10apathway10asignalling10aSystems biology1 aSebastián-Leon, Patricia1 aVidal, Enrique1 aMinguez, Pablo1 aConesa, Ana1 aTarazona, Sonia1 aAmadoz, Alicia1 aArmero, Carmen1 aSalavert, Francisco1 aVidal-Puig, Antonio1 aMontaner, David1 aDopazo, Joaquín uhttp://www.biomedcentral.com/1752-0509/8/121/abstract01799nas a2200217 4500008004100000022001400041245013800055210006900193260001600262300001200278490000700290520106000297653001501357653003501372653000801407100002301415700002901438700002001467700002101487856007301508 2014 eng d a1362-496200aA web tool for the design and management of panels of genes for targeted enrichment and massive sequencing for clinical applications.0 aweb tool for the design and management of panels of genes for ta c2014 May 26 aW83-W870 v423 aDisease targeted sequencing is gaining importance as a powerful and cost-effective application of high throughput sequencing technologies to the diagnosis. However, the lack of proper tools to process the data hinders its extensive adoption. Here we present TEAM, an intuitive and easy-to-use web tool that fills the gap between the predicted mutations and the final diagnostic in targeted enrichment sequencing analysis. The tool searches for known diagnostic mutations, corresponding to a disease panel, among the predicted patient’s variants. Diagnostic variants for the disease are taken from four databases of disease-related variants (HGMD-public, HUMSAVAR, ClinVar and COSMIC.) If no primary diagnostic variant is found, then a list of secondary findings that can help to establish a diagnostic is produced. TEAM also provides with an interface for the definition of and customization of panels, by means of which, genes and mutations can be added or discarded to adjust panel definitions. TEAM is freely available at: http://team.babelomics.org.10aDiagnostic10aTargeted enrichment sequencing10aWES1 aAlemán, Alejandro1 aGarcia-Garcia, Francisco1 aMedina, Ignacio1 aDopazo, Joaquín uhttp://nar.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=2486162602033nas a2200205 4500008004100000022001400041245013200055210006900187260001500256300001300271490000700284520134300291653002401634100002301658700002901681700002401710700002001734700002101754856005201775 2014 eng d a1362-496200aA web-based interactive framework to assist in the prioritization of disease candidate genes in whole-exome sequencing studies.0 awebbased interactive framework to assist in the prioritization o c2014 May 6 aW88-W93.0 v423 aWhole-exome sequencing has become a fundamental tool for the discovery of disease-related genes of familial diseases and the identification of somatic driver variants in cancer. However, finding the causal mutation among the enormous background of individual variability in a small number of samples is still a big challenge. Here we describe a web-based tool, BiERapp, which efficiently helps in the identification of causative variants in family and sporadic genetic diseases. The program reads lists of predicted variants (nucleotide substitutions and indels) in affected individuals or tumor samples and controls. In family studies, different modes of inheritance can easily be defined to filter out variants that do not segregate with the disease along the family. Moreover, BiERapp integrates additional information such as allelic frequencies in the general population and the most popular damaging scores to further narrow down the number of putative variants in successive filtering steps. BiERapp provides an interactive and user-friendly interface that implements the filtering strategy used in the context of a large-scale genomic project carried out by the Spanish Network for Research in Rare Diseases (CIBERER) in which more than 800 exomes have been analyzed. BiERapp is freely available at: http://bierapp.babelomics.org/10aNGS. prioritization1 aAlemán, Alejandro1 aGarcia-Garcia, Francisco1 aSalavert, Francisco1 aMedina, Ignacio1 aDopazo, Joaquín uhttp://nar.oxfordjournals.org/content/42/W1/W8801651nas a2200193 4500008004100000245012700041210006900168260001600237520097000253100002101223700002301244700002701267700001801294700002701312700002001339700002001359700002101379856005701400 2013 eng d00aAssessing Differential Expression Measurements by Highly Parallel Pyrosequencing and DNA Microarrays: A Comparative Study.0 aAssessing Differential Expression Measurements by Highly Paralle c2011 Sep 153 a

Abstract To explore the feasibility of pyrosequencing for quantitative differential gene expression analysis we have performed a comparative study of the results of the sequencing experiments to those obtained by a conventional DNA microarray platform. A conclusion from our analysis is that, over a threshold of 35 normalized reads per gene, the measurements of gene expression display a good correlation with the references. The observed concordance between pyrosequencing and DNA microarray platforms beyond the threshold was of 0.8, measured as a Pearson’s correlation coefficient. In differential gene expression the initial aim is the quantification the differences among transcripts when comparing experimental conditions. Thus, even in a scenario of low coverage the concordance in the measurements is quite acceptable. On the other hand, the comparatively longer read size obtained by pyrosequencing allows detecting unconventional splicing forms.

1 aAriño, Joaquín1 aCasamayor, Antonio1 aPérez, Julián, Perez1 aPedrola, Laia1 aAlvarez-Tejado, Miguel1 aMarbà, Martina1 aSantoyo, Javier1 aDopazo, Joaquín uhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3545353/02299nas a2200253 4500008004100000022001400041245013400055210006900189260001600258520136900274100003001643700002601673700002901699700002201728700001801750700003401768700001901802700002001821700001801841700002101859700002101880700001701901856012701918 2013 eng d a1949-255300aCapturing the biological impact of CDKN2A and MC1R genes as an early predisposing event in melanoma and non melanoma skin cancer.0 aCapturing the biological impact of CDKN2A and MC1R genes as an e c2013 Dec 163 aGermline mutations in CDKN2A and/or red hair color variants in MC1R genes are associated with an increased susceptibility to develop cutaneous melanoma or non melanoma skin cancer. We studied the impact of the CDKN2A germinal mutation p.G101W and MC1R variants on gene expression and transcription profiles associated with skin cancer. To this end we set-up primary skin cell co-cultures from siblings of melanoma prone-families that were later analyzed using the expression array approach. As a result, we found that 1535 transcripts were deregulated in CDKN2A mutated cells, with over-expression of immunity-related genes (HLA-DPB1, CLEC2B, IFI44, IFI44L, IFI27, IFIT1, IFIT2, SP110 and IFNK) and down-regulation of genes playing a role in the Notch signaling pathway. 3570 transcripts were deregulated in MC1R variant carriers. In particular, genes related to oxidative stress and DNA damage pathways were up-regulated as well as genes associated with neurodegenerative diseases such as Parkinson’s, Alzheimer and Huntington. Finally, we observed that the expression signatures indentified in phenotypically normal cells carrying CDKN2A mutations or MC1R variants are maintained in skin cancer tumors (melanoma and squamous cell carcinoma). These results indicate that transcriptome deregulation represents an early event critical for skin cancer development.1 aPuig-Butille, Joan, Anton1 aEscamez, Maria, José1 aGarcia-Garcia, Francisco1 aTell-Marti, Gemma1 aFabra, Angels1 aMartínez-Santamaría, Lucía1 aBadenas, Celia1 aAguilera, Paula1 aPevida, Marta1 aDopazo, Joaquín1 aDel Rio, Marcela1 aPuig, Susana uhttp://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path%5B%5D=1444&path%5B%5D=182402637nas a2200397 4500008004100000022001400041245009900055210006900154260000900223300001100232490000600243520136900249653003101618653001601649653002501665653002601690653002501716653003001741653002901771653001801800653001101818653003401829653002701863653002601890100001801916700002601934700002401960700002001984700001702004700001902021700002002040700002002060700001602080700001802096856012502114 2013 eng d a1932-620300aDefining the genomic signature of totipotency and pluripotency during early human development.0 aDefining the genomic signature of totipotency and pluripotency d c2013 ae621350 v83 a

The genetic mechanisms governing human pre-implantation embryo development and the in vitro counterparts, human embryonic stem cells (hESCs), still remain incomplete. Previous global genome studies demonstrated that totipotent blastomeres from day-3 human embryos and pluripotent inner cell masses (ICMs) from blastocysts, display unique and differing transcriptomes. Nevertheless, comparative gene expression analysis has revealed that no significant differences exist between hESCs derived from blastomeres versus those obtained from ICMs, suggesting that pluripotent hESCs involve a new developmental progression. To understand early human stages evolution, we developed an undifferentiation network signature (UNS) and applied it to a differential gene expression profile between single blastomeres from day-3 embryos, ICMs and hESCs. This allowed us to establish a unique signature composed of highly interconnected genes characteristic of totipotency (61 genes), in vivo pluripotency (20 genes), and in vitro pluripotency (107 genes), and which are also proprietary according to functional analysis. This systems biology approach has led to an improved understanding of the molecular and signaling processes governing human pre-implantation embryo development, as well as enabling us to comprehend how hESCs might adapt to in vitro culture conditions.

10aBlastocyst Inner Cell Mass10aBlastomeres10aCell Differentiation10aEmbryonic Development10aEmbryonic Stem Cells10aGene Expression Profiling10aGene Regulatory Networks10aGenome, Human10aHumans10aMolecular Sequence Annotation10aPluripotent Stem Cells10aTotipotent Stem Cells1 aGalan, Amparo1 aDiaz-Gimeno, Patricia1 aPoo, Maria, Eugenia1 aValbuena, Diana1 aSanchez, Eva1 aRuiz, Veronica1 aDopazo, Joaquin1 aMontaner, David1 aConesa, Ana1 aSimon, Carlos uhttp://clinbioinfosspa.es/content/defining-genomic-signature-totipotency-and-pluripotency-during-early-human-development02838nas a2200349 4500008004100000022001400041245010300055210006900158260001700227300001100244490000700255520180200262653001002064653001102074653003002085653001102115653000902126653001602135653000902151653003302160653003302193100001502226700001502241700001602256700001202272700001502284700001602299700001402315700001302329700001502342856013102357 2013 eng d a0393-974X00aDifferential gene-expression analysis defines a molecular pattern related to olive pollen allergy.0 aDifferential geneexpression analysis defines a molecular pattern c2013 Apr-Jun a337-500 v273 a

Analysis of gene-expression profiles by microarrays is useful for characterization of candidate genes, key regulatory networks, and to define phenotypes or molecular signatures which improve the diagnosis and/or classification of the allergic processes. We have used this approach in the study of olive pollen response in order to find differential molecular markers among responders and non-responders to this allergenic source. Five clinical groups, non-allergic, asymptomatic, allergic but not to olive pollen, untreated-olive-pollen allergic patients and olive-pollen allergic patients (under specific-immunotherapy), were assessed during and outside pollen seasons. Whole-genome gene expression analysis was performed in RNAs extracted from PBMCs. After assessment of data quality and principal components analysis (PCA), differential gene-expression, by multiple testing and, functional analyses by KEGG, for pathways and Gene-Ontology for biological processes were performed. Relevance was defined by fold change and corrected P values (less than 0.05). The most differential genes were validated by qRT-PCR in a larger set of individuals. Interestingly, gene-expression profiling obtained by PCA clearly showed five clusters of samples that correlated with the five clinical groups. Furthermore, differential gene expression and functional analyses revealed differential genes and pathways in the five clinical groups. The 93 most significant genes found were validated, and one set of 35 genes was able to discriminate profiles of olive pollen response. Our results, in addition to providing new information on allergic response, define a possible molecular signature for olive pollen allergy which could be useful for the diagnosis and treatment of this and other sensitizations.

10aAdult10aFemale10aGene Expression Profiling10aHumans10aMale10aMiddle Aged10aOlea10aPrincipal Component Analysis10aRhinitis, Allergic, Seasonal1 aAguerri, M1 aCalzada, D1 aMontaner, D1 aMata, M1 aFlorido, F1 aQuiralte, J1 aDopazo, J1 aLahoz, C1 aCardaba, B uhttp://clinbioinfosspa.es/content/differential-gene-expression-analysis-defines-molecular-pattern-related-olive-pollen-allergy00478nas a2200133 4500008004100000022002200041245005800063210005700121300001200178490000600190100002900196700002000225856009900245 2013 eng d a978-84-9858-872-900aDocencia en Estadística: Experiencias de Innovación0 aDocencia en Estadística Experiencias de Innovación a201-2100 v11 aGarcia-Garcia, Francisco1 aMontaner, David uhttp://clinbioinfosspa.es/content/docencia-en-estad%C3%ADstica-experiencias-de-innovaci%C3%B3n02655nas a2200421 4500008004100000022001400041245010400055210006900159260001700228300000900245490000800254520136600262653001501628653001001643653003201653653001001685653001001695653001101705653004201716653001101758653001101769653000901780653003001789653001301819100001901832700003401851700002701885700002601912700002801938700002301966700001901989700002902008700002002037700001702057700001802074700001902092856012202111 2013 eng d a1096-720600aExome sequencing identifies a new mutation in SERAC1 in a patient with 3-methylglutaconic aciduria.0 aExome sequencing identifies a new mutation in SERAC1 in a patien c2013 Sep-Oct a73-70 v1103 a

3-Methylglutaconic aciduria (3-MGA-uria) is a heterogeneous group of syndromes characterized by an increased excretion of 3-methylglutaconic and 3-methylglutaric acids. Five types of 3-MGA-uria (I to V) with different clinical presentations have been described. Causative mutations in TAZ, OPA3, DNAJC19, ATP12, ATP5E, and TMEM70 have been identified. After excluding the known genetic causes of 3-MGA-uria we used exome sequencing to investigate a patient with Leigh syndrome and 3-MGA-uria. We identified a homozygous variant in SERAC1 (c.202C>T; p.Arg68*), that generates a premature stop codon at position 68 of SERAC1 protein. Western blot analysis in patient's fibroblasts showed a complete absence of SERAC1 that was consistent with the prediction of a truncated protein and supports the pathogenic role of the mutation. During the course of this project a parallel study identified mutations in SERAC1 as the genetic cause of the disease in 15 patients with MEGDEL syndrome, which was compatible with the clinical and biochemical phenotypes of the patient described here. In addition, our patient developed microcephaly and optic atrophy, two features not previously reported in MEGDEL syndrome. We highlight the usefulness of exome sequencing to reveal the genetic bases of human rare diseases even if only one affected individual is available.

10aAdolescent10aAdult10aCarboxylic Ester Hydrolases10aChild10aExome10aFemale10aHigh-Throughput Nucleotide Sequencing10aHumans10aInfant10aMale10aMetabolism, Inborn Errors10amutation1 aTort, Frederic1 aGarcía-Silva, María, Teresa1 aFerrer-Cortès, Xènia1 aNavarro-Sastre, Aleix1 aGarcia-Villoria, Judith1 aColl, Maria, Josep1 aVidal, Enrique1 aJiménez-Almazán, Jorge1 aDopazo, Joaquin1 aBriones, Paz1 aElpeleg, Orly1 aRibes, Antonia uhttp://clinbioinfosspa.es/content/exome-sequencing-identifies-new-mutation-serac1-patient-3-methylglutaconic-aciduria02468nas a2200325 4500008004100000022001400041245005000055210004800105260001500153300001200168490000700180520163100187653000801818653001801826653001001844653001501854653003101869653000801900653000801908653000801916100002001924700002401944700002101968700002401989700002002013700001902033700001702052700002102069856005202090 2013 eng d a1362-496200aGenome Maps, a new generation genome browser.0 aGenome Maps a new generation genome browser c2013 Jun 8 aW41-W460 v413 aGenome browsers have gained importance as more genomes and related genomic information become available. However, the increase of information brought about by new generation sequencing technologies is, at the same time, causing a subtle but continuous decrease in the efficiency of conventional genome browsers. Here, we present Genome Maps, a genome browser that implements an innovative model of data transfer and management. The program uses highly efficient technologies from the new HTML5 standard, such as scalable vector graphics, that optimize workloads at both server and client sides and ensure future scalability. Thus, data management and representation are entirely carried out by the browser, without the need of any Java Applet, Flash or other plug-in technology installation. Relevant biological data on genes, transcripts, exons, regulatory features, single-nucleotide polymorphisms, karyotype and so forth, are imported from web services and are available as tracks. In addition, several DAS servers are already included in Genome Maps. As a novelty, this web-based genome browser allows the local upload of huge genomic data files (e.g. VCF or BAM) that can be dynamically visualized in real time at the client side, thus facilitating the management of medical data affected by privacy restrictions. Finally, Genome Maps can easily be integrated in any web application by including only a few lines of code. Genome Maps is an open source collaborative initiative available in the GitHub repository (https://github.com/compbio-bigdata-viz/genome-maps). Genome Maps is available at: http://www.genomemaps.org.10aBAM10agenome viewer10aHTML510ajavascript10aNext Generation Sequencing10aNGS10aSVG10aVCF1 aMedina, Ignacio1 aSalavert, Francisco1 aSánchez, Rubén1 aDe Maria, Alejandro1 aAlonso, Roberto1 aEscobar, Pablo1 aBleda, Marta1 aDopazo, Joaquín uhttp://nar.oxfordjournals.org/content/41/W1/W4102403nas a2200229 4500008004100000022001400041245013500055210006900190260001600259520156900275100002601844700002301870700002001893700002801913700002901941700002101970700002601991700002902017700002202046700002002068856008502088 2013 eng d a1460-218000aGrape antioxidant dietary fiber (GADF) inhibits intestinal polyposis in ApcMin/+ mice: relation to cell cycle and immune response.0 aGrape antioxidant dietary fiber GADF inhibits intestinal polypos c2013 Apr 243 aEpidemiological and experimental studies suggest that fiber and phenolic compounds might have a protective effect on the development of colon cancer in humans. Accordingly, we assessed the chemopreventive efficacy and associated mechanisms of action of a lyophilized red grape pomace containing proanthocyanidin-rich dietary fiber (Grape Antioxidant Dietary Fiber, GADF) on spontaneous intestinal tumorigenesis in the Apc(Min/+) mouse model. Mice were fed a standard diet (control group) or a 1% (w/w) GADF-supplemented diet (GADF group) for 6 weeks. GADF supplementation greatly reduced intestinal tumorigenesis, significantly decreasing the total number of polyps by 76%. Moreover, size distribution analysis showed a considerable reduction in all polyp size categories [diameter <1 mm (65%), 1-2 mm (67%) and >2 mm (87%)]. In terms of polyp formation in the proximal, middle and distal portions of the small intestine a decrease of 76%, 81% and 73% was observed respectively. Putative molecular mechanisms underlying the inhibition of intestinal tumorigenesis were investigated by comparison of microarray expression profiles of GADF-treated and non-treated mice. We observed that the effects of GADF are mainly associated with the induction of a G1 cell cycle arrest and the downregulation of genes related to the immune response and inflammation. Our findings show for the first time the efficacy and associated mechanisms of action of GADF against intestinal tumorigenesis in Apc(Min/+) mice, suggesting its potential for the prevention of colorectal cancer.1 aSánchez-Tena, Susana1 aLizarraga, Daneida1 aMiranda, Anibal1 aVinardell, Maria, Pilar1 aGarcia-Garcia, Francisco1 aDopazo, Joaquín1 aTorres, Josep, Lluís1 aSaura-Calixto, Fulgencio1 aCapellà, Gabriel1 aCascante, Marta uhttp://carcin.oxfordjournals.org/content/early/2013/04/23/carcin.bgt140.abstract03042nas a2200481 4500008004100000022001400041245012800055210006900183260001300252300001100265490000700276520158000283653001201863653001701875653001601892653001901908653001501927653002701942653002501969653001801994653002402012653002002036653001302056653001702069653002502086653002202111653002102133653000902154653000902163653001802172653001002190100002602200700002302226700002002249700002402269700002902293700002002322700002102342700002902363700002202392700002002414856012602434 2013 eng d a1460-218000aGrape antioxidant dietary fiber inhibits intestinal polyposis in ApcMin/+ mice: relation to cell cycle and immune response.0 aGrape antioxidant dietary fiber inhibits intestinal polyposis in c2013 Aug a1881-80 v343 a

Epidemiological and experimental studies suggest that fiber and phenolic compounds might have a protective effect on the development of colon cancer in humans. Accordingly, we assessed the chemopreventive efficacy and associated mechanisms of action of a lyophilized red grape pomace containing proanthocyanidin (PA)-rich dietary fiber [grape antioxidant dietary fiber (GADF)] on spontaneous intestinal tumorigenesis in the Apc(Min/+) mouse model. Mice were fed a standard diet (control group) or a 1% (w/w) GADF-supplemented diet (GADF group) for 6 weeks. GADF supplementation greatly reduced intestinal tumorigenesis, significantly decreasing the total number of polyps by 76%. Moreover, size distribution analysis showed a considerable reduction in all polyp size categories [diameter <1mm (65%), 1-2mm (67%) and >2mm (87%)]. In terms of polyp formation in the proximal, middle and distal portions of the small intestine, a decrease of 76, 81 and 73% was observed, respectively. Putative molecular mechanisms underlying the inhibition of intestinal tumorigenesis were investigated by comparison of microarray expression profiles of GADF-treated and non-treated mice. We observed that the effects of GADF are mainly associated with the induction of a G1 cell cycle arrest and the downregulation of genes related to the immune response and inflammation. Our findings show for the first time the efficacy and associated mechanisms of action of GADF against intestinal tumorigenesis in Apc(Min/+) mice, suggesting its potential for the prevention of colorectal cancer.

10aAnimals10aAntioxidants10aBody Weight10aCarcinogenesis10aCell Cycle10aCell Cycle Checkpoints10aColorectal Neoplasms10aDietary Fiber10aDietary Supplements10aDown-Regulation10aG1 Phase10aInflammation10aIntestinal Polyposis10aIntestinal Polyps10aIntestine, Small10aMale10aMice10aTranscriptome10aVitis1 aSánchez-Tena, Susana1 aLizarraga, Daneida1 aMiranda, Anibal1 aVinardell, Maria, P1 aGarcia-Garcia, Francisco1 aDopazo, Joaquin1 aTorres, Josep, L1 aSaura-Calixto, Fulgencio1 aCapellà, Gabriel1 aCascante, Marta uhttp://clinbioinfosspa.es/content/grape-antioxidant-dietary-fiber-inhibits-intestinal-polyposis-apcmin-mice-relation-cell02226nas a2200313 4500008004100000022001400041245008600055210006900141260001300210300001100223490000700234520127400241653001201515653001101527653001301538653000901551653002401560653002801584653002401612653001301636653001801649100003001667700002101697700002401718700002101742700002001763700002001783856010901803 2013 eng d a1362-496200aInferring the functional effect of gene expression changes in signaling pathways.0 aInferring the functional effect of gene expression changes in si c2013 Jul aW213-70 v413 a

Signaling pathways constitute a valuable source of information that allows interpreting the way in which alterations in gene activities affect to particular cell functionalities. There are web tools available that allow viewing and editing pathways, as well as representing experimental data on them. However, few methods aimed to identify the signaling circuits, within a pathway, associated to the biological problem studied exist and none of them provide a convenient graphical web interface. We present PATHiWAYS, a web-based signaling pathway visualization system that infers changes in signaling that affect cell functionality from the measurements of gene expression values in typical expression microarray case-control experiments. A simple probabilistic model of the pathway is used to estimate the probabilities for signal transmission from any receptor to any final effector molecule (taking into account the pathway topology) using for this the individual probabilities of gene product presence/absence inferred from gene expression values. Significant changes in these probabilities allow linking different cell functionalities triggered by the pathway to the biological problem studied. PATHiWAYS is available at: http://pathiways.babelomics.org/.

10aAnimals10aHumans10aInternet10aMice10aModels, Statistical10aReceptors, Cell Surface10aSignal Transduction10aSoftware10aTranscriptome1 aSebastián-Leon, Patricia1 aCarbonell, José1 aSalavert, Francisco1 aSánchez, Rubén1 aMedina, Ignacio1 aDopazo, Joaquin uhttp://clinbioinfosspa.es/content/inferring-functional-effect-gene-expression-changes-signaling-pathways02909nas a2200373 4500008004100000022001400041245016200055210006900217260001300286300001300299490000800312520168000320653001202000653002702012653002202039653001102061653002902072653002002101653001702121653001502138653003002153653001302183653001402196653001202210100002802222700001802250700003302268700002002301700002902321700002002350700001802370700002202388856012502410 2013 eng d a1522-153900aIntrauterine growth restriction is associated with cardiac ultrastructural and gene expression changes related to the energetic metabolism in a rabbit model.0 aIntrauterine growth restriction is associated with cardiac ultra c2013 Dec aH1752-600 v3053 a

Intrauterine growth restriction (IUGR) affects 7-10% of pregnancies and is associated with cardiovascular remodeling and dysfunction, which persists into adulthood. The underlying subcellular remodeling and cardiovascular programming events are still poorly documented. Cardiac muscle is central in the fetal adaptive mechanism to IUGR given its high energetic demands. The energetic homeostasis depends on the correct interaction of several molecular pathways and the adequate arrangement of intracellular energetic units (ICEUs), where mitochondria interact with the contractile machinery and the main cardiac ATPases to enable a quick and efficient energy transfer. We studied subcellular cardiac adaptations to IUGR in an experimental rabbit model. We evaluated the ultrastructure of ICEUs with transmission electron microscopy and observed an altered spatial arrangement in IUGR, with significant increases in cytosolic space between mitochondria and myofilaments. A global decrease of mitochondrial density was also observed. In addition, we conducted a global gene expression profile by advanced bioinformatics tools to assess the expression of genes involved in the cardiomyocyte energetic metabolism and identified four gene modules with a coordinated over-representation in IUGR: oxygen homeostasis (GO: 0032364), mitochondrial respiratory chain complex I (GO:0005747), oxidative phosphorylation (GO: 0006119), and NADH dehydrogenase activity (GO:0003954). These findings might contribute to changes in energetic homeostasis in IUGR. The potential persistence and role of these changes in long-term cardiovascular programming deserves further investigation.

10aAnimals10aDisease Models, Animal10aEnergy Metabolism10aFemale10aFetal Growth Retardation10agene expression10aMitochondria10aMyocardium10aOxidative Phosphorylation10aPlacenta10aPregnancy10aRabbits1 aGonzález-Tendero, Anna1 aTorre, Iratxe1 aGarcía-Cañadilla, Patricia1 aCrispi, Fátima1 aGarcia-Garcia, Francisco1 aDopazo, Joaquin1 aBijnens, Bart1 aGratacós, Eduard uhttp://clinbioinfosspa.es/content/intrauterine-growth-restriction-associated-cardiac-ultrastructural-and-gene-expression02926nas a2200445 4500008004100000022001400041245009600055210006900151260000900220300001100229490000600240520152900246653002101775653001401796653002101810653002301831653002101854653001101875653002001886653003001906653004301936653003001979653001102009653001602020653002602036653002402062653002602086100002702112700002102139700002902160700001602189700003002205700002002235700001702255700001802272700002402290700002002314700002102334856012502355 2013 eng d a1932-620300aMammosphere formation in breast carcinoma cell lines depends upon expression of E-cadherin.0 aMammosphere formation in breast carcinoma cell lines depends upo c2013 ae772810 v83 a

Tumors are heterogeneous at the cellular level where the ability to maintain tumor growth resides in discrete cell populations. Floating sphere-forming assays are broadly used to test stem cell activity in tissues, tumors and cell lines. Spheroids are originated from a small population of cells with stem cell features able to grow in suspension culture and behaving as tumorigenic in mice. We tested the ability of eleven common breast cancer cell lines representing the major breast cancer subtypes to grow as mammospheres, measuring the ability to maintain cell viability upon serial non-adherent passage. Only MCF7, T47D, BT474, MDA-MB-436 and JIMT1 were successfully propagated as long-term mammosphere cultures, measured as the increase in the number of viable cells upon serial non-adherent passages. Other cell lines tested (SKBR3, MDA-MB-231, MDA-MB-468 and MDA-MB-435) formed cell clumps that can be disaggregated mechanically, but cell viability drops dramatically on their second passage. HCC1937 and HCC1569 cells formed typical mammospheres, although they could not be propagated as long-term mammosphere cultures. All the sphere forming lines but MDA-MB-436 express E-cadherin on their surface. Knock down of E-cadherin expression in MCF-7 cells abrogated its ability to grow as mammospheres, while re-expression of E-cadherin in SKBR3 cells allow them to form mammospheres. Therefore, the mammosphere assay is suitable to reveal stem like features in breast cancer cell lines that express E-cadherin.

10aBreast Neoplasms10aCadherins10aCell Line, Tumor10aCell Proliferation10aCluster Analysis10aFemale10agene expression10aGene Expression Profiling10aGene Expression Regulation, Neoplastic10aGene Knockdown Techniques10aHumans10aMCF-7 Cells10aNeoplastic Stem Cells10aSpheroids, Cellular10aTumor Cells, Cultured1 aIglesias, Juan, Manuel1 aBeloqui, Izaskun1 aGarcia-Garcia, Francisco1 aLeis, Olatz1 aVazquez-Martin, Alejandro1 aEguiara, Arrate1 aCufi, Silvia1 aPavon, Andres1 aMenendez, Javier, A1 aDopazo, Joaquin1 aMartin, Angel, G uhttp://clinbioinfosspa.es/content/mammosphere-formation-breast-carcinoma-cell-lines-depends-upon-expression-e-cadherin-002347nas a2200253 4500008004100000245009500041210006900136260004200205300001300247490000600260520152900266100002701795700002101822700002901843700001601872700003001888700002001918700001701938700001801955700002501973700002001998700002202018856005302040 2013 eng d00aMammosphere Formation in Breast Carcinoma Cell Lines Depends upon Expression of E-cadherin0 aMammosphere Formation in Breast Carcinoma Cell Lines Depends upo bPublic Library of Sciencec2013/10/04 ae77281 -0 v83 a

Tumors are heterogeneous at the cellular level where the ability to maintain tumor growth resides in discrete cell populations. Floating sphere-forming assays are broadly used to test stem cell activity in tissues, tumors and cell lines. Spheroids are originated from a small population of cells with stem cell features able to grow in suspension culture and behaving as tumorigenic in mice. We tested the ability of eleven common breast cancer cell lines representing the major breast cancer subtypes to grow as mammospheres, measuring the ability to maintain cell viability upon serial non-adherent passage. Only MCF7, T47D, BT474, MDA-MB-436 and JIMT1 were successfully propagated as long-term mammosphere cultures, measured as the increase in the number of viable cells upon serial non-adherent passages. Other cell lines tested (SKBR3, MDA-MB-231, MDA-MB-468 and MDA-MB-435) formed cell clumps that can be disaggregated mechanically, but cell viability drops dramatically on their second passage. HCC1937 and HCC1569 cells formed typical mammospheres, although they could not be propagated as long-term mammosphere cultures. All the sphere forming lines but MDA-MB-436 express E-cadherin on their surface. Knock down of E-cadherin expression in MCF-7 cells abrogated its ability to grow as mammospheres, while re-expression of E-cadherin in SKBR3 cells allow them to form mammospheres. Therefore, the mammosphere assay is suitable to reveal stem like features in breast cancer cell lines that express E-cadherin.

1 aIglesias, Juan, Manuel1 aBeloqui, Izaskun1 aGarcia-Garcia, Francisco1 aLeis, Olatz1 aVazquez-Martin, Alejandro1 aEguiara, Arrate1 aCufi, Silvia1 aPavon, Andres1 aMenendez, Javier, A.1 aDopazo, Joaquin1 aMartin, Angel, G. uhttp://dx.doi.org/10.1371%2Fjournal.pone.007728102500nas a2200253 4500008004100000022001400041245014000055210006900195260000900264300001100273490000600284520158800290100002601878700003001904700002801934700002801962700001901990700002902009700002102038700002502059700002102084700002002105856012102125 2013 eng d a1932-620300aMaslinic Acid-Enriched Diet Decreases Intestinal Tumorigenesis in Apc(Min/+) Mice through Transcriptomic and Metabolomic Reprogramming.0 aMaslinic AcidEnriched Diet Decreases Intestinal Tumorigenesis in c2013 ae593920 v83 aChemoprevention is a pragmatic approach to reduce the risk of colorectal cancer, one of the leading causes of cancer-related death in western countries. In this regard, maslinic acid (MA), a pentacyclic triterpene extracted from wax-like coatings of olives, is known to inhibit proliferation and induce apoptosis in colon cancer cell lines without affecting normal intestinal cells. The present study evaluated the chemopreventive efficacy and associated mechanisms of maslinic acid treatment on spontaneous intestinal tumorigenesis in Apc(Min/+) mice. Twenty-two mice were randomized into 2 groups: control group and MA group, fed with a maslinic acid-supplemented diet for six weeks. MA treatment reduced total intestinal polyp formation by 45% (P<0.01). Putative molecular mechanisms associated with suppressing intestinal polyposis in Apc(Min/+) mice were investigated by comparing microarray expression profiles of MA-treated and control mice and by analyzing the serum metabolic profile using NMR techniques. The different expression phenotype induced by MA suggested that it exerts its chemopreventive action mainly by inhibiting cell-survival signaling and inflammation. These changes eventually induce G1-phase cell cycle arrest and apoptosis. Moreover, the metabolic changes induced by MA treatment were associated with a protective profile against intestinal tumorigenesis. These results show the efficacy and underlying mechanisms of MA against intestinal tumor development in the Apc(Min/+) mice model, suggesting its chemopreventive potential against colorectal cancer.1 aSánchez-Tena, Susana1 aReyes-Zurita, Fernando, J1 aDíaz-Moralli, Santiago1 aVinardell, Maria, Pilar1 aReed, Michelle1 aGarcia-Garcia, Francisco1 aDopazo, Joaquín1 aLupiáñez, José, A1 aGünther, Ulrich1 aCascante, Marta uhttp://clinbioinfosspa.es/content/maslinic-acid-enriched-diet-decreases-intestinal-tumorigenesis-apcmin-mice-through00733nas a2200229 4500008004100000020002200041245006900063210006800132260004000200653002900240653001400269653001300283653001100296653001600307100002700323700001700350700002400367700002100391700002000412700002000432856005100452 2013 eng d a978-3-642-36948-300aMulticore and Cloud-based Solutions for Genomic Variant Analysis0 aMulticore and Cloudbased Solutions for Genomic Variant Analysis aBerlin, HeidelbergbSpringer-Verlag10agenomic variant analysis10amulticore10amutation10aOpenMP10aweb service1 aGonzalez, Cristina, Y.1 aBleda, Marta1 aSalavert, Francisco1 aSánchez, Rubén1 aDopazo, Joaquin1 aMedina, Ignacio uhttp://dx.doi.org/10.1007/978-3-642-36949-0_3001635nas a2200289 4500008004100000022001400041245018800055210006900243260001600312520053300328100002400861700002400885700002600909700002500935700002400960700002200984700001801006700002101024700002901045700002901074700001801103700002401121700002401145700002501169700002101194856013001215 2013 eng d a1873-349200aNovel genes detected by transcriptional profiling from whole-blood cells in patients with early onset of acute coronary syndrome: Transcriptional profiling of acute coronary syndrome.0 aNovel genes detected by transcriptional profiling from wholebloo c2013 Mar 243 a{BACKGROUND: Genome-wide expression analysis using microarrays has been used as a research strategy to discovery new biomarkers and candidate genes for a number of diseases. We aim to find new biomarkers for the prediction of acute coronary syndrome (ACS) with a differentially expressed mRNA profiling approach using whole genomic expression analysis in a peripheral blood cell model from patients with early ACS. METHODS AND RESULTS: This study was carried out in two phases. On phase 1 a restricted clinical criteria (ACS-Ph11 aSilbiger, Vivian, N1 aLuchessi, André, D1 aHirata, Rosário, D C1 aLima-Neto, Lídio, G1 aCavichioli, Débora1 aCarracedo, Ángel1 aBrión, Maria1 aDopazo, Joaquín1 aGarcia-Garcia, Francisco1 aSantos, Elizabete, S Dos1 aRamos, Rui, F1 aSampaio, Marcelo, F1 aArmaganijan, Dikran1 aSousa, Amanda, G M R1 aHirata, Mario, H uhttp://clinbioinfosspa.es/content/novel-genes-detected-transcriptional-profiling-whole-blood-cells-patients-early-onset-acute02952nas a2200481 4500008004100000022001400041245013400055210006900189260001600258300001100274490000800285520141700293653002801710653002501738653001001763653001501773653001601788653002001804653002001824653003001844653001101874653000901885653001601894653004401910653001901954653001801973100002401991700002402015700002602039700002502065700002402090700002202114700001802136700002002154700002902174700002902203700001802232700002402250700002402274700002502298700002102323856012602344 2013 eng d a1873-349200aNovel genes detected by transcriptional profiling from whole-blood cells in patients with early onset of acute coronary syndrome.0 aNovel genes detected by transcriptional profiling from wholebloo c2013 Jun 05 a184-900 v4213 a

BACKGROUND: Genome-wide expression analysis using microarrays has been used as a research strategy to discovery new biomarkers and candidate genes for a number of diseases. We aim to find new biomarkers for the prediction of acute coronary syndrome (ACS) with a differentially expressed mRNA profiling approach using whole genomic expression analysis in a peripheral blood cell model from patients with early ACS.

METHODS AND RESULTS: This study was carried out in two phases. On phase 1 a restricted clinical criteria (ACS-Ph1, n=9 and CG-Ph1, n=6) was used in order to select potential mRNA biomarkers candidates. A subsequent phase 2 study was performed using selected phase 1 markers analyzed by RT-qPCR using a larger and independent casuistic (ACS-Ph2, n=74 and CG-Ph2, n=41). A total of 549 genes were found to be differentially expressed in the first 48 h after the ACS-Ph1. Technical and biological validation further confirmed that ALOX15, AREG, BCL2A1, BCL2L1, CA1, COX7B, ECHDC3, IL18R1, IRS2, KCNE1, MMP9, MYL4 and TREML4, are differentially expressed in both phases of this study.

CONCLUSIONS: Transcriptomic analysis by microarray technology demonstrated differential expression during a 48 h time course suggesting a potential use of some of these genes as biomarkers for very early stages of ACS, as well as for monitoring early cardiac ischemic recovery.

10aAcute Coronary Syndrome10aAcute-Phase Proteins10aAdult10abiomarkers10aBlood Cells10aEarly Diagnosis10agene expression10aGene Expression Profiling10aHumans10aMale10aMiddle Aged10aOligonucleotide Array Sequence Analysis10aRNA, Messenger10aTranscriptome1 aSilbiger, Vivian, N1 aLuchessi, André, D1 aHirata, Rosário, D C1 aLima-Neto, Lídio, G1 aCavichioli, Débora1 aCarracedo, Ángel1 aBrión, Maria1 aDopazo, Joaquin1 aGarcia-Garcia, Francisco1 aSantos, Elizabete, S Dos1 aRamos, Rui, F1 aSampaio, Marcelo, F1 aArmaganijan, Dikran1 aSousa, Amanda, G M R1 aHirata, Mario, H uhttp://clinbioinfosspa.es/content/novel-genes-detected-transcriptional-profiling-whole-blood-cells-patients-early-onset-002519nas a2200373 4500008004100000022001400041245006800055210006500123260001500188300000800203490000600211520145200217653000901669653001601678653002101694653002701715100002601742700001701768700002301785700002401808700001901832700002201851700002001873700002401893700001601917700002501933700002301958700002401981700002602005700002502031700002102056700001902077856004902096 2013 eng d a1750-117200aPathways systematically associated to Hirschsprung’s disease.0 aPathways systematically associated to Hirschsprung s disease c2013 Dec 2 a1870 v83 aDespite it has been reported that several loci are involved in Hirschsprung’s disease, the molecular basis of the disease remains yet essentially unknown. The study of collective properties of modules of functionally-related genes provides an efficient and sensitive statistical framework that can overcome sample size limitations in the study of rare diseases. Here, we present the extension of a previous study of a Spanish series of HSCR trios to an international cohort of 162 HSCR trios to validate the generality of the underlying functional basis of the Hirschsprung’s disease mechanisms previously found. The Pathway-Based Analysis (PBA) confirms a strong association of gene ontology (GO) modules related to signal transduction and its regulation, enteric nervous system (ENS) formation and other processes related to the disease. In addition, network analysis recovers sub-networks significantly associated to the disease, which contain genes related to the same functionalities, thus providing an independent validation of these findings. The functional profiles of association obtained for patients populations from different countries were compared to each other. While gene associations were different at each series, the main functional associations were identical in all the five populations. These observations would also explain the reported low reproducibility of associations of individual disease genes across populations.10aGWAS10aHirschprung10anetwork analysis10aPathway Based Analysis1 aFernández, Raquel, M1 aBleda, Marta1 aLuzón-Toro, Berta1 aGarcía-Alonso, Luz1 aArnold, Stacey1 aSribudiani, Yunia1 aBesmond, Claude1 aLantieri, Francesca1 aDoan, Betty1 aCeccherini, Isabella1 aLyonnet, Stanislas1 aHofstra, Robert, Mw1 aChakravarti, Aravinda1 aAntiňolo, Guillermo1 aDopazo, Joaquín1 aBorrego, Salud uhttp://www.ojrd.com/content/8/1/187/abstract02672nas a2200409 4500008004100000022001400041245006600055210006400121260001600185300000800201490000600209520145600215653001101671653003801682653001301720653002501733653001101758653000901769653003601778100002601814700001701840700002301857700002401880700001901904700002201923700002001945700002401965700001601989700002502005700002302030700002402053700002602077700002502103700002002128700001902148856009502167 2013 eng d a1750-117200aPathways systematically associated to Hirschsprung's disease.0 aPathways systematically associated to Hirschsprungs disease c2013 Dec 02 a1870 v83 a

Despite it has been reported that several loci are involved in Hirschsprung's disease, the molecular basis of the disease remains yet essentially unknown. The study of collective properties of modules of functionally-related genes provides an efficient and sensitive statistical framework that can overcome sample size limitations in the study of rare diseases. Here, we present the extension of a previous study of a Spanish series of HSCR trios to an international cohort of 162 HSCR trios to validate the generality of the underlying functional basis of the Hirschsprung's disease mechanisms previously found. The Pathway-Based Analysis (PBA) confirms a strong association of gene ontology (GO) modules related to signal transduction and its regulation, enteric nervous system (ENS) formation and other processes related to the disease. In addition, network analysis recovers sub-networks significantly associated to the disease, which contain genes related to the same functionalities, thus providing an independent validation of these findings. The functional profiles of association obtained for patients populations from different countries were compared to each other. While gene associations were different at each series, the main functional associations were identical in all the five populations. These observations would also explain the reported low reproducibility of associations of individual disease genes across populations.

10aFemale10aGenetic Predisposition to Disease10aGenotype10aHirschsprung Disease10aHumans10aMale10aPolymorphism, Single Nucleotide1 aFernández, Raquel, M1 aBleda, Marta1 aLuzón-Toro, Berta1 aGarcía-Alonso, Luz1 aArnold, Stacey1 aSribudiani, Yunia1 aBesmond, Claude1 aLantieri, Francesca1 aDoan, Betty1 aCeccherini, Isabella1 aLyonnet, Stanislas1 aHofstra, Robert, Mw1 aChakravarti, Aravinda1 aAntiňolo, Guillermo1 aDopazo, Joaquin1 aBorrego, Salud uhttp://clinbioinfosspa.es/content/pathways-systematically-associated-hirschsprungs-disease02722nas a2200505 4500008004100000022001400041245018900055210006900244260001300313300001000326490000700336520107200343653002801415653001001443653000901453653002201462653001101484653003801495653001101533653003001544653004401574653004301618653001601661653001101677653001701688653005001705653001401755653000901769653001601778653002001794653001401814653003201828653002801860653000901888653001901897653002101916100003001937700001901967700002001986700002002006700002902026700002002055700001702075856012402092 2013 eng d a1600-062500aRole of CPI-17 in restoring skin homoeostasis in cutaneous field of cancerization: effects of topical application of a film-forming medical device containing photolyase and UV filters.0 aRole of CPI17 in restoring skin homoeostasis in cutaneous field  c2013 Jul a494-60 v223 a

Cutaneous field of cancerization (CFC) is caused in part by the carcinogenic effect of the cyclobutane pyrimidine dimers CPD and 6-4 photoproducts (6-4PPs). Photoreactivation is carried out by photolyases which specifically recognize and repair both photoproducts. The study evaluates the molecular effects of topical application of a film-forming medical device containing photolyase and UV filters on the precancerous field in AK from seven patients. Skin improvement after treatment was confirmed in all patients by histopathological and molecular assessment. A gene set analysis showed that skin recovery was associated with biological processes involved in tissue homoeostasis and cell maintenance. The CFC response was associated with over-expression of the CPI-17 gene, and a dependence on the initial expression level was observed (P = 0.001). Low CPI-17 levels were directly associated with pro-inflammatory genes such as TNF (P = 0.012) and IL-1B (P = 0.07). Our results suggest a role for CPI-17 in restoring skin homoeostasis in CFC lesions.

10aAdministration, Topical10aAdult10aAged10aAged, 80 and over10aBiopsy10aDeoxyribodipyrimidine Photo-Lyase10aFemale10aGene Expression Profiling10aGene Expression Regulation, Enzymologic10aGene Expression Regulation, Neoplastic10aHomeostasis10aHumans10aInflammation10aIntracellular Signaling Peptides and Proteins10aLiposomes10aMale10aMiddle Aged10aMuscle Proteins10aPhenotype10aPhosphoprotein Phosphatases10aReactive Oxygen Species10aSkin10aSkin Neoplasms10aUltraviolet Rays1 aPuig-Butille, Joan, Anton1 aMalvehy, Josep1 aPotrony, Miriam1 aTrullas, Carles1 aGarcia-Garcia, Francisco1 aDopazo, Joaquin1 aPuig, Susana uhttp://clinbioinfosspa.es/content/role-cpi-17-restoring-skin-homoeostasis-cutaneous-field-cancerization-effects-topical03066nas a2200241 4500008004100000022001400041245015200055210006900207260000900276300001200285490000700297520223800304100002802542700003302570700002202603700002702625700003302652700003202685700002002717700001902737700002502756856004302781 2013 eng d a1090-053500aWhole-exome sequencing identifies novel compound heterozygous mutations in USH2A in Spanish patients with autosomal recessive retinitis pigmentosa.0 aWholeexome sequencing identifies novel compound heterozygous mut c2013 a2187-950 v193 aPURPOSE: Retinitis pigmentosa (RP) is an inherited retinal dystrophy characterized by extreme genetic and clinical heterogeneity. Thus, the diagnosis is not always easily performed due to phenotypic and genetic overlap. Current clinical practices have focused on the systematic evaluation of a set of known genes for each phenotype, but this approach may fail in patients with inaccurate diagnosis or infrequent genetic cause. In the present study, we investigated the genetic cause of autosomal recessive RP (arRP) in a Spanish family in which the causal mutation has not yet been identified with primer extension technology and resequencing. METHODS: We designed a whole-exome sequencing (WES)-based approach using NimbleGen SeqCap EZ Exome V3 sample preparation kit and the SOLiD 5500×l next-generation sequencing platform. We sequenced the exomes of both unaffected parents and two affected siblings. Exome analysis resulted in the identification of 43,204 variants in the index patient. All variants passing filter criteria were validated with Sanger sequencing to confirm familial segregation and absence in the control population. In silico prediction tools were used to determine mutational impact on protein function and the structure of the identified variants. RESULTS: Novel Usher syndrome type 2A (USH2A) compound heterozygous mutations, c.4325T>C (p.F1442S) and c.15188T>G (p.L5063R), located in exons 20 and 70, respectively, were identified as probable causative mutations for RP in this family. Family segregation of the variants showed the presence of both mutations in all affected members and in two siblings who were apparently asymptomatic at the time of family ascertainment. Clinical reassessment confirmed the diagnosis of RP in these patients. CONCLUSIONS: Using WES, we identified two heterozygous novel mutations in USH2A as the most likely disease-causing variants in a Spanish family diagnosed with arRP in which the cause of the disease had not yet been identified with commonly used techniques. Our data reinforce the clinical role of WES in the molecular diagnosis of highly heterogeneous genetic diseases where conventional genetic approaches have previously failed in achieving a proper diagnosis.1 aMéndez-Vidal, Cristina1 adel Pozo, María, González-1 aVela-Boza, Alicia1 aSantoyo-López, Javier1 aLópez-Domingo, Francisco, J1 aVázquez-Marouschek, Carmen1 aDopazo, Joaquin1 aBorrego, Salud1 aAntiňolo, Guillermo uhttp://www.molvis.org/molvis/v19/2187/02076nas a2200241 4500008004100000022001400041245014000055210006900195260001300264300001200277490000700289520129000296100001701586700002301603700002401626700002401650700002401674700001901698700001901717700002001736700002001756856005801776 2012 eng d a1362-496200aCellBase, a comprehensive collection of RESTful web services for retrieving relevant biological information from heterogeneous sources.0 aCellBase a comprehensive collection of RESTful web services for  c2012 Jul aW609-140 v403 aDuring the past years, the advances in high-throughput technologies have produced an unprecedented growth in the number and size of repositories and databases storing relevant biological data. Today, there is more biological information than ever but, unfortunately, the current status of many of these repositories is far from being optimal. Some of the most common problems are that the information is spread out in many small databases; frequently there are different standards among repositories and some databases are no longer supported or they contain too specific and unconnected information. In addition, data size is increasingly becoming an obstacle when accessing or storing biological data. All these issues make very difficult to extract and integrate information from different sources, to analyze experiments or to access and query this information in a programmatic way. CellBase provides a solution to the growing necessity of integration by easing the access to biological data. CellBase implements a set of RESTful web services that query a centralized database containing the most relevant biological data sources. The database is hosted in our servers and is regularly updated. CellBase documentation can be found at http://docs.bioinfo.cipf.es/projects/cellbase.1 aBleda, Marta1 aTárraga, Joaquín1 aDe Maria, Alejandro1 aSalavert, Francisco1 aGarcía-Alonso, Luz1 aCelma, Matilde1 aMartin, Ainoha1 aDopazo, Joaquin1 aMedina, Ignacio uhttp://nar.oxfordjournals.org/content/40/W1/W609.long02998nas a2200349 4500008004100000022001400041245015500055210006900210260000900279300001100288490000600299520188000305100002102185700001902206700001702225700002002242700002402262700002202286700002802308700002102336700002002357700002102377700002102398700002302419700002902442700001602471700001802487700002102505700002402526700001902550856007902569 2012 eng d a1932-620300aDevelopment, Characterization and Experimental Validation of a Cultivated Sunflower (Helianthus annuus L.) Gene Expression Oligonucleotide Microarray.0 aDevelopment Characterization and Experimental Validation of a Cu c2012 ae458990 v73 aOligonucleotide-based microarrays with accurate gene coverage represent a key strategy for transcriptional studies in orphan species such as sunflower, H. annuus L., which lacks full genome sequences. The goal of this study was the development and functional annotation of a comprehensive sunflower unigene collection and the design and validation of a custom sunflower oligonucleotide-based microarray. A large scale EST (>130,000 ESTs) curation, assembly and sequence annotation was performed using Blast2GO (www.blast2go.de). The EST assembly comprises 41,013 putative transcripts (12,924 contigs and 28,089 singletons). The resulting Sunflower Unigen Resource (SUR version 1.0) was used to design an oligonucleotide-based Agilent microarray for cultivated sunflower. This microarray includes a total of 42,326 features: 1,417 Agilent controls, 74 control probes for sunflower replicated 10 times (740 controls) and 40,169 different non-control probes. Microarray performance was validated using a model experiment examining the induction of senescence by water deficit. Pre-processing and differential expression analysis of Agilent microarrays was performed using the Bioconductor limma package. The analyses based on p-values calculated by eBayes (p<0.01) allowed the detection of 558 differentially expressed genes between water stress and control conditions; from these, ten genes were further validated by qPCR. Over-represented ontologies were identified using FatiScan in the Babelomics suite. This work generated a curated and trustable sunflower unigene collection, and a custom, validated sunflower oligonucleotide-based microarray using Agilent technology. Both the curated unigene collection and the validated oligonucleotide microarray provide key resources for sunflower genome analysis, transcriptional studies, and molecular breeding for crop improvement.1 aFernandez, Paula1 aSoria, Marcelo1 aBlesa, David1 aDirienzo, Julio1 aMoschen, Sebastián1 aRivarola, Máximo1 aClavijo, Bernardo, Jose1 aGonzalez, Sergio1 aPeluffo, Lucila1 aPríncipi, Dario1 aDosio, Guillermo1 aAguirrezabal, Luis1 aGarcia-Garcia, Francisco1 aConesa, Ana1 aHopp, Esteban1 aDopazo, Joaquín1 aHeinz, Ruth, Amelia1 aPaniego, Norma uhttp://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.004589902616nas a2200325 4500008004100000022001400041245012100055210006900176260001600245300000900261490000700270520154400277653002101821653001901842653002901861653002001890653003401910653001301944653001101957653003201968100002402000700002002024700001902044700001902063700002402082700001902106700002002125700002002145856012502165 2012 eng d a1362-496200aDiscovering the hidden sub-network component in a ranked list of genes or proteins derived from genomic experiments.0 aDiscovering the hidden subnetwork component in a ranked list of  c2012 Nov 01 ae1580 v403 a

Genomic experiments (e.g. differential gene expression, single-nucleotide polymorphism association) typically produce ranked list of genes. We present a simple but powerful approach which uses protein-protein interaction data to detect sub-networks within such ranked lists of genes or proteins. We performed an exhaustive study of network parameters that allowed us concluding that the average number of components and the average number of nodes per component are the parameters that best discriminate between real and random networks. A novel aspect that increases the efficiency of this strategy in finding sub-networks is that, in addition to direct connections, also connections mediated by intermediate nodes are considered to build up the sub-networks. The possibility of using of such intermediate nodes makes this approach more robust to noise. It also overcomes some limitations intrinsic to experimental designs based on differential expression, in which some nodes are invariant across conditions. The proposed approach can also be used for candidate disease-gene prioritization. Here, we demonstrate the usefulness of the approach by means of several case examples that include a differential expression analysis in Fanconi Anemia, a genome-wide association study of bipolar disorder and a genome-scale study of essentiality in cancer genes. An efficient and easy-to-use web interface (available at http://www.babelomics.org) based on HTML5 technologies is also provided to run the algorithm and represent the network.

10aBipolar Disorder10aFanconi Anemia10aGene Regulatory Networks10aGenes, Neoplasm10aGenome-Wide Association Study10aGenomics10aHumans10aProtein Interaction Mapping1 aGarcía-Alonso, Luz1 aAlonso, Roberto1 aVidal, Enrique1 aAmadoz, Alicia1 aDe Maria, Alejandro1 aMinguez, Pablo1 aMedina, Ignacio1 aDopazo, Joaquin uhttp://clinbioinfosspa.es/content/discovering-hidden-sub-network-component-ranked-list-genes-or-proteins-derived-genomic03458nas a2200469 4500008004100000022001400041245011000055210006900165260001600234300000800250490000700258520195800265653002402223653001202247653001802259653002502277653001802302653001802320653001702338653003002355653002202385653001002407653001602417653003102433653002202464653002802486653002102514653001402535653003202549653005202581653002302633653002702656653003402683653001602717653002402733653001102757100002602768700002102794700002002815700002602835856012702861 2012 eng d a1471-214800aDiversification of the expanded teleost-specific toll-like receptor family in Atlantic cod, Gadus morhua.0 aDiversification of the expanded teleostspecific tolllike recepto c2012 Dec 29 a2560 v123 a

BACKGROUND: Toll-like receptors (Tlrs) are major molecular pattern recognition receptors of the innate immune system. Atlantic cod (Gadus morhua) is the first vertebrate known to have lost most of the mammalian Tlr orthologues, particularly all bacterial recognising and other cell surface Tlrs. On the other hand, its genome encodes a unique repertoire of teleost-specific Tlrs. The aim of this study was to investigate if these duplicate Tlrs have been retained through adaptive evolution to compensate for the lack of other cell surface Tlrs in the cod genome.

RESULTS: In this study, one tlr21, 12 tlr22 and two tlr23 genes representing the teleost-specific Tlr family have been cloned and characterised in cod. Phylogenetic analysis grouped all tlr22 genes under a single clade, indicating that the multiple cod paralogues have arisen through lineage-specific duplications. All tlrs examined were transcribed in immune-related tissues as well as in stomach, gut and gonads of adult cod and were differentially expressed during early development. These tlrs were also differentially regulated following immune challenge by immersion with Vibrio anguillarum, indicating their role in the immune response. An increase in water temperature from 4 to 12°C was associated with a 5.5-fold down-regulation of tlr22d transcript levels in spleen. Maximum likelihood analysis with different evolution models revealed that tlr22 genes are under positive selection. A total of 24 codons were found to be positively selected, of which 19 are in the ligand binding region of ectodomain.

CONCLUSION: Positive selection pressure coupled with experimental evidence of differential expression strongly support the hypothesis that teleost-specific tlr paralogues in cod are undergoing neofunctionalisation and can recognise bacterial pathogen-associated molecular patterns to compensate for the lack of other cell surface Tlrs.

10aAmino Acid Sequence10aAnimals10aBinding Sites10aEvolution, Molecular10aFish Diseases10aFish Proteins10aGadus morhua10aGene Expression Profiling10aGenetic Variation10aGills10aHead Kidney10aHost-Pathogen Interactions10aModels, Molecular10aMolecular Sequence Data10aMultigene Family10aPhylogeny10aProtein Structure, Tertiary10aReverse Transcriptase Polymerase Chain Reaction10aSelection, Genetic10aSequence Analysis, DNA10aSequence Homology, Amino Acid10aTemperature10aToll-Like Receptors10aVibrio1 aSundaram, Arvind, Y M1 aKiron, Viswanath1 aDopazo, Joaquin1 aFernandes, Jorge, M O uhttp://clinbioinfosspa.es/content/diversification-expanded-teleost-specific-toll-receptor-family-atlantic-cod-gadus-morhua02277nas a2200193 4500008004100000022001400041245011200055210006900167260000900236300001100245490000600256520164600262100002401908700002101932700002101953700002001974700002001994856006902014 2012 eng d a1176-934300aEvolutionary Genomics of Genes Involved in Olfactory Behavior in the Drosophila melanogaster Species Group.0 aEvolutionary Genomics of Genes Involved in Olfactory Behavior in c2012 a89-1040 v83 aPrevious comparative genomic studies of genes involved in olfactory behavior in Drosophila focused only on particular gene families such as odorant receptor and/or odorant binding proteins. However, olfactory behavior has a complex genetic architecture that is orchestrated by many interacting genes. In this paper, we present a comparative genomic study of olfactory behavior in Drosophila including an extended set of genes known to affect olfactory behavior. We took advantage of the recent burst of whole genome sequences and the development of powerful statistical tools to analyze genomic data and test evolutionary and functional hypotheses of olfactory genes in the six species of the Drosophila melanogaster species group for which whole genome sequences are available. Our study reveals widespread purifying selection and limited incidence of positive selection on olfactory genes. We show that the pace of evolution of olfactory genes is mostly independent of the life cycle stage, and of the number of life cycle stages, in which they participate in olfaction. However, we detected a relationship between evolutionary rates and the position that the gene products occupy in the olfactory system, genes occupying central positions tend to be more constrained than peripheral genes. Finally, we demonstrate that specialization to one host does not seem to be associated with bursts of adaptive evolution in olfactory genes in D. sechellia and D. erecta, the two specialists species analyzed, but rather different lineages have idiosyncratic evolutionary histories in which both historical and ecological factors have been involved.1 aLavagnino, Nicolás1 aSerra, François1 aArbiza, Leonardo1 aDopazo, Hernán1 aHasson, Esteban uhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3273929/?tool=pubmed02782nas a2200253 4500008004100000022001400041245015200055210006900207260001600276520178700292100002502079700002602104700002902130700003102159700002802190700002602218700002802244700002702272700003302299700002702332700001602359700002902375856012402404 2012 eng d a1097-021500aExpression profiling shows differential molecular pathways and provides potential new diagnostic biomarkers for colorectal serrated adenocarcinoma.0 aExpression profiling shows differential molecular pathways and p c2012 Jun 143 aSerrated adenocarcinoma (SAC) is a recently recognized colorectal cancer (CRC) subtype accounting for 7.5-8.7% of CRCs. It has been shown that SAC has a poorer prognosis and has different molecular and immunohistochemical features compared to conventional carcinoma (CC) but, to date, only one previous study has analysed its mRNA expression profile by microarray. Using a different microarray platform, we have studied the molecular signature of 11 SACs and compared it with that of 15 matched CC with the aim of discerning the functions which characterize SAC biology and validating, at the mRNA and protein level, the most differentially expressed genes which were also tested using a validation set of 70 SACs and 70 CCs to assess their diagnostic and prognostic values. Microarray data showed a higher representation of morphogenesis-, hypoxia-, cytoskeleton- and vesicle transport-related functions and also an over-expression of fascin1 (actin-bundling protein associated with invasion) and the antiapoptotic gene hippocalcin in SAC all of which were validated both by qPCR and immunohistochemistry. Fascin1 expression was statistically associated with KRAS mutation with 88.6% sensitivity and 85.7% specificity for SAC diagnosis and the positivity of fascin1 or hippocalcin was highly suggestive of SAC diagnosis (sensitivity=100%). Evaluation of these markers in CRCs showing histological and molecular characteristics of high-level microsatellite instability (MSI-H) also helped to distinguish SACs from MSI-H CRCs. Molecular profiling demonstrates that SAC shows activation of distinct signalling pathways and that immunohistochemical fascin1 and hippocalcin expression can be reliably used for its differentiation from other CRC subtypes. © 2012 Wiley Periodicals, Inc.1 aConesa-Zamora, Pablo1 aGarcía-Solano, José1 aGarcia-Garcia, Francisco1 aTurpin, María, Del Carmen1 aTrujillo-Santos, Javier1 aTorres-Moreno, Daniel1 aOviedo-Ramírez, Isabel1 aCarbonell-Muñoz, Rosa1 aMuñoz-Delgado, Encarnación1 aRodriguez-Braun, Edith1 aConesa, Ana1 aPérez-Guillermo, Miguel uhttp://clinbioinfosspa.es/content/expression-profiling-shows-differential-molecular-pathways-and-provides-potential-new02970nas a2200313 4500008004100000022001400041245008300055210006900138260000900207300001100216490000600227520199700233653001202230653003302242653001102275653001702286653000902303653001802312653004402330653002502374653001902399653002702418100001902445700001902464700002002483700002002503700002002523856011302543 2012 eng d a1932-620300aExtensive translatome remodeling during ER stress response in mammalian cells.0 aExtensive translatome remodeling during ER stress response in ma c2012 ae359150 v73 a

In this work we have described the translatome of two mammalian cell lines, NIH3T3 and Jurkat, by scoring the relative polysome association of ∼10,000 mRNA under normal and ER stress conditions. We have found that translation efficiencies of mRNA correlated poorly with transcript abundance, although a general tendency was observed so that the highest translation efficiencies were found in abundant mRNA. Despite the differences found between mouse (NIH3T3) and human (Jurkat) cells, both cell types share a common translatome composed by ∼800-900 mRNA that encode proteins involved in basic cellular functions. Upon stress, an extensive remodeling in translatomes was observed so that translation of ∼50% of mRNA was inhibited in both cell types, this effect being more dramatic for those mRNA that accounted for most of the cell translation. Interestingly, we found two subsets comprising 1000-1500 mRNA whose translation resisted or was induced by stress. Translation arrest resistant class includes many mRNA encoding aminoacyl tRNA synthetases, ATPases and enzymes involved in DNA replication and stress response such as BiP. This class of mRNA is characterized by high translation rates in both control and stress conditions. Translation inducible class includes mRNA whose translation was relieved after stress, showing a high enrichment in early response transcription factors of bZIP and zinc finger C2H2 classes. Unlike yeast, a general coordination between changes in translation and transcription upon stress (potentiation) was not observed in mammalian cells. Among the different features of mRNA analyzed, we found a relevant association of translation efficiency with the presence of upstream ATG in the 5'UTR and with the length of coding sequence of mRNA, and a looser association with other parameters such as the length and the G+C content of 5'UTR. A model for translatome remodeling during the acute phase of stress response in mammalian cells is proposed.

10aAnimals10aEndoplasmic Reticulum Stress10aHumans10aJurkat Cells10aMice10aNIH 3T3 Cells10aOligonucleotide Array Sequence Analysis10aProtein Biosynthesis10aRNA, Messenger10aTranscription, Genetic1 aVentoso, Iván1 aKochetov, Alex1 aMontaner, David1 aDopazo, Joaquin1 aSantoyo, Javier uhttp://clinbioinfosspa.es/content/extensive-translatome-remodeling-during-er-stress-response-mammalian-cells02193nas a2200289 4500008004100000022001400041245014800055210006900203260001600272300000800288490000600296520126100302100002701563700001701590700002701607700002001634700002301654700002401677700002001701700002001721700002801741700002001769700002501789700002101814700001901835856004901854 2012 eng d a1750-117200aFour new loci associations discovered by pathway-based and network analyses of the genome-wide variability profile of Hirschsprung’s disease.0 aFour new loci associations discovered by pathwaybased and networ c2012 Dec 28 a1030 v73 aABSTRACT: Finding gene associations in rare diseases is frequently hampered by the reduced numbers of patients accessible. Conventional gene-based association tests rely on the availability of large cohorts, which constitutes a serious limitation for its application in this scenario. To overcome this problem we have used here a combined strategy in which a pathway-based analysis (PBA) has been initially conducted to prioritize candidate genes in a Spanish cohort of 53 trios of short-segment Hirschsprung’s disease. Candidate genes have been further validated in an independent population of 106 trios. The study revealed a strong association of 11 gene ontology (GO) modules related to signal transduction and its regulation, enteric nervous system (ENS) formation and other HSCR-related processes. Among the preselected candidates, a total of 4 loci, RASGEF1A, IQGAP2, DLC1 and CHRNA7, related to signal transduction and migration processes, were found to be significantly associated to HSCR. Network analysis also confirms their involvement in the network of already known disease genes. This approach, based on the study of functionally-related gene sets, requires of lower sample sizes and opens new opportunities for the study of rare diseases.1 aFernández, Raquel, Ma1 aBleda, Marta1 aNúñez-Torres, Rocío1 aMedina, Ignacio1 aLuzón-Toro, Berta1 aGarcía-Alonso, Luz1 aTorroglosa, Ana1 aMarbà, Martina1 aEnguix-Riego, Ma, Valle1 aMontaner, David1 aAntiňolo, Guillermo1 aDopazo, Joaquín1 aBorrego, Salud uhttp://www.ojrd.com/content/7/1/103/abstract02486nas a2200373 4500008004100000022001400041245014600055210006900201260001600270300000800286490000600294520125600300653001101556653003801567653003401605653001301639653002501652653001101677653000901688100002701697700001701724700002701741700002001768700002301788700002401811700002001835700002001855700002801875700002001903700002501923700002001948700001901968856012501987 2012 eng d a1750-117200aFour new loci associations discovered by pathway-based and network analyses of the genome-wide variability profile of Hirschsprung's disease.0 aFour new loci associations discovered by pathwaybased and networ c2012 Dec 28 a1030 v73 a

Finding gene associations in rare diseases is frequently hampered by the reduced numbers of patients accessible. Conventional gene-based association tests rely on the availability of large cohorts, which constitutes a serious limitation for its application in this scenario. To overcome this problem we have used here a combined strategy in which a pathway-based analysis (PBA) has been initially conducted to prioritize candidate genes in a Spanish cohort of 53 trios of short-segment Hirschsprung's disease. Candidate genes have been further validated in an independent population of 106 trios. The study revealed a strong association of 11 gene ontology (GO) modules related to signal transduction and its regulation, enteric nervous system (ENS) formation and other HSCR-related processes. Among the preselected candidates, a total of 4 loci, RASGEF1A, IQGAP2, DLC1 and CHRNA7, related to signal transduction and migration processes, were found to be significantly associated to HSCR. Network analysis also confirms their involvement in the network of already known disease genes. This approach, based on the study of functionally-related gene sets, requires of lower sample sizes and opens new opportunities for the study of rare diseases.

10aFemale10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGenotype10aHirschsprung Disease10aHumans10aMale1 aFernández, Raquel, Ma1 aBleda, Marta1 aNúñez-Torres, Rocío1 aMedina, Ignacio1 aLuzón-Toro, Berta1 aGarcía-Alonso, Luz1 aTorroglosa, Ana1 aMarbà, Martina1 aEnguix-Riego, Ma, Valle1 aMontaner, David1 aAntiňolo, Guillermo1 aDopazo, Joaquin1 aBorrego, Salud uhttp://clinbioinfosspa.es/content/four-new-loci-associations-discovered-pathway-based-and-network-analyses-genome-wide-003418nas a2200253 4500008004100000022001400041245011200055210006900167260000900236300000800245490000700253520257000260100002502830700003202855700001602887700001702903700002102920700002502941700002202966700001802988700002203006700001803028856011803046 2012 eng d a1471-216400aIdentification of yeast genes that confer resistance to chitosan oligosaccharide (COS) using chemogenomics.0 aIdentification of yeast genes that confer resistance to chitosan c2012 a2670 v133 aBACKGROUND: Chitosan oligosaccharide (COS), a deacetylated derivative of chitin, is an abundant, and renewable natural polymer. COS has higher antimicrobial properties than chitosan and is presumed to act by disrupting/permeabilizing the cell membranes of bacteria, yeast and fungi. COS is relatively non-toxic to mammals. By identifying the molecular and genetic targets of COS, we hope to gain a better understanding of the antifungal mode of action of COS. RESULTS: Three different chemogenomic fitness assays, haploinsufficiency (HIP), homozygous deletion (HOP), and multicopy suppression (MSP) profiling were combined with a transcriptomic analysis to gain insight in to the mode of action and mechanisms of resistance to chitosan oligosaccharides. The fitness assays identified 39 yeast deletion strains sensitive to COS and 21 suppressors of COS sensitivity. The genes identified are involved in processes such as RNA biology (transcription, translation and regulatory mechanisms), membrane functions (e.g. signalling, transport and targeting), membrane structural components, cell division, and proteasome processes. The transcriptomes of control wild type and 5 suppressor strains overexpressing ARL1, BCK2, ERG24, MSG5, or RBA50, were analyzed in the presence and absence of COS. Some of the up-regulated transcripts in the suppressor overexpressing strains exposed to COS included genes involved in transcription, cell cycle, stress response and the Ras signal transduction pathway. Down-regulated transcripts included those encoding protein folding components and respiratory chain proteins. The COS-induced transcriptional response is distinct from previously described environmental stress responses (i.e. thermal, salt, osmotic and oxidative stress) and pre-treatment with these well characterized environmental stressors provided little or any resistance to COS. CONCLUSIONS: Overexpression of the ARL1 gene, a member of the Ras superfamily that regulates membrane trafficking, provides protection against COS-induced cell membrane permeability and damage. We found that the ARL1 COS-resistant over-expression strain was as sensitive to Amphotericin B, Fluconazole and Terbinafine as the wild type cells and that when COS and Fluconazole are used in combination they act in a synergistic fashion. The gene targets of COS identified in this study indicate that COS’s mechanism of action is different from other commonly studied fungicides that target membranes, suggesting that COS may be an effective fungicide for drug-resistant fungal pathogens.1 aJaime, María, D L A1 aLopez-Llorca, Luis, Vicente1 aConesa, Ana1 aLee, Anna, Y1 aProctor, Michael1 aHeisler, Lawrence, E1 aGebbia, Marinella1 aGiaever, Guri1 aWestwood, Timothy1 aNislow, Corey uhttp://clinbioinfosspa.es/content/identification-yeast-genes-confer-resistance-chitosan-oligosaccharide-cos-using03355nas a2200529 4500008004100000022001400041245009200055210007000147260001300217300001100230490000600241520169800247653001801945653001801963653002301981653001502004653002602019653001302045653001702058653003002075653003002105653001702135653001102152653002102163653002702184653005002211653002202261653001202283653001502295653002702310653001502337653004402352653002102396653002402417100002002441700002402461700001802485700002002503700002902523700002002552700002202572700002302594700002302617700003002640700002202670856013302692 2012 eng d a2629-327700aIL1β induces mesenchymal stem cells migration and leucocyte chemotaxis through NF-κB.0 aIL1β induces mesenchymal stem cells migration and leucocyte chem c2012 Sep a905-160 v83 a

Mesenchymal stem cells are often transplanted into inflammatory environments where they are able to survive and modulate host immune responses through a poorly understood mechanism. In this paper we analyzed the responses of MSC to IL-1β: a representative inflammatory mediator. Microarray analysis of MSC treated with IL-1β revealed that this cytokine activateds a set of genes related to biological processes such as cell survival, cell migration, cell adhesion, chemokine production, induction of angiogenesis and modulation of the immune response. Further more detailed analysis by real-time PCR and functional assays revealed that IL-1β mainly increaseds the production of chemokines such as CCL5, CCL20, CXCL1, CXCL3, CXCL5, CXCL6, CXCL10, CXCL11 and CX(3)CL1, interleukins IL-6, IL-8, IL23A, IL32, Toll-like receptors TLR2, TLR4, CLDN1, metalloproteins MMP1 and MMP3, growth factors CSF2 and TNF-α, together with adhesion molecules ICAM1 and ICAM4. Functional analysis of MSC proliferation, migration and adhesion to extracellular matrix components revealed that IL-1β did not affect proliferation but also served to induce the secretion of trophic factors and adhesion to ECM components such as collagen and laminin. IL-1β treatment enhanced the ability of MSC to recruit monocytes and granulocytes in vitro. Blockade of NF-κβ transcription factor activation with IκB kinase beta (IKKβ) shRNA impaired MSC migration, adhesion and leucocyte recruitment, induced by IL-1β demonstrating that NF-κB pathway is an important downstream regulator of these responses. These findings are relevant to understanding the biological responses of MSC to inflammatory environments.

10aCell Adhesion10aCell Movement10aCell Proliferation10aChemokines10aChemotaxis, Leukocyte10aCollagen10aFibronectins10aGene Expression Profiling10aGene Knockdown Techniques10aHEK293 Cells10aHumans10aI-kappa B Kinase10aInflammation Mediators10aIntercellular Signaling Peptides and Proteins10aInterleukin-1beta10aLaminin10aLeukocytes10aMesenchymal Stem Cells10aNF-kappa B10aOligonucleotide Array Sequence Analysis10aRNA Interference10aSignal Transduction1 aCarrero, Rubén1 aCerrada, Inmaculada1 aLledó, Elisa1 aDopazo, Joaquin1 aGarcia-Garcia, Francisco1 aRubio, Mari-Paz1 aTrigueros, César1 aDorronsoro, Akaitz1 aRuiz-Sauri, Amparo1 aMontero, José, Anastasio1 aSepúlveda, Pilar uhttp://clinbioinfosspa.es/content/il1%CE%B2-induces-mesenchymal-stem-cells-migration-and-leucocyte-chemotaxis-through-nf-%CE%BAb01996nas a2200313 4500008004100000022001400041245007400055210006900129260001300198300001200211490000700223520105300230653001801283653002301301653001901324653002901343653001301372653001401385653001301399653002601412653001801438100001701456700002001473700002001493700002401513700002401537700002001561856010101581 2012 eng d a1362-496200aInferring the regulatory network behind a gene expression experiment.0 aInferring the regulatory network behind a gene expression experi c2012 Jul aW168-720 v403 a

Transcription factors (TFs) and miRNAs are the most important dynamic regulators in the control of gene expression in multicellular organisms. These regulatory elements play crucial roles in development, cell cycling and cell signaling, and they have also been associated with many diseases. The Regulatory Network Analysis Tool (RENATO) web server makes the exploration of regulatory networks easy, enabling a better understanding of functional modularity and network integrity under specific perturbations. RENATO is suitable for the analysis of the result of expression profiling experiments. The program analyses lists of genes and search for the regulators compatible with its activation or deactivation. Tests of single enrichment or gene set enrichment allow the selection of the subset of TFs or miRNAs significantly involved in the regulation of the query genes. RENATO also offers an interactive advanced graphical interface that allows exploring the regulatory network found.RENATO is available at: http://renato.bioinfo.cipf.es/.

10aBinding Sites10aDatabases, Genetic10aFanconi Anemia10aGene Regulatory Networks10aInternet10aMicroRNAs10aSoftware10aTranscription Factors10aTranscriptome1 aBleda, Marta1 aMedina, Ignacio1 aAlonso, Roberto1 aDe Maria, Alejandro1 aSalavert, Francisco1 aDopazo, Joaquin uhttp://clinbioinfosspa.es/content/inferring-regulatory-network-behind-gene-expression-experiment02674nas a2200313 4500008004100000022001400041245008800055210006900143260001600212300000700228490000600235520174000241653000801981100002101989700001602010700001602026700001902042700002002061700002602081700002002107700002902127700002802156700003302184700001702217700002702234700002502261700002002286856005402306 2012 eng d a1756-994X00aA map of human microRNA variation uncovers unexpectedly high levels of variability.0 amap of human microRNA variation uncovers unexpectedly high level c2012 Aug 20 a620 v43 aABSTRACT: BACKGROUND: MicroRNAs (miRNAs) are key components of the gene regulatory network in many species. During the past few years, these regulatory elements have been shown to be involved in an increasing number and range of diseases. Consequently, the compilation of a comprehensive map of natural variability in healthy population seems an obvious requirement for future research on miRNA-related pathologies. METHODS: Data on 14 populations from the 1000 Genomes Project were analysed, along with new data extracted from 60 exomes of healthy individuals from a southern Spain population, sequenced in the context of the Medical Genome Project, to derive an accurate map of miRNA variability. RESULTS: Despite the common belief that miRNAs are highly conserved elements, analysis of the sequences of the 1,152 individuals indicated that the observed level of variability is double what was expected. A total of 527 variants were found. Among these, 45 variants affected the recognition region of the corresponding miRNA and were found in 43 different miRNAs, 26 of which are known to be involved in 57 diseases. Different parts of the mature structure of the miRNA were affected to different degrees by variants, which suggests the existence of a selective pressure related to the relative functional impact of the change. Moreover, 41 variants showed a significant deviation from the Hardy-Weinberg equilibrium, which supports the existence of a selective process against some alleles. The average number of variants per individual in miRNAs was 28. CONCLUSIONS: Despite an expectation that miRNAs would be highly conserved genomic elements, our study reports a level of variability comparable to that observed for coding genes.10aNGS1 aCarbonell, José1 aAlloza, Eva1 aArce, Pablo1 aBorrego, Salud1 aSantoyo, Javier1 aRuiz-Ferrer, Macarena1 aMedina, Ignacio1 aJiménez-Almazán, Jorge1 aMéndez-Vidal, Cristina1 adel Pozo, María, González-1 aVela, Alicia1 aBhattacharya, Shomi, S1 aAntiňolo, Guillermo1 aDopazo, Joaquin uhttp://genomemedicine.com/content/4/8/62/abstract01733nas a2200193 4500008004100000022001400041245017100055210006900226260001600295520097200311100001801283700001601301700001801317700002101335700001801356700002201374700001801396856012501414 2012 eng d a1364-370300aMicroarray analysis of Etrog citron (Citrus medica L.) reveals changes in chloroplast, cell wall, peroxidase and symporter activities in response to viroid infection.0 aMicroarray analysis of Etrog citron Citrus medica L reveals chan c2012 Mar 153 aViroids are small (246-401 nucleotides), single-stranded, circular RNA molecules that infect several crop plants and can cause diseases of economic importance. Citrus are the hosts in which the largest number of viroids have been identified. Citrus exocortis viroid (CEVd), the causal agent of citrus exocortis disease, induces considerable losses in citrus crops. Changes in the gene expression profile during the early (pre-symptomatic) and late (post-symptomatic) stages of Etrog citron infected with CEVd were investigated using a citrus cDNA microarray. MaSigPro analysis was performed and, on the basis of gene expression profiles as a function of the time after infection, the differentially expressed genes were classified into five clusters. FatiScan analysis revealed significant enrichment of functional categories for each cluster, indicating that viroid infection triggers important changes in chloroplast, cell wall, peroxidase and symporter activities.1 aRizza, Serena1 aConesa, Ana1 aJuarez, José1 aCatara, Antonino1 aNavarro, Luis1 aDuran-Vila, Nuria1 aAncillo, Gema uhttp://clinbioinfosspa.es/content/microarray-analysis-etrog-citron-citrus-medica-l-reveals-changes-chloroplast-cell-wall02563nas a2200445 4500008004100000022001400041245010000055210006900155260001300224300001200237490000700249520111500256653001201371653002201383653003901405653002601444653002201470653004401492653001701536653003201553653000901585653002701594653005201621653002101673653002701694653001801721653003201739100002201771700001901793700001501812700002001827700002201847700001901869700002001888700002001908700002201928700002101950700002201971856012401993 2012 eng d a1530-686000aThe protease MT1-MMP drives a combinatorial proteolytic program in activated endothelial cells.0 aprotease MT1MMP drives a combinatorial proteolytic program in ac c2012 Nov a4481-940 v263 a

The mechanism by which proteolytic events translate into biological responses is not well understood. To explore the link of pericellular proteolysis to events relevant to capillary sprouting within the inflammatory context, we aimed at the identification of the collection of substrates of the protease MT1-MMP in endothelial tip cells induced by inflammatory stimuli. We applied quantitative proteomics to endothelial cells (ECs) derived from wild-type and MT1-MMP-null mice to identify the substrate repertoire of this protease in TNF-α-activated ECs. Bioinformatics analysis revealed a combinatorial MT1-MMP proteolytic program, in which combined rather than single substrate processing would determine biological decisions by activated ECs, including chemotaxis, cell motility and adhesion, and vasculature development. MT1-MMP-deficient ECs inefficiently processed several of these substrates (TSP1, CYR61, NID1, and SEM3C), validating the model. This novel concept of MT1-MMP-driven combinatorial proteolysis in angiogenesis might be extendable to proteolytic actions in other cellular contexts.

10aAnimals10aBlotting, Western10aCombinatorial Chemistry Techniques10aComputational Biology10aEndothelial Cells10aGene Expression Regulation, Enzymologic10aInflammation10aMatrix Metalloproteinase 1410aMice10aProtein Array Analysis10aReverse Transcriptase Polymerase Chain Reaction10aRNA Interference10aRNA, Small Interfering10aTranscriptome10aTumor Necrosis Factor-alpha1 aKoziol, Agnieszka1 aGonzalo, Pilar1 aMota, Alba1 aPollán, Angela1 aLorenzo, Cristina1 aColomé, Nuria1 aMontaner, David1 aDopazo, Joaquin1 aArribas, Joaquín1 aCanals, Francesc1 aArroyo, Alicia, G uhttp://clinbioinfosspa.es/content/protease-mt1-mmp-drives-combinatorial-proteolytic-program-activated-endothelial-cells01929nas a2200253 4500008004100000022001400041245006800055210006500123260001600188300001100204490000700215520118200222653000801404100003001412700002901442700002101471700001801492700001801510700002001528700002101548700002101569700001601590856006901606 2012 eng d a1367-481100aQualimap: evaluating next-generation sequencing alignment data.0 aQualimap evaluating nextgeneration sequencing alignment data c2012 Oct 15 a2678-90 v283 aMOTIVATION: The sequence alignment/map (SAM) and the binary alignment/map (BAM) formats have become the standard method of representation of nucleotide sequence alignments for next-generation sequencing data. SAM/BAM files usually contain information from tens to hundreds of millions of reads. Often, the sequencing technology, protocol and/or the selected mapping algorithm introduce some unwanted biases in these data. The systematic detection of such biases is a non-trivial task that is crucial to drive appropriate downstream analyses. RESULTS: We have developed Qualimap, a Java application that supports user-friendly quality control of mapping data, by considering sequence features and their genomic properties. Qualimap takes sequence alignment data and provides graphical and statistical analyses for the evaluation of data. Such quality-control data are vital for highlighting problems in the sequencing and/or mapping processes, which must be addressed prior to further analyses. AVAILABILITY: Qualimap is freely available from http://www.qualimap.org. CONTACT: aconesa@cipf.es SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.10aNGS1 aGarcía-Alcalde, Fernando1 aOkonechnikov, Konstantin1 aCarbonell, José1 aCruz, Luis, M1 aGötz, Stefan1 aTarazona, Sonia1 aDopazo, Joaquín1 aMeyer, Thomas, F1 aConesa, Ana uhttp://bioinformatics.oxfordjournals.org/content/28/20/2678.long01878nas a2200289 4500008004100000022001400041245008700055210006900142260000900211300001100220490000600231520100600237100002701243700002001270700002801290700001901318700002701337700002201364700001801386700002001404700002001424700001801444700002101462700002101483700002001504856006401524 2012 eng d a1748-567300aSelect your SNPs (SYSNPs): a web tool for automatic and massive selection of SNPs.0 aSelect your SNPs SYSNPs a web tool for automatic and massive sel c2012 a324-340 v63 aAssociation studies are the choice approach in the discovery of the genomic basis of complex traits. To carry out such analysis, researchers frequently need to (1) select optimally informative sets of Single Nucleotide Polymorphisms (SNPs) in candidate regions and (2) annotate the results of associations found by means of genome-wide SNP arrays. These are complex tasks, since many criteria have to be considered, including the SNPs’ functional properties, technological information and haplotype frequencies in given populations. SYSNPs implements algorithms that allow for efficient and simultaneous consideration of all the relevant criteria to obtain sets of SNPs that properly cover arbitrarily large lists of genes or genomic regions. Complementarily, SYSNPs allows for comprehensive functional annotation of SNPs linked to any given marker SNP. SYSNPs dramatically reduces the effort needed for SNP selection from days of searching various databases to a few minutes using a simple browser.1 aLorente-Galdos, Belén1 aMedina, Ignacio1 aMorcillo-Suarez, Carlos1 aHeredia, Txema1 aCarreño-Torres, Angel1 aSangrós, Ricardo1 aAlegre, Josep1 aPita, Guillermo1 aVellalta, Gemma1 aMalats, Nuria1 aPisano, David, G1 aDopazo, Joaquín1 aNavarro, Arcadi uhttp://inderscience.metapress.com/content/f76740x8071u513n/02231nas a2200325 4500008004100000022001400041245010200055210006900157260001300226300001100239490000700250520119100257653002301448653001101471653001301482653002701495653001401522653003601536653002501572653001301597100002001610700002101630700001801651700002801669700001801697700002001715700002301735700002301758856012401781 2012 eng d a1362-496200aSNPeffect 4.0: on-line prediction of molecular and structural effects of protein-coding variants.0 aSNPeffect 40 online prediction of molecular and structural effec c2012 Jan aD935-90 v403 a

Single nucleotide variants (SNVs) are, together with copy number variation, the primary source of variation in the human genome and are associated with phenotypic variation such as altered response to drug treatment and susceptibility to disease. Linking structural effects of non-synonymous SNVs to functional outcomes is a major issue in structural bioinformatics. The SNPeffect database (http://snpeffect.switchlab.org) uses sequence- and structure-based bioinformatics tools to predict the effect of protein-coding SNVs on the structural phenotype of proteins. It integrates aggregation prediction (TANGO), amyloid prediction (WALTZ), chaperone-binding prediction (LIMBO) and protein stability analysis (FoldX) for structural phenotyping. Additionally, SNPeffect holds information on affected catalytic sites and a number of post-translational modifications. The database contains all known human protein variants from UniProt, but users can now also submit custom protein variants for a SNPeffect analysis, including automated structure modeling. The new meta-analysis application allows plotting correlations between phenotypic features for a user-selected set of variants.

10aDatabases, Protein10aHumans10aInternet10aMeta-Analysis as Topic10aPhenotype10aPolymorphism, Single Nucleotide10aProtein Conformation10aProteins1 aDe Baets, Greet1 aVan Durme, Joost1 aReumers, Joke1 aMaurer-Stroh, Sebastian1 aVanhee, Peter1 aDopazo, Joaquin1 aSchymkowitz, Joost1 aRousseau, Frederic uhttp://clinbioinfosspa.es/content/snpeffect-40-line-prediction-molecular-and-structural-effects-protein-coding-variants03639nas a2200505 4500008004100000022001400041245012700055210006900182260000900251300001100260490000600271520212800277653001902405653001202424653002302436653001802459653002602477653001802503653000802521653001502529653002202544653003002566653002302596653001002619653002402629653002802653653000902681653002202690653001302712653001702725653001802742100001902760700001802779700002102797700001402818700001602832700002402848700002202872700002102894700002202915700001802937700001702955700003002972856013103002 2012 eng d a1932-620300aTranscriptome profiling of the intoxication response of Tenebrio molitor larvae to Bacillus thuringiensis Cry3Aa protoxin.0 aTranscriptome profiling of the intoxication response of Tenebrio c2012 ae346240 v73 aBacillus thuringiensis (Bt) crystal (Cry) proteins are effective against a select number of insect pests, but improvements are needed to increase efficacy and decrease time to mortality for coleopteran pests. To gain insight into the Bt intoxication process in Coleoptera, we performed RNA-Seq on cDNA generated from the guts of Tenebrio molitor larvae that consumed either a control diet or a diet containing Cry3Aa protoxin. Approximately 134,090 and 124,287 sequence reads from the control and Cry3Aa-treated groups were assembled into 1,318 and 1,140 contigs, respectively. Enrichment analyses indicated that functions associated with mitochondrial respiration, signalling, maintenance of cell structure, membrane integrity, protein recycling/synthesis, and glycosyl hydrolases were significantly increased in Cry3Aa-treated larvae, whereas functions associated with many metabolic processes were reduced, especially glycolysis, tricarboxylic acid cycle, and fatty acid synthesis. Microarray analysis was used to evaluate temporal changes in gene expression after 6, 12 or 24 h of Cry3Aa exposure. Overall, microarray analysis indicated that transcripts related to allergens, chitin-binding proteins, glycosyl hydrolases, and tubulins were induced, and those related to immunity and metabolism were repressed in Cry3Aa-intoxicated larvae. The 24 h microarray data validated most of the RNA-Seq data. Of the three intoxication intervals, larvae demonstrated more differential expression of transcripts after 12 h exposure to Cry3Aa. Gene expression examined by three different methods in control vs. Cry3Aa-treated larvae at the 24 h time point indicated that transcripts encoding proteins with chitin-binding domain 3 were the most differentially expressed in Cry3Aa-intoxicated larvae. Overall, the data suggest that T. molitor larvae mount a complex response to Cry3Aa during the initial 24 h of intoxication. Data from this study represent the largest genetic sequence dataset for T. molitor to date. Furthermore, the methods in this study are useful for comparative analyses in organisms lacking a sequenced genome.10aAdministration10aAnimals10aBacterial Proteins10aBase Sequence10aBiosynthetic Pathways10aComplementary10aDNA10aEndotoxins10aEnergy Metabolism10aGene Expression Profiling10aHemolysin Proteins10aLarva10aMicroarray Analysis10aMolecular Sequence Data10aOral10aSequence Analysis10aTenebrio10aTime Factors10aTranscriptome1 aOppert, Brenda1 aDowd, Scot, E1 aBouffard, Pascal1 aLi, Lewyn1 aConesa, Ana1 aLorenzen, Marcé, D1 aToutges, Michelle1 aMarshall, Jeremy1 aHuestis, Diana, L1 aFabrick, Jeff1 aOppert, Cris1 aJurat-Fuentes, Juan, Luis uhttp://clinbioinfosspa.es/content/transcriptome-profiling-intoxication-response-tenebrio-molitor-larvae-bacillus-thuringiensis02754nas a2200217 4500008004100000022001400041245012800055210006900183260000900252300000700261490000600268520203200274100002702306700003302333700003002366700002902396700002002425700001602445700001802461856005702479 2012 eng d a2193-180100aTransdifferentiation of MALME-3M and MCF-7 Cells toward Adipocyte-like Cells is Dependent on Clathrin-mediated Endocytosis.0 aTransdifferentiation of MALME3M and MCF7 Cells toward Adipocytel c2012 a440 v13 aABSTRACT: Enforced cell transdifferentiation of human cancer cells is a promising alternative to conventional chemotherapy. We previously identified albumin-associated lipid- and, more specifically, saturated fatty acid-induced transdifferentiation programs in human cancer cells (HCCLs). In this study, we further characterized the adipocyte-like cells, resulting from the transdifferentiation of human cancer cell lines MCF-7 and MALME-3M, and proposed a common mechanistic approach for these transdifferentiating programs. We showed the loss of pigmentation in MALME-3M cells treated with albumin-associated lipids, based on electron microscopic analysis, and the overexpression of perilipin 2 (PLIN2) by western blotting in MALME-3M and MCF-7 cells treated with unsaturated fatty acids. Comparing the gene expression profiles of naive melanoma MALME-3M cells and albumin-associated lipid-treated cells, based on RNA sequencing, we confirmed the transcriptional upregulation of some key adipogenic gene markers and also an alternative splicing of the adipogenic master regulator PPARG, that is probably related to the reported up regulated expression of the protein. Most importantly, these results also showed the upregulation of genes responsible for Clathrin (CLTC) and other adaptor-related proteins. An increase in CLTC expression in the transdifferentiated cells was confirmed by western blotting. Inactivation of CLTC by chlorpromazine (CHP), an inhibitor of CTLC mediated endocytosis (CME), and gene silencing by siRNAs, partially reversed the accumulation of neutral lipids observed in the transdifferentiated cells. These findings give a deeper insight into the phenotypic changes observed in HCCL to adipocyte-like transdifferentiation and point towards CME as a key pathway in distinct transdifferentiation programs. DISCLOSURES: Simon C and Aguilar-Gallardo C are co-inventors of the International Patent Application No. PCT/EP2011/004941 entitled "Methods for tumor treatment and adipogenesis differentiation".1 aCarcel-Trullols, Jaime1 aAguilar-Gallardo, Cristóbal1 aGarcía-Alcalde, Fernando1 aPardo-Cea, Miguel, Angel1 aDopazo, Joaquin1 aConesa, Ana1 aSimon, Carlos uhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3725915/00753nas a2200205 4500008004100000022001400041245011300055210006900168260001600237300001600253490000600269100001900275700001900294700002200313700002200335700002100357700002100378700002100399856012700420 2012 eng d a1545-596300aUsing GPUs for the Exact Alignment of Short-Read Genetic Sequences by Means of the Burrows-Wheeler Transform0 aUsing GPUs for the Exact Alignment of ShortRead Genetic Sequence cJan-07-2012 a1245 - 12560 v91 aTorres, J., S.1 aEspert, I., B.1 aDominguez, A., T.1 aGarcia, Hernendez1 aCastello, Medina1 aGimenez, Terraga1 aBlazquez, Dopazo uhttp://ieeexplore.ieee.org/document/6175888/http://xplorestaging.ieee.org/ielx5/8857/6202798/06175888.pdf?arnumber=617588802206nas a2200349 4500008004100000022001400041245011400055210006900169260001700238300001200255490000600267520098700273653001501260653001201275653002601287653002201313653002101335653002801356653001801384653004001402653002001442653002301462653002701485100002701512700003001539700003201569700003301601700003101634700003301665700003201698856012601730 2012 eng d a1557-996400aUsing GPUs for the exact alignment of short-read genetic sequences by means of the Burrows-Wheeler transform.0 aUsing GPUs for the exact alignment of shortread genetic sequence c2012 Jul-Aug a1245-560 v93 a

General Purpose Graphic Processing Units (GPGPUs) constitute an inexpensive resource for computing-intensive applications that could exploit an intrinsic fine-grain parallelism. This paper presents the design and implementation in GPGPUs of an exact alignment tool for nucleotide sequences based on the Burrows-Wheeler Transform. We compare this algorithm with state-of-the-art implementations of the same algorithm over standard CPUs, and considering the same conditions in terms of I/O. Excluding disk transfers, the implementation of the algorithm in GPUs shows a speedup larger than 12, when compared to CPU execution. This implementation exploits the parallelism by concurrently searching different sequences on the same reference search tree, maximizing memory locality and ensuring a symmetric access to the data. The paper describes the behavior of the algorithm in GPU, showing a good scalability in the performance, only limited by the size of the GPU inner memory.

10aAlgorithms10aAnimals10aComputational Biology10aComputer Graphics10aData Compression10aDrosophila melanogaster10aGenes, Insect10aImage Processing, Computer-Assisted10aModels, Genetic10aSequence Alignment10aSequence Analysis, DNA1 aTorres, Jose, Salavert1 aEspert, Ignacio, Blanquer1 aDomínguez, Andrés, Tomás1 aGarcía, Vicente, Hernández1 aCastelló, Ignacio, Medina1 aGiménez, Joaquín, Tárraga1 aBlázquez, Joaquín, Dopazo uhttp://clinbioinfosspa.es/content/using-gpus-exact-alignment-short-read-genetic-sequences-means-burrows-wheeler-transform01857nas a2200265 4500008004100000022001400041245011600055210006900171260001600240300001400256490000600270520098400276653003001260653001801290653001001308653000801318100002701326700003001353700002901383700002301412700002001435700002101455700002001476856009501496 2012 eng d a1557-996400aUsing GPUs for the Exact Alignment of Short-read Genetic Sequences by Means of the Burrows–Wheeler Transform.0 aUsing GPUs for the Exact Alignment of Shortread Genetic Sequence c2012 Mar 20 a1245-12560 v93 aGeneral Purpose Graphic Processing Units (GPGPUs) constitute an inexpensive resource for computing-intensive applications that could exploit an intrinsic fine-grain parallelism. This paper presents the design and implementation in GPGPUs of an exact alignment tool for nucleotide sequences based on the Burrows-Wheeler Transform. We compare this algorithm with state-of-the-art implementations of the same algorithm over standard CPUs, and considering the same conditions in terms of I/O. Excluding disk transfers, the implementation of the algorithm in GPUs shows a speedup larger than 12x, when compared to CPU execution. This implementation exploits the parallelism by concurrently searching different sequences on the same reference search tree, maximising memory locality and ensuring a symmetric access to the data. The article describes the behaviour of the algorithm in GPU, showing a good scalability in the performance, only limited by the size of the GPU inner memory.10aBurrows-Wheeler transform10aCPU execution10aGPGPU10aNGS1 aTorres, Jose, Salavert1 aEspert, Ignacio, Blanquer1 aDominguez, Andres, Tomas1 aHernendez, Vicente1 aMedina, Ignacio1 aTerraga, Joaquin1 aDopazo, Joaquin uhttp://ieeexplore.ieee.org.sire.ub.edu/xpl/articleDetails.jsp?reload=true&arnumber=617588802712nas a2200325 4500008004100000022001400041245015600055210006900211260001300280300001000293490000700303520157800310653002801888653002201916653004201938653001301980653003401993653001302027653003602040653001302076653002802089100002002117700002402137700001702161700002402178700002002202700002602222700002002248856011802268 2012 eng d a1362-496200aVARIANT: Command Line, Web service and Web interface for fast and accurate functional characterization of variants found by Next-Generation Sequencing.0 aVARIANT Command Line Web service and Web interface for fast and  c2012 Jul aW54-80 v403 a

The massive use of Next-Generation Sequencing (NGS) technologies is uncovering an unexpected amount of variability. The functional characterization of such variability, particularly in the most common form of variation found, the Single Nucleotide Variants (SNVs), has become a priority that needs to be addressed in a systematic way. VARIANT (VARIant ANalyis Tool) reports information on the variants found that include consequence type and annotations taken from different databases and repositories (SNPs and variants from dbSNP and 1000 genomes, and disease-related variants from the Genome-Wide Association Study (GWAS) catalog, Online Mendelian Inheritance in Man (OMIM), Catalog of Somatic Mutations in Cancer (COSMIC) mutations, etc). VARIANT also produces a rich variety of annotations that include information on the regulatory (transcription factor or miRNA-binding sites, etc.) or structural roles, or on the selective pressures on the sites affected by the variation. This information allows extending the conventional reports beyond the coding regions and expands the knowledge on the contribution of non-coding or synonymous variants to the phenotype studied. Contrarily to other tools, VARIANT uses a remote database and operates through efficient RESTful Web Services that optimize search and transaction operations. In this way, local problems of installation, update or disk size limitations are overcome without the need of sacrifice speed (thousands of variants are processed per minute). VARIANT is available at: http://variant.bioinfo.cipf.es.

10aDatabases, Nucleic Acid10aGenetic Variation10aHigh-Throughput Nucleotide Sequencing10aInternet10aMolecular Sequence Annotation10amutation10aPolymorphism, Single Nucleotide10aSoftware10aUser-Computer Interface1 aMedina, Ignacio1 aDe Maria, Alejandro1 aBleda, Marta1 aSalavert, Francisco1 aAlonso, Roberto1 aGonzalez, Cristina, Y1 aDopazo, Joaquin uhttp://clinbioinfosspa.es/content/variant-command-line-web-service-and-web-interface-fast-and-accurate-functional02869nas a2200493 4500008004100000022001400041245007000055210006800125260001600193300001100209490000600220520139500226653001801621653002701639653002101666653004101687653002001728653002401748653000901772653001101781653001801792653004201810653001101852653003701863653001301900653003801913653002701951653001301978100001701991700001902008700001802027700002502045700002102070700002002091700001902111700002602130700002302156700001802179700001602197700002402213700002002237700002002257856009802277 2012 eng d a1559-230800aWhole-genome bisulfite DNA sequencing of a DNMT3B mutant patient.0 aWholegenome bisulfite DNA sequencing of a DNMT3B mutant patient c2012 Jun 01 a542-500 v73 a

The immunodeficiency, centromere instability and facial anomalies (ICF) syndrome is associated to mutations of the DNA methyl-transferase DNMT3B, resulting in a reduction of enzyme activity. Aberrant expression of immune system genes and hypomethylation of pericentromeric regions accompanied by chromosomal instability were determined as alterations driving the disease phenotype. However, so far only technologies capable to analyze single loci were applied to determine epigenetic alterations in ICF patients. In the current study, we performed whole-genome bisulphite sequencing to assess alteration in DNA methylation at base pair resolution. Genome-wide we detected a decrease of methylation level of 42%, with the most profound changes occurring in inactive heterochromatic regions, satellite repeats and transposons. Interestingly, transcriptional active loci and ribosomal RNA repeats escaped global hypomethylation. Despite a genome-wide loss of DNA methylation the epigenetic landscape and crucial regulatory structures were conserved. Remarkably, we revealed a mislocated activity of mutant DNMT3B to H3K4me1 loci resulting in hypermethylation of active promoters. Functionally, we could associate alterations in promoter methylation with the ICF syndrome immunodeficient phenotype by detecting changes in genes related to the B-cell receptor mediated maturation pathway.

10aB-Lymphocytes10aCell Line, Transformed10aChild, Preschool10aDNA (Cytosine-5-)-Methyltransferases10aDNA Methylation10aEpigenesis, Genetic10aFace10aFemale10aGenome, Human10aHigh-Throughput Nucleotide Sequencing10aHumans10aImmunologic Deficiency Syndromes10amutation10aPrimary Immunodeficiency Diseases10aSequence Analysis, DNA10aSulfites1 aHeyn, Holger1 aVidal, Enrique1 aSayols, Sergi1 aSanchez-Mut, Jose, V1 aMoran, Sebastian1 aMedina, Ignacio1 aSandoval, Juan1 aSimó-Riudalbas, Laia1 aSzczesna, Karolina1 aHuertas, Dori1 aGatto, Sole1 aMatarazzo, Maria, R1 aDopazo, Joaquin1 aEsteller, Manel uhttp://clinbioinfosspa.es/content/whole-genome-bisulfite-dna-sequencing-dnmt3b-mutant-patient02092nas a2200241 4500008004100000245015300041210006900194260000900263300001100272490000600283520122100289100002001510700002301530700002101553700002401574700002101598700001801619700002201637700002001659700002301679700002401702856012401726 2011 eng d00aAnalysis of normal-tumour tissue interaction in tumours: prediction of prostate cancer features from the molecular profile of adjacent normal cells.0 aAnalysis of normaltumour tissue interaction in tumours predictio c2011 ae164920 v63 a

Statistical modelling, in combination with genome-wide expression profiling techniques, has demonstrated that the molecular state of the tumour is sufficient to infer its pathological state. These studies have been extremely important in diagnostics and have contributed to improving our understanding of tumour biology. However, their importance in in-depth understanding of cancer patho-physiology may be limited since they do not explicitly take into consideration the fundamental role of the tissue microenvironment in specifying tumour physiology. Because of the importance of normal cells in shaping the tissue microenvironment we formulate the hypothesis that molecular components of the profile of normal epithelial cells adjacent the tumour are predictive of tumour physiology. We addressed this hypothesis by developing statistical models that link gene expression profiles representing the molecular state of adjacent normal epithelial cells to tumour features in prostate cancer. Furthermore, network analysis showed that predictive genes are linked to the activity of important secreted factors, which have the potential to influence tumor biology, such as IL1, IGF1, PDGF BB, AGT, and TGFβ.

1 aTrevino, Victor1 aTadesse, Mahlet, G1 aVannucci, Marina1 aAl-Shahrour, Fatima1 aAntczak, Philipp1 aDurant, Sarah1 aBikfalvi, Andreas1 aDopazo, Joaquin1 aCampbell, Moray, J1 aFalciani, Francesco uhttp://clinbioinfosspa.es/content/analysis-normal-tumour-tissue-interaction-tumours-prediction-prostate-cancer-features03135nas a2200145 4500008004100000022001400041245012900055210006900184260001600253520254200269100002002811700002002831700001602851856012202867 2011 eng d a1468-435700aARSyN: a method for the identification and removal of systematic noise in multifactorial time course microarray experiments.0 aARSyN a method for the identification and removal of systematic  c2011 Nov 143 aTranscriptomic profiling experiments that aim to the identification of responsive genes in specific biological conditions are commonly set up under defined experimental designs that try to assess the effects of factors and their interactions on gene expression. Data from these controlled experiments, however, may also contain sources of unwanted noise that can distort the signal under study, affect the residuals of applied statistical models, and hamper data analysis. Commonly, normalization methods are applied to transcriptomics data to remove technical artifacts, but these are normally based on general assumptions of transcript distribution and greatly ignore both the characteristics of the experiment under consideration and the coordinative nature of gene expression. In this paper, we propose a novel methodology, ARSyN, for the preprocessing of microarray data that takes into account these 2 last aspects. By combining analysis of variance (ANOVA) modeling of gene expression values and multivariate analysis of estimated effects, the method identifies the nonstructured part of the signal associated to the experimental factors (the noise within the signal) and the structured variation of the ANOVA errors (the signal of the noise). By removing these noise fractions from the original data, we create a filtered data set that is rich in the information of interest and includes only the random noise required for inferential analysis. In this work, we focus on multifactorial time course microarray (MTCM) experiments with 2 factors: one quantitative such as time or dosage and the other qualitative, as tissue, strain, or treatment. However, the method can be used in other situations such as experiments with only one factor or more complex designs with more than 2 factors. The filtered data obtained after applying ARSyN can be further analyzed with the appropriate statistical technique to obtain the biological information required. To evaluate the performance of the filtering strategy, we have applied different statistical approaches for MTCM analysis to several real and simulated data sets, studying also the efficiency of these techniques. By comparing the results obtained with the original and ARSyN filtered data and also with other filtering techniques, we can conclude that the proposed method increases the statistical power to detect biological signals, especially in cases where there are high levels of structural noise. Software for ARSyN is freely available at http://www.ua.es/personal/mj.nueda.1 aNueda, Maria, J1 aFerrer, Alberto1 aConesa, Ana uhttp://clinbioinfosspa.es/content/arsyn-method-identification-and-removal-systematic-noise-multifactorial-time-course02550nas a2200145 4500008004100000245013600041210006900177260000900246300001100255490000600266520201400272100001902286700002002305856007902325 2011 eng d00aAssessing the biological significance of gene expression signatures and co-expression modules by studying their network properties.0 aAssessing the biological significance of gene expression signatu c2011 ae174740 v63 a

Microarray experiments have been extensively used to define signatures, which are sets of genes that can be considered markers of experimental conditions (typically diseases). Paradoxically, in spite of the apparent functional role that might be attributed to such gene sets, signatures do not seem to be reproducible across experiments. Given the close relationship between function and protein interaction, network properties can be used to study to what extent signatures are composed of genes whose resulting proteins show a considerable level of interaction (and consequently a putative common functional role).We have analysed 618 signatures and 507 modules of co-expression in cancer looking for significant values of four main protein-protein interaction (PPI) network parameters: connection degree, cluster coefficient, betweenness and number of components. A total of 3904 gene ontology (GO) modules, 146 KEGG pathways, and 263 Biocarta pathways have been used as functional modules of reference.Co-expression modules found in microarray experiments display a high level of connectivity, similar to the one shown by conventional modules based on functional definitions (GO, KEGG and Biocarta). A general observation for all the classes studied is that the networks formed by the modules improve their topological parameters when an external protein is allowed to be introduced within the paths (up to the 70% of GO modules show network parameters beyond the random expectation). This fact suggests that functional definitions are incomplete and some genes might still be missing. Conversely, signatures are clearly not capturing the altered functions in the corresponding studies. This is probably because the way in which the genes have been selected in the signatures is too conservative. These results suggest that gene selection methods which take into account relationships among genes should be superior to methods that assume independence among genes outside their functional contexts.

1 aMinguez, Pablo1 aDopazo, Joaquin uhttp://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.001747402485nas a2200229 4500008004100000245005800041210005500099260001600154300001200170490000700182520178000189100001801969700001901987700003002006700003102036700002202067700002202089700002102111700001902132700001602151856008802167 2011 eng d00aB2G-FAR, a species centered GO annotation repository.0 aB2GFAR a species centered GO annotation repository c2011 Feb 18 a919-9240 v273 a

MOTIVATION: Functional genomics research has expanded enormously in the last decade thanks to the cost-reduction in high-throughput technologies and the development of computational tools that generate, standardize and share information on gene and protein function such as the Gene Ontology (GO). Nevertheless many biologists, especially working with non-model organisms, still suffer from non-existing or low coverage functional annotation, or simply struggle retrieving, summarizing and querying these data. RESULTS: The Blast2GO Functional Annotation Repository (B2G-FAR) is a bioinformatics resource envisaged to provide functional information for otherwise uncharacterized sequence-data and offers data-mining tools to analyze a larger repertoire of species than currently available. This new annotation resource has been created by applying the Blast2GO functional annotation engine in a strongly high-throughput manner to the entire space of public available sequences. The resulting repository contains GO term predictions for over 13.2 million non-redundant protein sequences based on BLAST search alignments from the SIMAP database. We generated GO annotation for approximately 150.000 different taxa making available the 2000 species with the highest coverage through B2G-FAR. A second section within B2G-FAR holds functional annotations for 17 non-model organism Affymetrix GeneChips. Conclusions: B2G-FAR provides easy access to exhaustive functional annotation for 2000 species offering a good balance between quality and quantity, thereby supporting functional genomics research especially in the case of non-model organisms. AVAILABILITY: The annotation resource is available at http://b2gfar.bioinfo.cipf.es. CONTACT: aconesa@cipf.es, sgoetz@cipf.es.

1 aGötz, Stefan1 aArnold, Roland1 aSebastián-Leon, Patricia1 aMartín-Rodríguez, Samuel1 aTischler, Patrick1 aJehl, Marc-André1 aDopazo, Joaquín1 aRattei, Thomas1 aConesa, Ana uhttp://clinbioinfosspa.es/content/b2g-far-species-centered-go-annotation-repository02499nas a2200277 4500008004100000022001400041245005900055210005600114260001300170300001200183490000700195520165100202653001501853653002801868653003001896653003101926653001101957653002001968653004401988100002002032700003002052700002002082700002002102700001602122856008302138 2011 eng d a1549-546900aDifferential expression in RNA-seq: a matter of depth.0 aDifferential expression in RNAseq a matter of depth c2011 Dec a2213-230 v213 a

Next-generation sequencing (NGS) technologies are revolutionizing genome research, and in particular, their application to transcriptomics (RNA-seq) is increasingly being used for gene expression profiling as a replacement for microarrays. However, the properties of RNA-seq data have not been yet fully established, and additional research is needed for understanding how these data respond to differential expression analysis. In this work, we set out to gain insights into the characteristics of RNA-seq data analysis by studying an important parameter of this technology: the sequencing depth. We have analyzed how sequencing depth affects the detection of transcripts and their identification as differentially expressed, looking at aspects such as transcript biotype, length, expression level, and fold-change. We have evaluated different algorithms available for the analysis of RNA-seq and proposed a novel approach--NOISeq--that differs from existing methods in that it is data-adaptive and nonparametric. Our results reveal that most existing methodologies suffer from a strong dependency on sequencing depth for their differential expression calls and that this results in a considerable number of false positives that increases as the number of reads grows. In contrast, our proposed method models the noise distribution from the actual data, can therefore better adapt to the size of the data set, and is more effective in controlling the rate of false discoveries. This work discusses the true potential of RNA-seq for studying regulation at low expression ranges, the noise within RNA-seq data, and the issue of replication.

10aAlgorithms10aExpressed Sequence Tags10aGene Expression Profiling10aGene Expression Regulation10aHumans10aModels, Genetic10aOligonucleotide Array Sequence Analysis1 aTarazona, Sonia1 aGarcía-Alcalde, Fernando1 aDopazo, Joaquin1 aFerrer, Alberto1 aConesa, Ana uhttp://clinbioinfosspa.es/content/differential-expression-rna-seq-matter-depth02873nas a2200301 4500008004100000245015000041210006900191260001600260300001200276490000700288520183800295100001902133700002202152700002502174700002102199700002002220700002002240700001702260700002102277700002202298700002502320700002102345700002002366700001802386700002102404700002402425856012202449 2011 eng d00aDifferential Lipid Partitioning Between Adipocytes and Tissue Macrophages Modulates Macrophage Lipotoxicity and M2/M1 Polarization in Obese Mice.0 aDifferential Lipid Partitioning Between Adipocytes and Tissue Ma c2011 Jan 24 a797-8090 v603 a

OBJECTIVE Obesity-associated insulin resistance is characterized by a state of chronic, low-grade inflammation that is associated with the accumulation of M1 proinflammatory macrophages in adipose tissue. Although different evidence explains the mechanisms linking the expansion of adipose tissue and adipose tissue macrophage (ATM) polarization, in the current study we investigated the concept of lipid-induced toxicity as the pathogenic link that could explain the trigger of this response. RESEARCH DESIGN AND METHODS We addressed this question using isolated ATMs and adipocytes from genetic and diet-induced murine models of obesity. Through transcriptomic and lipidomic analysis, we created a model integrating transcript and lipid species networks simultaneously occurring in adipocytes and ATMs and their reversibility by thiazolidinedione treatment. RESULTS We show that polarization of ATMs is associated with lipid accumulation and the consequent formation of foam cell-like cells in adipose tissue. Our study reveals that early stages of adipose tissue expansion are characterized by M2-polarized ATMs and that progressive lipid accumulation within ATMs heralds the M1 polarization, a macrophage phenotype associated with severe obesity and insulin resistance. Furthermore, rosiglitazone treatment, which promotes redistribution of lipids toward adipocytes and extends the M2 ATM polarization state, prevents the lipid alterations associated with M1 ATM polarization. CONCLUSIONS Our data indicate that the M1 ATM polarization in obesity might be a macrophage-specific manifestation of a more general lipotoxic pathogenic mechanism. This indicates that strategies to optimize fat deposition and repartitioning toward adipocytes might improve insulin sensitivity by preventing ATM lipotoxicity and M1 polarization.

1 aPrieur, Xavier1 aMok, Crystal, Y L1 aVelagapudi, Vidya, R1 aNúñez, Vanessa1 aFuentes, Lucía1 aMontaner, David1 aIshikawa, Ko1 aCamacho, Alberto1 aBarbarroja, Nuria1 aO’Rahilly, Stephen1 aSethi, Jaswinder1 aDopazo, Joaquin1 aOresic, Matej1 aRicote, Mercedes1 aVidal-Puig, Antonio uhttp://clinbioinfosspa.es/content/differential-lipid-partitioning-between-adipocytes-and-tissue-macrophages-modulates01377nas a2200313 4500008004100000245005700041210005500098260001300153300001300166490000600179520044900185100001700634700002200651700002700673700002200700700002000722700002200742700001800764700001900782700001700801700003300818700002800851700002000879700002600899700002500925700001600950700002100966856007600987 2011 eng d00aDiscovery of an ebolavirus-like filovirus in europe.0 aDiscovery of an ebolaviruslike filovirus in europe c2011 Oct ae10023040 v73 a

Filoviruses, amongst the most lethal of primate pathogens, have only been reported as natural infections in sub-Saharan Africa and the Philippines. Infections of bats with the ebolaviruses and marburgviruses do not appear to be associated with disease. Here we report identification in dead insectivorous bats of a genetically distinct filovirus, provisionally named Lloviu virus, after the site of detection, Cueva del Lloviu, in Spain.

1 aNegredo, Ana1 aPalacios, Gustavo1 aVázquez-Morón, Sonia1 aGonzález, Félix1 aDopazo, Hernán1 aMolero, Francisca1 aJuste, Javier1 aQuetglas, Juan1 aSavji, Nazir1 aMartínez, Maria, de la Cruz1 aHerrera, Jesus, Enrique1 aPizarro, Manuel1 aHutchison, Stephen, K1 aEchevarría, Juan, E1 aLipkin, Ian1 aTenorio, Antonio uhttp://clinbioinfosspa.es/content/discovery-ebolavirus-filovirus-europe02438nas a2200169 4500008004100000245016300041210006900204260001500273490000600288520172300294100002202017700002902039700002902068700001902097700002202116856013002138 2011 eng d00aDoes singlet oxygen activate cell death in Arabidopsis cell suspension cultures? Analysis of the early transcriptional defence responses to high light stress.0 aDoes singlet oxygen activate cell death in Arabidopsis cell susp c2011 Dec 10 v63 a

Can Arabidopsis cell suspension cultures (ACSC) provide a useful working model to investigate genetically-controlled defence responses with signalling cascades starting in chloroplasts? In order to provide a convincing answer, we analysed the early transcriptional profile of Arabidopsis cells at high light (HL). The results showed that ACSC respond to HL in a manner that resembles the singlet oxygen ( ( 1) O 2)-mediated defence responses described for the conditional fluorescent (flu) mutant of Arabidopsis thaliana. The flu mutant is characterized by the accumulation of free protochlorophyllide (Pchlide) in plastids when put into darkness and the subsequent production of ( 1) O 2 when the light is on. In ACSC, ( 1) O 2 is produced in chloroplasts at HL when excess excitation energy flows into photosystem II (PSII). Other reactive oxygen species are also produced in ACSC at HL, but to a lesser extent. When the HL stress ceases, ACSC recovers the initial rate of oxygen evolution and cell growth continues. We can conclude that chloroplasts of ACSC are both photosynthetically active and capable of initiating ( 1) O 2-mediated signalling cascades that activate a broad range of genetically-controlled defence responses. The up-regulation of transcripts associated with the biosynthesis and signalling pathways of OPDA (12-oxophytodienoic acid) and ethylene (ET) suggests that the activated defence responses at HL are governed by these two hormones. In contrast to the flu mutant, the ( 1) O 2-mediated defence responses were independent of the up-regulation of EDS1 (enhanced disease susceptibility) required for the accumulation of salicylic acid (SA) and genetically-controlled cell death. 

1 aGutiérrez, Jorge1 aGonzález-Pérez, Sergio1 aGarcia-Garcia, Francisco1 aLorenzo, Oscar1 aArellano, Juan, B uhttp://clinbioinfosspa.es/content/does-singlet-oxygen-activate-cell-death-arabidopsis-cell-suspension-cultures-analysis-early03515nas a2200493 4500008004100000022001400041245012700055210006900182260001600251300000700267490000600274520197600280653001202256653002302268653001802291653001602309653002002325653001102345653003102356653002902387653002302416653002802439653000902467653001202476653002402488653002002512653001502532653002402547653002702571653003602598100001802634700003002652700002302682700002902705700002102734700002002755700001902775700001602794700001602810700002002826700002402846700002302870856012802893 2011 eng d a1755-879400aEarly peroxisome proliferator-activated receptor gamma regulated genes involved in expansion of pancreatic beta cell mass.0 aEarly peroxisome proliferatoractivated receptor gamma regulated  c2011 Dec 30 a860 v43 a

BACKGROUND: The progression towards type 2 diabetes depends on the allostatic response of pancreatic beta cells to synthesise and secrete enough insulin to compensate for insulin resistance. The endocrine pancreas is a plastic tissue able to expand or regress in response to the requirements imposed by physiological and pathophysiological states associated to insulin resistance such as pregnancy, obesity or ageing, but the mechanisms mediating beta cell mass expansion in these scenarios are not well defined. We have recently shown that ob/ob mice with genetic ablation of PPARγ2, a mouse model known as the POKO mouse failed to expand its beta cell mass. This phenotype contrasted with the appropriate expansion of the beta cell mass observed in their obese littermate ob/ob mice. Thus, comparison of these models islets particularly at early ages could provide some new insights on early PPARγ dependent transcriptional responses involved in the process of beta cell mass expansion

RESULTS: Here we have investigated PPARγ dependent transcriptional responses occurring during the early stages of beta cell adaptation to insulin resistance in wild type, ob/ob, PPARγ2 KO and POKO mice. We have identified genes known to regulate both the rate of proliferation and the survival signals of beta cells. Moreover we have also identified new pathways induced in ob/ob islets that remained unchanged in POKO islets, suggesting an important role for PPARγ in maintenance/activation of mechanisms essential for the continued function of the beta cell.

CONCLUSIONS: Our data suggest that the expansion of beta cell mass observed in ob/ob islets is associated with the activation of an immune response that fails to occur in POKO islets. We have also indentified other PPARγ dependent differentially regulated pathways including cholesterol biosynthesis, apoptosis through TGF-β signaling and decreased oxidative phosphorylation.

10aAnimals10aCell Proliferation10aCell Survival10aCholesterol10aDown-Regulation10aFemale10aGene Expression Regulation10aGene Knockout Techniques10aInsulin Resistance10aInsulin-Secreting Cells10aMice10aobesity10aOxidation-Reduction10aPhosphorylation10aPPAR gamma10aSignal Transduction10aTranscription, Genetic10aTransforming Growth Factor beta1 aVivas, Yurena1 aMartinez-Garcia, Cristina1 aIzquierdo, Adriana1 aGarcia-Garcia, Francisco1 aCallejas, Sergio1 aVelasco, Ismael1 aCampbell, Mark1 aRos, Manuel1 aDopazo, Ana1 aDopazo, Joaquin1 aVidal-Puig, Antonio1 aMedina-Gomez, Gema uhttp://clinbioinfosspa.es/content/early-peroxisome-proliferator-activated-receptor-gamma-regulated-genes-involved-expansion02590nas a2200217 4500008004100000245011200041210006900153260001600222300001200238490000800250520182000258100002902078700002202107700002902129700001802158700002102176700001902197700002302216700002202239856011102261 2011 eng d00aEarly transcriptional defence responses in Arabidopsis cell suspension culture under high light conditions.0 aEarly transcriptional defence responses in Arabidopsis cell susp c2011 Apr 29 a1439-560 v1563 a

The early transcriptional defence responses and ROS production in Arabidopsis cell suspension culture (ACSC), containing functional chloroplasts, were examined at high light (HL). The transcriptional analysis revealed that most of the ROS markers identified among the 449 transcripts with significant differential expression were transcripts specifically up-regulated by singlet oxygen (1O2). On the contrary, minimal correlation was established with transcripts specifically up-regulated by superoxide radical (O2•) or hydrogen peroxide (H2O2). The transcriptional analysis was supported by fluorescence microscopy experiments. The incubation of ACSC with the 1O2 sensor green reagent and 2’,7’-dichlorofluorescein diacetate showed that the 30-min-HL-treated cultures emitted fluorescence that corresponded with the production of 1O2, but not of H2O2. Furthermore, the in vivo photodamage of the D1 protein of photosystem II (PSII) indicated that the photogeneration of 1O2 took place within the PSII reaction centre. Functional enrichment analyses identified transcripts that are key components of the ROS signalling transduction pathway in plants as well as others encoding transcription factors that regulate both ROS scavenging and water deficit stress. A meta-analysis examining the transcriptional profiles of mutants and hormone treatments in Arabidopsis showed a high correlation between ACSC at HL and the flu mutant family of Arabidopsis, a producer of 1O2 in plastids. Intriguingly, a high correlation was also observed with aba1 and max4, two mutants with defects in the biosynthesis pathways of two key (apo)carotenoid-derived plant hormones (i.e. ABA and strigolactones, respectively). ACSC has proven to be a valuable system for studying early transcriptional responses to HL stress.

1 aGonzález-Pérez, Sergio1 aGutiérrez, Jorge1 aGarcia-Garcia, Francisco1 aOsuna, Daniel1 aDopazo, Joaquín1 aLorenzo, Oscar1 aRevuelta, José, L1 aArellano, Juan, B uhttp://www.plantphysiol.org/content/early/2011/04/29/pp.111.177766.short?keytype=ref&ijkey=ph5B6J2khjnqwzN03501nas a2200469 4500008004100000022001400041245011200055210006900167260001300236300001200249490000800261520192600269653001602195653002202211653002802233653002002261653001702281653002102298653003002319653003802349653002202387653001002409653001302419653004402432653003502476653002802511653003102539653005202570653001902622653002402641653002602665653002702691100002902718700002202747700002902769700001802798700002002816700001902836700002302855700002202878856013102900 2011 eng d a1532-254800aEarly transcriptional defense responses in Arabidopsis cell suspension culture under high-light conditions.0 aEarly transcriptional defense responses in Arabidopsis cell susp c2011 Jul a1439-560 v1563 a

The early transcriptional defense responses and reactive oxygen species (ROS) production in Arabidopsis (Arabidopsis thaliana) cell suspension culture (ACSC), containing functional chloroplasts, were examined at high light (HL). The transcriptional analysis revealed that most of the ROS markers identified among the 449 transcripts with significant differential expression were transcripts specifically up-regulated by singlet oxygen ((1)O(2)). On the contrary, minimal correlation was established with transcripts specifically up-regulated by superoxide radical or hydrogen peroxide. The transcriptional analysis was supported by fluorescence microscopy experiments. The incubation of ACSC with the (1)O(2) sensor green reagent and 2',7'-dichlorofluorescein diacetate showed that the 30-min-HL-treated cultures emitted fluorescence that corresponded with the production of (1)O(2) but not of hydrogen peroxide. Furthermore, the in vivo photodamage of the D1 protein of photosystem II indicated that the photogeneration of (1)O(2) took place within the photosystem II reaction center. Functional enrichment analyses identified transcripts that are key components of the ROS signaling transduction pathway in plants as well as others encoding transcription factors that regulate both ROS scavenging and water deficit stress. A meta-analysis examining the transcriptional profiles of mutants and hormone treatments in Arabidopsis showed a high correlation between ACSC at HL and the fluorescent mutant family of Arabidopsis, a producer of (1)O(2) in plastids. Intriguingly, a high correlation was also observed with ABA deficient1 and more axillary growth4, two mutants with defects in the biosynthesis pathways of two key (apo)carotenoid-derived plant hormones (i.e. abscisic acid and strigolactones, respectively). ACSC has proven to be a valuable system for studying early transcriptional responses to HL stress.

10aArabidopsis10aBlotting, Western10aCell Culture Techniques10aCells, Cultured10aChloroplasts10aCluster Analysis10aGene Expression Profiling10aGene Expression Regulation, Plant10aHydrogen Peroxide10aLight10amutation10aOligonucleotide Array Sequence Analysis10aPhotosystem II Protein Complex10aPlant Growth Regulators10aReproducibility of Results10aReverse Transcriptase Polymerase Chain Reaction10aRNA, Messenger10aSignal Transduction10aStress, Physiological10aTranscription, Genetic1 aGonzález-Pérez, Sergio1 aGutiérrez, Jorge1 aGarcia-Garcia, Francisco1 aOsuna, Daniel1 aDopazo, Joaquin1 aLorenzo, Oscar1 aRevuelta, José, L1 aArellano, Juan, B uhttp://clinbioinfosspa.es/content/early-transcriptional-defense-responses-arabidopsis-cell-suspension-culture-under-high-light02371nas a2200289 4500008004100000022001400041245012000055210006900175260001300244300001000257490000700267520143700274653001201711653002301723653002501746653002101771653002001792653001101812653001101823653000901834653002201843100002401865700002001889700002301909700002001932856012901952 2011 eng d a1477-405400aEvidence for short-time divergence and long-time conservation of tissue-specific expression after gene duplication.0 aEvidence for shorttime divergence and longtime conservation of t c2011 Sep a442-80 v123 a

Gene duplication is one of the main mechanisms by which genomes can acquire novel functions. It has been proposed that the retention of gene duplicates can be associated to processes of tissue expression divergence. These models predict that acquisition of divergent expression patterns should be acquired shortly after the duplication, and that larger divergence in tissue expression would be expected for paralogs, as compared to orthologs of a similar age. Many studies have shown that gene duplicates tend to have divergent expression patterns and that gene family expansions are associated with high levels of tissue specificity. However, the timeframe in which these processes occur have rarely been investigated in detail, particularly in vertebrates, and most analyses do not include direct comparisons of orthologs as a baseline for the expected levels of tissue specificity in absence of duplications. To assess the specific contribution of duplications to expression divergence, we combine here phylogenetic analyses and expression data from human and mouse. In particular, we study differences in spatial expression among human-mouse paralogs, specifically duplicated after the radiation of mammals, and compare them to pairs of orthologs in the same species. Our results show that gene duplication leads to increased levels of tissue specificity and that this tends to occur promptly after the duplication event.

10aAnimals10aConserved Sequence10aEvolution, Molecular10aGene Duplication10agene expression10aGenome10aHumans10aMice10aOrgan Specificity1 aHuerta-Cepas, Jaime1 aDopazo, Joaquin1 aHuynen, Martijn, A1 aGabaldón, Toni uhttp://clinbioinfosspa.es/content/evidence-short-time-divergence-and-long-time-conservation-tissue-specific-expression-after02093nas a2200169 4500008004100000245011500041210006900156260001600225520142700241100002501668700001701693700002101710700002401731700002001755700001901775856012901794 2011 eng d00aEvolution of the biosynthesis of di-myo-inositol phosphate, a marker of adaptation to hot marine environments.0 aEvolution of the biosynthesis of dimyoinositol phosphate a marke c2011 Oct 263 a

The synthesis of di-myo-inositol phosphate (DIP), a common compatible solute in hyperthermophiles, involves the consecutive actions of inositol-1-phosphate cytidylyltransferase (IPCT) and di-myo-inositol phosphate phosphate synthase (DIPPS). In most cases, both activities are present in a single gene product, but separate genes are also found in a few organisms. Genes for IPCT and DIPPS were found in the genomes of 33 organisms, all with thermophilic/hyperthermophilic lifestyles. Phylogeny of IPCT/DIPPS revealed an incongruent topology with 16S RNA phylogeny, thus suggesting horizontal gene transfer. The phylogenetic tree of the DIPPS domain was rooted by using phosphatidylinositol phosphate synthase sequences as out-group. The root locates at the separation of genomes with fused and split genes. We propose that the gene encoding DIPPS was recruited from the biosynthesis of phosphatidylinositol. The last DIP-synthesizing ancestor harboured separated genes for IPCT and DIPPS and this architecture was maintained in a crenarchaeal lineage, and transferred by horizontal gene transfer to hyperthermophilic marine Thermotoga species. It is plausible that the driving force for the assembly of those two genes in the early ancestor is related to the acquired advantage of DIP producers to cope with high temperature. This work corroborates the view that Archaea were the first hyperthermophilic organisms.

1 aGonçalves, Luís, G1 aBorges, Nuno1 aSerra, François1 aFernandes, Pedro, L1 aDopazo, Hernán1 aSantos, Helena uhttp://clinbioinfosspa.es/content/evolution-biosynthesis-di-myo-inositol-phosphate-marker-adaptation-hot-marine-environments01789nas a2200193 4500008004100000245015100041210006900192260001300261300001300274490000600287520104500293100002001338700001801358700002801376700002001404700002301424700002301447856012501470 2011 eng d00aAn evolutionary trade-off between protein turnover rate and protein aggregation favors a higher aggregation propensity in fast degrading proteins.0 aevolutionary tradeoff between protein turnover rate and protein  c2011 Jun ae10020900 v73 a

We previously showed the existence of selective pressure against protein aggregation by the enrichment of aggregation-opposing ’gatekeeper’ residues at strategic places along the sequence of proteins. Here we analyzed the relationship between protein lifetime and protein aggregation by combining experimentally determined turnover rates, expression data, structural data and chaperone interaction data on a set of more than 500 proteins. We find that selective pressure on protein sequences against aggregation is not homogeneous but that short-living proteins on average have a higher aggregation propensity and fewer chaperone interactions than long-living proteins. We also find that short-living proteins are more often associated to deposition diseases. These findings suggest that the efficient degradation of high-turnover proteins is sufficient to preclude aggregation, but also that factors that inhibit proteasomal activity, such as physiological ageing, will primarily affect the aggregation of short-living proteins.

1 aDe Baets, Greet1 aReumers, Joke1 aBlanco, Javier, Delgado1 aDopazo, Joaquin1 aSchymkowitz, Joost1 aRousseau, Frederic uhttp://clinbioinfosspa.es/content/evolutionary-trade-between-protein-turnover-rate-and-protein-aggregation-favors-higher00689nas a2200193 4500008004100000022001400041245010000055210006900155260000900224300000800233490000700241520001400248100002100262700002600283700001600309700002000325700002100345856012900366 2011 eng d a1471-222900aFortunella margarita Transcriptional Reprogramming Triggered by Xanthomonas citri subsp. citri.0 aFortunella margarita Transcriptional Reprogramming Triggered by  c2011 a1590 v113 aABSTRACT:1 aKhalaf, Abeer, A1 aGmitter, Frederick, G1 aConesa, Ana1 aDopazo, Joaquin1 aMoore, Gloria, A uhttp://clinbioinfosspa.es/content/fortunella-margarita-transcriptional-reprogramming-triggered-xanthomonas-citri-subsp-citri02524nas a2200169 4500008004100000245006800041210006600109260000900175300001200184490000600196520197400202100002102176700002102197700002002218700001802238856009802256 2011 eng d00aGenome-wide heterogeneity of nucleotide substitution model fit.0 aGenomewide heterogeneity of nucleotide substitution model fit c2011 a896-9080 v33 a

At a genomic scale, the patterns that have shaped molecular evolution are believed to be largely heterogeneous. Consequently, comparative analyses should use appropriate probabilistic substitution models that capture the main features under which different genomic regions have evolved. While efforts have concentrated in the development and understanding of model selection techniques, no descriptions of overall relative substitution model fit at the genome level have been reported. Here, we provide a characterization of best-fit substitution models across three genomic data sets including coding regions from mammals, vertebrates, and Drosophila (24,000 alignments). According to the Akaike Information Criterion (AIC), 82 of 88 models considered were selected as best-fit models at least in one occasion, although with very different frequencies. Most parameter estimates also varied broadly among genes. Patterns found for vertebrates and Drosophila were quite similar and often more complex than those found in mammals. Phylogenetic trees derived from models in the 95% confidence interval set showed much less variance and were significantly closer to the tree estimated under the best-fit model than trees derived from models outside this interval. Although alternative criteria selected simpler models than the AIC, they suggested similar patterns. All together our results show that at a genomic scale, different gene alignments for the same set of taxa are best explained by a large variety of different substitution models and that model choice has implications on different parameter estimates including the inferred phylogenetic trees. After taking into account the differences related to sample size, our results suggest a noticeable diversity in the underlying evolutionary process. All together, we conclude that the use of model selection techniques is important to obtain consistent phylogenetic estimates from real data at a genomic scale.

1 aArbiza, Leonardo1 aPatricio, Mateus1 aDopazo, Hernán1 aPosada, David uhttp://clinbioinfosspa.es/content/genome-wide-heterogeneity-nucleotide-substitution-model-fit02018nas a2200157 4500008004100000245013700041210006900178260001500247520137300262100001801635700001601653700002101669700002701690700001801717856012501735 2011 eng d00aHistone modifications and expression of DAM6 gene in peach are modulated during bud dormancy release in a cultivar-dependent manner.0 aHistone modifications and expression of DAM6 gene in peach are m c2011 Sep 73 a

• Bud dormancy release in many woody perennial plants responds to the seasonal accumulation of chilling stimulus. MADS-box transcription factors encoded by DORMANCY ASSOCIATED MADS-box (DAM) genes in peach (Prunus persica) are implicated in this pathway, but other regulatory factors remain to be identified. In addition, the regulation of DAM gene expression is not well known at the molecular level. • A microarray hybridization approach was performed to identify genes whose expression correlates with the bud dormancy-related behaviour in 10 different peach cultivars. Histone modifications in DAM6 gene were investigated by chromatin immunoprecipitation in two different cultivars. • The expression of DAM4-DAM6 and several genes related to abscisic acid and drought stress response correlated with the dormancy behaviour of peach cultivars. The trimethylation of histone H3 at K27 in the DAM6 promoter, coding region and the second large intron was preceded by a decrease in acetylated H3 and trimethylated H3K4 in the region of translation start, coinciding with repression of DAM6 during dormancy release. • Analysis of chromatin modifications reinforced the role of epigenetic mechanisms in DAM6 regulation and bud dormancy release, and highlighted common features with the vernalization process in Arabidopsis thaliana and cereals.

1 aLeida, Carmen1 aConesa, Ana1 aLlácer, Gerardo1 aBadenes, María, Luisa1 aRíos, Gabino uhttp://clinbioinfosspa.es/content/histone-modifications-and-expression-dam6-gene-peach-are-modulated-during-bud-dormancy02349nas a2200181 4500008004100000022001400041245015400055210006900209260001500278300000700293490000600300520173800306100001502044700002402059700002102083700001502104856004802119 2011 eng d a1755-879400aA large scale survey reveals that chromosomal copy-number alterations significantly affect gene modules involved in cancer initiation and progression0 alarge scale survey reveals that chromosomal copynumber alteratio c06/05/2011 a370 v43 a

Background

Recent observations point towards the existence of a large number of neighborhoods composed of functionally-related gene modules that lie together in the genome. This local component in the distribution of the functionality across chromosomes is probably affecting the own chromosomal architecture by limiting the possibilities in which genes can be arranged and distributed across the genome. As a direct consequence of this fact it is therefore presumable that diseases such as cancer, harboring DNA copy number alterations (CNAs), will have a symptomatology strongly dependent on modules of functionally-related genes rather than on a unique "important" gene.

Methods

We carried out a systematic analysis of more than 140,000 observations of CNAs in cancers and searched by enrichments in gene functional modules associated to high frequencies of loss or gains.

Results

The analysis of CNAs in cancers clearly demonstrates the existence of a significant pattern of loss of gene modules functionally related to cancer initiation and progression along with the amplification of modules of genes related to unspecific defense against xenobiotics (probably chemotherapeutical agents). With the extension of this analysis to an Array-CGH dataset (glioblastomas) from The Cancer Genome Atlas we demonstrate the validity of this approach to investigate the functional impact of CNAs.

Conclusions

The presented results indicate promising clinical and therapeutic implications. Our findings also directly point out to the necessity of adopting a function-centric, rather a gene-centric, view in the understanding of phenotypes or diseases harboring CNAs.

1 aAlloza, E.1 aAl-Shahrour, Fatima1 aCigudosa, J., C.1 aDopazo, J. uhttp://www.biomedcentral.com/1755-8794/4/3703586nas a2200649 4500008004100000022001400041245019000055210006900245260001600314300001200330490000700342520147500349653001801824653002201842653001201864653004901876653002501925653001401950653001701964653002101981653002502002653002002027653001902047653003002066653002902096653001102125653000902136653001802145653002802163653002802191653005202219653002902271653002402300653003002324653004802354653001802402100001402420700001802434700003002452700001602482700002002498700002002518700001702538700002402555700001902579700001902598700002802617700002002645700001902665700002802684700001802712700002202730700002002752700002002772700001902792856012502811 2011 eng d a1460-208300aLarge-scale transcriptional profiling and functional assays reveal important roles for Rho-GTPase signalling and SCL during haematopoietic differentiation of human embryonic stem cells.0 aLargescale transcriptional profiling and functional assays revea c2011 Dec 15 a4932-460 v203 a

Understanding the transcriptional cues that direct differentiation of human embryonic stem cells (hESCs) and human-induced pluripotent stem cells to defined and functional cell types is essential for future clinical applications. In this study, we have compared transcriptional profiles of haematopoietic progenitors derived from hESCs at various developmental stages of a feeder- and serum-free differentiation method and show that the largest transcriptional changes occur during the first 4 days of differentiation. Data mining on the basis of molecular function revealed Rho-GTPase signalling as a key regulator of differentiation. Inhibition of this pathway resulted in a significant reduction in the numbers of emerging haematopoietic progenitors throughout the differentiation window, thereby uncovering a previously unappreciated role for Rho-GTPase signalling during human haematopoietic development. Our analysis indicated that SCL was the 11th most upregulated transcript during the first 4 days of the hESC differentiation process. Overexpression of SCL in hESCs promoted differentiation to meso-endodermal lineages, the emergence of haematopoietic and erythro-megakaryocytic progenitors and accelerated erythroid differentiation. Importantly, intrasplenic transplantation of SCL-overexpressing hESC-derived haematopoietic cells enhanced recovery from induced acute anaemia without significant cell engraftment, suggesting a paracrine-mediated effect.

10aAcute Disease10aAnemia, Hemolytic10aAnimals10aBasic Helix-Loop-Helix Transcription Factors10aCell Differentiation10aCell Line10aCell Lineage10aCluster Analysis10aEmbryonic Stem Cells10aErythroid Cells10aFlow Cytometry10aGene Expression Profiling10aHematopoietic Stem Cells10aHumans10aMice10aMyeloid Cells10aParacrine Communication10aProto-Oncogene Proteins10aReverse Transcriptase Polymerase Chain Reaction10arho GTP-Binding Proteins10aSignal Transduction10aStem Cell Transplantation10aT-Cell Acute Lymphocytic Leukemia Protein 110aTranscriptome1 aYung, Sun1 aLedran, Maria1 aMoreno-Gimeno, Inmaculada1 aConesa, Ana1 aMontaner, David1 aDopazo, Joaquin1 aDimmick, Ian1 aSlater, Nicholas, J1 aMarenah, Lamin1 aReal, Pedro, J1 aParaskevopoulou, Iliana1 aBisbal, Viviana1 aBurks, Deborah1 aSantibanez-Koref, Mauro1 aMoreno, Ruben1 aMountford, Joanne1 aMenendez, Pablo1 aArmstrong, Lyle1 aLako, Majlinda uhttp://clinbioinfosspa.es/content/large-scale-transcriptional-profiling-and-functional-assays-reveal-important-roles-rho01038nas a2200229 4500008004100000245010000041210006900141260001300210300001100223490000700234520022900241100002600470700002500496700002500521700002200546700002300568700003700591700002200628700001600650700001800666856012400684 2011 eng d00aModeling human endometrial decidualization from the interaction between proteome and secretome.0 aModeling human endometrial decidualization from the interaction  c2011 Mar a706-160 v963 a

Decidualization of the human endometrium, which involves morphological and biochemical modifications of the endometrial stromal cells (ESCs), is a prerequisite for adequate trophoblast invasion and placenta formation.

1 aGarrido-Gomez, Tamara1 aDominguez, Francisco1 aLopez, Juan, Antonio1 aCamafeita, Emilio1 aQuiñonero, Alicia1 aMartinez-Conejero, Jose, Antonio1 aPellicer, Antonio1 aConesa, Ana1 aSimon, Carlos uhttp://clinbioinfosspa.es/content/modeling-human-endometrial-decidualization-interaction-between-proteome-and-secretome02919nas a2200433 4500008004100000022001400041245013300055210006900188260000900257300001100266490000600277520154700283653001201830653002801842653001001870653002201880653001101902653002301913653001101936653001201947653001301959653001301972653002301985653004402008653003002052653003102082653002502113653001802138100003302156700001902189700002202208700002002230700002002250700002002270700002002290700002002310700002502330856013002355 2011 eng d a1932-620300aMutation screening of multiple genes in Spanish patients with autosomal recessive retinitis pigmentosa by targeted resequencing.0 aMutation screening of multiple genes in Spanish patients with au c2011 ae278940 v63 a

Retinitis Pigmentosa (RP) is a heterogeneous group of inherited retinal dystrophies characterised ultimately by the loss of photoreceptor cells. RP is the leading cause of visual loss in individuals younger than 60 years, with a prevalence of about 1 in 4000. The molecular genetic diagnosis of autosomal recessive RP (arRP) is challenging due to the large genetic and clinical heterogeneity. Traditional methods for sequencing arRP genes are often laborious and not easily available and a screening technique that enables the rapid detection of the genetic cause would be very helpful in the clinical practice. The goal of this study was to develop and apply microarray-based resequencing technology capable of detecting both known and novel mutations on a single high-throughput platform. Hence, the coding regions and exon/intron boundaries of 16 arRP genes were resequenced using microarrays in 102 Spanish patients with clinical diagnosis of arRP. All the detected variations were confirmed by direct sequencing and potential pathogenicity was assessed by functional predictions and frequency in controls. For validation purposes 4 positive controls for variants consisting of previously identified changes were hybridized on the array. As a result of the screening, we detected 44 variants, of which 15 are very likely pathogenic detected in 14 arRP families (14%). Finally, the design of this array can easily be transformed in an equivalent diagnostic system based on targeted enrichment followed by next generation sequencing.

10aAlleles10aDNA Mutational Analysis10aExons10aGenetic Variation10aGenome10aHispanic or Latino10aHumans10aIntrons10aLanguage10amutation10aMutation, Missense10aOligonucleotide Array Sequence Analysis10aPolymerase Chain Reaction10aReproducibility of Results10aRetinitis pigmentosa10aUnited States1 adel Pozo, María, González-1 aBorrego, Salud1 aBarragán, Isabel1 aPieras, Juan, I1 aSantoyo, Javier1 aMatamala, Nerea1 aNaranjo, Belén1 aDopazo, Joaquin1 aAntiňolo, Guillermo uhttp://clinbioinfosspa.es/content/mutation-screening-multiple-genes-spanish-patients-autosomal-recessive-retinitis-pigmentosa02481nas a2200277 4500008004100000022001400041245007400055210006900129260000900198300001100207490000600218520162800224653002201852653002301874653001301897653001301910653003401923653002801957100002301985700002402008700001602032700002002048700001902068700001902087856009702106 2011 eng d a1932-620300amyKaryoView: a light-weight client for visualization of genomic data.0 amyKaryoView a lightweight client for visualization of genomic da c2011 ae263450 v63 a

The Distributed Annotation System (DAS) is a protocol for easy sharing and integration of biological annotations. In order to visualize feature annotations in a genomic context a client is required. Here we present myKaryoView, a simple light-weight DAS tool for visualization of genomic annotation. myKaryoView has been specifically configured to help analyse data derived from personal genomics, although it can also be used as a generic genome browser visualization. Several well-known data sources are provided to facilitate comparison of known genes and normal variation regions. The navigation experience is enhanced by simultaneous rendering of different levels of detail across chromosomes. A simple interface is provided to allow searches for any SNP, gene or chromosomal region. User-defined DAS data sources may also be added when querying the system. We demonstrate myKaryoView capabilities for adding user-defined sources with a set of genetic profiles of family-related individuals downloaded directly from 23andMe. myKaryoView is a web tool for visualization of genomic data specifically designed for direct-to-consumer genomic data that uses publicly available data distributed throughout the Internet. It does not require data to be held locally and it is capable of rendering any feature as long as it conforms to DAS specifications. Configuration and addition of sources to myKaryoView can be done through the interface. Here we show a proof of principle of myKaryoView's ability to display personal genomics data with 23andMe genome data sources. The tool is available at: http://mykaryoview.com.

10aComputer Graphics10aDatabases, Genetic10aGenomics10aInternet10aMolecular Sequence Annotation10aUser-Computer Interface1 aJimenez, Rafael, C1 aSalazar, Gustavo, A1 aGel, Bernat1 aDopazo, Joaquin1 aMulder, Nicola1 aCorpas, Manuel uhttp://clinbioinfosspa.es/content/mykaryoview-light-weight-client-visualization-genomic-data02573nas a2200301 4500008004100000022001400041245006900055210006600124260001300190300001300203490000600216520167900222653001201901653002301913653001501936653001901951653003401970653001302004653001202017653001402029653002302043653002702066100002102093700002102114700002002135700002002155856009602175 2011 eng d a1553-735800aNatural selection on functional modules, a genome-wide analysis.0 aNatural selection on functional modules a genomewide analysis c2011 Mar ae10010930 v73 a

Classically, the functional consequences of natural selection over genomes have been analyzed as the compound effects of individual genes. The current paradigm for large-scale analysis of adaptation is based on the observed significant deviations of rates of individual genes from neutral evolutionary expectation. This approach, which assumed independence among genes, has not been able to identify biological functions significantly enriched in positively selected genes in individual species. Alternatively, pooling related species has enhanced the search for signatures of selection. However, grouping signatures does not allow testing for adaptive differences between species. Here we introduce the Gene-Set Selection Analysis (GSSA), a new genome-wide approach to test for evidences of natural selection on functional modules. GSSA is able to detect lineage specific evolutionary rate changes in a notable number of functional modules. For example, in nine mammal and Drosophilae genomes GSSA identifies hundreds of functional modules with significant associations to high and low rates of evolution. Many of the detected functional modules with high evolutionary rates have been previously identified as biological functions under positive selection. Notably, GSSA identifies conserved functional modules with many positively selected genes, which questions whether they are exclusively selected for fitting genomes to environmental changes. Our results agree with previous studies suggesting that adaptation requires positive selection, but not every mutation under positive selection contributes to the adaptive dynamical process of the evolution of species.

10aAnimals10aDatabases, Genetic10aDrosophila10aGenome, Insect10aGenome-Wide Association Study10aGenomics10aMammals10aPhylogeny10aSelection, Genetic10aSequence Analysis, DNA1 aSerra, François1 aArbiza, Leonardo1 aDopazo, Joaquin1 aDopazo, Hernán uhttp://clinbioinfosspa.es/content/natural-selection-functional-modules-genome-wide-analysis01890nas a2200181 4500008004100000245013100041210006900172260001300241300001100254490000700265520119300272100002401465700002201489700002201511700002501533700002101558856012901579 2011 eng d00aN-glycosylation efficiency is determined by the distance to the C-terminus and the amino acid preceding an Asn-Ser-Thr sequon.0 aNglycosylation efficiency is determined by the distance to the C c2011 Jan a179-860 v203 a

N-glycosylation is the most common and versatile protein modification. In eukaryotic cells, this modification is catalyzed cotranslationally by the enzyme oligosaccharyltransferase, which targets the β-amide of the asparagine in an Asn-Xaa-Ser/Thr consensus sequon (where Xaa is any amino acid but proline) in nascent proteins as they enter the endoplasmic reticulum. Because modification of the glycosylation acceptor site on membrane proteins occurs in a compartment-specific manner, the presence of glycosylation is used to indicate membrane protein topology. Moreover, glycosylation sites can be added to gain topological information. In this study, we explored the determinants of N-glycosylation with the in vitro transcription/translation of a truncated model protein in the presence of microsomes and surveyed 25,488 glycoproteins, of which 2,533 glycosylation sites had been experimentally validated. We found that glycosylation efficiency was dependent on both the distance to the C-terminus and the nature of the amino acid that preceded the consensus sequon. These findings establish a broadly applicable method for membrane protein tagging in topological studies.

1 aBañó-Polo, Manuel1 aBaldin, Francesca1 aTamborero, Silvia1 aMarti-Renom, Marc, A1 aMingarro, Ismael uhttp://clinbioinfosspa.es/content/n-glycosylation-efficiency-determined-distance-c-terminus-and-amino-acid-preceding-asn-ser01129nas a2200169 4500008004100000245010300041210006900144260001500213300001000228490000700238520049600245100003000741700002900771700002100800700001600821856012200837 2011 eng d00aPaintomics: a web based tool for the joint visualization of transcriptomics and metabolomics data.0 aPaintomics a web based tool for the joint visualization of trans c2011 Jan 1 a137-90 v273 a

The development of the omics technologies such as transcriptomics, proteomics and metabolomics has made possible the realization of systems biology studies where biological systems are interrogated at different levels of biochemical activity (gene expression, protein activity and/or metabolite concentration). An effective approach to the analysis of these complex datasets is the joined visualization of the disparate biomolecular data on the framework of known biological pathways.

1 aGarcía-Alcalde, Fernando1 aGarcía-López, Federico1 aDopazo, Joaquín1 aConesa, Ana uhttp://clinbioinfosspa.es/content/paintomics-web-based-tool-joint-visualization-transcriptomics-and-metabolomics-data02020nas a2200349 4500008004100000022001400041245011700055210006900172260001300241300001100254490000700265520090400272653002501176653001301201653001301214653001401227653002301241653001301264100002101277700002101298700002301319700002001342700002101362700001701383700002401400700003301424700002401457700002001481700002001501700002001521856012901541 2011 eng d a1362-496200aPhylemon 2.0: a suite of web-tools for molecular evolution, phylogenetics, phylogenomics and hypotheses testing.0 aPhylemon 20 a suite of webtools for molecular evolution phylogen c2011 Jul aW470-40 v393 a

Phylemon 2.0 is a new release of the suite of web tools for molecular evolution, phylogenetics, phylogenomics and hypotheses testing. It has been designed as a response to the increasing demand of molecular sequence analyses for experts and non-expert users. Phylemon 2.0 has several unique features that differentiates it from other similar web resources: (i) it offers an integrated environment that enables evolutionary analyses, format conversion, file storage and edition of results; (ii) it suggests further analyses, thereby guiding the users through the web server; and (iii) it allows users to design and save phylogenetic pipelines to be used over multiple genes (phylogenomics). Altogether, Phylemon 2.0 integrates a suite of 30 tools covering sequence alignment reconstruction and trimming; tree reconstruction, visualization and manipulation; and evolutionary hypotheses testing.

10aEvolution, Molecular10aGenomics10aInternet10aPhylogeny10aSequence Alignment10aSoftware1 aSánchez, Rubén1 aSerra, François1 aTárraga, Joaquín1 aMedina, Ignacio1 aCarbonell, José1 aPulido, Luis1 aDe Maria, Alejandro1 aCapella-Gutíerrez, Salvador1 aHuerta-Cepas, Jaime1 aGabaldón, Toni1 aDopazo, Joaquin1 aDopazo, Hernán uhttp://clinbioinfosspa.es/content/phylemon-20-suite-web-tools-molecular-evolution-phylogenetics-phylogenomics-and-hypotheses01509nas a2200169 4500008004100000245009800041210006900139260001300208300001100221490000700232520088300239100002201122700003201144700002001176700002201196856012101218 2011 eng d00aPhylogenetic and in silico structural analysis of the Parkinson disease-related kinase PINK1.0 aPhylogenetic and in silico structural analysis of the Parkinson  c2011 Apr a369-780 v323 a

Parkinson disease (PD) is the second most common neurodegenerative disorder and is characterized by the loss of dopaminergic neurons in the substantia nigra. Mutations in PINK1 were shown to cause recessive familial PD, and today are proposed to be associated with the disease via mitochondrial dysfunction and oxidative damage. The PINK1 gene comprises eight exons, which encode a ubiquitously expressed 581 amino acid protein that contains an N-terminal mitochondrial targeting domain and a serine/threonine protein kinase. To better understand the relationship between PINK1 and PD we have first analyzed the evolutionary history of the gene showing its late emergence in evolution. In addition, we have modeled the three-dimensional structure of PINK1 and found some evidences that help to explain the effect of some PD-related mutations in this protein’s function.

1 aCardona, Fernando1 aSánchez-Mut, Jose, Vicente1 aDopazo, Hernán1 aPérez-Tur, Jordi uhttp://clinbioinfosspa.es/content/phylogenetic-and-silico-structural-analysis-parkinson-disease-related-kinase-pink101322nas a2200265 4500008004100000245009000041210006900131260000900200300000800209490000700217520047300224100001800697700001900715700002100734700001900755700002600774700002600800700001800826700001600844700002500860700002100885700001600906700002100922856011300943 2011 eng d00aProfiling the venom gland transcriptomes of Costa Rican snakes by 454 pyrosequencing.0 aProfiling the venom gland transcriptomes of Costa Rican snakes b c2011 a2590 v123 a

A long term research goal of venomics, of applied importance for improving current antivenom therapy, but also for drug discovery, is to understand the pharmacological potential of venoms. Individually or combined, proteomic and transcriptomic studies have demonstrated their feasibility to explore in depth the molecular diversity of venoms. In the absence of genome sequence, transcriptomes represent also valuable searchable databases for proteomic projects.

1 aDurban, Jordi1 aJuárez, Paula1 aAngulo, Yamileth1 aLomonte, Bruno1 aFlores-Diaz, Marietta1 aAlape-Girón, Alberto1 aSasa, Mahmood1 aSanz, Libia1 aGutiérrez, José, M1 aDopazo, Joaquín1 aConesa, Ana1 aCalvete, Juan, J uhttp://clinbioinfosspa.es/content/profiling-venom-gland-transcriptomes-costa-rican-snakes-454-pyrosequencing01456nas a2200253 4500008004100000245009300041210006900134260000900203300000700212490000700219520063100226100002300857700001500880700001900895700002300914700002800937700001500965700001700980700002100997700002401018700002001042700002001062856012001082 2011 eng d00aRecent human evolution has shaped geographical differences in susceptibility to disease.0 aRecent human evolution has shaped geographical differences in su c2011 a550 v123 a

Searching for associations between genetic variants and complex diseases has been a very active area of research for over two decades. More than 51,000 potential associations have been studied and published, a figure that keeps increasing, especially with the recent explosion of array-based Genome-Wide Association Studies. Even if the number of true associations described so far is high, many of the putative risk variants detected so far have failed to be consistently replicated and are widely considered false positives. Here, we focus on the world-wide patterns of replicability of published association studies.

1 aMarigorta, Urko, M1 aLao, Oscar1 aCasals, Ferran1 aCalafell, Francesc1 aMorcillo-Suarez, Carlos1 aFaria, Rui1 aBosch, Elena1 aSerra, François1 aBertranpetit, Jaume1 aDopazo, Hernán1 aNavarro, Arcadi uhttp://clinbioinfosspa.es/content/recent-human-evolution-has-shaped-geographical-differences-susceptibility-disease02322nas a2200241 4500008004100000245007500041210006900116260001300185300001100198490000700209520154000216100002401756700003301780700002101813700001901834700003501853700002001888700001801908700002701926700002001953700001701973856009001990 2011 eng d00aRole of tomato BRANCHED1-like genes in the control of shoot branching.0 aRole of tomato BRANCHED1like genes in the control of shoot branc c2011 Aug a701-140 v673 a

In angiosperms, shoot branching greatly determines overall plant architecture and affects fundamental aspects of plant life. Branching patterns are determined by genetic pathways conserved widely across angiosperms. In Arabidopsis thaliana (Brassicaceae, Rosidae) BRANCHED1 (BRC1) plays a central role in this process, acting locally to arrest axillary bud growth. In tomato (Solanum lycopersicum, Solanaceae, Asteridae) we have identified two BRC1-like paralogues, SlBRC1a and SlBRC1b. These genes are expressed in arrested axillary buds and both are down-regulated upon bud activation, although SlBRC1a is transcribed at much lower levels than SlBRC1b. Alternative splicing of SlBRC1a renders two transcripts that encode two BRC1-like proteins with different C-t domains due to a 3’-terminal frameshift. The phenotype of loss-of-function lines suggests that SlBRC1b has retained the ancestral role of BRC1 in shoot branch suppression. We have isolated the BRC1a and BRC1b genes of other Solanum species and have studied their evolution rates across the lineages. These studies indicate that, after duplication of an ancestral BRC1-like gene, BRC1b genes continued to evolve under a strong purifying selection that was consistent with the conserved function of SlBRC1b in shoot branching control. In contrast, the coding sequences of Solanum BRC1a genes have evolved at a higher evolution rate. Branch-site tests indicate that this difference does not reflect relaxation but rather positive selective pressure for adaptation.

1 aMartín-Trillo, Mar1 aGrandío, Eduardo, González1 aSerra, François1 aMarcel, Fabien1 aRodríguez-Buey, María, Luisa1 aSchmitz, Gregor1 aTheres, Klaus1 aBendahmane, Abdelhafid1 aDopazo, Hernán1 aCubas, Pilar uhttp://clinbioinfosspa.es/content/role-tomato-branched1-genes-control-shoot-branching01980nas a2200217 4500008004100000022001400041245007200055210006900127260000900196300001100205490000600216520130500222100001601527700002001543700002101563700002901584700002001613700002501633700002501658856007901683 2011 eng d a1932-620300aSexual selection halts the relaxation of protamine 2 among rodents.0 aSexual selection halts the relaxation of protamine 2 among roden c2011 ae292470 v63 aSexual selection has been proposed as the driving force promoting the rapid evolutionary changes observed in some reproductive genes including protamines. We test this hypothesis in a group of rodents which show marked differences in the intensity of sexual selection. Levels of sperm competition were not associated with the evolutionary rates of protamine 1 but, contrary to expectations, were negatively related to the evolutionary rate of cleaved- and mature-protamine 2. Since both domains were found to be under relaxation, our findings reveal an unforeseen role of sexual selection: to halt the degree of degeneration that proteins within families may experience due to functional redundancy. The degree of relaxation of protamine 2 in this group of rodents is such that in some species it has become dysfunctional and it is not expressed in mature spermatozoa. In contrast, protamine 1 is functionally conserved but shows directed positive selection on specific sites which are functionally relevant such as DNA-anchoring domains and phosphorylation sites. We conclude that in rodents protamine 2 is under relaxation and that sexual selection removes deleterious mutations among species with high levels of sperm competition to maintain the protein functional and the spermatozoa competitive.1 aLüke, Lena1 aVicens, Alberto1 aSerra, François1 aLuque-Larena, Juan, Jose1 aDopazo, Hernán1 aRoldan, Eduardo, R S1 aGomendio, Montserrat uhttp://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.002924701867nas a2200145 4500008004100000245008600041210006900127260001300196300001000209490000700219520134300226100001701569700002501586856011001611 2011 eng d00aStructure determination of genomic domains by satisfaction of spatial restraints.0 aStructure determination of genomic domains by satisfaction of sp c2011 Jan a25-350 v193 a

The three-dimensional (3D) architecture of a genome is non-random and known to facilitate the spatial colocalization of regulatory elements with the genes they regulate. Determining the 3D structure of a genome may therefore probe an essential step in characterizing how genes are regulated. Currently, there are several experimental and theoretical approaches that aim at determining the 3D structure of genomes and genomic domains; however, approaches integrating experiments and computation to identify the most likely 3D folding of a genome at medium to high resolutions have not been widely explored. Here, we review existing methodologies and propose that the integrative modeling platform ( http://www.integrativemodeling.org ), a computational package developed for structurally characterizing protein assemblies, could be used for integrating diverse experimental data towards the determination of the 3D architecture of genomic domains and entire genomes at unprecedented resolution. Our approach, through the visualization of looping interactions between distal regulatory elements, will allow for the characterization of global chromatin features and their relation to gene expression. We illustrate our work by outlining the recent determination of the 3D architecture of the α-globin domain in the human genome.

1 aBaù, Davide1 aMarti-Renom, Marc, A uhttp://clinbioinfosspa.es/content/structure-determination-genomic-domains-satisfaction-spatial-restraints01951nas a2200205 4500008004100000245007400041210006900115260001500184300001300199490000700212520125700219100002601476700003001502700002501532700002001557700001601577700002101593700003101614856010001645 2011 eng d00aSUS1 introns are required for efficient mRNA nuclear export in yeast.0 aSUS1 introns are required for efficient mRNA nuclear export in y c2011 Oct 1 a8599-6110 v393 a

Efficient coupling between mRNA synthesis and export is essential for gene expression. Sus1/ENY2, a component of the SAGA and TREX-2 complexes, is involved in both transcription and mRNA export. While most yeast genes lack introns, we previously reported that yeast SUS1 bears two. Here we show that this feature is evolutionarily conserved and critical for Sus1 function. We determine that while SUS1 splicing is inefficient, it responds to cellular conditions, and intronic mutations either promoting or blocking splicing lead to defects in mRNA export and cell growth. Consistent with this, we find that an intron-less SUS1 only partially rescues sus1Δ phenotypes. Remarkably, splicing of each SUS1 intron is also affected by the presence of the other and by SUS1 exonic sequences. Moreover, by following SUS1 RNA and protein levels we establish that nonsense-mediated decay (NMD) pathway and the splicing factor Mud2 both play a role in SUS1 expression. Our data (and those of the accompanying work by Hossain et al.) provide evidence of the involvement of splicing, translation, and decay in the regulation of early events in mRNP biogenesis; and imply the additional requirement for a balance in splicing isoforms from a single gene.

1 aCuenca-Bono, Bernardo1 aGarcía-Molinero, Varinia1 aPascual-García, Pau1 aDopazo, Hernán1 aLlopis, Ana1 aVilardell, Josep1 aRodríguez-Navarro, Susana uhttp://clinbioinfosspa.es/content/sus1-introns-are-required-efficient-mrna-nuclear-export-yeast01792nas a2200217 4500008004100000245010400041210007000145260001300215300001100228490000700239520104100246100001701287700002001304700002101324700002201345700001501367700002401382700001601406700002501422856012701447 2011 eng d00aThe three-dimensional folding of the α-globin gene domain reveals formation of chromatin globules.0 athreedimensional folding of the αglobin gene domain reveals form c2011 Jan a107-140 v183 a

We developed a general approach that combines chromosome conformation capture carbon copy (5C) with the Integrated Modeling Platform (IMP) to generate high-resolution three-dimensional models of chromatin at the megabase scale. We applied this approach to the ENm008 domain on human chromosome 16, containing the α-globin locus, which is expressed in K562 cells and silenced in lymphoblastoid cells (GM12878). The models accurately reproduce the known looping interactions between the α-globin genes and their distal regulatory elements. Further, we find using our approach that the domain folds into a single globular conformation in GM12878 cells, whereas two globules are formed in K562 cells. The central cores of these globules are enriched for transcribed genes, whereas nontranscribed chromatin is more peripheral. We propose that globule formation represents a higher-order folding state related to clustering of transcribed genes around shared transcription machineries, as previously observed by microscopy.

1 aBaù, Davide1 aSanyal, Amartya1 aLajoie, Bryan, R1 aCapriotti, Emidio1 aByron, Meg1 aLawrence, Jeanne, B1 aDekker, Job1 aMarti-Renom, Marc, A uhttp://clinbioinfosspa.es/content/three-dimensional-folding-%CE%B1-globin-gene-domain-reveals-formation-chromatin-globules02554nas a2200361 4500008004100000245014100041210006900182260001600251300003100267490000700298520145100305653001501756653002001771653001501791653001001806653000801816653000901824100002001833700002101853700001701874700002101891700001801912700001601930700002301946700002901969700002701998700002002025700002302045700002002068700002002088700002102108856006302129 2010 eng d00aBabelomics: an integrative platform for the analysis of transcriptomics, proteomics and genomic data with advanced functional profiling.0 aBabelomics an integrative platform for the analysis of transcrip c2010 May 16 aW210-W213. Featured in NAR0 v383 a

Babelomics is a response to the growing necessity of integrating and analyzing different types of genomic data in an environment that allows an easy functional interpretation of the results. Babelomics includes a complete suite of methods for the analysis of gene expression data that include normalization (covering most commercial platforms), pre-processing, differential gene expression (case-controls, multiclass, survival or continuous values), predictors, clustering; large-scale genotyping assays (case controls and TDTs, and allows population stratification analysis and correction). All these genomic data analysis facilities are integrated and connected to multiple options for the functional interpretation of the experiments. Different methods of functional enrichment or gene set enrichment can be used to understand the functional basis of the experiment analyzed. Many sources of biological information, which include functional (GO, KEGG, Biocarta, Reactome, etc.), regulatory (Transfac, Jaspar, ORegAnno, miRNAs, etc.), text-mining or protein-protein interaction modules can be used for this purpose. Finally a tool for the de novo functional annotation of sequences has been included in the system. This provides support for the functional analysis of non-model species. Mirrors of Babelomics or command line execution of their individual components are now possible. Babelomics is available at http://www.babelomics.org.

10ababelomics10agene expression10agenotyping10agepas10aGSA10aGWAS1 aMedina, Ignacio1 aCarbonell, José1 aPulido, Luis1 aMadeira, Sara, C1 aGoetz, Stefan1 aConesa, Ana1 aTárraga, Joaquín1 aPascual-Montano, Alberto1 aNogales-Cadenas, Ruben1 aSantoyo, Javier1 aGarcía, Francisco1 aMarbà, Martina1 aMontaner, David1 aDopazo, Joaquín uhttp://nar.oxfordjournals.org/content/38/suppl_2/W210.full02773nas a2200385 4500008004100000245011100041210006900152260001300221300001000234490000700244520152200251100002301773700002601796700001901822700002401841700002701865700002901892700002001921700002001941700002801961700001901989700002302008700002402031700002002055700001602075700002302091700001902114700002002133700002002153700002002173700002002193700002502213700002302238856012602261 2010 eng d00aChanges in the pattern of DNA methylation associate with twin discordance in systemic lupus erythematosus.0 aChanges in the pattern of DNA methylation associate with twin di c2010 Feb a170-90 v203 a

Monozygotic (MZ) twins are partially concordant for most complex diseases, including autoimmune disorders. Whereas phenotypic concordance can be used to study heritability, discordance suggests the role of non-genetic factors. In autoimmune diseases, environmentally driven epigenetic changes are thought to contribute to their etiology. Here we report the first high-throughput and candidate sequence analyses of DNA methylation to investigate discordance for autoimmune disease in twins. We used a cohort of MZ twins discordant for three diseases whose clinical signs often overlap: systemic lupus erythematosus (SLE), rheumatoid arthritis, and dermatomyositis. Only MZ twins discordant for SLE featured widespread changes in the DNA methylation status of a significant number of genes. Gene ontology analysis revealed enrichment in categories associated with immune function. Individual analysis confirmed the existence of DNA methylation and expression changes in genes relevant to SLE pathogenesis. These changes occurred in parallel with a global decrease in the 5-methylcytosine content that was concomitantly accompanied with changes in DNA methylation and expression levels of ribosomal RNA genes, although no changes in repetitive sequences were found. Our findings not only identify potentially relevant DNA methylation markers for the clinical characterization of SLE patients but also support the notion that epigenetic changes may be critical in the clinical manifestations of autoimmune disease.

1 aJavierre, Biola, M1 aFernandez, Agustin, F1 aRichter, Julia1 aAl-Shahrour, Fatima1 aMartin-Subero, Ignacio1 aRodriguez-Ubreva, Javier1 aBerdasco, Maria1 aFraga, Mario, F1 aO’Hanlon, Terrance, P1 aRider, Lisa, G1 aJacinto, Filipe, V1 aLopez-Longo, Javier1 aDopazo, Joaquin1 aForn, Marta1 aPeinado, Miguel, A1 aCarreño, Luis1 aSawalha, Amr, H1 aHarley, John, B1 aSiebert, Reiner1 aEsteller, Manel1 aMiller, Frederick, W1 aBallestar, Esteban uhttp://clinbioinfosspa.es/content/changes-pattern-dna-methylation-associate-twin-discordance-systemic-lupus-erythematosus03406nas a2200529 4500008004100000022001400041245007000055210006900125260000900194300000800203490000700211520186600218653000902084653002102093653001602114653002002130653002402150653001102174653003002185653001502215653001302230653001102243653001802254653001602272653001302288653002102301653004402322653002102366653003302387100002302420700002502443700001902468700001902487700002002506700002202526700002002548700002602568700002002594700002002614700002202634700002602656700001902682700002002701700002802721700002702749856010002776 2010 eng d a1465-542X00aDNA methylation epigenotypes in breast cancer molecular subtypes.0 aDNA methylation epigenotypes in breast cancer molecular subtypes c2010 aR770 v123 a

INTRODUCTION: Identification of gene expression based breast cancer subtypes is considered as a critical means of prognostication. Genetic mutations along with epigenetic alterations contribute to gene expression changes occurring in breast cancer. So far, these epigenetic contributions to sporadic breast cancer subtypes have not been well characterized, and there is only a limited understanding of the epigenetic mechanisms affected in those particular breast cancer subtypes. The present study was undertaken to dissect the breast cancer methylome and deliver specific epigenotypes associated with particular breast cancer subtypes.

METHODS: Using a microarray approach we analyzed DNA methylation in regulatory regions of 806 cancer related genes in 28 breast cancer paired samples. We subsequently performed substantial technical and biological validation by Pyrosequencing, investigating the top qualifying 19 CpG regions in independent cohorts encompassing 47 basal-like, 44 ERBB2+ overexpressing, 48 luminal A and 48 luminal B paired breast cancer/adjacent tissues. Using all-subset selection method, we identified the most subtype predictive methylation profiles in multivariable logistic regression analysis.

RESULTS: The approach efficiently recognized 15 individual CpG loci differentially methylated in breast cancer tumor subtypes. We further identify novel subtype specific epigenotypes which clearly demonstrate the differences in the methylation profiles of basal-like and human epidermal growth factor 2 (HER2)-overexpressing tumors.

CONCLUSIONS: Our results provide evidence that well defined DNA methylation profiles enables breast cancer subtype prediction and support the utilization of this biomarker for prognostication and therapeutic stratification of patients with breast cancer.

10aAged10aBreast Neoplasms10aCpG Islands10aDNA Methylation10aEpigenesis, Genetic10aFemale10aGene Expression Profiling10aGenes, p5310aGenotype10aHumans10aKi-67 Antigen10aMiddle Aged10amutation10aNeoplasm Grading10aOligonucleotide Array Sequence Analysis10aReceptor, ErbB-210aTumor Suppressor Protein p531 aBediaga, Naiara, G1 aAcha-Sagredo, Amelia1 aGuerra, Isabel1 aViguri, Amparo1 aAlbaina, Carmen1 aDiaz, Irune, Ruiz1 aRezola, Ricardo1 aAlberdi, Maria, Jesus1 aDopazo, Joaquin1 aMontaner, David1 aRenobales, Mertxe1 aFernandez, Agustin, F1 aField, John, K1 aFraga, Mario, F1 aLiloglou, Triantafillos1 ade Pancorbo, Marian, M uhttp://clinbioinfosspa.es/content/dna-methylation-epigenotypes-breast-cancer-molecular-subtypes02509nas a2200217 4500008004100000022001400041245005200055210005000107260001600157300000700173490000700180520188600187653002602073653002302099653001402122653001302136100002402149700002002173700002002193856007802213 2010 eng d a1471-210500aETE: a python Environment for Tree Exploration.0 aETE a python Environment for Tree Exploration c2010 Jan 13 a240 v113 a

BACKGROUND: Many bioinformatics analyses, ranging from gene clustering to phylogenetics, produce hierarchical trees as their main result. These are used to represent the relationships among different biological entities, thus facilitating their analysis and interpretation. A number of standalone programs are available that focus on tree visualization or that perform specific analyses on them. However, such applications are rarely suitable for large-scale surveys, in which a higher level of automation is required. Currently, many genome-wide analyses rely on tree-like data representation and hence there is a growing need for scalable tools to handle tree structures at large scale.

RESULTS: Here we present the Environment for Tree Exploration (ETE), a python programming toolkit that assists in the automated manipulation, analysis and visualization of hierarchical trees. ETE libraries provide a broad set of tree handling options as well as specific methods to analyze phylogenetic and clustering trees. Among other features, ETE allows for the independent analysis of tree partitions, has support for the extended newick format, provides an integrated node annotation system and permits to link trees to external data such as multiple sequence alignments or numerical arrays. In addition, ETE implements a number of built-in analytical tools, including phylogeny-based orthology prediction and cluster validation techniques. Finally, ETE's programmable tree drawing engine can be used to automate the graphical rendering of trees with customized node-specific visualizations.

CONCLUSIONS: ETE provides a complete set of methods to manipulate tree data structures that extends current functionality in other bioinformatic toolkits of a more general purpose. ETE is free software and can be downloaded from http://ete.cgenomics.org.

10aComputational Biology10aDatabases, Genetic10aPhylogeny10aSoftware1 aHuerta-Cepas, Jaime1 aDopazo, Joaquin1 aGabaldón, Toni uhttp://clinbioinfosspa.es/content/ete-python-environment-tree-exploration03755nas a2200625 4500008004100000022001400041245009800055210006900153260001600222300001100238490000600249520178700255653001002042653004902052653001102101653002102112653004902133653002502182653002902207653002402236653002802260653001102288653001902299653003802318653003402356653001302390653002302403653001102426653001502437653001102452653003602463653003702499653002902536653003802565653002002603653002002623653002002643653001702663100002102680700002002701700002402721700002702745700002102772700002202793700002202815700002502837700001702862700002002879700002102899700001902920700001902939700002102958700002602979856012403005 2010 eng d a1932-620300aExploring the link between germline and somatic genetic alterations in breast carcinogenesis.0 aExploring the link between germline and somatic genetic alterati c2010 Nov 22 ae140780 v53 a

Recent genome-wide association studies (GWASs) have identified candidate genes contributing to cancer risk through low-penetrance mutations. Many of these genes were unexpected and, intriguingly, included well-known players in carcinogenesis at the somatic level. To assess the hypothesis of a germline-somatic link in carcinogenesis, we evaluated the distribution of somatic gene labels within the ordered results of a breast cancer risk GWAS. This analysis suggested frequent influence on risk of genetic variation in loci encoding for "driver kinases" (i.e., kinases encoded by genes that showed higher somatic mutation rates than expected by chance and, therefore, whose deregulation may contribute to cancer development and/or progression). Assessment of these predictions using a population-based case-control study in Poland replicated the association for rs3732568 in EPHB1 (odds ratio (OR) = 0.79; 95% confidence interval (CI): 0.63-0.98; P(trend) = 0.031). Analyses by early age at diagnosis and by estrogen receptor α (ERα) tumor status indicated potential associations for rs6852678 in CDKL2 (OR = 0.32, 95% CI: 0.10-1.00; P(recessive) = 0.044) and rs10878640 in DYRK2 (OR = 2.39, 95% CI: 1.32-4.30; P(dominant) = 0.003), and for rs12765929, rs9836340, rs4707795 in BMPR1A, EPHA3 and EPHA7, respectively (ERα tumor status P(interaction)<0.05). The identification of three novel candidates as EPH receptor genes might indicate a link between perturbed compartmentalization of early neoplastic lesions and breast cancer risk and progression. Together, these data may lay the foundations for replication in additional populations and could potentially increase our knowledge of the underlying molecular mechanisms of breast carcinogenesis.

10aAdult10aBone Morphogenetic Protein Receptors, Type I10aBreast10aBreast Neoplasms10aCalcium-Calmodulin-Dependent Protein Kinases10aCase-Control Studies10aCyclin-Dependent Kinases10aDisease Progression10aEstrogen Receptor alpha10aFemale10aGene Frequency10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGenotype10aGerm-Line Mutation10aHumans10aOdds Ratio10aPoland10aPolymorphism, Single Nucleotide10aProtein Serine-Threonine Kinases10aProtein-Tyrosine Kinases10aReceptor Protein-Tyrosine Kinases10aReceptor, EphA310aReceptor, EphA710aReceptor, EphB110aRisk Factors1 aBonifaci, Núria1 aGórski, Bohdan1 aMasojć, Bartlomiej1 aWokołorczyk, Dominika1 aJakubowska, Anna1 aDębniak, Tadeusz1 aBerenguer, Antoni1 aMusach, Jordi, Serra1 aBrunet, Joan1 aDopazo, Joaquin1 aNarod, Steven, A1 aLubiński, Jan1 aLázaro, Conxi1 aCybulski, Cezary1 aPujana, Miguel, Angel uhttp://clinbioinfosspa.es/content/exploring-link-between-germline-and-somatic-genetic-alterations-breast-carcinogenesis03097nas a2200325 4500008004100000245012300041210006900164260001600233520197300249100001902222700001902241700002402260700002102284700001702305700003102322700002002353700003002373700002502403700002402428700001902452700001902471700002102490700002602511700002402537700002902561700001802590700002002608700001902628856012402647 2010 eng d00aFine-scale evolution: genomic, phenotypic and ecological differentiation in two coexisting Salinibacter ruber strains.0 aFinescale evolution genomic phenotypic and ecological differenti c2010 Feb 183 a

Genomic and metagenomic data indicate a high degree of genomic variation within microbial populations, although the ecological and evolutive meaning of this microdiversity remains unknown. Microevolution analyses, including genomic and experimental approaches, are so far very scarce for non-pathogenic bacteria. In this study, we compare the genomes, metabolomes and selected ecological traits of the strains M8 and M31 of the hyperhalophilic bacterium Salinibacter ruber that contain ribosomal RNA (rRNA) gene and intergenic regions that are identical in sequence and were simultaneously isolated from a Mediterranean solar saltern. Comparative analyses indicate that S. ruber genomes present a mosaic structure with conserved and hypervariable regions (HVRs). The HVRs or genomic islands, are enriched in transposases, genes related to surface properties, strain-specific genes and highly divergent orthologous. However, the many indels outside the HVRs indicate that genome plasticity extends beyond them. Overall, 10% of the genes encoded in the M8 genome are absent from M31 and could stem from recent acquisitions. S. ruber genomes also harbor 34 genes located outside HVRs that are transcribed during standard growth and probably derive from lateral gene transfers with Archaea preceding the M8/M31 divergence. Metabolomic analyses, phage susceptibility and competition experiments indicate that these genomic differences cannot be considered neutral from an ecological perspective. The results point to the avoidance of competition by micro-niche adaptation and response to viral predation as putative major forces that drive microevolution within these Salinibacter strains. In addition, this work highlights the extent of bacterial functional diversity and environmental adaptation, beyond the resolution of the 16S rRNA and internal transcribed spacers regions.The ISME Journal advance online publication, 18 February 2010; doi:10.1038/ismej.2010.6.

1 aPeña, Arantxa1 aTeeling, Hanno1 aHuerta-Cepas, Jaime1 aSantos, Fernando1 aYarza, Pablo1 aBrito-Echeverría, Jocelyn1 aLucio, Marianna1 aSchmitt-Kopplin, Philippe1 aMeseguer, Inmaculada1 aSchenowitz, Chantal1 aDossat, Carole1 aBarbe, Valerie1 aDopazo, Joaquín1 aRosselló-Mora, Ramon1 aSchüler, Margarete1 aGlöckner, Frank, Oliver1 aAmann, Rudolf1 aGabaldón, Toni1 aAntón, Josefa uhttp://clinbioinfosspa.es/content/fine-scale-evolution-genomic-phenotypic-and-ecological-differentiation-two-coexisting02599nas a2200229 4500008004100000245010300041210006900144260001500213300001200228490000800240520175600248100002902004700003802033700002802071700002902099700001802128700002002146700002002166700002302186700003002209856013002239 2010 eng d00aFM19G11, a new hypoxia-inducible factor (HIF) modulator, affects stem cell differentiation status.0 aFM19G11 a new hypoxiainducible factor HIF modulator affects stem c2010 Jan 8 a1333-420 v2853 a

The biology of the alpha subunits of hypoxia-inducible factors (HIFalpha) has expanded from their role in angiogenesis to their current position in the self-renewal and differentiation of stem cells. The results reported in this article show the discovery of FM19G11, a novel chemical entity that inhibits HIFalpha proteins that repress target genes of the two alpha subunits, in various tumor cell lines as well as in adult and embryonic stem cell models from rodents and humans, respectively. FM19G11 inhibits at nanomolar range the transcriptional and protein expression of Oct4, Sox2, Nanog, and Tgf-alpha undifferentiating factors, in adult rat and human embryonic stem cells, FM19G11 activity occurs in ependymal progenitor stem cells from rats (epSPC), a cell model reported for spinal cord regeneration, which allows the progression of oligodendrocyte cell differentiation in a hypoxic environment, has created interest in its characterization for pharmacological research. Experiments using small interfering RNA showed a significant depletion in Sox2 protein only in the case of HIF2alpha silencing, but not in HIF1alpha-mediated ablation. Moreover, chromatin immunoprecipitation data, together with the significant presence of functional hypoxia response element consensus sequences in the promoter region of Sox2, strongly validated that this factor behaves as a target gene of HIF2alpha in epSPCs. FM19G11 causes a reduction of overall histone acetylation with significant repression of p300, a histone acetyltransferase required as a co-factor for HIF-transcription activation. Arrays carried out in the presence and absence of the inhibitor showed the predominant involvement of epigenetic-associated events mediated by the drug.

1 aMoreno-Manzano, Victoria1 aRodríguez-Jiménez, Francisco, J1 aAceña-Bonilla, Jose, L1 aFustero-Lardíes, Santos1 aErceg, Slaven1 aDopazo, Joaquin1 aMontaner, David1 aStojkovic, Miodrag1 aSánchez-Puelles, Jose, M uhttp://clinbioinfosspa.es/content/fm19g11-new-hypoxia-inducible-factor-hif-modulator-affects-stem-cell-differentiation-status03015nas a2200541 4500008004100000022001400041245013100055210006900186260001300255300001100268490000700279520146000286653001501746653002301761653002701784653003001811653001301841653001101854653003001865653004401895653001401939653003001953653001301983653002001996100001102016700001902027700001802046700001302064700001802077700001802095700002102113700001402134700001602148700001802164700001202182700001402194700001202208700001202220700001102232700001402243700001802257700001702275700001702292700001202309700001102321700001602332856012502348 2010 eng d a1473-115000aFunctional analysis of multiple genomic signatures demonstrates that classification algorithms choose phenotype-related genes.0 aFunctional analysis of multiple genomic signatures demonstrates  c2010 Aug a310-230 v103 a

Gene expression signatures of toxicity and clinical response benefit both safety assessment and clinical practice; however, difficulties in connecting signature genes with the predicted end points have limited their application. The Microarray Quality Control Consortium II (MAQCII) project generated 262 signatures for ten clinical and three toxicological end points from six gene expression data sets, an unprecedented collection of diverse signatures that has permitted a wide-ranging analysis on the nature of such predictive models. A comprehensive analysis of the genes of these signatures and their nonredundant unions using ontology enrichment, biological network building and interactome connectivity analyses demonstrated the link between gene signatures and the biological basis of their predictive power. Different signatures for a given end point were more similar at the level of biological properties and transcriptional control than at the gene level. Signatures tended to be enriched in function and pathway in an end point and model-specific manner, and showed a topological bias for incoming interactions. Importantly, the level of biological similarity between different signatures for a given end point correlated positively with the accuracy of the signature predictions. These findings will aid the understanding, and application of predictive genomic signatures, and support their broader application in predictive medicine.

10aAlgorithms10aDatabases, Genetic10aEndpoint Determination10aGene Expression Profiling10aGenomics10aHumans10aNeural Networks, Computer10aOligonucleotide Array Sequence Analysis10aPhenotype10aPredictive Value of Tests10aProteins10aQuality Control1 aShi, W1 aBessarabova, M1 aDosymbekov, D1 aDezso, Z1 aNikolskaya, T1 aDudoladova, M1 aSerebryiskaya, T1 aBugrim, A1 aGuryanov, A1 aBrennan, R, J1 aShah, R1 aDopazo, J1 aChen, M1 aDeng, Y1 aShi, T1 aJurman, G1 aFurlanello, C1 aThomas, R, S1 aCorton, J, C1 aTong, W1 aShi, L1 aNikolsky, Y uhttp://clinbioinfosspa.es/content/functional-analysis-multiple-genomic-signatures-demonstrates-classification-algorithms01714nas a2200229 4500008004100000022001400041245009600055210006900151260001300220300001000233490000600243520095200249653003101201653002901232653001301261653002001274653001301294653002001307100001901327700002001346856011801366 2010 eng d a1744-838700aFunctional genomics and networks: new approaches in the extraction of complex gene modules.0 aFunctional genomics and networks new approaches in the extractio c2010 Feb a55-630 v73 a

The engine that makes the cell work is made of an intricate network of molecular interactions. Nowadays, the elements and relationships of this complex network can be studied with several types of high-throughput techniques. The dream of having a global picture of the cell from different perspectives that can jointly explain cell behavior is, at least technically, feasible. However, this task can only be accomplished by filling the gap between data and information. The availability of methods capable of accurately managing, integrating and analyzing the results from these experiments is crucial for this purpose. Here, we review the new challenges raised by the availability of different genomic data, as well as the new proposals presented to cope with the increasing data complexity. Special emphasis is given to approaches that explore the transcriptome trying to describe the modules of genes that account for the traits studied.

10aGene Expression Regulation10aGene Regulatory Networks10aGenomics10aProtein Binding10aProteins10aSystems biology1 aMinguez, Pablo1 aDopazo, Joaquin uhttp://clinbioinfosspa.es/content/functional-genomics-and-networks-new-approaches-extraction-complex-gene-modules02384nas a2200301 4500008004100000022001400041245010100055210006900156260001600225300001100241490000600252520140600258653001601664653002301680653003001703653001301733653001101746653004401757100001801801700002001819700001801839700002001857700001901877700002401896700002001920700001801940856012401958 2010 eng d a1932-620300aFunctional genomics of 5- to 8-cell stage human embryos by blastomere single-cell cDNA analysis.0 aFunctional genomics of 5 to 8cell stage human embryos by blastom c2010 Oct 26 ae136150 v53 a

Blastomere fate and embryonic genome activation (EGA) during human embryonic development are unsolved areas of high scientific and clinical interest. Forty-nine blastomeres from 5- to 8-cell human embryos have been investigated following an efficient single-cell cDNA amplification protocol to provide a template for high-density microarray analysis. The previously described markers, characteristic of Inner Cell Mass (ICM) (n = 120), stemness (n = 190) and Trophectoderm (TE) (n = 45), were analyzed, and a housekeeping pattern of 46 genes was established. All the human blastomeres from the 5- to 8-cell stage embryo displayed a common gene expression pattern corresponding to ICM markers (e.g., DDX3, FOXD3, LEFTY1, MYC, NANOG, POU5F1), stemness (e.g., POU5F1, DNMT3B, GABRB3, SOX2, ZFP42, TERT), and TE markers (e.g., GATA6, EOMES, CDX2, LHCGR). The EGA profile was also investigated between the 5-6- and 8-cell stage embryos, and compared to the blastocyst stage. Known genes (n = 92) such as depleted maternal transcripts (e.g., CCNA1, CCNB1, DPPA2) and embryo-specific activation (e.g., POU5F1, CDH1, DPPA4), as well as novel genes, were confirmed. In summary, the global single-cell cDNA amplification microarray analysis of the 5- to 8-cell stage human embryos reveals that blastomere fate is not committed to ICM or TE. Finally, new EGA features in human embryogenesis are presented.

10aBlastomeres10aDNA, Complementary10aGene Expression Profiling10aGenomics10aHumans10aOligonucleotide Array Sequence Analysis1 aGalan, Amparo1 aMontaner, David1 aPóo, Eugenia1 aValbuena, Diana1 aRuiz, Veronica1 aAguilar, Cristóbal1 aDopazo, Joaquin1 aSimon, Carlos uhttp://clinbioinfosspa.es/content/functional-genomics-5-8-cell-stage-human-embryos-blastomere-single-cell-cdna-analysis01406nas a2200157 4500008004100000245004400041210004300085260000900128300001100137490000800148520095000156100002101106700002301127700002401150856007401174 2010 eng d00aFunctional profiling methods in cancer.0 aFunctional profiling methods in cancer c2010 a363-740 v5763 a

The introduction of new high-throughput methodologies such as DNA microarrays constitutes a major breakthrough in cancer research. The unprecedented amount of data produced by such technologies has opened new avenues for interrogating living systems although, at the same time, it has demanded of the development of new data analytical methods as well as new strategies for testing hypotheses. A history of early successful applications in cancer boosted the use of microarrays and fostered further applications in other fields. Keeping the pace with these technologies, bioinformatics offers new solutions for data analysis and, what is more important, permits the formulation of a new class of hypotheses inspired in systems biology, more oriented to pathways or, in general, to modules of functionally related genes. Although these analytical methodologies are new, some options are already available and are discussed in this chapter.

1 aDopazo, Joaquín1 aGrützmann, Robert1 aPilarsky, Christian uhttp://clinbioinfosspa.es/content/functional-profiling-methods-cancer03317nas a2200613 4500008004100000022001400041245010400055210006900159260001600228300001100244490000700255520144400262653001901706653001201725653001501737653002801752653002501780653001701805653002501822653002001847653002001867653002501887653002201912653003001934653003101964653001101995653000902006653002602015653003602041653001102077653002702088653000902115653001502124653004102139100002302180700001602203700001902219700003002238700002702268700002102295700002002316700002002336700001702356700002002373700002702393700002202420700001802442700002902460700001802489700002002507700002202527700002302549856013102572 2010 eng d a1549-491800aHypoxia promotes efficient differentiation of human embryonic stem cells to functional endothelium.0 aHypoxia promotes efficient differentiation of human embryonic st c2010 Mar 31 a407-180 v283 a

Early development of mammalian embryos occurs in an environment of relative hypoxia. Nevertheless, human embryonic stem cells (hESC), which are derived from the inner cell mass of blastocyst, are routinely cultured under the same atmospheric conditions (21% O(2)) as somatic cells. We hypothesized that O(2) levels modulate gene expression and differentiation potential of hESC, and thus, we performed gene profiling of hESC maintained under normoxic or hypoxic (1% or 5% O(2)) conditions. Our analysis revealed that hypoxia downregulates expression of pluripotency markers in hESC but increases significantly the expression of genes associated with angio- and vasculogenesis including vascular endothelial growth factor and angiopoitein-like proteins. Consequently, we were able to efficiently differentiate hESC to functional endothelial cells (EC) by varying O(2) levels; after 24 hours at 5% O(2), more than 50% of cells were CD34+. Transplantation of resulting endothelial-like cells improved both systolic function and fractional shortening in a rodent model of myocardial infarction. Moreover, analysis of the infarcted zone revealed that transplanted EC reduced the area of fibrous scar tissue by 50%. Thus, use of hypoxic conditions to specify the endothelial lineage suggests a novel strategy for cellular therapies aimed at repair of damaged vasculature in pathologies such as cerebral ischemia and myocardial infarction.

10aAngiopoietin-110aAnimals10abiomarkers10aCell Culture Techniques10aCell Differentiation10aCell Hypoxia10aCell Transplantation10aCells, Cultured10aDown-Regulation10aEmbryonic Stem Cells10aEndothelial Cells10aGene Expression Profiling10aGene Expression Regulation10aHumans10aMale10aMyocardial Infarction10aNeovascularization, Physiologic10aOxygen10aPluripotent Stem Cells10aRats10aRats, Nude10aVascular Endothelial Growth Factor A1 aPrado-Lopez, Sonia1 aConesa, Ana1 aArmiñán, Ana1 aMartínez-Losa, Magdalena1 aEscobedo-Lucea, Carmen1 aGandia, Carolina1 aTarazona, Sonia1 aMelguizo, Dario1 aBlesa, David1 aMontaner, David1 aSanz-González, Silvia1 aSepúlveda, Pilar1 aGötz, Stefan1 aO'Connor, José, Enrique1 aMoreno, Ruben1 aDopazo, Joaquin1 aBurks, Deborah, J1 aStojkovic, Miodrag uhttp://clinbioinfosspa.es/content/hypoxia-promotes-efficient-differentiation-human-embryonic-stem-cells-functional-endothelium01700nas a2200265 4500008004100000245004500041210004400086260000900130300001300139490000600152520096600158653000801124653001401132100002001146700001601166700002701182700002001209700002001229700002301249700001901272700001901291700002001310700002001330856008401350 2010 eng d00aInitial genomics of the human nucleolus.0 aInitial genomics of the human nucleolus c2010 ae10008890 v63 a

We report for the first time the genomics of a nuclear compartment of the eukaryotic cell. 454 sequencing and microarray analysis revealed the pattern of nucleolus-associated chromatin domains (NADs) in the linear human genome and identified different gene families and certain satellite repeats as the major building blocks of NADs, which constitute about 4% of the genome. Bioinformatic evaluation showed that NAD-localized genes take part in specific biological processes, like the response to other organisms, odor perception, and tissue development. 3D FISH and immunofluorescence experiments illustrated the spatial distribution of NAD-specific chromatin within interphase nuclei and its alteration upon transcriptional changes. Altogether, our findings describe the nature of DNA sequences associated with the human nucleolus and provide insights into the function of the nucleolus in genome organization and establishment of nuclear architecture.

10aNGS10anucleolus1 aNémeth, Attila1 aConesa, Ana1 aSantoyo-López, Javier1 aMedina, Ignacio1 aMontaner, David1 aPéterfia, Bálint1 aSolovei, Irina1 aCremer, Thomas1 aDopazo, Joaquin1 aLängst, Gernot uhttp://www.plosgenetics.org/article/info%3Adoi%2F10.1371%2Fjournal.pgen.100088900628nas a2200133 4500008004100000022001400041245014400055210006900199260001600268300001400284490000700298110002000305856016900325 2010 eng d a1087-015600aThe MicroArray Quality Control (MAQC)-II study of common practices for the development and validation of microarray-based predictive models0 aMicroArray Quality Control MAQCII study of common practices for  cJan-08-2010 a827 - 8380 v281 aMAQC Consortium uhttp://www.nature.com/articles/nbt.1665http://www.nature.com/articles/nbt.1665.pdfhttp://www.nature.com/articles/nbt.1665.pdfhttp://www.nature.com/articles/nbt.166507842nas a2202545 4500008004100000245014500041210006900186260001300255300001100268490000700279520110300286100001601389700002201405700002201427700002101449700001701470700002301487700001801510700001801528700002601546700001901572700002501591700002201616700002301638700002301661700001801684700001901702700001701721700001201738700002201750700002301772700002301795700001401818700002401832700002001856700001701876700001601893700001701909700002001926700002201946700001701968700001701985700001502002700001602017700001502033700002402048700002102072700001802093700002702111700001802138700002002156700002002176700001902196700001802215700001602233700001702249700001502266700002002281700002102301700001802322700001402340700002402354700002002378700002202398700002002420700002702440700001102467700001402478700001302492700001802505700001702523700002602540700001302566700001302579700002302592700001902615700002202634700002202656700001802678700001902696700002102715700001502736700002102751700001602772700001602788700001702804700002702821700002302848700002102871700001702892700002702909700002002936700001702956700001502973700001402988700002203002700001703024700001903041700001703060700001703077700001503094700002203109700001603131700002703147700002003174700002403194700002003218700002603238700001703264700001503281700001603296700001403312700001703326700002603343700001603369700002203385700001703407700001503424700002103439700003003460700002103490700001903511700001603530700002603546700001203572700002303584700001403607700002303621700002103644700001803665700002003683700002403703700001503727700002403742700002103766700002003787700002103807700001903828700001703847700001103864700001703875700001803892700001303910700001703923700001303940700001403953700001703967700001303984700001903997700003204016700002004048700001904068700001904087700002404106700002004130700002104150700002404171700002104195700002404216700001804240700001904258700001704277700002004294700001704314700002104331700001804352700001704370700001204387700002504399700001904424700002404443700002604467700002504493700001504518700002004533700001704553700001904570700002304589700001604612700002104628700001904649700002004668700001704688700001604705700001504721700001804736700001704754700002204771700001804793700002004811700002504831700002304856700001804879700001504897700001704912700001404929700002204943700002104965700001904986700001605005700001905021700001505040700001205055700001405067700001505081700001705096700001405113700001505127700001505142700001705157700001605174700001605190700002605206856006405232 2010 eng d00aThe MicroArray Quality Control (MAQC)-II study of common practices for the development and validation of microarray-based predictive models.0 aMicroArray Quality Control MAQCII study of common practices for  c2010 Aug a827-380 v283 a

Gene expression data from microarrays are being applied to predict preclinical and clinical endpoints, but the reliability of these predictions has not been established. In the MAQC-II project, 36 independent teams analyzed six microarray data sets to generate predictive models for classifying a sample with respect to one of 13 endpoints indicative of lung or liver toxicity in rodents, or of breast cancer, multiple myeloma or neuroblastoma in humans. In total, >30,000 models were built using many combinations of analytical methods. The teams generated predictive models without knowing the biological meaning of some of the endpoints and, to mimic clinical reality, tested the models on data that had not been used for training. We found that model performance depended largely on the endpoint and team proficiency and that different approaches generated models of similar performance. The conclusions and recommendations from MAQC-II should be useful for regulatory agencies, study committees and independent investigators that evaluate methods for global gene expression analysis.

1 aShi, Leming1 aCampbell, Gregory1 aJones, Wendell, D1 aCampagne, Fabien1 aWen, Zhining1 aWalker, Stephen, J1 aSu, Zhenqiang1 aChu, Tzu-Ming1 aGoodsaid, Federico, M1 aPusztai, Lajos1 aShaughnessy, John, D1 aOberthuer, André1 aThomas, Russell, S1 aPaules, Richard, S1 aFielden, Mark1 aBarlogie, Bart1 aChen, Weijie1 aDu, Pan1 aFischer, Matthias1 aFurlanello, Cesare1 aGallas, Brandon, D1 aGe, Xijin1 aMegherbi, Dalila, B1 aSymmans, Fraser1 aWang, May, D1 aZhang, John1 aBitter, Hans1 aBrors, Benedikt1 aBushel, Pierre, R1 aBylesjo, Max1 aChen, Minjun1 aCheng, Jie1 aCheng, Jing1 aChou, Jeff1 aDavison, Timothy, S1 aDelorenzi, Mauro1 aDeng, Youping1 aDevanarayan, Viswanath1 aDix, David, J1 aDopazo, Joaquin1 aDorff, Kevin, C1 aElloumi, Fathi1 aFan, Jianqing1 aFan, Shicai1 aFan, Xiaohui1 aFang, Hong1 aGonzaludo, Nina1 aHess, Kenneth, R1 aHong, Huixiao1 aHuan, Jun1 aIrizarry, Rafael, A1 aJudson, Richard1 aJuraeva, Dilafruz1 aLababidi, Samir1 aLambert, Christophe, G1 aLi, Li1 aLi, Yanen1 aLi, Zhen1 aLin, Simon, M1 aLiu, Guozhen1 aLobenhofer, Edward, K1 aLuo, Jun1 aLuo, Wen1 aMcCall, Matthew, N1 aNikolsky, Yuri1 aPennello, Gene, A1 aPerkins, Roger, G1 aPhilip, Reena1 aPopovici, Vlad1 aPrice, Nathan, D1 aQian, Feng1 aScherer, Andreas1 aShi, Tieliu1 aShi, Weiwei1 aSung, Jaeyun1 aThierry-Mieg, Danielle1 aThierry-Mieg, Jean1 aThodima, Venkata1 aTrygg, Johan1 aVishnuvajjala, Lakshmi1 aWang, Sue, Jane1 aWu, Jianping1 aWu, Yichao1 aXie, Qian1 aYousef, Waleed, A1 aZhang, Liang1 aZhang, Xuegong1 aZhong, Sheng1 aZhou, Yiming1 aZhu, Sheng1 aArasappan, Dhivya1 aBao, Wenjun1 aLucas, Anne, Bergstrom1 aBerthold, Frank1 aBrennan, Richard, J1 aBuness, Andreas1 aCatalano, Jennifer, G1 aChang, Chang1 aChen, Rong1 aCheng, Yiyu1 aCui, Jian1 aCzika, Wendy1 aDemichelis, Francesca1 aDeng, Xutao1 aDosymbekov, Damir1 aEils, Roland1 aFeng, Yang1 aFostel, Jennifer1 aFulmer-Smentek, Stephanie1 aFuscoe, James, C1 aGatto, Laurent1 aGe, Weigong1 aGoldstein, Darlene, R1 aGuo, Li1 aHalbert, Donald, N1 aHan, Jing1 aHarris, Stephen, C1 aHatzis, Christos1 aHerman, Damir1 aHuang, Jianping1 aJensen, Roderick, V1 aJiang, Rui1 aJohnson, Charles, D1 aJurman, Giuseppe1 aKahlert, Yvonne1 aKhuder, Sadik, A1 aKohl, Matthias1 aLi, Jianying1 aLi, Li1 aLi, Menglong1 aLi, Quan-Zhen1 aLi, Shao1 aLi, Zhiguang1 aLiu, Jie1 aLiu, Ying1 aLiu, Zhichao1 aMeng, Lu1 aMadera, Manuel1 aMartinez-Murillo, Francisco1 aMedina, Ignacio1 aMeehan, Joseph1 aMiclaus, Kelci1 aMoffitt, Richard, A1 aMontaner, David1 aMukherjee, Piali1 aMulligan, George, J1 aNeville, Padraic1 aNikolskaya, Tatiana1 aNing, Baitang1 aPage, Grier, P1 aParker, Joel1 aParry, Mitchell1 aPeng, Xuejun1 aPeterson, Ron, L1 aPhan, John, H1 aQuanz, Brian1 aRen, Yi1 aRiccadonna, Samantha1 aRoter, Alan, H1 aSamuelson, Frank, W1 aSchumacher, Martin, M1 aShambaugh, Joseph, D1 aShi, Qiang1 aShippy, Richard1 aSi, Shengzhu1 aSmalter, Aaron1 aSotiriou, Christos1 aSoukup, Mat1 aStaedtler, Frank1 aSteiner, Guido1 aStokes, Todd, H1 aSun, Qinglan1 aTan, Pei-Yi1 aTang, Rong1 aTezak, Zivana1 aThorn, Brett1 aTsyganova, Marina1 aTurpaz, Yaron1 aVega, Silvia, C1 aVisintainer, Roberto1 avon Frese, Juergen1 aWang, Charles1 aWang, Eric1 aWang, Junwei1 aWang, Wei1 aWestermann, Frank1 aWilley, James, C1 aWoods, Matthew1 aWu, Shujian1 aXiao, Nianqing1 aXu, Joshua1 aXu, Lei1 aYang, Lun1 aZeng, Xiao1 aZhang, Jialu1 aZhang, Li1 aZhang, Min1 aZhao, Chen1 aPuri, Raj, K1 aScherf, Uwe1 aTong, Weida1 aWolfinger, Russell, D uhttp://www.nature.com/nbt/journal/v28/n8/full/nbt.1665.html02107nas a2200241 4500008004100000022001400041245005600055210005500111260001600166300001100182490000600193520139200199653002301591653003001614653002901644653001801673653001301691653001101704653002401715100002001739700002001759856008601779 2010 eng d a1932-620300aMultidimensional gene set analysis of genomic data.0 aMultidimensional gene set analysis of genomic data c2010 Apr 27 ae103480 v53 a

Understanding the functional implications of changes in gene expression, mutations, etc., is the aim of most genomic experiments. To achieve this, several functional profiling methods have been proposed. Such methods study the behaviour of different gene modules (e.g. gene ontology terms) in response to one particular variable (e.g. differential gene expression). In spite to the wealth of information provided by functional profiling methods, a common limitation to all of them is their inherent unidimensional nature. In order to overcome this restriction we present a multidimensional logistic model that allows studying the relationship of gene modules with different genome-scale measurements (e.g. differential expression, genotyping association, methylation, copy number alterations, heterozygosity, etc.) simultaneously. Moreover, the relationship of such functional modules with the interactions among the variables can also be studied, which produces novel results impossible to be derived from the conventional unidimensional functional profiling methods. We report sound results of gene sets associations that remained undetected by the conventional one-dimensional gene set analysis in several examples. Our findings demonstrate the potential of the proposed approach for the discovery of new cell functionalities with complex dependences on more than one variable.

10aDatabases, Genetic10aGene Expression Profiling10aGene Regulatory Networks10aGenome, Human10aGenomics10aHumans10aModels, Statistical1 aMontaner, David1 aDopazo, Joaquin uhttp://clinbioinfosspa.es/content/multidimensional-gene-set-analysis-genomic-data03040nas a2200565 4500008004100000022001400041245009600055210006900151260001300220300001400233490000700247520132400254653002401578653001201602653002501614653002801639653002401667653002501691653001701716653001101733653002101744653002201765653001101787653000901798653002801807653001301835653001301848653003601861653003201897653002501929653001001954653003301964100002201997700001902019700002602038700003302064700002002097700001802117700002302135700002202158700001802180700002402198700001902222700002102241700002202262700002002284700002702304700002502331856011802356 2010 eng d a1098-100400aMutation spectrum of EYS in Spanish patients with autosomal recessive retinitis pigmentosa.0 aMutation spectrum of EYS in Spanish patients with autosomal rece c2010 Nov aE1772-8000 v313 a

Retinitis pigmentosa (RP) is a heterogeneous group of inherited retinal dystrophies characterised ultimately by the loss of photoreceptor cells. We have recently identified a new gene(EYS) encoding an ortholog of Drosophila space maker (spam) as a commonly mutated gene in autosomal recessive RP. In the present study, we report the identification of 73 sequence variations in EYS, of which 28 are novel. Of these, 42.9% (12/28) are very likely pathogenic, 17.9% (5/28)are possibly pathogenic, whereas 39.3% (11/28) are SNPs. In addition, we have detected 3 pathogenic changes previously reported in other populations. We are also presenting the characterisation of EYS homologues in different species, and a detailed analysis of the EYS domains, with the identification of an interesting novel feature: a putative coiled-coil domain.Majority of the mutations in the arRP patients have been found within the domain structures of EYS. The minimum observed prevalence of distinct EYS mutations in our group of patients is of 15.9% (15/94), confirming a major involvement of EYS in the pathogenesis of arRP in the Spanish population. Along with the detection of three recurrent mutations in Caucasian population, our hypothesis of EYS being the first prevalent gene in arRP has been reinforced in the present study.

10aAmino Acid Sequence10aAnimals10aCase-Control Studies10aDNA Mutational Analysis10aDrosophila Proteins10aEvolution, Molecular10aEye Proteins10aFemale10aGenes, Recessive10aGenetic Variation10aHumans10aMale10aMolecular Sequence Data10amutation10aPedigree10aPolymorphism, Single Nucleotide10aProtein Structure, Tertiary10aRetinitis pigmentosa10aSpain10aStructural Homology, Protein1 aBarragán, Isabel1 aBorrego, Salud1 aPieras, Juan, Ignacio1 adel Pozo, María, González-1 aSantoyo, Javier1 aAyuso, Carmen1 aBaiget, Montserrat1 aMillán, José, M1 aMena, Marcela1 aEl-Aziz, Mai, M Abd1 aAudo, Isabelle1 aZeitz, Christina1 aLittink, Karin, W1 aDopazo, Joaquin1 aBhattacharya, Shomi, S1 aAntiňolo, Guillermo uhttp://clinbioinfosspa.es/content/mutation-spectrum-eys-spanish-patients-autosomal-recessive-retinitis-pigmentosa01811nas a2200145 4500008004100000245010300041210006900144260001600213300000800229490000700237520125000244100001801494700002401512856012901536 2010 eng d00aQuantifying the relationship between sequence and three-dimensional structure conservation in RNA.0 aQuantifying the relationship between sequence and threedimension c2010 Jun 15 a3220 v113 a

ABSTRACT: BACKGROUND: In recent years, the number of available RNA structures has rapidly grown reflecting the increased interest on RNA biology. Similarly to the studies carried out two decades ago for proteins, which gave the fundamental grounds for developing comparative protein structure prediction methods, we are now able to quantify the relationship between sequence and structure conservation in RNA. RESULTS: Here we introduce an all-against-all sequence- and three-dimensional (3D) structure-based comparison of a representative set of RNA structures, which have allowed us to quantitatively confirm that: (i) there is a measurable relationship between sequence and structure conservation that weakens for alignments resulting in below 60% sequence identity, (ii) evolution tends to conserve more RNA structure than sequence, and (iii) there is a twilight zone for RNA homology detection. DISCUSSION: The computational analysis here presented quantitatively describes the relationship between sequence and structure for RNA molecules and defines a twilight zone region for detecting RNA homology. Our work could represent the theoretical basis and limitations for future developments in comparative RNA 3D structure prediction.

1 aCapriotti, E.1 aMarti-Renom, M., A. uhttp://clinbioinfosspa.es/content/quantifying-relationship-between-sequence-and-three-dimensional-structure-conservation-rna00608nas a2200169 4500008004100000245010100041210006900142300001300211490000600224100002500230700001900255700002700274700001900301700002000320700002000340856007800360 2010 eng d00aSelection upon Genome Architecture: Conservation of Functional Neighborhoods with Changing Genes0 aSelection upon Genome Architecture Conservation of Functional Ne ae10009530 v61 aAl-Shahrour, Fátima1 aMinguez, Pablo1 aMarqués-Bonet, Tomás1 aGazave, Elodie1 aNavarro, Arcadi1 aDopazo, Joaquin uhttp://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.100095301781nas a2200277 4500008004100000022001400041245009200055210006900147260001300216300001200229490000700241520089700248653001501145653003001160653001301190653001301203653001801216653004401234653001301278100002401291700002101315700002001336700002001356700001601376856011101392 2010 eng d a1362-496200aSerial Expression Analysis: a web tool for the analysis of serial gene expression data.0 aSerial Expression Analysis a web tool for the analysis of serial c2010 Jul aW239-450 v383 a

Serial transcriptomics experiments investigate the dynamics of gene expression changes associated with a quantitative variable such as time or dosage. The statistical analysis of these data implies the study of global and gene-specific expression trends, the identification of significant serial changes, the comparison of expression profiles and the assessment of transcriptional changes in terms of cellular processes. We have created the SEA (Serial Expression Analysis) suite to provide a complete web-based resource for the analysis of serial transcriptomics data. SEA offers five different algorithms based on univariate, multivariate and functional profiling strategies framed within a user-friendly interface and a project-oriented architecture to facilitate the analysis of serial gene expression data sets from different perspectives. SEA is available at sea.bioinfo.cipf.es.

10aAlgorithms10aGene Expression Profiling10aInternet10aKinetics10aLinear Models10aOligonucleotide Array Sequence Analysis10aSoftware1 aNueda, Maria, José1 aCarbonell, José1 aMedina, Ignacio1 aDopazo, Joaquin1 aConesa, Ana uhttp://clinbioinfosspa.es/content/serial-expression-analysis-web-tool-analysis-serial-gene-expression-data02240nas a2200217 4500008004100000245012100041210007100162260001300233300001100246490000700257520147000264100001901734700002201753700001801775700002201793700002001815700001901835700001601854700002301870856012901893 2010 eng d00aSIMAP–a comprehensive database of pre-calculated protein sequence similarities, domains, annotations and clusters.0 aSIMAP–a comprehensive database of precalculated protein sequence c2010 Jan aD223-60 v383 a

The prediction of protein function as well as the reconstruction of evolutionary genesis employing sequence comparison at large is still the most powerful tool in sequence analysis. Due to the exponential growth of the number of known protein sequences and the subsequent quadratic growth of the similarity matrix, the computation of the Similarity Matrix of Proteins (SIMAP) becomes a computational intensive task. The SIMAP database provides a comprehensive and up-to-date pre-calculation of the protein sequence similarity matrix, sequence-based features and sequence clusters. As of September 2009, SIMAP covers 48 million proteins and more than 23 million non-redundant sequences. Novel features of SIMAP include the expansion of the sequence space by including databases such as ENSEMBL as well as the integration of metagenomes based on their consistent processing and annotation. Furthermore, protein function predictions by Blast2GO are pre-calculated for all sequences in SIMAP and the data access and query functions have been improved. SIMAP assists biologists to query the up-to-date sequence space systematically and facilitates large-scale downstream projects in computational biology. Access to SIMAP is freely provided through the web portal for individuals (http://mips.gsf.de/simap/) and for programmatic access through DAS (http://webclu.bio.wzw.tum.de/das/) and Web-Service (http://mips.gsf.de/webservices/services/SimapService2.0?wsdl).

1 aRattei, Thomas1 aTischler, Patrick1 aGötz, Stefan1 aJehl, Marc-André1 aHoser, Jonathan1 aArnold, Roland1 aConesa, Ana1 aMewes, Hans-Werner uhttp://clinbioinfosspa.es/content/simap%E2%80%93-comprehensive-database-pre-calculated-protein-sequence-similarities-domains02044nas a2200181 4500008004100000245008700041210006900128260001300197300001100210490000700221520141100228100002401639700002201663700002501685700002101710700001701731856011401748 2009 eng d00aAlignment of multiple protein structures based on sequence and structure features.0 aAlignment of multiple protein structures based on sequence and s c2009 Sep a569-740 v223 a

Comparing the structures of proteins is crucial to gaining insight into protein evolution and function. Here, we align the sequences of multiple protein structures by a dynamic programming optimization of a scoring function that is a sum of an affine gap penalty and terms dependent on various sequence and structure features (SALIGN). The features include amino acid residue type, residue position, residue accessible surface area, residue secondary structure state and the conformation of a short segment centered on the residue. The multiple alignment is built by following the ’guide’ tree constructed from the matrix of all pairwise protein alignment scores. Importantly, the method does not depend on the exact values of various parameters, such as feature weights and gap penalties, because the optimal alignment across a range of parameter values is found. Using multiple structure alignments in the HOMSTRAD database, SALIGN was benchmarked against MUSTANG for multiple alignments as well as against TM-align and CE for pairwise alignments. On the average, SALIGN produces a 15% improvement in structural overlap over HOMSTRAD and 14% over MUSTANG, and yields more equivalent structural positions than TM-align and CE in 90% and 95% of cases, respectively. The utility of accurate multiple structure alignment is illustrated by its application to comparative protein structure modeling.

1 aMadhusudhan, M., S.1 aWebb, Benjamin, M1 aMarti-Renom, Marc, A1 aEswar, Narayanan1 aSali, Andrej uhttp://clinbioinfosspa.es/content/alignment-multiple-protein-structures-based-sequence-and-structure-features01884nas a2200253 4500008004100000245010700041210006900148300001000217490000700227520107700234653001101311653002901322100002101351700002001372700001701392700001401409700001601423700001501439700001401454700002001468700001501488700002101503856010601524 2009 eng d00aAnalysis of chronic lymphotic leukemia transcriptomic profile: differences between molecular subgroups0 aAnalysis of chronic lymphotic leukemia transcriptomic profile di a68-790 v503 a

B cell chronic lymphocytic leukemia (CLL) is a lymphoproliferative disorder with a variable clinical course. Patients with unmutated IgV(H) gene show a shorter progression-free and overall survival than patients with immunoglobulin heavy chain variable regions (IgV(H)) gene mutated. In addition, BCL6 mutations identify a subgroup of patients with high risk of progression. Gene expression was analysed in 36 early-stage patients using high-density microarrays. Around 150 genes differentially expressed were found according to IgV(H) mutations, whereas no difference was found according to BCL6 mutations. Functional profiling methods allowed us to distinguish KEGG and gene ontology terms showing coordinated gene expression changes across subgroups of CLL. We validated a set of differentially expressed genes according to IgV(H) status, scoring them as putative prognostic markers in CLL. Among them, CRY1, LPL, CD82 and DUSP22 are the ones with at least equal or superior performance to ZAP70 which is actually the most used surrogate marker of IgV(H) status.

10acancer10amicroarray data analysis1 aLewintre, Jantus1 aMartin, Reinoso1 aMontaner, D.1 aMarin, M.1 aTerol, Jose1 aFarras, R.1 aBenet, I.1 aCalvete, J., J.1 aDopazo, J.1 aGarcia-Conde, J. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1912748200513nas a2200109 4500008004100000245010300041210007300144300001000217490000700227100001500234856015400249 2009 eng d00aBioinformática, Genómica y Evolución. Una alianza estratégica para la biología de este siglo.0 aBioinformática Genómica y Evolución Una alianza estratégica para a88-930 v191 aDopazo, H. uhttp://clinbioinfosspa.es/content/bioinform%C3%A1tica-gen%C3%B3mica-y-evoluci%C3%B3n-una-alianza-estrat%C3%A9gica-para-la-biolog%C3%ADa-de-este-siglo02292nam a2200145 4500008004100000022002200041245007500063210007300138260003500211300000800246520173700254100001501991700001602006856012402022 2009 eng d a978-84-92910-06-900aEvolución y Adaptación.150 años después del Origen de las Especies0 aEvolución y Adaptación150 años después del Origen de las Especie aValencia. EspañabObrapropia. a5103 a

Evolución y Adaptación: 150 años después del Origen de las Especies es un homenaje a la figura de Charles Darwin al cumplirse 200 años de su nacimiento y 150 años de la publicación que lo hiciese mundialmente famoso. En esta edición 101 autores convocados por la Sociedad Española de Biología Evolutiva han resumido su trabajo de investigación en 51 artículos. Estos se han agrupado en temáticas que abarcan los problemas de la evolución molecular, el cambio morfológico, la evolución del desarrollo, el origen de las especies y su interacción, la diversidad biológica, la evolución del comportamiento, la paleobiología, la evolución experimental, la evolución cultural y la evolución en la filosofía y la docencia. Muchos de estos trabajos representan décadas de constante investigación en el laboratorio y en el campo. El común denominador de los artículos que contiene este libro es el esfuerzo por transmitir a un público no necesariamente experto la actualidad de las investigaciones que en el campo de la adaptación y la evolución se desarrolla en diferentes laboratorios. Esta obra resume por lo tanto, gran parte de las investigaciones que  en materia de evolución biológica se realiza en España. Esta edición deja constancia entonces del "Hecho de la Evolución", y de la actualidad de teoría evolutiva moderna como cuerpo explicativo del mundo biológico 150 años después del origen de las especies. 

1 aDopazo, H.1 aNavarro, A. uhttp://clinbioinfosspa.es/content/evoluci%C3%B3n-y-adaptaci%C3%B3n150-a%C3%B1os-despu%C3%A9s-del-origen-de-las-especies03290nas a2200205 4500008004100000245014400041210006900185300001100254490000800265520221900273653002002492653002302512653017902535653018702714100001802901700002402919700001502943700002002958856010602978 2009 eng d00aExploring the antimicrobial action of a carbon monoxide-releasing compound through whole-genome transcription profiling of Escherichia coli0 aExploring the antimicrobial action of a carbon monoxidereleasing a813-240 v1553 a

We recently reported that carbon monoxide (CO) has bactericidal activity. To understand its mode of action we analysed the gene expression changes occurring when Escherichia coli, grown aerobically and anaerobically, is treated with the CO-releasing molecule CORM-2 (tricarbonyldichlororuthenium(II) dimer). Microarray analysis shows that the E. coli CORM-2 response is multifaceted, with a high number of differentially regulated genes spread through several functional categories, namely genes involved in inorganic ion transport and metabolism, regulators, and genes implicated in post-translational modification, such as chaperones. CORM-2 has a higher impact in E. coli cells grown anaerobically, as judged by the repression of genes belonging to eight functional classes which are not seen in the response of aerobically CORM-2-treated cells. The biological relevance of the variations caused by CORM-2 was substantiated by studying the CORM-2 sensitivity of selected E. coli mutants. The results show that the deletion of redox-sensing regulators SoxS and OxyR increased the sensitivity to CORM-2 and suggest that while SoxS plays an important role in protection against CORM-2 under both growth conditions, OxyR seems to participate only in the aerobic CORM-2 response. Under anaerobic conditions, we found that the heat-shock proteins IbpA and IbpB contribute to CORM-2 defence since the deletion of these genes increases the sensitivity of the strain. The induction of several met genes and the hypersensitivity to CORM-2 of the DeltametR, DeltametI and DeltametN mutant strains suggest that CO has effects on the methionine metabolism of E. coli. CORM-2 also affects the transcription of several E. coli biofilm-related genes and increases biofilm formation in E. coli. In particular, the absence of tqsA or bhsA increases the resistance of E. coli to CORM-2, and deletion of tsqA leads to a strain that has lost its capacity to form biofilm upon treatment with CORM-2. In spite of the relatively stable nature of the CO molecule, our results show that CO is able to trigger a significant alteration in the transcriptome of E. coli which necessarily has effects in several key metabolic pathways.

10aBacterial Genes10aBacterial/genetics10aBiofilms Carbon Monoxide/*metabolism Escherichia coli/*genetics/metabolism Escherichia coli Proteins/genetics/metabolism *Gene Expression Profiling Gene Expression Regulation10aRegulator Genetic Complementation Test Methionine/metabolism Microbial Viability Mutation Oligonucleotide Array Sequence Analysis Organometallic Compounds/*pharmacology Phenotype RNA1 aNobre, L., S.1 aAl-Shahrour, Fatima1 aDopazo, J.1 aSaraiva, L., M. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1924675203500nas a2200373 4500008004100000022001400041245014500055210006900200260001300269300001200282490000800294520221900302653001302521653002002534653002102554653003002575653003002605653004202635653002102677653002102698653003302719653001502752653002402767653001302791653004402804653002902848653001402877653001902891100002102910700002502931700002002956700002302976856012702999 2009 eng d a1350-087200aExploring the antimicrobial action of a carbon monoxide-releasing compound through whole-genome transcription profiling of Escherichia coli.0 aExploring the antimicrobial action of a carbon monoxidereleasing c2009 Mar a813-8240 v1553 a

We recently reported that carbon monoxide (CO) has bactericidal activity. To understand its mode of action we analysed the gene expression changes occurring when Escherichia coli, grown aerobically and anaerobically, is treated with the CO-releasing molecule CORM-2 (tricarbonyldichlororuthenium(II) dimer). Microarray analysis shows that the E. coli CORM-2 response is multifaceted, with a high number of differentially regulated genes spread through several functional categories, namely genes involved in inorganic ion transport and metabolism, regulators, and genes implicated in post-translational modification, such as chaperones. CORM-2 has a higher impact in E. coli cells grown anaerobically, as judged by the repression of genes belonging to eight functional classes which are not seen in the response of aerobically CORM-2-treated cells. The biological relevance of the variations caused by CORM-2 was substantiated by studying the CORM-2 sensitivity of selected E. coli mutants. The results show that the deletion of redox-sensing regulators SoxS and OxyR increased the sensitivity to CORM-2 and suggest that while SoxS plays an important role in protection against CORM-2 under both growth conditions, OxyR seems to participate only in the aerobic CORM-2 response. Under anaerobic conditions, we found that the heat-shock proteins IbpA and IbpB contribute to CORM-2 defence since the deletion of these genes increases the sensitivity of the strain. The induction of several met genes and the hypersensitivity to CORM-2 of the DeltametR, DeltametI and DeltametN mutant strains suggest that CO has effects on the methionine metabolism of E. coli. CORM-2 also affects the transcription of several E. coli biofilm-related genes and increases biofilm formation in E. coli. In particular, the absence of tqsA or bhsA increases the resistance of E. coli to CORM-2, and deletion of tsqA leads to a strain that has lost its capacity to form biofilm upon treatment with CORM-2. In spite of the relatively stable nature of the CO molecule, our results show that CO is able to trigger a significant alteration in the transcriptome of E. coli which necessarily has effects in several key metabolic pathways.

10aBiofilms10aCarbon Monoxide10aEscherichia coli10aEscherichia coli Proteins10aGene Expression Profiling10aGene Expression Regulation, Bacterial10aGenes, Bacterial10aGenes, Regulator10aGenetic Complementation Test10aMethionine10aMicrobial Viability10amutation10aOligonucleotide Array Sequence Analysis10aOrganometallic Compounds10aPhenotype10aRNA, Bacterial1 aNobre, Lígia, S1 aAl-Shahrour, Fátima1 aDopazo, Joaquin1 aSaraiva, Lígia, M uhttp://clinbioinfosspa.es/content/exploring-antimicrobial-action-carbon-monoxide-releasing-compound-through-whole-genome-001768nas a2200205 4500008004100000022001400041245006300055210006200118260001700180300001100197490000700208520113100215653002501346653002601371653001301397653001301410653002401423100002001447856009501467 2009 eng d a1873-286000aFormulating and testing hypotheses in functional genomics.0 aFormulating and testing hypotheses in functional genomics c2009 Feb-Mar a97-1070 v453 a

OBJECTIVE: The ultimate goal of any genome-scale experiment is to provide a functional interpretation of the results, relating the available genomic information to the hypotheses that originated the experiment.

METHODS AND RESULTS: Initially, this interpretation has been made on a pre-selection of relevant genes, based on the experimental values, followed by the study of the enrichment in some functional properties. Nevertheless, functional enrichment methods, demonstrated to have a flaw: the first step of gene selection was too stringent given that the cooperation among genes was ignored. The assumption that modules of genes related by relevant biological properties (functionality, co-regulation, chromosomal location, etc.) are the real actors of the cell biology lead to the development of new procedures, inspired in systems biology criteria, generically known as gene-set methods. These methods have been successfully used to analyze transcriptomic and large-scale genotyping experiments as well as to test other different genome-scale hypothesis in other fields such as phylogenomics.

10aBiological Evolution10aComputational Biology10aGenomics10aGenotype10aModels, Theoretical1 aDopazo, Joaquin uhttp://clinbioinfosspa.es/content/formulating-and-testing-hypotheses-functional-genomics-001598nas a2200145 4500008004100000245006200041210006200103300001100165490000700176520111100183653001501294653002201309100001501331856010601346 2009 eng d00aFormulating and testing hypotheses in functional genomics0 aFormulating and testing hypotheses in functional genomics a97-1070 v453 a

OBJECTIVE: The ultimate goal of any genome-scale experiment is to provide a functional interpretation of the results, relating the available genomic information to the hypotheses that originated the experiment. METHODS AND RESULTS: Initially, this interpretation has been made on a pre-selection of relevant genes, based on the experimental values, followed by the study of the enrichment in some functional properties. Nevertheless, functional enrichment methods, demonstrated to have a flaw: the first step of gene selection was too stringent given that the cooperation among genes was ignored. The assumption that modules of genes related by relevant biological properties (functionality, co-regulation, chromosomal location, etc.) are the real actors of the cell biology lead to the development of new procedures, inspired in systems biology criteria, generically known as gene-set methods. These methods have been successfully used to analyze transcriptomic and large-scale genotyping experiments as well as to test other different genome-scale hypothesis in other fields such as phylogenomics.

10ababelomics10agene set analysis1 aDopazo, J. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1878965902713nas a2200265 4500008004100000022001400041245005800055210005700113260001600170300000700186490001500193520188200208653002402090653003002114653004402144653001702188100002402205700002502229700002002254700002902274700002002303700002002323700001602343856008802359 2009 eng d a1471-210500aFunctional assessment of time course microarray data.0 aFunctional assessment of time course microarray data c2009 Jun 16 aS90 v10 Suppl 63 a

MOTIVATION: Time-course microarray experiments study the progress of gene expression along time across one or several experimental conditions. Most developed analysis methods focus on the clustering or the differential expression analysis of genes and do not integrate functional information. The assessment of the functional aspects of time-course transcriptomics data requires the use of approaches that exploit the activation dynamics of the functional categories to where genes are annotated.

METHODS: We present three novel methodologies for the functional assessment of time-course microarray data. i) maSigFun derives from the maSigPro method, a regression-based strategy to model time-dependent expression patterns and identify genes with differences across series. maSigFun fits a regression model for groups of genes labeled by a functional class and selects those categories which have a significant model. ii) PCA-maSigFun fits a PCA model of each functional class-defined expression matrix to extract orthogonal patterns of expression change, which are then assessed for their fit to a time-dependent regression model. iii) ASCA-functional uses the ASCA model to rank genes according to their correlation to principal time expression patterns and assess functional enrichment on a GSA fashion. We used simulated and experimental datasets to study these novel approaches. Results were compared to alternative methodologies.

RESULTS: Synthetic and experimental data showed that the different methods are able to capture different aspects of the relationship between genes, functions and co-expression that are biologically meaningful. The methods should not be considered as competitive but they provide different insights into the molecular and functional dynamic events taking place within the biological system under study.

10aComputer Simulation10aGene Expression Profiling10aOligonucleotide Array Sequence Analysis10aTime Factors1 aNueda, Maria, José1 aSebastián, Patricia1 aTarazona, Sonia1 aGarcia-Garcia, Francisco1 aDopazo, Joaquin1 aFerrer, Alberto1 aConesa, Ana uhttp://clinbioinfosspa.es/content/functional-assessment-time-course-microarray-data02417nas a2200469 4500008004100000022001400041245007800055210006900133260001300202300001300215490000700228520094000235653001001175653002101185653003001206653004101236653002601277653001101303653002101314653002201335653004401357653001901401653001801420653002701438100002001465700003001485700002701515700002501542700002101567700002401588700002801612700002601640700002701666700002401693700002201717700002101739700001501760700002001775700002301795700002101818856010801839 2009 eng d a1029-240300aFunctional signatures identified in B-cell non-Hodgkin lymphoma profiles.0 aFunctional signatures identified in Bcell nonHodgkin lymphoma pr c2009 Oct a1699-7080 v503 a

Gene-expression profiling in B-cell lymphomas has provided crucial data on specific lymphoma types, which can contribute to the identification of essential lymphoma survival genes and pathways. In this study, the gene-expression profiling data of all major B-cell lymphoma types were analyzed by unsupervised clustering. The transcriptome classification so obtained, was explored using gene set enrichment analysis generating a heatmap for B-cell lymphoma that identifies common lymphoma survival mechanisms and potential therapeutic targets, recognizing sets of coregulated genes and functional pathways expressed in different lymphoma types. Some of the most relevant signatures (stroma, cell cycle, B-cell receptor (BCR)) are shared by multiple lymphoma types or subclasses. A specific attention was paid to the analysis of BCR and coregulated pathways, defining molecular heterogeneity within multiple B-cell lymphoma types.

10aAdult10aCluster Analysis10aGene Expression Profiling10aGene Expression Regulation, Leukemic10aGenetic Heterogeneity10aHumans10aLymphoma, B-Cell10aNeoplasm Proteins10aOligonucleotide Array Sequence Analysis10aRNA, Messenger10aRNA, Neoplasm10aTranscription, Genetic1 aAggarwal, Mohit1 aSánchez-Beato, Margarita1 aGómez-López, Gonzalo1 aAl-Shahrour, Fátima1 aMartínez, Nerea1 aRodríguez, Antonia1 aRuiz-Ballesteros, Elena1 aCamacho, Francisca, I1 aPérez-Rosado, Alberto1 ade la Cueva, Paloma1 aArtiga, María, J1 aPisano, David, G1 aKimby, Eva1 aDopazo, Joaquin1 aVilluendas, Raquel1 aPiris, Miguel, A uhttp://clinbioinfosspa.es/content/functional-signatures-identified-b-cell-non-hodgkin-lymphoma-profiles03382nas a2200325 4500008004100000022001400041245007200055210006900127260001600196300000800212490000700220520234600227653001502573653002102588653004402609653002602653653002802679653001102707653003002718653001302748653001102761653004402772653003002816653003102846100002002877700001902897700002502916700002002941856009502961 2009 eng d a1471-216400aGene set internal coherence in the context of functional profiling.0 aGene set internal coherence in the context of functional profili c2009 Apr 27 a1970 v103 a

BACKGROUND: Functional profiling methods have been extensively used in the context of high-throughput experiments and, in particular, in microarray data analysis. Such methods use available biological information to define different types of functional gene modules (e.g. gene ontology -GO-, KEGG pathways, etc.) whose representation in a pre-defined list of genes is further studied. In the most popular type of microarray experimental designs (e.g. up- or down-regulated genes, clusters of co-expressing genes, etc.) or in other genomic experiments (e.g. Chip-on-chip, epigenomics, etc.) these lists are composed by genes with a high degree of co-expression. Therefore, an implicit assumption in the application of functional profiling methods within this context is that the genes corresponding to the modules tested are effectively defining sets of co-expressing genes. Nevertheless not all the functional modules are biologically coherent entities in terms of co-expression, which will eventually hinder its detection with conventional methods of functional enrichment.

RESULTS: Using a large collection of microarray data we have carried out a detailed survey of internal correlation in GO terms and KEGG pathways, providing a coherence index to be used for measuring functional module co-regulation. An unexpected low level of internal correlation was found among the modules studied. Only around 30% of the modules defined by GO terms and 57% of the modules defined by KEGG pathways display an internal correlation higher than the expected by chance.This information on the internal correlation of the genes within the functional modules can be used in the context of a logistic regression model in a simple way to improve their detection in gene expression experiments.

CONCLUSION: For the first time, an exhaustive study on the internal co-expression of the most popular functional categories has been carried out. Interestingly, the real level of coexpression within many of them is lower than expected (or even inexistent), which will preclude its detection by means of most conventional functional profiling methods. If the gene-to-function correlation information is used in functional profiling methods, the results obtained improve the ones obtained by conventional enrichment methods.

10aAlgorithms10aBreast Neoplasms10aCarcinoma, Intraductal, Noninfiltrating10aComputational Biology10aDatabases, Nucleic Acid10aFemale10aGene Expression Profiling10aGenomics10aHumans10aOligonucleotide Array Sequence Analysis10aPapillomavirus Infections10aReproducibility of Results1 aMontaner, David1 aMinguez, Pablo1 aAl-Shahrour, Fátima1 aDopazo, Joaquin uhttp://clinbioinfosspa.es/content/gene-set-internal-coherence-context-functional-profiling01715nas a2200265 4500008004100000245014300041210006900184300001300253490000700266520085600273653001501129653001301144653001101157653002701168653000801195100002001203700002001223700002101243700002601264700002101290700002301311700002401334700002001358856007101378 2009 eng d00aGene set-based analysis of polymorphisms: finding pathways or biological processes associated to traits in genome-wide association studies0 aGene setbased analysis of polymorphisms finding pathways or biol aW340-3440 v373 a

Genome-wide association studies have become a popular strategy to find associations of genes to traits of interest. Despite the high-resolution available today to carry out genotyping studies, the success of its application in real studies has been limited by the testing strategy used. As an alternative to brute force solutions involving the use of very large cohorts, we propose the use of the Gene Set Analysis (GSA), a different analysis strategy based on testing the association of modules of functionally related genes. We show here how the Gene Set-based Analysis of Polymorphisms (GeSBAP), which is a simple implementation of the GSA strategy for the analysis of genome-wide association studies, provides a significant increase in the power testing for this type of studies. GeSBAP is freely available at http://bioinfo.cipf.es/gesbap/

10ababelomics10agene set10aGESBAP10apathway-based analysis10aSNP1 aMedina, Ignacio1 aMontaner, David1 aBonifaci, Núria1 aPujana, Miguel, Angel1 aCarbonell, José1 aTárraga, Joaquín1 aAl-Shahrour, Fatima1 aDopazo, Joaquin uhttp://nar.oxfordjournals.org/cgi/content/abstract/37/suppl_2/W34002023nas a2200349 4500008004100000022001400041245014400055210006900199260001300268300001100281490000700292520085700299653002501156653002101181653001101202653001001213653002201223653003401245653001101279653003601290653001301326653002801339100002001367700002001387700002101407700002601428700002101454700002301475700002501498700002001523856013001543 2009 eng d a1362-496200aGene set-based analysis of polymorphisms: finding pathways or biological processes associated to traits in genome-wide association studies.0 aGene setbased analysis of polymorphisms finding pathways or biol c2009 Jul aW340-40 v373 a

Genome-wide association studies have become a popular strategy to find associations of genes to traits of interest. Despite the high-resolution available today to carry out genotyping studies, the success of its application in real studies has been limited by the testing strategy used. As an alternative to brute force solutions involving the use of very large cohorts, we propose the use of the Gene Set Analysis (GSA), a different analysis strategy based on testing the association of modules of functionally related genes. We show here how the Gene Set-based Analysis of Polymorphisms (GeSBAP), which is a simple implementation of the GSA strategy for the analysis of genome-wide association studies, provides a significant increase in the power testing for this type of studies. GeSBAP is freely available at http://bioinfo.cipf.es/gesbap/.

10aBiological Phenomena10aBreast Neoplasms10aFemale10aGenes10aGenetic Variation10aGenome-Wide Association Study10aHumans10aPolymorphism, Single Nucleotide10aSoftware10aUser-Computer Interface1 aMedina, Ignacio1 aMontaner, David1 aBonifaci, Núria1 aPujana, Miguel, Angel1 aCarbonell, José1 aTárraga, Joaquín1 aAl-Shahrour, Fátima1 aDopazo, Joaquin uhttp://clinbioinfosspa.es/content/gene-set-based-analysis-polymorphisms-finding-pathways-or-biological-processes-associated-001745nas a2200181 4500008004100000022002200041245009600063210007100159260002600230300001000256520107600266100002101342700001501363700001501378700001501393700001601408856013901424 2009 eng d a978-84-92910-06-900aGenómica Comparativa y Selección Natural. Aplicaciones en el Genoma Humano. Capítulo 1.60 aGenómica Comparativa y Selección Natural Aplicaciones en el Geno aValenciabObrapropia. a51-593 a

La búsqueda de los eventos adaptativos a nivel molecular que ha diferenciado el genoma humano del de nuestro pariente vivo más cercano, el chimpancé, ha sido una de las áreas de mayor investigación en genómica comparativa. Paralelamente, la predicción funcional de variantes genéticas en nuestra especie ha sido un área de intenso desarrollo en bioinformática. En este trabajo discutiremos resultados previos y otros más recientes que dan cuenta de estos desarrollos. Veremos que en todos los casos la estimación de las presiones selectivas a nivel de los genes individuales o de los residuos de las proteínas son el denominador común para discutir ambos aspectos. Finalmente mostraremos cómo el análisis de estas presiones selectivas por grupos funcionales de genes resulta una alternativa viable y con suficiente poder estadístico para el análisis de la adaptación y de las restricciones evolutivas a nivel genómico. 

1 aSerra, François1 aArbiza, L.1 aDopazo, H.1 aDopazo, H.1 aNavarro, A. uhttp://clinbioinfosspa.es/content/gen%C3%B3mica-comparativa-y-selecci%C3%B3n-natural-aplicaciones-en-el-genoma-humano-cap%C3%ADtulo-1602548nas a2200241 4500008004100000245006500041210006300106300000900169490000600178520182800184100001302012700002002025700001502045700001402060700001902074700001602093700001502109700001702124700002202141700001302163700002402176856010602200 2009 eng d00aA kernel for open source drug discovery in tropical diseases0 akernel for open source drug discovery in tropical diseases ae4180 v33 aBACKGROUND: Conventional patent-based drug development incentives work badly for the developing world, where commercial markets are usually small to non-existent. For this reason, the past decade has seen extensive experimentation with alternative R&D institutions ranging from private-public partnerships to development prizes. Despite extensive discussion, however, one of the most promising avenues-open source drug discovery-has remained elusive. We argue that the stumbling block has been the absence of a critical mass of preexisting work that volunteers can improve through a series of granular contributions. Historically, open source software collaborations have almost never succeeded without such "kernels". METHODOLOGY/PRINCIPAL FINDINGS: HERE, WE USE A COMPUTATIONAL PIPELINE FOR: (i) comparative structure modeling of target proteins, (ii) predicting the localization of ligand binding sites on their surfaces, and (iii) assessing the similarity of the predicted ligands to known drugs. Our kernel currently contains 143 and 297 protein targets from ten pathogen genomes that are predicted to bind a known drug or a molecule similar to a known drug, respectively. The kernel provides a source of potential drug targets and drug candidates around which an online open source community can nucleate. Using NMR spectroscopy, we have experimentally tested our predictions for two of these targets, confirming one and invalidating the other. CONCLUSIONS/SIGNIFICANCE: The TDI kernel, which is being offered under the Creative Commons attribution share-alike license for free and unrestricted use, can be accessed on the World Wide Web at http://www.tropicaldisease.org. We hope that the kernel will facilitate collaborative efforts towards the discovery of new drugs against parasites that cause tropical diseases.1 aOrti, L.1 aCarbajo, R., J.1 aPieper, U.1 aEswar, N.1 aMaurer, S., M.1 aRai, A., K.1 aTaylor, G.1 aTodd, M., H.1 aPineda-Lucena, A.1 aSali, A.1 aMarti-Renom, M., A. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1938128600678nas a2200229 4500008004100000245004900041210004700090300001000137490000700147100001300154700002000167700001500187700001400202700001900216700001600235700001500251700001700266700002200283700001300305700002400318856010600342 2009 eng d00aA kernel for the Tropical Disease Initiative0 akernel for the Tropical Disease Initiative a320-10 v271 aOrti, L.1 aCarbajo, R., J.1 aPieper, U.1 aEswar, N.1 aMaurer, S., M.1 aRai, A., K.1 aTaylor, G.1 aTodd, M., H.1 aPineda-Lucena, A.1 aSali, A.1 aMarti-Renom, M., A. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1935236202262nas a2200193 4500008004100000245016300041210006900204520151300273100001501786700002901801700001501830700001801845700001601863700002101879700002601900700002201926700001401948856010601962 2009 eng d00aMembrane transporters and carbon metabolism implicated in chloride homeostasis differentiate salt stress responses in tolerant and sensitive Citrus rootstocks0 aMembrane transporters and carbon metabolism implicated in chlori3 a

Salinity tolerance in Citrus is strongly related to leaf chloride accumulation. Both chloride homeostasis and specific genetic responses to Cl(-) toxicity are issues scarcely investigated in plants. To discriminate the transcriptomic network related to Cl(-) toxicity and salinity tolerance, we have used two Cl(-) salt treatments (NaCl and KCl) to perform a comparative microarray approach on two Citrus genotypes, the salt-sensitive Carrizo citrange, a poor Cl(-) excluder, and the tolerant Cleopatra mandarin, an efficient Cl(-) excluder. The data indicated that Cl(-) toxicity, rather than Na(+) toxicity and/or the concomitant osmotic perturbation, is the primary factor involved in the molecular responses of citrus plant leaves to salinity. A number of uncharacterized membrane transporter genes, like NRT1-2, were differentially regulated in the tolerant and the sensitive genotypes, suggesting its potential implication in Cl(-) homeostasis. Analyses of enriched functional categories showed that the tolerant rootstock induced wider stress responses in gene expression while repressing central metabolic processes such as photosynthesis and carbon utilization. These features were in agreement with phenotypic changes in the patterns of photosynthesis, transpiration, and stomatal conductance and support the concept that regulation of transpiration and its associated metabolic adjustments configure an adaptive response to salinity that reduces Cl(-) accumulation in the tolerant genotype.

1 aBrumos, J.1 aColmenero-Flores, J., M.1 aConesa, A.1 aIzquierdo, P.1 aSanchez, G.1 aIglesias, D., J.1 aLopez-Climent, M., F.1 aGomez-Cadenas, A.1 aTalon, M. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1919094402308nas a2200325 4500008004100000245009900041210006900140300001200209490000700221520117300228653001501401653003601416653004401452653003601496653009601532653005201628100001501680700001401695700001701709700001601726700001401742700001901756700001501775700001501790700001601805700002401821700001801845700001301863856010601876 2009 eng d00aMODBASE, a database of annotated comparative protein structure models and associated resources0 aMODBASE a database of annotated comparative protein structure mo aD347-540 v373 aMODBASE (http://salilab.org/modbase) is a database of annotated comparative protein structure models. The models are calculated by MODPIPE, an automated modeling pipeline that relies primarily on MODELLER for fold assignment, sequence-structure alignment, model building and model assessment (http:/salilab.org/modeller). MODBASE currently contains 5,152,695 reliable models for domains in 1,593,209 unique protein sequences; only models based on statistically significant alignments and/or models assessed to have the correct fold are included. MODBASE also allows users to calculate comparative models on demand, through an interface to the MODWEB modeling server (http://salilab.org/modweb). Other resources integrated with MODBASE include databases of multiple protein structure alignments (DBAli), structurally defined ligand binding sites (LIGBASE), predicted ligand binding sites (AnnoLyze), structurally defined binary domain interfaces (PIBASE) and annotated single nucleotide polymorphisms and somatic mutations found in human proteins (LS-SNP, LS-Mut). MODBASE models are also available through the Protein Model Portal (http://www.proteinmodelportal.org/).10a*Databases10aMolecular Mutation Polymorphism10aProtein Genomics Humans Ligands *Models10aProtein User-Computer Interface10aSingle Nucleotide Protein Folding Protein Interaction Domains and Motifs *Protein Structure10aTertiary Proteins/genetics *Structural Homology1 aPieper, U.1 aEswar, N.1 aWebb, B., M.1 aEramian, D.1 aKelly, L.1 aBarkan, D., T.1 aCarter, H.1 aMankoo, P.1 aKarchin, R.1 aMarti-Renom, M., A.1 aDavis, F., P.1 aSali, A. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1894828200811nas a2200265 4500008004100000022001400041245005600055210005500111300001100166490000700177100002100184700002300205700002100228700002100249700002300270700002300293700001800316700001500334700002000349700002300369700002700392700001600419700002100435856008900456 2009 eng d a1557-810000aModeling and managing experimental data using FuGE.0 aModeling and managing experimental data using FuGE a239-510 v131 aJones, Andrew, R1 aLister, Allyson, L1 aHermida, Leandro1 aWilkinson, Peter1 aEisenacher, Martin1 aBelhajjame, Khalid1 aGibson, Frank1 aLord, Phil1 aPocock, Matthew1 aRosenfelder, Heiko1 aSantoyo-López, Javier1 aWipat, Anil1 aPaton, Norman, W uhttp://clinbioinfosspa.es/content/modeling-and-managing-experimental-data-using-fuge02280nas a2200169 4500008004100000245007900041210006900120520169500189653002001884100001501904700001601919700001801935700002401953700001301977700001401990856010602004 2009 eng d00aModLink+: Improving fold recognition by using protein-protein interactions0 aModLink Improving fold recognition by using proteinprotein inter3 a

MOTIVATION: Several strategies have been developed to predict the fold of a target protein sequence, most of which are based on aligning the target sequence to other sequences of known structure. Previously, we demonstrated that the consideration of protein-protein interactions significantly increases the accuracy of fold assignment compared to PSI-BLAST sequence comparisons. A drawback of our method was the low number of proteins to which a fold could be assigned. Here, we present an improved version of the method that addresses this limitation. We also compare our method to other state-of-the-art fold assignment methodologies. RESULTS: Our approach (ModLink+) has been tested on 3,716 proteins with domain folds classified in the Structural Classification Of Proteins (SCOP) as well as known interacting partners in the Database of Interacting Proteins (DIP). For this test set, the ratio of success (PPV) on fold assignment increases from 75% for PSI-BLAST, 83% for HHSearch and 81% for PRC to more than 90% for ModLink+ at the e-value cutoff of 10(-3). Under this e-value, ModLink+ can assign a fold to 30-45% of the proteins in the test set, while our previous method could cover less than 25%. When applied to 6,384 proteins with unknown fold in the yeast proteome, ModLink+ combined with PSI-BLAST assigns a fold for domains in 3,738 proteins, while PSI-BLAST alone only covers 2,122 proteins, HHSearch 2,969 and PRC 2,826 proteins, using a threshold e-value that would represent a PPV higher than 82% for each method in the test set. AVAILABILITY: The ModLink+ server is freely accessible in the World Wide Web at http://sbi.imim.es/modlink/. CONTACT: boliva@imim.es.

10aprotein folding1 aFornes, O.1 aAragues, R.1 aEspadaler, J.1 aMarti-Renom, M., A.1 aSali, A.1 aOliva, B. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1935710000704nas a2200181 4500008004100000022001400041245013200055210006900187300000800256490000600264100002600270700001600296700001800312700002000330700002200350700001900372856013100391 2009 eng d a1756-050000aParallel changes in gene expression in peripheral blood mononuclear cells and the brain after maternal separation in the mouse.0 aParallel changes in gene expression in peripheral blood mononucl a1950 v21 avan Heerden, Johan, H1 aConesa, Ana1 aStein, Dan, J1 aMontaner, David1 aRussell, Vivienne1 aIlling, Nicola uhttp://clinbioinfosspa.es/content/parallel-changes-gene-expression-peripheral-blood-mononuclear-cells-and-brain-after-maternal00653nas a2200241 4500008004100000245004000041210003900081300001200120490000600132100001400138700001600152700001400168700001600182700001500198700001800213700001500231700002100246700002200267700001500289700002200304700001500326856007000341 2009 eng d00aPere Alberch: Originator of EvoDevo0 aPere Alberch Originator of EvoDevo a351-3530 v31 aReiss, JO1 aBurke, A, C1 aArcher, C1 aDe Renzi, M1 aDopazo, H.1 aEtxeberria, A1 aGale, E, A1 aHinchliffe, J, R1 ade la Rosa, Nuño1 aRose, C, S1 aRasskin-Gutman, D1 aMüller, G uhttp://clinbioinfosspa.es/content/pere-alberch-originator-evodevo00907nas a2200265 4500008004100000245010100041210006900142260000700211100002100218700002100239700002000260700002200280700001800302700002200320700002200342700002000364700002000384700001400404700001900418700001900437700001800456700002400474700001800498856012500516 2009 eng d00aPeripheral blood cells transcriptome to study new biomarkers for myocardial infarction follow up0 aPeripheral blood cells transcriptome to study new biomarkers for c061 aSilbiger, Vivian1 aLuchessi, André1 aHirata, Rosario1 aCarracedo, Ángel1 aBrión, Maria1 aNeto, Lidio, Lima1 aPastorelli, C, P.1 aDopazo, Joaquin1 aMontaner, David1 aGarcia, F1 aSampaio, M, P.1 aPereira, M, P.1 aSantos, E, S.1 aArmaganijan, Dikran1 aHirata, Mario uhttp://clinbioinfosspa.es/content/peripheral-blood-cells-transcriptome-study-new-biomarkers-myocardial-infarction-follow00491nas a2200157 4500008004100000022002900041245004900070210004900119260003900168300001200207100001600219700001500235700001600250700001800266856004900284 2009 eng d a1605663980, 97816056639800aProtein Interactions for Functional Genomics0 aProtein Interactions for Functional Genomics aHershey, USAbIdea Group Inc (IGI) a223-2381 aMinguez, P.1 aDopazo, J.1 aLi, Xiao-Li1 aNg, See-Kiong uhttp://books.google.es/books?id=pNyCy5GsqtkC01599nas a2200145 4500008004100000245006100041210006000102300001100162520114400173653000801317653001801325100002201343700002401365856006401389 2009 eng d00aSARA: a server for function annotation of RNA structures0 aSARA a server for function annotation of RNA structures agkp4333 a

Recent interest in non-coding RNA transcripts has resulted in a rapid increase of deposited RNA structures in the Protein Data Bank. However, a characterization and functional classification of the RNA structure and function space have only been partially addressed. Here, we introduce the SARA program for pair-wise alignment of RNA structures as a web server for structure-based RNA function assignment. The SARA server relies on the SARA program, which aligns two RNA structures based on a unit-vector root-mean-square approach. The likely accuracy of the SARA alignments is assessed by three different P-values estimating the statistical significance of the sequence, secondary structure and tertiary structure identity scores, respectively. Our benchmarks, which relied on a set of 419 RNA structures with known SCOR structural class, indicate that at a negative logarithm of mean P-value higher or equal than 2.5, SARA can assign the correct or a similar SCOR class to 81.4% and 95.3% of the benchmark set, respectively. The SARA server is freely accessible via the World Wide Web at http://sgu.bioinfo.cipf.es/services/SARA/.

10aRNA10aRNA structure1 aCapriotti, Emidio1 aMarti-Renom, M., A. uhttp://nar.oxfordjournals.org/cgi/content/abstract/gkp433v102586nas a2200193 4500008004100000245013300041210006900174520188100243653001502124653002302139653002202162100002202184700001502206700001502221700001402236700001902250700001702269856010602286 2009 eng d00aSexual selection drives weak positive selection in protamine genes and high promoter divergence, enhancing sperm competitiveness0 aSexual selection drives weak positive selection in protamine gen3 a

Phenotypic adaptations may be the result of changes in gene structure or gene regulation, but little is known about the evolution of gene expression. In addition, it is unclear whether the same selective forces may operate at both levels simultaneously. Reproductive proteins evolve rapidly, but the underlying selective forces promoting such rapid changes are still a matter of debate. In particular, the role of sexual selection in driving positive selection among reproductive proteins remains controversial, whereas its potential influence on changes in promoter regions has not been explored. Protamines are responsible for maintaining DNA in a compacted form in chromosomes in sperm and the available evidence suggests that they evolve rapidly. Because protamines condense DNA within the sperm nucleus, they influence sperm head shape. Here, we examine the influence of sperm competition upon protamine 1 and protamine 2 genes and their promoters, by comparing closely related species of Mus that differ in relative testes size, a reliable indicator of levels of sperm competition. We find evidence of positive selection in the protamine 2 gene in the species with the highest inferred levels of sperm competition. In addition, sperm competition levels across all species are strongly associated with high divergence in protamine 2 promoters that, in turn, are associated with sperm swimming speed. We suggest that changes in protamine 2 promoters are likely to enhance sperm swimming speed by making sperm heads more hydrodynamic. Such phenotypic changes are adaptive because sperm swimming speed may be a major determinant of fertilization success under sperm competition. Thus, when species have diverged recently, few changes in gene-coding sequences are found, while high divergence in promoters seems to be associated with the intensity of sexual selection.

10aAdaptation10apositive selection10asperm competition1 aMartin-Coello, J.1 aDopazo, H.1 aArbiza, L.1 aAusio, J.1 aRoldan, E., R.1 aGomendio, M. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1936473501732nas a2200277 4500008004100000022001400041245009700055210006900152260001300221300001200234490000700246520083000253653002201083653003701105653002301142653001101165653001301176653003201189653001301221100001901234700001801253700002001271700002501291700002001316856011801336 2009 eng d a1362-496200aSNOW, a web-based tool for the statistical analysis of protein-protein interaction networks.0 aSNOW a webbased tool for the statistical analysis of proteinprot c2009 Jul aW109-140 v373 a

Understanding the structure and the dynamics of the complex intercellular network of interactions that contributes to the structure and function of a living cell is one of the main challenges of today's biology. SNOW inputs a collection of protein (or gene) identifiers and, by using the interactome as scaffold, draws the connections among them, calculates several relevant network parameters and, as a novelty among the rest of tools of its class, it estimates their statistical significance. The parameters calculated for each node are: connectivity, betweenness and clustering coefficient. It also calculates the number of components, number of bicomponents and articulation points. An interactive network viewer is also available to explore the resulting network. SNOW is available at http://snow.bioinfo.cipf.es.

10aComputer Graphics10aData Interpretation, Statistical10aDatabases, Protein10aHumans10aInternet10aProtein Interaction Mapping10aSoftware1 aMinguez, Pablo1 aGötz, Stefan1 aMontaner, David1 aAl-Shahrour, Fátima1 aDopazo, Joaquin uhttp://clinbioinfosspa.es/content/snow-web-based-tool-statistical-analysis-protein-protein-interaction-networks-001472nas a2200205 4500008004100000245009600041210006900137300001300206490000700219520083200226653001601058653001201074653000901086100001901095700001301114700002001127700002401147700002001171856007501191 2009 eng d00aSNOW, a web-based tool for the statistical analysis of protein-protein interaction networks0 aSNOW a webbased tool for the statistical analysis of proteinprot aW109-1140 v373 a

Understanding the structure and the dynamics of the complex intercellular network of interactions that contributes to the structure and function of a living cell is one of the main challenges of today’s biology. SNOW inputs a collection of protein (or gene) identifiers and, by using the interactome as scaffold, draws the connections among them, calculates several relevant network parameters and, as a novelty among the rest of tools of its class, it estimates their statistical significance. The parameters calculated for each node are: connectivity, betweenness and clustering coefficient. It also calculates the number of components, number of bicomponents and articulation points. An interactive network viewer is also available to explore the resulting network. SNOW is available at http://snow.bioinfo.cipf.es.

10ainteractome10anetwork10asnow1 aMinguez, Pablo1 aGotz, S.1 aMontaner, David1 aAl-Shahrour, Fatima1 aDopazo, Joaquin uhttp://nar.oxfordjournals.org/content/early/2009/05/19/nar.gkp402.full00979nas a2200325 4500008004100000020001400041245008100055210006900136260004400205300001400249490000600263653001900269653001500288653001000303100002300313700002200336700002200358700001800380700002200398700001700420700002700437700002100464700001700485700002100502700001700523700003100540700001800571700002300589856004100612 2009 eng d a1548-709100aStatistical methods for analysis of high-throughput RNA interference screens0 aStatistical methods for analysis of highthroughput RNA interfere bNature Publishing Groupc2009/08//print a569 - 5750 v610agene silencing10aregulation10asiRNA1 aBirmingham, Amanda1 aSelfors, Laura, M1 aForster, Thorsten1 aWrobel, David1 aKennedy, Caleb, J1 aShanks, Emma1 aSantoyo-López, Javier1 aDunican, Dara, J1 aLong, Aideen1 aKelleher, Dermot1 aSmith, Queta1 aBeijersbergen, Roderick, L1 aGhazal, Peter1 aShamu, Caroline, E uhttp://dx.doi.org/10.1038/nmeth.135100479nas a2200157 4500008004100000245004000041210004000081250000800121260003700129653003000166100002400196700001800220700001900238700001500257856004900272 2009 eng d00aStructural Comparison and Alignment0 aStructural Comparison and Alignment a2nd aNew Jersey. USAbWiley-Blackwell10aStructural Bioinformatics1 aMarti-Renom, M., A.1 aCapriotti, E.1 aShindyalov, I.1 aBourne, P. uhttp://www.amazon.com/gp/product/0470181052/00463nas a2200121 4500008004100000245008700041210006900128260000700197300001000204490000600214100002000220856010100240 2009 eng d00aOn the Use of Functional Module Definitions in the Analysis of Genomic Experiments0 aUse of Functional Module Definitions in the Analysis of Genomic  c09 a47-470 v51 aDopazo, Joaquin uhttp://clinbioinfosspa.es/content/use-functional-module-definitions-analysis-genomic-experiments00387nas a2200109 4500008004100000245004800041210004800089260005700137100001800194700002400212856004100236 2008 eng d00aAssessment of protein structure predictions0 aAssessment of protein structure predictions aNew Jersey, USAbWorld Scientific Publishing Company1 aCapriotti, E.1 aMarti-Renom, M., A. uhttp://www.amazon.com/dp/9812778772/02142nas a2200253 4500008004100000245010200041210006900143300001100212490000700223520138600230653001501616653002401631100002401655700001801679700001601697700001401713700001501727700001601742700002001758700001501778700001701793700001501810856006301825 2008 eng d00aBabelomics: advanced functional profiling of transcriptomics, proteomics and genomics experiments0 aBabelomics advanced functional profiling of transcriptomics prot aW341-60 v363 a

We present a new version of Babelomics, a complete suite of web tools for the functional profiling of genome scale experiments, with new and improved methods as well as more types of functional definitions. Babelomics includes different flavours of conventional functional enrichment methods as well as more advanced gene set analysis methods that makes it a unique tool among the similar resources available. In addition to the well-known functional definitions (GO, KEGG), Babelomics includes new ones such as Biocarta pathways or text mining-derived functional terms. Regulatory modules implemented include transcriptional control (Transfac, CisRed) and other levels of regulation such as miRNA-mediated interference. Moreover, Babelomics allows for sub-selection of terms in order to test more focused hypothesis. Also gene annotation correspondence tables can be imported, which allows testing with user-defined functional modules. Finally, a tool for the ’de novo’ functional annotation of sequences has been included in the system. This allows using yet unannotated organisms in the program. Babelomics has been extensively re-engineered and now it includes the use of web services and Web 2.0 technology features, a new user interface with persistent sessions and a new extended database of gene identifiers. Babelomics is available at http://www.babelomics.org.

10ababelomics10afuntional profiling1 aAl-Shahrour, Fatima1 aCarbonell, J.1 aMinguez, P.1 aGoetz, S.1 aConesa, A.1 aTarraga, J.1 aMedina, Ignacio1 aAlloza, E.1 aMontaner, D.1 aDopazo, J. uhttp://nar.oxfordjournals.org/content/36/suppl_2/W341.long02872nas a2200241 4500008004100000245013000041210006900171300000700240490000600247520211000253653001302363653000902376653000802385100001702393700001802410700001302428700001402441700002002455700001502475700001502490700001902505856010602524 2008 eng d00aBiological processes, properties and molecular wiring diagrams of candidate low-penetrance breast cancer susceptibility genes0 aBiological processes properties and molecular wiring diagrams of a620 v13 a

ABSTRACT: BACKGROUND: Recent advances in whole-genome association studies (WGASs) for human cancer risk are beginning to provide the part lists of low-penetrance susceptibility genes. However, statistical analysis in these studies is complicated by the vast number of genetic variants examined and the weak effects observed, as a result of which constraints must be incorporated into the study design and analytical approach. In this scenario, biological attributes beyond the adjusted statistics generally receive little attention and, more importantly, the fundamental biological characteristics of low-penetrance susceptibility genes have yet to be determined. METHODS: We applied an integrative approach for identifying candidate low-penetrance breast cancer susceptibility genes, their characteristics and molecular networks through the analysis of diverse sources of biological evidence. RESULTS: First, examination of the distribution of Gene Ontology terms in ordered WGAS results identified asymmetrical distribution of Cell Communication and Cell Death processes linked to risk. Second, analysis of 11 different types of molecular or functional relationships in genomic and proteomic data sets defined the "omic" properties of candidate genes: i/ differential expression in tumors relative to normal tissue; ii/ somatic genomic copy number changes correlating with gene expression levels; iii/ differentially expressed across age at diagnosis; and iv/ expression changes after BRCA1 perturbation. Finally, network modeling of the effects of variants on germline gene expression showed higher connectivity than expected by chance between novel candidates and with known susceptibility genes, which supports functional relationships and provides mechanistic hypotheses of risk. CONCLUSION: This study proposes that cell communication and cell death are major biological processes perturbed in risk of breast cancer conferred by low-penetrance variants, and defines the common omic properties, molecular interactions and possible functional effects of candidate genes and proteins.

10agene set10aGWAS10aSNP1 aBonifaci, N.1 aBerenguer, A.1 aDiez, J.1 aReina, O.1 aMedina, Ignacio1 aDopazo, J.1 aMoreno, V.1 aPujana, M., A. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1909423001483nas a2200133 4500008004100000245007800041210006900119300001100188490000900199520100700208100001501215700001301230856010601243 2008 eng d00aBlast2GO: A Comprehensive Suite for Functional Analysis in Plant Genomics0 aBlast2GO A Comprehensive Suite for Functional Analysis in Plant  a6198320 v20083 a

Functional annotation of novel sequence data is a primary requirement for the utilization of functional genomics approaches in plant research. In this paper, we describe the Blast2GO suite as a comprehensive bioinformatics tool for functional annotation of sequences and data mining on the resulting annotations, primarily based on the gene ontology (GO) vocabulary. Blast2GO optimizes function transfer from homologous sequences through an elaborate algorithm that considers similarity, the extension of the homology, the database of choice, the GO hierarchy, and the quality of the original annotations. The tool includes numerous functions for the visualization, management, and statistical analysis of annotation results, including gene set enrichment analysis. The application supports InterPro, enzyme codes, KEGG pathways, GO direct acyclic graphs (DAGs), and GOSlim. Blast2GO is a suitable tool for plant genomics research because of its versatility, easy installation, and friendly use.

1 aConesa, A.1 aGotz, S. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1848357202659nas a2200253 4500008004100000245010800041210006900149300001000218490000700228520165100235653006101886653019201947100001402139700001302153700001302166700001802179700001702197700001502214700002002229700001602249700001502265700001902280856010602299 2008 eng d00aCLEAR-test: combining inference for differential expression and variability in microarray data analysis0 aCLEARtest combining inference for differential expression and va a33-450 v413 a

A common goal of microarray experiments is to detect genes that are differentially expressed under distinct experimental conditions. Several statistical tests have been proposed to determine whether the observed changes in gene expression are significant. The t-test assigns a score to each gene on the basis of changes in its expression relative to its estimated variability, in such a way that genes with a higher score (in absolute values) are more likely to be significant. Most variants of the t-test use the complete set of genes to influence the variance estimate for each single gene. However, no inference is made in terms of the variability itself. Here, we highlight the problem of low observed variances in the t-test, when genes with relatively small changes are declared differentially expressed. Alternatively, the z-test could be used although, unlike the t-test, it can declare differentially expressed genes with high observed variances. To overcome this, we propose to combine the z-test, which focuses on large changes, with a chi(2) test to evaluate variability. We call this procedure CLEAR-test and we provide a combined p-value that offers a compromise between both aspects. Analysis of three publicly available microarray datasets reveals the greater performance of the CLEAR-test relative to the t-test and alternative methods. Finally, empirical and simulated data analyses demonstrate the greater reproducibility and statistical power of the CLEAR-test and z-test with respect to current alternative methods. In addition, the CLEAR-test improves the z-test by capturing reproducible genes with high variability.

10a*Algorithms Artificial Intelligence *Data Interpretation10aStatistical Gene Expression Profiling/*methods Gene Expression Regulation/*physiology Oligonucleotide Array Sequence Analysis/*methods Proteome/*metabolism Signal Transduction/*physiology1 aValls, J.1 aGrau, M.1 aSole, X.1 aHernandez, P.1 aMontaner, D.1 aDopazo, J.1 aPeinado, M., A.1 aCapella, G.1 aMoreno, V.1 aPujana, M., A. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1759700900426nas a2200109 4500008004100000245006200041210006100103260004700164490000800211100001800219856007900237 2008 eng d00aComparative genomics-based prediction of protein function0 aComparative genomicsbased prediction of protein function bM. Starkey and R. Elaswarapu, Humana press0 v4391 aGabaldón, T. uhttp://www.springerprotocols.com/Abstract/doi/10.1007/978-1-59745-188-8_2603014nas a2200229 4500008004100000245012600041210006900167300001200236490000700248520187400255653014702129653025902276100002302535700001602558700001502574700002002589700001802609700002002627700001702647700001402664856010602678 2008 eng d00aControlled ovarian stimulation induces a functional genomic delay of the endometrium with potential clinical implications0 aControlled ovarian stimulation induces a functional genomic dela a4500-100 v933 a

CONTEXT: Controlled ovarian stimulation induces morphological, biochemical, and functional genomic modifications of the human endometrium during the window of implantation. OBJECTIVE: Our objective was to compare the gene expression profile of the human endometrium in natural vs. controlled ovarian stimulation cycles throughout the early-mid secretory transition using microarray technology. METHOD: Microarray data from 49 endometrial biopsies obtained from LH+1 to LH+9 (n=25) in natural cycles and from human chorionic gonadotropin (hCG) +1 to hCG+9 in controlled ovarian stimulation cycles (n=24) were analyzed using different methods, such as clustering, profiling of biological processes, and selection of differentially expressed genes, as implemented in Gene Expression Pattern Analysis Suite and Babelomics programs. RESULTS: Endometria from natural cycles followed different genomic patterns compared with controlled ovarian stimulation cycles in the transition from the pre-receptive (days LH/hCG+1 until LH/hCG+5) to the receptive phase (day LH+7/hCG+7). Specifically, we have demonstrated the existence of a 2-d delay in the activation/repression of two clusters composed by 218 and 133 genes, respectively, on day hCG+7 vs. LH+7. Many of these delayed genes belong to the class window of implantation genes affecting basic biological processes in the receptive endometrium. CONCLUSIONS: These results demonstrate that gene expression profiling of the endometrium is different between natural and controlled ovarian stimulation cycles in the receptive phase. Identification of these differentially regulated genes can be used to understand the different developmental profiles of receptive endometrium during controlled ovarian stimulation and to search for the best controlled ovarian stimulation treatment in terms of minimal endometrial impact.

10aAlgorithms Chorionic Gonadotropin/genetics Endometrium/cytology/pathology/*physiology/physiopathology Female Gene Expression Regulation Genome10aHuman Glutathione Peroxidase/genetics Humans Insulin-Like Growth Factor Binding Proteins/genetics Luteal Phase/physiology Luteinizing Hormone/genetics Menstrual Cycle Oligonucleotide Array Sequence Analysis Ovulation Induction/*methods RNA/genetics/isola1 aHorcajadas, J., A.1 aMinguez, P.1 aDopazo, J.1 aEsteban, F., J.1 aDominguez, F.1 aGiudice, L., C.1 aPellicer, A.1 aSimon, C. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1869787000545nas a2200157 4500008004100000245007400041210006900115260002300184300001200207100001800219700001200237700001600249700001600265700001300281856009300294 2008 eng d00aThe core of a minimal gene set: insights from natural reduced genomes0 acore of a minimal gene set insights from natural reduced genomes aUSAbThe MIT Press a347-3661 aGabaldón, T.1 aGil, R.1 aPeretó, J.1 aLatorre, A.1 aMoya, A. uhttp://clinbioinfosspa.es/content/core-minimal-gene-set-insights-natural-reduced-genomes01778nas a2200229 4500008004100000245010300041210006900144300001100213490000700224520087500231653007101106653013601177100001501313700001201328700002201340700001801362700001301380700001701393700001701410700001501427856010601442 2008 eng d00aDirect functional assessment of the composite phenotype through multivariate projection strategies0 aDirect functional assessment of the composite phenotype through  a373-830 v923 a

We present a novel approach for the analysis of transcriptomics data that integrates functional annotation of gene sets with expression values in a multivariate fashion, and directly assesses the relation of functional features to a multivariate space of response phenotypical variables. Multivariate projection methods are used to obtain new correlated variables for a set of genes that share a given function. These new functional variables are then related to the response variables of interest. The analysis of the principal directions of the multivariate regression allows for the identification of gene function features correlated with the phenotype. Two different transcriptomics studies are used to illustrate the statistical and interpretative aspects of the methodology. We demonstrate the superiority of the proposed method over equivalent approaches.

10aBreast Neoplasms/genetics Computational Biology/*methods Databases10aGenetic Female Gene Expression Profiling/*statistics & numerical data Humans Mathematical Computing Multivariate Analysis Phenotype1 aConesa, A.1 aBro, R.1 aGarcia-Garcia, F.1 aPrats, J., M.1 aGotz, S.1 aKjeldahl, K.1 aMontaner, D.1 aDopazo, J. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1865288801946nas a2200337 4500008004100000022001400041245010400055210006900159260001300228300001100241490000700252520087500259653002101134653002601155653002301181653001101204653003001215653001101245653002701256653002601283653001401309100001601323700001601339700002901355700002501384700001801409700002001427700002001447700002001467856012101487 2008 eng d a1089-864600aDirect functional assessment of the composite phenotype through multivariate projection strategies.0 aDirect functional assessment of the composite phenotype through  c2008 Dec a373-830 v923 a

We present a novel approach for the analysis of transcriptomics data that integrates functional annotation of gene sets with expression values in a multivariate fashion, and directly assesses the relation of functional features to a multivariate space of response phenotypical variables. Multivariate projection methods are used to obtain new correlated variables for a set of genes that share a given function. These new functional variables are then related to the response variables of interest. The analysis of the principal directions of the multivariate regression allows for the identification of gene function features correlated with the phenotype. Two different transcriptomics studies are used to illustrate the statistical and interpretative aspects of the methodology. We demonstrate the superiority of the proposed method over equivalent approaches.

10aBreast Neoplasms10aComputational Biology10aDatabases, Genetic10aFemale10aGene Expression Profiling10aHumans10aMathematical Computing10aMultivariate Analysis10aPhenotype1 aConesa, Ana1 aBro, Rasmus1 aGarcia-Garcia, Francisco1 aPrats, José, Manuel1 aGötz, Stefan1 aKjeldahl, Karin1 aMontaner, David1 aDopazo, Joaquin uhttp://clinbioinfosspa.es/content/direct-functional-assessment-composite-phenotype-through-multivariate-projection-001187nas a2200145 4500008004100000245013100041210006900172300000800241490000600249520062400255100001900879700001300898700002400911856010600935 2008 eng d00aEvolutionary potentials: structure specific knowledge-based potentials exploiting the evolutionary record of sequence homologs0 aEvolutionary potentials structure specific knowledgebased potent aR680 v93 aABSTRACT: We introduce a new type of knowledge-based potentials for protein structure prediction, called ’evolutionary potentials’, which are derived using a single experimental protein structure and all three-dimensional models of its homologous sequences. The new potentials have been benchmarked against other knowledge-based potentials, resulting in a significant increase in accuracy for model assessment. In contrast to standard knowledge-based potentials, we propose that evolutionary potentials capture key determinants of thermodynamic stability and specific sequence constraints required for fast folding.1 aPanjkovich, A.1 aMelo, F.1 aMarti-Renom, M., A. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1839751701564nas a2200229 4500008004100000022001400041245003200055210003100087260000900118300001100127490000800138520093500146653001201081653002601093653002001119653003001139653001101169653004401180100002001224700002501244856006501269 2008 eng d a1064-374500aExpression and microarrays.0 aExpression and microarrays c2008 a245-550 v4533 a

High throughput methodologies have increased by several orders of magnitude the amount of experimental microarray data available. Nevertheless, translating these data into useful biological knowledge remains a challenge. There is a risk of perceiving these methodologies as mere factories that produce never-ending quantities of data if a proper biological interpretation is not provided. Methods of interpreting these data are continuously evolving. Typically, a simple two-step approach has been used, in which genes of interest are first selected based on thresholds for the experimental values, and then enrichment in biologically relevant terms in the annotations of these genes is analyzed in a second step. For various reasons, such methods are quite poor in terms of performance and new procedures inspired by systems biology that directly address sets of functionally related genes are currently under development.

10aAnimals10aComputational Biology10agene expression10aGene Expression Profiling10aHumans10aOligonucleotide Array Sequence Analysis1 aDopazo, Joaquin1 aAl-Shahrour, Fátima uhttp://clinbioinfosspa.es/content/expression-and-microarrays02498nas a2200385 4500008004100000022001400041245007700055210006900132260001600201300001200217490000700229520130100236653002201537653003701559653003001596653001301626653001301639653004401652653001301696100002301709700002001732700002101752700002401773700001901797700001601816700002501832700002801857700001801885700001901903700002901922700001601951700002001967700002001987856010502007 2008 eng d a1362-496200aGEPAS, a web-based tool for microarray data analysis and interpretation.0 aGEPAS a webbased tool for microarray data analysis and interpret c2008 Jul 01 aW308-140 v363 a

Gene Expression Profile Analysis Suite (GEPAS) is one of the most complete and extensively used web-based packages for microarray data analysis. During its more than 5 years of activity it has continuously been updated to keep pace with the state-of-the-art in the changing microarray data analysis arena. GEPAS offers diverse analysis options that include well established as well as novel algorithms for normalization, gene selection, class prediction, clustering and functional profiling of the experiment. New options for time-course (or dose-response) experiments, microarray-based class prediction, new clustering methods and new tests for differential expression have been included. The new pipeliner module allows automating the execution of sequential analysis steps by means of a simple but powerful graphic interface. An extensive re-engineering of GEPAS has been carried out which includes the use of web services and Web 2.0 technology features, a new user interface with persistent sessions and a new extended database of gene identifiers. GEPAS is nowadays the most quoted web tool in its field and it is extensively used by researchers of many countries and its records indicate an average usage rate of 500 experiments per day. GEPAS, is available at http://www.gepas.org.

10aComputer Graphics10aDose-Response Relationship, Drug10aGene Expression Profiling10aInternet10aKinetics10aOligonucleotide Array Sequence Analysis10aSoftware1 aTárraga, Joaquín1 aMedina, Ignacio1 aCarbonell, José1 aHuerta-Cepas, Jaime1 aMinguez, Pablo1 aAlloza, Eva1 aAl-Shahrour, Fátima1 aVegas-Azcárate, Susana1 aGoetz, Stefan1 aEscobar, Pablo1 aGarcia-Garcia, Francisco1 aConesa, Ana1 aMontaner, David1 aDopazo, Joaquin uhttp://clinbioinfosspa.es/content/gepas-web-based-tool-microarray-data-analysis-and-interpretation-002205nas a2200301 4500008004100000245007600041210006900117300001200186490000700198520130100205653001001506653002901516100001601545700002001561700001801581700002101599700001601620700001501636700002401651700002301675700001401698700001601712700002201728700001501750700001701765700001501782856010601797 2008 eng d00aGEPAS, a web-based tool for microarray data analysis and interpretation0 aGEPAS a webbased tool for microarray data analysis and interpret aW308-140 v363 a

Gene Expression Profile Analysis Suite (GEPAS) is one of the most complete and extensively used web-based packages for microarray data analysis. During its more than 5 years of activity it has continuously been updated to keep pace with the state-of-the-art in the changing microarray data analysis arena. GEPAS offers diverse analysis options that include well established as well as novel algorithms for normalization, gene selection, class prediction, clustering and functional profiling of the experiment. New options for time-course (or dose-response) experiments, microarray-based class prediction, new clustering methods and new tests for differential expression have been included. The new pipeliner module allows automating the execution of sequential analysis steps by means of a simple but powerful graphic interface. An extensive re-engineering of GEPAS has been carried out which includes the use of web services and Web 2.0 technology features, a new user interface with persistent sessions and a new extended database of gene identifiers. GEPAS is nowadays the most quoted web tool in its field and it is extensively used by researchers of many countries and its records indicate an average usage rate of 500 experiments per day. GEPAS, is available at http://www.gepas.org.

10agepas10amicroarray data analysis1 aTarraga, J.1 aMedina, Ignacio1 aCarbonell, J.1 aHuerta-Cepas, J.1 aMinguez, P.1 aAlloza, E.1 aAl-Shahrour, Fatima1 aVegas-Azcarate, S.1 aGoetz, S.1 aEscobar, P.1 aGarcia-Garcia, F.1 aConesa, A.1 aMontaner, D.1 aDopazo, J. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1850880602717nas a2200385 4500008004100000022001400041245008300055210006900138260001300207300001200220490000700232520153300239653001201772653002601784653002201810653002301832653002801855653001001883653001301893653002701906653003101933653001301964653002701977100001802004700003302022700001802055700002102073700002902094700002402123700002302147700001802170700002002188700001602208856010702224 2008 eng d a1362-496200aHigh-throughput functional annotation and data mining with the Blast2GO suite.0 aHighthroughput functional annotation and data mining with the Bl c2008 Jun a3420-350 v363 a

Functional genomics technologies have been widely adopted in the biological research of both model and non-model species. An efficient functional annotation of DNA or protein sequences is a major requirement for the successful application of these approaches as functional information on gene products is often the key to the interpretation of experimental results. Therefore, there is an increasing need for bioinformatics resources which are able to cope with large amount of sequence data, produce valuable annotation results and are easily accessible to laboratories where functional genomics projects are being undertaken. We present the Blast2GO suite as an integrated and biologist-oriented solution for the high-throughput and automatic functional annotation of DNA or protein sequences based on the Gene Ontology vocabulary. The most outstanding Blast2GO features are: (i) the combination of various annotation strategies and tools controlling type and intensity of annotation, (ii) the numerous graphical features such as the interactive GO-graph visualization for gene-set function profiling or descriptive charts, (iii) the general sequence management features and (iv) high-throughput capabilities. We used the Blast2GO framework to carry out a detailed analysis of annotation behaviour through homology transfer and its impact in functional genomics research. Our aim is to offer biologists useful information to take into account when addressing the task of functionally characterizing their sequence data.

10aAnimals10aComputational Biology10aComputer Graphics10aDatabases, Genetic10aExpressed Sequence Tags10aGenes10aGenomics10aSequence Analysis, DNA10aSequence Analysis, Protein10aSoftware10aVocabulary, Controlled1 aGötz, Stefan1 aGarcía-Gómez, Juan, Miguel1 aTerol, Javier1 aWilliams, Tim, D1 aNagaraj, Shivashankar, H1 aNueda, Maria, José1 aRobles, Montserrat1 aTalon, Manuel1 aDopazo, Joaquin1 aConesa, Ana uhttp://clinbioinfosspa.es/content/high-throughput-functional-annotation-and-data-mining-blast2go-suite03685nas a2200937 4500008004100000022001400041245007800055210006900133260001300202300001100215490000600226520100100232653002601233653003201259653002301291653003801314653001301352653002601365653002401391110002301415700002301438700001901461700001801480700002501498700001801523700001901541700002101560700001601581700001601597700002901613700001701642700001901659700002201678700002501700700003101725700002501756700001601781700001901797700001601816700002001832700002601852700002501878700001901903700001901922700001801941700001901959700001401978700001901992700002002011700002002031700001702051700002002068700002102088700002402109700002102133700002102154700002102175700002202196700001802218700002002236700002302256700002402279700002502303700002002328700002002348700002002368700002002388700002202408700002002430700002302450700001702473700001602490700002702506700001802533700001802551700001902569700002002588700001802608700002302626856009802649 2008 eng d a1477-405400aInteroperability with Moby 1.0--it's better than sharing your toothbrush!0 aInteroperability with Moby 10its better than sharing your toothb c2008 May a220-310 v93 a

The BioMoby project was initiated in 2001 from within the model organism database community. It aimed to standardize methodologies to facilitate information exchange and access to analytical resources, using a consensus driven approach. Six years later, the BioMoby development community is pleased to announce the release of the 1.0 version of the interoperability framework, registry Application Programming Interface and supporting Perl and Java code-bases. Together, these provide interoperable access to over 1400 bioinformatics resources worldwide through the BioMoby platform, and this number continues to grow. Here we highlight and discuss the features of BioMoby that make it distinct from other Semantic Web Service and interoperability initiatives, and that have been instrumental to its deployment and use by a wide community of bioinformatics service providers. The standard, client software, and supporting code libraries are all freely available at http://www.biomoby.org/.

10aComputational Biology10aDatabase Management Systems10aDatabases, Factual10aInformation Storage and Retrieval10aInternet10aProgramming Languages10aSystems Integration1 aBioMoby Consortium1 aWilkinson, Mark, D1 aSenger, Martin1 aKawas, Edward1 aBruskiewich, Richard1 aGouzy, Jerome1 aNoirot, Celine1 aBardou, Philippe1 aNg, Ambrose1 aHaase, Dirk1 aSaiz, Enrique, de Andres1 aWang, Dennis1 aGibbons, Frank1 aGordon, Paul, M K1 aSensen, Christoph, W1 aCarrasco, Jose, Manuel Rod1 aFernández, José, M1 aShen, Lixin1 aLinks, Matthew1 aNg, Michael1 aOpushneva, Nina1 aNeerincx, Pieter, B T1 aLeunissen, Jack, A M1 aErnst, Rebecca1 aTwigger, Simon1 aUsadel, Bjorn1 aGood, Benjamin1 aWong, Yan1 aStein, Lincoln1 aCrosby, William1 aKarlsson, Johan1 aRoyo, Romina1 aPárraga, Iván1 aRamírez, Sergio1 aGelpi, Josep, Lluis1 aTrelles, Oswaldo1 aPisano, David, G1 aJimenez, Natalia1 aKerhornou, Arnaud1 aRosset, Roman1 aZamacola, Leire1 aTárraga, Joaquín1 aHuerta-Cepas, Jaime1 aCarazo, Jose, María1 aDopazo, Joaquin1 aGuigó, Roderic1 aNavarro, Arcadi1 aOrozco, Modesto1 aValencia, Alfonso1 aClaros, Gonzalo1 aPérez, Antonio, J1 aAldana, Jose1 aRojano, Mar1 aCruz, Raul, Fernandez-1 aNavas, Ismael1 aSchiltz, Gary1 aFarmer, Andrew1 aGessler, Damian1 aSchoof, Heiko1 aGroscurth, Andreas uhttp://clinbioinfosspa.es/content/interoperability-moby-10-its-better-sharing-your-toothbrush03310nas a2200841 4500008004100000245008100041210007100122300001100193490000600204520100100210653007501211653010801286100002201394700001501416700001401431700002001445700001401465700001501479700001501494700001101509700001401520700001401534700001301548700001601561700001901577700001901596700002101615700002201636700001301658700001401671700001101685700001801696700002101714700002201735700001401757700001601771700001501787700001301802700001301815700001401828700001501842700001701857700001301874700001601887700001601903700001801919700001601937700001901953700001601972700001801988700001502006700001702021700001602038700002102054700001902075700001502094700001402109700001602123700001502139700001702154700001902171700001802190700001502208700001902223700002602242700001402268700001602282700001502298700001602313700001502329700001802344856010602362 2008 eng d00aInteroperability with Moby 1.0–it’s better than sharing your toothbrush!0 aInteroperability with Moby 10–it s better than sharing your toot a220-310 v93 a

The BioMoby project was initiated in 2001 from within the model organism database community. It aimed to standardize methodologies to facilitate information exchange and access to analytical resources, using a consensus driven approach. Six years later, the BioMoby development community is pleased to announce the release of the 1.0 version of the interoperability framework, registry Application Programming Interface and supporting Perl and Java code-bases. Together, these provide interoperable access to over 1400 bioinformatics resources worldwide through the BioMoby platform, and this number continues to grow. Here we highlight and discuss the features of BioMoby that make it distinct from other Semantic Web Service and interoperability initiatives, and that have been instrumental to its deployment and use by a wide community of bioinformatics service providers. The standard, client software, and supporting code libraries are all freely available at http://www.biomoby.org/.

10aComputational Biology/*methods *Database Management Systems *Databases10aFactual Information Storage and Retrieval/*methods *Internet *Programming Languages Systems Integration1 aWilkinson, M., D.1 aSenger, M.1 aKawas, E.1 aBruskiewich, R.1 aGouzy, J.1 aNoirot, C.1 aBardou, P.1 aNg, A.1 aHaase, D.1 aEde, Saiz1 aWang, D.1 aGibbons, F.1 aGordon, P., M.1 aSensen, C., W.1 aCarrasco, J., M.1 aFernandez, J., M.1 aShen, L.1 aLinks, M.1 aNg, M.1 aOpushneva, N.1 aNeerincx, P., B.1 aLeunissen, J., A.1 aErnst, R.1 aTwigger, S.1 aUsadel, B.1 aGood, B.1 aWong, Y.1 aStein, L.1 aCrosby, W.1 aKarlsson, J.1 aRoyo, R.1 aParraga, I.1 aRamirez, S.1 aGelpi, J., L.1 aTrelles, O.1 aPisano, D., G.1 aJimenez, N.1 aKerhornou, A.1 aRosset, R.1 aZamacola, L.1 aTarraga, J.1 aHuerta-Cepas, J.1 aCarazo, J., M.1 aDopazo, J.1 aGuigo, R.1 aNavarro, A.1 aOrozco, M.1 aValencia, A.1 aClaros, M., G.1 aPerez, A., J.1 aAldana, J.1 aRojano, M., M.1 aCruz, Fernandez-Santa1 aNavas, I.1 aSchiltz, G.1 aFarmer, A.1 aGessler, D.1 aSchoof, H.1 aGroscurth, A. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1823880402702nas a2200253 4500008004100000245013300041210006900174300001100243490000700254520167500261653004701936653002901983653012302012653010502135100001602240700001402256700002002270700002102290700001802311700001502329700001702344700002002361856006702381 2008 eng d00aJoint annotation of coding and non-coding single nucleotide polymorphisms and mutations in the SNPeffect and PupaSuite databases0 aJoint annotation of coding and noncoding single nucleotide polym aD825-90 v363 a

Single nucleotide polymorphisms (SNPs) are, together with copy number variation, the primary source of variation in the human genome. SNPs are associated with altered response to drug treatment, susceptibility to disease and other phenotypic variation. Furthermore, during genetic screens for disease-associated mutations in groups of patients and control individuals, the distinction between disease causing mutation and polymorphism is often unclear. Annotation of the functional and structural implications of single nucleotide changes thus provides valuable information to interpret and guide experiments. The SNPeffect and PupaSuite databases are now synchronized to deliver annotations for both non-coding and coding SNP, as well as annotations for the SwissProt set of human disease mutations. In addition, SNPeffect now contains predictions of Tango2: an improved aggregation detector, and Waltz: a novel predictor of amyloid-forming sequences, as well as improved predictors for regions that are recognized by the Hsp70 family of chaperones. The new PupaSuite version incorporates predictions for SNPs in silencers and miRNAs including their targets, as well as additional methods for predicting SNPs in TFBSs and splice sites. Also predictions for mouse and rat genomes have been added. In addition, a PupaSuite web service has been developed to enable data access, programmatically. The combined database holds annotations for 4,965,073 regulatory as well as 133,505 coding human SNPs and 14,935 disease mutations, and phenotypic descriptions of 43,797 human proteins and is accessible via http://snpeffect.vib.be and http://pupasuite.bioinfo.cipf.es/.

10aAmino Acid Substitution Animals *Databases10aGenetic Genetic Diseases10aInborn/genetics HSP70 Heat-Shock Proteins/metabolism Humans Internet Mice MicroRNAs/metabolism *Mutation *Polymorphism10aSingle Nucleotide Proteins/chemistry/genetics RNA Splice Sites Rats Transcription Factors/metabolism1 aReumers, J.1 aConde, L.1 aMedina, Ignacio1 aMaurer-Stroh, S.1 aVan Durme, J.1 aDopazo, J.1 aRousseau, F.1 aSchymkowitz, J. uhttp://nar.oxfordjournals.org/cgi/content/full/36/suppl_1/D82502956nas a2200409 4500008004100000022001400041245013400055210006900189260001300258300001100271490000700282520167500289653002801964653001201992653002302004653002902027653003002056653001102086653001302097653000902110653001402119653001302133653003602146653001302182653000902195653002102204653002602225100001802251700001702269700002002286700002802306700002102334700002002355700002302375700002302398856012502421 2008 eng d a1362-496200aJoint annotation of coding and non-coding single nucleotide polymorphisms and mutations in the SNPeffect and PupaSuite databases.0 aJoint annotation of coding and noncoding single nucleotide polym c2008 Jan aD825-90 v363 a

Single nucleotide polymorphisms (SNPs) are, together with copy number variation, the primary source of variation in the human genome. SNPs are associated with altered response to drug treatment, susceptibility to disease and other phenotypic variation. Furthermore, during genetic screens for disease-associated mutations in groups of patients and control individuals, the distinction between disease causing mutation and polymorphism is often unclear. Annotation of the functional and structural implications of single nucleotide changes thus provides valuable information to interpret and guide experiments. The SNPeffect and PupaSuite databases are now synchronized to deliver annotations for both non-coding and coding SNP, as well as annotations for the SwissProt set of human disease mutations. In addition, SNPeffect now contains predictions of Tango2: an improved aggregation detector, and Waltz: a novel predictor of amyloid-forming sequences, as well as improved predictors for regions that are recognized by the Hsp70 family of chaperones. The new PupaSuite version incorporates predictions for SNPs in silencers and miRNAs including their targets, as well as additional methods for predicting SNPs in TFBSs and splice sites. Also predictions for mouse and rat genomes have been added. In addition, a PupaSuite web service has been developed to enable data access, programmatically. The combined database holds annotations for 4,965,073 regulatory as well as 133,505 coding human SNPs and 14,935 disease mutations, and phenotypic descriptions of 43,797 human proteins and is accessible via http://snpeffect.vib.be and http://pupasuite.bioinfo.cipf.es/.

10aAmino Acid Substitution10aAnimals10aDatabases, Genetic10aGenetic Diseases, Inborn10aHSP70 Heat-Shock Proteins10aHumans10aInternet10aMice10aMicroRNAs10amutation10aPolymorphism, Single Nucleotide10aProteins10aRats10aRNA Splice Sites10aTranscription Factors1 aReumers, Joke1 aConde, Lucia1 aMedina, Ignacio1 aMaurer-Stroh, Sebastian1 aVan Durme, Joost1 aDopazo, Joaquin1 aRousseau, Frederic1 aSchymkowitz, Joost uhttp://clinbioinfosspa.es/content/joint-annotation-coding-and-non-coding-single-nucleotide-polymorphisms-and-mutations-003221nas a2200181 4500008004100000245010900041210006900150300000800219490000600227520260800233100001502841700001402856700001502870700001502885700001502900700001802915856010602933 2008 eng d00aLarge-scale Gene Ontology analysis of plant transcriptome-derived sequences retrieved by AFLP technology0 aLargescale Gene Ontology analysis of plant transcriptomederived  a3470 v93 a

BACKGROUND: After 10-year-use of AFLP (Amplified Fragment Length Polymorphism) technology for DNA fingerprinting and mRNA profiling, large repertories of genome- and transcriptome-derived sequences are available in public databases for model, crop and tree species. AFLP marker systems have been and are being extensively exploited for genome scanning and gene mapping, as well as cDNA-AFLP for transcriptome profiling and differentially expressed gene cloning. The evaluation, annotation and classification of genomic markers and expressed transcripts would be of great utility for both functional genomics and systems biology research in plants. This may be achieved by means of the Gene Ontology (GO), consisting in three structured vocabularies (i.e. ontologies) describing genes, transcripts and proteins of any organism in terms of their associated cellular component, biological process and molecular function in a species-independent manner. In this paper, the functional annotation of about 8,000 AFLP-derived ESTs retrieved in the NCBI databases was carried out by using GO terminology. RESULTS: Descriptive statistics on the type, size and nature of gene sequences obtained by means of AFLP technology were calculated. The gene products associated with mRNA transcripts were then classified according to the three main GO vocabularies. A comparison of the functional content of cDNA-AFLP records was also performed by splitting the sequence dataset into monocots and dicots and by comparing them to all annotated ESTs of Arabidopsis and rice, respectively. On the whole, the statistical parameters adopted for the in silico AFLP-derived transcriptome-anchored sequence analysis proved to be critical for obtaining reliable GO results. Such an exhaustive annotation may offer a suitable platform for functional genomics, particularly useful in non-model species. CONCLUSION: Reliable GO annotations of AFLP-derived sequences can be gathered through the optimization of the experimental steps and the statistical parameters adopted. The Blast2GO software was shown to represent a comprehensive bioinformatics solution for an annotation-based functional analysis. According to the whole set of GO annotations, the AFLP technology generates thorough information for angiosperm gene products and shares common features across angiosperm species and families. The utility of this technology for structural and functional genomics in plants can be implemented by serial annotation analyses of genome-anchored fragments and organ/tissue-specific repertories of transcriptome-derived fragments.

1 aBotton, A.1 aGalla, G.1 aConesa, A.1 aBachem, C.1 aRamina, A.1 aBarcaccia, G. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1865264603267nas a2200517 4500008004100000022001400041245013100055210006900186260001600255300001200271490000700283520168900290653001201979653001501991653001002006653000902016653002202025653001402047653002502061653002502086653001102111653003002122653004302152653001102195653000902206653001602215653004402231653001402275653005202289653001802341653002402359653002202383100002102405700002502426700001302451700001502464700002902479700001702508700001602525700002002541700001402561700001602575700001502591700001602606856012702622 2008 eng d a1476-559400aMolecular profiling related to poor prognosis in thyroid carcinoma. Combining gene expression data and biological information.0 aMolecular profiling related to poor prognosis in thyroid carcino c2008 Mar 06 a1554-610 v273 a

Undifferentiated and poorly differentiated thyroid tumors are responsible for more than half of thyroid cancer patient deaths in spite of their low incidence. Conventional treatments do not obtain substantial benefits, and the lack of alternative approaches limits patient survival. Additionally, the absence of prognostic markers for well-differentiated tumors complicates patient-specific treatments and favors the progression of recurrent forms. In order to recognize the molecular basis involved in tumor dedifferentiation and identify potential markers for thyroid cancer prognosis prediction, we analysed the expression profile of 44 thyroid primary tumors with different degrees of dedifferentiation and aggressiveness using cDNA microarrays. Transcriptome comparison of dedifferentiated and well-differentiated thyroid tumors identified 1031 genes with >2-fold difference in absolute values and false discovery rate of <0.15. According to known molecular interaction and reaction networks, the products of these genes were mainly clustered in the MAPkinase signaling pathway, the TGF-beta signaling pathway, focal adhesion and cell motility, activation of actin polymerization and cell cycle. An exhaustive search in several databases allowed us to identify various members of the matrix metalloproteinase, melanoma antigen A and collagen gene families within the upregulated gene set. We also identified a prognosis classifier comprising just 30 transcripts with an overall accuracy of 95%. These findings may clarify the molecular mechanisms involved in thyroid tumor dedifferentiation and provide a potential prognosis predictor as well as targets for new therapies.

10aAdenoma10aAdolescent10aAdult10aAged10aBiomarkers, Tumor10aCarcinoma10aCarcinoma, Papillary10aCell Differentiation10aFemale10aGene Expression Profiling10aGene Expression Regulation, Neoplastic10aHumans10aMale10aMiddle Aged10aOligonucleotide Array Sequence Analysis10aPrognosis10aReverse Transcriptase Polymerase Chain Reaction10aRNA, Neoplasm10aSignal Transduction10aThyroid Neoplasms1 aMontero-Conde, C1 aMartín-Campos, J, M1 aLerma, E1 aGimenez, G1 aMartínez-Guitarte, J, L1 aCombalía, N1 aMontaner, D1 aMatías-Guiu, X1 aDopazo, J1 ade Leiva, A1 aRobledo, M1 aMauricio, D uhttp://clinbioinfosspa.es/content/molecular-profiling-related-poor-prognosis-thyroid-carcinoma-combining-gene-expression-003141nas a2200313 4500008004100000245013000041210006900171300001200240490000700252520169500259653011401954653003602068653016902104653009402273653012702367100002202494700002602516700001402542700001602556700003002572700001702602700001702619700002002636700001502656700001702671700001602688700001702704856010602721 2008 eng d00aMolecular profiling related to poor prognosis in thyroid carcinoma. Combining gene expression data and biological information0 aMolecular profiling related to poor prognosis in thyroid carcino a1554-610 v273 a

Undifferentiated and poorly differentiated thyroid tumors are responsible for more than half of thyroid cancer patient deaths in spite of their low incidence. Conventional treatments do not obtain substantial benefits, and the lack of alternative approaches limits patient survival. Additionally, the absence of prognostic markers for well-differentiated tumors complicates patient-specific treatments and favors the progression of recurrent forms. In order to recognize the molecular basis involved in tumor dedifferentiation and identify potential markers for thyroid cancer prognosis prediction, we analysed the expression profile of 44 thyroid primary tumors with different degrees of dedifferentiation and aggressiveness using cDNA microarrays. Transcriptome comparison of dedifferentiated and well-differentiated thyroid tumors identified 1031 genes with >2-fold difference in absolute values and false discovery rate of <0.15. According to known molecular interaction and reaction networks, the products of these genes were mainly clustered in the MAPkinase signaling pathway, the TGF-beta signaling pathway, focal adhesion and cell motility, activation of actin polymerization and cell cycle. An exhaustive search in several databases allowed us to identify various members of the matrix metalloproteinase, melanoma antigen A and collagen gene families within the upregulated gene set. We also identified a prognosis classifier comprising just 30 transcripts with an overall accuracy of 95%. These findings may clarify the molecular mechanisms involved in thyroid tumor dedifferentiation and provide a potential prognosis predictor as well as targets for new therapies.

10aAdenoma/genetics/metabolism/pathology Adolescent Adult Aged Carcinoma/genetics/metabolism/pathology Carcinoma10aBiological/*genetics/metabolism10aNeoplasm/genetics/metabolism Reverse Transcriptase Polymerase Chain Reaction Signal Transduction Thyroid Neoplasms/classification/*genetics/metabolism Tumor Markers10aNeoplastic Humans Male Middle Aged *Oligonucleotide Array Sequence Analysis Prognosis RNA10aPapillary/genetics/metabolism/pathology Cell Differentiation Female *Gene Expression Profiling *Gene Expression Regulation1 aMontero-Conde, C.1 aMartin-Campos, J., M.1 aLerma, E.1 aGimenez, G.1 aMartinez-Guitarte, J., L.1 aCombalia, N.1 aMontaner, D.1 aMatias-Guiu, X.1 aDopazo, J.1 ade Leiva, A.1 aRobledo, M.1 aMauricio, D. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1787390802125nas a2200301 4500008004100000022001400041245007500055210006900130260001300199300001100212490000700223520123800230653001801468653002101486653001001507653001301517653002101530653001101551653001401562653001301576653002901589653002301618100002401641700001801665700002001683700002001703856010001723 2008 eng d a1362-496200aPhylomeDB: a database for genome-wide collections of gene phylogenies.0 aPhylomeDB a database for genomewide collections of gene phylogen c2008 Jan aD491-60 v363 a

The complete collection of evolutionary histories of all genes in a genome, also known as phylome, constitutes a valuable source of information. The reconstruction of phylomes has been previously prevented by large demands of time and computer power, but is now feasible thanks to recent developments in computers and algorithms. To provide a publicly available repository of complete phylomes that allows researchers to access and store large-scale phylogenomic analyses, we have developed PhylomeDB. PhylomeDB is a database of complete phylomes derived for different genomes within a specific taxonomic range. All phylomes in the database are built using a high-quality phylogenetic pipeline that includes evolutionary model testing and alignment trimming phases. For each genome, PhylomeDB provides the alignments, phylogentic trees and tree-based orthology predictions for every single encoded protein. The current version of PhylomeDB includes the phylomes of Human, the yeast Saccharomyces cerevisiae and the bacterium Escherichia coli, comprising a total of 32 289 seed sequences with their corresponding alignments and 172 324 phylogenetic trees. PhylomeDB can be publicly accessed at http://phylomedb.bioinfo.cipf.es.

10aBase Sequence10aEscherichia coli10aGenes10aGenomics10aHistory, Ancient10aHumans10aPhylogeny10aProteins10aSaccharomyces cerevisiae10aSequence Alignment1 aHuerta-Cepas, Jaime1 aBueno, Anibal1 aDopazo, Joaquin1 aGabaldón, Toni uhttp://clinbioinfosspa.es/content/phylomedb-database-genome-wide-collections-gene-phylogenies-002003nas a2200181 4500008004100000245007400041210006900115300001100184490000700195520123100202653013101433653008301564100002101647700001401668700001501682700001801697856010601715 2008 eng d00aPhylomeDB: a database for genome-wide collections of gene phylogenies0 aPhylomeDB a database for genomewide collections of gene phylogen aD491-60 v363 aThe complete collection of evolutionary histories of all genes in a genome, also known as phylome, constitutes a valuable source of information. The reconstruction of phylomes has been previously prevented by large demands of time and computer power, but is now feasible thanks to recent developments in computers and algorithms. To provide a publicly available repository of complete phylomes that allows researchers to access and store large-scale phylogenomic analyses, we have developed PhylomeDB. PhylomeDB is a database of complete phylomes derived for different genomes within a specific taxonomic range. All phylomes in the database are built using a high-quality phylogenetic pipeline that includes evolutionary model testing and alignment trimming phases. For each genome, PhylomeDB provides the alignments, phylogentic trees and tree-based orthology predictions for every single encoded protein. The current version of PhylomeDB includes the phylomes of Human, the yeast Saccharomyces cerevisiae and the bacterium Escherichia coli, comprising a total of 32 289 seed sequences with their corresponding alignments and 172 324 phylogenetic trees. PhylomeDB can be publicly accessed at http://phylomedb.bioinfo.cipf.es.10aAncient Humans *Phylogeny Proteins/classification/genetics Saccharomyces cerevisiae/classification/genetics Sequence Alignment10aBase Sequence Escherichia coli/classification/genetics Genes *Genomics History1 aHuerta-Cepas, J.1 aBueno, A.1 aDopazo, J.1 aGabaldón, T. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1796229702031nas a2200253 4500008004100000245009200041210006900133300000800202490000600210520096700216653008801183653004501271653013401316653003101450653007301481100001801554700001401572700001501586700001901601700001301620700002401633700001401657856010601671 2008 eng d00aPrediction of enzyme function by combining sequence similarity and protein interactions0 aPrediction of enzyme function by combining sequence similarity a a2490 v93 aBACKGROUND: A number of studies have used protein interaction data alone for protein function prediction. Here, we introduce a computational approach for annotation of enzymes, based on the observation that similar protein sequences are more likely to perform the same function if they share similar interacting partners. RESULTS: The method has been tested against the PSI-BLAST program using a set of 3,890 protein sequences from which interaction data was available. For protein sequences that align with at least 40% sequence identity to a known enzyme, the specificity of our method in predicting the first three EC digits increased from 80% to 90% at 80% coverage when compared to PSI-BLAST. CONCLUSION: Our method can also be used in proteins for which homologous sequences with known interacting partners can be detected. Thus, our method could increase 10% the specificity of genome-wide enzyme predictions based on sequence matching by PSI-BLAST alone.10aAmino Acid *Software Structure-Activity Relationship Substrate Specificity/genetics10aAmino Acid Sequence/physiology Databases10aAutomated Predictive Value of Tests Protein Interaction Mapping Proteins/analysis/metabolism Sequence Alignment Sequence Analysis10aProtein *Sequence Homology10aProtein Enzymes/analysis/*metabolism Fuzzy Logic Pattern Recognition1 aEspadaler, J.1 aEswar, N.1 aQuerol, E.1 aAviles, F., X.1 aSali, A.1 aMarti-Renom, M., A.1 aOliva, B. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1850556202322nas a2200181 4500008004100000245005400041210005300095300001100148490000700159520158000166653005701746653002101803653014101824653002701965100001801992700002402010856010602034 2008 eng d00aRNA structure alignment by a unit-vector approach0 aRNA structure alignment by a unitvector approach ai112-80 v243 aMOTIVATION: The recent discovery of tiny RNA molecules such as microRNAs and small interfering RNA are transforming the view of RNA as a simple information transfer molecule. Similar to proteins, the native three-dimensional structure of RNA determines its biological activity. Therefore, classifying the current structural space is paramount for functionally annotating RNA molecules. The increasing numbers of RNA structures deposited in the PDB requires more accurate, automatic and benchmarked methods for RNA structure comparison. In this article, we introduce a new algorithm for RNA structure alignment based on a unit-vector approach. The algorithm has been implemented in the SARA program, which results in RNA structure pairwise alignments and their statistical significance. RESULTS: The SARA program has been implemented to be of general applicability even when no secondary structure can be calculated from the RNA structures. A benchmark against the ARTS program using a set of 1275 non-redundant pairwise structure alignments results in inverted approximately 6% extra alignments with at least 50% structurally superposed nucleotides and base pairs. A first attempt to perform RNA automatic functional annotation based on structure alignments indicates that SARA can correctly assign the deepest SCOR classification to >60% of the query structures. AVAILABILITY: The SARA program is freely available through a World Wide Web server http://sgu.bioinfo.cipf.es/services/SARA/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.10aAlgorithms Base Sequence Computer Simulation *Models10aChemical *Models10aMolecular Molecular Sequence Data Nucleic Acid Conformation RNA/*chemistry/*ultrastructure Sequence Alignment/*methods Sequence Analysis10aRNA/*methods *Software1 aCapriotti, E.1 aMarti-Renom, M., A. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1868981100474nas a2200097 4500008004100000245009300041210006900134260003200203100001500235856012600250 2008 eng d00aSelective Constraints and Human Disease Genes: Evolutionary and Bioinformatic Approaches0 aSelective Constraints and Human Disease Genes Evolutionary and B aUKbJohn Wiley & Sons, Ltd.1 aDopazo, H. uhttp://clinbioinfosspa.es/content/selective-constraints-and-human-disease-genes-evolutionary-and-bioinformatic-approaches00459nas a2200097 4500008004100000245007100041210006900112260007600181100001500257856008900272 2008 eng d00aSelective Constraints on Human Disease Mutations and Polymorphisms0 aSelective Constraints on Human Disease Mutations and Polymorphis aUKbHildegard Kehrer-Sawatzki & David N. Cooper. John Wiley & Sons, Ltd1 aDopazo, H. uhttp://eu.wiley.com/WileyCDA/WileyTitle/productCd-0470517468,descCd-description.html03449nas a2200877 4500008004100000022001400041245006300055210006200118260001300180300001000193490000700203520101900210653001201229653002301241653002301264653001101287653001501298653002701313653001401340653003601354653002801390653000901418653002501427653002701452110002001479700001801499700001701517700003001534700001701564700002401581700001501605700001801620700002401638700002001662700001701682700001801699700001901717700001601736700002401752700002001776700001901796700002101815700001901836700001601855700001701871700001901888700001801907700001701925700002201942700001701964700001901981700001802000700002302018700001802041700002002059700002002079700001802099700002102117700003402138700002202172700002102194700002302215700002202238700002302260700002002283700002002303700002202323700002202345700002002367700002002387700001802407700002002425700001902445700002002464856008702484 2008 eng d a1546-171800aSNP and haplotype mapping for genetic analysis in the rat.0 aSNP and haplotype mapping for genetic analysis in the rat c2008 May a560-60 v403 a

The laboratory rat is one of the most extensively studied model organisms. Inbred laboratory rat strains originated from limited Rattus norvegicus founder populations, and the inherited genetic variation provides an excellent resource for the correlation of genotype to phenotype. Here, we report a survey of genetic variation based on almost 3 million newly identified SNPs. We obtained accurate and complete genotypes for a subset of 20,238 SNPs across 167 distinct inbred rat strains, two rat recombinant inbred panels and an F2 intercross. Using 81% of these SNPs, we constructed high-density genetic maps, creating a large dataset of fully characterized SNPs for disease gene mapping. Our data characterize the population structure and illustrate the degree of linkage disequilibrium. We provide a detailed SNP map and demonstrate its utility for mapping of quantitative trait loci. This community resource is openly available and augments the genetic tools for this workhorse of physiological studies.

10aAnimals10aChromosome Mapping10aDatabases, Genetic10aGenome10aHaplotypes10aLinkage Disequilibrium10aPhylogeny10aPolymorphism, Single Nucleotide10aQuantitative Trait Loci10aRats10aRats, Inbred Strains10aRecombination, Genetic1 aSTAR Consortium1 aSaar, Kathrin1 aBeck, Alfred1 aBihoreau, Marie-Thérèse1 aBirney, Ewan1 aBrocklebank, Denise1 aChen, Yuan1 aCuppen, Edwin1 aDemonchy, Stephanie1 aDopazo, Joaquin1 aFlicek, Paul1 aFoglio, Mario1 aFujiyama, Asao1 aGut, Ivo, G1 aGauguier, Dominique1 aGuigó, Roderic1 aGuryev, Victor1 aHeinig, Matthias1 aHummel, Oliver1 aJahn, Niels1 aKlages, Sven1 aKren, Vladimir1 aKube, Michael1 aKuhl, Heiner1 aKuramoto, Takashi1 aKuroki, Yoko1 aLechner, Doris1 aLee, Young-Ae1 aLopez-Bigas, Nuria1 aLathrop, Mark1 aMashimo, Tomoji1 aMedina, Ignacio1 aMott, Richard1 aPatone, Giannino1 aPerrier-Cornet, Jeanne-Antide1 aPlatzer, Matthias1 aPravenec, Michal1 aReinhardt, Richard1 aSakaki, Yoshiyuki1 aSchilhabel, Markus1 aSchulz, Herbert1 aSerikawa, Tadao1 aShikhagaie, Medya1 aTatsumoto, Shouji1 aTaudien, Stefan1 aToyoda, Atsushi1 aVoigt, Birger1 aZelenika, Diana1 aZimdahl, Heike1 aHubner, Norbert uhttp://clinbioinfosspa.es/content/snp-and-haplotype-mapping-genetic-analysis-rat-003097nas a2200757 4500008004100000245006200041210006200103300001000165490000700175520101900182653004201201653001201243653007801255653004301333653006701376100001301443700001301456700002101469700001501490700002001505700001301525700001501538700001701553700001501570700001501585700001501600700001701615700001601632700001701648700001401665700001501679700001501694700001501709700001301724700001501737700001301752700001301765700001301778700001701791700001501808700001601823700001601839700002001855700002001875700001601895700002001911700001301931700001501944700002701959700001601986700001702002700001802019700001502037700001902052700001502071700001702086700001902103700001802122700001602140700001502156700001402171700001702185700001602202700001502218856010602233 2008 eng d00aSNP and haplotype mapping for genetic analysis in the rat0 aSNP and haplotype mapping for genetic analysis in the rat a560-60 v403 a

The laboratory rat is one of the most extensively studied model organisms. Inbred laboratory rat strains originated from limited Rattus norvegicus founder populations, and the inherited genetic variation provides an excellent resource for the correlation of genotype to phenotype. Here, we report a survey of genetic variation based on almost 3 million newly identified SNPs. We obtained accurate and complete genotypes for a subset of 20,238 SNPs across 167 distinct inbred rat strains, two rat recombinant inbred panels and an F2 intercross. Using 81% of these SNPs, we constructed high-density genetic maps, creating a large dataset of fully characterized SNPs for disease gene mapping. Our data characterize the population structure and illustrate the degree of linkage disequilibrium. We provide a detailed SNP map and demonstrate its utility for mapping of quantitative trait loci. This community resource is openly available and augments the genetic tools for this workhorse of physiological studies.

10aAnimals Chromosome Mapping *Databases10aGenetic10aGenetic Genome *Haplotypes Linkage Disequilibrium Phylogeny *Polymorphism10aInbred Strains/*genetics Recombination10aSingle Nucleotide *Quantitative Trait Loci Rats/*genetics Rats1 aSaar, K.1 aBeck, A.1 aBihoreau, M., T.1 aBirney, E.1 aBrocklebank, D.1 aChen, Y.1 aCuppen, E.1 aDemonchy, S.1 aDopazo, J.1 aFlicek, P.1 aFoglio, M.1 aFujiyama, A.1 aGut, I., G.1 aGauguier, D.1 aGuigo, R.1 aGuryev, V.1 aHeinig, M.1 aHummel, O.1 aJahn, N.1 aKlages, S.1 aKren, V.1 aKube, M.1 aKuhl, H.1 aKuramoto, T.1 aKuroki, Y.1 aLechner, D.1 aLee, Y., A.1 aLopez-Bigas, N.1 aLathrop, G., M.1 aMashimo, T.1 aMedina, Ignacio1 aMott, R.1 aPatone, G.1 aPerrier-Cornet, J., A.1 aPlatzer, M.1 aPravenec, M.1 aReinhardt, R.1 aSakaki, Y.1 aSchilhabel, M.1 aSchulz, H.1 aSerikawa, T.1 aShikhagaie, M.1 aTatsumoto, S.1 aTaudien, S.1 aToyoda, A.1 aVoigt, B.1 aZelenika, D.1 aZimdahl, H.1 aHubner, N. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1844359403447nas a2200253 4500008004100000245010700041210006900148300001200217490000700229520238400236653019002620653008902810100001402899700002402913700001702937700001602954700001502970700001602985700002403001700002603025700001703051700001903068856010603087 2008 eng d00aTime course profiling of the retinal transcriptome after optic nerve transection and optic nerve crush0 aTime course profiling of the retinal transcriptome after optic n a1050-630 v143 aPURPOSE: A time-course analysis of gene regulation in the adult rat retina after intraorbital nerve crush (IONC) and intraorbital nerve transection (IONT). METHODS: RNA was extracted from adult rat retinas undergoing either IONT or IONC at increasing times post-lesion. Affymetrix RAE230.2 arrays were hybridized and analyzed. Statistically regulated genes were annotated and functionally clustered. Arrays were validated by means of quantative reverse transcription polymerase chain reaction (qRT-PCR) on ten regulated genes at two times post-lesion. Western blotting and immunohistofluorescence for four pro-apoptotic proteins were performed on naive and injured retinas. Finally, custom signaling maps for IONT- and IONC-induced death response were generated (MetaCore, Genego Inc.). RESULTS: Here we show that over time, 3,219 sequences were regulated after IONT and 1,996 after IONC. Out of the total of regulated sequences, 1,078 were commonly regulated by both injuries. Interestingly, while IONT mainly triggers a gene upregulation-sustained over time, IONC causes a transitory downregulation. Functional clustering identified the regulation of high interest biologic processes, most importantly cell death wherein apoptosis was the most significant cluster. Ten death-related genes upregulated by both injuries were used for array validation by means of qRT-PCR. In addition, western blotting and immunohistofluorescence of total and active Caspase 3 (Casp3), tumor necrosis factor receptor type 1 associated death domain (TRADD), tumor necrosis factor receptor superfamily member 1a (TNFR1a), and c-fos were performed to confirm their protein regulation and expression pattern in naive and injured retinas. These analyses demonstrated that for these genes, protein regulation followed transcriptional regulation and that these pro-apoptotic proteins were expressed by retinal ganglion cells (RGCs). MetaCore-based death-signaling maps show that several apoptotic cascades were regulated in the retina following optic nerve injury and highlight the similarities and differences between IONT and IONC in cell death profiling. CONCLUSIONS: This comprehensive time course retinal transcriptome study comparing IONT and IONC lesions provides a unique valuable tool to understand the molecular mechanisms underlying optic nerve injury and to design neuroprotective protocols.10aAnimals Cell Death Cluster Analysis Female *Gene Expression Profiling Gene Expression Regulation *Nerve Crush Optic Nerve/*metabolism/*pathology Optic Nerve Injuries/*genetics Rats Rats10aSprague-Dawley Reproducibility of Results Retina/*metabolism/*pathology Time Factors1 aAgudo, M.1 aPerez-Marin, M., C.1 aLonngren, U.1 aSobrado, P.1 aConesa, A.1 aCanovas, I.1 aSalinas-Navarro, M.1 aMiralles-Imperial, J.1 aHallbook, F.1 aVidal-Sanz, M. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1855298002515nas a2200289 4500008004100000245007500041210006900116300001200185490000800197520143200205653002101637653001201658653007101670653010001741653010001841100002301941700001401964700001501978700001801993700002202011700002002033700001602053700001702069700001302086700002002099856010602119 2008 eng d00aTranscriptional profiling of mRNA expression in the mouse distal colon0 aTranscriptional profiling of mRNA expression in the mouse distal a2019-290 v1353 aBACKGROUND & AIMS: Intestinal epithelial cells and the myenteric plexus of the mouse gastrointestinal tract contain a circadian clock-based intrinsic time-keeping system. Because disruption of the biological clock has been associated with increased susceptibility to colon cancer and gastrointestinal symptoms, we aimed to identify rhythmically expressed genes in the mouse distal colon. METHODS: Microarray analysis was used to identify genes that were rhythmically expressed over a 24-hour light/dark cycle. The transcripts were then classified according to expression pattern, function, and association with physiologic and pathophysiologic processes of the colon. RESULTS: A circadian gene expression pattern was detected in approximately 3.7% of distal colonic genes. A large percentage of these genes were involved in cell signaling, differentiation, and proliferation and cell death. Of all the rhythmically expressed genes in the mouse colon, approximately 7% (64/906) have been associated with colorectal cancer formation (eg, B-cell leukemia/lymphoma-2 [Bcl2]) and 1.8% (18/906) with various colonic functions such as motility and secretion (eg, vasoactive intestinal polypeptide, cystic fibrosis transmembrane conductance regulator). CONCLUSIONS: A subset of genes in the murine colon follows a rhythmic expression pattern. These findings may have significant implications for colonic physiology and pathophysiology.10aAnimals Blotting10aGenetic10aInbred C57BL Microarray Analysis Proteins/*genetics/metabolism RNA10aMessenger/biosynthesis/*genetics Reverse Transcriptase Polymerase Chain Reaction *Transcription10aWestern Cell Proliferation Circadian Rhythm/*genetics Colon/cytology/*metabolism Male Mice Mice1 aHoogerwerf, W., A.1 aSinha, M.1 aConesa, A.1 aLuxon, B., A.1 aShahinian, V., B.1 aCornelissen, G.1 aHalberg, F.1 aBostwick, J.1 aTimm, J.1 aCassone, V., M. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1884855703144nas a2200277 4500008004100000245020600041210006900247300001200316490000700328520162000335653020401955653006002159653012202219653025902341100001602600700001502616700001502631700001402646700001502660700001802675700001802693700001702711700001702728700001502745856010602760 2008 eng d00aTranscriptome analysis provides new insights into liver changes induced in the rat upon dietary administration of the food additives butylated hydroxytoluene, curcumin, propyl gallate and thiabendazole0 aTranscriptome analysis provides new insights into liver changes  a2616-280 v463 aTranscriptomics was performed to gain insight into mechanisms of food additives butylated hydroxytoluene (BHT), curcumin (CC), propyl gallate (PG), and thiabendazole (TB), additives for which interactions in the liver can not be excluded. Additives were administered in diets for 28 days to Sprague-Dawley rats and cDNA microarray experiments were performed on hepatic RNA. BHT induced changes in the expression of 10 genes, including phase I (CYP2B1/2; CYP3A9; CYP2C6) and phase II metabolism (GST mu2). The CYP2B1/2 and GST expression findings were confirmed by real time RT-PCR, western blotting, and increased GST activity towards DCNB. CC altered the expression of 12 genes. Three out of these were related to peroxisomes (phytanoyl-CoA dioxygenase, enoyl-CoA hydratase; CYP4A3). Increased cyanide insensitive palmitoyl-CoA oxidation was observed, suggesting that CC is a weak peroxisome proliferator. TB changed the expression of 12 genes, including CYP1A2. In line, CYP1A2 protein expression was increased. The expression level of five genes, associated with p53 was found to change upon TB treatment, including p53 itself, GADD45alpha, DN-7, protein kinase C beta and serum albumin. These array experiments led to the novel finding that TB is capable of inducing p53 at the protein level, at least at the highest dose levels employed above the current NOAEL. The expression of eight genes changed upon PG administration. This study shows the value of gene expression profiling in food toxicology in terms of generating novel hypotheses on the mechanisms of action of food additives in relation to pathology.10aAnimals Aryl Hydrocarbon Hydroxylases/metabolism Body Weight/drug effects Butylated Hydroxytoluene/toxicity Curcumin/toxicity Cytochrome P-450 CYP1A2/metabolism Cytochrome P-450 CYP2B1/metabolism DNA10aComplementary/biosynthesis/genetics Data Interpretation10aSprague-Dawley Reverse Transcriptase Polymerase Chain Reaction Steroid Hydroxylases/metabolism Thiabendazole/toxicity10aStatistical *Diet Food Additives/*toxicity Gene Expression/drug effects *Gene Expression Profiling Glutathione Transferase/metabolism Liver/*drug effects Male Organ Size/drug effects Oxidation-Reduction Palmitoyl Coenzyme A/metabolism Propyl Gallate/toxi1 aStierum, R.1 aConesa, A.1 aHeijne, W.1 aOmmen, B.1 aJunker, K.1 aScott, M., P.1 aPrice, R., J.1 aMeredith, C.1 aLake, B., G.1 aGroten, J. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1853937702909nas a2200241 4500008004100000245013300041210006900174300001200243490000700255520182100262653009602083653009302179653007402272653002302346653008902369100001802458700001502476700001602491700001502507700001502522700002402537856010602561 2008 eng d00aUse of estimated evolutionary strength at the codon level improves the prediction of disease-related protein mutations in humans0 aUse of estimated evolutionary strength at the codon level improv a198-2040 v293 aPredicting the functional impact of protein variation is one of the most challenging problems in bioinformatics. A rapidly growing number of genome-scale studies provide large amounts of experimental data, allowing the application of rigorous statistical approaches for predicting whether a given single point mutation has an impact on human health. Up until now, existing methods have limited their source data to either protein or gene information. Novel in this work, we take advantage of both and focus on protein evolutionary information by using estimated selective pressures at the codon level. Here we introduce a new method (SeqProfCod) to predict the likelihood that a given protein variant is associated with human disease or not. Our method relies on a support vector machine (SVM) classifier trained using three sources of information: protein sequence, multiple protein sequence alignments, and the estimation of selective pressure at the codon level. SeqProfCod has been benchmarked with a large dataset of 8,987 single point mutations from 1,434 human proteins from SWISS-PROT. It achieves 82% overall accuracy and a correlation coefficient of 0.59, indicating that the estimation of the selective pressure helps in predicting the functional impact of single-point mutations. Moreover, this study demonstrates the synergic effect of combining two sources of information for predicting the functional effects of protein variants: protein sequence/profile-based information and the evolutionary estimation of the selective pressures at the codon level. The results of large-scale application of SeqProfCod over all annotated point mutations in SWISS-PROT (available for download at http://sgu.bioinfo.cipf.es/services/Omidios/; last accessed: 24 August 2007), could be used to support clinical studies.10aAlgorithms Codon/genetics Computational Biology/*methods *DNA Mutational Analysis Databases10aHuman Humans Iduronic Acid/analogs & derivatives/metabolism *Point Mutation Polymorphism10aMolecular *Genetic Predisposition to Disease Genetic Variation Genome10aProtein *Evolution10aSingle Nucleotide Proteins/chemistry/*genetics Tumor Suppressor Protein p53/genetics1 aCapriotti, E.1 aArbiza, L.1 aCasadio, R.1 aDopazo, J.1 aDopazo, H.1 aMarti-Renom, M., A. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1793514803089nas a2200385 4500008004100000022001400041245013400055210006900189260001300258300001200271490000700283520182800290653001502118653001002133653002602143653002302169653002802192653002502220653003802245653002202283653001802305653001102323653001802334653001902352653003602371653001302407653003302420100002202453700002102475700001802496700002002514700002002534700002502554856012402579 2008 eng d a1098-100400aUse of estimated evolutionary strength at the codon level improves the prediction of disease-related protein mutations in humans.0 aUse of estimated evolutionary strength at the codon level improv c2008 Jan a198-2040 v293 a

Predicting the functional impact of protein variation is one of the most challenging problems in bioinformatics. A rapidly growing number of genome-scale studies provide large amounts of experimental data, allowing the application of rigorous statistical approaches for predicting whether a given single point mutation has an impact on human health. Up until now, existing methods have limited their source data to either protein or gene information. Novel in this work, we take advantage of both and focus on protein evolutionary information by using estimated selective pressures at the codon level. Here we introduce a new method (SeqProfCod) to predict the likelihood that a given protein variant is associated with human disease or not. Our method relies on a support vector machine (SVM) classifier trained using three sources of information: protein sequence, multiple protein sequence alignments, and the estimation of selective pressure at the codon level. SeqProfCod has been benchmarked with a large dataset of 8,987 single point mutations from 1,434 human proteins from SWISS-PROT. It achieves 82% overall accuracy and a correlation coefficient of 0.59, indicating that the estimation of the selective pressure helps in predicting the functional impact of single-point mutations. Moreover, this study demonstrates the synergic effect of combining two sources of information for predicting the functional effects of protein variants: protein sequence/profile-based information and the evolutionary estimation of the selective pressures at the codon level. The results of large-scale application of SeqProfCod over all annotated point mutations in SWISS-PROT (available for download at http://sgu.bioinfo.cipf.es/services/Omidios/; last accessed: 24 August 2007), could be used to support clinical studies.

10aAlgorithms10aCodon10aComputational Biology10aDatabases, Protein10aDNA Mutational Analysis10aEvolution, Molecular10aGenetic Predisposition to Disease10aGenetic Variation10aGenome, Human10aHumans10aIduronic Acid10aPoint Mutation10aPolymorphism, Single Nucleotide10aProteins10aTumor Suppressor Protein p531 aCapriotti, Emidio1 aArbiza, Leonardo1 aCasadio, Rita1 aDopazo, Joaquin1 aDopazo, Hernán1 aMarti-Renom, Marc, A uhttp://clinbioinfosspa.es/content/use-estimated-evolutionary-strength-codon-level-improves-prediction-disease-related-003856nas a2200385 4500008004100000245011000041210006900151300000700220490000600227520253000233653016602763653002902929653009302958100001403051700001503065700002203080700001503102700001403117700001503131700001303146700001503159700001403174700001503188700002103203700001303224700001403237700001503251700001703266700001903283700001503302700001603317700001703333700001403350856010603364 2007 eng d00aAnalysis of 13000 unique Citrus clusters associated with fruit quality, production and salinity tolerance0 aAnalysis of 13000 unique Citrus clusters associated with fruit q a310 v83 aBACKGROUND: Improvement of Citrus, the most economically important fruit crop in the world, is extremely slow and inherently costly because of the long-term nature of tree breeding and an unusual combination of reproductive characteristics. Aside from disease resistance, major commercial traits in Citrus are improved fruit quality, higher yield and tolerance to environmental stresses, especially salinity. RESULTS: A normalized full length and 9 standard cDNA libraries were generated, representing particular treatments and tissues from selected varieties (Citrus clementina and C. sinensis) and rootstocks (C. reshni, and C. sinenis x Poncirus trifoliata) differing in fruit quality, resistance to abscission, and tolerance to salinity. The goal of this work was to provide a large expressed sequence tag (EST) collection enriched with transcripts related to these well appreciated agronomical traits. Towards this end, more than 54000 ESTs derived from these libraries were analyzed and annotated. Assembly of 52626 useful sequences generated 15664 putative transcription units distributed in 7120 contigs, and 8544 singletons. BLAST annotation produced significant hits for more than 80% of the hypothetical transcription units and suggested that 647 of these might be Citrus specific unigenes. The unigene set, composed of 13000 putative different transcripts, including more than 5000 novel Citrus genes, was assigned with putative functions based on similarity, GO annotations and protein domains CONCLUSION: Comparative genomics with Arabidopsis revealed the presence of putative conserved orthologs and single copy genes in Citrus and also the occurrence of both gene duplication events and increased number of genes for specific pathways. In addition, phylogenetic analysis performed on the ammonium transporter family and glycosyl transferase family 20 suggested the existence of Citrus paralogs. Analysis of the Citrus gene space showed that the most important metabolic pathways known to affect fruit quality were represented in the unigene set. Overall, the similarity analyses indicated that the sequences of the genes belonging to these varieties and rootstocks were essentially identical, suggesting that the differential behaviour of these species cannot be attributed to major sequence divergences. This Citrus EST assembly contributes both crucial information to discover genes of agronomical interest and tools for genetic and genomic analyses, such as the development of new markers and microarrays.10aAcclimatization/*genetics Amino Acid Motifs Citrus/*genetics Cluster Analysis Expressed Sequence Tags Fruit/genetics Gene Duplication *Gene Expression Regulation10aPlant Gene Library Genes10aPlant Genomics Molecular Sequence Data Multigene Family Phylogeny *Salts/adverse effects1 aTerol, J.1 aConesa, A.1 aColmenero, J., M.1 aCercos, M.1 aTadeo, F.1 aAgusti, J.1 aAlos, E.1 aAndres, F.1 aSoler, G.1 aBrumos, J.1 aIglesias, D., J.1 aGotz, S.1 aLegaz, F.1 aArgout, X.1 aCourtois, B.1 aOllitrault, P.1 aDossat, C.1 aWincker, P.1 aMorillon, R.1 aTalon, M. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1725432702500nas a2200253 4500008004100000245008800041210006900129300000700198490001400205520139900219653007701618653005701695653019901752653003901951653002701990100002402017700001402041700002402055700001802079700001502097700001502112700001302127856010602140 2007 eng d00aThe AnnoLite and AnnoLyze programs for comparative annotation of protein structures0 aAnnoLite and AnnoLyze programs for comparative annotation of pro aS40 v8 Suppl 43 aBACKGROUND: Advances in structural biology, including structural genomics, have resulted in a rapid increase in the number of experimentally determined protein structures. However, about half of the structures deposited by the structural genomics consortia have little or no information about their biological function. Therefore, there is a need for tools for automatically and comprehensively annotating the function of protein structures. We aim to provide such tools by applying comparative protein structure annotation that relies on detectable relationships between protein structures to transfer functional annotations. Here we introduce two programs, AnnoLite and AnnoLyze, which use the structural alignments deposited in the DBAli database. DESCRIPTION: AnnoLite predicts the SCOP, CATH, EC, InterPro, PfamA, and GO terms with an average sensitivity of 90% and average precision of 80%. AnnoLyze predicts ligand binding site and domain interaction patches with an average sensitivity of 70% and average precision of 30%, correctly localizing binding sites for small molecules in 95% of its predictions. CONCLUSION: The AnnoLite and AnnoLyze programs for comparative annotation of protein structures can reliably and automatically annotate new protein structures. The programs are fully accessible via the Internet as part of the DBAli suite of tools at http://salilab.org/DBAli/.10a*Algorithms Amino Acid Sequence Confidence Intervals Data Interpretation10aAmino Acid *Software Structure-Activity Relationship10aProtein Information Storage and Retrieval/methods Molecular Sequence Data Proteins/*chemistry/classification/*metabolism Sensitivity and Specificity Sequence Alignment/*methods Sequence Analysis10aProtein/*methods Sequence Homology10aStatistical *Databases1 aMarti-Renom, M., A.1 aRossi, A.1 aAl-Shahrour, Fatima1 aDavis, F., P.1 aPieper, U.1 aDopazo, J.1 aSali, A. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1757014703226nas a2200433 4500008004100000245012400041210006900165300001100234490000700245520156900252653002601821653003101847653001201878653013601890653023502026653003902261100002202300700002202322700001802344700001702362700001602379700001402395700001502409700001902424700001402443700001602457700002402473700002302497700002302520700001802543700001602561700002302577700001602600700002002616700001502636700001902651700001602670856010602686 2007 eng d00aAssociation study of 69 genes in the ret pathway identifies low-penetrance loci in sporadic medullary thyroid carcinoma0 aAssociation study of 69 genes in the ret pathway identifies lowp a9561-70 v673 aTo date, few association studies have been done to better understand the genetic basis for the development of sporadic medullary thyroid carcinoma (sMTC). To identify additional low-penetrance genes, we have done a two-stage case-control study in two European populations using high-throughput genotyping. We selected 417 single nucleotide polymorphisms (SNP) belonging to 69 genes either related to RET signaling pathway/functions or involved in key processes for cancer development. TagSNPs and functional variants were included where possible. These SNPs were initially studied in the largest known series of sMTC cases (n = 266) and controls (n = 422), all of Spanish origin. In stage II, an independent British series of 155 sMTC patients and 531 controls was included to validate the previous results. Associations were assessed by an exhaustive analysis of individual SNPs but also considering gene- and linkage disequilibrium-based haplotypes. This strategy allowed us to identify seven low-penetrance genes, six of them (STAT1, AURKA, BCL2, CDKN2B, CDK6, and COMT) consistently associated with sMTC risk in the two case-control series and a seventh (HRAS) with individual SNPs and haplotypes associated with sMTC in the Spanish data set. The potential role of CDKN2B was confirmed by a functional assay showing a role of a SNP (rs7044859) in the promoter region in altering the binding of the transcription factor HNF1. These results highlight the utility of association studies using homogeneous series of cases for better understanding complex diseases.10a80 and over Carcinoma10aAdolescent Adult Aged Aged10aGenetic10aGenetic Proto-Oncogene Proteins c-ret/*genetics/metabolism Signal Transduction Thyroid Neoplasms/*genetics/metabolism Transcription10aMedullary/*genetics/metabolism Case-Control Studies Cyclin-Dependent Kinase Inhibitor p15/biosynthesis/genetics Female Genetic Predisposition to Disease Germ-Line Mutation Haplotypes Humans Male Middle Aged Penetrance Polymorphism10aSingle Nucleotide Promoter Regions1 aRuiz-Llorente, S.1 aMontero-Conde, C.1 aMilne, R., L.1 aMoya, C., M.1 aCebrian, A.1 aLeton, R.1 aCascon, A.1 aMercadillo, F.1 aLanda, I.1 aBorrego, S.1 ade Nanclares, Perez1 aAlvarez-Escola, C.1 aDiaz-Perez, J., A.1 aCarracedo, A.1 aUrioste, M.1 aGonzalez-Neira, A.1 aBenitez, J.1 aSantisteban, P.1 aDopazo, J.1 aPonder, B., A.1 aRobledo, M. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1790906702608nas a2200217 4500008004100000245009500041210006900136300001200205490000600217520172500223653008401948653002102032653012902053653002102182100001602203700001302219700001402232700002402246700001402270856010602284 2007 eng d00aCharacterization of protein hubs by inferring interacting motifs from protein interactions0 aCharacterization of protein hubs by inferring interacting motifs a1761-710 v33 aThe characterization of protein interactions is essential for understanding biological systems. While genome-scale methods are available for identifying interacting proteins, they do not pinpoint the interacting motifs (e.g., a domain, sequence segments, a binding site, or a set of residues). Here, we develop and apply a method for delineating the interacting motifs of hub proteins (i.e., highly connected proteins). The method relies on the observation that proteins with common interaction partners tend to interact with these partners through a common interacting motif. The sole input for the method are binary protein interactions; neither sequence nor structure information is needed. The approach is evaluated by comparing the inferred interacting motifs with domain families defined for 368 proteins in the Structural Classification of Proteins (SCOP). The positive predictive value of the method for detecting proteins with common SCOP families is 75% at sensitivity of 10%. Most of the inferred interacting motifs were significantly associated with sequence patterns, which could be responsible for the common interactions. We find that yeast hubs with multiple interacting motifs are more likely to be essential than hubs with one or two interacting motifs, thus rationalizing the previously observed correlation between essentiality and the number of interacting partners of a protein. We also find that yeast hubs with multiple interacting motifs evolve slower than the average protein, contrary to the hubs with one or two interacting motifs. The proposed method will help us discover unknown interacting motifs and provide biological insights about protein hubs and their roles in interaction networks.10aAmino Acid Motifs Amino Acid Sequence Binding Sites Computer Simulation *Models10aChemical *Models10aMolecular Molecular Sequence Data Protein Binding Protein Interaction Mapping/*methods Proteins/*chemistry Sequence Analysis10aProtein/*methods1 aAragues, R.1 aSali, A.1 aBonet, J.1 aMarti-Renom, M., A.1 aOliva, B. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1794170500423nas a2200097 4500008004100000245005700041210005400098260007600152100001500228856008200243 2007 eng d00aClustering - Class discovery in the post-genomic era0 aClustering Class discovery in the postgenomic era aNew York, USAbSpringer-Verlag, W. Dubitzky, M. Granzow and D.P. Berrar1 aDopazo, J. uhttp://clinbioinfosspa.es/content/clustering-class-discovery-post-genomic-era02151nas a2200277 4500008004100000245005200041210005100093300001100144490000700155520104000162653008701202653005701289653019401346653003901540653002701579100002401606700001501630700002401645700001401669700001401683700001801697700002401715700001501739700001301754856010601767 2007 eng d00aDBAli tools: mining the protein structure space0 aDBAli tools mining the protein structure space aW393-70 v353 aThe DBAli tools use a comprehensive set of structural alignments in the DBAli database to leverage the structural information deposited in the Protein Data Bank (PDB). These tools include (i) the DBAlit program that allows users to input the 3D coordinates of a protein structure for comparison by MAMMOTH against all chains in the PDB; (ii) the AnnoLite and AnnoLyze programs that annotate a target structure based on its stored relationships to other structures; (iii) the ModClus program that clusters structures by sequence and structure similarities; (iv) the ModDom program that identifies domains as recurrent structural fragments and (v) an implementation of the COMPARER method in the SALIGN command in MODELLER that creates a multiple structure alignment for a set of related protein structures. Thus, the DBAli tools, which are freely accessible via the World Wide Web at http://salilab.org/DBAli/, allow users to mine the protein structure space by establishing relationships between protein structures and their functions.10a*Algorithms Amino Acid Sequence Computational Biology/*methods Data Interpretation10aAmino Acid *Software Structure-Activity Relationship10aProtein Internet Molecular Sequence Data Protein Conformation Proteins/*chemistry/classification/*metabolism Pseudomonas aeruginosa/*metabolism Sequence Alignment/*methods Sequence Analysis10aProtein/*methods Sequence Homology10aStatistical *Databases1 aMarti-Renom, M., A.1 aPieper, U.1 aMadhusudhan, M., S.1 aRossi, A.1 aEswar, N.1 aDavis, F., P.1 aAl-Shahrour, Fatima1 aDopazo, J.1 aSali, A. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1747851302296nas a2200421 4500008004100000022001400041245005300055210005100108260001300159300001100172490000700183520104700190653001501237653002401252653002601276653003701302653002301339653001301362653002801375653002501403653001301428653002701441653002301468653003101491653003401522653001301556653003601569100002501605700001901630700002201649700001801671700002101689700001901710700002501729700002001754700001701774856008301791 2007 eng d a1362-496200aDBAli tools: mining the protein structure space.0 aDBAli tools mining the protein structure space c2007 Jul aW393-70 v353 a

The DBAli tools use a comprehensive set of structural alignments in the DBAli database to leverage the structural information deposited in the Protein Data Bank (PDB). These tools include (i) the DBAlit program that allows users to input the 3D coordinates of a protein structure for comparison by MAMMOTH against all chains in the PDB; (ii) the AnnoLite and AnnoLyze programs that annotate a target structure based on its stored relationships to other structures; (iii) the ModClus program that clusters structures by sequence and structure similarities; (iv) the ModDom program that identifies domains as recurrent structural fragments and (v) an implementation of the COMPARER method in the SALIGN command in MODELLER that creates a multiple structure alignment for a set of related protein structures. Thus, the DBAli tools, which are freely accessible via the World Wide Web at http://salilab.org/DBAli/, allow users to mine the protein structure space by establishing relationships between protein structures and their functions.

10aAlgorithms10aAmino Acid Sequence10aComputational Biology10aData Interpretation, Statistical10aDatabases, Protein10aInternet10aMolecular Sequence Data10aProtein Conformation10aProteins10aPseudomonas aeruginosa10aSequence Alignment10aSequence Analysis, Protein10aSequence Homology, Amino Acid10aSoftware10aStructure-Activity Relationship1 aMarti-Renom, Marc, A1 aPieper, Ursula1 aMadhusudhan, M, S1 aRossi, Andrea1 aEswar, Narayanan1 aDavis, Fred, P1 aAl-Shahrour, Fátima1 aDopazo, Joaquin1 aSali, Andrej uhttp://clinbioinfosspa.es/content/dbali-tools-mining-protein-structure-space-002714nas a2200253 4500008004100000245009200041210006900133300001300202490000700215520168800222653010801910653001202018653001902030653005802049653012102107100001802228700001502246700002302261700002202284700001902306700001402325700001502339856010602354 2007 eng d00aDiscovering gene expression patterns in time course microarray experiments by ANOVA-SCA0 aDiscovering gene expression patterns in time course microarray e a1792-8000 v233 aMOTIVATION: Designed microarray experiments are used to investigate the effects that controlled experimental factors have on gene expression and learn about the transcriptional responses associated with external variables. In these datasets, signals of interest coexist with varying sources of unwanted noise in a framework of (co)relation among the measured variables and with the different levels of the studied factors. Discovering experimentally relevant transcriptional changes require methodologies that take all these elements into account. RESULTS: In this work, we develop the application of the Analysis of variance-simultaneous component analysis (ANOVA-SCA) Smilde et al. Bioinformatics, (2005) to the analysis of multiple series time course microarray data as an example of multifactorial gene expression profiling experiments. We denoted this implementation as ASCA-genes. We show how the combination of ANOVA-modeling and a dimension reduction technique is effective in extracting targeted signals from data by-passing structural noise. The methodology is valuable for identifying main and secondary responses associated with the experimental factors and spotting relevant experimental conditions. We additionally propose a novel approach for gene selection in the context of the relation of individual transcriptional patterns to global gene expression signals. We demonstrate the methodology on both real and synthetic datasets. AVAILABILITY: ASCA-genes has been implemented in the statistical language R and is available at http://www.ivia.es/centrodegenomica/bioinformatics.htm. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.10aAlgorithms *Analysis of Variance Computational Biology/*methods Computer Simulation Data Interpretation10aGenetic10aGenetic Models10aStatistical Gene Expression Profiling/*methods Models10aStatistical Oligonucleotide Array Sequence Analysis/*methods Principal Component Analysis Time Factors Transcription1 aNueda, M., J.1 aConesa, A.1 aWesterhuis, J., A.1 aHoefsloot, H., C.1 aSmilde, A., K.1 aTalon, M.1 aFerrer, A. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1751925002985nas a2200421 4500008004100000022001400041245007000055210006800125260001600193300000800209490000600217520169900223653003601922653003001958653004301988653001102031653000902042653002302051653002002074653002402094653002202118653001402140653002402154653003202178653001902210653002402229653002002253100002202273700002402295700002002319700002502339700001602364700001702380700002202397700002002419700002602439856009802465 2007 eng d a1471-216400aEvidence for systems-level molecular mechanisms of tumorigenesis.0 aEvidence for systemslevel molecular mechanisms of tumorigenesis c2007 Jun 20 a1850 v83 a

BACKGROUND: Cancer arises from the consecutive acquisition of genetic alterations. Increasing evidence suggests that as a consequence of these alterations, molecular interactions are reprogrammed in the context of highly connected and regulated cellular networks. Coordinated reprogramming would allow the cell to acquire the capabilities for malignant growth.

RESULTS: Here, we determine the coordinated function of cancer gene products (i.e., proteins encoded by differentially expressed genes in tumors relative to healthy tissue counterparts, hereafter referred to as "CGPs") defined as their topological properties and organization in the interactome network. We show that CGPs are central to information exchange and propagation and that they are specifically organized to promote tumorigenesis. Centrality is identified by both local (degree) and global (betweenness and closeness) measures, and systematically appears in down-regulated CGPs. Up-regulated CGPs do not consistently exhibit centrality, but both types of cancer products determine the overall integrity of the network structure. In addition to centrality, down-regulated CGPs show topological association that correlates with common biological processes and pathways involved in tumorigenesis.

CONCLUSION: Given the current limited coverage of the human interactome, this study proposes that tumorigenesis takes place in a specific and organized way at the molecular systems-level and suggests a model that comprises the precise down-regulation of groups of topologically-associated proteins involved in particular functions, orchestrated with the up-regulation of specific proteins.

10aCell Transformation, Neoplastic10aGene Expression Profiling10aGene Expression Regulation, Neoplastic10aHumans10aMale10aModels, Biological10aModels, Genetic10aModels, Statistical10aNeoplasm Proteins10aNeoplasms10aProstatic Neoplasms10aProtein Interaction Mapping10aRNA, Messenger10aSignal Transduction10aSystems biology1 aHernández, Pilar1 aHuerta-Cepas, Jaime1 aMontaner, David1 aAl-Shahrour, Fátima1 aValls, Joan1 aGómez, Laia1 aCapellà, Gabriel1 aDopazo, Joaquin1 aPujana, Miguel, Angel uhttp://clinbioinfosspa.es/content/evidence-systems-level-molecular-mechanisms-tumorigenesis-002784nas a2200301 4500008004100000245006900041210006800110300000800178490000600186520165900192653002501851653002201876653001901898653006101917653007001978653003402048653013602082100001802218700002102236700001702257700002402274700001402298700001402312700001602326700001502342700001902357856010602376 2007 eng d00aEvidence for systems-level molecular mechanisms of tumorigenesis0 aEvidence for systemslevel molecular mechanisms of tumorigenesis a1850 v83 aBACKGROUND: Cancer arises from the consecutive acquisition of genetic alterations. Increasing evidence suggests that as a consequence of these alterations, molecular interactions are reprogrammed in the context of highly connected and regulated cellular networks. Coordinated reprogramming would allow the cell to acquire the capabilities for malignant growth. RESULTS: Here, we determine the coordinated function of cancer gene products (i.e., proteins encoded by differentially expressed genes in tumors relative to healthy tissue counterparts, hereafter referred to as "CGPs") defined as their topological properties and organization in the interactome network. We show that CGPs are central to information exchange and propagation and that they are specifically organized to promote tumorigenesis. Centrality is identified by both local (degree) and global (betweenness and closeness) measures, and systematically appears in down-regulated CGPs. Up-regulated CGPs do not consistently exhibit centrality, but both types of cancer products determine the overall integrity of the network structure. In addition to centrality, down-regulated CGPs show topological association that correlates with common biological processes and pathways involved in tumorigenesis. CONCLUSION: Given the current limited coverage of the human interactome, this study proposes that tumorigenesis takes place in a specific and organized way at the molecular systems-level and suggests a model that comprises the precise down-regulation of groups of topologically-associated proteins involved in particular functions, orchestrated with the up-regulation of specific proteins.10a*Cell Transformation10aBiological Models10aGenetic Models10aMessenger/metabolism Signal Transduction Systems Biology10aNeoplastic *Gene Expression Profiling *Gene Expression Regulation10aNeoplastic Humans Male Models10aStatistical Neoplasm Proteins/*physiology Neoplasms/etiology/*genetics Prostatic Neoplasms/genetics Protein Interaction Mapping RNA1 aHernandez, P.1 aHuerta-Cepas, J.1 aMontaner, D.1 aAl-Shahrour, Fatima1 aValls, J.1 aGomez, L.1 aCapella, G.1 aDopazo, J.1 aPujana, M., A. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1758491500519nas a2200121 4500008004100000245007600041210006900117260004900186100001600235700002300251700001500274856010800289 2007 eng d00af single nucleotide polymorphism arrays: Design, tools and applications0 af single nucleotide polymorphism arrays Design tools and applica aNew York, USAbTaylor & Francis, F. Falciani1 aRobledo, M.1 aGonzález-Neira, A1 aDopazo, J. uhttp://clinbioinfosspa.es/content/f-single-nucleotide-polymorphism-arrays-design-tools-and-applications02196nas a2200217 4500008004100000245016500041210006900206300001000275490000700285520140700292653001501699653003501714100002401749700001601773700001601789700002001805700001501825700001701840700001501857856010601872 2007 eng d00aFatiGO +: a functional profiling tool for genomic data. Integration of functional annotation, regulatory motifs and interaction data with microarray experiments0 aFatiGO a functional profiling tool for genomic data Integration  aW91-60 v353 a

The ultimate goal of any genome-scale experiment is to provide a functional interpretation of the data, relating the available information with the hypotheses that originated the experiment. Thus, functional profiling methods have become essential in diverse scenarios such as microarray experiments, proteomics, etc. We present the FatiGO+, a web-based tool for the functional profiling of genome-scale experiments, specially oriented to the interpretation of microarray experiments. In addition to different functional annotations (gene ontology, KEGG pathways, Interpro motifs, Swissprot keywords and text-mining based bioentities related to diseases and chemical compounds) FatiGO+ includes, as a novelty, regulatory and structural information. The regulatory information used includes predictions of targets for distinct regulatory elements (obtained from the Transfac and CisRed databases). Additionally FatiGO+ uses predictions of target motifs of miRNA to infer which of these can be activated or deactivated in the sample of genes studied. Finally, properties of gene products related to their relative location and connections in the interactome have also been used. Also, enrichment of any of these functional terms can be directly analysed on chromosomal coordinates. FatiGO+ can be found at: http://www.fatigoplus.org and within the Babelomics environment http://www.babelomics.org.

10ababelomics10afunctional enrichment analysys1 aAl-Shahrour, Fatima1 aMinguez, P.1 aTarraga, J.1 aMedina, Ignacio1 aAlloza, E.1 aMontaner, D.1 aDopazo, J. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1747850402675nas a2200385 4500008004100000022001400041245016600055210006900221260001300290300001000303490000700313520140700320653002201727653001201749653001801761653002601779653003001805653001001835653001301845653001101858653001301869653004401882653002601926653001301952653002401965653002601989100002502015700001902040700002302059700002002082700001602102700002002118700002002138856013102158 2007 eng d a1362-496200aFatiGO +: a functional profiling tool for genomic data. Integration of functional annotation, regulatory motifs and interaction data with microarray experiments.0 aFatiGO a functional profiling tool for genomic data Integration  c2007 Jul aW91-60 v353 a

The ultimate goal of any genome-scale experiment is to provide a functional interpretation of the data, relating the available information with the hypotheses that originated the experiment. Thus, functional profiling methods have become essential in diverse scenarios such as microarray experiments, proteomics, etc. We present the FatiGO+, a web-based tool for the functional profiling of genome-scale experiments, specially oriented to the interpretation of microarray experiments. In addition to different functional annotations (gene ontology, KEGG pathways, Interpro motifs, Swissprot keywords and text-mining based bioentities related to diseases and chemical compounds) FatiGO+ includes, as a novelty, regulatory and structural information. The regulatory information used includes predictions of targets for distinct regulatory elements (obtained from the Transfac and CisRed databases). Additionally FatiGO+ uses predictions of target motifs of miRNA to infer which of these can be activated or deactivated in the sample of genes studied. Finally, properties of gene products related to their relative location and connections in the interactome have also been used. Also, enrichment of any of these functional terms can be directly analysed on chromosomal coordinates. FatiGO+ can be found at: http://www.fatigoplus.org and within the Babelomics environment http://www.babelomics.org.

10aAmino Acid Motifs10aAnimals10aBinding Sites10aComputational Biology10aGene Expression Profiling10aGenes10aGenomics10aHumans10aInternet10aOligonucleotide Array Sequence Analysis10aProgramming Languages10aSoftware10aSystems Integration10aTranscription Factors1 aAl-Shahrour, Fátima1 aMinguez, Pablo1 aTárraga, Joaquín1 aMedina, Ignacio1 aAlloza, Eva1 aMontaner, David1 aDopazo, Joaquin uhttp://clinbioinfosspa.es/content/fatigo-functional-profiling-tool-genomic-data-integration-functional-annotation-regulatory-002090nas a2200169 4500008004100000245011600041210006900157300000900226490000600235520123000241653007701471653008501548653014401633100001801777700001901795856010601814 2007 eng d00aFrom endosymbiont to host-controlled organelle: the hijacking of mitochondrial protein synthesis and metabolism0 aFrom endosymbiont to hostcontrolled organelle the hijacking of m ae2190 v33 aMitochondria are eukaryotic organelles that originated from the endosymbiosis of an alpha-proteobacterium. To gain insight into the evolution of the mitochondrial proteome as it proceeded through the transition from a free-living cell to a specialized organelle, we compared a reconstructed ancestral proteome of the mitochondrion with the proteomes of alpha-proteobacteria as well as with the mitochondrial proteomes in yeast and man. Overall, there has been a large turnover of the mitochondrial proteome during the evolution of mitochondria. Early in the evolution of the mitochondrion, proteins involved in cell envelope synthesis have virtually disappeared, whereas proteins involved in replication, transcription, cell division, transport, regulation, and signal transduction have been replaced by eukaryotic proteins. More than half of what remains from the mitochondrial ancestor in modern mitochondria corresponds to translation, including post-translational modifications, and to metabolic pathways that are directly, or indirectly, involved in energy conversion. Altogether, the results indicate that the eukaryotic host has hijacked the proto-mitochondrion, taking control of its protein synthesis and metabolism.10aComputer Simulation DNA Mutational Analysis/methods Evolution *Evolution10aGenetic Organelles/physiology Protein Biosynthesis/*genetics Symbiosis/*genetics10aMolecular Fungal Proteins/*physiology Genetic Variation/genetics Humans Mitochondria/*physiology Mitochondrial Proteins/*physiology *Models1 aGabaldón, T.1 aHuynen, M., A. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1798326502367nas a2200229 4500008004100000245007200041210006900113300000800182490000600190520145600196653010501652653001501757653013601772100002401908700001501932700001501947700002101962700001601983700001701999700001502016856010602031 2007 eng d00aFrom genes to functional classes in the study of biological systems0 aFrom genes to functional classes in the study of biological syst a1140 v83 a

BACKGROUND: With the popularization of high-throughput techniques, the need for procedures that help in the biological interpretation of results has increased enormously. Recently, new procedures inspired in systems biology criteria have started to be developed. RESULTS: Here we present FatiScan, a web-based program which implements a threshold-independent test for the functional interpretation of large-scale experiments that does not depend on the pre-selection of genes based on the multiple application of independent tests to each gene. The test implemented aims to directly test the behaviour of blocks of functionally related genes, instead of focusing on single genes. In addition, the test does not depend on the type of the data used for obtaining significance values, and consequently different types of biologically informative terms (gene ontology, pathways, functional motifs, transcription factor binding sites or regulatory sites from CisRed) can be applied to different classes of genome-scale studies. We exemplify its application in microarray gene expression, evolution and interactomics. CONCLUSION: Methods for gene set enrichment which, in addition, are independent from the original data and experimental design constitute a promising alternative for the functional profiling of genome-scale experiments. A web server that performs the test described and other similar ones can be found at: http://www.babelomics.org.

10aAlgorithms Chromosome Mapping/*methods Computer Simulation Gene Expression Profiling/methods *Models10ababelomics10aBiological Multigene Family/*physiology Signal Transduction/*physiology *Software Systems Biology/*methods *User-Computer Interface1 aAl-Shahrour, Fatima1 aArbiza, L.1 aDopazo, H.1 aHuerta-Cepas, J.1 aMinguez, P.1 aMontaner, D.1 aDopazo, J. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1740759602514nas a2200337 4500008004100000022001400041245007300055210006900128260001600197300000800213490000600221520148900227653001501716653002301731653002401754653003001778653002301808653002101831653002401852653001301876653002001889653002801909100002501937700002101962700002001983700002402003700001902027700002002046700002002066856009002086 2007 eng d a1471-210500aFrom genes to functional classes in the study of biological systems.0 aFrom genes to functional classes in the study of biological syst c2007 Apr 03 a1140 v83 a

BACKGROUND: With the popularization of high-throughput techniques, the need for procedures that help in the biological interpretation of results has increased enormously. Recently, new procedures inspired in systems biology criteria have started to be developed.

RESULTS: Here we present FatiScan, a web-based program which implements a threshold-independent test for the functional interpretation of large-scale experiments that does not depend on the pre-selection of genes based on the multiple application of independent tests to each gene. The test implemented aims to directly test the behaviour of blocks of functionally related genes, instead of focusing on single genes. In addition, the test does not depend on the type of the data used for obtaining significance values, and consequently different types of biologically informative terms (gene ontology, pathways, functional motifs, transcription factor binding sites or regulatory sites from CisRed) can be applied to different classes of genome-scale studies. We exemplify its application in microarray gene expression, evolution and interactomics.

CONCLUSION: Methods for gene set enrichment which, in addition, are independent from the original data and experimental design constitute a promising alternative for the functional profiling of genome-scale experiments. A web server that performs the test described and other similar ones can be found at: http://www.babelomics.org.

10aAlgorithms10aChromosome Mapping10aComputer Simulation10aGene Expression Profiling10aModels, Biological10aMultigene Family10aSignal Transduction10aSoftware10aSystems biology10aUser-Computer Interface1 aAl-Shahrour, Fátima1 aArbiza, Leonardo1 aDopazo, Hernán1 aHuerta-Cepas, Jaime1 aMinguez, Pablo1 aMontaner, David1 aDopazo, Joaquin uhttp://clinbioinfosspa.es/content/genes-functional-classes-study-biological-systems-000426nas a2200109 4500008004100000245005200041210005200093260004900145100001500194700002400209856008300233 2007 eng d00aFunctional annotation of microarray experiments0 aFunctional annotation of microarray experiments aNew York, USAbTaylor & Francis, F. Falciani1 aDopazo, J.1 aAl-Shahrour, Fatima uhttp://clinbioinfosspa.es/content/functional-annotation-microarray-experiments01766nas a2200205 4500008004100000022001400041245009400055210006900149260001600218300001000234490000600244520105200250100001701302700002001319700002701339700002301366700002501389700002001414856012601434 2007 eng d a0973-206300aFunctional profiling and gene expression analysis of chromosomal copy number alterations.0 aFunctional profiling and gene expression analysis of chromosomal c2007 Apr 10 a432-50 v13 a

Contrarily to the traditional view in which only one or a few key genes were supposed to be the causative factors of diseases, we discuss the importance of considering groups of functionally related genes in the study of pathologies characterised by chromosomal copy number alterations. Recent observations have reported the existence of regions in higher eukaryotic chromosomes (including humans) containing genes of related function that show a high degree of coregulation. Copy number alterations will consequently affect to clusters of functionally related genes, which will be the final causative agents of the diseased phenotype, in many cases. Therefore, we propose that the functional profiling of the regions affected by copy number alterations must be an important aspect to take into account in the understanding of this type of pathologies. To illustrate this, we present an integrated study of DNA copy number variations, gene expression along with the functional profiling of chromosomal regions in a case of multiple myeloma.

1 aConde, Lucia1 aMontaner, David1 aBurguet-Castell, Jordi1 aTárraga, Joaquín1 aAl-Shahrour, Fátima1 aDopazo, Joaquin uhttp://clinbioinfosspa.es/content/functional-profiling-and-gene-expression-analysis-chromosomal-copy-number-alterations-001696nas a2200193 4500008004100000245009300041210006900134300001000203490000600213520105200219653001501271100001401286700001701300700002401317700001601341700002401357700001501381856010601396 2007 eng d00aFunctional profiling and gene expression analysis of chromosomal copy number alterations0 aFunctional profiling and gene expression analysis of chromosomal a432-50 v13 a

Contrarily to the traditional view in which only one or a few key genes were supposed to be the causative factors of diseases, we discuss the importance of considering groups of functionally related genes in the study of pathologies characterised by chromosomal copy number alterations. Recent observations have reported the existence of regions in higher eukaryotic chromosomes (including humans) containing genes of related function that show a high degree of coregulation. Copy number alterations will consequently affect to clusters of functionally related genes, which will be the final causative agents of the diseased phenotype, in many cases. Therefore, we propose that the functional profiling of the regions affected by copy number alterations must be an important aspect to take into account in the understanding of this type of pathologies. To illustrate this, we present an integrated study of DNA copy number variations, gene expression along with the functional profiling of chromosomal regions in a case of multiple myeloma.

10ababelomics1 aConde, L.1 aMontaner, D.1 aBurguet-Castell, J.1 aTarraga, J.1 aAl-Shahrour, Fatima1 aDopazo, J. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1759793501718nas a2200277 4500008004100000022001400041245009000055210006900145260001600214300001100230490000700241520077800248653002801026653002301054653003001077653003801107653003201145653001301177653002001190653002401210100001901234700002501253700002001278700002001298856012201318 2007 eng d a1367-481100aFunctional profiling of microarray experiments using text-mining derived bioentities.0 aFunctional profiling of microarray experiments using textmining  c2007 Nov 15 a3098-90 v233 a

MOTIVATION: The increasing use of microarray technologies brought about a parallel demand in methods for the functional interpretation of the results. Beyond the conventional functional annotations for genes, such as gene ontology, pathways, etc. other sources of information are still to be exploited. Text-mining methods allow extracting informative terms (bioentities) with different functional, chemical, clinical, etc. meanings, that can be associated to genes. We show how to use these associations within an appropriate statistical framework and how to apply them through easy-to-use, web-based environments to the functional interpretation of microarray experiments. Functional enrichment and gene set enrichment tests using bioentities are presented.

10aArtificial Intelligence10aDatabases, Protein10aGene Expression Profiling10aInformation Storage and Retrieval10aNatural Language Processing10aProteins10aResearch Design10aSystems Integration1 aMinguez, Pablo1 aAl-Shahrour, Fátima1 aMontaner, David1 aDopazo, Joaquin uhttp://clinbioinfosspa.es/content/functional-profiling-microarray-experiments-using-text-mining-derived-bioentities-001608nas a2200193 4500008004100000245008900041210006900130300001100199490000700210520077100217653003900988653001501027653019401042100001601236700002401252700001701276700001501293856010601308 2007 eng d00aFunctional profiling of microarray experiments using text-mining derived bioentities0 aFunctional profiling of microarray experiments using textmining  a3098-90 v233 a

MOTIVATION: The increasing use of microarray technologies brought about a parallel demand in methods for the functional interpretation of the results. Beyond the conventional functional annotations for genes, such as gene ontology, pathways, etc. other sources of information are still to be exploited. Text-mining methods allow extracting informative terms (bioentities) with different functional, chemical, clinical, etc. meanings, that can be associated to genes. We show how to use these associations within an appropriate statistical framework and how to apply them through easy-to-use, web-based environments to the functional interpretation of microarray experiments. Functional enrichment and gene set enrichment tests using bioentities are presented.

10aArtificial Intelligence *Databases10ababelomics10aProtein Gene Expression Profiling/*methods Information Storage and Retrieval/*methods *Natural Language Processing Proteins/*classification/*metabolism Research/*methods Systems Integration1 aMinguez, P.1 aAl-Shahrour, Fatima1 aMontaner, D.1 aDopazo, J. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1785541502363nas a2200193 4500008004100000245002200041210001800063300000900081490000600090520176400096653003301860653000801893653009301901100002101994700001502015700001502030700001802045856010602063 2007 eng d00aThe human phylome0 ahuman phylome aR1090 v83 aBACKGROUND: Phylogenomics analyses serve to establish evolutionary relationships among organisms and their genes. A phylome, the complete collection of all gene phylogenies in a genome, constitutes a valuable source of information, but its use in large genomes still constitutes a technical challenge. The use of phylomes also requires the development of new methods that help us to interpret them. RESULTS: We reconstruct here the human phylome, which includes the evolutionary relationships of all human proteins and their homologs among 39 fully sequenced eukaryotes. Phylogenetic techniques used include alignment trimming, branch length optimization, evolutionary model testing and maximum likelihood and Bayesian methods. Although differences with alternative topologies are minor, most of the trees support the Coelomata and Unikont hypotheses as well as the grouping of primates with laurasatheria to the exclusion of rodents. We assess the extent of gene duplication events and their relationship with the functional roles of the protein families involved. We find support for at least one, and probably two, rounds of whole genome duplications before vertebrate radiation. Using a novel algorithm that is independent from a species phylogeny, we derive orthology and paralogy relationships of human proteins among eukaryotic genomes. CONCLUSION: Topological variations among phylogenies for different genes are to be expected, highlighting the danger of gene-sampling effects in phylogenomic analyses. Several links can be established between the functions of gene families duplicated at certain phylogenetic splits and major evolutionary transitions in those lineages. The pipeline implemented here can be easily adapted for use in other organisms.10aAnimals *Evolution Evolution10aDNA10aMolecular Gene Duplication *Genome Humans *Phylogeny Proteins/genetics Sequence Analysis1 aHuerta-Cepas, J.1 aDopazo, H.1 aDopazo, J.1 aGabaldón, T. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1756792402732nas a2200205 4500008004100000245017300041210006900214300000800283490000600291520176400297653006302061653002302124653005002147653015802197100001302355700002302368700001502391700001402406856010602420 2007 eng d00aIdentification of conserved domains in the promoter regions of nitric oxide synthase 2: implications for the species-specific transcription and evolutionary differences0 aIdentification of conserved domains in the promoter regions of n a2710 v83 aBACKGROUND: The majority of the genes involved in the inflammatory response are highly conserved in mammals. These genes are not significantly expressed under normal conditions and are mainly regulated at the transcription and prost-transcriptional level. Transcription from the promoters of these genes is very dependent on NF-kappaB activation, which integrates the response to diverse extracellular stresses. However, in spite of the high conservation of the pattern of promoter regulation in kappaB-regulated genes, there is inter-species diversity in some genes. One example is nitric oxide synthase 2 (NOS-2), which exhibits a species-specific pattern of expression in response to infection or pro-inflammatory challenge. RESULTS: We have conducted a comparative genomic analysis of NOS-2 with different bioinformatic approaches. This analysis shows that in the NOS-2 gene promoter the position and the evolutionary divergence of some conserved regions are different in rodents and non-rodent mammals, and in particular in primates. Two not previously described distal regions in rodents that are similar to the unique upstream region responsible of the NF-kappaB activation of NOS-2 in humans are fragmented and translocated to different locations in the rodent promoters. The rodent sequences moreover lack the functional kappaB sites and IFN-gamma response sites present in the homologous human, rhesus monkey and chimpanzee regions. The absence of kappaB binding in these regions was confirmed by electrophoretic mobility shift assays. CONCLUSION: The data presented reveal divergence between rodents and other mammals in the location and functionality of conserved regions of the NOS-2 promoter containing NF-kappaB and IFN-gamma response elements.10aAnimals Base Sequence Conserved Sequence Enhancer Elements10aGenetic *Evolution10aGenetic Response Elements Species Specificity10aMolecular Humans Inflammation/metabolism Interferon-gamma/metabolism Mice NF-kappa B/metabolism Nitric Oxide Synthase Type II/*genetics *Promoter Regions1 aRico, D.1 aVaquerizas, J., M.1 aDopazo, H.1 aBosca, L. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1768618202054nas a2200385 4500008004100000022001400041245012300055210006900178260001300247300001000260490000700270520079500277653001201072653002101084653002601105653002201131653003001153653001101183653001301194653002001207653003101227653004401258653002601302653001301328653002401341653002801365100001701393700002001410700002701430700002301457700002001480700002501500700002001525856012301545 2007 eng d a1362-496200aISACGH: a web-based environment for the analysis of Array CGH and gene expression which includes functional profiling.0 aISACGH a webbased environment for the analysis of Array CGH and  c2007 Jul aW81-50 v353 a

We present the ISACGH, a web-based system that allows for the combination of genomic data with gene expression values and provides different options for functional profiling of the regions found. Several visualization options offer a convenient representation of the results. Different efficient methods for accurate estimation of genomic copy number from array-CGH hybridization data have been included in the program. Moreover, the connection to the gene expression analysis package GEPAS allows the use of different facilities for data pre-processing and analysis. A DAS server allows exporting the results to the Ensembl viewer where contextual genomic information can be obtained. The program is freely available at: http://isacgh.bioinfo.cipf.es or within http://www.gepas.org.

10aAnimals10aCluster Analysis10aComputational Biology10aComputer Graphics10aGene Expression Profiling10aHumans10aInternet10aModels, Genetic10aNucleic Acid Hybridization10aOligonucleotide Array Sequence Analysis10aProgramming Languages10aSoftware10aSystems Integration10aUser-Computer Interface1 aConde, Lucia1 aMontaner, David1 aBurguet-Castell, Jordi1 aTárraga, Joaquín1 aMedina, Ignacio1 aAl-Shahrour, Fátima1 aDopazo, Joaquin uhttp://clinbioinfosspa.es/content/isacgh-web-based-environment-analysis-array-cgh-and-gene-expression-which-includes-001792nas a2200217 4500008004100000245012200041210006900163300001000232490000700242520078800249653013601037653016501173100001401338700001701352700002401369700001601393700002001409700002401429700001501453856010601468 2007 eng d00aISACGH: a web-based environment for the analysis of Array CGH and gene expression which includes functional profiling0 aISACGH a webbased environment for the analysis of Array CGH and  aW81-50 v353 aWe present the ISACGH, a web-based system that allows for the combination of genomic data with gene expression values and provides different options for functional profiling of the regions found. Several visualization options offer a convenient representation of the results. Different efficient methods for accurate estimation of genomic copy number from array-CGH hybridization data have been included in the program. Moreover, the connection to the gene expression analysis package GEPAS allows the use of different facilities for data pre-processing and analysis. A DAS server allows exporting the results to the Ensembl viewer where contextual genomic information can be obtained. The program is freely available at: http://isacgh.bioinfo.cipf.es or within http://www.gepas.org.10aAnimals Cluster Analysis Computational Biology/*methods Computer Graphics Gene Expression Profiling/*methods Humans Internet Models10aGenetic *Nucleic Acid Hybridization Oligonucleotide Array Sequence Analysis/*methods Programming Languages *Software Systems Integration User-Computer Interface1 aConde, L.1 aMontaner, D.1 aBurguet-Castell, J.1 aTarraga, J.1 aMedina, Ignacio1 aAl-Shahrour, Fatima1 aDopazo, J. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1746849900555nas a2200169 4500008004100000022001800041245005100059210005100110260005300161300001200214653001500226100001500241700001600256700001400272700001700286856008200303 2007 eng d a0-4153-7853-200aMicroarray Technology in Agricultural Research0 aMicroarray Technology in Agricultural Research bF. Falciani. Publisher: Taylor and Francis Group a173-20910ababelomics1 aConesa, A.1 aForment, J.1 aGadea, J.1 avan Dijk, J. uhttp://clinbioinfosspa.es/content/microarray-technology-agricultural-research00491nas a2200157 4500008004100000022002200041245005800063210005800121260002100179300001200200490000700212100001700219700002400236700001500260856005800275 2007 eng d a978-3-540-71991-500aNew Trends in the Analysis of Functional Genomic Data0 aNew Trends in the Analysis of Functional Genomic Data aBerlinbSpringer a576-5800 v121 aMontaner, D.1 aAl-Shahrour, Fatima1 aDopazo, J. uhttp://www.springerlink.com/content/m62p07r8111004vr/02580nas a2200253 4500008004100000245009100041210006900132300001200201490000700213520154400220653002301764653025501787100001702042700001702059700002502076700001802101700002102119700002002140700001302160700002002173700001302193700001402206856010602220 2007 eng d00aPeroxisomeDB: a database for the peroxisomal proteome, functional genomics and disease0 aPeroxisomeDB a database for the peroxisomal proteome functional  aD815-220 v353 aPeroxisomes are essential organelles of eukaryotic origin, ubiquitously distributed in cells and organisms, playing key roles in lipid and antioxidant metabolism. Loss or malfunction of peroxisomes causes more than 20 fatal inherited conditions. We have created a peroxisomal database (http://www.peroxisomeDB.org) that includes the complete peroxisomal proteome of Homo sapiens and Saccharomyces cerevisiae, by gathering, updating and integrating the available genetic and functional information on peroxisomal genes. PeroxisomeDB is structured in interrelated sections ’Genes’, ’Functions’, ’Metabolic pathways’ and ’Diseases’, that include hyperlinks to selected features of NCBI, ENSEMBL and UCSC databases. We have designed graphical depictions of the main peroxisomal metabolic routes and have included updated flow charts for diagnosis. Precomputed BLAST, PSI-BLAST, multiple sequence alignment (MUSCLE) and phylogenetic trees are provided to assist in direct multispecies comparison to study evolutionary conserved functions and pathways. Highlights of the PeroxisomeDB include new tools developed for facilitating (i) identification of novel peroxisomal proteins, by means of identifying proteins carrying peroxisome targeting signal (PTS) motifs, (ii) detection of peroxisomes in silico, particularly useful for screening the deluge of newly sequenced genomes. PeroxisomeDB should contribute to the systematic characterization of the peroxisomal proteome and facilitate system biology approaches on the organelle.10aAnimals *Databases10aProtein Genomics Humans Internet Mice Peroxisomal Disorders/*genetics Peroxisomes/*metabolism Protein Sorting Signals Proteome/chemistry/*genetics/*physiology Rats Saccharomyces cerevisiae Proteins/genetics/physiology Software User-Computer Interface1 aSchluter, A.1 aFourcade, S.1 aDomenech-Estevez, E.1 aGabaldón, T.1 aHuerta-Cepas, J.1 aBerthommier, G.1 aRipp, R.1 aWanders, R., J.1 aPoch, O.1 aPujol, A. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1713519002437nas a2200265 4500008004100000245009200041210006900133300001100202490000700213520143600220653005301656653002601709653002201735653005701757653004501814653008601859100001601945700002001961700001501981700002101996700001802017700001502035700001502050856010602065 2007 eng d00aPhylemon: a suite of web tools for molecular evolution, phylogenetics and phylogenomics0 aPhylemon a suite of web tools for molecular evolution phylogenet aW38-420 v353 aPhylemon is an online platform for phylogenetic and evolutionary analyses of molecular sequence data. It has been developed as a web server that integrates a suite of different tools selected among the most popular stand-alone programs in phylogenetic and evolutionary analysis. It has been conceived as a natural response to the increasing demand of data analysis of many experimental scientists wishing to add a molecular evolution and phylogenetics insight into their research. Tools included in Phylemon cover a wide yet selected range of programs: from the most basic for multiple sequence alignment to elaborate statistical methods of phylogenetic reconstruction including methods for evolutionary rates analyses and molecular adaptation. Phylemon has several features that differentiates it from other resources: (i) It offers an integrated environment that enables the direct concatenation of evolutionary analyses, the storage of results and handles required data format conversions, (ii) Once an outfile is produced, Phylemon suggests the next possible analyses, thus guiding the user and facilitating the integration of multi-step analyses, and (iii) users can define and save complete pipelines for specific phylogenetic analysis to be automatically used on many genes in subsequent sessions or multiple genes in a single session (phylogenomics). The Phylemon web server is available at http://phylemon.bioinfo.cipf.es.10aAnimals Computational Biology/*methods Databases10aDNA Sequence Analysis10aGenetic Evolution10aMolecular Genetic Techniques Humans *Internet Models10aProtein Software User-Computer Interface10aStatistical *Phylogeny Programming Languages Sequence Alignment Sequence Analysis1 aTarraga, J.1 aMedina, Ignacio1 aArbiza, L.1 aHuerta-Cepas, J.1 aGabaldón, T.1 aDopazo, J.1 aDopazo, H. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1745234601384nas a2200193 4500008004100000245007300041210006900114300001000183490000700193520078700200653001500987653001001002653001501012100002001027700001701047700001601064700001501080856009501095 2007 eng d00aProphet, a web-based tool for class prediction using microarray data0 aProphet a webbased tool for class prediction using microarray da a390-10 v233 a

Sample classification and class prediction is the aim of many gene expression studies. We present a web-based application, Prophet, which builds prediction rules and allows using them for further sample classification. Prophet automatically chooses the best classifier, along with the optimal selection of genes, using a strategy that renders unbiased cross-validated errors. Prophet is linked to different microarray data analysis modules, and includes a unique feature: the possibility of performing the functional interpretation of the molecular signature found. Availability: Prophet can be found at the URL http://prophet.bioinfo.cipf.es/ or within the GEPAS package at http://www.gepas.org/ Supplementary information: http://gepas.bioinfo.cipf.es/tutorial/prophet.html.

10ababelomics10agepas10apredictors1 aMedina, Ignacio1 aMontaner, D.1 aTarraga, J.1 aDopazo, J. uhttp://bioinformatics.oxfordjournals.org/cgi/content/full/23/3/390?view=long&pmid=1713858701778nas a2200205 4500008004100000245007500041210006900116300001300185490000800198520097700206653011101183653003901294653004101333100002001374700001401394700002401408700001701432700001701449856010601466 2007 eng d00aProtein translocation into peroxisomes by ring-shaped import receptors0 aProtein translocation into peroxisomes by ringshaped import rece a4795-8020 v5813 aFolded and functional proteins destined for translocation from the cytosol into the peroxisomal matrix are recognized by two different peroxisomal import receptors, Pex5p and Pex7p. Both cargo-loaded receptors dock on the same translocon components, followed by cargo release and receptor recycling, as part of the complete translocation process. Recent structural and functional evidence on the Pex5p receptor has provided insight on the molecular requirements of specific cargo recognition, while the remaining processes still remain largely elusive. Comparison of experimental structures of Pex5p and a structural model of Pex7p reveal that both receptors are built by ring-like arrangements with cargo binding sites, central to the respective structures. Although, molecular insight into the complete peroxisomal translocon still remains to be determined, emerging data allow to deduce common molecular principles that may hold for other translocation systems as well.10aAmino Acid Sequence Binding Sites Humans Molecular Sequence Data Peroxisomes/*metabolism Protein Structure10aCytoplasmic and Nuclear/*chemistry10aTertiary Protein Transport Receptors1 aStanley, W., A.1 aFodor, K.1 aMarti-Renom, M., A.1 aSchliebs, W.1 aWilmanns, M. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1788404200409nas a2200109 4500008004100000245004200041210004200083260002400125100001800149700001900167856011300186 2007 eng d00aReconstruction of ancestral proteomes0 aReconstruction of ancestral proteomes aOxfordbD. Liberles1 aGabaldón, T.1 aHuynen, M., A. uhttp://www.us.oup.com/us/catalog/general/subject/LifeSciences/EvolutionaryBiology/?view=usa&ci=978019929918802657nas a2200277 4500008004100000245007600041210006900117300001200186490000600198520157700204653011001781653008001891653001701971653001801988653005402006653006902060100001802129700002102147700001502168700001802183700001402201700001802215700002102233700001902254856010602273 2007 eng d00aSpatial differentiation in the vegetative mycelium of Aspergillus niger0 aSpatial differentiation in the vegetative mycelium of Aspergillu a2311-220 v63 aFungal mycelia are exposed to heterogenic substrates. The substrate in the central part of the colony has been (partly) degraded, whereas it is still unexplored at the periphery of the mycelium. We here assessed whether substrate heterogeneity is a main determinant of spatial gene expression in colonies of Aspergillus niger. This question was addressed by analyzing whole-genome gene expression in five concentric zones of 7-day-old maltose- and xylose-grown colonies. Expression profiles at the periphery and the center were clearly different. More than 25% of the active genes showed twofold differences in expression between the inner and outermost zones of the colony. Moreover, 9% of the genes were expressed in only one of the five concentric zones, showing that a considerable part of the genome is active in a restricted part of the colony only. Statistical analysis of expression profiles of colonies that had either been or not been transferred to fresh xylose-containing medium showed that differential expression in a colony is due to the heterogeneity of the medium (e.g., genes involved in secretion, genes encoding proteases, and genes involved in xylose metabolism) as well as to medium-independent mechanisms (e.g., genes involved in nitrate metabolism and genes involved in cell wall synthesis and modification). Thus, we conclude that the mycelia of 7-day-old colonies of A. niger are highly differentiated. This conclusion is also indicated by the fact that distinct zones of the colony grow and secrete proteins, even after transfer to fresh medium.10aAspergillus niger/*metabolism Cell Wall/metabolism Fungal Proteins/metabolism *Gene Expression Regulation10aBiological Mycelium/*metabolism Oligonucleotide Array Sequence Analysis RNA10aFungal Genes10aFungal Genome10aFungal Glucans/chemistry Maltose/chemistry Models10aFungal Time Factors Trans-Activators/metabolism Xylose/chemistry1 aLevin, A., M.1 ade Vries, R., P.1 aConesa, A.1 ade Bekker, C.1 aTalon, M.1 aMenke, H., H.1 avan Peij, N., N.1 aWosten, H., A. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1795151302088nas a2200217 4500008004100000245006100041210006100102300001200163490000800175520132100183653013101504653002201635653001601657100001801673700001601691700001601707700001201723700001601735700001301751856010601764 2007 eng d00aStructural analyses of a hypothetical minimal metabolism0 aStructural analyses of a hypothetical minimal metabolism a1751-620 v3623 aBy integrating data from comparative genomics and large-scale deletion studies, we previously proposed a minimal gene set comprising 206 protein-coding genes. To evaluate the consistency of the metabolism encoded by such a minimal genome, we have carried out a series of computational analyses. Firstly, the topology of the minimal metabolism was compared with that of the reconstructed networks from natural bacterial genomes. Secondly, the robustness of the metabolic network was evaluated by simulated mutagenesis and, finally, the stoichiometric consistency was assessed by automatically deriving the steady-state solutions from the reaction set. The results indicated that the proposed minimal metabolism presents stoichiometric consistency and that it is organized as a complex power-law network with topological parameters falling within the expected range for a natural metabolism of its size. The robustness analyses revealed that most random mutations do not alter the topology of the network significantly, but do cause significant damage by preventing the synthesis of several compounds or compromising the stoichiometric consistency of the metabolism. The implications that these results have on the origins of metabolic complexity and the theoretical design of an artificial minimal cell are discussed.10a*Cell Physiological Phenomena Cells/*metabolism Cluster Analysis *Computer Simulation *Metabolic Networks and Pathways *Models10aBiological Models10aStatistical1 aGabaldón, T.1 aPeretó, J.1 aMontero, F.1 aGil, R.1 aLatorre, A.1 aMoya, A. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1751002201951nas a2200265 4500008004100000245009000041210006900131300001200200490000800212520099700220653008201217653001201299653011301311100001501424700001501439700001601454700001401470700001601484700001501500700001501515700001901530700001501549700001501564856010601579 2007 eng d00aTranscriptional response of Citrus aurantifolia to infection by Citrus tristeza virus0 aTranscriptional response of Citrus aurantifolia to infection by  a298-3060 v3673 aChanges in gene expression of Mexican lime plants in response to infection with a severe (T305) or a mild (T385) isolate of Citrus tristeza virus (CTV) were analyzed using a cDNA microarray containing 12,672 probes to 6875 different citrus genes. Statistically significant (P<0.01) expression changes of 334 genes were detected in response to infection with isolate T305, whereas infection with T385 induced no significant change. Induced genes included 145 without significant similarity with known sequences and 189 that were classified in seven functional categories. Genes related with response to stress and defense were the main category and included 28% of the genes induced. Selected transcription changes detected by microarray analysis were confirmed by quantitative real-time RT-PCR. Changes detected in the transcriptome upon infecting lime with T305 may be associated either with symptom expression, with a strain-specific defense mechanism, or with a general response to stress.10aCitrus/*genetics/physiology/virology Closterovirus/genetics/*physiology Genes10aGenetic10aPlant Oligonucleotide Array Sequence Analysis Reverse Transcriptase Polymerase Chain Reaction *Transcription1 aGandia, M.1 aConesa, A.1 aAncillo, G.1 aGadea, J.1 aForment, J.1 aPallas, V.1 aFlores, R.1 aDuran-Vila, N.1 aMoreno, P.1 aGuerri, J. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1761743102187nas a2200157 4500008004100000245009000041210006900131300001100200490000700211520142200218653023401640653001201874100001301886700002401899856010601923 2006 eng d00aAccuracy of sequence alignment and fold assessment using reduced amino acid alphabets0 aAccuracy of sequence alignment and fold assessment using reduced a986-950 v633 aReduced or simplified amino acid alphabets group the 20 naturally occurring amino acids into a smaller number of representative protein residues. To date, several reduced amino acid alphabets have been proposed, which have been derived and optimized by a variety of methods. The resulting reduced amino acid alphabets have been applied to pattern recognition, generation of consensus sequences from multiple alignments, protein folding, and protein structure prediction. In this work, amino acid substitution matrices and statistical potentials were derived based on several reduced amino acid alphabets and their performance assessed in a large benchmark for the tasks of sequence alignment and fold assessment of protein structure models, using as a reference frame the standard alphabet of 20 amino acids. The results showed that a large reduction in the total number of residue types does not necessarily translate into a significant loss of discriminative power for sequence alignment and fold assessment. Therefore, some definitions of a few residue types are able to encode most of the relevant sequence/structure information that is present in the 20 standard amino acids. Based on these results, we suggest that the use of reduced amino acid alphabets may allow to increasing the accuracy of current substitution matrices and statistical potentials for the prediction of protein structure of remote homologs.10aAmino Acid Sequence Amino Acids/*chemistry/classification/*metabolism Consensus Sequence Molecular Sequence Data Oxidation-Reduction *Protein Folding Proteins/*chemistry/*metabolism Sequence Alignment/*methods Structural Homology10aProtein1 aMelo, F.1 aMarti-Renom, M., A. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1650624301445nas a2200253 4500008004100000245010300041210006900144300001100213490000700224520068700231653001500918653002500933100002400958700001600982700001600998700001701014700001501031700002301046700001401069700001701083700001301100700001501113856006301128 2006 eng d00aBABELOMICS: a systems biology perspective in the functional annotation of genome-scale experiments0 aBABELOMICS a systems biology perspective in the functional annot aW472-60 v343 a

We present a new version of Babelomics, a complete suite of web tools for functional analysis of genome-scale experiments, with new and improved tools. New functionally relevant terms have been included such as CisRed motifs or bioentities obtained by text-mining procedures. An improved indexing has considerably speeded up several of the modules. An improved version of the FatiScan method for studying the coordinate behaviour of groups of functionally related genes is presented, along with a similar tool, the Gene Set Enrichment Analysis. Babelomics is now more oriented to test systems biology inspired hypotheses. Babelomics can be found at http://www.babelomics.org.

10ababelomics10afunctional profiling1 aAl-Shahrour, Fatima1 aMinguez, P.1 aTarraga, J.1 aMontaner, D.1 aAlloza, E.1 aVaquerizas, J., M.1 aConde, L.1 aBlaschke, C.1 aVera, J.1 aDopazo, J. uhttp://nar.oxfordjournals.org/content/34/suppl_2/W472.long01043nas a2200121 4500008004100000245005300041210005200094300001100146490000600157520063700163100001500800856010600815 2006 eng d00aBioinformatics and cancer: an essential alliance0 aBioinformatics and cancer an essential alliance a409-150 v83 a

Modern research in cancer has been revolutionized by the introduction of new high-throughput methodologies such as DNA microarrays. Keeping the pace with these technologies, the bioinformatics offer new solutions for data analysis and, what is more important, it permits to formulate a new class of hypothesis inspired in systems biology, more oriented to blocks of functionally-related genes. Although software implementations for this new methodologies is new there are some options already available. Bioinformatic solutions for other high-throughput techniques such as array-CGH of large-scale genotyping is also revised.

1 aDopazo, J. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1679039302376nas a2200229 4500008004100000245009300041210006900134300001200203490000800215520165600223653001501879100001701894700001301911700001501924700001801939700001701957700001901974700001801993700001502011700001402026856010602040 2006 eng d00aBlast2GO goes grid: developing a grid-enabled prototype for functional genomics analysis0 aBlast2GO goes grid developing a gridenabled prototype for functi a194-2040 v1203 a

The vast amount in complexity of data generated in Genomic Research implies that new dedicated and powerful computational tools need to be developed to meet their analysis requirements. Blast2GO (B2G) is a bioinformatics tool for Gene Ontology-based DNA or protein sequence annotation and function-based data mining. The application has been developed with the aim of affering an easy-to-use tool for functional genomics research. Typical B2G users are middle size genomics labs carrying out sequencing, ETS and microarray projects, handling datasets up to several thousand sequences. In the current version of B2G. The power and analytical potential of both annotation and function data-mining is somehow restricted to the computational power behind each particular installation. In order to be able to offer the possibility of an enhanced computational capacity within this bioinformatics application, a Grid component is being developed. A prototype has been conceived for the particular problem of speeding up the Blast searches to obtain fast results for large datasets. Many efforts have been done in the literature concerning the speeding up of Blast searches, but few of them deal with the use of large heterogeneous production Grid Infrastructures. These are the infrastructures that could reach the largest number of resources and the best load balancing for data access. The Grid Service under development will analyse requests based on the number of sequences, splitting them accordingly to the available resources. Lower-level computation will be performed through MPIBLAST. The software architecture is based on the WSRF standard.

10ababelomics1 aAparicio, G.1 aGotz, S.1 aConesa, A.1 aSegrelles, D.1 aBlanquer, I.1 aGarcia, J., M.1 aHernandez, V.1 aRobles, M.1 aTalon, M. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1682313802005nas a2200253 4500008004100000245005800041210005800099300001300157490001400170520105600184653008801240653002101328653012901349653003101478100001401509700001301523700002401536700002401560700001601584700001701600700001501617700001301632856010601645 2006 eng d00aComparative protein structure modeling using Modeller0 aComparative protein structure modeling using Modeller aUnit 5 60 vChapter 53 aFunctional characterization of a protein sequence is one of the most frequent problems in biology. This task is usually facilitated by accurate three-dimensional (3-D) structure of the studied protein. In the absence of an experimentally determined structure, comparative or homology modeling can sometimes provide a useful 3-D model for a protein that is related to at least one known protein structure. Comparative modeling predicts the 3-D structure of a given protein sequence (target) based primarily on its alignment to one or more proteins of known structure (templates). The prediction process consists of fold assignment, target-template alignment, model building, and model evaluation. This unit describes how to calculate comparative models using the program MODELLER and discusses all four steps of comparative modeling, frequently observed errors, and some applications. Modeling lactate dehydrogenase from Trichomonas vaginalis (TvLDH) is described as an example. The download and installation of the MODELLER software is also described.10aAlgorithms Amino Acid Sequence Computer Simulation Crystallography/*methods *Models10aChemical *Models10aMolecular Molecular Sequence Data Protein Conformation Protein Folding Proteins/*chemistry/*ultrastructure Sequence Analysis10aProtein/*methods *Software1 aEswar, N.1 aWebb, B.1 aMarti-Renom, M., A.1 aMadhusudhan, M., S.1 aEramian, D.1 aShen, M., Y.1 aPieper, U.1 aSali, A. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1842876702131nas a2200217 4500008004100000245007200041210006900113300001200182490000700194520144000201653001201641653002101653653003601674100001601710700001701726700001401743700001301757700001301770700002401783856010601807 2006 eng d00aA composite score for predicting errors in protein structure models0 acomposite score for predicting errors in protein structure model a1653-660 v153 aReliable prediction of model accuracy is an important unsolved problem in protein structure modeling. To address this problem, we studied 24 individual assessment scores, including physics-based energy functions, statistical potentials, and machine learning-based scoring functions. Individual scores were also used to construct approximately 85,000 composite scoring functions using support vector machine (SVM) regression. The scores were tested for their abilities to identify the most native-like models from a set of 6000 comparative models of 20 representative protein structures. Each of the 20 targets was modeled using a template of <30% sequence identity, corresponding to challenging comparative modeling cases. The best SVM score outperformed all individual scores by decreasing the average RMSD difference between the model identified as the best of the set and the model with the lowest RMSD (DeltaRMSD) from 0.63 A to 0.45 A, while having a higher Pearson correlation coefficient to RMSD (r=0.87) than any other tested score. The most accurate score is based on a combination of the DOPE non-hydrogen atom statistical potential; surface, contact, and combined statistical potentials from MODPIPE; and two PSIPRED/DSSP scores. It was implemented in the SVMod program, which can now be applied to select the final model in various modeling problems, including fold assignment, target-template alignment, and loop modeling.10a*Models10aMolecular Models10aTheoretical Proteins/*chemistry1 aEramian, D.1 aShen, M., Y.1 aDevos, D.1 aMelo, F.1 aSali, A.1 aMarti-Renom, M., A. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1675160601615nas a2200133 4500008004100000245008900041210006900130300001200199490000800211520100500219653013301224100001801357856010601375 2006 eng d00aComputational approaches for the prediction of protein function in the mitochondrion0 aComputational approaches for the prediction of protein function  aC1121-80 v2913 aUnderstanding a complex biological system, such as the mitochondrion, requires the identification of the complete repertoire of proteins targeted to the organelle, the characterization of these, and finally, the elucidation of the functional and physical interactions that occur within the mitochondrion. In the last decade, significant developments have contributed to increase our understanding of the mitochondrion, and among these, computational research has played a significant role. Not only general bioinformatics tools have been applied in the context of the mitochondrion, but also some computational techniques have been specifically developed to address problems that arose from within the mitochondrial research field. In this review the contribution of bioinformatics to mitochondrial biology is addressed through a survey of current computational methods that can be applied to predict which proteins will be localized to the mitochondrion and to unravel their functional interactions.10a*Computational Biology *Computer Simulation Humans Mitochondria/*metabolism Mitochondrial Proteins/genetics/*metabolism Mutation1 aGabaldón, T. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1687083002539nas a2200265 4500008004100000245016000041210006900201300001200270490000700282520126500289653009401554653019301648653013501841653002601976100002102002700001702023700001902040700002002059700001502079700001502094700002002109700001802129700002002147856010602167 2006 eng d00aDevelopment of the GENIPOL European flounder (Platichthys flesus) microarray and determination of temporal transcriptional responses to cadmium at low dose0 aDevelopment of the GENIPOL European flounder Platichthys flesus  a6479-880 v403 aWe have constructed a high density, 13 270-clone cDNA array for the sentinel fish species European flounder (Platichthys flesus), combining clones from suppressive subtractive hybridization and a liver cDNA library; DNA sequences of 5211 clones were determined. Fish were treated by single intraperitoneal injection with 50 micrograms cadmium chloride per kilogram body weight, a dose relevant to environmental exposures, and hepatic gene expression changes were determined at 1, 2, 4, 8, and 16 days postinjection in comparison to saline-treated controls. Gene expression responses were confirmed by real-time reverse transcription polymerase chain reaction (RT-PCR). Blast2GO gene ontology analysis highlighted a general induction of the unfolded protein response, response to oxidative stress, protein synthesis, transport, and degradation pathways, while apoptosis, cell cycle, cytoskeleton, and cytokine genes were also affected. Transcript levels of cytochrome P450 1A (CYP1A) were repressed and vitellogenin altered, real-time PCR showed induction of metallothionein. We thus describe the establishment of a useful resource for ecotoxicogenomics and the determination of the temporal molecular responses to cadmium, a prototypical heavy metal pollutant.10aAnimals Cadmium Chloride/administration & dosage/*pharmacology Dose-Response Relationship10aDevelopmental/drug effects Liver/drug effects/growth & development/metabolism Oligonucleotide Array Sequence Analysis/*methods Reverse Transcriptase Polymerase Chain Reaction Transcription10aDrug Environmental Monitoring/methods Flounder/*genetics/growth & development Gene Expression Profiling Gene Expression Regulation10aGenetic/*drug effects1 aWilliams, T., D.1 aDiab, A., M.1 aGeorge, S., G.1 aGodfrey, R., E.1 aSabine, V.1 aConesa, A.1 aMinchin, S., D.1 aWatts, P., C.1 aChipman, J., K. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1712058400743nas a2200169 4500008004100000245006300041210006300104300000800167490000600175520016700181653003400348653002200382653003500404100001500439700001300454856010600467 2006 eng d00aDiscovery and hypothesis generation through bioinformatics0 aDiscovery and hypothesis generation through bioinformatics a3070 v73 aA report on the 4th European Conference on Computational Biology and the 6th Spanish Annual Meeting on Bioinformatics, Madrid, Spain, 28 September-1 October 2005.10a*Computational Biology Genome10aGenetic Phylogeny10aHuman *Genomics Humans *Models1 aDopazo, J.1 aAloy, P. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1652222402830nas a2200277 4500008004100000245011000041210006900151300001100220490000700231520162300238653016301861653002002024653018602044653004602230100001802276700001402294700002302308700001802331700001402349700001702363700001502380700001902395700001602414700001602430856010602446 2006 eng d00aERCC4 associated with breast cancer risk: a two-stage case-control study using high-throughput genotyping0 aERCC4 associated with breast cancer risk a twostage casecontrol  a9420-70 v663 aThe failure of linkage studies to identify further high-penetrance susceptibility genes for breast cancer points to a polygenic model, with more common variants having modest effects on risk, as the most likely candidate. We have carried out a two-stage case-control study in two European populations to identify low-penetrance genes for breast cancer using high-throughput genotyping. Single-nucleotide polymorphisms (SNPs) were selected across preselected cancer-related genes, choosing tagSNPs and functional variants where possible. In stage 1, genotype frequencies for 640 SNPs in 111 genes were compared between 864 breast cancer cases and 845 controls from the Spanish population. In stage 2, candidate SNPs identified in stage 1 (nominal P < 0.01) were tested in a Finnish series of 884 cases and 1,104 controls. Of the 10 candidate SNPs in seven genes identified in stage 1, one (rs744154) on intron 1 of ERCC4, a gene belonging to the nucleotide excision repair pathway, was associated with recessive protection from breast cancer after adjustment for multiple testing in stage 2 (odds ratio, 0.57; Bonferroni-adjusted P = 0.04). After considering potential functional SNPs in the region of high linkage disequilibrium that extends across the entire gene and upstream into the promoter region, we concluded that rs744154 itself could be causal. Although intronic, it is located on the first intron, in a region that is highly conserved across species, and could therefore be functionally important. This study suggests that common intronic variation in ERCC4 is associated with protection from breast cancer.10a80 and over Breast Neoplasms/epidemiology/*genetics/pathology Case-Control Studies DNA-Binding Proteins/genetics/*physiology Female Finland/epidemiology Genes10aAdult Aged Aged10aRecessive Genetic Predisposition to Disease Genotype Humans Introns/genetics Linkage Disequilibrium Middle Aged Neoplasm Proteins/genetics/*physiology Neoplasm Staging *Polymorphism10aSingle Nucleotide Risk Spain/epidemiology1 aMilne, R., L.1 aRibas, G.1 aGonzalez-Neira, A.1 aFagerholm, R.1 aSalas, A.1 aGonzalez, E.1 aDopazo, J.1 aNevanlinna, H.1 aRobledo, M.1 aBenitez, J. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1701859601522nas a2200205 4500008004100000245013200041210006900173300000700242490000600249520054800255653009100803653004200894653014400936653006001080100001701140700002301157700001501180700001501195856010601210 2006 eng d00aExploring the reasons for the large density of triplex-forming oligonucleotide target sequences in the human regulatory regions0 aExploring the reasons for the large density of triplexforming ol a630 v73 aBACKGROUND: DNA duplex sequences that can be targets for triplex formation are highly over-represented in the human genome, especially in regulatory regions. RESULTS: Here we studied using bioinformatics tools several properties of triplex target sequences in an attempt to determine those that make these sequences so special in the genome. CONCLUSION: Our results strongly suggest that the unique physical properties of these sequences make them particularly suitable as "separators" between protein-recognition sites in the promoter region.10aAnimals Base Sequence Computational Biology DNA/chemistry/*genetics/*metabolism Genome10aGenetic/genetics Regulatory Sequences10aHuman/genetics Humans Mice Nucleic Acid Conformation Nucleotides/genetics Oligonucleotides/chemistry/*genetics/*metabolism Promoter Regions10aNucleic Acid/*genetics Transcription Factors/metabolism1 aGoni, J., R.1 aVaquerizas, J., M.1 aDopazo, J.1 aOrozco, M. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1656681701588nas a2200157 4500008004100000245005600041210005600097300001200153490000700165520107100172653001501243653002201258653002901280100001501309856010601324 2006 eng d00aFunctional interpretation of microarray experiments0 aFunctional interpretation of microarray experiments a398-4100 v103 a

Over the past few years, due to the popularisation of high-throughput methodologies such as DNA microarrays, the possibility of obtaining experimental data has increased significantly. Nevertheless, the interpretation of the results, which involves translating these data into useful biological knowledge, still remains a challenge. The methods and strategies used for this interpretation are in continuous evolution and new proposals are constantly arising. Initially, a two-step approach was used in which genes of interest were initially selected, based on thresholds that consider only experimental values, and then in a second, independent step the enrichment of these genes in biologically relevant terms, was analysed. For different reasons, these methods are relatively poor in terms of performance and a new generation of procedures, which draw inspiration from systems biology criteria, are currently under development. Such procedures, aim to directly test the behaviour of blocks of functionally related genes, instead of focusing on single genes.

10ababelomics10aDiabetes Mellitus10amicroarray data analysis1 aDopazo, J. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1706951602399nas a2200157 4500008004100000245009100041210006900132300001000201490000700211520184000218653001502058100001602073700002402089700001502113856011302128 2006 eng d00aA function-centric approach to the biological interpretation of microarray time-series0 afunctioncentric approach to the biological interpretation of mic a57-660 v173 a

The interpretation of microarray experiments is commonly addressed by means a two-step approach in which the relevant genes are firstly selected uniquely on the basis of their experimental values (ignoring their coordinate behaviors) and in a second step their functional properties are studied to hypothesize about the biological roles they are fulfilling in the cell. Recently, different methods (e.g. GSEA or FatiScan) have been proposed to study the coordinate behavior of blocks of functionally-related genes. These methods study the distribution of functional information across lists of genes ranked according their different experimental values in a static situation, such as the comparison between two classes (e.g. healthy controls versus diseased cases). Nevertheless there is no an equivalent way of studying a dynamic situation from a functional point of view. We present a method for the functional analysis of microarrays series in which the experiments display autocorrelation between successive points (e.g. time series, dose-response experiments, etc.) The method allows to recover the dynamics of the molecular roles fulfilled by the genes along the series which provides a novel approach to functional interpretation of such experiments. The method finds blocks of functionally-related genes which are significantly and coordinately over-expressed at different points of the series. This method draws inspiration from systems biology given that the analysis does not focus on individual properties of genes but on collective behaving blocks of functionally-related genes. The FatiScan algorithm used in the method proposed is available at: http://fatiscan.bioinfo.cipf.es, or within the Babelomics suite: http://www.babelomics.org. Additional material is available at: http://bioinfo.cipf.es/data/plasmodium.

10ababelomics1 aMinguez, P.1 aAl-Shahrour, Fatima1 aDopazo, J. uhttp://clinbioinfosspa.es/content/function-centric-approach-biological-interpretation-microarray-time-series03074nas a2200325 4500008004100000245011200041210006900153300001100222490000700233520182100240653001102061653002302072653009602095653012202191653006602313653004102379653002302420100001402443700001602457700001302473700001402486700002602500700002402526700001902550700001502569700001602584700002102600700002102621856010602642 2006 eng d00aIdentification of overexpressed genes in frequently gained/amplified chromosome regions in multiple myeloma0 aIdentification of overexpressed genes in frequently gainedamplif a184-910 v913 aBACKGROUND AND OBJECTIVES: Multiple myeloma (MM) is a malignancy characterized by clonal expansion of plasma cells. In 50% of the cases, the neoplastic transformation begins with a chromosomal translocation that juxtaposes the IGH gene locus to an oncogene. Gene copy number changes are also frequent in MM but less characterized than in other neoplasias. We aimed to characterize genes that are amplified and overexpressed in human myeloma cell lines (HMCL) to provide putative molecular targets for MM therapy. DESIGN AND METHODS: Nine HMCL were characterized by fluorescent in situ hybridization, comparative genomic hybridization (CGH) and cDNA microarrays for gene expression profiling and copy number changes. RESULTS: After defining the IGH-translocations present in the cell lines, we conducted expression-profiling analysis. Supervised analysis identified 166 genes with significantly different expression among the cell lines harboring MMSET/FGFR3 (4p16), MAF (16q) and CCND1 (11q13) rearrangements. Array-CGH was then performed. Five chromosomes recurrently affected by gains/amplifications in primary samples and cell lines were analyzed in detail. Sixty amplified and overexpressed genes were found and 25 (42%) of them were only overexpressed when amplified; moreover, six showed a significant association between overexpression and gain/amplification. We also found co-amplification and overexpression for genes located within the same amplicons, such as MALT1 and BCL2. INTERPRETATION AND CONCLUSIONS: Parallel analysis of gene copy numbers and expression levels by cDNA microarray in MM allowed efficient identification of genes whose expression levels are elevated because of increased copy number. This is the first time that MALT1 and BCL2 have been shown to be overexpressed and amplified in MM.10aB-Cell10aCaspases Cell Line10aHuman *Gene Amplification Gene Dosage Gene Expression Profiling *Gene Expression Regulation10aMarginal Zone/genetics Multiple Myeloma/*genetics Neoplasm Proteins/genetics Proto-Oncogene Proteins c-bcl-2/genetics10aNeoplasm Humans Immunoglobulin Heavy Chains/genetics Lymphoma10aNeoplastic Gene Rearrangement *Genes10aTumor *Chromosomes1 aLargo, C.1 aAlvarez, S.1 aSaez, B.1 aBlesa, D.1 aMartin-Subero, J., I.1 aGonzalez-Garcia, I.1 aBrieva, J., A.1 aDopazo, J.1 aSiebert, R.1 aCalasanz, M., J.1 aCigudosa, J., C. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1646130200398nas a2200097 4500008004100000245004000041210004000081260008600121100001500207856007800222 2006 eng d00aLa clasificación de los organismos0 aLa clasificación de los organismos aBuenos AiresbCurtis, Barnes, Schnek & Flores. 2da, Editorial Medica Panamericana1 aDopazo, H. uhttp://clinbioinfosspa.es/content/la-clasificaci%C3%B3n-de-los-organismos02048nas a2200157 4500008004100000245010400041210006900145300001200214490000700226520134600233653015401579100001401733700002401747700001301771856010601784 2006 eng d00aLocalization of binding sites in protein structures by optimization of a composite scoring function0 aLocalization of binding sites in protein structures by optimizat a2366-800 v153 aThe rise in the number of functionally uncharacterized protein structures is increasing the demand for structure-based methods for functional annotation. Here, we describe a method for predicting the location of a binding site of a given type on a target protein structure. The method begins by constructing a scoring function, followed by a Monte Carlo optimization, to find a good scoring patch on the protein surface. The scoring function is a weighted linear combination of the z-scores of various properties of protein structure and sequence, including amino acid residue conservation, compactness, protrusion, convexity, rigidity, hydrophobicity, and charge density; the weights are calculated from a set of previously identified instances of the binding-site type on known protein structures. The scoring function can easily incorporate different types of information useful in localization, thus increasing the applicability and accuracy of the approach. To test the method, 1008 known protein structures were split into 20 different groups according to the type of the bound ligand. For nonsugar ligands, such as various nucleotides, binding sites were correctly identified in 55%-73% of the cases. The method is completely automated (http://salilab.org/patcher) and can be applied on a large scale in a structural genomics setting.10aAmino Acid Sequence Binding Sites Biomechanics Hydrophobicity Ligands *Monte Carlo Method Protein Conformation Proteins/*chemistry Static Electricity1 aRossi, A.1 aMarti-Renom, M., A.1 aSali, A. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1696364501934nas a2200193 4500008004100000245012000041210006900161300001300230490000700243520110800250653010701358653001901465653008801484100001501572700001801587700001501605700001401620856010601634 2006 eng d00amaSigPro: a method to identify significantly differential expression profiles in time-course microarray experiments0 amaSigPro a method to identify significantly differential express a1096-1020 v223 aMOTIVATION: Multi-series time-course microarray experiments are useful approaches for exploring biological processes. In this type of experiments, the researcher is frequently interested in studying gene expression changes along time and in evaluating trend differences between the various experimental groups. The large amount of data, multiplicity of experimental conditions and the dynamic nature of the experiments poses great challenges to data analysis. RESULTS: In this work, we propose a statistical procedure to identify genes that show different gene expression profiles across analytical groups in time-course experiments. The method is a two-regression step approach where the experimental groups are identified by dummy variables. The procedure first adjusts a global regression model with all the defined variables to identify differentially expressed genes, and in second a variable selection strategy is applied to study differences between groups and to find statistically significant different profiles. The methodology is illustrated on both a real and a simulated microarray dataset.10a*Algorithms Computer Simulation Gene Expression/*physiology Gene Expression Profiling/*methods *Models10aGenetic Models10aStatistical Oligonucleotide Array Sequence Analysis/*methods *Software Time Factors1 aConesa, A.1 aNueda, M., J.1 aFerrer, A.1 aTalon, M. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1648133302671nas a2200349 4500008004100000245009900041210006900140300001100209490000700220520147800227653002901705653002701734653004401761653005601805653004001861653008301901100001501984700001401999700001802013700001602031700002402047700001402071700002402085700001602109700001702125700001602142700001702158700001402175700001302189700001302202856010602215 2006 eng d00aMODBASE: a database of annotated comparative protein structure models and associated resources0 aMODBASE a database of annotated comparative protein structure mo aD291-50 v343 aMODBASE (http://salilab.org/modbase) is a database of annotated comparative protein structure models for all available protein sequences that can be matched to at least one known protein structure. The models are calculated by MODPIPE, an automated modeling pipeline that relies on MODELLER for fold assignment, sequence-structure alignment, model building and model assessment (http:/salilab.org/modeller). MODBASE is updated regularly to reflect the growth in protein sequence and structure databases, and improvements in the software for calculating the models. MODBASE currently contains 3 094 524 reliable models for domains in 1 094 750 out of 1 817 889 unique protein sequences in the UniProt database (July 5, 2005); only models based on statistically significant alignments and models assessed to have the correct fold despite insignificant alignments are included. MODBASE also allows users to generate comparative models for proteins of interest with the automated modeling server MODWEB (http://salilab.org/modweb). Our other resources integrated with MODBASE include comprehensive databases of multiple protein structure alignments (DBAli, http://salilab.org/dbali), structurally defined ligand binding sites and structurally defined binary domain interfaces (PIBASE, http://salilab.org/pibase) as well as predictions of ligand binding sites, interactions between yeast proteins, and functional consequences of human nsSNPs (LS-SNP, http://salilab.org/LS-SNP).10aBinding Sites *Databases10aMolecular Polymorphism10aProtein Humans Internet Ligands *Models10aProtein Systems Integration User-Computer Interface10aSingle Nucleotide Protein Structure10aTertiary Proteins/*chemistry/genetics/metabolism Software *Structural Homology1 aPieper, U.1 aEswar, N.1 aDavis, F., P.1 aBraberg, H.1 aMadhusudhan, M., S.1 aRossi, A.1 aMarti-Renom, M., A.1 aKarchin, R.1 aWebb, B., M.1 aEramian, D.1 aShen, M., Y.1 aKelly, L.1 aMelo, F.1 aSali, A. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1638186901882nas a2200313 4500008004100000245005200041210005100093300001200144490000700156520100300163653001001166653002901176100001701205700001601222700002101238700001601259700002301275700001401298700001601312700001301328700001801341700001401359700001901373700001501392700001601407700002401423700001501447856010601462 2006 eng d00aNext station in microarray data analysis: GEPAS0 aNext station in microarray data analysis GEPAS aW486-910 v343 a

The Gene Expression Profile Analysis Suite (GEPAS) has been running for more than four years. During this time it has evolved to keep pace with the new interests and trends in the still changing world of microarray data analysis. GEPAS has been designed to provide an intuitive although powerful web-based interface that offers diverse analysis options from the early step of preprocessing (normalization of Affymetrix and two-colour microarray experiments and other preprocessing options), to the final step of the functional annotation of the experiment (using Gene Ontology, pathways, PubMed abstracts etc.), and include different possibilities for clustering, gene selection, class prediction and array-comparative genomic hybridization management. GEPAS is extensively used by researchers of many countries and its records indicate an average usage rate of 400 experiments per day. The web-based pipeline for microarray gene expression data, GEPAS, is available at http://www.gepas.org.

10agepas10amicroarray data analysis1 aMontaner, D.1 aTarraga, J.1 aHuerta-Cepas, J.1 aBurguet, J.1 aVaquerizas, J., M.1 aConde, L.1 aMinguez, P.1 aVera, J.1 aMukherjee, S.1 aValls, J.1 aPujana, M., A.1 aAlloza, E.1 aHerrero, J.1 aAl-Shahrour, Fatima1 aDopazo, J. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1684505601646nas a2200217 4500008004100000245007200041210006900113300001000182490000800192520083200200653001501032653002101047653007301068653002601141653004201167653005901209100001501268700002401283700001501307856010601322 2006 eng d00aOntology-driven approaches to analyzing data in functional genomics0 aOntologydriven approaches to analyzing data in functional genomi a67-860 v3163 a

Ontologies are fundamental knowledge representations that provide not only standards for annotating and indexing biological information, but also the basis for implementing functional classification and interpretation models. This chapter discusses the application of gene ontology (GO) for predictive tasks in functional genomics. It focuses on the problem of analyzing functional patterns associated with gene products. This chapter is divided into two main parts. The first part overviews GO and its applications for the development of functional classification models. The second part presents two methods for the characterization of genomic information using GO. It discusses methods for measuring functional similarity of gene products, and a tool for supporting gene expression clustering analysis and validation.

10ababelomics10aCluster Analysis10aCluster Analysis Computational Biology/*methods *Data Interpretation10aComputational Biology10aStatistical Gene Expression Profiling10aStatistical Gene Expression Profiling *Genomics Humans1 aAzuaje, F.1 aAl-Shahrour, Fatima1 aDopazo, J. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1667140102737nas a2200181 4500008004100000245005300041210005300094300000600147490000600153520218900159100001802348700001302366700002102379700001602400700001402416700001902430856010602449 2006 eng d00aOrigin and evolution of the peroxisomal proteome0 aOrigin and evolution of the peroxisomal proteome a80 v13 aBACKGROUND: Peroxisomes are ubiquitous eukaryotic organelles involved in various oxidative reactions. Their enzymatic content varies between species, but the presence of common protein import and organelle biogenesis systems support a single evolutionary origin. The precise scenario for this origin remains however to be established. The ability of peroxisomes to divide and import proteins post-translationally, just like mitochondria and chloroplasts, supports an endosymbiotic origin. However, this view has been challenged by recent discoveries that mutant, peroxisome-less cells restore peroxisomes upon introduction of the wild-type gene, and that peroxisomes are formed from the Endoplasmic Reticulum. The lack of a peroxisomal genome precludes the use of classical analyses, as those performed with mitochondria or chloroplasts, to settle the debate. We therefore conducted large-scale phylogenetic analyses of the yeast and rat peroxisomal proteomes. RESULTS : Our results show that most peroxisomal proteins (39-58%) are of eukaryotic origin, comprising all proteins involved in organelle biogenesis or maintenance. A significant fraction (13-18%), consisting mainly of enzymes, has an alpha-proteobacterial origin and appears to be the result of the recruitment of proteins originally targeted to mitochondria. Consistent with the findings that peroxisomes are formed in the Endoplasmic Reticulum, we find that the most universally conserved Peroxisome biogenesis and maintenance proteins are homologous to proteins from the Endoplasmic Reticulum Assisted Decay pathway. CONCLUSION: Altogether our results indicate that the peroxisome does not have an endosymbiotic origin and that its proteins were recruited from pools existing within the primitive eukaryote. Moreover the reconstruction of primitive peroxisomal proteomes suggests that ontogenetically as well as phylogenetically, peroxisomes stem from the Endoplasmic Reticulum. REVIEWERS: This article was reviewed by Arcady Mushegian, Gaspar Jekely and John Logsdon. OPEN PEER REVIEW: Reviewed by Arcady Mushegian, Gaspar Jekely and John Logsdon. For the full reviews, please go to the Reviewers’ comments section.1 aGabaldón, T.1 aSnel, B.1 avan Zimmeren, F.1 aHemrika, W.1 aTabak, H.1 aHuynen, M., A. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1655631402542nas a2200181 4500008004100000245010000041210006900141300000800210490000600218520184100224653001502065653004302080653008602123100001502209700001502224700001502239856010602254 2006 eng d00aPositive selection, relaxation, and acceleration in the evolution of the human and chimp genome0 aPositive selection relaxation and acceleration in the evolution  ae380 v23 aFor years evolutionary biologists have been interested in searching for the genetic bases underlying humanness. Recent efforts at a large or a complete genomic scale have been conducted to search for positively selected genes in human and in chimp. However, recently developed methods allowing for a more sensitive and controlled approach in the detection of positive selection can be employed. Here, using 13,198 genes, we have deduced the sets of genes involved in rate acceleration, positive selection, and relaxation of selective constraints in human, in chimp, and in their ancestral lineage since the divergence from murids. Significant deviations from the strict molecular clock were observed in 469 human and in 651 chimp genes. The more stringent branch-site test of positive selection detected 108 human and 577 chimp positively selected genes. An important proportion of the positively selected genes did not show a significant acceleration in rates, and similarly, many of the accelerated genes did not show significant signals of positive selection. Functional differentiation of genes under rate acceleration, positive selection, and relaxation was not statistically significant between human and chimp with the exception of terms related to G-protein coupled receptors and sensory perception. Both of these were over-represented under relaxation in human in relation to chimp. Comparing differences between derived and ancestral lineages, a more conspicuous change in trends seems to have favored positive selection in the human lineage. Since most of the positively selected genes are different under the same functional categories between these species, we suggest that the individual roles of the alternative positively selected genes may be an important factor underlying biological differences between these species.10aAdaptation10aBiological/genetics Animals *Evolution10aMolecular Genome/*genetics Humans Pan troglodytes/*genetics *Selection (Genetics)1 aArbiza, L.1 aDopazo, J.1 aDopazo, H. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1668301901783nas a2200253 4500008004100000245010200041210006900143300001100212490000700223520089100230653004301121653008001164653002701244653005601271100001401327700002301341700001501364700001501379700001601394700001701410700002001427700001501447856006701462 2006 eng d00aPupaSuite: finding functional single nucleotide polymorphisms for large-scale genotyping purposes0 aPupaSuite finding functional single nucleotide polymorphisms for aW621-50 v343 a

We have developed a web tool, PupaSuite, for the selection of single nucleotide polymorphisms (SNPs) with potential phenotypic effect, specifically oriented to help in the design of large-scale genotyping projects. PupaSuite uses a collection of data on SNPs from heterogeneous sources and a large number of pre-calculated predictions to offer a flexible and intuitive interface for selecting an optimal set of SNPs. It improves the functionality of PupaSNP and PupasView programs and implements new facilities such as the analysis of user’s data to derive haplotypes with functional information. A new estimator of putative effect of polymorphisms has been included that uses evolutionary information. Also SNPeffect database predictions have been included. The PupaSuite web interface is accessible through http://pupasuite.bioinfo.cipf.es and through http://www.pupasnp.org.

10aAlgorithms Computer Graphics Databases10aMolecular Genotype Haplotypes Internet Linkage Disequilibrium *Polymorphism10aNucleic Acid Evolution10aSingle Nucleotide *Software User-Computer Interface1 aConde, L.1 aVaquerizas, J., M.1 aDopazo, H.1 aArbiza, L.1 aReumers, J.1 aRousseau, F.1 aSchymkowitz, J.1 aDopazo, J. uhttp://nar.oxfordjournals.org/cgi/content/full/34/suppl_2/W62102791nas a2200193 4500008004100000245009800041210006900139300001200208490000800220520199800228653005602226653012802282100001302410700001802423700002402441700001302465700001302478856010602491 2006 eng d00aRefinement of protein structures by iterative comparative modeling and CryoEM density fitting0 aRefinement of protein structures by iterative comparative modeli a1655-680 v3573 aWe developed a method for structure characterization of assembly components by iterative comparative protein structure modeling and fitting into cryo-electron microscopy (cryoEM) density maps. Specifically, we calculate a comparative model of a given component by considering many alternative alignments between the target sequence and a related template structure while optimizing the fit of a model into the corresponding density map. The method relies on the previously developed Moulder protocol that iterates over alignment, model building, and model assessment. The protocol was benchmarked using 20 varied target-template pairs of known structures with less than 30% sequence identity and corresponding simulated density maps at resolutions from 5A to 25A. Relative to the models based on the best existing sequence profile alignment methods, the percentage of C(alpha) atoms that are within 5A of the corresponding C(alpha) atoms in the superposed native structure increases on average from 52% to 66%, which is half-way between the starting models and the models from the best possible alignments (82%). The test also reveals that despite the improvements in the accuracy of the fitness function, this function is still the bottleneck in reducing the remaining errors. To demonstrate the usefulness of the protocol, we applied it to the upper domain of the P8 capsid protein of rice dwarf virus that has been studied by cryoEM at 6.8A. The C(alpha) root-mean-square deviation of the model based on the remotely related template, bluetongue virus VP7, improved from 8.7A to 6.0A, while the best possible model has a C(alpha) RMSD value of 5.3A. Moreover, the resulting model fits better into the cryoEM density map than the initial template structure. The method is being implemented in our program MODELLER for protein structure modeling by satisfaction of spatial restraints and will be applicable to the rapidly increasing number of cryoEM density maps of macromolecular assemblies.10aAmino Acid Sequence Cryoelectron Microscopy *Models10aMolecular Molecular Sequence Data Plant Viruses/chemistry *Protein Conformation Software Viral Proteins/*chemistry/genetics1 aTopf, M.1 aBaker, M., L.1 aMarti-Renom, M., A.1 aChiu, W.1 aSali, A. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1649020700503nas a2200133 4500008004100000022001600041245010000057210006900157260003700226100001900263700001300282700001700295856005700312 2006 eng d a0-387-3452700aReliable and specific protein function prediction by combining homology with genomic(s) context0 aReliable and specific protein function prediction by combining h bF. Eisenhaber, Landes Bioscience1 aHuynen, M., A.1 aSnel, B.1 aT, Gabaldón uhttp://www.landesbioscience.com/iu/output.php?id=47902859nas a2200301 4500008004100000245009400041210006900135300001300204490000800217520172300225653007401948653002202022653001902044653002402063653002802087653002002115653015502135653002502290100001502315700001402330700001702344700001602361700002202377700002202399700001502421700001502436856010602451 2006 eng d00aSelective pressures at a codon-level predict deleterious mutations in human disease genes0 aSelective pressures at a codonlevel predict deleterious mutation a1390-4040 v3583 aDeleterious mutations affecting biological function of proteins are constantly being rejected by purifying selection from the gene pool. The non-synonymous/synonymous substitution rate ratio (omega) is a measure of selective pressure on amino acid replacement mutations for protein-coding genes. Different methods have been developed in order to predict non-synonymous changes affecting gene function. However, none has considered the estimation of selective constraints acting on protein residues. Here, we have used codon-based maximum likelihood models in order to estimate the selective pressures on the individual amino acid residues of a well-known model protein: p53. We demonstrate that the number of residues under strong purifying selection in p53 is much higher than those that are strictly conserved during the evolution of the species. In agreement with theoretical expectations, residues that have been noted to be of structural relevance, or in direct association with DNA, were among those showing the highest signals of purifying selection. Conversely, those changing according to a neutral, or nearly neutral mode of evolution, were observed to be irrelevant for protein function. Finally, using more than 40 human disease genes, we demonstrate that residues evolving under strong selective pressures (omega<0.1) are significantly associated (p<0.01) with human disease. We hypothesize that non-synonymous change on amino acids showing omega<0.1 will most likely affect protein function. The application of this evolutionary prediction at a genomic scale will provide an a priori hypothesis of the phenotypic effect of non-synonymous coding single nucleotide polymorphisms (SNPs) in the human genome.10aAmino Acid Sequence Amino Acid Substitution Codon/*genetics Databases10aGenetic Evolution10aGenetic Models10aHuman Humans Models10aInborn/*genetics Genome10aMolecular Genes10aMolecular Molecular Sequence Data *Mutation Neoplasms/genetics Proteins/genetics *Selection (Genetics) Tumor Suppressor Protein p53/chemistry/genetics10ap53 Genetic Diseases1 aArbiza, L.1 aDuchi, S.1 aMontaner, D.1 aBurguet, J.1 aPantoja-Uceda, D.1 aPineda-Lucena, A.1 aDopazo, J.1 aDopazo, H. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1658474602070nas a2200205 4500008004100000245006600041210006500107300001100172490000700183520128000190653004201470653002501512653010401537653004001641100002401681700002401705700001601729700001301745856010601758 2006 eng d00aVariable gap penalty for protein sequence-structure alignment0 aVariable gap penalty for protein sequencestructure alignment a129-330 v193 aThe penalty for inserting gaps into an alignment between two protein sequences is a major determinant of the alignment accuracy. Here, we present an algorithm for finding a globally optimal alignment by dynamic programming that can use a variable gap penalty (VGP) function of any form. We also describe a specific function that depends on the structural context of an insertion or deletion. It penalizes gaps that are introduced within regions of regular secondary structure, buried regions, straight segments and also between two spatially distant residues. The parameters of the penalty function were optimized on a set of 240 sequence pairs of known structure, spanning the sequence identity range of 20-40%. We then tested the algorithm on another set of 238 sequence pairs of known structures. The use of the VGP function increases the number of correctly aligned residues from 81.0 to 84.5% in comparison with the optimized affine gap penalty function; this difference is statistically significant according to Student’s t-test. We estimate that the new algorithm allows us to produce comparative models with an additional approximately 7 million accurately modeled residues in the approximately 1.1 million proteins that are detectably related to a known structure.10aAlgorithms Amino Acid Sequence Models10aAmino Acid *Software10aMolecular Molecular Sequence Data Proteins/*chemistry Sequence Alignment/*methods Sequence Analysis10aProtein/*methods *Sequence Homology1 aMadhusudhan, M., S.1 aMarti-Renom, M., A.1 aSanchez, R.1 aSali, A. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1642384602676nas a2200313 4500008004100000245005400041210005100095300000900146490000800155520141200163653011201575653025901687100001401946700002101960700002601981700002102007700001502028700001802043700002102061700003202082700002002114700002602134700002002160700001802180700001702198700001902215700002202234856010602256 2005 eng d00aAn anaerobic mitochondrion that produces hydrogen0 aanaerobic mitochondrion that produces hydrogen a74-90 v4343 aHydrogenosomes are organelles that produce ATP and hydrogen, and are found in various unrelated eukaryotes, such as anaerobic flagellates, chytridiomycete fungi and ciliates. Although all of these organelles generate hydrogen, the hydrogenosomes from these organisms are structurally and metabolically quite different, just like mitochondria where large differences also exist. These differences have led to a continuing debate about the evolutionary origin of hydrogenosomes. Here we show that the hydrogenosomes of the anaerobic ciliate Nyctotherus ovalis, which thrives in the hindgut of cockroaches, have retained a rudimentary genome encoding components of a mitochondrial electron transport chain. Phylogenetic analyses reveal that those proteins cluster with their homologues from aerobic ciliates. In addition, several nucleus-encoded components of the mitochondrial proteome, such as pyruvate dehydrogenase and complex II, were identified. The N. ovalis hydrogenosome is sensitive to inhibitors of mitochondrial complex I and produces succinate as a major metabolic end product–biochemical traits typical of anaerobic mitochondria. The production of hydrogen, together with the presence of a genome encoding respiratory chain components, and biochemical features characteristic of anaerobic mitochondria, identify the N. ovalis organelle as a missing link between mitochondria and hydrogenosomes.10a*Anaerobiosis Animals Ciliophora/*cytology/genetics/*metabolism/ultrastructure Cockroaches/parasitology DNA10aMitochondrial/genetics Electron Transport Electron Transport Complex I/antagonists & inhibitors/metabolism Genome Glucose/metabolism Hydrogen/*metabolism Mitochondria/enzymology/genetics/*metabolism/ultrastructure Molecular Sequence Data Open Reading Fra1 aBoxma, B.1 ade Graaf, R., M.1 avan der Staay, G., W.1 avan Alen, T., A.1 aRicard, G.1 aGabaldón, T.1 avan Hoek, A., H.1 avan der Staay, S., Y. Moon-1 aKoopman, W., J.1 avan Hellemond, J., J.1 aTielens, A., G.1 aFriedrich, T.1 aVeenhuis, M.1 aHuynen, M., A.1 aHackstein, J., H. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1574430202090nas a2200193 4500008004100000245012600041210006900167300001100236490000700247520144700254653001501701653002501716100002401741700001601765700002301781700001401804700001501818856006301833 2005 eng d00aBABELOMICS: a suite of web tools for functional annotation and analysis of groups of genes in high-throughput experiments0 aBABELOMICS a suite of web tools for functional annotation and an aW460-40 v333 a

We present Babelomics, a complete suite of web tools for the functional analysis of groups of genes in high-throughput experiments, which includes the use of information on Gene Ontology terms, interpro motifs, KEGG pathways, Swiss-Prot keywords, analysis of predicted transcription factor binding sites, chromosomal positions and presence in tissues with determined histological characteristics, through five integrated modules: FatiGO (fast assignment and transference of information), FatiWise, transcription factor association test, GenomeGO and tissues mining tool, respectively. Additionally, another module, FatiScan, provides a new procedure that integrates biological information in combination with experimental results in order to find groups of genes with modest but coordinate significant differential behaviour. FatiScan is highly sensitive and is capable of finding significant asymmetries in the distribution of genes of common function across a list of ordered genes even if these asymmetries were not extreme. The strong multiple-testing nature of the contrasts made by the tools is taken into account. All the tools are integrated in the gene expression analysis package GEPAS. Babelomics is the natural evolution of our tool FatiGO (which analysed almost 22,000 experiments during the last year) to include more sources on information and new modes of using it. Babelomics can be found at http://www.babelomics.org.

10ababelomics10afunctional profiling1 aAl-Shahrour, Fatima1 aMinguez, P.1 aVaquerizas, J., M.1 aConde, L.1 aDopazo, J. uhttp://nar.oxfordjournals.org/content/33/suppl_2/W460.long01401nas a2200193 4500008004100000245010600041210006900147300001100216490000700227520075600234653001500990100001501005700001301020700002501033700001401058700001401072700001501086856010601101 2005 eng d00aBlast2GO: a universal tool for annotation, visualization and analysis in functional genomics research0 aBlast2GO a universal tool for annotation visualization and analy a3674-60 v213 a

SUMMARY: We present here Blast2GO (B2G), a research tool designed with the main purpose of enabling Gene Ontology (GO) based data mining on sequence data for which no GO annotation is yet available. B2G joints in one application GO annotation based on similarity searches with statistical analysis and highlighted visualization on directed acyclic graphs. This tool offers a suitable platform for functional genomics research in non-model species. B2G is an intuitive and interactive desktop application that allows monitoring and comprehension of the whole annotation and analysis process. AVAILABILITY: Blast2GO is freely available via Java Web Start at http://www.blast2go.de. SUPPLEMENTARY MATERIAL: http://www.blast2go.de -> Evaluation.

10ababelomics1 aConesa, A.1 aGotz, S.1 aGarcia-Gomez, J., M.1 aTerol, J.1 aTalon, M.1 aRobles, M. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1608147401615nas a2200181 4500008004100000245012100041210006900162300001000231490000800241520089300249653003301142653008301175100001901258700001901277700001801296700001301314856010601327 2005 eng d00aCombining data from genomes, Y2H and 3D structure indicates that BolA is a reductase interacting with a glutaredoxin0 aCombining data from genomes Y2H and 3D structure indicates that  a591-60 v5793 aGenomes, functional genomics data and 3D structure reflect different aspects of protein function. Here, we combine these data to predict that BolA, a widely distributed protein family with unknown function, is a reductase that interacts with a glutaredoxin. Comparisons at the 3D structure level as well as at the sequence profile level indicate homology between BolA and OsmC, an enzyme that reduces organic peroxides. Complementary to this, comparative analyses of genomes and genomics data provide strong evidence of an interaction between BolA and the mono-thiol glutaredoxin family. The interaction between BolA and a mono-thiol glutaredoxin is of particular interest because BolA does not, in contrast to its homolog OsmC, have evolutionarily conserved cysteines to provide it with reducing equivalents. We propose that BolA uses the mono-thiol glutaredoxin as the source for these.10a*Genome Glutaredoxins Models10aMolecular Oxidoreductases/chemistry/*metabolism Phylogeny Protein Conformation1 aHuynen, M., A.1 aSpronk, C., A.1 aGabaldón, T.1 aSnel, B. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1567081302167nas a2200301 4500008004100000245008600041210006900127300001100196490000700207520100200214653012701216653002601343653013701369653003901506653001801545100002001563700001901583700001901602700001901621700001401640700002401654700001701678700001801695700001301713700001901726700001401745856010601759 2005 eng d00aThe C-type lectin fold as an evolutionary solution for massive sequence variation0 aCtype lectin fold as an evolutionary solution for massive sequen a886-920 v123 aOnly few instances are known of protein folds that tolerate massive sequence variation for the sake of binding diversity. The most extensively characterized is the immunoglobulin fold. We now add to this the C-type lectin (CLec) fold, as found in the major tropism determinant (Mtd), a retroelement-encoded receptor-binding protein of Bordetella bacteriophage. Variation in Mtd, with its approximately 10(13) possible sequences, enables phage adaptation to Bordetella spp. Mtd is an intertwined, pyramid-shaped trimer, with variable residues organized by its CLec fold into discrete receptor-binding sites. The CLec fold provides a highly static scaffold for combinatorial display of variable residues, probably reflecting a different evolutionary solution for balancing diversity against stability from that in the immunoglobulin fold. Mtd variants are biased toward the receptor pertactin, and there is evidence that the CLec fold is used broadly for sequence variation by related retroelements.10aAmino Acid Sequence Bacterial Outer Membrane Proteins/*chemistry Bacteriophages/*metabolism Bordetella/*virology Evolution10aBordetella/*chemistry10aC-Type/*chemistry Molecular Sequence Data Protein Conformation Protein Folding Viral Proteins/*chemistry/*genetics Virulence Factors10aMolecular Genetic Variation Genome10aViral Lectins1 aMcMahon, S., A.1 aMiller, J., L.1 aLawton, J., A.1 aKerkow, D., E.1 aHodes, A.1 aMarti-Renom, M., A.1 aDoulatov, S.1 aNarayanan, E.1 aSali, A.1 aMiller, J., F.1 aGhosh, P. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1617032400463nas a2200121 4500008004100000245006300041210006300104260003500167653001500202100001500217700001500232856009400247 2005 eng d00aData analysis and visualisation in genomics and proteomics0 aData analysis and visualisation in genomics and proteomics bWiley, F. Azuaje and J. Dopazo10ababelomics1 aAzuaje, F.1 aDopazo, J. uhttp://clinbioinfosspa.es/content/data-analysis-and-visualisation-genomics-and-proteomics00525nas a2200121 4500008004100000245009500041210006900136260003500205100001500240700001500255700001200270856012100282 2005 eng d00aData and Predictive Model Integration: an Overview of Key Concepts, Problems and Solutions0 aData and Predictive Model Integration an Overview of Key Concept bWiley, F. Azuaje and J. Dopazo1 aAzuaje, F.1 aDopazo, J.1 aWang, H uhttp://clinbioinfosspa.es/content/data-and-predictive-model-integration-overview-key-concepts-problems-and-solutions02245nas a2200253 4500008004100000245008600041210006900127300001100196490000800207520134200215653001501557653003601572653012101608653002301729100001801752700001601770700001401786700002401800700001501824700001901839700001301858700001401871856010601885 2005 eng d00aDetecting remotely related proteins by their interactions and sequence similarity0 aDetecting remotely related proteins by their interactions and se a7151-60 v1023 aThe function of an uncharacterized protein is usually inferred either from its homology to, or its interactions with, characterized proteins. Here, we use both sequence similarity and protein interactions to identify relationships between remotely related protein sequences. We rely on the fact that homologous sequences share similar interactions, and, therefore, the set of interacting partners of the partners of a given protein is enriched by its homologs. The approach was bench-marked by assigning the fold and functional family to test sequences of known structure. Specifically, we relied on 1,434 proteins with known folds, as defined in the Structural Classification of Proteins (SCOP) database, and with known interacting partners, as defined in the Database of Interacting Proteins (DIP). For this subset, the specificity of fold assignment was increased from 54% for position-specific iterative BLAST to 75% for our approach, with a concomitant increase in sensitivity for a few percentage points. Similarly, the specificity of family assignment at the e-value threshold of 10(-8) was increased from 70% to 87%. The proposed method would be a useful tool for large-scale automated discovery of remote relationships between protein sequences, given its unique reliance on sequence similarity and protein-protein interactions.10aAmino Acid10aComputational Biology Databases10aMolecular Protein Conformation Protein Folding Proteins/*genetics/*metabolism Proteomics/*methods *Sequence Homology10aProtein *Evolution1 aEspadaler, J.1 aAragues, R.1 aEswar, N.1 aMarti-Renom, M., A.1 aQuerol, E.1 aAviles, F., X.1 aSali, A.1 aOliva, B. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1588337203705nas a2200805 4500008004100000245010800041210006900149300001100218490000700229520133100236653002501567653010901592653000801701653010501709653007501814100001601889700001401905700001501919700001701934700001501951700001501966700001301981700001501994700001602009700002002025700001502045700002102060700001502081700001802096700001502114700002902129700001502158700001702173700001502190700002802205700001502233700001602248700001402264700002602278700001602304700001502320700002102335700001602356700001902372700002002391700001702411700002702428700001702455700001502472700001602487700001502503700002502518700002002543700001302563700001602576700002202592700001302614700001602627700001402643700001402657700001402671700001402685700001502699700001502714700001602729700001402745700001702759700001702776856010602793 2005 eng d00aDevelopment of a citrus genome-wide EST collection and cDNA microarray as resources for genomic studies0 aDevelopment of a citrus genomewide EST collection and cDNA micro a375-910 v573 aA functional genomics project has been initiated to approach the molecular characterization of the main biological and agronomical traits of citrus. As a key part of this project, a citrus EST collection has been generated from 25 cDNA libraries covering different tissues, developmental stages and stress conditions. The collection includes a total of 22,635 high-quality ESTs, grouped in 11,836 putative unigenes, which represent at least one third of the estimated number of genes in the citrus genome. Functional annotation of unigenes which have Arabidopsis orthologues (68% of all unigenes) revealed gene representation in every major functional category, suggesting that a genome-wide EST collection was obtained. A Citrus clementina Hort. ex Tan. cv. Clemenules genomic library, that will contribute to further characterization of relevant genes, has also been constructed. To initiate the analysis of citrus transcriptome, we have developed a cDNA microarray containing 12,672 probes corresponding to 6875 putative unigenes of the collection. Technical characterization of the microarray showed high intra- and inter-array reproducibility, as well as a good range of sensitivity. We have also validated gene expression data achieved with this microarray through an independent technique such as RNA gel blot analysis.10aCitrus/*genetics DNA10aComplementary/chemistry/genetics *Expressed Sequence Tags Gene Expression Profiling Gene Library *Genome10aDNA10aPlant Genomics/*methods Molecular Sequence Data Oligonucleotide Array Sequence Analysis/*methods RNA10aPlant/genetics/metabolism Reproducibility of Results Sequence Analysis1 aForment, J.1 aGadea, J.1 aHuerta, L.1 aAbizanda, L.1 aAgusti, J.1 aAlamar, S.1 aAlos, E.1 aAndres, F.1 aArribas, R.1 aBeltran, J., P.1 aBerbel, A.1 aBlazquez, M., A.1 aBrumos, J.1 aCanas, L., A.1 aCercos, M.1 aColmenero-Flores, J., M.1 aConesa, A.1 aEstables, B.1 aGandia, M.1 aGarcia-Martinez, J., L.1 aGimeno, J.1 aGisbert, A.1 aGomez, G.1 aGonzalez-Candelas, L.1 aGranell, A.1 aGuerri, J.1 aLafuente, M., T.1 aMadueno, F.1 aMarcos, J., F.1 aMarques, M., C.1 aMartinez, F.1 aMartinez-Godoy, M., A.1 aMiralles, S.1 aMoreno, P.1 aNavarro, L.1 aPallas, V.1 aPerez-Amador, M., A.1 aPerez-Valle, J.1 aPons, C.1 aRodrigo, I.1 aRodriguez, P., L.1 aRoyo, C.1 aSerrano, R.1 aSoler, G.1 aTadeo, F.1 aTalon, M.1 aTerol, J.1 aTrenor, M.1 aVaello, L.1 aVicente, O.1 aVidal, Ch1 aZacarias, L.1 aConejero, V. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1583012802842nas a2200205 4500008004100000245013300041210006900174300001200243490000700255520183200262653001502094653013902109653003602248653010202284653008402386100002402470700002102494700001502515856010602530 2005 eng d00aDiscovering molecular functions significantly related to phenotypes by combining gene expression data and biological information0 aDiscovering molecular functions significantly related to phenoty a2988-930 v213 a

MOTIVATION: The analysis of genome-scale data from different high throughput techniques can be used to obtain lists of genes ordered according to their different behaviours under distinct experimental conditions corresponding to different phenotypes (e.g. differential gene expression between diseased samples and controls, different response to a drug, etc.). The order in which the genes appear in the list is a consequence of the biological roles that the genes play within the cell, which account, at molecular scale, for the macroscopic differences observed between the phenotypes studied. Typically, two steps are followed for understanding the biological processes that differentiate phenotypes at molecular level: first, genes with significant differential expression are selected on the basis of their experimental values and subsequently, the functional properties of these genes are analysed. Instead, we present a simple procedure which combines experimental measurements with available biological information in a way that genes are simultaneously tested in groups related by common functional properties. The method proposed constitutes a very sensitive tool for selecting genes with significant differential behaviour in the experimental conditions tested. RESULTS: We propose the use of a method to scan ordered lists of genes. The method allows the understanding of the biological processes operating at molecular level behind the macroscopic experiment from which the list was generated. This procedure can be useful in situations where it is not possible to obtain statistically significant differences based on the experimental measurements (e.g. low prevalence diseases, etc.). Two examples demonstrate its application in two microarray experiments and the type of information that can be extracted.

10ababelomics10aBiological Neoplasm Proteins/genetics/*metabolism Phenotype Software Structure-Activity Relationship Systems Integration Tumor Markers10aBiological/genetics/*metabolism10aBreast Neoplasms/genetics/*metabolism Computer Simulation *Database Management Systems *Databases10aProtein Documentation/methods Gene Expression Profiling/*methods Humans *Models1 aAl-Shahrour, Fatima1 aDiaz-Uriarte, R.1 aDopazo, J. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1584070201232nas a2200121 4500008004100000245006600041210006500107300001000172490000600182520079800188100001800986856010601004 2005 eng d00aEvolution of proteins and proteomes: a phylogenetics approach0 aEvolution of proteins and proteomes a phylogenetics approach a51-610 v13 aThe study of evolutionary relationships among protein sequences was one of the first applications of bioinformatics. Since then, and accompanying the wealth of biological data produced by genome sequencing and other high-throughput techniques, the use of bioinformatics in general and phylogenetics in particular has been gaining ground in the study of protein and proteome evolution. Nowadays, the use of phylogenetics is instrumental not only to infer the evolutionary relationships among species and their genome sequences, but also to reconstruct ancestral states of proteins and proteomes and hence trace the paths followed by evolution. Here I survey recent progress in the elucidation of mechanisms of protein and proteome evolution in which phylogenetics has played a determinant role.1 aGabaldón, T. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1932585302221nas a2200157 4500008004100000245005800041210005600099300000800155490000600163520157700169653010501746653007601851100001501927700001501942856010601957 2005 eng d00aGenome-scale evidence of the nematode-arthropod clade0 aGenomescale evidence of the nematodearthropod clade aR410 v63 aBACKGROUND: The issue of whether coelomates form a single clade, the Coelomata, or whether all animals that moult an exoskeleton (such as the coelomate arthropods and the pseudocoelomate nematodes) form a distinct clade, the Ecdysozoa, is the most puzzling issue in animal systematics and a major open-ended subject in evolutionary biology. Previous single-gene and genome-scale analyses designed to resolve the issue have produced contradictory results. Here we present the first genome-scale phylogenetic evidence that strongly supports the Ecdysozoa hypothesis. RESULTS: Through the most extensive phylogenetic analysis carried out to date, the complete genomes of 11 eukaryotic species have been analyzed in order to find homologous sequences derived from 18 human chromosomes. Phylogenetic analysis of datasets showing an increased adjustment to equal evolutionary rates between nematode and arthropod sequences produced a gradual change from support for Coelomata to support for Ecdysozoa. Transition between topologies occurred when fast-evolving sequences of Caenorhabditis elegans were removed. When chordate, nematode and arthropod sequences were constrained to fit equal evolutionary rates, the Ecdysozoa topology was statistically accepted whereas Coelomata was rejected. CONCLUSIONS: The reliability of a monophyletic group clustering arthropods and nematodes was unequivocally accepted in datasets where traces of the long-branch attraction effect were removed. This is the first phylogenomic evidence to strongly support the ’moulting clade’ hypothesis.10aAnimals Arthropods/*classification/genetics Caenorhabditis elegans/classification/genetics Evolution10aMolecular *Genome Genomics Nematoda/*classification/genetics *Phylogeny1 aDopazo, H.1 aDopazo, J. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1589286902188nas a2200241 4500008004100000245009500041210006900136300001200205490000700217520141200224653001001636653002901646100002301675700001401698700002001712700001601732700001601748700002101764700002401785700001601809700001501825856010601840 2005 eng d00aGEPAS, an experiment-oriented pipeline for the analysis of microarray gene expression data0 aGEPAS an experimentoriented pipeline for the analysis of microar aW616-200 v333 a

The Gene Expression Profile Analysis Suite, GEPAS, has been running for more than three years. With >76,000 experiments analysed during the last year and a daily average of almost 300 analyses, GEPAS can be considered a well-established and widely used platform for gene expression microarray data analysis. GEPAS is oriented to the analysis of whole series of experiments. Its design and development have been driven by the demands of the biomedical community, probably the most active collective in the field of microarray users. Although clustering methods have obviously been implemented in GEPAS, our interest has focused more on methods for finding genes differentially expressed among distinct classes of experiments or correlated to diverse clinical outcomes, as well as on building predictors. There is also a great interest in CGH-arrays which fostered the development of the corresponding tool in GEPAS: InSilicoCGH. Much effort has been invested in GEPAS for developing and implementing efficient methods for functional annotation of experiments in the proper statistical framework. Thus, the popular FatiGO has expanded to a suite of programs for functional annotation of experiments, including information on transcription factor binding sites, chromosomal location and tissues. The web-based pipeline for microarray gene expression data, GEPAS, is available at http://www.gepas.org.

10agepas10amicroarray data analysis1 aVaquerizas, J., M.1 aConde, L.1 aYankilevich, P.1 aCabezon, A.1 aMinguez, P.1 aDiaz-Uriarte, R.1 aAl-Shahrour, Fatima1 aHerrero, J.1 aDopazo, J. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1598054801413nas a2200181 4500008004100000245005600041210005500097300001100152490000700163520072100170653007700891653008700968100001701055700001501072700002101087700001701108856010601125 2005 eng d00aHCAD, closing the gap between breakpoints and genes0 aHCAD closing the gap between breakpoints and genes aD511-30 v333 aRecurrent chromosome aberrations are an important resource when associating human pathologies to specific genes. However, for technical reasons a large number of chromosome breakpoints are defined only at the level of cytobands and many of the genes involved remain unidentified. We developed a web-based information system that mines the scientific literature and generates textual and comprehensive information on all human breakpoints. We show that the statistical analysis of this textual information and its combination with genomic data can identify genes directly involved in DNA rearrangements. The Human Chromosome Aberration Database (HCAD) is publicly accessible at http://www.pdg.cnb.uam.es/UniPub/HCAD/.10a*Chromosome Breakage Chromosome Disorders/diagnosis/*genetics *Databases10aGenetic Genes *Genetic Predisposition to Disease Humans PubMed Systems Integration1 aHoffmann, R.1 aDopazo, J.1 aCigudosa, J., C.1 aValencia, A. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1560825002607nas a2200181 4500008004100000245009100041210006900132300001200201490000700213520184100220653007402061653005202135653007802187100001602265700002302281700001502304856010602319 2005 eng d00aHighly specific and accurate selection of siRNAs for high-throughput functional assays0 aHighly specific and accurate selection of siRNAs for highthrough a1376-820 v213 aMOTIVATION: Small interfering RNA (siRNA) is widely used in functional genomics to silence genes by decreasing their expression to study the resulting phenotypes. The possibility of performing large-scale functional assays by gene silencing accentuates the necessity of a software capable of the high-throughput design of highly specific siRNA. The main objective sought was the design of a large number of siRNAs with appropriate thermodynamic properties and, especially, high specificity. Since all the available procedures require, to some extent, manual processing of the results to guarantee specific results, specificity constitutes to date, the major obstacle to the complete automation of all the steps necessary for the selection of optimal candidate siRNAs. RESULT: Here, we present a program that for the first time completely automates the search for siRNAs. In SiDE, the most complete set of rules for the selection of siRNA candidates (including G+C content, nucleotides at determined positions, thermodynamic properties, propensity to form internal hairpins, etc.) is implemented and moreover, specificity is achieved by a conceptually new method. After selecting possible siRNA candidates with the optimal functional properties, putative unspecific matches, which can cause cross-hybridization, are checked in databases containing a unique entry for each gene. These truly non-redundant databases are constructed from the genome annotations (Ensembl). Also intron/exon boundaries, presence of polymorphisms (single nucleotide polymorphisms) specificity for either gene or transcript, and other features can be selected to be considered in the design of siRNAs. AVAILABILITY: The program is available as a web server at http://side.bioinfo.cnio.es. The program was written under the GPL license. CONTACT: jdopazo@cnio.es.10a*Algorithms Base Sequence *Gene Silencing Molecular Sequence Data RNA10aRNA/*methods *Software *User-Computer Interface10aSmall Interfering/*genetics Sequence Alignment/*methods Sequence Analysis1 aSantoyo, J.1 aVaquerizas, J., M.1 aDopazo, J. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1559135700533nas a2200121 4500008004100000245010500041210006900146260003500215300000800250100001500258700001500273856012300288 2005 eng d00aIntegrative Data Analysis and Visualization: Introduction to Critical Problems, Goals and Challenges0 aIntegrative Data Analysis and Visualization Introduction to Crit bWiley, F. Azuaje and J. Dopazo a3-91 aAzuaje, F.1 aDopazo, J. uhttp://clinbioinfosspa.es/content/integrative-data-analysis-and-visualization-introduction-critical-problems-goals-and01787nas a2200181 4500008004100000245012500041210006900166300001300235490001500248520091200263653004401175653003901219653014701258653005701405100001801462700001901480856010601499 2005 eng d00aLineage-specific gene loss following mitochondrial endosymbiosis and its potential for function prediction in eukaryotes0 aLineagespecific gene loss following mitochondrial endosymbiosis  aii144-500 v21 Suppl 23 aMOTIVATION: The endosymbiotic origin of mitochondria has resulted in a massive horizontal transfer of genetic material from an alpha-proteobacterium to the early eukaryotes. Using large-scale phylogenetic analysis we have previously identified 630 orthologous groups of proteins derived from this event. Here we show that this proto-mitochondrial protein set has undergone extensive lineage-specific gene loss in the eukaryotes, with an average of three losses per orthologous group in a phylogeny of nine species. This gene loss has resulted in a high variability of the alphaproteobacterial-derived gene content of present-day eukaryotic genomes that might reflect functional adaptation to different environments. Proteins functioning in the same biochemical pathway tend to have a similar history of gene loss events, and we use this property to predict functional interactions among proteins in our set.10aAnimals Chromosome Mapping/*methods DNA10aMitochondrial/*genetics *Evolution10aMolecular *Gene Deletion Genetic Variation/genetics Humans Linkage Disequilibrium/*genetics Mitochondrial Proteins/*genetics Sequence Homology10aNucleic Acid Species Specificity Symbiosis/*genetics1 aGabaldón, T.1 aHuynen, M., A. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1620409402687nas a2200337 4500008004100000245010400041210006900145300001000214490000700224520138200231653003401613653006501647653002501712653001001737653003201747653003301779653003201812653019101844100001502035700002202050700002602072700001602098700002502114700001402139700002202153700001602175700001502191700002102206700001602227856010602243 2005 eng d00aA novel candidate region linked to development of both pheochromocytoma and head/neck paraganglioma0 anovel candidate region linked to development of both pheochromoc a260-80 v423 aAlthough the histologic distinction between pheochromocytomas and head and neck paragangliomas is clear, little is known about the genetic differences between them. To date, various sets of genes have been found to be involved in inherited susceptibility to developing both tumor types, but the genes involved in sporadic pathogenesis are still unknown. To define new candidate regions, we performed CGH analysis on 29 pheochromocytomas and on 24 paragangliomas mainly of head and neck origin (20 of 24), which allowed us to differentiate between the two tumor types. Loss of 3q was significantly more frequent in pheochromocytomas, and loss of 1q appeared only in paragangliomas. We also found gain of 11q13 to be a significantly frequent alteration in malignant cases of both types. In addition, recurrent loss of 8p22-23 was found in 62% of pheochromocytomas (including all malignant cases) versus in 33% of paragangliomas, suggesting that this region contains candidate genes involved in the pathogenesis of this abnormality. Using FISH analysis on tissue microarrays, we confirmed genomic deletion of this region in 55% of pheochromocytomas compared to 12% of paragangliomas. Loss of 8p22-23 appears to be an important event in the sporadic development of these tumors, and additional molecular studies are necessary to identify candidate genes in this chromosomal region.10a80 and over Child Chromosomes10aAdolescent Adrenal Gland Neoplasms/*genetics Adult Aged Aged10aBiological/*genetics10aHuman10aPair 1/genetics Chromosomes10aPair 11/genetics Chromosomes10aPair 3/genetics Chromosomes10aPair 8/genetics Female Gene Deletion Head and Neck Neoplasms/*genetics Humans Male Middle Aged Nucleic Acid Hybridization Paraganglioma/*genetics Pheochromocytoma/*genetics Tumor Markers1 aCascon, A.1 aRuiz-Llorente, S.1 aRodriguez-Perales, S.1 aHonrado, E.1 aMartinez-Ramirez, A.1 aLeton, R.1 aMontero-Conde, C.1 aBenitez, J.1 aDopazo, J.1 aCigudosa, J., C.1 aRobledo, M. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1560934700399nas a2200121 4500008004100000245003900041210003900080260003500119300001100154100002400165700001500189856007300204 2005 eng d00aOntologies and functional genomics0 aOntologies and functional genomics bWiley, F. Azuaje and J. Dopazo a99-1021 aAl-Shahrour, Fatima1 aDopazo, J. uhttp://clinbioinfosspa.es/content/ontologies-and-functional-genomics02968nas a2200337 4500008004100000245012900041210006900170300000900239490000700248520175600255653010902011653003502120653001702155653006002172653007102232100001702303700001602320700001502336700001602351700001502367700001602382700001802398700002102416700001302437700001502450700001402465700001502479700001402494700001602508856010602524 2005 eng d00aPhenotypic characterization of BRCA1 and BRCA2 tumors based in a tissue microarray study with 37 immunohistochemical markers0 aPhenotypic characterization of BRCA1 and BRCA2 tumors based in a a5-140 v903 aFamilial breast cancers that are associated with BRCA1 or BRCA2 germline mutations differ in both their morphological and immunohistochemical characteristics. To further characterize the molecular difference between genotypes, the authors evaluated the expression of 37 immunohistochemical markers in a tissue microarray (TMA) containing cores from 20 BRCA1, 14 BRCA2, and 59 sporadic age-matched breast carcinomas. Markers analyzed included, amog others, common markers in breast cancer, such as hormone receptors, p53 and HER2, along with 15 molecules involved in cell cycle regulation, such as cyclins, cyclin dependent kinases (CDK) and CDK inhibitors (CDKI), apoptosis markers, such as BCL2 and active caspase 3, and two basal/myoepithelial markers (CK 5/6 and P-cadherin). In addition, we analyzed the amplification of CCND1, CCNE, HER2 and MYC by FISH.Unsupervised cluster data analysis of both hereditary and sporadic cases using the complete set of immunohistochemical markers demonstrated that most BRCA1-associated carcinomas grouped in a branch of ER-, HER2-negative tumors that expressed basal cell markers and/or p53 and had higher expression of activated caspase 3. The cell cycle proteins associated with these tumors were E2F6, cyclins A, B1 and E, SKP2 and Topo IIalpha. In contrast, most BRCA2-associated carcinomas grouped in a branch composed by ER/PR/BCL2-positive tumors with a higher expression of the cell cycle proteins cyclin D1, cyclin D3, p27, p16, p21, CDK4, CDK2 and CDK1. In conclusion, our study in hereditary breast cancer tumors analyzing 37 immunohistochemical markers, define the molecular differences between BRCA1 and BRCA2 tumors with respect to hormonal receptors, cell cycle, apoptosis and basal cell markers.10aAdult Apoptosis Breast Neoplasms/*genetics/*pathology Cell Cycle Proteins Cluster Analysis Female *Genes10aBiological/genetics/metabolism10aBRCA1 *Genes10aBRCA2 Humans Immunohistochemistry In Situ Hybridization10aFluorescence Phenotype Spain *Tissue Array Analysis *Tumor Markers1 aPalacios, J.1 aHonrado, E.1 aOsorio, A.1 aCazorla, A.1 aSarrio, D.1 aBarroso, A.1 aRodriguez, S.1 aCigudosa, J., C.1 aDiez, O.1 aAlonso, C.1 aLerma, E.1 aDopazo, J.1 aRivas, C.1 aBenitez, J. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1577052102881nas a2200397 4500008004100000245016800041210006900209300001200278490000700290520143600297653010101733653002201834653001001856653008301866653003301949653003301982653003302015653003202048653005102080100001602131700002102147700001502168700001602183700001602199700001602215700001602231700001802247700001602265700001402281700001302295700002102308700001502329700001702344700001602361856010602377 2005 eng d00aA predictor based on the somatic genomic changes of the BRCA1/BRCA2 breast cancer tumors identifies the non-BRCA1/BRCA2 tumors with BRCA1 promoter hypermethylation0 apredictor based on the somatic genomic changes of the BRCA1BRCA2 a1146-530 v113 aThe genetic changes underlying in the development and progression of familial breast cancer are poorly understood. To identify a somatic genetic signature of tumor progression for each familial group, BRCA1, BRCA2, and non-BRCA1/BRCA2 (BRCAX) tumors, by high-resolution comparative genomic hybridization, we have analyzed 77 tumors previously characterized for BRCA1 and BRCA2 germ line mutations. Based on a combination of the somatic genetic changes observed at the six most different chromosomal regions and the status of the estrogen receptor, we developed using random forests a molecular classifier, which assigns to a given tumor a probability to belong either to the BRCA1 or to the BRCA2 class. Because 76.5% (26 of 34) of the BRCAX cases were classified with our predictor to the BRCA1 class with a probability of >50%, we analyzed the BRCA1 promoter region for aberrant methylation in all the BRCAX cases. We found that 15 of the 34 BRCAX analyzed tumors had hypermethylation of the BRCA1 gene. When we considered the predictor, we observed that all the cases with this epigenetic event were assigned to the BRCA1 class with a probability of >50%. Interestingly, 84.6% of the cases (11 of 13) assigned to the BRCA1 class with a probability >80% had an aberrant methylation of the BRCA1 promoter. This fact suggests that somatic BRCA1 inactivation could modify the profile of tumor progression in most of the BRCAX cases.10aBRCA1 Protein/*genetics BRCA2 Protein/*genetics Breast Neoplasms/*genetics/pathology Chromosomes10aGenetic/*genetics10aHuman10aHuman Humans Male Mutation Nucleic Acid Hybridization/methods Promoter Regions10aPair 12/genetics Chromosomes10aPair 15/genetics Chromosomes10aPair 18/genetics Chromosomes10aPair 2/genetics Chromosomes10aPair 8/genetics *DNA Methylation Female Genome1 aAlvarez, S.1 aDiaz-Uriarte, R.1 aOsorio, A.1 aBarroso, A.1 aMelchor, L.1 aPaz, M., F.1 aHonrado, E.1 aRodriguez, R.1 aUrioste, M.1 aValle, L.1 aDiez, O.1 aCigudosa, J., C.1 aDopazo, J.1 aEsteller, M.1 aBenitez, J. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1570918202075nas a2200205 4500008004100000245012600041210006900167300001100236490000700247520124100254653010501495653005601600100001401656700002301670700002101693700001901714700001501733700001501748856010601763 2005 eng d00aPupasView: a visual tool for selecting suitable SNPs, with putative pathological effect in genes, for genotyping purposes0 aPupasView a visual tool for selecting suitable SNPs with putativ aW501-50 v333 aWe have developed a web tool, PupasView, for the selection of single nucleotide polymorphisms (SNPs) with potential phenotypic effect. PupasView constitutes an interactive environment in which functional information and population frequency data can be used as sequential filters over linkage disequilibrium parameters to obtain a final list of SNPs optimal for genotyping purposes. PupasView is the first resource that integrates phenotypic effects caused by SNPs at both the translational and the transcriptional level. PupasView retrieves SNPs that could affect conserved regions that the cellular machinery uses for the correct processing of genes (intron/exon boundaries or exonic splicing enhancers), predicted transcription factor binding sites and changes in amino acids in the proteins for which a putative pathological effect is calculated. The program uses the mapping of SNPs in the genome provided by Ensembl. PupasView will be of much help in studies of multifactorial disorders, where the use of functional SNPs will increase the sensitivity of the identification of the genes responsible for the disease. The PupasView web interface is accessible through http://pupasview.ochoa.fib.es and through http://www.pupasnp.org.10aComputer Graphics Genes *Genetic Predisposition to Disease Genotype Internet Phenotype *Polymorphism10aSingle Nucleotide *Software User-Computer Interface1 aConde, L.1 aVaquerizas, J., M.1 aFerrer-Costa, C.1 ade la Cruz, X.1 aOrozco, M.1 aDopazo, J. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1598052200733nas a2200229 4500008004100000245005000041210004900091260010900140300001200249490000600261100001400267700001300281700001400294700001400308700001900322700001300341700001500354700001600369700002200385700001300407856008300420 2005 eng d00aSalinibacter ruber: genomics and biogeography0 aSalinibacter ruber genomics and biogeography aDordrecht, NetherlandsbNina Gunde-Cimerman, Ana Plemenitas, and Aharon Oren. Kluwer Academic Publishers a257-2660 v91 aAntón, J1 aPeña, A1 aValens, M1 aSantos, F1 aGlöckner, F.O1 aBauer, M1 aDopazo, J.1 aHerrero, J.1 aRosselló-Mora, R1 aAmann, R uhttp://clinbioinfosspa.es/content/salinibacter-ruber-genomics-and-biogeography02633nas a2200181 4500008004100000245011500041210006900156300001100225490000800236520169000244653015501934653019202089653001202281100001802293700001502311700001902326856010602345 2005 eng d00aTracing the evolution of a large protein complex in the eukaryotes, NADH:ubiquinone oxidoreductase (Complex I)0 aTracing the evolution of a large protein complex in the eukaryot a857-700 v3483 aThe increasing availability of sequenced genomes enables the reconstruction of the evolutionary history of large protein complexes. Here, we trace the evolution of NADH:ubiquinone oxidoreductase (Complex I), which has increased in size, by so-called supernumary subunits, from 14 subunits in the bacteria to 30 in the plants and algae, 37 in the fungi and 46 in the mammals. Using a combination of pair-wise and profile-based sequence comparisons at the levels of proteins and the DNA of the sequenced eukaryotic genomes, combined with phylogenetic analyses to establish orthology relationships, we were able to (1) trace the origin of six of the supernumerary subunits to the alpha-proteobacterial ancestor of the mitochondria, (2) detect previously unidentified homology relations between subunits from fungi and mammals, (3) detect previously unidentified subunits in the genomes of several species and (4) document several cases of gene duplications among supernumerary subunits in the eukaryotes. One of these, a duplication of N7BM (B17.2), is particularly interesting as it has been lost from genomes that have also lost Complex I proteins, making it a candidate for a Complex I interacting protein. A parsimonious reconstruction of eukaryotic Complex I evolution shows an initial increase in size that predates the separation of plants, fungi and metazoa, followed by a gradual adding and incidental losses of subunits in the various evolutionary lineages. This evolutionary scenario is in contrast to that for Complex I in the prokaryotes, for which the combination of several separate, and previously independently functioning modules into a single complex has been proposed.10aAmino Acid Sequence Animals Computational Biology Electron Transport Complex I/*chemistry/*genetics/metabolism Eukaryotic Cells/*enzymology *Evolution10aMolecular Humans Molecular Sequence Data Photosynthesis Phylogeny Plastids/enzymology Protein Binding Protein Subunits/chemistry/genetics/metabolism Sequence Alignment Structural Homology10aProtein1 aGabaldón, T.1 aRainey, D.1 aHuynen, M., A. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1584301801857nas a2200169 4500008004100000245008800041210006900129300001200198490000800210520119800218653001501416653010001431100001901531700001801550700001301568856010601581 2005 eng d00aVariation and evolution of biomolecular systems: searching for functional relevance0 aVariation and evolution of biomolecular systems searching for fu a1839-450 v5793 aThe availability of genome sequences and functional genomics data from multiple species enables us to compare the composition of biomolecular systems like biochemical pathways and protein complexes between species. Here, we review small- and large-scale, "genomics-based" approaches to biomolecular systems variation. In general, caution is required when comparing the results of bioinformatics analyses of genomes or of functional genomics data between species. Limitations to the sensitivity of sequence analysis tools and the noisy nature of genomics data tend to lead to systematic overestimates of the amount of variation. Nevertheless, the results from detailed manual analyses, and of large-scale analyses that filter out systematic biases, point to a large amount of variation in the composition of biomolecular systems. Such observations challenge our understanding of the function of the systems and their individual components and can potentially facilitate the identification and functional characterization of sub-systems within a system. Mapping the inter-species variation of complex biomolecular systems on a phylogenetic species tree allows one to reconstruct their evolution.10a*Evolution10aMolecular Genetic Variation Multiprotein Complexes/*genetics Phylogeny Protein Binding/genetics1 aHuynen, M., A.1 aGabaldón, T.1 aSnel, B. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1576356102319nas a2200181 4500008004100000245005300041210005300094300001200147490000700159520157000166653006801736653008501804653008101889100002401970700002401994700001302018856010602031 2004 eng d00aAlignment of protein sequences by their profiles0 aAlignment of protein sequences by their profiles a1071-870 v133 aThe accuracy of an alignment between two protein sequences can be improved by including other detectably related sequences in the comparison. We optimize and benchmark such an approach that relies on aligning two multiple sequence alignments, each one including one of the two protein sequences. Thirteen different protocols for creating and comparing profiles corresponding to the multiple sequence alignments are implemented in the SALIGN command of MODELLER. A test set of 200 pairwise, structure-based alignments with sequence identities below 40% is used to benchmark the 13 protocols as well as a number of previously described sequence alignment methods, including heuristic pairwise sequence alignment by BLAST, pairwise sequence alignment by global dynamic programming with an affine gap penalty function by the ALIGN command of MODELLER, sequence-profile alignment by PSI-BLAST, Hidden Markov Model methods implemented in SAM and LOBSTER, pairwise sequence alignment relying on predicted local structure by SEA, and multiple sequence alignment by CLUSTALW and COMPASS. The alignment accuracies of the best new protocols were significantly better than those of the other tested methods. For example, the fraction of the correctly aligned residues relative to the structure-based alignment by the best protocol is 56%, which can be compared with the accuracies of 26%, 42%, 43%, 48%, 50%, 49%, 43%, and 43% for the other methods, respectively. The new method is currently applied to large-scale comparative protein structure modeling of all known sequences.10a*Algorithms Amino Acid Sequence Computational Biology Databases10aProtein Markov Chains Molecular Sequence Data *Protein Folding Protein Structure10aTertiary Proteins/*chemistry *Sequence Alignment Sequence Homology *Software1 aMarti-Renom, M., A.1 aMadhusudhan, M., S.1 aSali, A. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1504473601390nas a2200169 4500008004100000245006900041210006700110300001100177490000700188520056300195653024500758653005201003100002301055700001501078700002101093856010601114 2004 eng d00aDNMAD: web-based diagnosis and normalization for microarray data0 aDNMAD webbased diagnosis and normalization for microarray data a3656-80 v203 aSUMMARY: We present a web server for Diagnosis and Normalization of MicroArray Data (DNMAD). DNMAD includes several common data transformations such as spatial and global robust local regression or multiple slide normalization, and allows for detecting several kinds of errors that result from the manipulation and the image analysis of the arrays. This tool offers a user-friendly interface, and is completely integrated within the Gene Expression Pattern Analysis Suite (GEPAS). AVAILABILITY: The tool is accessible on-line at http://dnmad.bioinfo.cnio.es.10aAlgorithms Database Management Systems Gene Expression Profiling/*methods/standards Information Storage and Retrieval/*methods *Internet Oligonucleotide Array Sequence Analysis/*methods/standards Sequence Alignment/methods Sequence Analysis10aDNA/*methods *Software *User-Computer Interface1 aVaquerizas, J., M.1 aDopazo, J.1 aDiaz-Uriarte, R. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1524709402177nas a2200313 4500008004100000245013500041210006900176260001500245300001200260490000700272520116700279100003001446700002301476700001901499700002001518700002701538700002701565700002101592700001901613700001601632700002101648700002401669700002401693700002001717700002201737700001801759700002001777856006601797 2004 eng d00aExpression profiling of T-cell lymphomas differentiates peripheral and lymphoblastic lymphomas and defines survival related genes.0 aExpression profiling of Tcell lymphomas differentiates periphera c2004 Aug 1 a4971-820 v103 a

PURPOSE: T-Cell lymphomas constitute heterogeneous and aggressive tumors in which pathogenic alterations remain largely unknown. Expression profiling has demonstrated to be a useful tool for molecular classification of tumors. EXPERIMENTAL DESIGN: Using DNA microarrays (CNIO-OncoChip) containing 6386 cancer-related genes, we established the expression profiling of T-cell lymphomas and compared them to normal lymphocytes and lymph nodes. RESULTS: We found significant differences between the peripheral and lymphoblastic T-cell lymphomas, which include a deregulation of nuclear factor-kappaB signaling pathway. We also identify differentially expressed genes between peripheral T-cell lymphoma tumors and normal T lymphocytes or reactive lymph nodes, which could represent candidate tumor markers of these lymphomas. Additionally, a close relationship between genes associated to survival and those that differentiate among the stages of disease and responses to therapy was found. CONCLUSIONS: Our results reflect the value of gene expression profiling to gain insight about the molecular alterations involved in the pathogenesis of T-cell lymphomas.

1 aMartinez-Delgado, Beatriz1 aMeléndez, Barbara1 aCuadros, Marta1 aAlvarez, Javier1 aCastrillo, Jose, Maria1 aDe La Parte, Ana, Ruiz1 aMollejo, Manuela1 aBellas, Carmen1 aDiaz, Ramon1 aLombardía, Luis1 aAl-Shahrour, Fatima1 aDomínguez, Orlando1 aCascon, Alberto1 aRobledo, Mercedes1 aRivas, Carmen1 aBenitez, Javier uhttp://clincancerres.aacrjournals.org/content/10/15/4971.long01450nas a2200193 4500008004100000245010400041210006900145300001100214490000700225520063300232653005000865653001500915653002700930653016800957100002401125700002101149700001501170856007101185 2004 eng d00aFatiGO: a web tool for finding significant associations of Gene Ontology terms with groups of genes0 aFatiGO a web tool for finding significant associations of Gene O a578-800 v203 a

We present a simple but powerful procedure to extract Gene Ontology (GO) terms that are significantly over- or under-represented in sets of genes within the context of a genome-scale experiment (DNA microarray, proteomics, etc.). Said procedure has been implemented as a web application, FatiGO, allowing for easy and interactive querying. FatiGO, which takes the multiple-testing nature of statistical contrast into account, currently includes GO associations for diverse organisms (human, mouse, fly, worm and yeast) and the TrEMBL/Swissprot GOAnnotations@EBI correspondences from the European Bioinformatics Institute.

10a*Algorithms Artificial Intelligence Databases10ababelomics10aDNA/*methods *Software10aGenetic Gene Expression Profiling/*methods *Hypermedia Information Storage and Retrieval/*methods *Internet *Phylogeny Sequence Alignment/methods Sequence Analysis1 aAl-Shahrour, Fatima1 aDiaz-Uriarte, R.1 aDopazo, J. uhttp://bioinformatics.oxfordjournals.org/content/20/4/578.abstract02990nas a2200325 4500008004100000245013600041210006900177300001100246490000700257520176100264653001602025653002602041653001002067653003402077653003402111653011302145653008802258100001702346700002102363700001602384700002502400700002702425700001502452700002102467700001402488700001502502700002502517700001602542856010602558 2004 eng d00aGene expression analysis of chromosomal regions with gain or loss of genetic material detected by comparative genomic hybridization0 aGene expression analysis of chromosomal regions with gain or los a353-650 v413 aComparative genomic hybridization (CGH) has been widely used to detect copy number alterations in cancer and to identify regions containing candidate tumor-responsible genes; however, gene expression changes have been described only in highly amplified regions (amplicons). To study the overall impact of slight copy number changes on gene expression, we analyzed 16 T-cell lymphomas by using CGH and a custom-designed cDNA microarray containing 7,657 genes and expressed sequence tags related to tumorigenesis. We evaluated mean gene expression and variability within CGH-altered regions and explored the relationship between the effects of the gene and its position within these regions. Minimally overlapping CGH candidate areas (6q25, 13q21-q22, and 19q13.1) revealed a weak relationship between altered genomic content and gene expression. However, some candidate genes showed modified expression within these regions in the majority of tumors; these candidate genes were evaluated and confirmed in another independent series of 23 T-cell lymphomas by use of the same cDNA microarray and by FISH on a tissue microarray. When all the CGH regions detected for each tumor were considered, we found a significant increase or decrease in the mean expression of the genes contained in gained or lost regions, respectively. In addition, we found that the expression of a gene was dependent not only on its position within an altered region but also on its own mechanism of regulation: genes in the same altered region responded very differently to the gain or loss of genetic material. Supplementary material for this article can be found on the Genes, Chromosomes, and Cancer website at http://www.interscience.wiley.com/jpages/1045-2257/suppmat/index.html.10aChromosomes10aFluorescence Lymphoma10aHuman10aPair 13/*genetics Chromosomes10aPair 19/*genetics Chromosomes10aPair 6/*genetics Expressed Sequence Tags *Gene Dosage Gene Expression Profiling Humans In Situ Hybridization10aT-Cell/*genetics Nucleic Acid Hybridization Oligonucleotide Array Sequence Analysis1 aMelendez, B.1 aDiaz-Uriarte, R.1 aCuadros, M.1 aMartinez-Ramirez, A.1 aFernandez-Piqueras, J.1 aDopazo, A.1 aCigudosa, J., C.1 aRivas, C.1 aDopazo, J.1 aMartinez-Delgado, B.1 aBenitez, J. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1538226100551nas a2200133 4500008004100000245011100041210006900152300001000221100001200231700001500243700001900258700001500277856012500292 2004 eng d00aGene expression Correlation and Gene Ontology-Based Similarity: An Assessment of Quantitative Relationship0 aGene expression Correlation and Gene OntologyBased Similarity An a25-311 aWang, H1 aAzuaje, F.1 aBodenreider, O1 aDopazo, J. uhttp://clinbioinfosspa.es/content/gene-expression-correlation-and-gene-ontology-based-similarity-assessment-quantitative03269nas a2200337 4500008004100000245010000041210006900141300001200210490000700222520201600229653008002245653005102325653005202376653014002428100001502568700001402583700001602597700002402613700001802637700001902655700001702674700001402691700002402705700001402729700001302743700001902756700001802775700001902793700001302812856010602825 2004 eng d00aMODBASE, a database of annotated comparative protein structure models, and associated resources0 aMODBASE a database of annotated comparative protein structure mo aD217-220 v323 aMODBASE (http://salilab.org/modbase) is a relational database of annotated comparative protein structure models for all available protein sequences matched to at least one known protein structure. The models are calculated by MODPIPE, an automated modeling pipeline that relies on the MODELLER package for fold assignment, sequence-structure alignment, model building and model assessment (http:/salilab.org/modeller). MODBASE uses the MySQL relational database management system for flexible querying and CHIMERA for viewing the sequences and structures (http://www.cgl.ucsf.edu/chimera/). MODBASE is updated regularly to reflect the growth in protein sequence and structure databases, as well as improvements in the software for calculating the models. For ease of access, MODBASE is organized into different data sets. The largest data set contains 1,26,629 models for domains in 659,495 out of 1,182,126 unique protein sequences in the complete Swiss-Prot/TrEMBL database (August 25, 2003); only models based on alignments with significant similarity scores and models assessed to have the correct fold despite insignificant alignments are included. Another model data set supports target selection and structure-based annotation by the New York Structural Genomics Research Consortium; e.g. the 53 new structures produced by the consortium allowed us to characterize structurally 24,113 sequences. MODBASE also contains binding site predictions for small ligands and a set of predicted interactions between pairs of modeled sequences from the same genome. Our other resources associated with MODBASE include a comprehensive database of multiple protein structure alignments (DBALI, http://salilab.org/dbali) as well as web servers for automated comparative modeling with MODPIPE (MODWEB, http://salilab. org/modweb), modeling of loops in protein structures (MODLOOP, http://salilab.org/modloop) and predicting functional consequences of single nucleotide polymorphisms (SNPWEB, http://salilab. org/snpweb).10aAmino Acid Sequence Animals Binding Sites *Computational Biology *Databases10aMolecular Molecular Sequence Data Polymorphism10aProtein Genomics Humans Internet Ligands Models10aSingle Nucleotide Protein Binding Protein Conformation Proteins/*chemistry/genetics Sequence Alignment Software User-Computer Interface1 aPieper, U.1 aEswar, N.1 aBraberg, H.1 aMadhusudhan, M., S.1 aDavis, F., P.1 aStuart, A., C.1 aMirkovic, N.1 aRossi, A.1 aMarti-Renom, M., A.1 aFiser, A.1 aWebb, B.1 aGreenblatt, D.1 aHuang, C., C.1 aFerrin, T., E.1 aSali, A. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1468139802102nas a2200217 4500008004100000245007500041210006900116300001200185490000700197520140300204653001001607653002901617100001601646700002301662700002401685700001401709700001501723700002501738700001501763856010601778 2004 eng d00aNew challenges in gene expression data analysis and the extended GEPAS0 aNew challenges in gene expression data analysis and the extended aW485-910 v323 a

Since the first papers published in the late nineties, including, for the first time, a comprehensive analysis of microarray data, the number of questions that have been addressed through this technique have both increased and diversified. Initially, interest focussed on genes coexpressing across sets of experimental conditions, implying, essentially, the use of clustering techniques. Recently, however, interest has focussed more on finding genes differentially expressed among distinct classes of experiments, or correlated to diverse clinical outcomes, as well as in building predictors. In addition to this, the availability of accurate genomic data and the recent implementation of CGH arrays has made mapping expression and genomic data on the chromosomes possible. There is also a clear demand for methods that allow the automatic transfer of biological information to the results of microarray experiments. Different initiatives, such as the Gene Ontology (GO) consortium, pathways databases, protein functional motifs, etc., provide curated annotations for genes. Whereas many resources on the web focus mainly on clustering methods, GEPAS has evolved to cope with the aforementioned new challenges that have recently arisen in the field of microarray data analysis. The web-based pipeline for microarray gene expression data, GEPAS, is available at http://gepas.bioinfo.cnio.es.

10agepas10amicroarray data analysis1 aHerrero, J.1 aVaquerizas, J., M.1 aAl-Shahrour, Fatima1 aConde, L.1 aMateos, A.1 aDiaz-Uriarte, J., S.1 aDopazo, J. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1521543400480nas a2200145 4500008004100000245003100041210003100072300000900103490000600112653006100118100001400179700001700193700001800210856010600228 2004 eng d00aPerceptions about postdocs0 aPerceptions about postdocs a11040 v510aEurope *Fellowships and Scholarships *Research Personnel1 aVella, F.1 aMietchen, D.1 aGabaldón, T. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1557792001756nas a2200145 4500008004100000245011900041210006900160300001200229490001500241520120200256100001501458700001601473700001501489856010601504 2004 eng d00aPhylogenomics and the number of characters required for obtaining an accurate phylogeny of eukaryote model species0 aPhylogenomics and the number of characters required for obtainin ai116-210 v20 Suppl 13 a

MOTIVATION: Through the most extensive phylogenomic analysis carried out to date, complete genomes of 11 eukaryotic species have been examined in order to find the homologous of more than 25,000 amino acid sequences. These sequences correspond to the exons of more than 3000 genes and were used as presence/absence characters to test one of the most controversial hypotheses concerning animal evolution, namely the Ecdysozoa hypothesis. Distance, maximum parsimony and Bayesian methods of phylogenetic reconstruction were used to test the hypothesis. RESULTS: The reliability of the ecdysozoa, grouping arthropods and nematodes in a single clade was unequivocally rejected in all the consensus trees. The Coelomata clade, grouping arthropods and chordates, was supported by the highest statistical confidence in all the reconstructions. The study of the dependence of the genomes’ tree accuracy on the number of exons used, demonstrated that an unexpectedly larger number of characters are necessary to obtain robust phylogenies. Previous studies supporting ecdysozoa, could not guarantee an accurate phylogeny because the number of characters used was clearly below the minimum required.

1 aDopazo, H.1 aSantoyo, J.1 aDopazo, J. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1526278902058nas a2200169 4500008004100000245006600041210006600107300001100173490000700184520119200191653019701383653012101580653004401701100001801745700001901763856010601782 2004 eng d00aPrediction of protein function and pathways in the genome era0 aPrediction of protein function and pathways in the genome era a930-440 v613 aThe growing number of completely sequenced genomes adds new dimensions to the use of sequence analysis to predict protein function. Compared with the classical knowledge transfer from one protein to a similar sequence (homology-based function prediction), knowledge about the corresponding genes in other genomes (orthology-based function prediction) provides more specific information about the protein’s function, while the analysis of the sequence in its genomic context (context-based function prediction) provides information about its functional context. Whereas homology-based methods predict the molecular function of a protein, genomic context methods predict the biological process in which it plays a role. These complementary approaches can be combined to elucidate complete functional networks and biochemical pathways from the genome sequence of an organism. Here we review recent advances in the field of genomic-context based methods of protein function prediction. Techniques are highlighted with examples, including an analysis that combines information from genomic-context with homology to predict a role of the RNase L inhibitor in the maturation of ribosomal RNA.10aATP-Binding Cassette Transporters/genetics/metabolism Amino Acid Sequence Animals Artificial Gene Fusion Base Sequence Chaperonins/genetics/metabolism Chromosomes/genetics/metabolism Evolution10aMolecular *Genome Genomics Humans Molecular Sequence Data Phylogeny *Proteins/classification/genetics/metabolism RNA10aRibosomal/metabolism Sequence Alignment1 aGabaldón, T.1 aHuynen, M., A. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1509501302164nas a2200229 4500008004100000245009400041210006900135300001100204490000700215520128900222653008201511653001201593653009301605100001401698700002301712700001601735700002401751700002201775700001601797700001501813856010601828 2004 eng d00aPupaSNP Finder: a web tool for finding SNPs with putative effect at transcriptional level0 aPupaSNP Finder a web tool for finding SNPs with putative effect  aW242-80 v323 aWe have developed a web tool, PupaSNP Finder (PupaSNP for short), for high-throughput searching for single nucleotide polymorphisms (SNPs) with potential phenotypic effect. PupaSNP takes as its input lists of genes (or generates them from chromosomal coordinates) and retrieves SNPs that could affect the conserved regions that the cellular machinery uses for the correct processing of genes (intron/exon boundaries or exonic splicing enhancers), predicted transcription factor binding sites (TFBS) and changes in amino acids in the proteins. The program uses the mapping of SNPs in the genome provided by Ensembl. Additionally, user-defined SNPs (not yet mapped in the genome) can be easily provided to the program. Also, additional functional information from Gene Ontology, OMIM and homologies in other model organisms is provided. In contrast to other programs already available, which focus only on SNPs with possible effect in the protein, PupaSNP includes SNPs with possible transcriptional effect. PupaSNP will be of significant help in studies of multifactorial disorders, where the use of functional SNPs will increase the sensitivity of identification of the genes responsible for the disease. The PupaSNP web interface is accessible through http://pupasnp.bioinfo.cnio.es.10aAmino Acid Substitution Binding Sites Humans Internet Phenotype *Polymorphism10aGenetic10aSingle Nucleotide RNA Splicing *Software Transcription Factors/metabolism *Transcription1 aConde, L.1 aVaquerizas, J., M.1 aSantoyo, J.1 aAl-Shahrour, Fatima1 aRuiz-Llorente, S.1 aRobledo, M.1 aDopazo, J. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1521538801755nas a2200145 4500008004100000245003900041210003900080300001100119490000900130520117400139653015301313100001801466700001901484856010601503 2004 eng d00aShaping the mitochondrial proteome0 aShaping the mitochondrial proteome a212-200 v16593 aMitochondria are eukaryotic organelles that originated from a single bacterial endosymbiosis some 2 billion years ago. The transition from the ancestral endosymbiont to the modern mitochondrion has been accompanied by major changes in its protein content, the so-called proteome. These changes included complete loss of some bacterial pathways, amelioration of others and gain of completely new complexes of eukaryotic origin such as the ATP/ADP translocase and most of the mitochondrial protein import machinery. This renewal of proteins has been so extensive that only 14-16% of modern mitochondrial proteome has an origin that can be traced back to the bacterial endosymbiont. The rest consists of proteins of diverse origin that were eventually recruited to function in the organelle. This shaping of the proteome content reflects the transformation of mitochondria into a highly specialized organelle that, besides ATP production, comprises a variety of functions within the eukaryotic metabolism. Here we review recent advances in the fields of comparative genomics and proteomics that are throwing light on the origin and evolution of the mitochondrial proteome.10aAnimals Biological Transport Energy Metabolism Eukaryotic Cells/physiology *Evolution Humans Mitochondria/*physiology Phylogeny Proteome/*physiology1 aGabaldón, T.1 aHuynen, M., A. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1557605402302nas a2200205 4500008004100000245012700041210006900168300001100237490000700248520137200255653006101627653007901688653013001767100001701897700002401914700001801938700001301956700002101969856010601990 2004 eng d00aStructure-based assessment of missense mutations in human BRCA1: implications for breast and ovarian cancer predisposition0 aStructurebased assessment of missense mutations in human BRCA1 i a3790-70 v643 aThe BRCA1 gene from individuals at risk of breast and ovarian cancers can be screened for the presence of mutations. However, the cancer association of most alleles carrying missense mutations is unknown, thus creating significant problems for genetic counseling. To increase our ability to identify cancer-associated mutations in BRCA1, we set out to use the principles of protein three-dimensional structure as well as the correlation between the cancer-associated mutations and those that abolish transcriptional activation. Thirty-one of 37 missense mutations of known impact on the transcriptional activation function of BRCA1 are readily rationalized in structural terms. Loss-of-function mutations involve nonconservative changes in the core of the BRCA1 C-terminus (BRCT) fold or are localized in a groove that presumably forms a binding site involved in the transcriptional activation by BRCA1; mutations that do not abolish transcriptional activation are either conservative changes in the core or are on the surface outside of the putative binding site. Next, structure-based rules for predicting functional consequences of a given missense mutation were applied to 57 germ-line BRCA1 variants of unknown cancer association. Such a structure-based approach may be helpful in an integrated effort to identify mutations that predispose individuals to cancer.10aBRCA1 Genetic Predisposition to Disease Humans *Mutation10aBRCA1 Protein/*chemistry/genetics Breast Neoplasms/*genetics Female *Genes10aMissense Ovarian Neoplasms/*genetics Pedigree Protein Conformation Structure-Activity Relationship Transcriptional Activation1 aMirkovic, N.1 aMarti-Renom, M., A.1 aWeber, B., L.1 aSali, A.1 aMonteiro, A., N. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1517298501309nas a2200145 4500008004100000245010100041210006900142300001100211490000600222520077700228100001601005700002101021700001501042856010601057 2003 eng d00aAn approach to inferring transcriptional regulation among genes from large-scale expression data0 aapproach to inferring transcriptional regulation among genes fro a148-540 v43 aThe use of DNA microarrays opens up the possibility of measuring the expression levels of thousands of genes simultaneously under different conditions. Time-course experiments allow researchers to study the dynamics of gene interactions. The inference of genetic networks from such measures can give important insights for the understanding of a variety of biological problems. Most of the existing methods for genetic network reconstruction require many experimental data points, or can only be applied to the reconstruction of small subnetworks. Here we present a method that reduces the dimensionality of the dataset and then extracts the significant dynamic correlations among genes. The method requires a number of points achievable in common time-course experiments.1 aHerrero, J.1 aDiaz-Uriarte, R.1 aDopazo, J. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1862909702356nas a2200265 4500008004100000245006200041210006200103300001000165490000700175520124200182653003001424653007301454653007501527653004901602653004201651653004301693653005001736653007501786653005801861100001901919700001601938700001501954700001501969856010601984 2003 eng d00aComparing bacterial genomes through conservation profiles0 aComparing bacterial genomes through conservation profiles a991-80 v133 aWe constructed two-dimensional representations of profiles of gene conservation across different genomes using the genome of Escherichia coli as a model. These profiles permit both the visualization at the genome level of different traits in the organism studied and, at the same time, reveal features related to the genomes analyzed (such as defective genomes or genomes that lack a particular system). Conserved genes are not uniformly distributed along the E. coli genome but tend to cluster together. The study of gene distribution patterns across genomes is important for the understanding of how sets of genes seem to be dependent on each other, probably having some functional link. This provides additional evidence that can be used for the elucidation of the function of unannotated genes. Clustering these patterns produces families of genes which can be arranged in a hierarchy of closeness. In this way, functions can be defined at different levels of generality depending on the level of the hierarchy that is studied. The combined study of conservation and phenotypic traits opens up the possibility of defining phenotype/genotype associations, and ultimately inferring the gene or genes responsible for a particular trait.10aBacterial Genotype Models10aBacterial/genetics Cluster Analysis Conserved Sequence/*genetics DNA10aBacterial/genetics Escherichia coli/classification/*genetics Evolution10aBacterial/genetics Gene Order/genetics Genes10aBacterial/genetics/physiology *Genome10aChromosome Mapping/methods Chromosomes10aGenetic Phenotype Phylogeny Sequence Homology10aMolecular Gene Expression Profiling/methods Gene Expression Regulation10aNucleic Acid Species Specificity Terminology as Topic1 aMartin, M., J.1 aHerrero, J.1 aMateos, A.1 aDopazo, J. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1269532402057nas a2200301 4500008004100000245006000041210005900101300001100160490000700171520105900178653002501237653001201262653007701274653003201351653007901383100001601462700001901478700002401497700001901521700002401540700001401564700001401578700001401592700001701606700001301623700001301636856010601649 2003 eng d00aEVA: Evaluation of protein structure prediction servers0 aEVA Evaluation of protein structure prediction servers a3311-50 v313 aEVA (http://cubic.bioc.columbia.edu/eva/) is a web server for evaluation of the accuracy of automated protein structure prediction methods. The evaluation is updated automatically each week, to cope with the large number of existing prediction servers and the constant changes in the prediction methods. EVA currently assesses servers for secondary structure prediction, contact prediction, comparative protein structure modelling and threading/fold recognition. Every day, sequences of newly available protein structures in the Protein Data Bank (PDB) are sent to the servers and their predictions are collected. The predictions are then compared to the experimental structures once a week; the results are published on the EVA web pages. Over time, EVA has accumulated prediction results for a large number of proteins, ranging from hundreds to thousands, depending on the prediction method. This large sample assures that methods are compared reliably. As a result, EVA provides useful information to developers as well as users of prediction methods.10aAutomation Databases10aProtein10aProtein Internet *Protein Conformation Protein Folding Protein Structure10aProtein Structural Homology10aSecondary Proteins/chemistry Reproducibility of Results *Sequence Analysis1 aKoh, I., Y.1 aEyrich, V., A.1 aMarti-Renom, M., A.1 aPrzybylski, D.1 aMadhusudhan, M., S.1 aEswar, N.1 aGrana, O.1 aPazos, F.1 aValencia, A.1 aSali, A.1 aRost, B. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1282431502305nas a2200205 4500008004100000245007400041210006900115300001200184490000800196520129400204653014101498653005201639653021501691653002601906100001101932700001501943700001701958700001801975856010601993 2003 eng d00aExamining the role of glutamic acid 183 in chloroperoxidase catalysis0 aExamining the role of glutamic acid 183 in chloroperoxidase cata a13855-90 v2783 aSite-directed mutagenesis has been used to investigate the role of glutamic acid 183 in chloroperoxidase catalysis. Based on the x-ray crystallographic structure of chloroperoxidase, Glu-183 is postulated to function on distal side of the heme prosthetic group as an acid-base catalyst in facilitating the reaction between the peroxidase and hydrogen peroxide with the formation of Compound I. In contrast, the other members of the heme peroxidase family use a histidine residue in this role. Plasmids have now been constructed in which the codon for Glu-183 is replaced with a histidine codon. The mutant recombinant gene has been expressed in Aspergillus niger. An analysis of the produced mutant gene shows that the substitution of Glu-183 with a His residue is detrimental to the chlorination and dismutation activity of chloroperoxidase. The activity is reduced by 85 and 50% of wild type activity, respectively. However, quite unexpectedly, the epoxidation activity of the mutant enzyme is significantly enhanced approximately 2.5-fold. These results show that Glu-183 is important but not essential for the chlorination activity of chloroperoxidase. It is possible that the increased epoxidation of the mutant enzyme is based on an increase in the hydrophobicity of the active site.10aAspergillus niger/metabolism Catalase/metabolism Catalysis Chloride Peroxidase/*chemistry/*metabolism Chlorine/metabolism Chromatography10aIon Exchange Circular Dichroism Crystallography10aPolyacrylamide Gel Fungi/enzymology Glutamic Acid/*chemistry Histidine/chemistry/metabolism Hydrogen-Ion Concentration Immunoblotting Isoelectric Focusing Mutation Oxidoreductases/metabolism Plasmids/metabolism10aX-Ray Electrophoresis1 aYi, X.1 aConesa, A.1 aPunt, P., J.1 aHager, L., P. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1257647701226nas a2200169 4500008004100000245003900041210003900080300001000119490000700129520049600136653021400632653005200846100001600898700002100914700001500935856010600950 2003 eng d00aGene expression data preprocessing0 aGene expression data preprocessing a655-60 v193 aWe present an interactive web tool for preprocessing microarray gene expression data. It analyses the data, suggests the most appropriate transformations and proceeds with them after user agreement. The normal preprocessing steps include scale transformations, management of missing values, replicate handling, flat pattern filtering and pattern standardization and they are required before performing any pattern analysis. The processed data set can be sent to other pattern analysis tools.10a*Database Management Systems Gene Expression Profiling/*methods Information Storage and Retrieval/methods Internet Oligonucleotide Array Sequence Analysis/*methods Sequence Alignment/*methods Sequence Analysis10aDNA/*methods *Software *User-Computer Interface1 aHerrero, J.1 aDiaz-Uriarte, R.1 aDopazo, J. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1265172601500nas a2200217 4500008004100000245007700041210006900118300001100187490000700198520080200205653001001007653002901017100001601046700002401062700002101086700001501107700002301122700001601145700001501161856010601176 2003 eng d00aGEPAS: A web-based resource for microarray gene expression data analysis0 aGEPAS A webbased resource for microarray gene expression data an a3461-70 v313 a

We present a web-based pipeline for microarray gene expression profile analysis, GEPAS, which stands for Gene Expression Profile Analysis Suite (http://gepas.bioinfo.cnio.es). GEPAS is composed of different interconnected modules which include tools for data pre-processing, two-conditions comparison, unsupervised and supervised clustering (which include some of the most popular methods as well as home made algorithms) and several tests for differential gene expression among different classes, continuous variables or survival analysis. A multiple purpose tool for data mining, based on Gene Ontology, is also linked to the tools, which constitutes a very convenient way of analysing clustering results. On-line tutorials are available from our main web server (http://bioinfo.cnio.es).

10agepas10amicroarray data analysis1 aHerrero, J.1 aAl-Shahrour, Fatima1 aDiaz-Uriarte, R.1 aMateos, A.1 aVaquerizas, J., M.1 aSantoyo, J.1 aDopazo, J. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1282434502406nas a2200205 4500008004100000245005300041210005100094300001000145490000700155520166900162653001601831653008601847653001901933653007101952100001502023700001902038700001602057700002102073856010602094 2003 eng d00aA model for the emergence of adaptive subsystems0 amodel for the emergence of adaptive subsystems a27-560 v653 aWe investigate the interaction of learning and evolution in a changing environment. A stable learning capability is regarded as an emergent adaptive system evolved by natural selection of genetic variants. We consider the evolution of an asexual population. Each genotype can have ’fixed’ and ’flexible’ alleles. The former express themselves as synaptic connections that remain unchanged during ontogeny and the latter as synapses that can be adjusted through a learning algorithm. Evolution is modelled using genetic algorithms and the changing environment is represented by two optimal synaptic patterns that alternate a fixed number of times during the ’life’ of the individuals. The amplitude of the change is related to the Hamming distance between the two optimal patterns and the rate of change to the frequency with which both exchange roles. This model is an extension of that of Hinton and Nowlan in which the fitness is given by a probabilistic measure of the Hamming distance to the optimum. We find that two types of evolutionary pathways are possible depending upon how difficult (costly) it is to cope with the changes of the environment. In one case the population loses the learning ability, and the individuals inherit fixed synapses that are optimal in only one of the environmental states. In the other case a flexible subsystem emerges that allows the individuals to adapt to the changes of the environment. The model helps us to understand how an adaptive subsystem can emerge as the result of the tradeoff between the exploitation of a congenital structure and the exploration of the adaptive capabilities practised by learning.10a*Adaptation10aBiological Algorithms Alleles Animals Evolution Genotype Humans *Learning *Models10aGenetic Models10aStatistical Neural Networks (Computer) Phenotype Synapses/genetics1 aDopazo, H.1 aGordon, M., B.1 aPerazzo, R.1 aRisau-Gusman, S. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1259711501742nas a2200217 4500008004100000245007200041210006900113300001000182490000700192520087900199653006301078653004601141653012601187100001801313700001501331700001901346700002401365700001601389700001301405856010601418 2003 eng d00aModView, visualization of multiple protein sequences and structures0 aModView visualization of multiple protein sequences and structur a165-60 v193 aSUMMARY: We describe ModView, a web application for visualization of multiple protein sequences and structures. ModView integrates a multiple structure viewer, a multiple sequence alignment editor, and a database querying engine. It is possible to interactively manipulate hundreds of proteins, to visualize conservative and variable residues, active and binding sites, fragments, and domains in protein families, as well as to display large macromolecular complexes such as ribosomes or viruses. As a Netscape plug-in, ModView can be included in HTML pages along with text and figures, which makes it useful for teaching and presentations. ModView is also suitable as a graphical interface to various databases because it can be controlled through JavaScript commands and called from CGI scripts. AVAILABILITY: ModView is available at http://guitar.rockefeller.edu/modview.10a*Database Management Systems Documentation/methods Imaging10aProtein/*methods *User-Computer Interface10aThree-Dimensional/methods Protein Conformation Proteins/*chemistry/genetics Sequence Alignment/*methods Sequence Analysis1 aIlyin, V., A.1 aPieper, U.1 aStuart, A., C.1 aMarti-Renom, M., A.1 aMcMahan, L.1 aSali, A. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1249931300772nas a2200145 4500008004100000245005700041210005600098300000800154490000800162653016300170653015000333100001800483700001900501856010600520 2003 eng d00aReconstruction of the proto-mitochondrial metabolism0 aReconstruction of the protomitochondrial metabolism a6090 v30110aAerobiosis Algorithms Alphaproteobacteria/chemistry/genetics/*metabolism Amino Acids/metabolism Animals Bacterial Proteins/chemistry/*metabolism Genome Genome10aBacterial Glycerol/metabolism Humans Lipid Metabolism Mitochondria/chemistry/genetics/*metabolism Phylogeny *Proteome Symbiosis Yeasts/metabolism1 aGabaldón, T.1 aHuynen, M., A. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1289393401823nas a2200289 4500008004100000245006600041210006600107300001200173490000700185520083500192653004601027653002001073653011301093653003201206100001401238700001301252700001701265700001401282700001801296700001501314700001901329700002401348700002401372700001801396700001301414856010601427 2003 eng d00aTools for comparative protein structure modeling and analysis0 aTools for comparative protein structure modeling and analysis a3375-800 v313 aThe following resources for comparative protein structure modeling and analysis are described (http://salilab.org): MODELLER, a program for comparative modeling by satisfaction of spatial restraints; MODWEB, a web server for automated comparative modeling that relies on PSI-BLAST, IMPALA and MODELLER; MODLOOP, a web server for automated loop modeling that relies on MODELLER; MOULDER, a CPU intensive protocol of MODWEB for building comparative models based on distant known structures; MODBASE, a comprehensive database of annotated comparative models for all sequences detectably related to a known structure; MODVIEW, a Netscape plugin for Linux that integrates viewing of multiple sequences and structures; and SNPWEB, a web server for structure-based prediction of the functional impact of a single amino acid substitution.10aAmino Acid *Software *Structural Homology10aInternet Models10aMolecular Protein Folding Proteins/chemistry Reproducibility of Results Sequence Alignment Sequence Homology10aProtein Systems Integration1 aEswar, N.1 aJohn, B.1 aMirkovic, N.1 aFiser, A.1 aIlyin, V., A.1 aPieper, U.1 aStuart, A., C.1 aMarti-Renom, M., A.1 aMadhusudhan, M., S.1 aYerkovich, B.1 aSali, A. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1282433100606nas a2200133 4500008004100000245011000041210006900151260004900220300001200269100002100281700002400302700001500326856013100341 2003 eng d00aUse of GO Terms to Understand the Biological Significance of Microarray Differential Gene Expression Data0 aUse of GO Terms to Understand the Biological Significance of Mic bKluwer Academic, K. F. Johnson and S. M. Lin a233-2471 aDíaz-Uriarte, R1 aAl-Shahrour, Fatima1 aDopazo, J. uhttp://clinbioinfosspa.es/content/use-go-terms-understand-biological-significance-microarray-differential-gene-expression-data00715nas a2200181 4500008004100000245013000041210006900171260003000240300001000270653001500280100002400295700001600319700001500335700001600350700002100366700001500387856013100402 2003 eng d00aUsing Gene Ontology on genome-scale studies to find significant associations of biologically relevant terms to group of genes0 aUsing Gene Ontology on genomescale studies to find significant a aNew York, USAbIEEE Press a43-5210ababelomics1 aAl-Shahrour, Fatima1 aHerrero, J.1 aMateos, A.1 aSantoyo, J.1 aDíaz-Uriarte, R1 aDopazo, J. uhttp://clinbioinfosspa.es/content/using-gene-ontology-genome-scale-studies-find-significant-associations-biologically-relevant01648nas a2200241 4500008004100000245010900041210006900150300001100219490000700230520055300237653010300790653018900893653008001082100001601162700001401178700001601192700001501208700001701223700002201240700002101262700001701283856010601300 2002 eng d00aBioinformatics methods for the analysis of expression arrays: data clustering and information extraction0 aBioinformatics methods for the analysis of expression arrays dat a269-830 v983 aExpression arrays facilitate the monitoring of changes in the expression patterns of large collections of genes. The analysis of expression array data has become a computationally-intensive task that requires the development of bioinformatics technology for a number of key stages in the process, such as image analysis, database storage, gene clustering and information extraction. Here, we review the current trends in each of these areas, with particular emphasis on the development of the related technology being carried out within our groups.10aAbstracting and Indexing as Topic/methods *Cluster Analysis *Database Management Systems Databases10aComputer-Assisted/methods Information Storage and Retrieval/*methods Internet Medline National Library of Medicine (U.S.) Oligonucleotide Array Sequence Analysis/*methods United States10aGenetic Gene Expression Gene Expression Profiling/*methods Image Processing1 aTamames, J.1 aClark, D.1 aHerrero, J.1 aDopazo, J.1 aBlaschke, C.1 aFernandez, J., M.1 aOliveros, J., C.1 aValencia, A. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1214199202286nas a2200193 4500008004100000245009100041210006900132300001100201490000700212520140500219653025701624653001201881100001501893700001501908700001901923700002701942700001701969856010601986 2002 eng d00aCalnexin overexpression increases manganese peroxidase production in Aspergillus niger0 aCalnexin overexpression increases manganese peroxidase productio a846-510 v683 aHeme-containing peroxidases from white rot basidiomycetes, in contrast to most proteins of fungal origin, are poorly produced in industrial filamentous fungal strains. Factors limiting peroxidase production are believed to operate at the posttranslational level. In particular, insufficient availability of the prosthetic group which is required for peroxidase biosynthesis has been proposed to be an important bottleneck. In this work, we analyzed the role of two components of the secretion pathway, the chaperones calnexin and binding protein (BiP), in the production of a fungal peroxidase. Expression of the Phanerochaete chrysosporium manganese peroxidase (MnP) in Aspergillus niger resulted in an increase in the expression level of the clxA and bipA genes. In a heme-supplemented medium, where MnP was shown to be overproduced to higher levels, induction of clxA and bipA was also higher. Overexpression of these two chaperones in an MnP-producing strain was analyzed for its effect on MnP production. Whereas bipA overexpression seriously reduced MnP production, overexpression of calnexin resulted in a four- to fivefold increase in the extracellular MnP levels. However, when additional heme was provided in the culture medium, calnexin overexpression had no synergistic effect on MnP production. The possible function of these two chaperones in MnP maturation and production is discussed.10aAspergillus niger/*enzymology/genetics Calcium-Binding Proteins/*metabolism Calnexin Culture Media *Fungal Proteins HSP70 Heat-Shock Proteins/metabolism Heme/metabolism Peroxidases/*biosynthesis/genetics Phanerochaete/enzymology/genetics Transformation10aGenetic1 aConesa, A.1 aJeenes, D.1 aArcher, D., B.1 avan den Hondel, C., A.1 aPunt, P., J. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1182322701191nas a2200157 4500008004100000245011600041210006900157300001100226490000600237520046000243653007400703653011900777100001600896700001500912856010600927 2002 eng d00aCombining hierarchical clustering and self-organizing maps for exploratory analysis of gene expression patterns0 aCombining hierarchical clustering and selforganizing maps for ex a467-700 v13 aSelf-organizing maps (SOM) constitute an alternative to classical clustering methods because of its linear run times and superior performance to deal with noisy data. Nevertheless, the clustering obtained with SOM is dependent on the relative sizes of the clusters. Here, we show how the combination of SOM with hierarchical clustering methods constitutes an excellent tool for exploratory analysis of massive data like DNA microarray expression patterns.10aCluster Analysis Computational Biology/methods *Gene Expression Genes10aFungal/genetics *Genome Oligonucleotide Array Sequence Analysis/*methods Statistics as Topic/*methods Time Factors1 aHerrero, J.1 aDopazo, J. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1264591901632nas a2200193 4500008004100000245007600041210006900117300001000186490000700196520078800203653023600991100001701227700001901244700001501263700001501278700001601293700002301309856010601332 2002 eng d00aFilamentous fungi as cell factories for heterologous protein production0 aFilamentous fungi as cell factories for heterologous protein pro a200-60 v203 aFilamentous fungi have been used as sources of metabolites and enzymes for centuries. For about two decades, molecular genetic tools have enabled us to use these organisms to express extra copies of both endogenous and exogenous genes. This review of current practice reveals that molecular tools have enabled several new developments. But it has been process development that has driven the final breakthrough to achieving commercially relevant quantities of protein. Recent research into gene expression in filamentous fungi has explored their wealth of genetic diversity with a view to exploiting them as expression hosts and as a source of new genes. Inevitably, the progress in the ’genomics’ technology will further develop high-throughput technologies for these organisms.10aFermentation/genetics/physiology Fungi/*genetics/*metabolism Humans Interleukin-6/analysis/*biosynthesis/genetics Peroxidases/analysis/*biosynthesis/genetics Protein Conformation Recombinant Proteins/analysis/*biosynthesis/genetics1 aPunt, P., J.1 avan Biezen, N.1 aConesa, A.1 aAlbers, A.1 aMangnus, J.1 avan den Hondel, C. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1194337501436nas a2200157 4500008004100000245005900041210005800100300001100158490000700169520072900176653020800905100001501113700001701128700002701145856010601172 2002 eng d00aFungal peroxidases: molecular aspects and applications0 aFungal peroxidases molecular aspects and applications a143-580 v933 aPeroxidases are oxidoreductases that utilize hydrogen peroxide to catalyze oxidative reactions. A large number of peroxidases have been identified in fungal species and are being characterized at the molecular level. In this manuscript we review the current knowledge on the molecular aspects of this type of enzymes. We present an overview of the research efforts undertaken in deciphering the structural basis of the catalytic properties of fungal peroxidases and discuss molecular genetics and protein homology aspects of this enzyme class. Finally, we summarize the potential biotechnological applications of these enzymes and evaluate recent advances on their expression in heterologous systems for production purposes.10aAmino Acid Sequence Binding Sites Biotechnology Catalysis Fungi/*enzymology Molecular Sequence Data Peroxidases/chemistry/*genetics/metabolism Recombinant Proteins Sequence Homology Substrate Specificity1 aConesa, A.1 aPunt, P., J.1 avan den Hondel, C., A. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1173872103136nas a2200397 4500008004100000245010000041210006900141300001200210490000800222520146400230653015401694653005901848653001301907653008901920653015002009653006702159653003702226653008702263653001102350100001502361700001902376700001402395700001502409700001602424700001802440700003002458700002602488700001802514700001402532700001802546700001602564700001902580700001502599700001802614856010602632 2002 eng d00aIdentification of genes involved in resistance to interferon-alpha in cutaneous T-cell lymphoma0 aIdentification of genes involved in resistance to interferonalph a1825-370 v1613 aInterferon-alpha therapy has been shown to be active in the treatment of mycosis fungoides although the individual response to this therapy is unpredictable and dependent on essentially unknown factors. In an effort to better understand the molecular mechanisms of interferon-alpha resistance we have developed an interferon-alpha resistant variant from a sensitive cutaneous T-cell lymphoma cell line. We have performed expression analysis to detect genes differentially expressed between both variants using a cDNA microarray including 6386 cancer-implicated genes. The experiments showed that resistance to interferon-alpha is consistently associated with changes in the expression of a set of 39 genes, involved in signal transduction, apoptosis, transcription regulation, and cell growth. Additional studies performed confirm that STAT1 and STAT3 expression and interferon-alpha induction and activation are not altered between both variants. The gene MAL, highly overexpressed by resistant cells, was also found to be expressed by tumoral cells in a series of cutaneous T-cell lymphoma patients treated with interferon-alpha and/or photochemotherapy. MAL expression was associated with longer time to complete remission. Time-course experiments of the sensitive and resistant cells showed a differential expression of a subset of genes involved in interferon-response (1 to 4 hours), cell growth and apoptosis (24 to 48 hours.), and signal transduction.10aAntineoplastic Agents/*pharmacology/therapeutic use Carrier Proteins/biosynthesis/genetics DNA-Binding Proteins/biosynthesis/genetics Drug Resistance10aBiological Oligonucleotide Array Sequence Analysis RNA10aCultured10aCutaneous/diagnosis/drug therapy/*genetics/metabolism *Membrane Glycoproteins Models10aInterleukin-1 Reproducibility of Results STAT1 Transcription Factor STAT3 Transcription Factor Trans-Activators/biosynthesis/genetics Tumor Cells10aNeoplasm Gene Expression Profiling *Gene Expression Regulation10aNeoplasm/biosynthesis *Receptors10aNeoplastic Humans Interferon-alpha/*pharmacology/therapeutic use Kinetics Lymphoma10aT-Cell1 aTracey, L.1 aVilluendas, R.1 aOrtiz, P.1 aDopazo, A.1 aSpiteri, I.1 aLombardia, L.1 aRodriguez-Peralto, J., L.1 aFernandez-Herrera, J.1 aHernandez, A.1 aFraga, J.1 aDominguez, O.1 aHerrero, J.1 aAlonso, M., A.1 aDopazo, J.1 aPiris, M., A. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1241452900792nam a2200169 4500008004100000245017300041210006900214260003900283300001300322100001900335700002600354700001900380700002000399700002000419700002000439856016300459 2002 eng d00aMethods of Microarray Data Analysis IISupervised Neural Networks for Clustering Conditions in DNA Array Data After Reducing Noise by Clustering Gene Expression Profiles0 aMethods of Microarray Data Analysis IISupervised Neural Networks aBostonbKluwer Academic Publishers a91 - 1031 aLin, Simon, M.1 aJohnson, Kimberly, F.1 aMateos, Alvaro1 aHerrero, Javier1 aTamames, Javier1 aDopazo, Joaquin uhttp://www.springerlink.com/index/10.1007/b112982http://link.springer.com/10.1007/0-306-47598-7_7http://www.springerlink.com/index/pdf/10.1007/0-306-47598-7_700362nas a2200109 4500008004100000245004400041210004400085260002000129300001000149100001500159856007800174 2002 eng d00aMicroarray Data Processing And Analysis0 aMicroarray Data Processing And Analysis bKluwer Academic a43-631 aDopazo, J. uhttp://clinbioinfosspa.es/content/microarray-data-processing-and-analysis01632nas a2200193 4500008004100000245007000041210006900111300001100180490000700191520092300198653004001121653008301161100002401244700002401268700001401292700001301306700001301319856010601332 2002 eng d00aReliability of assessment of protein structure prediction methods0 aReliability of assessment of protein structure prediction method a435-400 v103 a

The reliability of ranking of protein structure modeling methods is assessed. The assessment is based on the parametric Student’s t test and the nonparametric Wilcox signed rank test of statistical significance of the difference between paired samples. The approach is applied to the ranking of the comparative modeling methods tested at the fourth meeting on Critical Assessment of Techniques for Protein Structure Prediction (CASP). It is shown that the 14 CASP4 test sequences may not be sufficient to reliably distinguish between the top eight methods, given the model quality differences and their standard deviations. We suggest that CASP needs to be supplemented by an assessment of protein structure prediction methods that is automated, continuous in time, based on several criteria applied to a large number of models, and with quantitative statistical reliability assigned to each characterization.

10a*Computer Simulation Humans *Models10aMolecular *Protein Conformation Proteins/*chemistry Reproducibility of Results1 aMarti-Renom, M., A.1 aMadhusudhan, M., S.1 aFiser, A.1 aRost, B.1 aSali, A. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1200544100607nas a2200145 4500008004100000245013500041210006900176260002000245300001100265100001500276700001600291700001600307700001500323856012300338 2002 eng d00aSupervised Neural Networks For Clustering Conditions In DNA Array Data After Reducing Noise By Clustering Gene Expression Profiles0 aSupervised Neural Networks For Clustering Conditions In DNA Arra bKluwer Academic a91-1031 aMateos, A.1 aHerrero, J.1 aTamames, J.1 aDopazo, J. uhttp://clinbioinfosspa.es/content/supervised-neural-networks-clustering-conditions-dna-array-data-after-reducing-noise02866nas a2200193 4500008004100000245011400041210006900155300001200224490000700236520197100243653025902214100001502473700001502488700001502503700001102518700001702529700002002546856010602566 2002 eng d00aSystematic learning of gene functional classes from DNA array expression data by using multilayer perceptrons0 aSystematic learning of gene functional classes from DNA array ex a1703-150 v123 aRecent advances in microarray technology have opened new ways for functional annotation of previously uncharacterised genes on a genomic scale. This has been demonstrated by unsupervised clustering of co-expressed genes and, more importantly, by supervised learning algorithms. Using prior knowledge, these algorithms can assign functional annotations based on more complex expression signatures found in existing functional classes. Previously, support vector machines (SVMs) and other machine-learning methods have been applied to a limited number of functional classes for this purpose. Here we present, for the first time, the comprehensive application of supervised neural networks (SNNs) for functional annotation. Our study is novel in that we report systematic results for 100 classes in the Munich Information Center for Protein Sequences (MIPS) functional catalog. We found that only 10% of these are learnable (based on the rate of false negatives). A closer analysis reveals that false positives (and negatives) in a machine-learning context are not necessarily "false" in a biological sense. We show that the high degree of interconnections among functional classes confounds the signatures that ought to be learned for a unique class. We term this the "Borges effect" and introduce two new numerical indices for its quantification. Our analysis indicates that classification systems with a lower Borges effect are better suitable for machine learning. Furthermore, we introduce a learning procedure for combining false positives with the original class. We show that in a few iterations this process converges to a gene set that is learnable with considerably low rates of false positives and negatives and contains genes that are biologically related to the original class, allowing for a coarse reconstruction of the interactions between associated biological pathways. We exemplify this methodology using the well-studied tricarboxylic acid cycle.10aAlgorithms Artificial Intelligence Citric Acid Cycle/genetics Cluster Analysis Computational Biology/methods Gene Expression Profiling/*methods/statistics & numerical data Genes/*physiology Genetic Heterogeneity Neural Networks (Computer) Oligonucleotide1 aMateos, A.1 aDopazo, J.1 aJansen, R.1 aTu, Y.1 aGerstein, M.1 aStolovitzky, G. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1242175700641nas a2200133 4500008004100000245018000041210006900221260003200290100001400322700001500336700001600351700001500367856012500382 2002 eng d00aUnsupervised reduction of the dimensionality followed by supervised learning with a perceptron improves the classification of conditions in DNA microarray gene expression data0 aUnsupervised reduction of the dimensionality followed by supervi aMartigny, SwitzerlandbIEEE1 aConde, L.1 aMateos, A.1 aHerrero, J.1 aDopazo, J. uhttp://ieeexplore.ieee.org/document/1030019/http://xplorestaging.ieee.org/ielx5/8007/22134/01030019.pdf?arnumber=103001902774nas a2200313 4500008004100000245014600041210006900187300001300256490000800269520115600277653004801433653003001481653005001511653023501561653012201796653010201918653014402020100002002164700001502184700002102199700002202220700001702242700002402259700001302283700002002296700001902316700001902335856010602354 2002 eng d00aUse of single point mutations in domain I of beta 2-glycoprotein I to determine fine antigenic specificity of antiphospholipid autoantibodies0 aUse of single point mutations in domain I of beta 2glycoprotein  a7097-1030 v1693 aAutoantibodies against beta(2)-glycoprotein I (beta(2)GPI) appear to be a critical feature of the antiphospholipid syndrome (APS). As determined using domain deletion mutants, human autoantibodies bind to the first of five domains present in beta(2)GPI. In this study the fine detail of the domain I epitope has been examined using 10 selected mutants of whole beta(2)GPI containing single point mutations in the first domain. The binding to beta(2)GPI was significantly affected by a number of single point mutations in domain I, particularly by mutations in the region of aa 40-43. Molecular modeling predicted these mutations to affect the surface shape and electrostatic charge of a facet of domain I. Mutation K19E also had an effect, albeit one less severe and involving fewer patients. Similar results were obtained in two different laboratories using affinity-purified anti-beta(2)GPI in a competitive inhibition ELISA and with whole serum in a direct binding ELISA. This study confirms that anti-beta(2)GPI autoantibodies bind to domain I, and that the charged surface patch defined by residues 40-43 contributes to a dominant target epitope.10aAmino Acid Substitution/genetics Antibodies10aAntibody/genetics Binding10aAntiphospholipid/blood/*metabolism Antibodies10aCompetitive/genetics/immunology Enzyme-Linked Immunosorbent Assay/methods Epitopes/analysis/*immunology/metabolism Glycine/genetics Glycoproteins/biosynthesis/*genetics/*immunology/isolation & purification/metabolism Humans Models10aMolecular Peptide Fragments/genetics/immunology/isolation & purification/metabolism *Point Mutation Protein Structure10aMonoclonal/blood/metabolism Antiphospholipid Syndrome/immunology Arginine/genetics *Binding Sites10aTertiary/genetics Recombinant Proteins/biosynthesis/immunology/isolation & purification/metabolism Static Electricity beta 2-Glycoprotein I1 aIverson, G., M.1 aReddel, S.1 aVictoria, E., J.1 aCockerill, K., A.1 aWang, Y., X.1 aMarti-Renom, M., A.1 aSali, A.1 aMarquis, D., M.1 aKrilis, S., A.1 aLinnik, M., D. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1247114600616nas a2200133 4500008004100000245016500041210006900206260002000275300001200295100001500307700001600322700001500338856012900353 2002 eng d00aUsing perceptrons for supervised classification of DNA microarray samples: obtaining the optimal level of information and finding differentially expressed genes0 aUsing perceptrons for supervised classification of DNA microarra bJ.R. Dorronsoro a577-5821 aMateos, A.1 aHerrero, J.1 aDopazo, J. uhttp://clinbioinfosspa.es/content/using-perceptrons-supervised-classification-dna-microarray-samples-obtaining-optimal-level02311nas a2200361 4500008004100000245009500041210006900136300001100205490000600216520111600222653009801338653003901436653003101475653000801506653005901514100001501573700001601588700001601604700001601620700001601636700001601652700001701668700002101685700001501706700002101721700001601742700001401758700001401772700001501786700001601801700002601817856010601843 2001 eng d00aAnnotated draft genomic sequence from a Streptococcus pneumoniae type 19F clinical isolate0 aAnnotated draft genomic sequence from a Streptococcus pneumoniae a99-1250 v73 aThe public availability of numerous microbial genomes is enabling the analysis of bacterial biology in great detail and with an unprecedented, organism-wide and taxon-wide, broad scope. Streptococcus pneumoniae is one of the most important bacterial pathogens throughout the world. We present here sequences and functional annotations for 2.1-Mbp of pneumococcal DNA, covering more than 90% of the total estimated size of the genome. The sequenced strain is a clinical isolate resistant to macrolides and tetracycline. It carries a type 19F capsular locus, but multilocus sequence typing for several conserved genetic loci suggests that the strain sequenced belongs to a pneumococcal lineage that most often expresses a serotype 15 capsular polysaccharide. A total of 2,046 putative open reading frames (ORFs) longer than 100 amino acids were identified (average of 1,009 bp per ORF), including all described two-component systems and aminoacyl tRNA synthetases. Comparisons to other complete, or nearly complete, bacterial genomes were made and are presented in a graphical form for all the predicted proteins.10aBacterial Molecular Sequence Data Pneumococcal Infections/*microbiology Prokaryotic Cells RNA10aBacterial/chemistry/genetics Genes10aBacterial/genetics *Genome10aDNA10aTransfer/metabolism Streptococcus pneumoniae/*genetics1 aDopazo, J.1 aMendoza, A.1 aHerrero, J.1 aCaldara, F.1 aHumbert, Y.1 aFriedli, L.1 aGuerrier, M.1 aGrand-Schenk, E.1 aGandin, C.1 ade Francesco, M.1 aPolissi, A.1 aBuell, G.1 aFeger, G.1 aGarcia, E.1 aPeitsch, M.1 aGarcia-Bustos, J., F. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1144234802134nas a2200241 4500008004100000245005900041210005800100300001100158490000700169520128500176653008301461653003201544653003201576653005801608100001601666700001301682700002401695700001401719700001901733700001901752700001501771856010601786 2001 eng d00aClassification of protein disulphide-bridge topologies0 aClassification of protein disulphidebridge topologies a477-870 v153 aThe preferential occurrence of certain disulphide-bridge topologies in proteins has prompted us to design a method and a program, KNOT-MATCH, for their classification. The program has been applied to a database of proteins with less than 65% homology and more than two disulphide bridges. We have investigated whether there are topological preferences that can be used to group proteins and if these can be applied to gain insight into the structural or functional relationships among them. The classification has been performed by Density Search and Hierarchical Clustering Techniques, yielding thirteen main protein classes from the superimposition and clustering process. It is noteworthy that besides the disulphide bridges, regular secondary structures and loops frequently become correctly aligned. Although the lack of significant sequence similarity among some clustered proteins precludes the easy establishment of evolutionary relationships, the program permits us to find out important structural or functional residues upon the superimposition of two protein structures apparently unrelated. The derived classification can be very useful for finding relationships among proteins which would escape detection by current sequence or topology-based analytical algorithms.10aAlgorithms Computer Simulation Databases as Topic Disulfides/*chemistry Models10aMolecular Protein Structure10aSecondary Protein Structure10aTertiary Proteins/*chemistry/*classification Software1 aMas, J., M.1 aAloy, P.1 aMarti-Renom, M., A.1 aOliva, B.1 ade Llorens, R.1 aAviles, F., X.1 aQuerol, E. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1139474001688nas a2200169 4500008004100000245010100041210006900142300001100211490000800222520084700230653026001077100001501337700001601352700002701368700001701395856010601412 2001 eng d00aC-terminal propeptide of the Caldariomyces fumago chloroperoxidase: an intramolecular chaperone?0 aCterminal propeptide of the Caldariomyces fumago chloroperoxidas a117-200 v5033 aThe Caldariomyces fumago chloroperoxidase (CPO) is synthesised as a 372-aa precursor which undergoes two proteolytic processing events: removal of a 21-aa N-terminal signal peptide and of a 52-aa C-terminal propeptide. The Aspergillus niger expression system developed for CPO was used to get insight into the function of this C-terminal propeptide. A. niger transformants expressing a CPO protein from which the C-terminal propeptide was deleted failed in producing any extracellular CPO activity, although the CPO polypeptide was synthesised. Expression of the full-length gene in an A. niger strain lacking the KEX2-like protease PclA also resulted in the production of CPO cross-reactive material into the culture medium, but no CPO activity. Based on these results, a function of the C-terminal propeptide in CPO maturation is indicated.10aAmino Acid Sequence Ascomycota/*enzymology/genetics Aspergillus niger/genetics Base Sequence Chloride Peroxidase/biosynthesis/*chemistry/genetics DNA Primers/genetics Enzyme Precursors/biosynthesis/chemistry/genetics Gene Expression Molecular Chaperones/b1 aConesa, A.1 aWeelink, G.1 avan den Hondel, C., A.1 aPunt, P., J. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1151386601470nas a2200169 4500008004100000245005400041210005300095300001000148490000700158520082200165653003700987653011501024100002401139700001801163700001301181856010601194 2001 eng d00aDBAli: a database of protein structure alignments0 aDBAli a database of protein structure alignments a746-70 v173 aSUMMARY: The DBAli database includes approximately 35000 alignments of pairs of protein structures from SCOP (Lo Conte et al., Nucleic Acids Res., 28, 257-259, 2000) and CE (Shindyalov and Bourne, Protein Eng., 11, 739-747, 1998). DBAli is linked to several resources, including Compare3D (Shindyalov and Bourne, http://www.sdsc.edu/pb/software.htm, 1999) and ModView (Ilyin and Sali, http://guitar.rockefeller.edu/ModView/, 2001) for visualizing sequence alignments and structure superpositions. A flexible search of DBAli by protein sequence and structure properties allows construction of subsets of alignments suitable for a number of applications, such as benchmarking of sequence-sequence and sequence-structure alignment methods under a variety of conditions. AVAILABILITY: http://guitar.rockefeller.edu/DBAli/10aComputational Biology *Databases10aProtein Proteins/*chemistry/*genetics Sequence Alignment/*statistics & numerical data Software Software Design1 aMarti-Renom, M., A.1 aIlyin, V., A.1 aSali, A. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1152437901566nas a2200229 4500008004100000245008100041210006900122300001100191490000700202520078900209653007500998100001901073700002401092700001901116700002401135700001401159700001401173700001701187700001301204700001301217856010601230 2001 eng d00aEVA: continuous automatic evaluation of protein structure prediction servers0 aEVA continuous automatic evaluation of protein structure predict a1242-30 v173 aEvaluation of protein structure prediction methods is difficult and time-consuming. Here, we describe EVA, a web server for assessing protein structure prediction methods, in an automated, continuous and large-scale fashion. Currently, EVA evaluates the performance of a variety of prediction methods available through the internet. Every week, the sequences of the latest experimentally determined protein structures are sent to prediction servers, results are collected, performance is evaluated, and a summary is published on the web. EVA has so far collected data for more than 3000 protein chains. These results may provide valuable insight to both developers and users of prediction methods. AVAILABILITY: http://cubic.bioc.columbia.edu/eva. CONTACT: eva@cubic.bioc.columbia.edu10aAutomation Internet *Protein Conformation Proteins/*analysis *Software1 aEyrich, V., A.1 aMarti-Renom, M., A.1 aPrzybylski, D.1 aMadhusudhan, M., S.1 aFiser, A.1 aPazos, F.1 aValencia, A.1 aSali, A.1 aRost, B. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1175124001692nas a2200193 4500008004100000245012800041210006900169300001300238490000800251520081300259653019901072100001501271700002101286700002101307700002001328700002701348700001701375856010601392 2001 eng d00aExpression of the Caldariomyces fumago chloroperoxidase in Aspergillus niger and characterization of the recombinant enzyme0 aExpression of the Caldariomyces fumago chloroperoxidase in Asper a17635-400 v2763 aThe Caldariomyces fumago chloroperoxidase was successfully expressed in Aspergillus niger. The recombinant enzyme was produced in the culture medium as an active protein and could be purified by a three-step purification procedure. The catalytic behavior of recombinant chloroperoxidase (rCPO) was studied and compared with that of native CPO. The specific chlorination activity (47 units/nmol) of rCPO and its pH optimum (pH 2.75) were very similar to those of native CPO. rCPO catalyzes the oxidation of various substrates in comparable yields and selectivities to native CPO. Indole was oxidized to 2-oxindole with 99% selectivity and thioanisole to the corresponding R-sulfoxide (enantiomeric excess >98%). Incorporation of (18)O from labeled H(2)18O(2) into the oxidized products was 100% in both cases.10aAspergillus niger/enzymology/genetics Catalysis Chloride Peroxidase/biosynthesis/*genetics Fungal Proteins/biosynthesis/*genetics Recombinant Proteins/biosynthesis/genetics Substrate Specificity1 aConesa, A.1 avan De Velde, F.1 avan Rantwijk, F.1 aSheldon, R., A.1 avan den Hondel, C., A.1 aPunt, P., J. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1127870102638nas a2200157 4500008004100000245009500041210006900136300001100205490000700216520196500223653013802188100001602326700001702342700001502359856010602374 2001 eng d00aA hierarchical unsupervised growing neural network for clustering gene expression patterns0 ahierarchical unsupervised growing neural network for clustering  a126-360 v173 aMOTIVATION: We describe a new approach to the analysis of gene expression data coming from DNA array experiments, using an unsupervised neural network. DNA array technologies allow monitoring thousands of genes rapidly and efficiently. One of the interests of these studies is the search for correlated gene expression patterns, and this is usually achieved by clustering them. The Self-Organising Tree Algorithm, (SOTA) (Dopazo,J. and Carazo,J.M. (1997) J. Mol. Evol., 44, 226-233), is a neural network that grows adopting the topology of a binary tree. The result of the algorithm is a hierarchical cluster obtained with the accuracy and robustness of a neural network. RESULTS: SOTA clustering confers several advantages over classical hierarchical clustering methods. SOTA is a divisive method: the clustering process is performed from top to bottom, i.e. the highest hierarchical levels are resolved before going to the details of the lowest levels. The growing can be stopped at the desired hierarchical level. Moreover, a criterion to stop the growing of the tree, based on the approximate distribution of probability obtained by randomisation of the original data set, is provided. By means of this criterion, a statistical support for the definition of clusters is proposed. In addition, obtaining average gene expression patterns is a built-in feature of the algorithm. Different neurons defining the different hierarchical levels represent the averages of the gene expression patterns contained in the clusters. Since SOTA runtimes are approximately linear with the number of items to be classified, it is especially suitable for dealing with huge amounts of data. The method proposed is very general and applies to any data providing that they can be coded as a series of numbers and that a computable measure of similarity between data items can be used. AVAILABILITY: A server running the program can be found at: http://bioinfo.cnio.es/sotarray.10a*Algorithms Automatic Data Processing *Gene Expression Profiling *Neural Networks (Computer) *Oligonucleotide Array Sequence Analysis1 aHerrero, J.1 aValencia, A.1 aDopazo, J. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1123806802532nas a2200229 4500008004100000245015400041210006900195300001000264490000700274520149500281653013001776653009301906653007401999100001802073700001902091700002002110700001702130700001802147700001502165700001602180856010602196 2001 eng d00aIdentification of optimal regions for phylogenetic studies on VP1 gene of foot-and-mouth disease virus: analysis of types A and O Argentinean viruses0 aIdentification of optimal regions for phylogenetic studies on VP a31-450 v323 aAn analysis of the informative content of sequence stretches on the foot-and-mouth disease virus (FMDV) VPI gene was applied to two important viral serotypes: A and O. Several sequence regions were identified to allow the reconstruction of phylogenetic trees equivalent to those derived from the whole VPI gene. The optimal informative regions for sequence windows of 150 to 250 nt were predicted between positions 250 and 550 of the gene. The sequences spanning the 250 nt of the 3’ end (positions 400 to 650), extensively used for FMDV phylogenetic analyses, showed a lower informative content. In spite of this, the use of sequences from this region allowed the derivation of phylogenetic trees for type A and type O FMDVs which showed topologies similar to those previously reported for the whole VP1 gene. When the sequences determined for viruses isolated in Argentina, between 1990 and 1993, were included in these analyses, the results obtained revealed features of the circulation of type A and type O viruses in the field, in the months that preceded the eradication of the disease in this country. Type A viruses were closely related to an Argentinean vaccine strain, and defined an independent cluster within this serotype. Among the type O viruses analysed, two groups were distinguished; one was closely related to the South American vaccine strains, while the other was grouped with viruses of the O3 subtype. In addition, a detailed phylogeny for type A FMDV is presented.10aAmino Acid Sequence Animals Aphthovirus/classification/*genetics Base Sequence Capsid/chemistry/*genetics Capsid Proteins DNA10aComplementary/chemistry Molecular Sequence Data *Phylogeny Polymerase Chain Reaction RNA10aViral/chemistry/genetics Serotyping Viral Proteins/analysis/*genetics1 aNunez, J., I.1 aMartin, M., J.1 aPiccone, M., E.1 aCarrillo, E.1 aPalma, E., L.1 aDopazo, J.1 aSobrino, F. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1125417501764nas a2200169 4500008004100000245006700041210006700108300001100175490000800186520121300194100001501407700001601422700001601438700001701454700001701471856010601488 2001 eng d00aMethods and approaches in the analysis of gene expression data0 aMethods and approaches in the analysis of gene expression data a93-1120 v2503 a

The application of high-density DNA array technology to monitor gene transcription has been responsible for a real paradigm shift in biology. The majority of research groups now have the ability to measure the expression of a significant proportion of the human genome in a single experiment, resulting in an unprecedented volume of data being made available to the scientific community. As a consequence of this, the storage, analysis and interpretation of this information present a major challenge. In the field of immunology the analysis of gene expression profiles has opened new areas of investigation. The study of cellular responses has revealed that cells respond to an activation signal with waves of co-ordinated gene expression profiles and that the components of these responses are the key to understanding the specific mechanisms which lead to phenotypic differentiation. The discovery of ’cell type specific’ gene expression signatures have also helped the interpretation of the mechanisms leading to disease progression. Here we review the principles behind the most commonly used data analysis methods and discuss the approaches that have been employed in immunological research.

1 aDopazo, J.1 aZanders, E.1 aDragoni, I.1 aAmphlett, G.1 aFalciani, F. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1125122401507nas a2200181 4500008004100000245005800041210005600099300001100155490000700166520081000173653011500983653005001098100001501148700001901163700001601182700002101198856010601219 2001 eng d00aA model for the interaction of learning and evolution0 amodel for the interaction of learning and evolution a117-340 v633 aWe present a simple model in order to discuss the interaction of the genetic and behavioral systems throughout evolution. This considers a set of adaptive perceptrons in which some of their synapses can be updated through a learning process. This framework provides an extension of the well-known Hinton and Nowlan model by blending together some learning capability and other (rigid) genetic effects that contribute to the fitness. We find a halting effect in the evolutionary dynamics, in which the transcription of environmental data into genetic information is hindered by learning, instead of stimulated as is usually understood by the so-called Baldwin effect. The present results are discussed and compared with those reported in the literature. An interpretation is provided of the halting effect.10aAlgorithms Alleles Animals *Evolution Genotype Humans *Learning *Neural Networks (Computer) Numerical Analysis10aComputer-Assisted Phenotype Synapses/genetics1 aDopazo, H.1 aGordon, M., B.1 aPerazzo, R.1 aRisau-Gusman, S. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1114687901950nas a2200229 4500008004100000245009500041210006900136300001000205490000700215520116100222653001401383653005301397653002801450653003701478100001801515700001501533700001901548700001501567700001901582700001301601856010601614 2001 eng d00aPhylogenetic analysis of viroid and viroid-like satellite RNAs from plants: a reassessment0 aPhylogenetic analysis of viroid and viroidlike satellite RNAs fr a155-90 v533 aThe proposed monophyletic origin of a group of subviral plant pathogens (viroids and viroid-like satellite RNAs), as well as the phylogenetic relationships and the resulting taxonomy of these entities, has been recently questioned. The criticism comes from the (apparent) lack of sequence similarity among these RNAs necessary to reliably infer a phylogeny. Here we show that, despite their low overall sequence similarity, a sequence alignment manually adjusted to take into account all the local similarities and the insertions/deletions and duplications/rearrangements described in the literature for viroids and viroid-like satellite RNA, along with the use of an appropriate estimator of genetic distances, constitutes a data set suitable for a phylogenetic reconstruction. When the likelihood-mapping method was applied to this data set, the tree-likeness obtained was higher than that corresponding to a sequence alignment that does not take into consideration the local similarities. In addition, bootstrap analysis also supports the major groups previously proposed and the reconstruction is consistent with the biological properties of this RNAs.10aEvolution10aMolecular *Phylogeny Plant Viruses/*genetics RNA10aSatellite/*genetics RNA10aViral/genetics Viroids/*genetics1 aElena, S., F.1 aDopazo, J.1 ade la Pena, M.1 aFlores, R.1 aDiener, T., O.1 aMoya, A. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1147968601536nas a2200169 4500008004100000245007200041210006700113300001100180490000700191520084500198653014001043100001501183700001701198700001801215700002701233856010601260 2001 eng d00aThe secretion pathway in filamentous fungi: a biotechnological view0 asecretion pathway in filamentous fungi a biotechnological view a155-710 v333 aThe high capacity of the secretion machinery of filamentous fungi has been widely exploited for the production of homologous and heterologous proteins; however, our knowledge of the fungal secretion pathway is still at an early stage. Most of the knowledge comes from models developed in yeast and higher eukaryotes, which have served as reference for the studies on fungal species. In this review we compile the data accumulated in recent years on the molecular basis of fungal secretion, emphasizing the relevance of these data for the biotechnological use of the fungal cell and indicating how this information has been applied in attempts to create improved production strains. We also present recent emerging approaches that promise to provide answers to fundamental questions on the molecular genetics of the fungal secretory pathway.10aAnimals Biotechnology/*methods Fungal Proteins/*genetics/*metabolism Fungi/*genetics/*metabolism Humans Recombinant Proteins/metabolism1 aConesa, A.1 aPunt, P., J.1 avan Luijk, N.1 avan den Hondel, C., A. uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11495573