@article {805, title = {Drug-target identification in COVID-19 disease mechanisms using computational systems biology approaches.}, journal = {Front Immunol}, volume = {14}, year = {2024}, month = {2023}, pages = {1282859}, abstract = {

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.

}, keywords = {Computer Simulation, COVID-19, drug repositioning, Humans, SARS-CoV-2, Systems biology}, issn = {1664-3224}, doi = {10.3389/fimmu.2023.1282859}, author = {Niarakis, Anna and Ostaszewski, Marek and Mazein, Alexander and Kuperstein, Inna and Kutmon, Martina and Gillespie, Marc E and Funahashi, Akira and Acencio, Marcio Luis and Hemedan, Ahmed and Aichem, Michael and Klein, Karsten and Czauderna, Tobias and Burtscher, Felicia and Yamada, Takahiro G and Hiki, Yusuke and Hiroi, Noriko F and Hu, Finterly and Pham, Nhung and Ehrhart, Friederike and Willighagen, Egon L and Valdeolivas, Alberto and Dugourd, Aur{\'e}lien and Messina, Francesco and Esteban-Medina, Marina and Pe{\~n}a-Chilet, Maria and Rian, Kinza and Soliman, Sylvain and Aghamiri, Sara Sadat and Puniya, Bhanwar Lal and Naldi, Aur{\'e}lien and Helikar, Tom{\'a}{\v s} and Singh, Vidisha and Fern{\'a}ndez, Marco Fari{\~n}as and Bermudez, Viviam and Tsirvouli, Eirini and Montagud, Arnau and No{\"e}l, Vincent and Ponce-de-Leon, Miguel and Maier, Dieter and Bauch, Angela and Gyori, Benjamin M and Bachman, John A and Luna, Augustin and Pi{\~n}ero, Janet and Furlong, Laura I and Balaur, Irina and Rougny, Adrien and Jarosz, Yohan and Overall, Rupert W and Phair, Robert and Perfetto, Livia and Matthews, Lisa and Rex, Devasahayam Arokia Balaya and Orlic-Milacic, Marija and Gomez, Luis Cristobal Monraz and De Meulder, Bertrand and Ravel, Jean Marie and Jassal, Bijay and Satagopam, Venkata and Wu, Guanming and Golebiewski, Martin and Gawron, Piotr and Calzone, Laurence and Beckmann, Jacques S and Evelo, Chris T and D{\textquoteright}Eustachio, Peter and Schreiber, Falk and Saez-Rodriguez, Julio and Dopazo, Joaquin and Kuiper, Martin and Valencia, Alfonso and Wolkenhauer, Olaf and Kitano, Hiroaki and Barillot, Emmanuel and Auffray, Charles and Balling, Rudi and Schneider, Reinhard} } @article {804, title = {The mechanistic functional landscape of retinitis pigmentosa: a machine learning-driven approach to therapeutic target discovery.}, journal = {J Transl Med}, volume = {22}, year = {2024}, month = {2024 Feb 06}, pages = {139}, abstract = {

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.

}, keywords = {Animals, Mice, Retinitis pigmentosa, Signal Transduction}, issn = {1479-5876}, doi = {10.1186/s12967-024-04911-7}, author = {Esteban-Medina, Marina and Loucera, Carlos and Rian, Kinza and Velasco, Sheyla and Olivares-Gonz{\'a}lez, Lorena and Rodrigo, Regina and Dopazo, Joaquin and Pe{\~n}a-Chilet, Maria} } @article {769, title = {A crowdsourcing database for the copy-number variation of the Spanish population.}, journal = {Hum Genomics}, volume = {17}, year = {2023}, month = {2023 Mar 09}, pages = {20}, abstract = {

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.

}, issn = {1479-7364}, doi = {10.1186/s40246-023-00466-8}, author = {L{\'o}pez-L{\'o}pez, Daniel and Rold{\'a}n, Gema and Fernandez-Rueda, Jose L and Bostelmann, Gerrit and Carmona, Rosario and Aquino, Virginia and Perez-Florido, Javier and Ortuno, Francisco and Pita, Guillermo and N{\'u}{\~n}ez-Torres, Roc{\'\i}o and Gonz{\'a}lez-Neira, Anna and Pe{\~n}a-Chilet, Maria and Dopazo, Joaquin} } @article {766, title = {Detection 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.}, journal = {Int J Mol Sci}, volume = {24}, year = {2023}, month = {2023 Jan 26}, abstract = {

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.

}, issn = {1422-0067}, doi = {10.3390/ijms24032419}, author = {Perez-Florido, Javier and Casimiro-Soriguer, Carlos S and Ortuno, Francisco and Fernandez-Rueda, Jose L and Aguado, Andrea and Lara, Mar{\'\i}a and Riazzo, Cristina and Rodriguez-Iglesias, Manuel A and Camacho-Martinez, Pedro and Merino-Diaz, Laura and Pupo-Ledo, Inmaculada and de Salazar, Adolfo and Vi{\~n}uela, Laura and Fuentes, Ana and Chueca, Natalia and Garc{\'\i}a, Federico and Dopazo, Joaquin and Lepe, Jose A} } @article {795, title = {Visualization of automatically combined disease maps and pathway diagrams for rare diseases.}, journal = {Front Bioinform}, volume = {3}, year = {2023}, month = {2023}, pages = {1101505}, abstract = {

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/.

}, issn = {2673-7647}, doi = {10.3389/fbinf.2023.1101505}, author = {Gawron, Piotr and Hoksza, David and Pi{\~n}ero, Janet and Pe{\~n}a-Chilet, Maria and Esteban-Medina, Marina and Fernandez-Rueda, Jose Luis and Colonna, Vincenza and Smula, Ewa and Heirendt, Laurent and Ancien, Fran{\c c}ois and Grou{\`e}s, Valentin and Satagopam, Venkata P and Schneider, Reinhard and Dopazo, Joaquin and Furlong, Laura I and Ostaszewski, Marek} } @article {762, title = {Assessing the Impact of SARS-CoV-2 Lineages and Mutations on Patient Survival.}, journal = {Viruses}, volume = {14}, year = {2022}, month = {2022 Aug 27}, abstract = {

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.

}, keywords = {COVID-19, Genome, Viral, Humans, mutation, Pandemics, Phylogeny, SARS-CoV-2}, issn = {1999-4915}, doi = {10.3390/v14091893}, author = {Loucera, Carlos and Perez-Florido, Javier and Casimiro-Soriguer, Carlos S and Ortuno, Francisco M and Carmona, Rosario and Bostelmann, Gerrit and Mart{\'\i}nez-Gonz{\'a}lez, L Javier and Mu{\~n}oyerro-Mu{\~n}iz, Dolores and Villegas, Rom{\'a}n and Rodr{\'\i}guez-Ba{\~n}o, Jes{\'u}s and Romero-G{\'o}mez, Manuel and Lorusso, Nicola and Garcia-Le{\'o}n, Javier and Navarro-Mar{\'\i}, Jose M and Camacho-Martinez, Pedro and Merino-Diaz, Laura and Salazar, Adolfo de and Vi{\~n}uela, Laura and Lepe, Jose A and Garc{\'\i}a, Federico and Dopazo, Joaquin} } @article {763, title = {Endoglin and MMP14 Contribute to Ewing Sarcoma Spreading by Modulation of Cell-Matrix Interactions.}, journal = {Int J Mol Sci}, volume = {23}, year = {2022}, month = {2022 Aug 04}, abstract = {

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.

}, keywords = {Bone Neoplasms, Endoglin, Humans, Matrix Metalloproteinase 14, Proteomics, Receptors, Growth Factor, Sarcoma, Ewing, Signal Transduction}, issn = {1422-0067}, doi = {10.3390/ijms23158657}, author = {Puerto-Camacho, Pilar and Diaz-Martin, Juan and Olmedo-Pelayo, Joaqu{\'\i}n and Bolado-Carrancio, Alfonso and Salguero-Aranda, Carmen and Jord{\'a}n-P{\'e}rez, Carmen and Esteban-Medina, Marina and Alamo-Alvarez, Inmaculada and Delgado-Bellido, Daniel and Lobo-Selma, Laura and Dopazo, Joaquin and Sastre, Ana and Alonso, Javier and Gr{\"u}newald, Thomas G P and Bernabeu, Carmelo and Byron, Adam and Brunton, Valerie G and Amaral, Ana Teresa and de Alava, Enrique} } @article {754, title = {Incidence and Prevalence of Children{\textquoteright}s Diffuse Lung Disease in Spain.}, journal = {Arch Bronconeumol}, volume = {58}, year = {2022}, month = {2022 Jan}, pages = {22-29}, abstract = {

BACKGROUND: Children{\textquoteright}s diffuse lung disease, also known as children{\textquoteright}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.

}, issn = {1579-2129}, doi = {10.1016/j.arbres.2021.06.001}, author = {Torrent-Vernetta, Alba and Gaboli, Mirella and Castillo-Corull{\'o}n, Silvia and Mond{\'e}jar-L{\'o}pez, Pedro and Sanz Santiago, Ver{\'o}nica and Costa-Colomer, Jordi and Osona, Borja and Torres-Borrego, Javier and de la Serna-Bl{\'a}zquez, Olga and Bell{\'o}n Alonso, Sara and Caro Aguilera, Pilar and Gimeno-D{\'\i}az de Atauri, {\'A}lvaro and Valenzuela Soria, Alfredo and Ayats, Roser and Martin de Vicente, Carlos and Velasco Gonz{\'a}lez, Valle and Moure Gonz{\'a}lez, Jos{\'e} Domingo and Canino Calder{\'\i}n, Elisa Mar{\'\i}a and Pastor-Vivero, Mar{\'\i}a Dolores and Villar {\'A}lvarez, Mar{\'\i}a {\'A}ngeles and Rovira-Amigo, Sandra and Iglesias Serrano, Ignacio and D{\'\i}ez Izquierdo, Ana and de Mir Messa, In{\'e}s and Gartner, Silvia and Navarro, Alexandra and Baz-Red{\'o}n, Noelia and Carmona, Rosario and Camats-Tarruella, N{\'u}ria and Fern{\'a}ndez-Cancio, M{\'o}nica and Rapp, Christina and Dopazo, Joaquin and Griese, Matthias and Moreno-Gald{\'o}, Antonio} } @article {760, title = {Novel genes and sex differences in COVID-19 severity.}, journal = {Hum Mol Genet}, year = {2022}, month = {2022 Jun 16}, abstract = {

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.

}, issn = {1460-2083}, doi = {10.1093/hmg/ddac132}, author = {Cruz, Raquel and Almeida, Silvia Diz-de and Heredia, Miguel L{\'o}pez and Quintela, In{\'e}s and Ceballos, Francisco C and Pita, Guillermo and Lorenzo-Salazar, Jos{\'e} M and Gonz{\'a}lez-Montelongo, Rafaela and Gago-Dom{\'\i}nguez, Manuela and Porras, Marta Sevilla and Casta{\~n}o, Jair Antonio Tenorio and Nevado, Juli{\'a}n and Aguado, Jose Mar{\'\i}a and Aguilar, Carlos and Aguilera-Albesa, Sergio and Almadana, Virginia and Almoguera, Berta and Alvarez, Nuria and Andreu-Bernabeu, {\'A}lvaro and Arana-Arri, Eunate and Arango, Celso and Arranz, Mar{\'\i}a J and Artiga, Maria-Jesus and Baptista-Rosas, Ra{\'u}l C and Barreda-S{\'a}nchez, Mar{\'\i}a and Belhassen-Garcia, Moncef and Bezerra, Joao F and Bezerra, Marcos A C and Boix-Palop, Luc{\'\i}a and Bri{\'o}n, Maria and Brugada, Ram{\'o}n and Bustos, Matilde and Calder{\'o}n, Enrique J and Carbonell, Cristina and Castano, Luis and Castelao, Jose E and Conde-Vicente, Rosa and Cordero-Lorenzana, M Lourdes and Cortes-Sanchez, Jose L and Corton, Marta and Darnaude, M Teresa and De Martino-Rodr{\'\i}guez, Alba and Campo-P{\'e}rez, Victor and Bustamante, Aranzazu Diaz and Dom{\'\i}nguez-Garrido, Elena and Luchessi, Andr{\'e} D and Eir{\'o}s, Roc{\'\i}o and Sanabria, Gladys Mercedes Estigarribia and Fari{\~n}as, Mar{\'\i}a Carmen and Fern{\'a}ndez-Robelo, Ux{\'\i}a and Fern{\'a}ndez-Rodr{\'\i}guez, Amanda and Fern{\'a}ndez-Villa, Tania and Gil-Fournier, Bel{\'e}n and G{\'o}mez-Arrue, Javier and {\'A}lvarez, Beatriz Gonz{\'a}lez and Quir{\'o}s, Fernan Gonzalez Bernaldo and Gonz{\'a}lez-Pe{\~n}as, Javier and Guti{\'e}rrez-Bautista, Juan F and Herrero, Mar{\'\i}a Jos{\'e} and Herrero-Gonzalez, Antonio and Jimenez-Sousa, Mar{\'\i}a A and Lattig, Mar{\'\i}a Claudia and Borja, Anabel Liger and Lopez-Rodriguez, Rosario and Mancebo, Esther and Mart{\'\i}n-L{\'o}pez, Caridad and Mart{\'\i}n, Vicente and Martinez-Nieto, Oscar and Martinez-Lopez, Iciar and Martinez-Resendez, Michel F and Martinez-Perez, {\'A}ngel and Mazzeu, Juliana A and Mac{\'\i}as, Eleuterio Merayo and Minguez, Pablo and Cuerda, Victor Moreno and Silbiger, Vivian N and Oliveira, Silviene F and Ortega-Paino, Eva and Parellada, Mara and Paz-Artal, Estela and Santos, Ney P C and P{\'e}rez-Matute, Patricia and Perez, Patricia and P{\'e}rez-Tom{\'a}s, M Elena and Perucho, Teresa and Pinsach-Abuin, Mel Lina and Pompa-Mera, Ericka N and Porras-Hurtado, Gloria L and Pujol, Aurora and Le{\'o}n, Soraya Ramiro and Resino, Salvador and Fernandes, Marianne R and Rodr{\'\i}guez-Ruiz, Emilio and Rodriguez-Artalejo, Fernando and Rodriguez-Garcia, Jos{\'e} A and Ruiz-Cabello, Francisco and Ruiz-Hornillos, Javier and Ryan, Pablo and Soria, Jos{\'e} Manuel and Souto, Juan Carlos and Tamayo, Eduardo and Tamayo-Velasco, Alvaro and Taracido-Fernandez, Juan Carlos and Teper, Alejandro and Torres-Tobar, Lilian and Urioste, Miguel and Valencia-Ramos, Juan and Y{\'a}{\~n}ez, Zuleima and Zarate, Ruth and Nakanishi, Tomoko and Pigazzini, Sara and Degenhardt, Frauke and Butler-Laporte, Guillaume and Maya-Miles, Douglas and Bujanda, Luis and Bouysran, Youssef and Palom, Adriana and Ellinghaus, David and Mart{\'\i}nez-Bueno, Manuel and Rolker, Selina and Amitrano, Sara and Roade, Luisa and Fava, Francesca and Spinner, Christoph D and Prati, Daniele and Bernardo, David and Garc{\'\i}a, Federico and Darcis, Gilles and Fern{\'a}ndez-Cadenas, Israel and Holter, Jan Cato and Banales, Jesus M and Frithiof, Robert and Duga, Stefano and Asselta, Rosanna and Pereira, Alexandre C and Romero-G{\'o}mez, Manuel and Nafr{\'\i}a-Jim{\'e}nez, Beatriz and Hov, Johannes R and Migeotte, Isabelle and Renieri, Alessandra and Planas, Anna M and Ludwig, Kerstin U and Buti, Maria and Rahmouni, Souad and Alarc{\'o}n-Riquelme, Marta E and Schulte, Eva C and Franke, Andre and Karlsen, Tom H and Valenti, Luca and Zeberg, Hugo and Richards, Brent and Ganna, Andrea and Boada, Merc{\`e} and Rojas, Itziar and Ruiz, Agust{\'\i}n and S{\'a}nchez, Pascual and Real, Luis Miguel and Guill{\'e}n-Navarro, Encarna and Ayuso, Carmen and Gonz{\'a}lez-Neira, Anna and Riancho, Jos{\'e} A and Rojas-Martinez, Augusto and Flores, Carlos and Lapunzina, Pablo and Carracedo, {\'A}ngel} } @article {759, title = {Protein and functional isoform levels and genetic variants of the BAFF and APRIL pathway components in systemic lupus erythematosus.}, journal = {Sci Rep}, volume = {12}, year = {2022}, month = {2022 Jul 02}, pages = {11219}, abstract = {

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.

}, issn = {2045-2322}, doi = {10.1038/s41598-022-15549-0}, author = {Ortiz-Aljaro, Pilar and Montes-Cano, Marco Antonio and Garc{\'\i}a-Lozano, Jos{\'e}-Ra{\'u}l and Aquino, Virginia and Carmona, Rosario and Perez-Florido, Javier and Garc{\'\i}a-Hern{\'a}ndez, Francisco Jos{\'e} and Dopazo, Joaquin and Gonz{\'a}lez-Escribano, Mar{\'\i}a Francisca} } @article {765, title = {An SPM-Enriched Marine Oil Supplement Shifted Microglia Polarization toward M2, Ameliorating Retinal Degeneration in Mice.}, journal = {Antioxidants (Basel)}, volume = {12}, year = {2022}, month = {2022 Dec 30}, abstract = {

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.

}, issn = {2076-3921}, doi = {10.3390/antiox12010098}, author = {Olivares-Gonz{\'a}lez, Lorena and Velasco, Sheyla and Gallego, Idoia and Esteban-Medina, Marina and Puras, Gustavo and Loucera, Carlos and Mart{\'\i}nez-Romero, Alicia and Pe{\~n}a-Chilet, Maria and Pedraz, Jos{\'e} Luis and Rodrigo, Regina} } @article {736, title = {COVID19 Disease Map, a computational knowledge repository of virus-host interaction mechanisms.}, journal = {Mol Syst Biol}, volume = {17}, year = {2021}, month = {2021 10}, pages = {e10387}, abstract = {

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.

}, keywords = {Antiviral Agents, Computational Biology, Computer Graphics, COVID-19, Cytokines, Data Mining, Databases, Factual, Gene Expression Regulation, Host Microbial Interactions, Humans, Immunity, Cellular, Immunity, Humoral, Immunity, Innate, Lymphocytes, Metabolic Networks and Pathways, Myeloid Cells, Protein Interaction Mapping, SARS-CoV-2, Signal Transduction, Software, Transcription Factors, Viral Proteins}, issn = {1744-4292}, doi = {10.15252/msb.202110387}, author = {Ostaszewski, Marek and Niarakis, Anna and Mazein, Alexander and Kuperstein, Inna and Phair, Robert and Orta-Resendiz, Aurelio and Singh, Vidisha and Aghamiri, Sara Sadat and Acencio, Marcio Luis and Glaab, Enrico and Ruepp, Andreas and Fobo, Gisela and Montrone, Corinna and Brauner, Barbara and Frishman, Goar and Monraz G{\'o}mez, Luis Crist{\'o}bal and Somers, Julia and Hoch, Matti and Kumar Gupta, Shailendra and Scheel, Julia and Borlinghaus, Hanna and Czauderna, Tobias and Schreiber, Falk and Montagud, Arnau and Ponce de Leon, Miguel and Funahashi, Akira and Hiki, Yusuke and Hiroi, Noriko and Yamada, Takahiro G and Dr{\"a}ger, Andreas and Renz, Alina and Naveez, Muhammad and Bocskei, Zsolt and Messina, Francesco and B{\"o}rnigen, Daniela and Fergusson, Liam and Conti, Marta and Rameil, Marius and Nakonecnij, Vanessa and Vanhoefer, Jakob and Schmiester, Leonard and Wang, Muying and Ackerman, Emily E and Shoemaker, Jason E and Zucker, Jeremy and Oxford, Kristie and Teuton, Jeremy and Kocakaya, Ebru and Summak, G{\"o}k{\c c}e Ya{\u g}mur and Hanspers, Kristina and Kutmon, Martina and Coort, Susan and Eijssen, Lars and Ehrhart, Friederike and Rex, Devasahayam Arokia Balaya and Slenter, Denise and Martens, Marvin and Pham, Nhung and Haw, Robin and Jassal, Bijay and Matthews, Lisa and Orlic-Milacic, Marija and Senff Ribeiro, Andrea and Rothfels, Karen and Shamovsky, Veronica and Stephan, Ralf and Sevilla, Cristoffer and Varusai, Thawfeek and Ravel, Jean-Marie and Fraser, Rupsha and Ortseifen, Vera and Marchesi, Silvia and Gawron, Piotr and Smula, Ewa and Heirendt, Laurent and Satagopam, Venkata and Wu, Guanming and Riutta, Anders and Golebiewski, Martin and Owen, Stuart and Goble, Carole and Hu, Xiaoming and Overall, Rupert W and Maier, Dieter and Bauch, Angela and Gyori, Benjamin M and Bachman, John A and Vega, Carlos and Grou{\`e}s, Valentin and Vazquez, Miguel and Porras, Pablo and Licata, Luana and Iannuccelli, Marta and Sacco, Francesca and Nesterova, Anastasia and Yuryev, Anton and de Waard, Anita and Turei, Denes and Luna, Augustin and Babur, Ozgun and Soliman, Sylvain and Valdeolivas, Alberto and Esteban-Medina, Marina and Pe{\~n}a-Chilet, Maria and Rian, Kinza and Helikar, Tom{\'a}{\v s} and Puniya, Bhanwar Lal and Modos, Dezso and Treveil, Agatha and Olbei, Marton and De Meulder, Bertrand and Ballereau, Stephane and Dugourd, Aur{\'e}lien and Naldi, Aur{\'e}lien and No{\"e}l, Vincent and Calzone, Laurence and Sander, Chris and Demir, Emek and Korcsmaros, Tamas and Freeman, Tom C and Aug{\'e}, Franck and Beckmann, Jacques S and Hasenauer, Jan and Wolkenhauer, Olaf and Wilighagen, Egon L and Pico, Alexander R and Evelo, Chris T and Gillespie, Marc E and Stein, Lincoln D and Hermjakob, Henning and D{\textquoteright}Eustachio, Peter and Saez-Rodriguez, Julio and Dopazo, Joaquin and Valencia, Alfonso and Kitano, Hiroaki and Barillot, Emmanuel and Auffray, Charles and Balling, Rudi and Schneider, Reinhard} } @article {701, title = {CSVS, a crowdsourcing database of the Spanish population genetic variability.}, journal = {Nucleic Acids Res}, volume = {49}, year = {2021}, month = {2021 01 08}, pages = {D1130-D1137}, abstract = {

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/.

}, keywords = {Alleles, Chromosome Mapping, Crowdsourcing, Databases, Genetic, Exome, Gene Frequency, Genetic Variation, Genetics, Population, Genome, Human, Genomics, Humans, Internet, Precision Medicine, Software, Spain}, issn = {1362-4962}, doi = {10.1093/nar/gkaa794}, author = {Pe{\~n}a-Chilet, Maria and Rold{\'a}n, Gema and Perez-Florido, Javier and Ortuno, Francisco M and Carmona, Rosario and Aquino, Virginia and L{\'o}pez-L{\'o}pez, Daniel and Loucera, Carlos and Fernandez-Rueda, Jose L and Gallego, Asunci{\'o}n and Garcia-Garcia, Francisco and Gonz{\'a}lez-Neira, Anna and Pita, Guillermo and N{\'u}{\~n}ez-Torres, Roc{\'\i}o and Santoyo-L{\'o}pez, Javier and Ayuso, Carmen and Minguez, Pablo and Avila-Fernandez, Almudena and Corton, Marta and Moreno-Pelayo, Miguel {\'A}ngel and Morin, Mat{\'\i}as and Gallego-Martinez, Alvaro and Lopez-Escamez, Jose A and Borrego, Salud and Anti{\v n}olo, Guillermo and Amigo, Jorge and Salgado-Garrido, Josefa and Pasalodos-Sanchez, Sara and Morte, Beatriz and Carracedo, {\'A}ngel and Alonso, {\'A}ngel and Dopazo, Joaquin} } @article {720, title = {A DNA damage repair gene-associated signature predicts responses of patients with advanced soft-tissue sarcoma to treatment with trabectedin.}, journal = {Mol Oncol}, volume = {15}, year = {2021}, month = {2021 12}, pages = {3691-3705}, abstract = {

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.

}, issn = {1878-0261}, doi = {10.1002/1878-0261.12996}, author = {Moura, David S and Pe{\~n}a-Chilet, Maria and Cordero Varela, Juan Antonio and Alvarez-Alegret, Ramiro and Agra-Pujol, Carolina and Izquierdo, Francisco and Ramos, Rafael and Ortega-Medina, Luis and Martin-Davila, Francisco and Castilla-Ramirez, Carolina and Hernandez-Leon, Carmen Nieves and Romagosa, Cleofe and Vaz Salgado, Maria Angeles and Lavernia, Javier and Bagu{\'e}, Silvia and Mayodormo-Aranda, Empar and Vicioso, Luis and Hern{\'a}ndez Barcel{\'o}, Jose Emilio and Rubio-Casadevall, Jordi and de Juan, Ana and Fia{\~n}o-Valverde, Maria Concepcion and Hindi, Nadia and Lopez-Alvarez, Maria and Lacerenza, Serena and Dopazo, Joaquin and Gutierrez, Antonio and Alvarez, Rosa and Valverde, Claudia and Martinez-Trufero, Javier and Martin-Broto, Javier} } @article {744, title = {Highly accurate whole-genome imputation of SARS-CoV-2 from partial or low-quality sequences.}, journal = {Gigascience}, volume = {10}, year = {2021}, month = {2021 12 02}, abstract = {

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.

}, keywords = {Genome, Viral, Phylogeny, SARS-CoV-2, Whole Genome Sequencing}, issn = {2047-217X}, doi = {10.1093/gigascience/giab078}, author = {Ortuno, Francisco M and Loucera, Carlos and Casimiro-Soriguer, Carlos S and Lepe, Jose A and Camacho Martinez, Pedro and Merino Diaz, Laura and de Salazar, Adolfo and Chueca, Natalia and Garc{\'\i}a, Federico and Perez-Florido, Javier and Dopazo, Joaquin} } @article {711, title = {Mechanistic modeling of the SARS-CoV-2 disease map.}, journal = {BioData Min}, volume = {14}, year = {2021}, month = {2021 Jan 21}, pages = {5}, abstract = {

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.

}, issn = {1756-0381}, doi = {10.1186/s13040-021-00234-1}, author = {Rian, Kinza and Esteban-Medina, Marina and Hidalgo, Marta R and Cubuk, Cankut and Falco, Matias M and Loucera, Carlos and Gunyel, Devrim and Ostaszewski, Marek and Pe{\~n}a-Chilet, Maria and Dopazo, Joaquin} } @article {714, title = {The NCI Genomic Data Commons}, journal = {Nature Genetics}, year = {2021}, month = {Oct-02-2022}, issn = {1061-4036}, doi = {10.1038/s41588-021-00791-5}, url = {http://www.nature.com/articles/s41588-021-00791-5}, author = {Heath, Allison P. and Ferretti, Vincent and Agrawal, Stuti and An, Maksim and Angelakos, James C. and Arya, Renuka and Bajari, Rosita and Baqar, Bilal and Barnowski, Justin H. B. and Burt, Jeffrey and Catton, Ann and Chan, Brandon F. and Chu, Fay and Cullion, Kim and Davidsen, Tanja and Do, Phuong-My and Dompierre, Christian and Ferguson, Martin L. and Fitzsimons, Michael S. and Ford, Michael and Fukuma, Miyuki and Gaheen, Sharon and Ganji, Gajanan L. and Garcia, Tzintzuni I. and George, Sameera S. and Gerhard, Daniela S. and Gerthoffert, Francois and Gomez, Fauzi and Han, Kang and Hernandez, Kyle M. and Issac, Biju and Jackson, Richard and Jensen, Mark A. and Joshi, Sid and Kadam, Ajinkya and Khurana, Aishmit and Kim, Kyle M. J. and Kraft, Victoria E. and Li, Shenglai and Lichtenberg, Tara M. and Lodato, Janice and Lolla, Laxmi and Martinov, Plamen and Mazzone, Jeffrey A. and Miller, Daniel P. and Miller, Ian and Miller, Joshua S. and Miyauchi, Koji and Murphy, Mark W. and Nullet, Thomas and Ogwara, Rowland O. and Ortu{\~n}o, Francisco M. and Pedrosa, Jes{\'u}s and Pham, Phuong L. and Popov, Maxim Y. and Porter, James J. and Powell, Raymond and Rademacher, Karl and Reid, Colin P. and Rich, Samantha and Rogel, Bessie and Sahni, Himanso and Savage, Jeremiah H. and Schmitt, Kyle A. and Simmons, Trevar J. and Sislow, Joseph and Spring, Jonathan and Stein, Lincoln and Sullivan, Sean and Tang, Yajing and Thiagarajan, Mathangi and Troyer, Heather D. and Wang, Chang and Wang, Zhining and West, Bedford L. and Wilmer, Alex and Wilson, Shane and Wu, Kaman and Wysocki, William P. and Xiang, Linda and Yamada, Joseph T. and Yang, Liming and Yu, Christine and Yung, Christina K. and Zenklusen, Jean Claude and Zhang, Junjun and Zhang, Zhenyu and Zhao, Yuanheng and Zubair, Ariz and Staudt, Louis M. and Grossman, Robert L.} } @article {742, title = {Reporting guidelines for human microbiome research: the STORMS checklist.}, journal = {Nat Med}, volume = {27}, year = {2021}, month = {2021 11}, pages = {1885-1892}, abstract = {

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 {\textquoteright}Strengthening The Organization and Reporting of Microbiome Studies{\textquoteright} (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.

}, keywords = {Computational Biology, Dysbiosis, Humans, Microbiota, Observational Studies as Topic, Research Design, Translational Science, Biomedical}, issn = {1546-170X}, doi = {10.1038/s41591-021-01552-x}, author = {Mirzayi, Chloe and Renson, Audrey and Zohra, Fatima and Elsafoury, Shaimaa and Geistlinger, Ludwig and Kasselman, Lora J and Eckenrode, Kelly and van de Wijgert, Janneke and Loughman, Amy and Marques, Francine Z and MacIntyre, David A and Arumugam, Manimozhiyan and Azhar, Rimsha and Beghini, Francesco and Bergstrom, Kirk and Bhatt, Ami and Bisanz, Jordan E and Braun, Jonathan and Bravo, Hector Corrada and Buck, Gregory A and Bushman, Frederic and Casero, David and Clarke, Gerard and Collado, Maria Carmen and Cotter, Paul D and Cryan, John F and Demmer, Ryan T and Devkota, Suzanne and Elinav, Eran and Escobar, Juan S and Fettweis, Jennifer and Finn, Robert D and Fodor, Anthony A and Forslund, Sofia and Franke, Andre and Furlanello, Cesare and Gilbert, Jack and Grice, Elizabeth and Haibe-Kains, Benjamin and Handley, Scott and Herd, Pamela and Holmes, Susan and Jacobs, Jonathan P and Karstens, Lisa and Knight, Rob and Knights, Dan and Koren, Omry and Kwon, Douglas S and Langille, Morgan and Lindsay, Brianna and McGovern, Dermot and McHardy, Alice C and McWeeney, Shannon and Mueller, Noel T and Nezi, Luigi and Olm, Matthew and Palm, Noah and Pasolli, Edoardo and Raes, Jeroen and Redinbo, Matthew R and R{\"u}hlemann, Malte and Balfour Sartor, R and Schloss, Patrick D and Schriml, Lynn and Segal, Eran and Shardell, Michelle and Sharpton, Thomas and Smirnova, Ekaterina and Sokol, Harry and Sonnenburg, Justin L and Srinivasan, Sujatha and Thingholm, Louise B and Turnbaugh, Peter J and Upadhyay, Vaibhav and Walls, Ramona L and Wilmes, Paul and Yamada, Takuji and Zeller, Georg and Zhang, Mingyu and Zhao, Ni and Zhao, Liping and Bao, Wenjun and Culhane, Aedin and Devanarayan, Viswanath and Dopazo, Joaquin and Fan, Xiaohui and Fischer, Matthias and Jones, Wendell and Kusko, Rebecca and Mason, Christopher E and Mercer, Tim R and Sansone, Susanna-Assunta and Scherer, Andreas and Shi, Leming and Thakkar, Shraddha and Tong, Weida and Wolfinger, Russ and Hunter, Christopher and Segata, Nicola and Huttenhower, Curtis and Dowd, Jennifer B and Jones, Heidi E and Waldron, Levi} } @article {719, title = {Taxonomic variations in the gut microbiome of gout patients with and without tophi might have a functional impact on urate metabolism.}, journal = {Mol Med}, volume = {27}, year = {2021}, month = {2021 05 24}, pages = {50}, abstract = {

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.

}, keywords = {Biodiversity, Computational Biology, Dysbiosis, Gastrointestinal Microbiome, Gout, Humans, Metagenome, metagenomics, Protein Interaction Mapping, Protein Interaction Maps, Uric Acid}, issn = {1528-3658}, doi = {10.1186/s10020-021-00311-5}, author = {M{\'e}ndez-Salazar, Eder Orlando and V{\'a}zquez-Mellado, Janitzia and Casimiro-Soriguer, Carlos S and Dopazo, Joaquin and Cubuk, Cankut and Zamudio-Cuevas, Yessica and Francisco-Balderas, Adriana and Mart{\'\i}nez-Flores, Karina and Fern{\'a}ndez-Torres, Javier and Lozada-P{\'e}rez, Carlos and Pineda, Carlos and S{\'a}nchez-Gonz{\'a}lez, Austreberto and Silveira, Luis H and Burguete-Garc{\'\i}a, Ana I and Orbe-Orihuela, Citlalli and Lagunas-Mart{\'\i}nez, Alfredo and Vazquez-Gomez, Alonso and L{\'o}pez-Reyes, Alberto and Palacios-Gonz{\'a}lez, Berenice and Mart{\'\i}nez-Nava, Gabriela Ang{\'e}lica} } @article {715, title = {Uniform genomic data analysis in the NCI Genomic Data CommonsAbstract}, journal = {Nature Communications}, volume = {12}, year = {2021}, month = {Jan-12-2021}, doi = {10.1038/s41467-021-21254-9}, url = {http://www.nature.com/articles/s41467-021-21254-9}, author = {Zhang, Zhenyu and Hernandez, Kyle and Savage, Jeremiah and Li, Shenglai and Miller, Dan and Agrawal, Stuti and Ortuno, Francisco and Staudt, Louis M. and Heath, Allison and Grossman, Robert L.} } @article {712, title = {A versatile workflow to integrate RNA-seq genomic and transcriptomic data into mechanistic models of signaling pathways.}, journal = {PLoS Comput Biol}, volume = {17}, year = {2021}, month = {2021 02}, pages = {e1008748}, abstract = {

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.

}, keywords = {Algorithms, Cell Line, Tumor, Computational Biology, Databases, Factual, Gene Expression Profiling, Genomics, High-Throughput Nucleotide Sequencing, Humans, Models, Theoretical, mutation, RNA-seq, Signal Transduction, Software, Transcriptome, whole exome sequencing, Workflow}, issn = {1553-7358}, doi = {10.1371/journal.pcbi.1008748}, author = {Garrido-Rodriguez, Mart{\'\i}n and L{\'o}pez-L{\'o}pez, Daniel and Ortuno, Francisco M and Pe{\~n}a-Chilet, Maria and Mu{\~n}oz, Eduardo and Calzado, Marco A and Dopazo, Joaquin} } @article {689, title = {COVID-19 Disease Map, building a computational repository of SARS-CoV-2 virus-host interaction mechanisms.}, journal = {Sci Data}, volume = {7}, year = {2020}, month = {2020 05 05}, pages = {136}, keywords = {Betacoronavirus, Computational Biology, Coronavirus Infections, COVID-19, Databases, Factual, Host Microbial Interactions, Host-Pathogen Interactions, Humans, International Cooperation, Models, Biological, Pandemics, Pneumonia, Viral, SARS-CoV-2}, issn = {2052-4463}, doi = {10.1038/s41597-020-0477-8}, author = {Ostaszewski, Marek and Mazein, Alexander and Gillespie, Marc E and Kuperstein, Inna and Niarakis, Anna and Hermjakob, Henning and Pico, Alexander R and Willighagen, Egon L and Evelo, Chris T and Hasenauer, Jan and Schreiber, Falk and Dr{\"a}ger, Andreas and Demir, Emek and Wolkenhauer, Olaf and Furlong, Laura I and Barillot, Emmanuel and Dopazo, Joaquin and Orta-Resendiz, Aurelio and Messina, Francesco and Valencia, Alfonso and Funahashi, Akira and Kitano, Hiroaki and Auffray, Charles and Balling, Rudi and Schneider, Reinhard} } @article {693, title = {Immune Cell Associations with Cancer Risk.}, journal = {iScience}, volume = {23}, year = {2020}, month = {2020 Jul 24}, pages = {101296}, abstract = {

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.

}, issn = {2589-0042}, doi = {10.1016/j.isci.2020.101296}, author = {Palomero, Luis and Galv{\'a}n-Femen{\'\i}a, Ivan and de Cid, Rafael and Esp{\'\i}n, Roderic and Barnes, Daniel R and Blommaert, Eline and Gil-Gil, Miguel and Falo, Catalina and Stradella, Agostina and Ouchi, Dan and Roso-Llorach, Albert and Violan, Concepci{\'o} and Pe{\~n}a-Chilet, Maria and Dopazo, Joaquin and Extremera, Ana Isabel and Garc{\'\i}a-Valero, Mar and Herranz, Carmen and Mateo, Francesca and Mereu, Elisabetta and Beesley, Jonathan and Chenevix-Trench, Georgia and Roux, Cecilia and Mak, Tak and Brunet, Joan and Hakem, Razq and Gorrini, Chiara and Antoniou, Antonis C and L{\'a}zaro, Conxi and Pujana, Miquel Angel} } @article {692, title = {Towards Improving Skin Cancer Diagnosis by Integrating Microarray and RNA-Seq Datasets.}, journal = {IEEE J Biomed Health Inform}, volume = {24}, year = {2020}, month = {2020 07}, pages = {2119-2130}, abstract = {

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.

}, keywords = {Biomarkers, Tumor, Computational Biology, Diagnosis, Computer-Assisted, Gene Expression Profiling, Humans, Machine Learning, RNA-seq, Skin Neoplasms}, issn = {2168-2208}, doi = {10.1109/JBHI.2019.2953978}, author = {Galvez, Juan M and Castillo-Secilla, Daniel and Herrera, Luis J and Valenzuela, Olga and Caba, Octavio and Prados, Jose C and Ortuno, Francisco M and Rojas, Ignacio} } @article {397, title = {The effects of death and post-mortem cold ischemia on human tissue transcriptomes.}, journal = {Nat Commun}, volume = {9}, year = {2018}, month = {2018 02 13}, pages = {490}, abstract = {

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.

}, keywords = {Blood, Cold Ischemia, Death, Female, gene expression, Humans, Models, Biological, Postmortem Changes, RNA, Messenger, Stochastic Processes, Transcriptome}, issn = {2041-1723}, doi = {10.1038/s41467-017-02772-x}, author = {Ferreira, Pedro G and Mu{\~n}oz-Aguirre, Manuel and Reverter, Ferran and S{\'a} Godinho, Caio P and Sousa, Abel and Amadoz, Alicia and Sodaei, Reza and Hidalgo, Marta R and Pervouchine, Dmitri and Carbonell-Caballero, Jos{\'e} and Nurtdinov, Ramil and Breschi, Alessandra and Amador, Raziel and Oliveira, Patr{\'\i}cia and Cubuk, Cankut and Curado, Jo{\~a}o and Aguet, Fran{\c c}ois and Oliveira, Carla and Dopazo, Joaquin and Sammeth, Michael and Ardlie, Kristin G and Guig{\'o}, Roderic} } @article {398, title = {Genomics of the origin and evolution of Citrus.}, journal = {Nature}, volume = {554}, year = {2018}, month = {2018 02 15}, pages = {311-316}, abstract = {

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.

}, keywords = {Asia, Southeastern, Biodiversity, citrus, Crop Production, Evolution, Molecular, Genetic Speciation, Genome, Plant, Genomics, Haplotypes, Heterozygote, History, Ancient, Human Migration, Hybridization, Genetic, Phylogeny}, issn = {1476-4687}, doi = {10.1038/nature25447}, author = {Wu, Guohong Albert and Terol, Javier and Iba{\~n}ez, Victoria and L{\'o}pez-Garc{\'\i}a, Antonio and P{\'e}rez-Rom{\'a}n, Estela and Borred{\'a}, Carles and Domingo, Concha and Tadeo, Francisco R and Carbonell-Caballero, Jos{\'e} and Alonso, Roberto and Curk, Franck and Du, Dongliang and Ollitrault, Patrick and Roose, Mikeal L and Dopazo, Joaquin and Gmitter, Frederick G and Rokhsar, Daniel S and Talon, Manuel} } @article {1230, title = {A new parallel pipeline for DNA methylation analysis of long reads datasets.}, journal = {BMC bioinformatics}, volume = {18}, year = {2017}, month = {2017 Mar 09}, pages = {161}, abstract = {BACKGROUND: 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.}, keywords = {Methyl-Seq, NGS}, issn = {1471-2105}, doi = {10.1186/s12859-017-1574-3}, url = {http://bmcbioinformatics.biomedcentral.com/articles/10.1186/s12859-017-1574-3}, author = {Olanda, Ricardo and P{\'e}rez, Mariano and Ordu{\~n}a, Juan M and T{\'a}rraga, Joaqu{\'\i}n and Joaqu{\'\i}n Dopazo} } @article {450, title = {Screening of CD96 and ASXL1 in 11 patients with Opitz C or Bohring-Opitz syndromes.}, journal = {Am J Med Genet A}, volume = {170A}, year = {2016}, month = {2016 Jan}, pages = {24-31}, abstract = {

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.

}, keywords = {Adolescent, Antigens, CD, Child, Child, Preschool, Craniosynostoses, Exome, Female, High-Throughput Nucleotide Sequencing, Humans, Infant, Intellectual Disability, Male, mutation, Pedigree, Phenotype, Prognosis, Repressor Proteins}, issn = {1552-4833}, doi = {10.1002/ajmg.a.37418}, author = {Urreizti, Roser and Roca-Ayats, Neus and Trepat, Judith and Garcia-Garcia, Francisco and Alem{\'a}n, Alejandro and Orteschi, Daniela and Marangi, Giuseppe and Neri, Giovanni and Opitz, John M and Dopazo, Joaquin and Cormand, Bru and Vilageliu, Llu{\"\i}sa and Balcells, Susana and Grinberg, Daniel} } @article {461, title = {Family-based genome-wide association study in Patagonia confirms the association of the DMD locus and cleft lip and palate.}, journal = {Eur J Oral Sci}, volume = {123}, year = {2015}, month = {2015 Oct}, pages = {381-384}, abstract = {

The etiology of cleft lip with or without cleft palate (CL{\textpm}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{\textpm}P. We attempted to confirm the role of X-linked genes in the etiology of isolated CL{\textpm}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{\textpm}P. We conducted an exploratory analysis of the X chromosome to identify candidate regions associated with CL{\textpm}P. Four genomic segments were identified, two of which showed a statistically significant association with CL{\textpm}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{\textpm}P. The MID1 and OFD1 genes were not included in the four potential CL{\textpm}P-associated X-chromosome genomic segments.

}, issn = {1600-0722}, doi = {10.1111/eos.12212}, author = {Fonseca, Renata F and de Carvalho, Fl{\'a}via M and Poletta, Fernando A and Montaner, David and Dopazo, Joaquin and Mereb, Juan C and Moreira, Miguel A M and Seuanez, Hector N and Vieira, Alexandre R and Castilla, Eduardo E and Orioli, I{\^e}da M} } @article {1149, title = {A Parallel and Sensitive Software Tool for Methylation Analysis on Multicore Platforms.}, journal = {Bioinformatics (Oxford, England)}, volume = {31}, number = {19}, year = {2015}, month = {2015 Jun 10}, pages = {3130-3138}, abstract = {MOTIVATION: 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.}, keywords = {BS-seq, HPC, methylation, NGS}, issn = {1367-4811}, doi = {10.1093/bioinformatics/btv357}, url = {http://bioinformatics.oxfordjournals.org/content/31/19/3130.long}, author = {T{\'a}rraga, Joaqu{\'\i}n and P{\'e}rez, Mariano and Ordu{\~n}a, Juan M and Duato, Jos{\'e} and Medina, Ignacio and Joaqu{\'\i}n Dopazo} } @article {1074, title = {A Comprehensive DNA Methylation Profile of Epithelial-to-Mesenchymal Transition.}, journal = {Cancer research}, volume = {74}, number = {19}, year = {2014}, month = {2014 Aug 8}, pages = {5608{\textendash}19}, abstract = {Epithelial-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.}, keywords = {Methyl-Seq, Methylomics, Next Generation Sequencing}, issn = {1538-7445}, doi = {10.1158/0008-5472.CAN-13-3659}, url = {http://www.ncbi.nlm.nih.gov/pubmed/25106427}, author = {Carmona, F Javier and Davalos, Veronica and Vidal, Enrique and Gomez, Antonio and Heyn, Holger and Hashimoto, Yutaka and Vizoso, Miguel and Martinez-Cardus, Anna and Sayols, Sergi and Ferreira, Humberto and Sanchez-Mut, Jose and Moran, Sebastian and Margeli, Mireia and Castella, Eva and Berdasco, Maria and Stefansson, Olafur Andri and Eyfjord, Jorunn E and Gonzalez-Suarez, Eva and Dopazo, Joaquin and Orozco, Modesto and Gut, Ivo and Esteller, Manel} } @article {484, title = {Two novel mutations in the BCKDK (branched-chain keto-acid dehydrogenase kinase) gene are responsible for a neurobehavioral deficit in two pediatric unrelated patients.}, journal = {Hum Mutat}, volume = {35}, year = {2014}, month = {2014 Apr}, pages = {470-7}, abstract = {

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{\textquoteright} 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.

}, keywords = {Amino Acids, Branched-Chain, Developmental Disabilities, Fibroblasts, Humans, Male, Mutation, Missense, Nervous System Diseases, Pediatrics, Protein Kinases}, issn = {1098-1004}, doi = {10.1002/humu.22513}, author = {Garc{\'\i}a-Cazorla, Angels and Oyarzabal, Alfonso and Fort, Joana and Robles, Concepci{\'o}n and Castej{\'o}n, Esperanza and Ruiz-Sala, Pedro and Bodoy, Susanna and Merinero, Bego{\~n}a and Lopez-Sala, Anna and Dopazo, Joaquin and Nunes, Virginia and Ugarte, Magdalena and Artuch, Rafael and Palac{\'\i}n, Manuel and Rodr{\'\i}guez-Pombo, Pilar and Alcaide, Patricia and Navarrete, Rosa and Sanz, Paloma and Font-Llitj{\'o}s, Mariona and Vilaseca, Ma Antonia and Ormaizabal, Aida and Pristoupilova, Anna and Agull{\'o}, Sergi Beltran} } @article {1041, title = {Two Novel Mutations in the BCKDK Gene (Branched-Chain Keto-Acid Dehydrogenase Kinase) are Responsible of a Neurobehavioral Deficit in two Pediatric Unrelated Patients.}, journal = {Human mutation}, volume = {35}, number = {4}, year = {2014}, month = {2014 Jan 21}, pages = {470-7}, abstract = {Inactivating 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{\textquoteright} 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.}, issn = {1098-1004}, doi = {10.1002/humu.22513}, url = {http://onlinelibrary.wiley.com/doi/10.1002/humu.22513/abstract}, author = {Garc{\'\i}a-Cazorla, Angels and Oyarzabal, Alfonso and Fort, Joana and Robles, Concepci{\'o}n and Castej{\'o}n, Esperanza and Ruiz-Sala, Pedro and Bodoy, Susanna and Merinero, Bego{\~n}a and Lopez-Sala, Anna and Joaqu{\'\i}n Dopazo and Nunes, Virginia and Ugarte, Magdalena and Artuch, Rafael and Palac{\'\i}n, Manuel and Rodr{\'\i}guez-Pombo, Pilar} } @article {913, title = {Expression profiling shows differential molecular pathways and provides potential new diagnostic biomarkers for colorectal serrated adenocarcinoma.}, journal = {International journal of cancer. Journal international du cancer}, year = {2012}, month = {2012 Jun 14}, abstract = {Serrated 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. {\textcopyright} 2012 Wiley Periodicals, Inc.}, issn = {1097-0215}, doi = {10.1002/ijc.27674}, author = {Conesa-Zamora, Pablo and Garc{\'\i}a-Solano, Jos{\'e} and Garcia-Garcia, Francisco and Del Carmen Turpin, Mar{\'\i}a and Trujillo-Santos, Javier and Torres-Moreno, Daniel and Oviedo-Ram{\'\i}rez, Isabel and Carbonell-Mu{\~n}oz, Rosa and Mu{\~n}oz-Delgado, Encarnaci{\'o}n and Rodriguez-Braun, Edith and Ana Conesa and P{\'e}rez-Guillermo, Miguel} } @article {938, title = {Qualimap: evaluating next-generation sequencing alignment data.}, journal = {Bioinformatics (Oxford, England)}, volume = {28}, year = {2012}, month = {2012 Oct 15}, pages = {2678-9}, abstract = {MOTIVATION: 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.}, keywords = {NGS}, issn = {1367-4811}, doi = {10.1093/bioinformatics/bts503}, url = {http://bioinformatics.oxfordjournals.org/content/28/20/2678.long}, author = {Garc{\'\i}a-Alcalde, Fernando and Okonechnikov, Konstantin and Carbonell, Jos{\'e} and Cruz, Luis M and G{\"o}tz, Stefan and Sonia Tarazona and Joaqu{\'\i}n Dopazo and Meyer, Thomas F and Ana Conesa} } @article {949, title = {Transcriptome profiling of the intoxication response of Tenebrio molitor larvae to Bacillus thuringiensis Cry3Aa protoxin.}, journal = {PloS one}, volume = {7}, year = {2012}, month = {2012}, pages = {e34624}, abstract = {Bacillus 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.}, keywords = {Administration, Animals, Bacterial Proteins, Base Sequence, Biosynthetic Pathways, Complementary, DNA, Endotoxins, Energy Metabolism, Gene Expression Profiling, Hemolysin Proteins, Larva, Microarray Analysis, Molecular Sequence Data, Oral, Sequence Analysis, Tenebrio, Time Factors, Transcriptome}, issn = {1932-6203}, doi = {10.1371/journal.pone.0034624}, author = {Oppert, Brenda and Dowd, Scot E and Bouffard, Pascal and Li, Lewyn and Ana Conesa and Lorenzen, Marc{\'e} D and Toutges, Michelle and Marshall, Jeremy and Huestis, Diana L and Fabrick, Jeff and Oppert, Cris and Jurat-Fuentes, Juan Luis} } @article {21266330, title = {Differential Lipid Partitioning Between Adipocytes and Tissue Macrophages Modulates Macrophage Lipotoxicity and M2/M1 Polarization in Obese Mice.}, journal = {Diabetes}, volume = {60}, number = {3}, year = {2011}, month = {2011 Jan 24}, pages = {797-809}, abstract = {

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.

}, author = {Prieur, Xavier and Mok, Crystal Y L and Velagapudi, Vidya R and N{\'u}{\~n}ez, Vanessa and Fuentes, Luc{\'\i}a and Montaner, David and Ishikawa, Ko and Camacho, Alberto and Barbarroja, Nuria and O{\textquoteright}Rahilly, Stephen and Sethi, Jaswinder and Dopazo, Joaquin and Oresic, Matej and Ricote, Mercedes and Vidal-Puig, Antonio} } @article {21531897, title = {Early transcriptional defence responses in Arabidopsis cell suspension culture under high light conditions.}, journal = {Plant physiology}, volume = {156}, number = {3}, year = {2011}, month = {2011 Apr 29}, pages = {1439-56}, abstract = {

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{\textquoteright},7{\textquoteright}-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.

}, url = {http://www.plantphysiol.org/content/early/2011/04/29/pp.111.177766.short?keytype=ref\&ijkey=ph5B6J2khjnqwzN}, author = {Gonz{\'a}lez-P{\'e}rez, Sergio and Guti{\'e}rrez, Jorge and Garcia-Garcia, Francisco and Osuna, Daniel and Joaqu{\'\i}n Dopazo and Lorenzo, Oscar and Revuelta, Jos{\'e} L and Arellano, Juan B} } @article {532, title = {Early transcriptional defense responses in Arabidopsis cell suspension culture under high-light conditions.}, journal = {Plant Physiol}, volume = {156}, year = {2011}, month = {2011 Jul}, pages = {1439-56}, abstract = {

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{\textquoteright},7{\textquoteright}-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.

}, keywords = {Arabidopsis, Blotting, Western, Cell Culture Techniques, Cells, Cultured, Chloroplasts, Cluster Analysis, Gene Expression Profiling, Gene Expression Regulation, Plant, Hydrogen Peroxide, Light, mutation, Oligonucleotide Array Sequence Analysis, Photosystem II Protein Complex, Plant Growth Regulators, Reproducibility of Results, Reverse Transcriptase Polymerase Chain Reaction, RNA, Messenger, Signal Transduction, Stress, Physiological, Transcription, Genetic}, issn = {1532-2548}, doi = {10.1104/pp.111.177766}, author = {Gonz{\'a}lez-P{\'e}rez, Sergio and Guti{\'e}rrez, Jorge and Garcia-Garcia, Francisco and Osuna, Daniel and Dopazo, Joaquin and Lorenzo, Oscar and Revuelta, Jos{\'e} L and Arellano, Juan B} } @article {20028698, title = {Changes in the pattern of DNA methylation associate with twin discordance in systemic lupus erythematosus.}, journal = {Genome research}, volume = {20}, year = {2010}, month = {2010 Feb}, pages = {170-9}, abstract = {

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.

}, author = {Javierre, Biola M and Fernandez, Agustin F and Richter, Julia and Fatima Al-Shahrour and Martin-Subero, J Ignacio and Rodriguez-Ubreva, Javier and Berdasco, Maria and Fraga, Mario F and O{\textquoteright}Hanlon, Terrance P and Rider, Lisa G and Jacinto, Filipe V and Lopez-Longo, F Javier and Dopazo, Joaquin and Forn, Marta and Peinado, Miguel A and Carre{\~n}o, Luis and Sawalha, Amr H and Harley, John B and Siebert, Reiner and Esteller, Manel and Miller, Frederick W and Ballestar, Esteban} } @article {572, title = {Hypoxia promotes efficient differentiation of human embryonic stem cells to functional endothelium.}, journal = {Stem Cells}, volume = {28}, year = {2010}, month = {2010 Mar 31}, pages = {407-18}, abstract = {

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.

}, keywords = {Angiopoietin-1, Animals, biomarkers, Cell Culture Techniques, Cell Differentiation, Cell Hypoxia, Cell Transplantation, Cells, Cultured, Down-Regulation, Embryonic Stem Cells, Endothelial Cells, Gene Expression Profiling, Gene Expression Regulation, Humans, Male, Myocardial Infarction, Neovascularization, Physiologic, Oxygen, Pluripotent Stem Cells, Rats, Rats, Nude, Vascular Endothelial Growth Factor A}, issn = {1549-4918}, doi = {10.1002/stem.295}, author = {Prado-Lopez, Sonia and Conesa, Ana and Armi{\~n}{\'a}n, Ana and Mart{\'\i}nez-Losa, Magdalena and Escobedo-Lucea, Carmen and Gandia, Carolina and Tarazona, Sonia and Melguizo, Dario and Blesa, David and Montaner, David and Sanz-Gonz{\'a}lez, Silvia and Sep{\'u}lveda, Pilar and G{\"o}tz, Stefan and O{\textquoteright}Connor, Jos{\'e} Enrique and Moreno, Ruben and Dopazo, Joaquin and Burks, Deborah J and Stojkovic, Miodrag} } @article {20676074, title = {The MicroArray Quality Control (MAQC)-II study of common practices for the development and validation of microarray-based predictive models.}, journal = {Nature biotechnology}, volume = {28}, year = {2010}, month = {2010 Aug}, pages = {827-38}, abstract = {

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.

}, url = {http://www.nature.com/nbt/journal/v28/n8/full/nbt.1665.html}, author = {Shi, Leming and Campbell, Gregory and Jones, Wendell D and Campagne, Fabien and Wen, Zhining and Walker, Stephen J and Su, Zhenqiang and Chu, Tzu-Ming and Goodsaid, Federico M and Pusztai, Lajos and Shaughnessy, John D and Oberthuer, Andr{\'e} and Thomas, Russell S and Paules, Richard S and Fielden, Mark and Barlogie, Bart and Chen, Weijie and Du, Pan and Fischer, Matthias and Furlanello, Cesare and Gallas, Brandon D and Ge, Xijin and Megherbi, Dalila B and Symmans, W Fraser and Wang, May D and Zhang, John and Bitter, Hans and Brors, Benedikt and Bushel, Pierre R and Bylesjo, Max and Chen, Minjun and Cheng, Jie and Cheng, Jing and Chou, Jeff and Davison, Timothy S and Delorenzi, Mauro and Deng, Youping and Devanarayan, Viswanath and Dix, David J and Dopazo, Joaquin and Dorff, Kevin C and Elloumi, Fathi and Fan, Jianqing and Fan, Shicai and Fan, Xiaohui and Fang, Hong and Gonzaludo, Nina and Hess, Kenneth R and Hong, Huixiao and Huan, Jun and Irizarry, Rafael A and Judson, Richard and Juraeva, Dilafruz and Lababidi, Samir and Lambert, Christophe G and Li, Li and Li, Yanen and Li, Zhen and Lin, Simon M and Liu, Guozhen and Lobenhofer, Edward K and Luo, Jun and Luo, Wen and McCall, Matthew N and Nikolsky, Yuri and Pennello, Gene A and Perkins, Roger G and Philip, Reena and Popovici, Vlad and Price, Nathan D and Qian, Feng and Scherer, Andreas and Shi, Tieliu and Shi, Weiwei and Sung, Jaeyun and Thierry-Mieg, Danielle and Thierry-Mieg, Jean and Thodima, Venkata and Trygg, Johan and Vishnuvajjala, Lakshmi and Wang, Sue Jane and Wu, Jianping and Wu, Yichao and Xie, Qian and Yousef, Waleed A and Zhang, Liang and Zhang, Xuegong and Zhong, Sheng and Zhou, Yiming and Zhu, Sheng and Arasappan, Dhivya and Bao, Wenjun and Lucas, Anne Bergstrom and Berthold, Frank and Brennan, Richard J and Buness, Andreas and Catalano, Jennifer G and Chang, Chang and Chen, Rong and Cheng, Yiyu and Cui, Jian and Czika, Wendy and Demichelis, Francesca and Deng, Xutao and Dosymbekov, Damir and Eils, Roland and Feng, Yang and Fostel, Jennifer and Fulmer-Smentek, Stephanie and Fuscoe, James C and Gatto, Laurent and Ge, Weigong and Goldstein, Darlene R and Guo, Li and Halbert, Donald N and Han, Jing and Harris, Stephen C and Hatzis, Christos and Herman, Damir and Huang, Jianping and Jensen, Roderick V and Jiang, Rui and Johnson, Charles D and Jurman, Giuseppe and Kahlert, Yvonne and Khuder, Sadik A and Kohl, Matthias and Li, Jianying and Li, Li and Li, Menglong and Li, Quan-Zhen and Li, Shao and Li, Zhiguang and Liu, Jie and Liu, Ying and Liu, Zhichao and Meng, Lu and Madera, Manuel and Martinez-Murillo, Francisco and Medina, Ignacio and Meehan, Joseph and Miclaus, Kelci and Moffitt, Richard A and Montaner, David and Mukherjee, Piali and Mulligan, George J and Neville, Padraic and Nikolskaya, Tatiana and Ning, Baitang and Page, Grier P and Parker, Joel and Parry, R Mitchell and Peng, Xuejun and Peterson, Ron L and Phan, John H and Quanz, Brian and Ren, Yi and Riccadonna, Samantha and Roter, Alan H and Samuelson, Frank W and Schumacher, Martin M and Shambaugh, Joseph D and Shi, Qiang and Shippy, Richard and Si, Shengzhu and Smalter, Aaron and Sotiriou, Christos and Soukup, Mat and Staedtler, Frank and Steiner, Guido and Stokes, Todd H and Sun, Qinglan and Tan, Pei-Yi and Tang, Rong and Tezak, Zivana and Thorn, Brett and Tsyganova, Marina and Turpaz, Yaron and Vega, Silvia C and Visintainer, Roberto and von Frese, Juergen and Wang, Charles and Wang, Eric and Wang, Junwei and Wang, Wei and Westermann, Frank and Willey, James C and Woods, Matthew and Wu, Shujian and Xiao, Nianqing and Xu, Joshua and Xu, Lei and Yang, Lun and Zeng, Xiao and Zhang, Jialu and Zhang, Li and Zhang, Min and Zhao, Chen and Puri, Raj K and Scherf, Uwe and Tong, Weida and Wolfinger, Russell D} } @article {19381286, title = {A kernel for open source drug discovery in tropical diseases}, journal = {PLoS Negl Trop Dis}, volume = {3}, number = {4}, year = {2009}, note = {Orti, Leticia Carbajo, Rodrigo J Pieper, Ursula Eswar, Narayanan Maurer, Stephen M Rai, Arti K Taylor, Ginger Todd, Matthew H Pineda-Lucena, Antonio Sali, Andrej Marti-Renom, Marc A United States PLoS neglected tropical diseases PLoS Negl Trop Dis. 2009;3(4):e418. Epub 2009 Apr 21.}, pages = {e418}, abstract = {BACKGROUND: 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.}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=19381286}, author = {Orti, L. and Carbajo, R. J. and Pieper, U. and Eswar, N. and Maurer, S. M. and Rai, A. K. and Taylor, G. and Todd, M. H. and Pineda-Lucena, A. and Sali, A. and M. A. Marti-Renom} } @article {19352362, title = {A kernel for the Tropical Disease Initiative}, journal = {Nat Biotechnol}, volume = {27}, number = {4}, year = {2009}, note = {

Orti, Leticia Carbajo, Rodrigo J Pieper, Ursula Eswar, Narayanan Maurer, Stephen M Rai, Arti K Taylor, Ginger Todd, Matthew H Pineda-Lucena, Antonio Sali, Andrej Marti-Renom, Marc A P01 AI035707/AI/NIAID NIH HHS/United States P01 GM71790/GM/NIGMS NIH HHS/United States R01 GM54762/GM/NIGMS NIH HHS/United States U54 GM074945/GM/NIGMS NIH HHS/United States Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov{\textquoteright}t United States Nature biotechnology Nat Biotechnol. 2009 Apr;27(4):320-1.

}, pages = {320-1}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=19352362}, author = {Orti, L. and Carbajo, R. J. and Pieper, U. and Eswar, N. and Maurer, S. M. and Rai, A. K. and Taylor, G. and Todd, M. H. and Pineda-Lucena, A. and Sali, A. and M. A. Marti-Renom} } @article {19357100, title = {ModLink+: Improving fold recognition by using protein-protein interactions}, journal = {Bioinformatics}, year = {2009}, note = {

Journal article Bioinformatics (Oxford, England) Bioinformatics. 2009 Apr 8.

}, abstract = {

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.

}, keywords = {protein folding}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=19357100}, author = {Fornes, O. and Aragues, R. and Espadaler, J. and M. A. Marti-Renom and Sali, A. and Oliva, B.} } @article {595, title = {Interoperability with Moby 1.0--it{\textquoteright}s better than sharing your toothbrush!}, journal = {Brief Bioinform}, volume = {9}, year = {2008}, month = {2008 May}, pages = {220-31}, abstract = {

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/.

}, keywords = {Computational Biology, Database Management Systems, Databases, Factual, Information Storage and Retrieval, Internet, Programming Languages, Systems Integration}, issn = {1477-4054}, doi = {10.1093/bib/bbn003}, author = {Wilkinson, Mark D and Senger, Martin and Kawas, Edward and Bruskiewich, Richard and Gouzy, Jerome and Noirot, Celine and Bardou, Philippe and Ng, Ambrose and Haase, Dirk and Saiz, Enrique de Andres and Wang, Dennis and Gibbons, Frank and Gordon, Paul M K and Sensen, Christoph W and Carrasco, Jose Manuel Rodriguez and Fern{\'a}ndez, Jos{\'e} M and Shen, Lixin and Links, Matthew and Ng, Michael and Opushneva, Nina and Neerincx, Pieter B T and Leunissen, Jack A M and Ernst, Rebecca and Twigger, Simon and Usadel, Bjorn and Good, Benjamin and Wong, Yan and Stein, Lincoln and Crosby, William and Karlsson, Johan and Royo, Romina and P{\'a}rraga, Iv{\'a}n and Ram{\'\i}rez, Sergio and Gelpi, Josep Lluis and Trelles, Oswaldo and Pisano, David G and Jimenez, Natalia and Kerhornou, Arnaud and Rosset, Roman and Zamacola, Leire and T{\'a}rraga, Joaqu{\'\i}n and Huerta-Cepas, Jaime and Carazo, Jose Mar{\'\i}a and Dopazo, Joaquin and Guig{\'o}, Roderic and Navarro, Arcadi and Orozco, Modesto and Valencia, Alfonso and Claros, M Gonzalo and P{\'e}rez, Antonio J and Aldana, Jose and Rojano, M Mar and Fernandez-Santa Cruz, Raul and Navas, Ismael and Schiltz, Gary and Farmer, Andrew and Gessler, Damian and Schoof, Heiko and Groscurth, Andreas} } @article {18238804, title = {Interoperability with Moby 1.0{\textendash}it{\textquoteright}s better than sharing your toothbrush!}, journal = {Brief Bioinform}, volume = {9}, number = {3}, year = {2008}, note = {

BioMoby Consortium Wilkinson, Mark D Senger, Martin Kawas, Edward Bruskiewich, Richard Gouzy, Jerome Noirot, Celine Bardou, Philippe Ng, Ambrose Haase, Dirk Saiz, Enrique de Andres Wang, Dennis Gibbons, Frank Gordon, Paul M K Sensen, Christoph W Carrasco, Jose Manuel Rodriguez Fernandez, Jose M Shen, Lixin Links, Matthew Ng, Michael Opushneva, Nina Neerincx, Pieter B T Leunissen, Jack A M Ernst, Rebecca Twigger, Simon Usadel, Bjorn Good, Benjamin Wong, Yan Stein, Lincoln Crosby, William Karlsson, Johan Royo, Romina Parraga, Ivan Ramirez, Sergio Gelpi, Josep Lluis Trelles, Oswaldo Pisano, David G Jimenez, Natalia Kerhornou, Arnaud Rosset, Roman Zamacola, Leire Tarraga, Joaquin Huerta-Cepas, Jaime Carazo, Jose Maria Dopazo, Joaquin Guigo, Roderic Navarro, Arcadi Orozco, Modesto Valencia, Alfonso Claros, M Gonzalo Perez, Antonio J Aldana, Jose Rojano, M Mar Fernandez-Santa Cruz, Raul Navas, Ismael Schiltz, Gary Farmer, Andrew Gessler, Damian Schoof, Heiko Groscurth, Andreas Research Support, Non-U.S. Gov{\textquoteright}t Review England Briefings in bioinformatics Brief Bioinform. 2008 May;9(3):220-31. Epub 2008 Jan 31.

}, pages = {220-31}, abstract = {

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/.

}, keywords = {Computational Biology/*methods *Database Management Systems *Databases, Factual Information Storage and Retrieval/*methods *Internet *Programming Languages Systems Integration}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=18238804}, author = {Wilkinson, M. D. and Senger, M. and Kawas, E. and Bruskiewich, R. and Gouzy, J. and Noirot, C. and Bardou, P. and Ng, A. and Haase, D. and Saiz Ede, A. and Wang, D. and Gibbons, F. and Gordon, P. M. and Sensen, C. W. and Carrasco, J. M. and Fernandez, J. M. and Shen, L. and Links, M. and Ng, M. and Opushneva, N. and Neerincx, P. B. and Leunissen, J. A. and Ernst, R. and Twigger, S. and Usadel, B. and Good, B. and Wong, Y. and Stein, L. and Crosby, W. and Karlsson, J. and Royo, R. and Parraga, I. and Ramirez, S. and Gelpi, J. L. and Trelles, O. and Pisano, D. G. and Jimenez, N. and Kerhornou, A. and Rosset, R. and Zamacola, L. and Tarraga, J. and Huerta-Cepas, J. and Carazo, J. M. and Dopazo, J. and R. Guigo and Navarro, A. and Orozco, M. and Valencia, A. and Claros, M. G. and Perez, A. J. and Aldana, J. and Rojano, M. M. and Fernandez-Santa Cruz, R. and Navas, I. and Schiltz, G. and Farmer, A. and Gessler, D. and Schoof, H. and Groscurth, A.} } @article {18505562, title = {Prediction of enzyme function by combining sequence similarity and protein interactions}, journal = {BMC Bioinformatics}, volume = {9}, year = {2008}, note = {Espadaler, Jordi Eswar, Narayanan Querol, Enrique Aviles, Francesc X Sali, Andrej Marti-Renom, Marc A Oliva, Baldomero GM54762/GM/NIGMS NIH HHS/United States GM71790/GM/NIGMS NIH HHS/United States GM74929/GM/NIGMS NIH HHS/United States GM74945/GM/NIGMS NIH HHS/United States Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov{\textquoteright}t England BMC bioinformatics BMC Bioinformatics. 2008 May 27;9:249.}, pages = {249}, abstract = {BACKGROUND: 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.}, keywords = {Amino Acid *Software Structure-Activity Relationship Substrate Specificity/genetics, Amino Acid Sequence/physiology Databases, Automated Predictive Value of Tests Protein Interaction Mapping Proteins/analysis/metabolism Sequence Alignment Sequence Analysis, Protein *Sequence Homology, Protein Enzymes/analysis/*metabolism Fuzzy Logic Pattern Recognition}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=18505562}, author = {Espadaler, J. and Eswar, N. and Querol, E. and Aviles, F. X. and Sali, A. and M. A. Marti-Renom and Oliva, B.} } @article {18539377, title = {Transcriptome analysis provides new insights into liver changes induced in the rat upon dietary administration of the food additives butylated hydroxytoluene, curcumin, propyl gallate and thiabendazole}, journal = {Food Chem Toxicol}, volume = {46}, number = {8}, year = {2008}, note = {Stierum, Rob Conesa, Ana Heijne, Wilbert Ommen, Ben van Junker, Karin Scott, Mary P Price, Roger J Meredith, Clive Lake, Brian G Groten, John Research Support, Non-U.S. Gov{\textquoteright}t England Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association Food Chem Toxicol. 2008 Aug;46(8):2616-28. Epub 2008 Apr 25.}, pages = {2616-28}, abstract = {Transcriptomics 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.}, keywords = {Animals Aryl Hydrocarbon Hydroxylases/metabolism Body Weight/drug effects Butylated Hydroxytoluene/toxicity Curcumin/toxicity Cytochrome P-450 CYP1A2/metabolism Cytochrome P-450 CYP2B1/metabolism DNA, Complementary/biosynthesis/genetics Data Interpretation, Sprague-Dawley Reverse Transcriptase Polymerase Chain Reaction Steroid Hydroxylases/metabolism Thiabendazole/toxicity, Statistical *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/toxi}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=18539377}, author = {Stierum, R. and A. Conesa and Heijne, W. and Ommen, B. and Junker, K. and Scott, M. P. and Price, R. J. and Meredith, C. and Lake, B. G. and Groten, J.} } @article {17254327, title = {Analysis of 13000 unique Citrus clusters associated with fruit quality, production and salinity tolerance}, journal = {BMC Genomics}, volume = {8}, year = {2007}, note = {Terol, Javier Conesa, Ana Colmenero, Jose M Cercos, Manuel Tadeo, Francisco Agusti, Javier Alos, Enriqueta Andres, Fernando Soler, Guillermo Brumos, Javier Iglesias, Domingo J Gotz, Stefan Legaz, Francisco Argout, Xavier Courtois, Brigitte Ollitrault, Patrick Dossat, Carole Wincker, Patrick Morillon, Raphael Talon, Manuel Comparative Study Research Support, Non-U.S. Gov{\textquoteright}t England BMC genomics BMC Genomics. 2007 Jan 25;8:31.}, pages = {31}, abstract = {BACKGROUND: 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.}, keywords = {Acclimatization/*genetics Amino Acid Motifs Citrus/*genetics Cluster Analysis Expressed Sequence Tags Fruit/genetics Gene Duplication *Gene Expression Regulation, Plant Gene Library Genes, Plant Genomics Molecular Sequence Data Multigene Family Phylogeny *Salts/adverse effects}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=17254327}, author = {Terol, J. and A. Conesa and Colmenero, J. M. and Cercos, M. and Tadeo, F. and Agusti, J. and Alos, E. and Andres, F. and Soler, G. and Brumos, J. and Iglesias, D. J. and Gotz, S. and Legaz, F. and Argout, X. and Courtois, B. and Ollitrault, P. and Dossat, C. and Wincker, P. and Morillon, R. and Talon, M.} } @article {17941705, title = {Characterization of protein hubs by inferring interacting motifs from protein interactions}, journal = {PLoS Comput Biol}, volume = {3}, number = {9}, year = {2007}, note = {Aragues, Ramon Sali, Andrej Bonet, Jaume Marti-Renom, Marc A Oliva, Baldo PN2 EY016525,/EY/NEI NIH HHS/United States U54 RR022220/RR/NCRR NIH HHS/United States Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov{\textquoteright}t United States PLoS computational biology PLoS Comput Biol. 2007 Sep;3(9):1761-71. Epub 2007 Jul 30.}, pages = {1761-71}, abstract = {The 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.}, keywords = {Amino Acid Motifs Amino Acid Sequence Binding Sites Computer Simulation *Models, Chemical *Models, Molecular Molecular Sequence Data Protein Binding Protein Interaction Mapping/*methods Proteins/*chemistry Sequence Analysis, Protein/*methods}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=17941705}, author = {Aragues, R. and Sali, A. and Bonet, J. and M. A. Marti-Renom and Oliva, B.} } @article {16566817, title = {Exploring the reasons for the large density of triplex-forming oligonucleotide target sequences in the human regulatory regions}, journal = {BMC Genomics}, volume = {7}, year = {2006}, note = {Goni, Josep Ramon Vaquerizas, Juan Manuel Dopazo, Joaquin Orozco, Modesto Research Support, Non-U.S. Gov{\textquoteright}t England BMC genomics BMC Genomics. 2006 Mar 27;7:63.}, pages = {63}, abstract = {BACKGROUND: 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.}, keywords = {Animals Base Sequence Computational Biology DNA/chemistry/*genetics/*metabolism Genome, Genetic/genetics Regulatory Sequences, Human/genetics Humans Mice Nucleic Acid Conformation Nucleotides/genetics Oligonucleotides/chemistry/*genetics/*metabolism Promoter Regions, Nucleic Acid/*genetics Transcription Factors/metabolism}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=16566817}, author = {Goni, J. R. and Vaquerizas, J. M. and Dopazo, J. and Orozco, M.} } @article {15883372, title = {Detecting remotely related proteins by their interactions and sequence similarity}, journal = {Proc Natl Acad Sci U S A}, volume = {102}, number = {20}, year = {2005}, note = {Espadaler, Jordi Aragues, Ramon Eswar, Narayanan Marti-Renom, Marc A Querol, Enrique Aviles, Francesc X Sali, Andrej Oliva, Baldomero R01 GM54762/GM/NIGMS NIH HHS/United States Comparative Study Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov{\textquoteright}t Research Support, U.S. Gov{\textquoteright}t, P.H.S. United States Proceedings of the National Academy of Sciences of the United States of America Proc Natl Acad Sci U S A. 2005 May 17;102(20):7151-6. Epub 2005 May 9.}, pages = {7151-6}, abstract = {The 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.}, keywords = {Amino Acid, Computational Biology Databases, Molecular Protein Conformation Protein Folding Proteins/*genetics/*metabolism Proteomics/*methods *Sequence Homology, Protein *Evolution}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=15883372}, author = {Espadaler, J. and Aragues, R. and Eswar, N. and M. A. Marti-Renom and Querol, E. and Aviles, F. X. and Sali, A. and Oliva, B.} } @article {15770521, title = {Phenotypic characterization of BRCA1 and BRCA2 tumors based in a tissue microarray study with 37 immunohistochemical markers}, journal = {Breast Cancer Res Treat}, volume = {90}, number = {1}, year = {2005}, note = {Palacios, Jose Honrado, Emiliano Osorio, Ana Cazorla, Alicia Sarrio, David Barroso, Alicia Rodriguez, Sandra Cigudosa, Juan C Diez, Orland Alonso, Carmen Lerma, Enrique Dopazo, Joaquin Rivas, Carmen Benitez, Javier Research Support, Non-U.S. Gov{\textquoteright}t Netherlands Breast cancer research and treatment Breast Cancer Res Treat. 2005 Mar;90(1):5-14.}, pages = {5-14}, abstract = {Familial 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.}, keywords = {Adult Apoptosis Breast Neoplasms/*genetics/*pathology Cell Cycle Proteins Cluster Analysis Female *Genes, Biological/genetics/metabolism, BRCA1 *Genes, BRCA2 Humans Immunohistochemistry In Situ Hybridization, Fluorescence Phenotype Spain *Tissue Array Analysis *Tumor Markers}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=15770521}, author = {Palacios, J. and Honrado, E. and Osorio, A. and Cazorla, A. and Sarrio, D. and Barroso, A. and Rodriguez, S. and Cigudosa, J. C. and Diez, O. and Alonso, C. and Lerma, E. and Dopazo, J. and Rivas, C. and Benitez, J.} } @article {15709182, title = {A predictor based on the somatic genomic changes of the BRCA1/BRCA2 breast cancer tumors identifies the non-BRCA1/BRCA2 tumors with BRCA1 promoter hypermethylation}, journal = {Clin Cancer Res}, volume = {11}, number = {3}, year = {2005}, note = {Alvarez, Sara Diaz-Uriarte, Ramon Osorio, Ana Barroso, Alicia Melchor, Lorenzo Paz, Maria Fe Honrado, Emiliano Rodriguez, Raquel Urioste, Miguel Valle, Laura Diez, Orland Cigudosa, Juan Cruz Dopazo, Joaquin Esteller, Manel Benitez, Javier Comparative Study Research Support, Non-U.S. Gov{\textquoteright}t United States Clinical cancer research : an official journal of the American Association for Cancer Research Clin Cancer Res. 2005 Feb 1;11(3):1146-53.}, pages = {1146-53}, abstract = {The 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.}, keywords = {BRCA1 Protein/*genetics BRCA2 Protein/*genetics Breast Neoplasms/*genetics/pathology Chromosomes, Genetic/*genetics, Human, Human Humans Male Mutation Nucleic Acid Hybridization/methods Promoter Regions, Pair 12/genetics Chromosomes, Pair 15/genetics Chromosomes, Pair 18/genetics Chromosomes, Pair 2/genetics Chromosomes, Pair 8/genetics *DNA Methylation Female Genome}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=15709182}, author = {Alvarez, S. and Diaz-Uriarte, R. and Osorio, A. and Barroso, A. and Melchor, L. and Paz, M. F. and Honrado, E. and Rodriguez, R. and Urioste, M. and Valle, L. and Diez, O. and Cigudosa, J. C. and Dopazo, J. and Esteller, M. and Benitez, J.} } @article {15980522, title = {PupasView: a visual tool for selecting suitable SNPs, with putative pathological effect in genes, for genotyping purposes}, journal = {Nucleic Acids Res}, volume = {33}, number = {Web Server issue}, year = {2005}, note = {Conde, Lucia Vaquerizas, Juan M Ferrer-Costa, Carles de la Cruz, Xavier Orozco, Modesto Dopazo, Joaquin Research Support, Non-U.S. Gov{\textquoteright}t England Nucleic acids research Nucleic Acids Res. 2005 Jul 1;33(Web Server issue):W501-5.}, pages = {W501-5}, abstract = {We 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.}, keywords = {Computer Graphics Genes *Genetic Predisposition to Disease Genotype Internet Phenotype *Polymorphism, Single Nucleotide *Software User-Computer Interface}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=15980522}, author = {L. Conde and Vaquerizas, J. M. and Ferrer-Costa, C. and de la Cruz, X. and Orozco, M. and Dopazo, J.} } @article {12141992, title = {Bioinformatics methods for the analysis of expression arrays: data clustering and information extraction}, journal = {J Biotechnol}, volume = {98}, number = {2-3}, year = {2002}, note = {Tamames, Javier Clark, Dominic Herrero, Javier Dopazo, Joaquin Blaschke, Christian Fernandez, Jose M Oliveros, Juan C Valencia, Alfonso Review Netherlands Journal of biotechnology J Biotechnol. 2002 Sep 25;98(2-3):269-83.}, pages = {269-83}, abstract = {Expression 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.}, keywords = {Abstracting and Indexing as Topic/methods *Cluster Analysis *Database Management Systems Databases, Computer-Assisted/methods Information Storage and Retrieval/*methods Internet Medline National Library of Medicine (U.S.) Oligonucleotide Array Sequence Analysis/*methods United States, Genetic Gene Expression Gene Expression Profiling/*methods Image Processing}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=12141992}, author = {J. Tamames and Clark, D. and Herrero, J. and Dopazo, J. and Blaschke, C. and Fernandez, J. M. and Oliveros, J. C. and Valencia, A.} } @article {12414529, title = {Identification of genes involved in resistance to interferon-alpha in cutaneous T-cell lymphoma}, journal = {Am J Pathol}, volume = {161}, number = {5}, year = {2002}, note = {Tracey, Lorraine Villuendas, Raquel Ortiz, Pablo Dopazo, Ana Spiteri, Inmaculada Lombardia, Luis Rodriguez-Peralto, Jose L Fernandez-Herrera, Jesus Hernandez, Almudena Fraga, Javier Dominguez, Orlando Herrero, Javier Alonso, Miguel A Dopazo, Joaquin Piris, Miguel A Research Support, Non-U.S. Gov{\textquoteright}t United States The American journal of pathology Am J Pathol. 2002 Nov;161(5):1825-37.}, pages = {1825-37}, abstract = {Interferon-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.}, keywords = {Antineoplastic Agents/*pharmacology/therapeutic use Carrier Proteins/biosynthesis/genetics DNA-Binding Proteins/biosynthesis/genetics Drug Resistance, Biological Oligonucleotide Array Sequence Analysis RNA, Cultured, Cutaneous/diagnosis/drug therapy/*genetics/metabolism *Membrane Glycoproteins Models, Interleukin-1 Reproducibility of Results STAT1 Transcription Factor STAT3 Transcription Factor Trans-Activators/biosynthesis/genetics Tumor Cells, Neoplasm Gene Expression Profiling *Gene Expression Regulation, Neoplasm/biosynthesis *Receptors, Neoplastic Humans Interferon-alpha/*pharmacology/therapeutic use Kinetics Lymphoma, T-Cell}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=12414529}, author = {Tracey, L. and Villuendas, R. and Ortiz, P. and Dopazo, A. and Spiteri, I. and Lombardia, L. and Rodriguez-Peralto, J. L. and Fernandez-Herrera, J. and Hernandez, A. and Fraga, J. and Dominguez, O. and Herrero, J. and Alonso, M. A. and Dopazo, J. and Piris, M. A.} } @article {11394740, title = {Classification of protein disulphide-bridge topologies}, journal = {J Comput Aided Mol Des}, volume = {15}, number = {5}, year = {2001}, note = {Mas, J M Aloy, P Marti-Renom, M A Oliva, B de Llorens, R Aviles, F X Querol, E Comparative Study Research Support, Non-U.S. Gov{\textquoteright}t Netherlands Journal of computer-aided molecular design J Comput Aided Mol Des. 2001 May;15(5):477-87.}, pages = {477-87}, abstract = {The 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.}, keywords = {Algorithms Computer Simulation Databases as Topic Disulfides/*chemistry Models, Molecular Protein Structure, Secondary Protein Structure, Tertiary Proteins/*chemistry/*classification Software}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=11394740}, author = {Mas, J. M. and Aloy, P. and M. A. Marti-Renom and Oliva, B. and de Llorens, R. and Aviles, F. X. and Querol, E.} }