@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 {796, title = {Defective extracellular matrix remodeling in brown adipose tissue is associated with fibro-inflammation and reduced diet-induced thermogenesis.}, journal = {Cell Rep}, volume = {42}, year = {2023}, month = {2023 Jun 13}, pages = {112640}, abstract = {

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

}, issn = {2211-1247}, doi = {10.1016/j.celrep.2023.112640}, author = {Pellegrinelli, Vanessa and Figueroa-Ju{\'a}rez, Elizabeth and Samuelson, Isabella and U-Din, Mueez and Rodriguez-Fdez, Sonia and Virtue, Samuel and Leggat, Jennifer and Cubuk, Cankut and Peirce, Vivian J and Niemi, Tarja and Campbell, Mark and Rodriguez-Cuenca, Sergio and Dopazo, Joaquin and Carobbio, Stefania and Virtanen, Kirsi A and Vidal-Puig, Antonio} } @article {767, title = {Metabolic reprogramming by Acly inhibition using SB-204990 alters glucoregulation and modulates molecular mechanisms associated with aging.}, journal = {Commun Biol}, volume = {6}, year = {2023}, month = {2023 Mar 08}, pages = {250}, abstract = {

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

}, issn = {2399-3642}, doi = {10.1038/s42003-023-04625-4}, author = {Sola-Garc{\'\i}a, Alejandro and C{\'a}liz-Molina, Mar{\'\i}a {\'A}ngeles and Espadas, Isabel and Petr, Michael and Panadero-Mor{\'o}n, Concepci{\'o}n and Gonz{\'a}lez-Mor{\'a}n, Daniel and Mart{\'\i}n-V{\'a}zquez, Mar{\'\i}a Eugenia and Narbona-P{\'e}rez, {\'A}lvaro Jes{\'u}s and L{\'o}pez-Noriega, Livia and Mart{\'\i}nez-Corrales, Guillermo and L{\'o}pez-Fern{\'a}ndez-Sobrino, Ra{\'u}l and Carmona-Marin, Lina M and Mart{\'\i}nez-Force, Enrique and Yanes, Oscar and Vinaixa, Maria and L{\'o}pez-L{\'o}pez, Daniel and Reyes, Jos{\'e} Carlos and Dopazo, Joaquin and Mart{\'\i}n, Franz and Gauthier, Benoit R and Scheibye-Knudsen, Morten and Capilla-Gonz{\'a}lez, Vivian and Mart{\'\i}n-Montalvo, Alejandro} } @article {764, title = {Polystyrene nanoplastics affect transcriptomic and epigenomic signatures of human fibroblasts and derived induced pluripotent stem cells: Implications for human health.}, journal = {Environ Pollut}, year = {2023}, month = {2022 Dec 09}, pages = {120849}, abstract = {

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

}, issn = {1873-6424}, doi = {10.1016/j.envpol.2022.120849}, author = {Stojkovic, Miodrag and Ortu{\~n}o Guzm{\'a}n, Francisco Manuel and Han, Dongjun and Stojkovic, Petra and Dopazo, Joaquin and Stankovic, Konstantina M} } @article {774, title = {Rapid degeneration of iPSC-derived motor neurons lacking Gdap1 engages a mitochondrial-sustained innate immune response.}, journal = {Cell Death Discov}, volume = {9}, year = {2023}, month = {2023 Jul 01}, pages = {217}, abstract = {

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

}, issn = {2058-7716}, doi = {10.1038/s41420-023-01531-w}, author = {Le{\'o}n, Marian and Prieto, Javier and Molina-Navarro, Mar{\'\i}a Micaela and Garcia-Garcia, Francisco and Barneo-Mu{\~n}oz, Manuela and Ponsoda, Xavier and S{\'a}ez, Rosana and Palau, Francesc and Dopazo, Joaquin and Izpisua Belmonte, Juan Carlos and Torres, Josema} } @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 {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 {726, title = {A comprehensive database for integrated analysis of omics data in autoimmune diseases.}, journal = {BMC Bioinformatics}, volume = {22}, year = {2021}, month = {2021 Jun 24}, pages = {343}, abstract = {

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

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

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

}, keywords = {Autoimmune Diseases, Computational Biology, Databases, Factual, Humans}, issn = {1471-2105}, doi = {10.1186/s12859-021-04268-4}, author = {Martorell-Marug{\'a}n, Jordi and L{\'o}pez-Dom{\'\i}nguez, Ra{\'u}l and Garc{\'\i}a-Moreno, Adri{\'a}n and Toro-Dom{\'\i}nguez, Daniel and Villatoro-Garc{\'\i}a, Juan Antonio and Barturen, Guillermo and Mart{\'\i}n-G{\'o}mez, Adoraci{\'o}n and Troule, Kevin and G{\'o}mez-L{\'o}pez, Gonzalo and Al-Shahrour, F{\'a}tima and Gonz{\'a}lez-Rumayor, V{\'\i}ctor and Pe{\~n}a-Chilet, Maria and Dopazo, Joaquin and Saez-Rodriguez, Julio and Alarc{\'o}n-Riquelme, Marta E and Carmona-S{\'a}ez, Pedro} } @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 {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 {734, title = {Orchestrating and sharing large multimodal data for transparent and reproducible research.}, journal = {Nat Commun}, volume = {12}, year = {2021}, month = {2021 10 04}, pages = {5797}, abstract = {

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

}, issn = {2041-1723}, doi = {10.1038/s41467-021-25974-w}, author = {Mammoliti, Anthony and Smirnov, Petr and Nakano, Minoru and Safikhani, Zhaleh and Eeles, Christopher and Seo, Heewon and Nair, Sisira Kadambat and Mer, Arvind S and Smith, Ian and Ho, Chantal and Beri, Gangesh and Kusko, Rebecca and Lin, Eva and Yu, Yihong and Martin, Scott and Hafner, Marc and Haibe-Kains, Benjamin} } @article {723, title = {Phylogenetic Analysis of the 2020 West Nile Virus (WNV) Outbreak in Andalusia (Spain)}, journal = {Viruses}, volume = {13}, year = {2021}, month = {Jan-05-2021}, pages = {836}, doi = {10.3390/v13050836}, url = {https://www.mdpi.com/1999-4915/13/5/836 }, author = {Casimiro-Soriguer, Carlos S. and Perez-Florido, Javier and Fernandez-Rueda, Jose L. and Pedrosa-Corral, Irene and Guillot-Sulay, Vicente and Lorusso, Nicola and Martinez-Gonzalez, Luis Javier and Navarro-Mar{\'\i}, Jose M. and Dopazo, Joaquin and Sanbonmatsu-G{\'a}mez, Sara} } @article {732, title = {Presenilin-1 Mutations Are a Cause of Primary Lateral Sclerosis-Like Syndrome.}, journal = {Front Mol Neurosci}, volume = {14}, year = {2021}, month = {2021}, pages = {721047}, abstract = {

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

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

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

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

}, issn = {1662-5099}, doi = {10.3389/fnmol.2021.721047}, author = {V{\'a}zquez-Costa, Juan Francisco and Pay{\'a}-Montes, Mar{\'\i}a and Mart{\'\i}nez-Molina, Marina and Jaijo, Teresa and Szymanski, Jazek and Maz{\'o}n, Miguel and Sopena-Novales, Pablo and P{\'e}rez-Tur, Jordi and Sevilla, Teresa} } @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 {722, title = {Schuurs{\textendash}Hoeijmakers Syndrome (PACS1 Neurodevelopmental Disorder): Seven Novel Patients and a Review}, journal = {Genes}, volume = {12}, year = {2021}, month = {Jan-05-2021}, pages = {738}, doi = {10.3390/genes12050738}, url = {https://www.mdpi.com/2073-4425/12/5/738https://www.mdpi.com/2073-4425/12/5/738/pdf}, author = {Tenorio-Casta{\~n}o, Jair and Morte, Beatriz and Nevado, Juli{\'a}n and Mart{\'\i}nez-Glez, V{\'\i}ctor and Santos-Simarro, Fernando and Garc{\'\i}a-Mi{\~n}aur, Sixto and Palomares-Bralo, Mar{\'\i}a and Pacio-M{\'\i}guez, Marta and G{\'o}mez, Beatriz and Arias, Pedro and Alcochea, Alba and Carri{\'o}n, Juan and Arias, Patricia and Almoguera, Berta and L{\'o}pez-Grondona, Fermina and Lorda-Sanchez, Isabel and Gal{\'a}n-G{\'o}mez, Enrique and Valenzuela, Irene and M{\'e}ndez Perez, Mar{\'\i}a and Cusc{\'o}, Iv{\'o}n and Barros, Francisco and Pi{\'e}, Juan and Ramos, Sergio and Ramos, Feliciano and Kuechler, Alma and Tizzano, Eduardo and Ayuso, Carmen and Kaiser, Frank and P{\'e}rez-Jurado, Luis and Carracedo, {\'A}ngel and Lapunzina, Pablo} } @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 {611, title = {Association of a single nucleotide polymorphism in the ubxn6 gene with long-term non-progression phenotype in HIV-positive individuals.}, journal = {Clin Microbiol Infect}, volume = {26}, year = {2020}, month = {2020 Jan}, pages = {107-114}, abstract = {

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

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

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

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

}, keywords = {Adaptor Proteins, Vesicular Transport, Autophagy-Related Proteins, Caveolin 1, Cohort Studies, Dendritic Cells, Disease Progression, Gene Frequency, Gene Knockdown Techniques, Genetic Association Studies, HeLa Cells, HIV Infections, HIV Long-Term Survivors, HIV-1, Humans, Macrophages, Oligonucleotide Array Sequence Analysis, Phenotype, Polymorphism, Single Nucleotide, whole exome sequencing}, issn = {1469-0691}, doi = {10.1016/j.cmi.2019.05.015}, author = {D{\'\i}ez-Fuertes, F and De La Torre-Tarazona, H E and Calonge, E and Pernas, M and Bermejo, M and Garc{\'\i}a-P{\'e}rez, J and {\'A}lvarez, A and Capa, L and Garc{\'\i}a-Garc{\'\i}a, F and Saumoy, M and Riera, M and Boland-Auge, A and L{\'o}pez-Gal{\'\i}ndez, C and Lathrop, M and Dopazo, J and Sakuntabhai, A and Alcam{\'\i}, J} } @article {696, title = {Community Assessment of the Predictability of Cancer Protein and Phosphoprotein Levels from Genomics and Transcriptomics.}, journal = {Cell Syst}, volume = {11}, year = {2020}, month = {2020 08 26}, pages = {186-195.e9}, abstract = {

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

}, keywords = {Crowdsourcing, Female, Genomics, Humans, Machine Learning, Male, Neoplasms, Phosphoproteins, Proteins, Proteomics, Transcriptome}, issn = {2405-4720}, doi = {10.1016/j.cels.2020.06.013}, author = {Yang, Mi and Petralia, Francesca and Li, Zhi and Li, Hongyang and Ma, Weiping and Song, Xiaoyu and Kim, Sunkyu and Lee, Heewon and Yu, Han and Lee, Bora and Bae, Seohui and Heo, Eunji and Kaczmarczyk, Jan and St{\k e}pniak, Piotr and Warcho{\l}, Micha{\l} and Yu, Thomas and Calinawan, Anna P and Boutros, Paul C and Payne, Samuel H and Reva, Boris and Boja, Emily and Rodriguez, Henry and Stolovitzky, Gustavo and Guan, Yuanfang and Kang, Jaewoo and Wang, Pei and Feny{\"o}, David and Saez-Rodriguez, Julio} } @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 {729, title = {The ELIXIR Human Copy Number Variations Community: building bioinformatics infrastructure for research.}, journal = {F1000Res}, volume = {9}, year = {2020}, month = {2020}, chapter = {1229}, abstract = {

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

}, keywords = {Computational Biology, DNA Copy Number Variations, High-Throughput Nucleotide Sequencing, Humans}, issn = {2046-1402}, doi = {10.12688/f1000research.24887.1}, author = {Salgado, David and Armean, Irina M and Baudis, Michael and Beltran, Sergi and Capella-Gut{\'\i}errez, Salvador and Carvalho-Silva, Denise and Dominguez Del Angel, Victoria and Dopazo, Joaquin and Furlong, Laura I and Gao, Bo and Garcia, Leyla and Gerloff, Dietlind and Gut, Ivo and Gyenesei, Attila and Habermann, Nina and Hancock, John M and Hanauer, Marc and Hovig, Eivind and Johansson, Lennart F and Keane, Thomas and Korbel, Jan and Lauer, Katharina B and Laurie, Steve and Lesko{\v s}ek, Brane and Lloyd, David and Marqu{\'e}s-Bonet, Tom{\'a}s and Mei, Hailiang and Monostory, Katalin and Pi{\~n}ero, Janet and Poterlowicz, Krzysztof and Rath, Ana and Samarakoon, Pubudu and Sanz, Ferran and Saunders, Gary and Sie, Daoud and Swertz, Morris A and Tsukanov, Kirill and Valencia, Alfonso and Vidak, Marko and Yenyxe Gonz{\'a}lez, Cristina and Ylstra, Bauke and B{\'e}roud, Christophe} } @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 {707, title = {Nivolumab and sunitinib combination in advanced soft tissue sarcomas: a multicenter, single-arm, phase Ib/II trial.}, journal = {J Immunother Cancer}, volume = {8}, year = {2020}, month = {2020 11}, abstract = {

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

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

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

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

}, keywords = {Adult, Aged, Antineoplastic Agents, Immunological, Female, Humans, Male, Middle Aged, Nivolumab, Sarcoma, Sunitinib, Young Adult}, issn = {2051-1426}, doi = {10.1136/jitc-2020-001561}, author = {Martin-Broto, Javier and Hindi, Nadia and Grignani, Giovanni and Martinez-Trufero, Javier and Redondo, Andres and Valverde, Claudia and Stacchiotti, Silvia and Lopez-Pousa, Antonio and D{\textquoteright}Ambrosio, Lorenzo and Gutierrez, Antonio and Perez-Vega, Herminia and Encinas-Tobajas, Victor and de Alava, Enrique and Collini, Paola and Pe{\~n}a-Chilet, Maria and Dopazo, Joaquin and Carrasco-Garcia, Irene and Lopez-Alvarez, Maria and Moura, David S and Lopez-Martin, Jose A} } @article {665, title = {Optimised molecular genetic diagnostics of Fanconi anaemia by whole exome sequencing and functional studies.}, journal = {J Med Genet}, volume = {57}, year = {2020}, month = {2020 04}, pages = {258-268}, abstract = {

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

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

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

}, keywords = {Cell Line, DNA Copy Number Variations, DNA Repair, DNA-Binding Proteins, Fanconi Anemia, Fanconi Anemia Complementation Group A Protein, Female, Gene Knockout Techniques, Genetic Predisposition to Disease, Humans, Male, Mutation, Missense, Polymorphism, Single Nucleotide, whole exome sequencing}, issn = {1468-6244}, doi = {10.1136/jmedgenet-2019-106249}, author = {Bogliolo, Massimo and Pujol, Roser and Aza-Carmona, Miriam and Mu{\~n}oz-Subirana, N{\'u}ria and Rodriguez-Santiago, Benjamin and Casado, Jos{\'e} Antonio and Rio, Paula and Bauser, Christopher and Reina-Castill{\'o}n, Judith and Lopez-Sanchez, Marcos and Gonzalez-Quereda, Lidia and Gallano, Pia and Catal{\'a}, Albert and Ruiz-Llobet, Ana and Badell, Isabel and Diaz-Heredia, Cristina and Hladun, Raquel and Senent, Leonort and Argiles, Bienvenida and Bergua Burgues, Juan Miguel and Ba{\~n}ez, Fatima and Arrizabalaga, Beatriz and L{\'o}pez Almaraz, Ricardo and Lopez, Monica and Figuera, {\'A}ngela and Molin{\'e}s, Antonio and P{\'e}rez de Soto, Inmaculada and Hernando, In{\'e}s and Mu{\~n}oz, Juan Antonio and Del Rosario Marin, Maria and Balma{\~n}a, Judith and Stjepanovic, Neda and Carrasco, Estela and Cuesta, Isabel and Cosuelo, Jos{\'e} Miguel and Regueiro, Alexandra and Moraleda Jimenez, Jos{\'e} and Galera-Mi{\~n}arro, Ana Maria and Rosi{\~n}ol, Laura and Carri{\'o}, Anna and Bel{\'e}ndez-Bieler, Cristina and Escudero Soto, Antonio and Cela, Elena and de la Mata, Gregorio and Fern{\'a}ndez-Delgado, Rafael and Garcia-Pardos, Maria Carmen and S{\'a}ez-Villaverde, Raquel and Barraga{\~n}o, Marta and Portugal, Raquel and Lendinez, Francisco and Hernadez, Ines and Vagace, Jos{\'e} Manue and Tapia, Maria and Nieto, Jos{\'e} and Garcia, Marta and Gonzalez, Macarena and Vicho, Cristina and Galvez, Eva and Valiente, Alberto and Antelo, Maria Luisa and Ancliff, Phil and Garc{\'\i}a, Francisco and Dopazo, Joaquin and Sevilla, Julian and Paprotka, Tobias and P{\'e}rez-Jurado, Luis Alberto and Bueren, Juan and Surralles, Jordi} } @article {653, title = {Pazopanib for treatment of typical solitary fibrous tumours: a multicentre, single-arm, phase 2 trial.}, journal = {Lancet Oncol}, volume = {21}, year = {2020}, month = {2020 03}, pages = {456-466}, abstract = {

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

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

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

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

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

}, keywords = {Aged, Female, Follow-Up Studies, Humans, Indazoles, Male, Middle Aged, Neoplasm Metastasis, Prognosis, Prospective Studies, Protein Kinase Inhibitors, Pyrimidines, Response Evaluation Criteria in Solid Tumors, Solitary Fibrous Tumors, Sulfonamides, Survival Rate}, issn = {1474-5488}, doi = {10.1016/S1470-2045(19)30826-5}, author = {Martin-Broto, Javier and Cruz, Josefina and Penel, Nicolas and Le Cesne, Axel and Hindi, Nadia and Luna, Pablo and Moura, David S and Bernabeu, Daniel and de Alava, Enrique and Lopez-Guerrero, Jose Antonio and Dopazo, Joaquin and Pe{\~n}a-Chilet, Maria and Gutierrez, Antonio and Collini, Paola and Karanian, Marie and Redondo, Andres and Lopez-Pousa, Antonio and Grignani, Giovanni and Diaz-Martin, Juan and Marcilla, David and Fernandez-Serra, Antonio and Gonzalez-Aguilera, Cristina and Casali, Paolo G and Blay, Jean-Yves and Stacchiotti, Silvia} } @article {694, title = {Platform to study intracellular polystyrene nanoplastic pollution and clinical outcomes.}, journal = {Stem Cells}, volume = {38}, year = {2020}, month = {2020 10 01}, pages = {1321-1325}, abstract = {

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

}, keywords = {Environmental Pollution, Humans, Induced Pluripotent Stem Cells, Intracellular Space, Nanoparticles, Plastics, Polystyrenes, Transcriptome, Treatment Outcome}, issn = {1549-4918}, doi = {10.1002/stem.3244}, author = {Bojic, Sanja and Falco, Matias M and Stojkovic, Petra and Ljujic, Biljana and Gazdic Jankovic, Marina and Armstrong, Lyle and Markovic, Nebojsa and Dopazo, Joaquin and Lako, Majlinda and Bauer, Roman and Stojkovic, Miodrag} } @article {705, title = {SMN1 copy-number and sequence variant analysis from next-generation sequencing data.}, journal = {Hum Mutat}, volume = {41}, year = {2020}, month = {2020 12}, pages = {2073-2077}, abstract = {

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

}, keywords = {Base Sequence, DNA Copy Number Variations, High-Throughput Nucleotide Sequencing, Humans, Reproducibility of Results, Software, Survival of Motor Neuron 1 Protein}, issn = {1098-1004}, doi = {10.1002/humu.24120}, author = {L{\'o}pez-L{\'o}pez, Daniel and Loucera, Carlos and Carmona, Rosario and Aquino, Virginia and Salgado, Josefa and Pasalodos, Sara and Miranda, Mar{\'\i}a and Alonso, {\'A}ngel and Dopazo, Joaquin} } @article {612, title = {Community assessment to advance computational prediction of cancer drug combinations in a pharmacogenomic screen.}, journal = {Nat Commun}, volume = {10}, year = {2019}, month = {2019 06 17}, pages = {2674}, abstract = {

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

}, keywords = {ADAM17 Protein, Antineoplastic Combined Chemotherapy Protocols, Benchmarking, Biomarkers, Tumor, Cell Line, Tumor, Computational Biology, Datasets as Topic, Drug Antagonism, Drug Resistance, Neoplasm, Drug Synergism, Genomics, Humans, Molecular Targeted Therapy, mutation, Neoplasms, pharmacogenetics, Phosphatidylinositol 3-Kinases, Phosphoinositide-3 Kinase Inhibitors, Treatment Outcome}, issn = {2041-1723}, doi = {10.1038/s41467-019-09799-2}, author = {Menden, Michael P and Wang, Dennis and Mason, Mike J and Szalai, Bence and Bulusu, Krishna C and Guan, Yuanfang and Yu, Thomas and Kang, Jaewoo and Jeon, Minji and Wolfinger, Russ and Nguyen, Tin and Zaslavskiy, Mikhail and Jang, In Sock and Ghazoui, Zara and Ahsen, Mehmet Eren and Vogel, Robert and Neto, Elias Chaibub and Norman, Thea and Tang, Eric K Y and Garnett, Mathew J and Veroli, Giovanni Y Di and Fawell, Stephen and Stolovitzky, Gustavo and Guinney, Justin and Dry, Jonathan R and Saez-Rodriguez, Julio} } @article {422, title = {Differential metabolic activity and discovery of therapeutic targets using summarized metabolic pathway models.}, journal = {NPJ Syst Biol Appl}, volume = {5}, year = {2019}, month = {2019}, pages = {7}, abstract = {

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

}, keywords = {Computational Biology, Computer Simulation, Drug discovery, Gene Regulatory Networks, Humans, Internet, Metabolic Networks and Pathways, Models, Biological, Neoplasms, Phenotype, Software, Transcriptome}, issn = {2056-7189}, doi = {10.1038/s41540-019-0087-2}, author = {Cubuk, Cankut and Hidalgo, Marta R and Amadoz, Alicia and Rian, Kinza and Salavert, Francisco and Pujana, Miguel A and Mateo, Francesca and Herranz, Carmen and Carbonell-Caballero, Jos{\'e} and Dopazo, Joaquin} } @article {423, title = {Pazopanib for treatment of advanced malignant and dedifferentiated solitary fibrous tumour: a multicentre, single-arm, phase 2 trial.}, journal = {Lancet Oncol}, volume = {20}, year = {2019}, month = {2019 01}, pages = {134-144}, abstract = {

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

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

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

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

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

}, keywords = {Adult, Aged, Angiogenesis Inhibitors, Antineoplastic Agents, Female, Humans, Indazoles, Male, Middle Aged, Multivariate Analysis, Pyrimidines, Response Evaluation Criteria in Solid Tumors, Soft Tissue Neoplasms, Solitary Fibrous Tumors, Sulfonamides, Survival Analysis}, issn = {1474-5488}, doi = {10.1016/S1470-2045(18)30676-4}, author = {Martin-Broto, Javier and Stacchiotti, Silvia and Lopez-Pousa, Antonio and Redondo, Andres and Bernabeu, Daniel and de Alava, Enrique and Casali, Paolo G and Italiano, Antoine and Gutierrez, Antonio and Moura, David S and Pe{\~n}a-Chilet, Maria and Diaz-Martin, Juan and Biscuola, Michele and Taron, Miguel and Collini, Paola and Ranchere-Vince, Dominique and Garcia Del Muro, Xavier and Grignani, Giovanni and Dumont, Sarah and Martinez-Trufero, Javier and Palmerini, Emanuela and Hindi, Nadia and Sebio, Ana and Dopazo, Joaquin and Dei Tos, Angelo Paolo and LeCesne, Axel and Blay, Jean-Yves and Cruz, Josefina} } @article {428, title = {A crowdsourced analysis to identify ab initio molecular signatures predictive of susceptibility to viral infection}, journal = {Nature Communications}, volume = {9}, year = {2018}, month = {Jan-12-2018}, doi = {10.1038/s41467-018-06735-8}, url = {http://www.nature.com/articles/s41467-018-06735-8http://www.nature.com/articles/s41467-018-06735-8.pdfhttp://www.nature.com/articles/s41467-018-06735-8.pdfhttp://www.nature.com/articles/s41467-018-06735-8}, author = {Fourati, Slim and Talla, Aarthi and Mahmoudian, Mehrad and Burkhart, Joshua G. and Kl{\'e}n, Riku and Henao, Ricardo and Yu, Thomas and Ayd{\i}n, Zafer and Yeung, Ka Yee and Ahsen, Mehmet Eren and Almugbel, Reem and Jahandideh, Samad and Liang, Xiao and Nordling, Torbj{\"o}rn E. M. and Shiga, Motoki and Stanescu, Ana and Vogel, Robert and Pandey, Gaurav and Chiu, Christopher and McClain, Micah T. and Woods, Christopher W. and Ginsburg, Geoffrey S. and Elo, Laura L. and Tsalik, Ephraim L. and Mangravite, Lara M. and Sieberts, Solveig K.} } @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 {410, title = {LRH-1 agonism favours an immune-islet dialogue which protects against diabetes mellitus.}, journal = {Nat Commun}, volume = {9}, year = {2018}, month = {2018 04 16}, pages = {1488}, abstract = {

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

}, keywords = {Animals, Apoptosis, Cell Communication, Cell Survival, Diabetes Mellitus, Experimental, Diabetes Mellitus, Type 2, Female, Gene Expression Regulation, Humans, Hypoglycemic Agents, Immunity, Innate, insulin, Insulin-Secreting Cells, Islets of Langerhans, Islets of Langerhans Transplantation, Macrophages, Male, Mice, Mice, Inbred C57BL, Phenalenes, Receptors, Cytoplasmic and Nuclear, Streptozocin, T-Lymphocytes, Regulatory, Transplantation, Heterologous}, issn = {2041-1723}, doi = {10.1038/s41467-018-03943-0}, author = {Cobo-Vuilleumier, Nadia and Lorenzo, Petra I and Rodr{\'\i}guez, Noelia Garc{\'\i}a and Herrera G{\'o}mez, Irene de Gracia and Fuente-Martin, Esther and L{\'o}pez-Noriega, Livia and Mellado-Gil, Jos{\'e} Manuel and Romero-Zerbo, Silvana-Yanina and Baqui{\'e}, Mathurin and Lachaud, Christian Claude and Stifter, Katja and Perdomo, German and Bugliani, Marco and De Tata, Vincenzo and Bosco, Domenico and Parnaud, Geraldine and Pozo, David and Hmadcha, Abdelkrim and Florido, Javier P and Toscano, Miguel G and de Haan, Peter and Schoonjans, Kristina and S{\'a}nchez Palaz{\'o}n, Luis and Marchetti, Piero and Schirmbeck, Reinhold and Mart{\'\i}n-Montalvo, Alejandro and Meda, Paolo and Soria, Bernat and Berm{\'u}dez-Silva, Francisco-Javier and St-Onge, Luc and Gauthier, Benoit R} } @article {407, title = {The modular network structure of the mutational landscape of Acute Myeloid Leukemia.}, journal = {PLoS One}, volume = {13}, year = {2018}, month = {2018}, pages = {e0202926}, abstract = {

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

}, keywords = {Adult, Aged, Cytodiagnosis, Female, Gene Regulatory Networks, Genetic Association Studies, Genetic Heterogeneity, Humans, Karyotype, Leukemia, Myeloid, Acute, Male, Middle Aged, mutation, Neoplasm Proteins, Nucleophosmin, Prognosis, whole exome sequencing}, issn = {1932-6203}, doi = {10.1371/journal.pone.0202926}, author = {Ib{\'a}{\~n}ez, Mariam and Carbonell-Caballero, Jos{\'e} and Such, Esperanza and Garc{\'\i}a-Alonso, Luz and Liquori, Alessandro and L{\'o}pez-Pav{\'\i}a, Mar{\'\i}a and LLop, Marta and Alonso, Carmen and Barrag{\'a}n, Eva and G{\'o}mez-Segu{\'\i}, In{\'e}s and Neef, Alexander and Herv{\'a}s, David and Montesinos, Pau and Sanz, Guillermo and Sanz, Miguel Angel and Dopazo, Joaquin and Cervera, Jos{\'e}} } @article {434, title = {High throughput estimation of functional cell activities reveals disease mechanisms and predicts relevant clinical outcomes.}, journal = {Oncotarget}, volume = {8}, year = {2017}, month = {2017 Jan 17}, pages = {5160-5178}, abstract = {

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

}, keywords = {Computational Biology, gene expression, Gene Regulatory Networks, Humans, mutation, Neoplasms, Precision Medicine, Sequence Analysis, RNA, Signal Transduction}, issn = {1949-2553}, doi = {10.18632/oncotarget.14107}, author = {Hidalgo, Marta R and Cubuk, Cankut and Amadoz, Alicia and Salavert, Francisco and Carbonell-Caballero, Jos{\'e} and Dopazo, Joaquin} } @article {433, title = {Mutations in TRAPPC11 are associated with a congenital disorder of glycosylation.}, journal = {Hum Mutat}, volume = {38}, year = {2017}, month = {2017 02}, pages = {148-151}, abstract = {

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

}, keywords = {Abnormalities, Multiple, Alleles, Amino Acid Substitution, Brain, Congenital Disorders of Glycosylation, Genotype, Humans, Magnetic Resonance Imaging, Male, mutation, Phenotype, Vesicular Transport Proteins, Whole Genome Sequencing}, issn = {1098-1004}, doi = {10.1002/humu.23145}, author = {Matalonga, Leslie and Bravo, Miren and Serra-Peinado, Carla and Garc{\'\i}a-Pelegr{\'\i}, Elisabeth and Ugarteburu, Olatz and Vidal, Silvia and Llambrich, Maria and Quintana, Ester and Fuster-Jorge, Pedro and Gonzalez-Bravo, Maria Nieves and Beltran, Sergi and Dopazo, Joaquin and Garcia-Garcia, Francisco and Foulquier, Fran{\c c}ois and Matthijs, Gert and Mills, Philippa and Ribes, Antonia and Egea, Gustavo and Briones, Paz and Tort, Frederic and Gir{\'o}s, Marisa} } @article {1231, title = {Whole exome sequencing coupled with unbiased functional analysis reveals new Hirschsprung disease genes.}, journal = {Genome biology}, volume = {18}, year = {2017}, month = {2017 Mar 08}, pages = {48}, abstract = {BACKGROUND: Hirschsprung disease (HSCR), which is congenital obstruction of the bowel, results from a failure of enteric nervous system (ENS) progenitors to migrate, proliferate, differentiate, or survive within the distal intestine. Previous studies that have searched for genes underlying HSCR have focused on ENS-related pathways and genes not fitting the current knowledge have thus often been ignored. We identify and validate novel HSCR genes using whole exome sequencing (WES), burden tests, in silico prediction, unbiased in vivo analyses of the mutated genes in zebrafish, and expression analyses in zebrafish, mouse, and human. RESULTS: We performed de novo mutation (DNM) screening on 24 HSCR trios. We identify 28 DNMs in 21 different genes. Eight of the DNMs we identified occur in RET, the main HSCR gene, and the remaining 20 DNMs reside in genes not reported in the ENS. Knockdown of all 12 genes with missense or loss-of-function DNMs showed that the orthologs of four genes (DENND3, NCLN, NUP98, and TBATA) are indispensable for ENS development in zebrafish, and these results were confirmed by CRISPR knockout. These genes are also expressed in human and mouse gut and/or ENS progenitors. Importantly, the encoded proteins are linked to neuronal processes shared by the central nervous system and the ENS. CONCLUSIONS: Our data open new fields of investigation into HSCR pathology and provide novel insights into the development of the ENS. Moreover, the study demonstrates that functional analyses of genes carrying DNMs are warranted to delineate the full genetic architecture of rare complex diseases.}, keywords = {Hirschprung, Rare Disease, WES}, issn = {1474-760X}, doi = {10.1186/s13059-017-1174-6}, url = {http://genomebiology.biomedcentral.com/articles/10.1186/s13059-017-1174-6}, author = {Gui, Hongsheng and Schriemer, Duco and Cheng, William W and Chauhan, Rajendra K and Anti{\v n}olo, Guillermo and Berrios, Courtney and Bleda, Marta and Brooks, Alice S and Brouwer, Rutger W W and Burns, Alan J and Cherny, Stacey S and Dopazo, Joaquin and Eggen, Bart J L and Griseri, Paola and Jalloh, Binta and Le, Thuy-Linh and Lui, Vincent C H and Luz{\'o}n-Toro, Berta and Matera, Ivana and Ngan, Elly S W and Pelet, Anna and Ruiz-Ferrer, Macarena and Sham, Pak C and Shepherd, Iain T and So, Man-Ting and Sribudiani, Yunia and Tang, Clara S M and van den Hout, Mirjam C G N and van der Linde, Herma C and van Ham, Tjakko J and van IJcken, Wilfred F J and Verheij, Joke B G M and Amiel, Jeanne and Borrego, Salud and Ceccherini, Isabella and Chakravarti, Aravinda and Lyonnet, Stanislas and Tam, Paul K H and Garcia-Barcel{\'o}, Maria-Merc{\`e} and Hofstra, Robert Mw} } @article {431, title = {Whole exome sequencing coupled with unbiased functional analysis reveals new Hirschsprung disease genes}, journal = {Genome Biology}, volume = {18}, year = {2017}, month = {Jan-12-2017}, doi = {10.1186/s13059-017-1174-6}, url = {http://genomebiology.biomedcentral.com/articles/10.1186/s13059-017-1174-6http://link.springer.com/content/pdf/10.1186/s13059-017-1174-6.pdf}, author = {Gui, Hongsheng and Schriemer, Duco and Cheng, William W. and Chauhan, Rajendra K. and Anti{\v n}olo, Guillermo and Berrios, Courtney and Bleda, Marta and Brooks, Alice S. and Brouwer, Rutger W. W. and Burns, Alan J. and Cherny, Stacey S. and Dopazo, Joaquin and Eggen, Bart J. L. and Griseri, Paola and Jalloh, Binta and Le, Thuy-Linh and Lui, Vincent C. H. and Luz{\'o}n-Toro, Berta and Matera, Ivana and Ngan, Elly S. W. and Pelet, Anna and Ruiz-Ferrer, Macarena and Sham, Pak C. and Shepherd, Iain T. and So, Man-Ting and Sribudiani, Yunia and Tang, Clara S. M. and van den Hout, Mirjam C. G. N. and van der Linde, Herma C. and van Ham, Tjakko J. and van IJcken, Wilfred F. J. and Verheij, Joke B. G. M. and Amiel, Jeanne and Borrego, Salud and Ceccherini, Isabella and Chakravarti, Aravinda and Lyonnet, Stanislas and Tam, Paul K. H. and Garcia-Barcel{\'o}, Maria-Merc{\`e} and Hofstra, Robert M. W.} } @article {1184, title = {267 Spanish exomes reveal population-specific differences in disease-related genetic variation.}, journal = {Molecular biology and evolution}, year = {2016}, month = {2016 Jan 13}, abstract = {Recent results from large-scale genomic projects suggest that allele frequencies, which are highly relevant for medical purposes, differ considerably across different populations. The need for a detailed catalogue of local variability motivated the whole exome sequencing of 267 unrelated individuals, representative of the healthy Spanish population. Like in other studies, a considerable number of rare variants were found (almost one third of the described variants). There were also relevant differences in allelic frequencies in polymorphic variants, including about 10,000 polymorphisms private to the Spanish population. The allelic frequencies of variants conferring susceptibility to complex diseases (including cancer, schizophrenia, Alzheimer disease, type 2 diabetes and other pathologies) were overall similar to those of other populations. However, the trend is the opposite for variants linked to Mendelian and rare diseases (including several retinal degenerative dystrophies and cardiomyopathies) that show marked frequency differences between populations. Interestingly, a correspondence between differences in allelic frequencies and disease prevalence was found, highlighting the relevance of frequency differences in disease risk. These differences are also observed in variants that disrupt known drug binding sites, suggesting an important role for local variability in population-specific drug resistances or adverse effects. We have made the Spanish population variant server web page that contains population frequency information for the complete list of 170,888 variant positions we found publicly available (http://spv.babelomics.org/), We show that it if fundamental to determine population-specific variant frequencies in order to distinguish real disease associations from population-specific polymorphisms.}, keywords = {disease, NGS, polymorphisms, Population genomics, prioritization, SNP}, issn = {1537-1719}, doi = {10.1093/molbev/msw005}, url = {https://mbe.oxfordjournals.org/content/early/2016/02/17/molbev.msw005.full}, author = {Joaqu{\'\i}n Dopazo and Amadoz, Alicia and Bleda, Marta and Garc{\'\i}a-Alonso, Luz and Alem{\'a}n, Alejandro and Garcia-Garcia, Francisco and Rodriguez, Juan A and Daub, Josephine T and Muntan{\'e}, Gerard and Antonio Rueda and Vela-Boza, Alicia and L{\'o}pez-Domingo, Francisco J and Florido, Javier P and Arce, Pablo and Ruiz-Ferrer, Macarena and M{\'e}ndez-Vidal, Cristina and Arnold, Todd E and Spleiss, Olivia and Alvarez-Tejado, Miguel and Navarro, Arcadi and Bhattacharya, Shomi S and Borrego, Salud and Santoyo-L{\'o}pez, Javier and Anti{\v n}olo, Guillermo} } @article {1203, title = {Actionable pathways: interactive discovery of therapeutic targets using signaling pathway models.}, journal = {Nucleic acids research}, year = {2016}, month = {2016 May 2}, abstract = {The discovery of actionable targets is crucial for targeted therapies and is also a constituent part of the drug discovery process. The success of an intervention over a target depends critically on its contribution, within the complex network of gene interactions, to the cellular processes responsible for disease progression or therapeutic response. Here we present PathAct, a web server that predicts the effect that interventions over genes (inhibitions or activations that simulate knock-outs, drug treatments or over-expressions) can have over signal transmission within signaling pathways and, ultimately, over the cell functionalities triggered by them. PathAct implements an advanced graphical interface that provides a unique interactive working environment in which the suitability of potentially actionable genes, that could eventually become drug targets for personalized or individualized therapies, can be easily tested. The PathAct tool can be found at: http://pathact.babelomics.org.}, keywords = {actionable genes, Disease mechanism, drug action mechanism, Drug discovery, pathway analysis, personalized medicine, signalling, therapeutic targets}, issn = {1362-4962}, doi = {10.1093/nar/gkw369}, url = {http://nar.oxfordjournals.org/content/early/2016/05/02/nar.gkw369.full}, author = {Salavert, Francisco and Hidago, Marta R and Amadoz, Alicia and Cubuk, Cankut and Medina, Ignacio and Crespo, Daniel and Carbonell-Caballero, Jos{\'e} and Joaqu{\'\i}n Dopazo} } @article {1182, title = {Assessment of Targeted Next-Generation Sequencing as a Tool for the Diagnosis of Charcot-Marie-Tooth Disease and Hereditary Motor Neuropathy.}, journal = {The Journal of molecular diagnostics : JMD}, year = {2016}, month = {2016 Jan 2}, abstract = {Charcot-Marie-Tooth disease is characterized by broad genetic heterogeneity with >50 known disease-associated genes. Mutations in some of these genes can cause a pure motor form of hereditary motor neuropathy, the genetics of which are poorly characterized. We designed a panel comprising 56 genes associated with Charcot-Marie-Tooth disease/hereditary motor neuropathy. We validated this diagnostic tool by first testing 11 patients with pathological mutations. A cohort of 33 affected subjects was selected for this study. The DNAJB2 c.352+1G>A mutation was detected in two cases; novel changes and/or variants with low frequency (<1\%) were found in 12 cases. There were no candidate variants in 18 cases, and amplification failed for one sample. The DNAJB2 c.352+1G>A mutation was also detected in three additional families. On haplotype analysis, all of the patients from these five families shared the same haplotype; therefore, the DNAJB2 c.352+1G>A mutation may be a founder event. Our gene panel allowed us to perform a very rapid and cost-effective screening of genes involved in Charcot-Marie-Tooth disease/hereditary motor neuropathy. Our diagnostic strategy was robust in terms of both coverage and read depth for all of the genes and patient samples. These findings demonstrate the difficulty in achieving a definitive molecular diagnosis because of the complexity of interpreting new variants and the genetic heterogeneity that is associated with these neuropathies.}, keywords = {Charcot-Marie-Tooth, CMT, Diagnostic, NGS, Panels, rare diseases, Targeted resequencing}, issn = {1943-7811}, doi = {10.1016/j.jmoldx.2015.10.005}, url = {http://www.sciencedirect.com/science/article/pii/S1525157815002615}, author = {Lupo, Vincenzo and Garcia-Garcia, Francisco and Sancho, Paula and Tello, Cristina and Garc{\'\i}a-Romero, Mar and Villarreal, Liliana and Alberti, Antonia and Sivera, Rafael and Joaqu{\'\i}n Dopazo and Pascual-Pascual, Samuel I and M{\'a}rquez-Infante, Celedonio and Casasnovas, Carlos and Sevilla, Teresa and Espin{\'o}s, Carmen} } @article {1198, title = {Chronic subordination stress selectively downregulates the insulin signaling pathway in liver and skeletal muscle but not in adipose tissue of male mice.}, journal = {Stress (Amsterdam, Netherlands)}, year = {2016}, month = {2016 Mar 7}, pages = {1-11}, abstract = {Chronic stress has been associated with obesity, glucose intolerance, and insulin resistance. We developed a model of chronic psychosocial stress (CPS) in which subordinate mice are vulnerable to obesity and the metabolic-like syndrome while dominant mice exhibit a healthy metabolic phenotype. Here we tested the hypothesis that the metabolic difference between subordinate and dominant mice is associated with changes in functional pathways relevant for insulin sensitivity, glucose and lipid homeostasis. Male mice were exposed to CPS for four weeks and fed either a standard diet or a high-fat diet (HFD). We first measured, by real-time PCR candidate genes, in the liver, skeletal muscle, and the perigonadal white adipose tissue (pWAT). Subsequently, we used a probabilistic analysis approach to analyze different ways in which signals can be transmitted across the pathways in each tissue. Results showed that subordinate mice displayed a drastic downregulation of the insulin pathway in liver and muscle, indicative of insulin resistance, already on standard diet. Conversely, pWAT showed molecular changes suggestive of facilitated fat deposition in an otherwise insulin-sensitive tissue. The molecular changes in subordinate mice fed a standard diet were greater compared to HFD-fed controls. Finally, dominant mice maintained a substantially normal metabolic and molecular phenotype even when fed a HFD. Overall, our data demonstrate that subordination stress is a potent stimulus for the downregulation of the insulin signaling pathway in liver and muscle and a major risk factor for the development of obesity, insulin resistance, and type 2 diabetes mellitus.}, keywords = {Adipose tissue, insulin, IRS1, IRS2, metabolic syndrome, obesity, pathway analysis}, issn = {1607-8888}, doi = {10.3109/10253890.2016.1151491}, url = {http://www.tandfonline.com/doi/abs/10.3109/10253890.2016.1151491?journalCode=ists20}, author = {Sanghez, Valentina and Cubuk, Cankut and Sebasti{\'a}n-Leon, Patricia and Carobbio, Stefania and Dopazo, Joaquin and Vidal-Puig, Antonio and Bartolomucci, Alessandro} } @article {436, title = {Dysfunctional mitochondrial fission impairs cell reprogramming.}, journal = {Cell Cycle}, volume = {15}, year = {2016}, month = {2016 Dec}, pages = {3240-3250}, abstract = {

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

}, keywords = {Animals, Cell Cycle Checkpoints, Cellular Reprogramming, DNA Damage, G2 Phase, Gene Knockdown Techniques, Mice, Mitochondrial Dynamics, Mitosis, Nerve Tissue Proteins, Pluripotent Stem Cells, Transcription Factors}, issn = {1551-4005}, doi = {10.1080/15384101.2016.1241930}, author = {Prieto, Javier and Le{\'o}n, Marian and Ponsoda, Xavier and Garcia-Garcia, Francisco and Bort, Roque and Serna, Eva and Barneo-Mu{\~n}oz, Manuela and Palau, Francesc and Dopazo, Joaquin and L{\'o}pez-Garc{\'\i}a, Carlos and Torres, Josema} } @article {1211, title = {Extension of human lncRNA transcripts by RACE coupled with long-read high-throughput sequencing (RACE-Seq).}, journal = {Nature communications}, volume = {7}, year = {2016}, month = {2016}, pages = {12339}, abstract = {Long non-coding RNAs (lncRNAs) constitute a large, yet mostly uncharacterized fraction of the mammalian transcriptome. Such characterization requires a comprehensive, high-quality annotation of their gene structure and boundaries, which is currently lacking. Here we describe RACE-Seq, an experimental workflow designed to address this based on RACE (rapid amplification of cDNA ends) and long-read RNA sequencing. We apply RACE-Seq to 398 human lncRNA genes in seven tissues, leading to the discovery of 2,556 on-target, novel transcripts. About 60\% of the targeted loci are extended in either 5{\textquoteright} or 3{\textquoteright}, often reaching genomic hallmarks of gene boundaries. Analysis of the novel transcripts suggests that lncRNAs are as long, have as many exons and undergo as much alternative splicing as protein-coding genes, contrary to current assumptions. Overall, we show that RACE-Seq is an effective tool to annotate an organism{\textquoteright}s deep transcriptome, and compares favourably to other targeted sequencing techniques.}, issn = {2041-1723}, doi = {10.1038/ncomms12339}, url = {http://www.nature.com/articles/ncomms12339}, author = {Lagarde, Julien and Uszczynska-Ratajczak, Barbara and Santoyo-L{\'o}pez, Javier and Gonzalez, Jose Manuel and Tapanari, Electra and Mudge, Jonathan M and Steward, Charles A and Wilming, Laurens and Tanzer, Andrea and Howald, C{\'e}dric and Chrast, Jacqueline and Vela-Boza, Alicia and Antonio Rueda and L{\'o}pez-Domingo, Francisco J and Dopazo, Joaquin and Reymond, Alexandre and Guig{\'o}, Roderic and Harrow, Jennifer} } @article {559, title = {Extension of human lncRNA transcripts by RACE coupled with long-read high-throughput sequencing (RACE-Seq)}, journal = {Nature Communications}, volume = {7}, year = {2016}, month = {Jan-11-2016}, doi = {10.1038/ncomms12339}, url = {http://www.nature.com/articles/ncomms12339http://www.nature.com/articles/ncomms12339.pdfhttp://www.nature.com/articles/ncomms12339.pdfhttp://www.nature.com/articles/ncomms12339}, author = {Lagarde, Julien and Uszczynska-Ratajczak, Barbara and Santoyo-L{\'o}pez, Javier and Gonzalez, Jose Manuel and Tapanari, Electra and Mudge, Jonathan M. and Steward, Charles A. and Wilming, Laurens and Tanzer, Andrea and Howald, C{\'e}dric and Chrast, Jacqueline and Vela-Boza, Alicia and Rueda, Antonio and Lopez-Domingo, Francisco J. and Dopazo, Joaquin and Reymond, Alexandre and Guig{\'o}, Roderic and Harrow, Jennifer} } @article {441, title = {Highly sensitive and ultrafast read mapping for RNA-seq analysis.}, journal = {DNA Res}, volume = {23}, year = {2016}, month = {2016 Apr}, pages = {93-100}, abstract = {

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

}, keywords = {Genomics, High-Throughput Nucleotide Sequencing, Humans, Sensitivity and Specificity, Sequence Analysis, RNA, Transcriptome}, issn = {1756-1663}, doi = {10.1093/dnares/dsv039}, author = {Medina, I and T{\'a}rraga, J and Mart{\'\i}nez, H and Barrachina, S and Castillo, M I and Paschall, J and Salavert-Torres, J and Blanquer-Espert, I and Hern{\'a}ndez-Garc{\'\i}a, V and Quintana-Ort{\'\i}, E S and Dopazo, J} } @article {561, title = {Human DNA methylomes of neurodegenerative diseases show common epigenomic patterns.}, journal = {Transl Psychiatry}, volume = {6}, year = {2016}, month = {2016 Jan 19}, pages = {e718}, abstract = {

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

}, keywords = {Adult, Aged, Aged, 80 and over, DNA Methylation, Epigenomics, Female, Humans, Male, Middle Aged, neurodegenerative diseases, Prefrontal Cortex, Tissue Array Analysis}, issn = {2158-3188}, doi = {10.1038/tp.2015.214}, author = {Sanchez-Mut, J V and Heyn, H and Vidal, E and Moran, S and Sayols, S and Delgado-Morales, R and Schultz, M D and Ansoleaga, B and Garcia-Esparcia, P and Pons-Espinal, M and de Lagran, M M and Dopazo, J and Rabano, A and Avila, J and Dierssen, M and Lott, I and Ferrer, I and Ecker, J R and Esteller, M} } @article {437, title = {Identification of the Photoreceptor Transcriptional Co-Repressor SAMD11 as Novel Cause of Autosomal Recessive Retinitis Pigmentosa.}, journal = {Sci Rep}, volume = {6}, year = {2016}, month = {2016 10 13}, pages = {35370}, abstract = {

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

}, keywords = {Aged, Animals, Co-Repressor Proteins, Codon, Nonsense, Cohort Studies, Comparative Genomic Hybridization, Consanguinity, DNA Mutational Analysis, Exome, Eye Proteins, Female, Gene Expression Regulation, Genes, Recessive, Homeodomain Proteins, Homozygote, Humans, Male, Mice, Middle Aged, Polymorphism, Single Nucleotide, Protein Interaction Mapping, Retina, Retinal Dystrophies, Retinal Rod Photoreceptor Cells, Retinitis pigmentosa, Spain, Trans-Activators, Transcription Factors}, issn = {2045-2322}, doi = {10.1038/srep35370}, author = {Corton, M and Avila-Fern{\'a}ndez, A and Campello, L and S{\'a}nchez, M and Benavides, B and L{\'o}pez-Molina, M I and Fern{\'a}ndez-S{\'a}nchez, L and S{\'a}nchez-Alcudia, R and da Silva, L R J and Reyes, N and Mart{\'\i}n-Garrido, E and Zurita, O and Fern{\'a}ndez-San Jos{\'e}, P and P{\'e}rez-Carro, R and Garc{\'\i}a-Garc{\'\i}a, F and Dopazo, J and Garc{\'\i}a-Sandoval, B and Cuenca, N and Ayuso, C} } @article {453, title = {The Mutational Landscape of Acute Promyelocytic Leukemia Reveals an Interacting Network of Co-Occurrences and Recurrent Mutations.}, journal = {PLoS One}, volume = {11}, year = {2016}, month = {2016}, pages = {e0148346}, abstract = {

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

}, keywords = {Exome, Gene Regulatory Networks, Genome, Human, Humans, INDEL Mutation, Leukemia, Promyelocytic, Acute, mutation, Mutation Rate, Polymorphism, Single Nucleotide, Reproducibility of Results}, issn = {1932-6203}, doi = {10.1371/journal.pone.0148346}, author = {Ib{\'a}{\~n}ez, Mariam and Carbonell-Caballero, Jos{\'e} and Garc{\'\i}a-Alonso, Luz and Such, Esperanza and Jim{\'e}nez-Almaz{\'a}n, Jorge and Vidal, Enrique and Barrag{\'a}n, Eva and L{\'o}pez-Pav{\'\i}a, Mar{\'\i}a and LLop, Marta and Mart{\'\i}n, Iv{\'a}n and G{\'o}mez-Segu{\'\i}, In{\'e}s and Montesinos, Pau and Sanz, Miguel A and Dopazo, Joaquin and Cervera, Jos{\'e}} } @article {449, title = {Mutations in the MORC2 gene cause axonal Charcot-Marie-Tooth disease.}, journal = {Brain}, volume = {139}, year = {2016}, month = {2016 Jan}, pages = {62-72}, abstract = {

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

}, keywords = {Adult, Aged, Animals, Axons, Charcot-Marie-Tooth Disease, Female, gene expression, Humans, Infant, Male, Mice, Middle Aged, mutation, Pedigree, Phenotype, Sciatic Nerve, Sural Nerve, Transcription Factors, Young Adult}, issn = {1460-2156}, doi = {10.1093/brain/awv311}, author = {Sevilla, Teresa and Lupo, Vincenzo and Mart{\'\i}nez-Rubio, Dolores and Sancho, Paula and Sivera, Rafael and Chumillas, Mar{\'\i}a J and Garc{\'\i}a-Romero, Mar and Pascual-Pascual, Samuel I and Muelas, Nuria and Dopazo, Joaquin and V{\'\i}lchez, Juan J and Palau, Francesc and Espin{\'o}s, Carmen} } @article {442, title = {Progress in pharmacogenetics: consortiums and new strategies.}, journal = {Drug Metab Pers Ther}, volume = {31}, year = {2016}, month = {2016 Mar}, pages = {17-23}, abstract = {

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

}, keywords = {Cooperative Behavior, Genome-Wide Association Study, High-Throughput Screening Assays, Humans, Patient Care Team, pharmacogenetics, Polymorphism, Single Nucleotide, Precision Medicine}, issn = {2363-8915}, doi = {10.1515/dmpt-2015-0039}, author = {Maro{\~n}as, Olalla and Latorre, Ana and Dopazo, Joaquin and Pirmohamed, Munir and Rodr{\'\i}guez-Antona, Cristina and Siest, G{\'e}rard and Carracedo, {\'A}ngel and LLerena, Adri{\'a}n} } @article {438, title = {Web-based network analysis and visualization using CellMaps.}, journal = {Bioinformatics}, volume = {32}, year = {2016}, month = {2016 10 01}, pages = {3041-3}, abstract = {

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

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

CONTACT: jdopazo@cipf.es

SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

}, keywords = {Biochemical Phenomena, Internet, Software}, issn = {1367-4811}, doi = {10.1093/bioinformatics/btw332}, author = {Salavert, Francisco and Garc{\'\i}a-Alonso, Luz and S{\'a}nchez, Rub{\'e}n and Alonso, Roberto and Bleda, Marta and Medina, Ignacio and Dopazo, Joaquin} } @article {558, title = {Whole exome sequencing of Rett syndrome-like patients reveals the mutational diversity of the clinical phenotype.}, journal = {Hum Genet}, volume = {135}, year = {2016}, month = {2016 12}, pages = {1343-1354}, abstract = {

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

}, keywords = {Adolescent, Adult, Animals, Caenorhabditis elegans, Carrier Proteins, Cell Cycle Proteins, Child, Child, Preschool, DNA Mutational Analysis, Exome, Female, Forkhead Transcription Factors, Genetic Variation, High-Throughput Nucleotide Sequencing, Humans, Methyl-CpG-Binding Protein 2, mutation, Nerve Tissue Proteins, Protein Serine-Threonine Kinases, Receptors, Nicotinic, Rett Syndrome}, issn = {1432-1203}, doi = {10.1007/s00439-016-1721-3}, author = {Lucariello, Mario and Vidal, Enrique and Vidal, Silvia and Saez, Mauricio and Roa, Laura and Huertas, Dori and Pineda, Merc{\`e} and Dalf{\'o}, Esther and Dopazo, Joaquin and Jurado, Paola and Armstrong, Judith and Esteller, Manel} } @article {1128, title = {Assessing the impact of mutations found in next generation sequencing data over human signaling pathways.}, journal = {Nucleic acids research}, volume = {43}, number = {W1}, year = {2015}, month = {2015 Apr 16}, pages = {W270-W275}, abstract = {Modern sequencing technologies produce increasingly detailed data on genomic variation. However, conventional methods for relating either individual variants or mutated genes to phenotypes present known limitations given the complex, multigenic nature of many diseases or traits. Here we present PATHiVar, a web-based tool that integrates genomic variation data with gene expression tissue information. PATHiVar constitutes a new generation of genomic data analysis methods that allow studying variants found in next generation sequencing experiment in the context of signaling pathways. Simple Boolean models of pathways provide detailed descriptions of the impact of mutations in cell functionality so as, recurrences in functionality failures can easily be related to diseases, even if they are produced by mutations in different genes. Patterns of changes in signal transmission circuits, often unpredictable from individual genes mutated, correspond to patterns of affected functionalities that can be related to complex traits such as disease progression, drug response, etc. PATHiVar is available at: http://pathivar.babelomics.org.}, keywords = {NGS, pathways, signalling, Systems biology}, issn = {1362-4962}, doi = {10.1093/nar/gkv349}, url = {http://nar.oxfordjournals.org/content/43/W1/W270}, author = {Hernansaiz-Ballesteros, Rosa D and Salavert, Francisco and Sebasti{\'a}n-Leon, Patricia and Alem{\'a}n, Alejandro and Medina, Ignacio and Joaqu{\'\i}n Dopazo} } @article {1129, title = {Babelomics 5.0: functional interpretation for new generations of genomic data.}, journal = {Nucleic acids research}, volume = {43}, number = {W1}, year = {2015}, month = {2015 Apr 20}, pages = {W117-W121}, abstract = {Babelomics has been running for more than one decade offering a user-friendly interface for the functional analysis of gene expression and genomic data. Here we present its fifth release, which includes support for Next Generation Sequencing data including gene expression (RNA-seq), exome or genome resequencing. Babelomics has simplified its interface, being now more intuitive. Improved visualization options, such as a genome viewer as well as an interactive network viewer, have been implemented. New technical enhancements at both, client and server sides, makes the user experience faster and more dynamic. Babelomics offers user-friendly access to a full range of methods that cover: (i) primary data analysis, (ii) a variety of tests for different experimental designs and (iii) different enrichment and network analysis algorithms for the interpretation of the results of such tests in the proper functional context. In addition to the public server, local copies of Babelomics can be downloaded and installed. Babelomics is freely available at: http://www.babelomics.org.}, keywords = {babelomics, data integration, gene set analysis, interactome, network analysis, NGS, RNA-seq, Systems biology, transcriptomics}, issn = {1362-4962}, doi = {10.1093/nar/gkv384}, url = {http://nar.oxfordjournals.org/content/43/W1/W117}, author = {Alonso, Roberto and Salavert, Francisco and Garcia-Garcia, Francisco and Carbonell-Caballero, Jos{\'e} and Bleda, Marta and Garc{\'\i}a-Alonso, Luz and Sanchis-Juan, Alba and Perez-Gil, Daniel and Marin-Garcia, Pablo and S{\'a}nchez, Rub{\'e}n and Cubuk, Cankut and Hidalgo, Marta R and Amadoz, Alicia and Hernansaiz-Ballesteros, Rosa D and Alem{\'a}n, Alejandro and T{\'a}rraga, Joaqu{\'\i}n and Montaner, David and Medina, Ignacio and Dopazo, Joaquin} } @article {1132, title = {Combining tumor genome simulation with crowdsourcing to benchmark somatic single-nucleotide-variant detection.}, journal = {Nature methods}, year = {2015}, month = {2015 May 18}, abstract = {The detection of somatic mutations from cancer genome sequences is key to understanding the genetic basis of disease progression, patient survival and response to therapy. Benchmarking is needed for tool assessment and improvement but is complicated by a lack of gold standards, by extensive resource requirements and by difficulties in sharing personal genomic information. To resolve these issues, we launched the ICGC-TCGA DREAM Somatic Mutation Calling Challenge, a crowdsourced benchmark of somatic mutation detection algorithms. Here we report the BAMSurgeon tool for simulating cancer genomes and the results of 248 analyses of three in silico tumors created with it. Different algorithms exhibit characteristic error profiles, and, intriguingly, false positives show a trinucleotide profile very similar to one found in human tumors. Although the three simulated tumors differ in sequence contamination (deviation from normal cell sequence) and in subclonality, an ensemble of pipelines outperforms the best individual pipeline in all cases. BAMSurgeon is available at https://github.com/adamewing/bamsurgeon/.}, keywords = {cancer, NGS, variant calling}, issn = {1548-7105}, doi = {10.1038/nmeth.3407}, url = {http://www.nature.com/nmeth/journal/vaop/ncurrent/full/nmeth.3407.html}, author = {Ewing, Adam D and Houlahan, Kathleen E and Hu, Yin and Ellrott, Kyle and Caloian, Cristian and Yamaguchi, Takafumi N and Bare, J Christopher and P{\textquoteright}ng, Christine and Waggott, Daryl and Sabelnykova, Veronica Y and Kellen, Michael R and Norman, Thea C and Haussler, David and Friend, Stephen H and Stolovitzky, Gustavo and Margolin, Adam A and Stuart, Joshua M and Boutros, Paul C}, editor = {ICGC-TCGA DREAM Somatic Mutation Calling Challenge participants and Liu Xi and Ninad Dewal and Yu Fan and Wenyi Wang and David Wheeler and Andreas Wilm and Grace Hui Ting and Chenhao Li and Denis Bertrand and Niranjan Nagarajan and Qing-Rong Chen and Chih-Hao Hsu and Ying Hu and Chunhua Yan and Warren Kibbe and Daoud Meerzaman and Kristian Cibulskis and Mara Rosenberg and Louis Bergelson and Adam Kiezun and Amie Radenbaugh and Anne-Sophie Sertier and Anthony Ferrari and Laurie Tonton and Kunal Bhutani and Nancy F Hansen and Difei Wang and Lei Song and Zhongwu Lai and Liao, Yang and Shi, Wei and Carbonell-Caballero, Jos{\'e} and Joaqu{\'\i}n Dopazo and Cheryl C K Lau and Justin Guinney} } @article {1160, title = {Comparative gene expression study of the vestibular organ of the Igf1 deficient mouse using whole-transcript arrays.}, journal = {Hearing research}, year = {2015}, month = {2015 Sep 1}, abstract = {The auditory and vestibular organs form the inner ear and have a common developmental origin. Insulin like growth factor 1 (IGF-1) has a central role in the development of the cochlea and maintenance of hearing. Its deficiency causes sensorineural hearing loss in man and mice. During chicken early development, IGF-1 modulates neurogenesis of the cochleovestibular ganglion but no further studies have been conducted to explore the potential role of IGF-1 in the vestibular system. In this study we have compared the whole transcriptome of the vestibular organ from wild type and Igf1(-/-) mice at different developmental and postnatal times. RNA was prepared from E18.5, P15 and P90 vestibular organs of Igf1(-/-) and Igf1(+/+) mice and the transcriptome analysed in triplicates using Affymetrix{\textregistered} Mouse Gene 1.1 ST Array Plates. These plates are whole-transcript arrays that include probes to measure both messenger (mRNA) and long intergenic non-coding RNA transcripts (lincRNA), with a coverage of over 28 thousand coding transcripts and over 7 thousands non-coding transcripts. Given the complexity of the data we used two different methods VSN-RMA and mmBGX to analyse and compare the data. This is to better evaluate the number of false positives and to quantify uncertainty of low signals. We identified a number of differentially expressed genes that we described using functional analysis and validated using RT-qPCR. The morphology of the vestibular organ did not show differences between genotypes and no evident alterations were observed in the vestibular sensory areas of the null mice. However, well-defined cellular alterations were found in the vestibular neurons with respect their number and size. Although these mice did not show a dramatic vestibular phenotype, we conducted a functional analysis on differentially expressed genes between genotypes and across time. This was with the aim to identify new pathways that are involved in the development of the vestibular organ as well as pathways that maybe affected by the lack of IGF-1 and be associated to the morphological changes of the vestibular neurons that we observed in the Igf1(-/-) mice.}, issn = {1878-5891}, doi = {10.1016/j.heares.2015.08.016}, url = {http://www.sciencedirect.com/science/article/pii/S0378595515001835}, author = {Rodr{\'\i}guez-de la Rosa, Lourdes and S{\'a}nchez-Calder{\'o}n, Hortensia and Contreras, Julio and Murillo-Cuesta, Silvia and Falagan, Sandra and Avenda{\~n}o, Carlos and Joaqu{\'\i}n Dopazo and Varela-Nieto, Isabel and Milo, Marta} } @article {456, title = {The EGR2 gene is involved in axonal Charcot-Marie-Tooth disease.}, journal = {Eur J Neurol}, volume = {22}, year = {2015}, month = {2015 Dec}, pages = {1548-55}, abstract = {

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

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

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

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

}, keywords = {Adult, Aged, Aged, 80 and over, Axons, Charcot-Marie-Tooth Disease, Early Growth Response Protein 2, Exome, Female, Humans, Male, Middle Aged, mutation, Pedigree, Phenotype, Severity of Illness Index, Young Adult}, issn = {1468-1331}, doi = {10.1111/ene.12782}, author = {Sevilla, T and Sivera, R and Mart{\'\i}nez-Rubio, D and Lupo, V and Chumillas, M J and Calpena, E and Dopazo, J and V{\'\i}lchez, J J and Palau, F and Espin{\'o}s, C} } @article {1171, title = {Exome sequencing reveals a high genetic heterogeneity on familial Hirschsprung disease.}, journal = {Scientific reports}, volume = {5}, year = {2015}, month = {2015}, pages = {16473}, abstract = {Hirschsprung disease (HSCR; OMIM 142623) is a developmental disorder characterized by aganglionosis along variable lengths of the distal gastrointestinal tract, which results in intestinal obstruction. Interactions among known HSCR genes and/or unknown disease susceptibility loci lead to variable severity of phenotype. Neither linkage nor genome-wide association studies have efficiently contributed to completely dissect the genetic pathways underlying this complex genetic disorder. We have performed whole exome sequencing of 16 HSCR patients from 8 unrelated families with SOLID platform. Variants shared by affected relatives were validated by Sanger sequencing. We searched for genes recurrently mutated across families. Only variations in the FAT3 gene were significantly enriched in five families. Within-family analysis identified compound heterozygotes for AHNAK and several genes (N = 23) with heterozygous variants that co-segregated with the phenotype. Network and pathway analyses facilitated the discovery of polygenic inheritance involving FAT3, HSCR known genes and their gene partners. Altogether, our approach has facilitated the detection of more than one damaging variant in biologically plausible genes that could jointly contribute to the phenotype. Our data may contribute to the understanding of the complex interactions that occur during enteric nervous system development and the etiopathology of familial HSCR.}, keywords = {babelomics, Hirschprung, NGS, prioritization}, issn = {2045-2322}, doi = {10.1038/srep16473}, url = {http://www.nature.com/articles/srep16473}, author = {Luz{\'o}n-Toro, Berta and Gui, Hongsheng and Ruiz-Ferrer, Macarena and Sze-Man Tang, Clara and Fern{\'a}ndez, Raquel M and Sham, Pak-Chung and Torroglosa, Ana and Kwong-Hang Tam, Paul and Espino-Pais{\'a}n, Laura and Cherny, Stacey S and Bleda, Marta and Enguix-Riego, Mar{\'\i}a Del Valle and Joaqu{\'\i}n Dopazo and Anti{\v n}olo, Guillermo and Garcia-Barcel{\'o}, Maria-Merc{\`e} and Borrego, Salud} } @article {471, title = {Exome sequencing reveals a high genetic heterogeneity on familial Hirschsprung disease}, journal = {Scientific Reports}, volume = {5}, year = {2015}, month = {Jan-12-2015}, doi = {10.1038/srep16473}, url = {http://www.nature.com/articles/srep16473http://www.nature.com/articles/srep16473.pdfhttp://www.nature.com/articles/srep16473.pdfhttp://www.nature.com/articles/srep16473}, author = {Luz{\'o}n-Toro, Berta and Gui, Hongsheng and Ruiz-Ferrer, Macarena and Sze-Man Tang, Clara and Fern{\'a}ndez, Raquel M. and Sham, Pak-Chung and Torroglosa, Ana and Kwong-Hang Tam, Paul and Espino-Pais{\'a}n, Laura and Cherny, Stacey S. and Bleda, Marta and Enguix-Riego, Mar{\'\i}a Del Valle and Dopazo, Joaquin and Anti{\v n}olo, Guillermo and Garcia-Barcel{\'o}, Maria-Merc{\`e} and Borrego, Salud} } @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 {472, title = {Fast inexact mapping using advanced tree exploration on backward search methods.}, journal = {BMC Bioinformatics}, volume = {16}, year = {2015}, month = {2015 Jan 28}, pages = {18}, abstract = {

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

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

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

}, keywords = {Algorithms, Genome, Human, Genomics, High-Throughput Nucleotide Sequencing, Humans, Sequence Alignment, Sequence Analysis, DNA, Software}, issn = {1471-2105}, doi = {10.1186/s12859-014-0438-3}, author = {Salavert, Jos{\'e} and Tom{\'a}s, Andr{\'e}s and T{\'a}rraga, Joaqu{\'\i}n and Medina, Ignacio and Dopazo, Joaquin and Blanquer, Ignacio} } @article {474, title = {Using activation status of signaling pathways as mechanism-based biomarkers to predict drug sensitivity.}, journal = {Sci Rep}, volume = {5}, year = {2015}, month = {2015 Dec 18}, pages = {18494}, abstract = {

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

}, keywords = {Algorithms, Antineoplastic Agents, biomarkers, Cell Line, Tumor, Cell Survival, gene expression, Humans, Lethal Dose 50, Neoplasms, Phosphorylation, Proteins, Signal Transduction}, issn = {2045-2322}, doi = {10.1038/srep18494}, author = {Amadoz, Alicia and Sebasti{\'a}n-Leon, Patricia and Vidal, Enrique and Salavert, Francisco and Dopazo, Joaquin} } @article {1127, title = {Whole Exome Sequencing Reveals ZNF408 as a New Gene Associated With Autosomal Recessive Retinitis Pigmentosa with Vitreal Alterations.}, journal = {Human molecular genetics}, volume = {24}, number = {14}, year = {2015}, month = {2015 Apr 16}, pages = {4037-4048}, abstract = {Retinitis Pigmentosa (RP) is a group of progressive inherited retinal dystrophies that cause visual impairment as a result of photoreceptor cell death. RP is heterogeneous, both clinically and genetically making difficult to establish precise genotype-phenotype correlations. In a Spanish family with autosomal recessive RP (arRP), homozygosity mapping and whole exome sequencing led to the identification of a homozygous mutation (c.358_359delGT; p.Ala122Leufs*2) in the ZNF408 gene. A screening performed in 217 additional unrelated families revealed another homozygous mutation (c.1621C>T; p.Arg541Cys) in an isolated RP case. ZNF408 encodes a transcription factor that harbors ten predicted C2H2-type fingers thought to be implicated in DNA binding. To elucidate the ZNF408 role in the retina and the pathogenesis of these mutations we have performed different functional studies. By immunohistochemical analysis in healthy human retina, we identified that ZNF408 is expressed in both cone and rod photoreceptors, in a specific type of amacrine and ganglion cells, and in retinal blood vessels. ZNF408 revealed a cytoplasmic localization and a nuclear distribution in areas corresponding with the euchromatin fraction. Immunolocalization studies showed a partial mislocalization of the p.Arg541Cys mutant protein retaining part of the WT protein in the cytoplasm. Our study demonstrates that ZNF408, previously associated with Familial Exudative Vitreoretinopathy (FEVR), is a new gene causing arRP with vitreous condensations supporting the evidence that this protein plays additional functions into the human retina.}, issn = {1460-2083}, doi = {10.1093/hmg/ddv140}, url = {http://hmg.oxfordjournals.org/content/early/2015/04/16/hmg.ddv140.abstract}, author = {Avila-Fernandez, Almudena and Perez-Carro, Raquel and Corton, Marta and Lopez-Molina, Maria Isabel and Campello, Laura and Garanto, Alex and Fernadez-Sanchez, Laura and Duijkers, Lonneke and Lopez-Martinez, Miguel Angel and Riveiro-Alvarez, Rosa and da Silva, Luciana Rodrigues Jacy and Sanchez-Alcudia, Roc{\'\i}o and Martin-Garrido, Esther and Reyes, Noelia and Garcia-Garcia, Francisco and Dopazo, Joaquin and Garcia-Sandoval, Blanca and Collin, Rob W and Cuenca, Nicolas and Ayuso, Carmen} } @article {463, title = {Whole-exome sequencing reveals ZNF408 as a new gene associated with autosomal recessive retinitis pigmentosa with vitreal alterations.}, journal = {Hum Mol Genet}, volume = {24}, year = {2015}, month = {2015 Jul 15}, pages = {4037-48}, abstract = {

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

}, keywords = {Amino Acid Sequence, Animals, Chlorocebus aethiops, Chromosome Mapping, COS Cells, DNA-Binding Proteins, Exome, Genome-Wide Association Study, High-Throughput Nucleotide Sequencing, Homozygote, Humans, Molecular Sequence Data, Mutant Proteins, Pedigree, Retina, Retinal Cone Photoreceptor Cells, Retinal Rod Photoreceptor Cells, Retinitis pigmentosa, Transcription Factors}, issn = {1460-2083}, doi = {10.1093/hmg/ddv140}, author = {Avila-Fernandez, Almudena and Perez-Carro, Raquel and Corton, Marta and Lopez-Molina, Maria Isabel and Campello, Laura and Garanto, Alejandro and Fernandez-Sanchez, Laura and Duijkers, Lonneke and Lopez-Martinez, Miguel Angel and Riveiro-Alvarez, Rosa and da Silva, Luciana Rodrigues Jacy and Sanchez-Alcudia, Roc{\'\i}o and Martin-Garrido, Esther and Reyes, Noelia and Garcia-Garcia, Francisco and Dopazo, Joaquin and Garcia-Sandoval, Blanca and Collin, Rob W J and Cuenca, Nicolas and Ayuso, Carmen} } @article {1076, title = {Acceleration of short and long DNA read mapping without loss of accuracy using suffix array.}, journal = {Bioinformatics (Oxford, England)}, volume = {30}, year = {2014}, month = {2014 Aug 20}, pages = {3396-3398}, abstract = {HPG Aligner applies suffix arrays for DNA read mapping. This implementation produces a highly sensitive and extremely fast mapping of DNA reads that scales up almost linearly with read length. The approach presented here is faster (over 20x for long reads) and more sensitive (over 98\% in a wide range of read lengths) than the current, state-of-the-art mappers. HPG Aligner is not only an optimal alternative for current sequencers but also the only solution available to cope with longer reads and growing throughputs produced by forthcoming sequencing technologies.}, keywords = {NGS, short read mapping. HPC. suffix arrays}, issn = {1367-4811}, doi = {10.1093/bioinformatics/btu553}, url = {http://bioinformatics.oxfordjournals.org/content/early/2014/08/19/bioinformatics.btu553.long}, author = {T{\'a}rraga, Joaqu{\'\i}n and Arnau, Vicente and Martinez, Hector and Moreno, Raul and Cazorla, Diego and Salavert-Torres, Jos{\'e} and Blanquer-Espert, Ignacio and Joaqu{\'\i}n Dopazo and Medina, Ignacio} } @article {1087, title = {Assessing technical performance in differential gene expression experiments with external spike-in RNA control ratio mixtures.}, journal = {Nature communications}, volume = {5}, year = {2014}, month = {2014}, pages = {5125}, abstract = {There is a critical need for standard approaches to assess, report and compare the technical performance of genome-scale differential gene expression experiments. Here we assess technical performance with a proposed standard {\textquoteright}dashboard{\textquoteright} of metrics derived from analysis of external spike-in RNA control ratio mixtures. These control ratio mixtures with defined abundance ratios enable assessment of diagnostic performance of differentially expressed transcript lists, limit of detection of ratio (LODR) estimates and expression ratio variability and measurement bias. The performance metrics suite is applicable to analysis of a typical experiment, and here we also apply these metrics to evaluate technical performance among laboratories. An interlaboratory study using identical samples shared among 12 laboratories with three different measurement processes demonstrates generally consistent diagnostic power across 11 laboratories. Ratio measurement variability and bias are also comparable among laboratories for the same measurement process. We observe different biases for measurement processes using different mRNA-enrichment protocols.}, keywords = {RNA-seq}, issn = {2041-1723}, doi = {10.1038/ncomms6125}, url = {http://www.nature.com/ncomms/2014/140925/ncomms6125/full/ncomms6125.html}, author = {Munro, Sarah A and Lund, Steven P and Pine, P Scott and Binder, Hans and Clevert, Djork-Arn{\'e} and Ana Conesa and Dopazo, Joaquin and Fasold, Mario and Hochreiter, Sepp and Hong, Huixiao and Jafari, Nadereh and Kreil, David P and Labaj, Pawe{\l} P and Li, Sheng and Liao, Yang and Lin, Simon M and Meehan, Joseph and Mason, Christopher E and Santoyo-L{\'o}pez, Javier and Setterquist, Robert A and Shi, Leming and Shi, Wei and Smyth, Gordon K and Stralis-Pavese, Nancy and Su, Zhenqiang and Tong, Weida and Wang, Charles and Wang, Jian and Xu, Joshua and Ye, Zhan and Yang, Yong and Yu, Ying and Salit, Marc} } @article {1077, title = {A comprehensive assessment of RNA-seq accuracy, reproducibility and information content by the Sequencing Quality Control Consortium.}, journal = {Nature biotechnology}, volume = {32}, year = {2014}, month = {2014 Aug 24}, pages = {903{\textendash}914}, abstract = {We present primary results from the Sequencing Quality Control (SEQC) project, coordinated by the US Food and Drug Administration. Examining Illumina HiSeq, Life Technologies SOLiD and Roche 454 platforms at multiple laboratory sites using reference RNA samples with built-in controls, we assess RNA sequencing (RNA-seq) performance for junction discovery and differential expression profiling and compare it to microarray and quantitative PCR (qPCR) data using complementary metrics. At all sequencing depths, we discover unannotated exon-exon junctions, with >80\% validated by qPCR. We find that measurements of relative expression are accurate and reproducible across sites and platforms if specific filters are used. In contrast, RNA-seq and microarrays do not provide accurate absolute measurements, and gene-specific biases are observed for all examined platforms, including qPCR. Measurement performance depends on the platform and data analysis pipeline, and variation is large for transcript-level profiling. The complete SEQC data sets, comprising >100 billion reads (10Tb), provide unique resources for evaluating RNA-seq analyses for clinical and regulatory settings.}, keywords = {NGS, RNA-seq, SEQC}, issn = {1546-1696}, doi = {10.1038/nbt.2957}, url = {http://www.nature.com/nbt/journal/vaop/ncurrent/full/nbt.2957.html}, author = {Su, Z. and Labaj, P.P. and .... and Dopazo, J. and .... and Mason, C.E. and Shi, L} } @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 {1035, title = {Deciphering intrafamilial phenotypic variability by exome sequencing in a Bardet{\textendash}Biedl family}, journal = {Molecular Genetics \& Genomic Medicine}, volume = {2}, number = {2}, year = {2014}, pages = {124-133}, abstract = {Bardet{\textendash}Biedl syndrome (BBS) is a model ciliopathy characterized by a wide range of clinical variability. The heterogeneity of this condition is reflected in the number of underlying gene defects and the epistatic interactions between the proteins encoded. BBS is generally inherited in an autosomal recessive trait. However, in some families, mutations across different loci interact to modulate the expressivity of the phenotype. In order to investigate the magnitude of epistasis in one BBS family with remarkable intrafamilial phenotypic variability, we designed an exome sequencing{\textendash}based approach using SOLID 5500xl platform. This strategy allowed the reliable detection of the primary causal mutations in our family consisting of two novel compound heterozygous mutations in McKusick{\textendash}Kaufman syndrome (MKKS) gene (p.D90G and p.V396F). Additionally, exome sequencing enabled the detection of one novel heterozygous NPHP4 variant which is predicted to activate a cryptic acceptor splice site and is only present in the most severely affected patient. Here, we provide an exome sequencing analysis of a BBS family and show the potential utility of this tool, in combination with network analysis, to detect disease-causing mutations and second-site modifiers. Our data demonstrate how next-generation sequencing (NGS) can facilitate the dissection of epistatic phenomena, and shed light on the genetic basis of phenotypic variability.}, doi = {10.1002/mgg3.50}, url = {http://onlinelibrary.wiley.com/doi/10.1002/mgg3.50/full}, author = {Gonz{\'a}lez-del Pozo, Mar{\'\i}a and M{\'e}ndez-Vidal, Cristina and Santoyo-L{\'o}pez, Javier and Vela-Boza, Alicia and Nereida Bravo-Gil and Antonio Rueda and Garc{\'\i}a-Alonso, Luz and V{\'a}zquez-Marouschek, Carmen and Joaqu{\'\i}n Dopazo and Borrego, Salud and Anti{\v n}olo, Guillermo} } @article {486, title = {Deciphering intrafamilial phenotypic variability by exome sequencing in a Bardet-Biedl family.}, journal = {Mol Genet Genomic Med}, volume = {2}, year = {2014}, month = {2014 Mar}, pages = {124-33}, abstract = {

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

}, issn = {2324-9269}, doi = {10.1002/mgg3.50}, author = {Gonz{\'a}lez-del Pozo, Mar{\'\i}a and M{\'e}ndez-Vidal, Cristina and Santoyo-L{\'o}pez, Javier and Vela-Boza, Alicia and Bravo-Gil, Nereida and Rueda, Antonio and Garc{\'\i}a-Alonso, Luz and V{\'a}zquez-Marouschek, Carmen and Dopazo, Joaquin and Borrego, Salud and Anti{\v n}olo, Guillermo} } @article {1083, title = {A New Overgrowth Syndrome is Due to Mutations in RNF125.}, journal = {Human mutation}, volume = {35}, year = {2014}, month = {2014 Sep 5}, pages = {1436{\textendash}1441}, abstract = {Overgrowth syndromes (OGS) are a group of disorders in which all parameters of growth and physical development are above the mean for age and sex. We evaluated a series of 270 families from the Spanish Overgrowth Syndrome Registry with no known overgrowth syndrome. We identified one de novo deletion and three missense mutations in RNF125 in six patients from 4 families with overgrowth, macrocephaly, intellectual disability, mild hydrocephaly, hypoglycaemia and inflammatory diseases resembling Sj{\"o}gren syndrome. RNF125 encodes an E3 ubiquitin ligase and is a novel gene of OGS. Our studies of the RNF125 pathway point to upregulation of RIG-I-IPS1-MDA5 and/or disruption of the PI3K-AKT and interferon signaling pathways as the putative final effectors. This article is protected by copyright. All rights reserved.}, keywords = {NGS, prioritization, Rare Disease}, issn = {1098-1004}, doi = {10.1002/humu.22689}, url = {http://onlinelibrary.wiley.com/doi/10.1002/humu.22689/abstract}, author = {Tenorio, Jair and Mansilla, Alicia and Valencia, Mar{\'\i}a and Mart{\'\i}nez-Glez, V{\'\i}ctor and Romanelli, Valeria and Arias, Pedro and Castrej{\'o}n, Nerea and Poletta, Fernando and Guill{\'e}n-Navarro, Encarna and Gordo, Gema and Mansilla, Elena and Garc{\'\i}a-Santiago, F{\'e} and Gonz{\'a}lez-Casado, Isabel and Vallesp{\'\i}n, Elena and Palomares, Mar{\'\i}a and Mori, Mar{\'\i}a A and Santos-Simarro, Fernando and Garc{\'\i}a-Mi{\~n}aur, Sixto and Fern{\'a}ndez, Luis and Mena, Roc{\'\i}o and Benito-Sanz, Sara and Del Pozo, Angela and Silla, Juan Carlos and Iba{\~n}ez, Kristina and L{\'o}pez-Granados, Eduardo and Mart{\'\i}n-Trujillo, Alex and Montaner, David and Heath, Karen E and Campos-Barros, Angel and Joaqu{\'\i}n Dopazo and Nevado, Juli{\'a}n and Monk, David and Ruiz-P{\'e}rez, V{\'\i}ctor L and Lapunzina, Pablo} } @article {482, title = {ngsCAT: a tool to assess the efficiency of targeted enrichment sequencing.}, journal = {Bioinformatics}, volume = {30}, year = {2014}, month = {2014 Jun 15}, pages = {1767-8}, abstract = {

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

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

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

}, keywords = {Exome, Genome, Human, High-Throughput Nucleotide Sequencing, Humans, Sequence Analysis, DNA, Software}, issn = {1367-4811}, doi = {10.1093/bioinformatics/btu108}, author = {L{\'o}pez-Domingo, Francisco J and Florido, Javier P and Rueda, Antonio and Dopazo, Joaquin and Santoyo-L{\'o}pez, Javier} } @article {494, title = {The role of the interactome in the maintenance of deleterious variability in human populations.}, journal = {Mol Syst Biol}, volume = {10}, year = {2014}, month = {2014 Sep 26}, pages = {752}, abstract = {

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

}, keywords = {Alleles, Exome, Gene Library, Genetic Variation, Genetics, Population, Genome, Human, Genomics, Humans, Models, Genetic, mutation, Phenotype, Protein Conformation, Protein Interaction Maps, Sequence Analysis, DNA, Whites}, issn = {1744-4292}, doi = {10.15252/msb.20145222}, author = {Garc{\'\i}a-Alonso, Luz and Jim{\'e}nez-Almaz{\'a}n, Jorge and Carbonell-Caballero, Jos{\'e} and Vela-Boza, Alicia and Santoyo-L{\'o}pez, Javier and Anti{\v n}olo, Guillermo and Dopazo, Joaquin} } @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 {1093, title = {Understanding disease mechanisms with models of signaling pathway activities.}, journal = {BMC systems biology}, volume = {8}, year = {2014}, month = {2014 Oct 25}, pages = {121}, abstract = {BackgroundUnderstanding the aspects of the cell functionality that account for disease or drug action mechanisms is one of the main challenges in the analysis of genomic data and is on the basis of the future implementation of precision medicine.ResultsHere we propose a simple probabilistic model in which signaling pathways are separated into elementary sub-pathways or signal transmission circuits (which ultimately trigger cell functions) and then transforms gene expression measurements into probabilities of activation of such signal transmission circuits. Using this model, differential activation of such circuits between biological conditions can be estimated. Thus, circuit activation statuses can be interpreted as biomarkers that discriminate among the compared conditions. This type of mechanism-based biomarkers accounts for cell functional activities and can easily be associated to disease or drug action mechanisms. The accuracy of the proposed model is demonstrated with simulations and real datasets.ConclusionsThe proposed model provides detailed information that enables the interpretation disease mechanisms as a consequence of the complex combinations of altered gene expression values. Moreover, it offers a framework for suggesting possible ways of therapeutic intervention in a pathologically perturbed system.}, keywords = {Disease mechanism, pathway, signalling, Systems biology}, issn = {1752-0509}, doi = {10.1186/s12918-014-0121-3}, url = {http://www.biomedcentral.com/1752-0509/8/121/abstract}, author = {Sebasti{\'a}n-Leon, Patricia and Vidal, Enrique and Minguez, Pablo and Ana Conesa and Sonia Tarazona and Amadoz, Alicia and Armero, Carmen and Salavert, Francisco and Vidal-Puig, Antonio and Montaner, David and Joaqu{\'\i}n Dopazo} } @article {565, title = {Understanding disease mechanisms with models of signaling pathway activities}, journal = {BMC systems biology}, volume = {8}, year = {2014}, month = {10}, pages = {121}, doi = {10.1186/s12918-014-0121-3}, author = {Sebasti{\'a}n-Leon, Patricia and Vidal, Enrique and Minguez, Pablo and Conesa, Ana and Tarazona, Sonia and Amadoz, Alicia and Armero, Carmen and Salavert Torres, Francisco and Vidal-Puig, Antonio and Montaner, David and Dopazo, Joaquin} } @article {1051, title = {A web-based interactive framework to assist in the prioritization of disease candidate genes in whole-exome sequencing studies.}, journal = {Nucleic acids research}, volume = {42}, year = {2014}, month = {2014 May 6}, pages = {W88-W93.}, abstract = {Whole-exome sequencing has become a fundamental tool for the discovery of disease-related genes of familial diseases and the identification of somatic driver variants in cancer. However, finding the causal mutation among the enormous background of individual variability in a small number of samples is still a big challenge. Here we describe a web-based tool, BiERapp, which efficiently helps in the identification of causative variants in family and sporadic genetic diseases. The program reads lists of predicted variants (nucleotide substitutions and indels) in affected individuals or tumor samples and controls. In family studies, different modes of inheritance can easily be defined to filter out variants that do not segregate with the disease along the family. Moreover, BiERapp integrates additional information such as allelic frequencies in the general population and the most popular damaging scores to further narrow down the number of putative variants in successive filtering steps. BiERapp provides an interactive and user-friendly interface that implements the filtering strategy used in the context of a large-scale genomic project carried out by the Spanish Network for Research in Rare Diseases (CIBERER) in which more than 800 exomes have been analyzed. BiERapp is freely available at: http://bierapp.babelomics.org/}, keywords = {NGS. prioritization}, issn = {1362-4962}, doi = {10.1093/nar/gku407}, url = {http://nar.oxfordjournals.org/content/42/W1/W88}, author = {Alem{\'a}n, Alejandro and Garcia-Garcia, Francisco and Salavert, Francisco and Medina, Ignacio and Joaqu{\'\i}n Dopazo} } @article {21919703, title = {Assessing Differential Expression Measurements by Highly Parallel Pyrosequencing and DNA Microarrays: A Comparative Study.}, journal = {Omics : a journal of integrative biology}, year = {2013}, month = {2011 Sep 15}, abstract = {

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

}, doi = {10.1089/omi.2011.0065}, url = {http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3545353/}, author = {Ari{\~n}o, Joaqu{\'\i}n and Casamayor, Antonio and P{\'e}rez, Juli{\'a}n Perez and Pedrola, Laia and Alvarez-Tejado, Miguel and Marb{\`a}, Martina and Santoyo, Javier and Joaqu{\'\i}n Dopazo} } @article {503, title = {Defining the genomic signature of totipotency and pluripotency during early human development.}, journal = {PLoS One}, volume = {8}, year = {2013}, month = {2013}, pages = {e62135}, abstract = {

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

}, keywords = {Blastocyst Inner Cell Mass, Blastomeres, Cell Differentiation, Embryonic Development, Embryonic Stem Cells, Gene Expression Profiling, Gene Regulatory Networks, Genome, Human, Humans, Molecular Sequence Annotation, Pluripotent Stem Cells, Totipotent Stem Cells}, issn = {1932-6203}, doi = {10.1371/journal.pone.0062135}, author = {Galan, Amparo and Diaz-Gimeno, Patricia and Poo, Maria Eugenia and Valbuena, Diana and Sanchez, Eva and Ruiz, Veronica and Dopazo, Joaquin and Montaner, David and Conesa, Ana and Simon, Carlos} } @article {1003, title = {Genome Maps, a new generation genome browser.}, journal = {Nucleic acids research}, volume = {41}, number = {W1}, year = {2013}, month = {2013 Jun 8}, pages = {W41-W46}, abstract = {Genome browsers have gained importance as more genomes and related genomic information become available. However, the increase of information brought about by new generation sequencing technologies is, at the same time, causing a subtle but continuous decrease in the efficiency of conventional genome browsers. Here, we present Genome Maps, a genome browser that implements an innovative model of data transfer and management. The program uses highly efficient technologies from the new HTML5 standard, such as scalable vector graphics, that optimize workloads at both server and client sides and ensure future scalability. Thus, data management and representation are entirely carried out by the browser, without the need of any Java Applet, Flash or other plug-in technology installation. Relevant biological data on genes, transcripts, exons, regulatory features, single-nucleotide polymorphisms, karyotype and so forth, are imported from web services and are available as tracks. In addition, several DAS servers are already included in Genome Maps. As a novelty, this web-based genome browser allows the local upload of huge genomic data files (e.g. VCF or BAM) that can be dynamically visualized in real time at the client side, thus facilitating the management of medical data affected by privacy restrictions. Finally, Genome Maps can easily be integrated in any web application by including only a few lines of code. Genome Maps is an open source collaborative initiative available in the GitHub repository (https://github.com/compbio-bigdata-viz/genome-maps). Genome Maps is available at: http://www.genomemaps.org.}, keywords = {BAM, genome viewer, HTML5, javascript, Next Generation Sequencing, NGS, SVG, VCF}, issn = {1362-4962}, doi = {10.1093/nar/gkt530}, url = {http://nar.oxfordjournals.org/content/41/W1/W41}, author = {Medina, Ignacio and Salavert, Francisco and S{\'a}nchez, Rub{\'e}n and De Maria, Alejandro and Alonso, Roberto and Escobar, Pablo and Bleda, Marta and Joaqu{\'\i}n Dopazo} } @article {957, title = {Grape antioxidant dietary fiber (GADF) inhibits intestinal polyposis in ApcMin/+ mice: relation to cell cycle and immune response.}, journal = {Carcinogenesis}, year = {2013}, month = {2013 Apr 24}, abstract = {Epidemiological and experimental studies suggest that fiber and phenolic compounds might have a protective effect on the development of colon cancer in humans. Accordingly, we assessed the chemopreventive efficacy and associated mechanisms of action of a lyophilized red grape pomace containing proanthocyanidin-rich dietary fiber (Grape Antioxidant Dietary Fiber, GADF) on spontaneous intestinal tumorigenesis in the Apc(Min/+) mouse model. Mice were fed a standard diet (control group) or a 1\% (w/w) GADF-supplemented diet (GADF group) for 6 weeks. GADF supplementation greatly reduced intestinal tumorigenesis, significantly decreasing the total number of polyps by 76\%. Moreover, size distribution analysis showed a considerable reduction in all polyp size categories [diameter <1 mm (65\%), 1-2 mm (67\%) and >2 mm (87\%)]. In terms of polyp formation in the proximal, middle and distal portions of the small intestine a decrease of 76\%, 81\% and 73\% was observed respectively. Putative molecular mechanisms underlying the inhibition of intestinal tumorigenesis were investigated by comparison of microarray expression profiles of GADF-treated and non-treated mice. We observed that the effects of GADF are mainly associated with the induction of a G1 cell cycle arrest and the downregulation of genes related to the immune response and inflammation. Our findings show for the first time the efficacy and associated mechanisms of action of GADF against intestinal tumorigenesis in Apc(Min/+) mice, suggesting its potential for the prevention of colorectal cancer.}, issn = {1460-2180}, doi = {10.1093/carcin/bgt140}, url = {http://carcin.oxfordjournals.org/content/early/2013/04/23/carcin.bgt140.abstract}, author = {S{\'a}nchez-Tena, Susana and Lizarraga, Daneida and Miranda, Anibal and Vinardell, Maria Pilar and Garcia-Garcia, Francisco and Joaqu{\'\i}n Dopazo and Torres, Josep Llu{\'\i}s and Saura-Calixto, Fulgencio and Capell{\`a}, Gabriel and Cascante, Marta} } @article {497, title = {Grape antioxidant dietary fiber inhibits intestinal polyposis in ApcMin/+ mice: relation to cell cycle and immune response.}, journal = {Carcinogenesis}, volume = {34}, year = {2013}, month = {2013 Aug}, pages = {1881-8}, abstract = {

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

}, keywords = {Animals, Antioxidants, Body Weight, Carcinogenesis, Cell Cycle, Cell Cycle Checkpoints, Colorectal Neoplasms, Dietary Fiber, Dietary Supplements, Down-Regulation, G1 Phase, Inflammation, Intestinal Polyposis, Intestinal Polyps, Intestine, Small, Male, Mice, Transcriptome, Vitis}, issn = {1460-2180}, doi = {10.1093/carcin/bgt140}, author = {S{\'a}nchez-Tena, Susana and Lizarraga, Daneida and Miranda, Anibal and Vinardell, Maria P and Garcia-Garcia, Francisco and Dopazo, Joaquin and Torres, Josep L and Saura-Calixto, Fulgencio and Capell{\`a}, Gabriel and Cascante, Marta} } @article {500, title = {Inferring the functional effect of gene expression changes in signaling pathways.}, journal = {Nucleic Acids Res}, volume = {41}, year = {2013}, month = {2013 Jul}, pages = {W213-7}, abstract = {

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

}, keywords = {Animals, Humans, Internet, Mice, Models, Statistical, Receptors, Cell Surface, Signal Transduction, Software, Transcriptome}, issn = {1362-4962}, doi = {10.1093/nar/gkt451}, author = {Sebasti{\'a}n-Leon, Patricia and Carbonell, Jos{\'e} and Salavert, Francisco and S{\'a}nchez, Rub{\'e}n and Medina, Ignacio and Dopazo, Joaquin} } @article {952, title = {Maslinic Acid-Enriched Diet Decreases Intestinal Tumorigenesis in Apc(Min/+) Mice through Transcriptomic and Metabolomic Reprogramming.}, journal = {PloS one}, volume = {8}, year = {2013}, month = {2013}, pages = {e59392}, abstract = {Chemoprevention is a pragmatic approach to reduce the risk of colorectal cancer, one of the leading causes of cancer-related death in western countries. In this regard, maslinic acid (MA), a pentacyclic triterpene extracted from wax-like coatings of olives, is known to inhibit proliferation and induce apoptosis in colon cancer cell lines without affecting normal intestinal cells. The present study evaluated the chemopreventive efficacy and associated mechanisms of maslinic acid treatment on spontaneous intestinal tumorigenesis in Apc(Min/+) mice. Twenty-two mice were randomized into 2 groups: control group and MA group, fed with a maslinic acid-supplemented diet for six weeks. MA treatment reduced total intestinal polyp formation by 45\% (P<0.01). Putative molecular mechanisms associated with suppressing intestinal polyposis in Apc(Min/+) mice were investigated by comparing microarray expression profiles of MA-treated and control mice and by analyzing the serum metabolic profile using NMR techniques. The different expression phenotype induced by MA suggested that it exerts its chemopreventive action mainly by inhibiting cell-survival signaling and inflammation. These changes eventually induce G1-phase cell cycle arrest and apoptosis. Moreover, the metabolic changes induced by MA treatment were associated with a protective profile against intestinal tumorigenesis. These results show the efficacy and underlying mechanisms of MA against intestinal tumor development in the Apc(Min/+) mice model, suggesting its chemopreventive potential against colorectal cancer.}, issn = {1932-6203}, doi = {10.1371/journal.pone.0059392}, author = {S{\'a}nchez-Tena, Susana and Reyes-Zurita, Fernando J and D{\'\i}az-Moralli, Santiago and Vinardell, Maria Pilar and Reed, Michelle and Garcia-Garcia, Francisco and Joaqu{\'\i}n Dopazo and Lupi{\'a}{\~n}ez, Jos{\'e} A and G{\"u}nther, Ulrich and Cascante, Marta} } @conference {567, title = {Multicore and Cloud-based Solutions for Genomic Variant Analysis}, booktitle = {Proceedings of the 18th International Conference on Parallel Processing Workshops}, year = {2013}, publisher = {Springer-Verlag}, organization = {Springer-Verlag}, address = {Berlin, Heidelberg}, keywords = {genomic variant analysis, multicore, mutation, OpenMP, web service}, isbn = {978-3-642-36948-3}, doi = {10.1007/978-3-642-36949-0_30}, url = {http://dx.doi.org/10.1007/978-3-642-36949-0_30}, author = {Gonzalez, Cristina Y. and Bleda, Marta and Salavert, Francisco and S{\'a}nchez, Rub{\'e}n and Dopazo, Joaquin and Medina, Ignacio} } @article {507, title = {Novel genes detected by transcriptional profiling from whole-blood cells in patients with early onset of acute coronary syndrome.}, journal = {Clin Chim Acta}, volume = {421}, year = {2013}, month = {2013 Jun 05}, pages = {184-90}, abstract = {

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

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

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

}, keywords = {Acute Coronary Syndrome, Acute-Phase Proteins, Adult, biomarkers, Blood Cells, Early Diagnosis, gene expression, Gene Expression Profiling, Humans, Male, Middle Aged, Oligonucleotide Array Sequence Analysis, RNA, Messenger, Transcriptome}, issn = {1873-3492}, doi = {10.1016/j.cca.2013.03.011}, author = {Silbiger, Vivian N and Luchessi, Andr{\'e} D and Hirata, Ros{\'a}rio D C and Lima-Neto, L{\'\i}dio G and Cavichioli, D{\'e}bora and Carracedo, {\'A}ngel and Bri{\'o}n, Maria and Dopazo, Joaquin and Garcia-Garcia, Francisco and Dos Santos, Elizabete S and Ramos, Rui F and Sampaio, Marcelo F and Armaganijan, Dikran and Sousa, Amanda G M R and Hirata, Mario H} } @article {953, title = {Novel genes detected by transcriptional profiling from whole-blood cells in patients with early onset of acute coronary syndrome: Transcriptional profiling of acute coronary syndrome.}, journal = {Clinica chimica acta; international journal of clinical chemistry}, year = {2013}, month = {2013 Mar 24}, abstract = {{BACKGROUND: Genome-wide expression analysis using microarrays has been used as a research strategy to discovery new biomarkers and candidate genes for a number of diseases. We aim to find new biomarkers for the prediction of acute coronary syndrome (ACS) with a differentially expressed mRNA profiling approach using whole genomic expression analysis in a peripheral blood cell model from patients with early ACS. METHODS AND RESULTS: This study was carried out in two phases. On phase 1 a restricted clinical criteria (ACS-Ph1}, issn = {1873-3492}, doi = {10.1016/j.cca.2013.03.011}, author = {Silbiger, Vivian N and Luchessi, Andr{\'e} D and Hirata, Ros{\'a}rio D C and Lima-Neto, L{\'\i}dio G and Cavichioli, D{\'e}bora and Carracedo, {\'A}ngel and Bri{\'o}n, Maria and Joaqu{\'\i}n Dopazo and Garcia-Garcia, Francisco and Dos Santos, Elizabete S and Ramos, Rui F and Sampaio, Marcelo F and Armaganijan, Dikran and Sousa, Amanda G M R and Hirata, Mario H} } @article {1033, title = {Pathways systematically associated to Hirschsprung{\textquoteright}s disease.}, journal = {Orphanet journal of rare diseases}, volume = {8}, year = {2013}, month = {2013 Dec 2}, pages = {187}, abstract = {Despite it has been reported that several loci are involved in Hirschsprung{\textquoteright}s disease, the molecular basis of the disease remains yet essentially unknown. The study of collective properties of modules of functionally-related genes provides an efficient and sensitive statistical framework that can overcome sample size limitations in the study of rare diseases. Here, we present the extension of a previous study of a Spanish series of HSCR trios to an international cohort of 162 HSCR trios to validate the generality of the underlying functional basis of the Hirschsprung{\textquoteright}s disease mechanisms previously found. The Pathway-Based Analysis (PBA) confirms a strong association of gene ontology (GO) modules related to signal transduction and its regulation, enteric nervous system (ENS) formation and other processes related to the disease. In addition, network analysis recovers sub-networks significantly associated to the disease, which contain genes related to the same functionalities, thus providing an independent validation of these findings. The functional profiles of association obtained for patients populations from different countries were compared to each other. While gene associations were different at each series, the main functional associations were identical in all the five populations. These observations would also explain the reported low reproducibility of associations of individual disease genes across populations.}, keywords = {GWAS, Hirschprung, network analysis, Pathway Based Analysis}, issn = {1750-1172}, doi = {10.1186/1750-1172-8-187}, url = {http://www.ojrd.com/content/8/1/187/abstract}, author = {Fern{\'a}ndez, Raquel M and Bleda, Marta and Luz{\'o}n-Toro, Berta and Garc{\'\i}a-Alonso, Luz and Arnold, Stacey and Sribudiani, Yunia and Besmond, Claude and Lantieri, Francesca and Doan, Betty and Ceccherini, Isabella and Lyonnet, Stanislas and Hofstra, Robert Mw and Chakravarti, Aravinda and Anti{\v n}olo, Guillermo and Joaqu{\'\i}n Dopazo and Borrego, Salud} } @article {495, title = {Pathways systematically associated to Hirschsprung{\textquoteright}s disease.}, journal = {Orphanet J Rare Dis}, volume = {8}, year = {2013}, month = {2013 Dec 02}, pages = {187}, abstract = {

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

}, keywords = {Female, Genetic Predisposition to Disease, Genotype, Hirschsprung Disease, Humans, Male, Polymorphism, Single Nucleotide}, issn = {1750-1172}, doi = {10.1186/1750-1172-8-187}, author = {Fern{\'a}ndez, Raquel M and Bleda, Marta and Luz{\'o}n-Toro, Berta and Garc{\'\i}a-Alonso, Luz and Arnold, Stacey and Sribudiani, Yunia and Besmond, Claude and Lantieri, Francesca and Doan, Betty and Ceccherini, Isabella and Lyonnet, Stanislas and Hofstra, Robert Mw and Chakravarti, Aravinda and Anti{\v n}olo, Guillermo and Dopazo, Joaquin and Borrego, Salud} } @article {1032, title = {Whole-exome sequencing identifies novel compound heterozygous mutations in USH2A in Spanish patients with autosomal recessive retinitis pigmentosa.}, journal = {Molecular vision}, volume = {19}, year = {2013}, month = {2013}, pages = {2187-95}, abstract = {PURPOSE: Retinitis pigmentosa (RP) is an inherited retinal dystrophy characterized by extreme genetic and clinical heterogeneity. Thus, the diagnosis is not always easily performed due to phenotypic and genetic overlap. Current clinical practices have focused on the systematic evaluation of a set of known genes for each phenotype, but this approach may fail in patients with inaccurate diagnosis or infrequent genetic cause. In the present study, we investigated the genetic cause of autosomal recessive RP (arRP) in a Spanish family in which the causal mutation has not yet been identified with primer extension technology and resequencing. METHODS: We designed a whole-exome sequencing (WES)-based approach using NimbleGen SeqCap EZ Exome V3 sample preparation kit and the SOLiD 5500{\texttimes}l next-generation sequencing platform. We sequenced the exomes of both unaffected parents and two affected siblings. Exome analysis resulted in the identification of 43,204 variants in the index patient. All variants passing filter criteria were validated with Sanger sequencing to confirm familial segregation and absence in the control population. In silico prediction tools were used to determine mutational impact on protein function and the structure of the identified variants. RESULTS: Novel Usher syndrome type 2A (USH2A) compound heterozygous mutations, c.4325T>C (p.F1442S) and c.15188T>G (p.L5063R), located in exons 20 and 70, respectively, were identified as probable causative mutations for RP in this family. Family segregation of the variants showed the presence of both mutations in all affected members and in two siblings who were apparently asymptomatic at the time of family ascertainment. Clinical reassessment confirmed the diagnosis of RP in these patients. CONCLUSIONS: Using WES, we identified two heterozygous novel mutations in USH2A as the most likely disease-causing variants in a Spanish family diagnosed with arRP in which the cause of the disease had not yet been identified with commonly used techniques. Our data reinforce the clinical role of WES in the molecular diagnosis of highly heterogeneous genetic diseases where conventional genetic approaches have previously failed in achieving a proper diagnosis.}, issn = {1090-0535}, url = {http://www.molvis.org/molvis/v19/2187/}, author = {M{\'e}ndez-Vidal, Cristina and Gonz{\'a}lez-del Pozo, Mar{\'\i}a and Vela-Boza, Alicia and Santoyo-L{\'o}pez, Javier and L{\'o}pez-Domingo, Francisco J and V{\'a}zquez-Marouschek, Carmen and Dopazo, Joaquin and Borrego, Salud and Anti{\v n}olo, Guillermo} } @article {916, title = {CellBase, a comprehensive collection of RESTful web services for retrieving relevant biological information from heterogeneous sources.}, journal = {Nucleic acids research}, volume = {40}, year = {2012}, month = {2012 Jul}, pages = {W609-14}, abstract = {During the past years, the advances in high-throughput technologies have produced an unprecedented growth in the number and size of repositories and databases storing relevant biological data. Today, there is more biological information than ever but, unfortunately, the current status of many of these repositories is far from being optimal. Some of the most common problems are that the information is spread out in many small databases; frequently there are different standards among repositories and some databases are no longer supported or they contain too specific and unconnected information. In addition, data size is increasingly becoming an obstacle when accessing or storing biological data. All these issues make very difficult to extract and integrate information from different sources, to analyze experiments or to access and query this information in a programmatic way. CellBase provides a solution to the growing necessity of integration by easing the access to biological data. CellBase implements a set of RESTful web services that query a centralized database containing the most relevant biological data sources. The database is hosted in our servers and is regularly updated. CellBase documentation can be found at http://docs.bioinfo.cipf.es/projects/cellbase.}, issn = {1362-4962}, doi = {10.1093/nar/gks575}, url = {http://nar.oxfordjournals.org/content/40/W1/W609.long}, author = {Bleda, Marta and T{\'a}rraga, Joaqu{\'\i}n and De Maria, Alejandro and Salavert, Francisco and Garc{\'\i}a-Alonso, Luz and Celma, Matilde and Martin, Ainoha and Dopazo, Joaquin and Medina, Ignacio} } @article {931, title = {Development, Characterization and Experimental Validation of a Cultivated Sunflower (Helianthus annuus L.) Gene Expression Oligonucleotide Microarray.}, journal = {PloS one}, volume = {7}, year = {2012}, month = {2012}, pages = {e45899}, abstract = {Oligonucleotide-based microarrays with accurate gene coverage represent a key strategy for transcriptional studies in orphan species such as sunflower, H. annuus L., which lacks full genome sequences. The goal of this study was the development and functional annotation of a comprehensive sunflower unigene collection and the design and validation of a custom sunflower oligonucleotide-based microarray. A large scale EST (>130,000 ESTs) curation, assembly and sequence annotation was performed using Blast2GO (www.blast2go.de). The EST assembly comprises 41,013 putative transcripts (12,924 contigs and 28,089 singletons). The resulting Sunflower Unigen Resource (SUR version 1.0) was used to design an oligonucleotide-based Agilent microarray for cultivated sunflower. This microarray includes a total of 42,326 features: 1,417 Agilent controls, 74 control probes for sunflower replicated 10 times (740 controls) and 40,169 different non-control probes. Microarray performance was validated using a model experiment examining the induction of senescence by water deficit. Pre-processing and differential expression analysis of Agilent microarrays was performed using the Bioconductor limma package. The analyses based on p-values calculated by eBayes (p<0.01) allowed the detection of 558 differentially expressed genes between water stress and control conditions; from these, ten genes were further validated by qPCR. Over-represented ontologies were identified using FatiScan in the Babelomics suite. This work generated a curated and trustable sunflower unigene collection, and a custom, validated sunflower oligonucleotide-based microarray using Agilent technology. Both the curated unigene collection and the validated oligonucleotide microarray provide key resources for sunflower genome analysis, transcriptional studies, and molecular breeding for crop improvement.}, issn = {1932-6203}, doi = {10.1371/journal.pone.0045899}, url = {http://www.plosone.org/article/info\%3Adoi\%2F10.1371\%2Fjournal.pone.0045899}, author = {Fernandez, Paula and Soria, Marcelo and Blesa, David and Dirienzo, Julio and Moschen, Sebasti{\'a}n and Rivarola, M{\'a}ximo and Clavijo, Bernardo Jose and Gonzalez, Sergio and Peluffo, Lucila and Pr{\'\i}ncipi, Dario and Dosio, Guillermo and Aguirrezabal, Luis and Garcia-Garcia, Francisco and Ana Conesa and Hopp, Esteban and Joaqu{\'\i}n Dopazo and Heinz, Ruth Amelia and Paniego, Norma} } @article {513, title = {Diversification of the expanded teleost-specific toll-like receptor family in Atlantic cod, Gadus morhua.}, journal = {BMC Evol Biol}, volume = {12}, year = {2012}, month = {2012 Dec 29}, pages = {256}, abstract = {

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

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

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

}, keywords = {Amino Acid Sequence, Animals, Binding Sites, Evolution, Molecular, Fish Diseases, Fish Proteins, Gadus morhua, Gene Expression Profiling, Genetic Variation, Gills, Head Kidney, Host-Pathogen Interactions, Models, Molecular, Molecular Sequence Data, Multigene Family, Phylogeny, Protein Structure, Tertiary, Reverse Transcriptase Polymerase Chain Reaction, Selection, Genetic, Sequence Analysis, DNA, Sequence Homology, Amino Acid, Temperature, Toll-Like Receptors, Vibrio}, issn = {1471-2148}, doi = {10.1186/1471-2148-12-256}, author = {Sundaram, Arvind Y M and Kiron, Viswanath and Dopazo, Joaquin and Fernandes, Jorge M O} } @article {902, title = {Evolutionary Genomics of Genes Involved in Olfactory Behavior in the Drosophila melanogaster Species Group.}, journal = {Evolutionary bioinformatics online}, volume = {8}, year = {2012}, month = {2012}, pages = {89-104}, abstract = {Previous comparative genomic studies of genes involved in olfactory behavior in Drosophila focused only on particular gene families such as odorant receptor and/or odorant binding proteins. However, olfactory behavior has a complex genetic architecture that is orchestrated by many interacting genes. In this paper, we present a comparative genomic study of olfactory behavior in Drosophila including an extended set of genes known to affect olfactory behavior. We took advantage of the recent burst of whole genome sequences and the development of powerful statistical tools to analyze genomic data and test evolutionary and functional hypotheses of olfactory genes in the six species of the Drosophila melanogaster species group for which whole genome sequences are available. Our study reveals widespread purifying selection and limited incidence of positive selection on olfactory genes. We show that the pace of evolution of olfactory genes is mostly independent of the life cycle stage, and of the number of life cycle stages, in which they participate in olfaction. However, we detected a relationship between evolutionary rates and the position that the gene products occupy in the olfactory system, genes occupying central positions tend to be more constrained than peripheral genes. Finally, we demonstrate that specialization to one host does not seem to be associated with bursts of adaptive evolution in olfactory genes in D. sechellia and D. erecta, the two specialists species analyzed, but rather different lineages have idiosyncratic evolutionary histories in which both historical and ecological factors have been involved.}, issn = {1176-9343}, doi = {10.4137/EBO.S8484}, url = {http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3273929/?tool=pubmed}, author = {Lavagnino, Nicol{\'a}s and Serra, Fran{\c c}ois and Arbiza, Leonardo and Dopazo, Hern{\'a}n and Hasson, Esteban} } @article {514, title = {Extensive translatome remodeling during ER stress response in mammalian cells.}, journal = {PLoS One}, volume = {7}, year = {2012}, month = {2012}, pages = {e35915}, abstract = {

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

}, keywords = {Animals, Endoplasmic Reticulum Stress, Humans, Jurkat Cells, Mice, NIH 3T3 Cells, Oligonucleotide Array Sequence Analysis, Protein Biosynthesis, RNA, Messenger, Transcription, Genetic}, issn = {1932-6203}, doi = {10.1371/journal.pone.0035915}, author = {Ventoso, Iv{\'a}n and Kochetov, Alex and Montaner, David and Dopazo, Joaquin and Santoyo, Javier} } @article {516, title = {IL1β induces mesenchymal stem cells migration and leucocyte chemotaxis through NF-κB.}, journal = {Stem Cell Rev Rep}, volume = {8}, year = {2012}, month = {2012 Sep}, pages = {905-16}, abstract = {

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

}, keywords = {Cell Adhesion, Cell Movement, Cell Proliferation, Chemokines, Chemotaxis, Leukocyte, Collagen, Fibronectins, Gene Expression Profiling, Gene Knockdown Techniques, HEK293 Cells, Humans, I-kappa B Kinase, Inflammation Mediators, Intercellular Signaling Peptides and Proteins, Interleukin-1beta, Laminin, Leukocytes, Mesenchymal Stem Cells, NF-kappa B, Oligonucleotide Array Sequence Analysis, RNA Interference, Signal Transduction}, issn = {2629-3277}, doi = {10.1007/s12015-012-9364-9}, author = {Carrero, Rub{\'e}n and Cerrada, Inmaculada and Lled{\'o}, Elisa and Dopazo, Joaquin and Garcia-Garcia, Francisco and Rubio, Mari-Paz and Trigueros, C{\'e}sar and Dorronsoro, Akaitz and Ruiz-Sauri, Amparo and Montero, Jos{\'e} Anastasio and Sep{\'u}lveda, Pilar} } @article {517, title = {Inferring the regulatory network behind a gene expression experiment.}, journal = {Nucleic Acids Res}, volume = {40}, year = {2012}, month = {2012 Jul}, pages = {W168-72}, abstract = {

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

}, keywords = {Binding Sites, Databases, Genetic, Fanconi Anemia, Gene Regulatory Networks, Internet, MicroRNAs, Software, Transcription Factors, Transcriptome}, issn = {1362-4962}, doi = {10.1093/nar/gks573}, author = {Bleda, Marta and Medina, Ignacio and Alonso, Roberto and De Maria, Alejandro and Salavert, Francisco and Dopazo, Joaquin} } @article {920, title = {A map of human microRNA variation uncovers unexpectedly high levels of variability.}, journal = {Genome medicine}, volume = {4}, year = {2012}, month = {2012 Aug 20}, pages = {62}, abstract = {ABSTRACT: BACKGROUND: MicroRNAs (miRNAs) are key components of the gene regulatory network in many species. During the past few years, these regulatory elements have been shown to be involved in an increasing number and range of diseases. Consequently, the compilation of a comprehensive map of natural variability in healthy population seems an obvious requirement for future research on miRNA-related pathologies. METHODS: Data on 14 populations from the 1000 Genomes Project were analysed, along with new data extracted from 60 exomes of healthy individuals from a southern Spain population, sequenced in the context of the Medical Genome Project, to derive an accurate map of miRNA variability. RESULTS: Despite the common belief that miRNAs are highly conserved elements, analysis of the sequences of the 1,152 individuals indicated that the observed level of variability is double what was expected. A total of 527 variants were found. Among these, 45 variants affected the recognition region of the corresponding miRNA and were found in 43 different miRNAs, 26 of which are known to be involved in 57 diseases. Different parts of the mature structure of the miRNA were affected to different degrees by variants, which suggests the existence of a selective pressure related to the relative functional impact of the change. Moreover, 41 variants showed a significant deviation from the Hardy-Weinberg equilibrium, which supports the existence of a selective process against some alleles. The average number of variants per individual in miRNAs was 28. CONCLUSIONS: Despite an expectation that miRNAs would be highly conserved genomic elements, our study reports a level of variability comparable to that observed for coding genes.}, keywords = {NGS}, issn = {1756-994X}, doi = {10.1186/gm363}, url = {http://genomemedicine.com/content/4/8/62/abstract}, author = {Carbonell, Jos{\'e} and Alloza, Eva and Arce, Pablo and Borrego, Salud and Santoyo, Javier and Ruiz-Ferrer, Macarena and Medina, Ignacio and Jim{\'e}nez-Almaz{\'a}n, Jorge and M{\'e}ndez-Vidal, Cristina and Gonz{\'a}lez-del Pozo, Mar{\'\i}a and Vela, Alicia and Bhattacharya, Shomi S and Anti{\v n}olo, Guillermo and Dopazo, Joaquin} } @article {939, title = {Select your SNPs (SYSNPs): a web tool for automatic and massive selection of SNPs.}, journal = {International journal of data mining and bioinformatics}, volume = {6}, year = {2012}, month = {2012}, pages = {324-34}, abstract = {Association studies are the choice approach in the discovery of the genomic basis of complex traits. To carry out such analysis, researchers frequently need to (1) select optimally informative sets of Single Nucleotide Polymorphisms (SNPs) in candidate regions and (2) annotate the results of associations found by means of genome-wide SNP arrays. These are complex tasks, since many criteria have to be considered, including the SNPs{\textquoteright} functional properties, technological information and haplotype frequencies in given populations. SYSNPs implements algorithms that allow for efficient and simultaneous consideration of all the relevant criteria to obtain sets of SNPs that properly cover arbitrarily large lists of genes or genomic regions. Complementarily, SYSNPs allows for comprehensive functional annotation of SNPs linked to any given marker SNP. SYSNPs dramatically reduces the effort needed for SNP selection from days of searching various databases to a few minutes using a simple browser.}, issn = {1748-5673}, url = {http://inderscience.metapress.com/content/f76740x8071u513n/}, author = {Lorente-Galdos, Bel{\'e}n and Medina, Ignacio and Morcillo-Suarez, Carlos and Heredia, Txema and Carre{\~n}o-Torres, Angel and Sangr{\'o}s, Ricardo and Alegre, Josep and Pita, Guillermo and Vellalta, Gemma and Malats, Nuria and Pisano, David G and Joaqu{\'\i}n Dopazo and Navarro, Arcadi} } @article {519, title = {SNPeffect 4.0: on-line prediction of molecular and structural effects of protein-coding variants.}, journal = {Nucleic Acids Res}, volume = {40}, year = {2012}, month = {2012 Jan}, pages = {D935-9}, abstract = {

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

}, keywords = {Databases, Protein, Humans, Internet, Meta-Analysis as Topic, Phenotype, Polymorphism, Single Nucleotide, Protein Conformation, Proteins}, issn = {1362-4962}, doi = {10.1093/nar/gkr996}, author = {De Baets, Greet and Van Durme, Joost and Reumers, Joke and Maurer-Stroh, Sebastian and Vanhee, Peter and Dopazo, Joaquin and Schymkowitz, Joost and Rousseau, Frederic} } @article {1028, title = {Transdifferentiation of MALME-3M and MCF-7 Cells toward Adipocyte-like Cells is Dependent on Clathrin-mediated Endocytosis.}, journal = {SpringerPlus}, volume = {1}, year = {2012}, month = {2012}, pages = {44}, abstract = {ABSTRACT: Enforced cell transdifferentiation of human cancer cells is a promising alternative to conventional chemotherapy. We previously identified albumin-associated lipid- and, more specifically, saturated fatty acid-induced transdifferentiation programs in human cancer cells (HCCLs). In this study, we further characterized the adipocyte-like cells, resulting from the transdifferentiation of human cancer cell lines MCF-7 and MALME-3M, and proposed a common mechanistic approach for these transdifferentiating programs. We showed the loss of pigmentation in MALME-3M cells treated with albumin-associated lipids, based on electron microscopic analysis, and the overexpression of perilipin 2 (PLIN2) by western blotting in MALME-3M and MCF-7 cells treated with unsaturated fatty acids. Comparing the gene expression profiles of naive melanoma MALME-3M cells and albumin-associated lipid-treated cells, based on RNA sequencing, we confirmed the transcriptional upregulation of some key adipogenic gene markers and also an alternative splicing of the adipogenic master regulator PPARG, that is probably related to the reported up regulated expression of the protein. Most importantly, these results also showed the upregulation of genes responsible for Clathrin (CLTC) and other adaptor-related proteins. An increase in CLTC expression in the transdifferentiated cells was confirmed by western blotting. Inactivation of CLTC by chlorpromazine (CHP), an inhibitor of CTLC mediated endocytosis (CME), and gene silencing by siRNAs, partially reversed the accumulation of neutral lipids observed in the transdifferentiated cells. These findings give a deeper insight into the phenotypic changes observed in HCCL to adipocyte-like transdifferentiation and point towards CME as a key pathway in distinct transdifferentiation programs. DISCLOSURES: Simon C and Aguilar-Gallardo C are co-inventors of the International Patent Application No. PCT/EP2011/004941 entitled "Methods for tumor treatment and adipogenesis differentiation".}, issn = {2193-1801}, doi = {10.1186/2193-1801-1-44}, url = {http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3725915/}, author = {Carcel-Trullols, Jaime and Aguilar-Gallardo, Crist{\'o}bal and Garc{\'\i}a-Alcalde, Fernando and Pardo-Cea, Miguel Angel and Dopazo, Joaquin and Ana Conesa and Simon, Carlos} } @article {523, title = {VARIANT: Command Line, Web service and Web interface for fast and accurate functional characterization of variants found by Next-Generation Sequencing.}, journal = {Nucleic Acids Res}, volume = {40}, year = {2012}, month = {2012 Jul}, pages = {W54-8}, abstract = {

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

}, keywords = {Databases, Nucleic Acid, Genetic Variation, High-Throughput Nucleotide Sequencing, Internet, Molecular Sequence Annotation, mutation, Polymorphism, Single Nucleotide, Software, User-Computer Interface}, issn = {1362-4962}, doi = {10.1093/nar/gks572}, author = {Medina, Ignacio and De Maria, Alejandro and Bleda, Marta and Salavert, Francisco and Alonso, Roberto and Gonzalez, Cristina Y and Dopazo, Joaquin} } @article {524, title = {Whole-genome bisulfite DNA sequencing of a DNMT3B mutant patient.}, journal = {Epigenetics}, volume = {7}, year = {2012}, month = {2012 Jun 01}, pages = {542-50}, abstract = {

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

}, keywords = {B-Lymphocytes, Cell Line, Transformed, Child, Preschool, DNA (Cytosine-5-)-Methyltransferases, DNA Methylation, Epigenesis, Genetic, Face, Female, Genome, Human, High-Throughput Nucleotide Sequencing, Humans, Immunologic Deficiency Syndromes, mutation, Primary Immunodeficiency Diseases, Sequence Analysis, DNA, Sulfites}, issn = {1559-2308}, doi = {10.4161/epi.20523}, author = {Heyn, Holger and Vidal, Enrique and Sayols, Sergi and Sanchez-Mut, Jose V and Moran, Sebastian and Medina, Ignacio and Sandoval, Juan and Sim{\'o}-Riudalbas, Laia and Szczesna, Karolina and Huertas, Dori and Gatto, Sole and Matarazzo, Maria R and Dopazo, Joaquin and Esteller, Manel} } @article {21335611, title = {B2G-FAR, a species centered GO annotation repository.}, journal = {Bioinformatics (Oxford, England)}, volume = {27}, number = {7}, year = {2011}, month = {2011 Feb 18}, pages = {919-924}, abstract = {

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

}, author = {G{\"o}tz, Stefan and Arnold, Roland and Sebasti{\'a}n-Leon, Patricia and Mart{\'\i}n-Rodr{\'\i}guez, Samuel and Tischler, Patrick and Jehl, Marc-Andr{\'e} and Joaqu{\'\i}n Dopazo and Rattei, Thomas and Ana Conesa} } @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 {22039362, title = {Discovery of an ebolavirus-like filovirus in europe.}, journal = {PLoS pathogens}, volume = {7}, year = {2011}, month = {2011 Oct}, pages = {e1002304}, abstract = {

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

}, author = {Negredo, Ana and Palacios, Gustavo and V{\'a}zquez-Mor{\'o}n, Sonia and Gonz{\'a}lez, F{\'e}lix and Dopazo, Hern{\'a}n and Molero, Francisca and Juste, Javier and Quetglas, Juan and Savji, Nazir and de la Cruz Mart{\'\i}nez, Maria and Herrera, Jesus Enrique and Pizarro, Manuel and Hutchison, Stephen K and Echevarr{\'\i}a, Juan E and Lipkin, W Ian and Tenorio, Antonio} } @article {22026421, title = {Evolution of the biosynthesis of di-myo-inositol phosphate, a marker of adaptation to hot marine environments.}, journal = {Environmental microbiology}, year = {2011}, month = {2011 Oct 26}, abstract = {

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

}, doi = {10.1111/j.1462-2920.2011.02621.x}, author = {Gon{\c c}alves, Lu{\'\i}s G and Borges, Nuno and Serra, Fran{\c c}ois and Fernandes, Pedro L and Dopazo, Hern{\'a}n and Santos, Helena} } @article {21731483, title = {An evolutionary trade-off between protein turnover rate and protein aggregation favors a higher aggregation propensity in fast degrading proteins.}, journal = {PLoS computational biology}, volume = {7}, year = {2011}, month = {2011 Jun}, pages = {e1002090}, abstract = {

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

}, doi = {10.1371/journal.pcbi.1002090}, author = {De Baets, Greet and Reumers, Joke and Delgado Blanco, Javier and Dopazo, Joaquin and Schymkowitz, Joost and Rousseau, Frederic} } @article {535, title = {Large-scale transcriptional profiling and functional assays reveal important roles for Rho-GTPase signalling and SCL during haematopoietic differentiation of human embryonic stem cells.}, journal = {Hum Mol Genet}, volume = {20}, year = {2011}, month = {2011 Dec 15}, pages = {4932-46}, abstract = {

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

}, keywords = {Acute Disease, Anemia, Hemolytic, Animals, Basic Helix-Loop-Helix Transcription Factors, Cell Differentiation, Cell Line, Cell Lineage, Cluster Analysis, Embryonic Stem Cells, Erythroid Cells, Flow Cytometry, Gene Expression Profiling, Hematopoietic Stem Cells, Humans, Mice, Myeloid Cells, Paracrine Communication, Proto-Oncogene Proteins, Reverse Transcriptase Polymerase Chain Reaction, rho GTP-Binding Proteins, Signal Transduction, Stem Cell Transplantation, T-Cell Acute Lymphocytic Leukemia Protein 1, Transcriptome}, issn = {1460-2083}, doi = {10.1093/hmg/ddr431}, author = {Yung, Sun and Ledran, Maria and Moreno-Gimeno, Inmaculada and Conesa, Ana and Montaner, David and Dopazo, Joaquin and Dimmick, Ian and Slater, Nicholas J and Marenah, Lamin and Real, Pedro J and Paraskevopoulou, Iliana and Bisbal, Viviana and Burks, Deborah and Santibanez-Koref, Mauro and Moreno, Ruben and Mountford, Joanne and Menendez, Pablo and Armstrong, Lyle and Lako, Majlinda} } @article {21190976, title = {Modeling human endometrial decidualization from the interaction between proteome and secretome.}, journal = {The Journal of clinical endocrinology and metabolism}, volume = {96}, year = {2011}, month = {2011 Mar}, pages = {706-16}, abstract = {

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

}, author = {Garrido-Gomez, Tamara and Dominguez, Francisco and Lopez, Juan Antonio and Camafeita, Emilio and Qui{\~n}onero, Alicia and Martinez-Conejero, Jose Antonio and Pellicer, Antonio and Ana Conesa and Simon, Carlos} } @article {536, title = {Mutation screening of multiple genes in Spanish patients with autosomal recessive retinitis pigmentosa by targeted resequencing.}, journal = {PLoS One}, volume = {6}, year = {2011}, month = {2011}, pages = {e27894}, abstract = {

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

}, keywords = {Alleles, DNA Mutational Analysis, Exons, Genetic Variation, Genome, Hispanic or Latino, Humans, Introns, Language, mutation, Mutation, Missense, Oligonucleotide Array Sequence Analysis, Polymerase Chain Reaction, Reproducibility of Results, Retinitis pigmentosa, United States}, issn = {1932-6203}, doi = {10.1371/journal.pone.0027894}, author = {Gonz{\'a}lez-del Pozo, Mar{\'\i}a and Borrego, Salud and Barrag{\'a}n, Isabel and Pieras, Juan I and Santoyo, Javier and Matamala, Nerea and Naranjo, Bel{\'e}n and Dopazo, Joaquin and Anti{\v n}olo, Guillermo} } @article {541, title = {myKaryoView: a light-weight client for visualization of genomic data.}, journal = {PLoS One}, volume = {6}, year = {2011}, month = {2011}, pages = {e26345}, abstract = {

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

}, keywords = {Computer Graphics, Databases, Genetic, Genomics, Internet, Molecular Sequence Annotation, User-Computer Interface}, issn = {1932-6203}, doi = {10.1371/journal.pone.0026345}, author = {Jimenez, Rafael C and Salazar, Gustavo A and Gel, Bernat and Dopazo, Joaquin and Mulder, Nicola and Corpas, Manuel} } @article {537, title = {Natural selection on functional modules, a genome-wide analysis.}, journal = {PLoS Comput Biol}, volume = {7}, year = {2011}, month = {2011 Mar}, pages = {e1001093}, abstract = {

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

}, keywords = {Animals, Databases, Genetic, Drosophila, Genome, Insect, Genome-Wide Association Study, Genomics, Mammals, Phylogeny, Selection, Genetic, Sequence Analysis, DNA}, issn = {1553-7358}, doi = {10.1371/journal.pcbi.1001093}, author = {Serra, Fran{\c c}ois and Arbiza, Leonardo and Dopazo, Joaquin and Dopazo, Hern{\'a}n} } @article {539, title = {Phylemon 2.0: a suite of web-tools for molecular evolution, phylogenetics, phylogenomics and hypotheses testing.}, journal = {Nucleic Acids Res}, volume = {39}, year = {2011}, month = {2011 Jul}, pages = {W470-4}, abstract = {

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

}, keywords = {Evolution, Molecular, Genomics, Internet, Phylogeny, Sequence Alignment, Software}, issn = {1362-4962}, doi = {10.1093/nar/gkr408}, author = {S{\'a}nchez, Rub{\'e}n and Serra, Fran{\c c}ois and T{\'a}rraga, Joaqu{\'\i}n and Medina, Ignacio and Carbonell, Jos{\'e} and Pulido, Luis and De Maria, Alejandro and Capella-Gut{\'\i}errez, Salvador and Huerta-Cepas, Jaime and Gabald{\'o}n, Toni and Dopazo, Joaquin and Dopazo, Hern{\'a}n} } @article {21412950, title = {Phylogenetic and in silico structural analysis of the Parkinson disease-related kinase PINK1.}, journal = {Human mutation}, volume = {32}, year = {2011}, month = {2011 Apr}, pages = {369-78}, abstract = {

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

}, doi = {10.1002/humu.21444}, author = {Cardona, Fernando and S{\'a}nchez-Mut, Jose Vicente and Dopazo, Hern{\'a}n and P{\'e}rez-Tur, Jordi} } @article {21605378, title = {Profiling the venom gland transcriptomes of Costa Rican snakes by 454 pyrosequencing.}, journal = {BMC genomics}, volume = {12}, year = {2011}, month = {2011}, pages = {259}, abstract = {

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

}, author = {Durban, Jordi and Ju{\'a}rez, Paula and Angulo, Yamileth and Lomonte, Bruno and Flores-Diaz, Marietta and Alape-Gir{\'o}n, Alberto and Sasa, Mahmood and Sanz, Libia and Guti{\'e}rrez, Jos{\'e} M and Joaqu{\'\i}n Dopazo and Ana Conesa and Calvete, Juan J} } @article {21261943, title = {Recent human evolution has shaped geographical differences in susceptibility to disease.}, journal = {BMC genomics}, volume = {12}, year = {2011}, month = {2011}, pages = {55}, abstract = {

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

}, author = {Marigorta, Urko M and Lao, Oscar and Casals, Ferran and Calafell, Francesc and Morcillo-Suarez, Carlos and Faria, Rui and Bosch, Elena and Serra, Fran{\c c}ois and Bertranpetit, Jaume and Dopazo, Hern{\'a}n and Navarro, Arcadi} } @article {21554455, title = {Role of tomato BRANCHED1-like genes in the control of shoot branching.}, journal = {The Plant journal : for cell and molecular biology}, volume = {67}, year = {2011}, month = {2011 Aug}, pages = {701-14}, abstract = {

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

}, doi = {10.1111/j.1365-313X.2011.04629.x}, author = {Mart{\'\i}n-Trillo, Mar and Grand{\'\i}o, Eduardo Gonz{\'a}lez and Serra, Fran{\c c}ois and Marcel, Fabien and Rodr{\'\i}guez-Buey, Mar{\'\i}a Luisa and Schmitz, Gregor and Theres, Klaus and Bendahmane, Abdelhafid and Dopazo, Hern{\'a}n and Cubas, Pilar} } @article {903, title = {Sexual selection halts the relaxation of protamine 2 among rodents.}, journal = {PloS one}, volume = {6}, year = {2011}, month = {2011}, pages = {e29247}, abstract = {Sexual selection has been proposed as the driving force promoting the rapid evolutionary changes observed in some reproductive genes including protamines. We test this hypothesis in a group of rodents which show marked differences in the intensity of sexual selection. Levels of sperm competition were not associated with the evolutionary rates of protamine 1 but, contrary to expectations, were negatively related to the evolutionary rate of cleaved- and mature-protamine 2. Since both domains were found to be under relaxation, our findings reveal an unforeseen role of sexual selection: to halt the degree of degeneration that proteins within families may experience due to functional redundancy. The degree of relaxation of protamine 2 in this group of rodents is such that in some species it has become dysfunctional and it is not expressed in mature spermatozoa. In contrast, protamine 1 is functionally conserved but shows directed positive selection on specific sites which are functionally relevant such as DNA-anchoring domains and phosphorylation sites. We conclude that in rodents protamine 2 is under relaxation and that sexual selection removes deleterious mutations among species with high levels of sperm competition to maintain the protein functional and the spermatozoa competitive.}, issn = {1932-6203}, doi = {10.1371/journal.pone.0029247}, url = {http://www.plosone.org/article/info\%3Adoi\%2F10.1371\%2Fjournal.pone.0029247}, author = {L{\"u}ke, Lena and Vicens, Alberto and Serra, Fran{\c c}ois and Luque-Larena, Juan Jose and Dopazo, Hern{\'a}n and Roldan, Eduardo R S and Gomendio, Montserrat} } @article {21131981, title = {The three-dimensional folding of the α-globin gene domain reveals formation of chromatin globules.}, journal = {Nature structural \& molecular biology}, volume = {18}, year = {2011}, month = {2011 Jan}, pages = {107-14}, abstract = {

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

}, author = {Ba{\`u}, Davide and Sanyal, Amartya and Lajoie, Bryan R and Capriotti, Emidio and Byron, Meg and Lawrence, Jeanne B and Dekker, Job and Marti-Renom, Marc A} } @article {20478823, title = {Babelomics: an integrative platform for the analysis of transcriptomics, proteomics and genomic data with advanced functional profiling.}, journal = {Nucleic Acids Research}, volume = {38}, year = {2010}, month = {2010 May 16}, pages = {W210-W213. Featured in NAR}, chapter = {Featured in NAR}, abstract = {

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

}, keywords = {babelomics, gene expression, genotyping, gepas, GSA, GWAS}, url = {http://nar.oxfordjournals.org/content/38/suppl_2/W210.full}, author = {Medina, Ignacio and Carbonell, Jos{\'e} and Pulido, Luis and Madeira, Sara C and Goetz, Stefan and Ana Conesa and T{\'a}rraga, Joaqu{\'\i}n and Pascual-Montano, Alberto and Nogales-Cadenas, Ruben and Santoyo, Javier and Garc{\'\i}a, Francisco and Marb{\`a}, Martina and Montaner, David and Joaqu{\'\i}n Dopazo} } @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 {20164864, title = {Fine-scale evolution: genomic, phenotypic and ecological differentiation in two coexisting Salinibacter ruber strains.}, journal = {The ISME journal}, year = {2010}, month = {2010 Feb 18}, abstract = {

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

}, author = {Pe{\~n}a, Arantxa and Teeling, Hanno and Huerta-Cepas, Jaime and Santos, Fernando and Yarza, Pablo and Brito-Echeverr{\'\i}a, Jocelyn and Lucio, Marianna and Schmitt-Kopplin, Philippe and Meseguer, Inmaculada and Schenowitz, Chantal and Dossat, Carole and Barbe, Valerie and Joaqu{\'\i}n Dopazo and Rossell{\'o}-Mora, Ramon and Sch{\"u}ler, Margarete and Gl{\"o}ckner, Frank Oliver and Amann, Rudolf and Gabald{\'o}n, Toni and Ant{\'o}n, Josefa} } @article {19897487, title = {FM19G11, a new hypoxia-inducible factor (HIF) modulator, affects stem cell differentiation status.}, journal = {The Journal of biological chemistry}, volume = {285}, year = {2010}, month = {2010 Jan 8}, pages = {1333-42}, abstract = {

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

}, author = {Moreno-Manzano, Victoria and Rodr{\'\i}guez-Jim{\'e}nez, Francisco J and Ace{\~n}a-Bonilla, Jose L and Fustero-Lard{\'\i}es, Santos and Erceg, Slaven and Dopazo, Joaquin and Montaner, David and Stojkovic, Miodrag and S{\'a}nchez-Puelles, Jose M} } @article {542, title = {Functional analysis of multiple genomic signatures demonstrates that classification algorithms choose phenotype-related genes.}, journal = {Pharmacogenomics J}, volume = {10}, year = {2010}, month = {2010 Aug}, pages = {310-23}, abstract = {

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

}, keywords = {Algorithms, Databases, Genetic, Endpoint Determination, Gene Expression Profiling, Genomics, Humans, Neural Networks, Computer, Oligonucleotide Array Sequence Analysis, Phenotype, Predictive Value of Tests, Proteins, Quality Control}, issn = {1473-1150}, doi = {10.1038/tpj.2010.35}, author = {Shi, W and Bessarabova, M and Dosymbekov, D and Dezso, Z and Nikolskaya, T and Dudoladova, M and Serebryiskaya, T and Bugrim, A and Guryanov, A and Brennan, R J and Shah, R and Dopazo, J and Chen, M and Deng, Y and Shi, T and Jurman, G and Furlanello, C and Thomas, R S and Corton, J C and Tong, W and Shi, L and Nikolsky, Y} } @article {553, title = {Functional genomics of 5- to 8-cell stage human embryos by blastomere single-cell cDNA analysis.}, journal = {PLoS One}, volume = {5}, year = {2010}, month = {2010 Oct 26}, pages = {e13615}, abstract = {

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

}, keywords = {Blastomeres, DNA, Complementary, Gene Expression Profiling, Genomics, Humans, Oligonucleotide Array Sequence Analysis}, issn = {1932-6203}, doi = {10.1371/journal.pone.0013615}, author = {Galan, Amparo and Montaner, David and P{\'o}o, M Eugenia and Valbuena, Diana and Ruiz, Veronica and Aguilar, Crist{\'o}bal and Dopazo, Joaquin and Simon, Carlos} } @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 {20361057, title = {Initial genomics of the human nucleolus.}, journal = {PLoS genetics}, volume = {6}, year = {2010}, month = {2010}, pages = {e1000889}, abstract = {

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

}, keywords = {NGS, nucleolus}, doi = {10.1371/journal.pgen.1000889}, url = {http://www.plosgenetics.org/article/info\%3Adoi\%2F10.1371\%2Fjournal.pgen.1000889}, author = {N{\'e}meth, Attila and Ana Conesa and Santoyo-L{\'o}pez, Javier and Medina, Ignacio and Montaner, David and P{\'e}terfia, B{\'a}lint and Solovei, Irina and Cremer, Thomas and Dopazo, Joaquin and L{\"a}ngst, Gernot} } @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 {575, title = {Mutation spectrum of EYS in Spanish patients with autosomal recessive retinitis pigmentosa.}, journal = {Hum Mutat}, volume = {31}, year = {2010}, month = {2010 Nov}, pages = {E1772-800}, abstract = {

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

}, keywords = {Amino Acid Sequence, Animals, Case-Control Studies, DNA Mutational Analysis, Drosophila Proteins, Evolution, Molecular, Eye Proteins, Female, Genes, Recessive, Genetic Variation, Humans, Male, Molecular Sequence Data, mutation, Pedigree, Polymorphism, Single Nucleotide, Protein Structure, Tertiary, Retinitis pigmentosa, Spain, Structural Homology, Protein}, issn = {1098-1004}, doi = {10.1002/humu.21334}, author = {Barrag{\'a}n, Isabel and Borrego, Salud and Pieras, Juan Ignacio and Gonz{\'a}lez-del Pozo, Mar{\'\i}a and Santoyo, Javier and Ayuso, Carmen and Baiget, Montserrat and Mill{\'a}n, Jos{\'e} M and Mena, Marcela and Abd El-Aziz, Mai M and Audo, Isabelle and Zeitz, Christina and Littink, Karin W and Dopazo, Joaquin and Bhattacharya, Shomi S and Anti{\v n}olo, Guillermo} } @article {19587024, title = {Alignment of multiple protein structures based on sequence and structure features.}, journal = {Protein engineering, design \& selection : PEDS}, volume = {22}, year = {2009}, month = {2009 Sep}, pages = {569-74}, abstract = {

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

}, author = {Madhusudhan, M. S. and Webb, Benjamin M and Marti-Renom, Marc A and Eswar, Narayanan and Sali, Andrej} } @article {578, title = {Exploring the antimicrobial action of a carbon monoxide-releasing compound through whole-genome transcription profiling of Escherichia coli.}, journal = {Microbiology (Reading)}, volume = {155}, year = {2009}, month = {2009 Mar}, pages = {813-824}, abstract = {

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

}, keywords = {Biofilms, Carbon Monoxide, Escherichia coli, Escherichia coli Proteins, Gene Expression Profiling, Gene Expression Regulation, Bacterial, Genes, Bacterial, Genes, Regulator, Genetic Complementation Test, Methionine, Microbial Viability, mutation, Oligonucleotide Array Sequence Analysis, Organometallic Compounds, Phenotype, RNA, Bacterial}, issn = {1350-0872}, doi = {10.1099/mic.0.023911-0}, author = {Nobre, L{\'\i}gia S and Al-Shahrour, F{\'a}tima and Dopazo, Joaquin and Saraiva, L{\'\i}gia M} } @article {19246752, title = {Exploring the antimicrobial action of a carbon monoxide-releasing compound through whole-genome transcription profiling of Escherichia coli}, journal = {Microbiology}, volume = {155}, number = {Pt 3}, year = {2009}, note = {

Nobre, Ligia S Al-Shahrour, Fatima Dopazo, Joaquin Saraiva, Ligia M Research Support, Non-U.S. Gov{\textquoteright}t England Microbiology (Reading, England) Microbiology. 2009 Mar;155(Pt 3):813-24.

}, pages = {813-24}, abstract = {

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

}, keywords = {Bacterial Genes, Bacterial/genetics, Biofilms Carbon Monoxide/*metabolism Escherichia coli/*genetics/metabolism Escherichia coli Proteins/genetics/metabolism *Gene Expression Profiling Gene Expression Regulation, Regulator Genetic Complementation Test Methionine/metabolism Microbial Viability Mutation Oligonucleotide Array Sequence Analysis Organometallic Compounds/*pharmacology Phenotype RNA}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=19246752}, author = {Nobre, L. S. and Fatima Al-Shahrour and Dopazo, J. and Saraiva, L. M.} } @article {580, title = {Functional assessment of time course microarray data.}, journal = {BMC Bioinformatics}, volume = {10 Suppl 6}, year = {2009}, month = {2009 Jun 16}, pages = {S9}, abstract = {

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

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

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

}, keywords = {Computer Simulation, Gene Expression Profiling, Oligonucleotide Array Sequence Analysis, Time Factors}, issn = {1471-2105}, doi = {10.1186/1471-2105-10-S6-S9}, author = {Nueda, Maria Jos{\'e} and Sebasti{\'a}n, Patricia and Tarazona, Sonia and Garcia-Garcia, Francisco and Dopazo, Joaquin and Ferrer, Alberto and Conesa, Ana} } @article {581, title = {Functional signatures identified in B-cell non-Hodgkin lymphoma profiles.}, journal = {Leuk Lymphoma}, volume = {50}, year = {2009}, month = {2009 Oct}, pages = {1699-708}, abstract = {

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

}, keywords = {Adult, Cluster Analysis, Gene Expression Profiling, Gene Expression Regulation, Leukemic, Genetic Heterogeneity, Humans, Lymphoma, B-Cell, Neoplasm Proteins, Oligonucleotide Array Sequence Analysis, RNA, Messenger, RNA, Neoplasm, Transcription, Genetic}, issn = {1029-2403}, doi = {10.1080/10428190903189035}, author = {Aggarwal, Mohit and S{\'a}nchez-Beato, Margarita and G{\'o}mez-L{\'o}pez, Gonzalo and Al-Shahrour, F{\'a}tima and Mart{\'\i}nez, Nerea and Rodr{\'\i}guez, Antonia and Ruiz-Ballesteros, Elena and Camacho, Francisca I and P{\'e}rez-Rosado, Alberto and de la Cueva, Paloma and Artiga, Mar{\'\i}a J and Pisano, David G and Kimby, Eva and Dopazo, Joaquin and Villuendas, Raquel and Piris, Miguel A} } @inbook {761, title = {Gen{\'o}mica Comparativa y Selecci{\'o}n Natural. Aplicaciones en el Genoma Humano. Cap{\'\i}tulo 1.6}, booktitle = {Evoluci{\'o}n y Adaptac{\'o}n. 150 a{\~n}os despu{\'e}s del Origen de las Especies}, year = {2009}, pages = {51-59}, publisher = {Obrapropia.}, organization = {Obrapropia.}, chapter = {19}, address = {Valencia}, abstract = {

La b\úsqueda de los eventos adaptativos a nivel molecular que ha diferenciado el genoma humano del de nuestro pariente vivo m\ás cercano, el chimpanc\é, ha sido una de las \áreas de mayor investigaci\ón en gen\ómica comparativa. Paralelamente, la predicci\ón funcional de variantes gen\éticas en nuestra especie ha sido un \área de intenso desarrollo en bioinform\ática. En este trabajo discutiremos resultados previos y otros m\ás recientes que dan cuenta de estos desarrollos. Veremos que en todos los casos la estimaci\ón de las presiones selectivas a nivel de los genes individuales o de los residuos de las prote\ínas son el denominador com\ún para discutir ambos aspectos. Finalmente mostraremos c\ómo el an\álisis de estas presiones selectivas por grupos funcionales de genes resulta una alternativa viable y con suficiente poder estad\ístico para el an\álisis de la adaptaci\ón y de las restricciones evolutivas a nivel gen\ómico.\ 

}, issn = {978-84-92910-06-9}, author = {Serra, Fran{\c c}ois and Arbiza, L. and H. Dopazo}, editor = {H. Dopazo and Navarro, A.} } @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 {19190944, title = {Membrane transporters and carbon metabolism implicated in chloride homeostasis differentiate salt stress responses in tolerant and sensitive Citrus rootstocks}, journal = {Funct Integr Genomics}, year = {2009}, note = {

Journal article Functional \& integrative genomics Funct Integr Genomics. 2009 Feb 4.

}, abstract = {

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

}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=19190944}, author = {Brumos, J. and Colmenero-Flores, J. M. and A. Conesa and Izquierdo, P. and Sanchez, G. and Iglesias, D. J. and Lopez-Climent, M. F. and Gomez-Cadenas, A. and Talon, M.} } @article {18948282, title = {MODBASE, a database of annotated comparative protein structure models and associated resources}, journal = {Nucleic Acids Res}, volume = {37}, number = {Database issue}, year = {2009}, note = {Pieper, Ursula Eswar, Narayanan Webb, Ben M Eramian, David Kelly, Libusha Barkan, David T Carter, Hannah Mankoo, Parminder Karchin, Rachel Marti-Renom, Marc A Davis, Fred P Sali, Andrej GM08284/GM/NIGMS NIH HHS/United States P01 GM71790/GM/NIGMS NIH HHS/United States R01 GM54762/GM/NIGMS NIH HHS/United States U01 GM61390/GM/NIGMS NIH HHS/United States U54 GM074929/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 Research Support, U.S. Gov{\textquoteright}t, Non-P.H.S. England Nucleic acids research Nucleic Acids Res. 2009 Jan;37(Database issue):D347-54. Epub 2008 Oct 23.}, pages = {D347-54}, abstract = {MODBASE (http://salilab.org/modbase) is a database of annotated comparative protein structure models. The models are calculated by MODPIPE, an automated modeling pipeline that relies primarily on MODELLER for fold assignment, sequence-structure alignment, model building and model assessment (http:/salilab.org/modeller). MODBASE currently contains 5,152,695 reliable models for domains in 1,593,209 unique protein sequences; only models based on statistically significant alignments and/or models assessed to have the correct fold are included. MODBASE also allows users to calculate comparative models on demand, through an interface to the MODWEB modeling server (http://salilab.org/modweb). Other resources integrated with MODBASE include databases of multiple protein structure alignments (DBAli), structurally defined ligand binding sites (LIGBASE), predicted ligand binding sites (AnnoLyze), structurally defined binary domain interfaces (PIBASE) and annotated single nucleotide polymorphisms and somatic mutations found in human proteins (LS-SNP, LS-Mut). MODBASE models are also available through the Protein Model Portal (http://www.proteinmodelportal.org/).}, keywords = {*Databases, Molecular Mutation Polymorphism, Protein Genomics Humans Ligands *Models, Protein User-Computer Interface, Single Nucleotide Protein Folding Protein Interaction Domains and Motifs *Protein Structure, Tertiary Proteins/genetics *Structural Homology}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=18948282}, author = {Pieper, U. and Eswar, N. and Webb, B. M. and Eramian, D. and Kelly, L. and Barkan, D. T. and Carter, H. and Mankoo, P. and Karchin, R. and M. A. Marti-Renom and Davis, F. P. and Sali, A.} } @article { PubMed_19441879, title = {Modeling and managing experimental data using FuGE.}, journal = {OMICS}, volume = {13}, number = {3}, year = {2009}, pages = {239-51}, issn = {1557-8100}, author = {Andrew R Jones and Allyson L Lister and Leandro Hermida and Peter Wilkinson and Martin Eisenacher and Khalid Belhajjame and Frank Gibson and Phil Lord and Matthew Pocock and Heiko Rosenfelder and Santoyo-L{\'o}pez, Javier and Anil Wipat and Norman W Paton} } @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 { PubMed_19781058, title = {Parallel changes in gene expression in peripheral blood mononuclear cells and the brain after maternal separation in the mouse.}, journal = {BMC Res Notes}, volume = {2}, year = {2009}, pages = {195}, issn = {1756-0500}, author = {Johan H van Heerden and Ana Conesa and Dan J Stein and Montaner, David and Vivienne Russell and Nicola Illing} } @conference {585, title = {Peripheral blood cells transcriptome to study new biomarkers for myocardial infarction follow up}, year = {2009}, month = {06}, author = {Silbiger, Vivian and Luchessi, Andr{\'e} and Hirata, Rosario and Carracedo, {\'A}ngel and Bri{\'o}n, Maria and Lima Neto, Lidio and P. Pastorelli, C and Dopazo, Joaquin and Montaner, David and Garcia, F and P. Sampaio, M and P. Pereira, M and S. Santos, E and Armaganijan, Dikran and Hirata, Mario} } @article {722, title = {Statistical methods for analysis of high-throughput RNA interference screens}, journal = {Nature Methods}, volume = {6}, year = {2009}, note = {

10.1038/nmeth.1351

}, month = {2009/08//print}, pages = {569 - 575}, publisher = {Nature Publishing Group}, keywords = {gene silencing, regulation, siRNA}, isbn = {1548-7091}, url = {http://dx.doi.org/10.1038/nmeth.1351}, author = {Birmingham, Amanda and Selfors, Laura M and Forster, Thorsten and Wrobel, David and Kennedy, Caleb J and Shanks, Emma and Santoyo-L{\'o}pez, Javier and Dunican, Dara J and Long, Aideen and Kelleher, Dermot and Smith, Queta and Beijersbergen, Roderick L and Ghazal, Peter and Shamu, Caroline E} } @inbook {469, title = {Structural Comparison and Alignment}, booktitle = {Structural Bioinformatics}, year = {2009}, publisher = {Wiley-Blackwell}, organization = {Wiley-Blackwell}, edition = {2nd}, address = {New Jersey. USA}, keywords = {Structural Bioinformatics}, url = {http://www.amazon.com/gp/product/0470181052/}, author = {M. A. Marti-Renom and E. Capriotti and Shindyalov, I. and Bourne, P.} } @article {17597009, title = {CLEAR-test: combining inference for differential expression and variability in microarray data analysis}, journal = {J Biomed Inform}, volume = {41}, number = {1}, year = {2008}, note = {

Valls, Joan Grau, Monica Sole, Xavier Hernandez, Pilar Montaner, David Dopazo, Joaquin Peinado, Miguel A Capella, Gabriel Moreno, Victor Pujana, Miguel Angel Comparative Study Research Support, Non-U.S. Gov{\textquoteright}t United States Journal of biomedical informatics J Biomed Inform. 2008 Feb;41(1):33-45. Epub 2007 May 17.

}, pages = {33-45}, abstract = {

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

}, keywords = {*Algorithms Artificial Intelligence *Data Interpretation, Statistical Gene Expression Profiling/*methods Gene Expression Regulation/*physiology Oligonucleotide Array Sequence Analysis/*methods Proteome/*metabolism Signal Transduction/*physiology}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=17597009}, author = {Valls, J. and Grau, M. and Sole, X. and Hernandez, P. and Montaner, D. and Dopazo, J. and Peinado, M. A. and Capella, G. and Moreno, V. and Pujana, M. A.} } @article {18697870, title = {Controlled ovarian stimulation induces a functional genomic delay of the endometrium with potential clinical implications}, journal = {J Clin Endocrinol Metab}, volume = {93}, number = {11}, year = {2008}, note = {

Horcajadas, Jose A Minguez, Pablo Dopazo, Joaquin Esteban, Francisco J Dominguez, Francisco Giudice, Linda C Pellicer, Antonio Simon, Carlos Research Support, Non-U.S. Gov{\textquoteright}t United States The Journal of clinical endocrinology and metabolism J Clin Endocrinol Metab. 2008 Nov;93(11):4500-10. Epub 2008 Aug 12.

}, pages = {4500-10}, abstract = {

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

}, keywords = {Algorithms Chorionic Gonadotropin/genetics Endometrium/cytology/pathology/*physiology/physiopathology Female Gene Expression Regulation Genome, Human Glutathione Peroxidase/genetics Humans Insulin-Like Growth Factor Binding Proteins/genetics Luteal Phase/physiology Luteinizing Hormone/genetics Menstrual Cycle Oligonucleotide Array Sequence Analysis Ovulation Induction/*methods RNA/genetics/isola}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=18697870}, author = {Horcajadas, J. A. and Minguez, P. and Dopazo, J. and Esteban, F. J. and Dominguez, F. and Giudice, L. C. and Pellicer, A. and Simon, C.} } @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 {18086700, title = {Joint annotation of coding and non-coding single nucleotide polymorphisms and mutations in the SNPeffect and PupaSuite databases}, journal = {Nucleic Acids Res}, volume = {36}, number = {Database issue}, year = {2008}, note = {

Reumers, Joke Conde, Lucia Medina, Ignacio Maurer-Stroh, Sebastian Van Durme, Joost Dopazo, Joaquin Rousseau, Frederic Schymkowitz, Joost Research Support, Non-U.S. Gov{\textquoteright}t England Nucleic acids research Nucleic Acids Res. 2008 Jan;36(Database issue):D825-9. Epub 2007 Dec 17.

}, pages = {D825-9}, abstract = {

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

}, keywords = {Amino Acid Substitution Animals *Databases, Genetic Genetic Diseases, Inborn/genetics HSP70 Heat-Shock Proteins/metabolism Humans Internet Mice MicroRNAs/metabolism *Mutation *Polymorphism, Single Nucleotide Proteins/chemistry/genetics RNA Splice Sites Rats Transcription Factors/metabolism}, url = {http://nar.oxfordjournals.org/cgi/content/full/36/suppl_1/D825}, author = {Reumers, J. and L. Conde and Medina, Ignacio and Maurer-Stroh, S. and Van Durme, J. and Dopazo, J. and Rousseau, F. and Schymkowitz, J.} } @article {596, title = {Joint annotation of coding and non-coding single nucleotide polymorphisms and mutations in the SNPeffect and PupaSuite databases.}, journal = {Nucleic Acids Res}, volume = {36}, year = {2008}, month = {2008 Jan}, pages = {D825-9}, abstract = {

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

}, keywords = {Amino Acid Substitution, Animals, Databases, Genetic, Genetic Diseases, Inborn, HSP70 Heat-Shock Proteins, Humans, Internet, Mice, MicroRNAs, mutation, Polymorphism, Single Nucleotide, Proteins, Rats, RNA Splice Sites, Transcription Factors}, issn = {1362-4962}, doi = {10.1093/nar/gkm979}, author = {Reumers, Joke and Conde, Lucia and Medina, Ignacio and Maurer-Stroh, Sebastian and Van Durme, Joost and Dopazo, Joaquin and Rousseau, Frederic and Schymkowitz, Joost} } @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 {599, title = {SNP and haplotype mapping for genetic analysis in the rat.}, journal = {Nat Genet}, volume = {40}, year = {2008}, month = {2008 May}, pages = {560-6}, abstract = {

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

}, keywords = {Animals, Chromosome Mapping, Databases, Genetic, Genome, Haplotypes, Linkage Disequilibrium, Phylogeny, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Rats, Rats, Inbred Strains, Recombination, Genetic}, issn = {1546-1718}, doi = {10.1038/ng.124}, author = {Saar, Kathrin and Beck, Alfred and Bihoreau, Marie-Th{\'e}r{\`e}se and Birney, Ewan and Brocklebank, Denise and Chen, Yuan and Cuppen, Edwin and Demonchy, Stephanie and Dopazo, Joaquin and Flicek, Paul and Foglio, Mario and Fujiyama, Asao and Gut, Ivo G and Gauguier, Dominique and Guig{\'o}, Roderic and Guryev, Victor and Heinig, Matthias and Hummel, Oliver and Jahn, Niels and Klages, Sven and Kren, Vladimir and Kube, Michael and Kuhl, Heiner and Kuramoto, Takashi and Kuroki, Yoko and Lechner, Doris and Lee, Young-Ae and Lopez-Bigas, Nuria and Lathrop, G Mark and Mashimo, Tomoji and Medina, Ignacio and Mott, Richard and Patone, Giannino and Perrier-Cornet, Jeanne-Antide and Platzer, Matthias and Pravenec, Michal and Reinhardt, Richard and Sakaki, Yoshiyuki and Schilhabel, Markus and Schulz, Herbert and Serikawa, Tadao and Shikhagaie, Medya and Tatsumoto, Shouji and Taudien, Stefan and Toyoda, Atsushi and Voigt, Birger and Zelenika, Diana and Zimdahl, Heike and Hubner, Norbert} } @article {18443594, title = {SNP and haplotype mapping for genetic analysis in the rat}, journal = {Nat Genet}, volume = {40}, number = {5}, year = {2008}, note = {

STAR Consortium Saar, Kathrin Beck, Alfred Bihoreau, Marie-Therese Birney, Ewan Brocklebank, Denise Chen, Yuan Cuppen, Edwin Demonchy, Stephanie Dopazo, Joaquin Flicek, Paul Foglio, Mario Fujiyama, Asao Gut, Ivo G Gauguier, Dominique Guigo, Roderic Guryev, Victor Heinig, Matthias Hummel, Oliver Jahn, Niels Klages, Sven Kren, Vladimir Kube, Michael Kuhl, Heiner Kuramoto, Takashi Kuroki, Yoko Lechner, Doris Lee, Young-Ae Lopez-Bigas, Nuria Lathrop, G Mark Mashimo, Tomoji Medina, Ignacio Mott, Richard Patone, Giannino Perrier-Cornet, Jeanne-Antide Platzer, Matthias Pravenec, Michal Reinhardt, Richard Sakaki, Yoshiyuki Schilhabel, Markus Schulz, Herbert Serikawa, Tadao Shikhagaie, Medya Tatsumoto, Shouji Taudien, Stefan Toyoda, Atsushi Voigt, Birger Zelenika, Diana Zimdahl, Heike Hubner, Norbert 057733/Z/99/A/Wellcome Trust/United Kingdom 066780/Z/01/Z/Wellcome Trust/United Kingdom Research Support, Non-U.S. Gov{\textquoteright}t Technical Report United States Nature genetics Nat Genet. 2008 May;40(5):560-6.

}, pages = {560-6}, abstract = {

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

}, keywords = {Animals Chromosome Mapping *Databases, Genetic, Genetic Genome *Haplotypes Linkage Disequilibrium Phylogeny *Polymorphism, Inbred Strains/*genetics Recombination, Single Nucleotide *Quantitative Trait Loci Rats/*genetics Rats}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=18443594}, author = {K. Saar and A. Beck and M. T. Bihoreau and E. Birney and D. Brocklebank and Y. Chen and E. Cuppen and S. Demonchy and Dopazo, J. and P. Flicek and M. Foglio and A. Fujiyama and I. G. Gut and D. Gauguier and R. Guigo and V. Guryev and M. Heinig and O. Hummel and N. Jahn and S. Klages and V. Kren and M. Kube and H. Kuhl and Kuramoto, T. and Kuroki, Y. and Lechner, D. and Lee, Y. A. and Lopez-Bigas, N. and Lathrop, G. M. and Mashimo, T. and Medina, Ignacio and Mott, R. and Patone, G. and Perrier-Cornet, J. A. and Platzer, M. and Pravenec, M. and Reinhardt, R. and Sakaki, Y. and Schilhabel, M. and Schulz, H. and Serikawa, T. and Shikhagaie, M. and Tatsumoto, S. and Taudien, S. and Toyoda, A. and Voigt, B. and Zelenika, D. and Zimdahl, H. and Hubner, N.} } @article {18552980, title = {Time course profiling of the retinal transcriptome after optic nerve transection and optic nerve crush}, journal = {Mol Vis}, volume = {14}, year = {2008}, note = {Agudo, Marta Perez-Marin, Maria Cruz Lonngren, Ulrika Sobrado, Paloma Conesa, Ana Canovas, Isabel Salinas-Navarro, Manuel Miralles-Imperial, Jaime Hallbook, Finn Vidal-Sanz, Manuel Research Support, Non-U.S. Gov{\textquoteright}t United States Molecular vision Mol Vis. 2008 Jun 3;14:1050-63.}, pages = {1050-63}, abstract = {PURPOSE: A time-course analysis of gene regulation in the adult rat retina after intraorbital nerve crush (IONC) and intraorbital nerve transection (IONT). METHODS: RNA was extracted from adult rat retinas undergoing either IONT or IONC at increasing times post-lesion. Affymetrix RAE230.2 arrays were hybridized and analyzed. Statistically regulated genes were annotated and functionally clustered. Arrays were validated by means of quantative reverse transcription polymerase chain reaction (qRT-PCR) on ten regulated genes at two times post-lesion. Western blotting and immunohistofluorescence for four pro-apoptotic proteins were performed on naive and injured retinas. Finally, custom signaling maps for IONT- and IONC-induced death response were generated (MetaCore, Genego Inc.). RESULTS: Here we show that over time, 3,219 sequences were regulated after IONT and 1,996 after IONC. Out of the total of regulated sequences, 1,078 were commonly regulated by both injuries. Interestingly, while IONT mainly triggers a gene upregulation-sustained over time, IONC causes a transitory downregulation. Functional clustering identified the regulation of high interest biologic processes, most importantly cell death wherein apoptosis was the most significant cluster. Ten death-related genes upregulated by both injuries were used for array validation by means of qRT-PCR. In addition, western blotting and immunohistofluorescence of total and active Caspase 3 (Casp3), tumor necrosis factor receptor type 1 associated death domain (TRADD), tumor necrosis factor receptor superfamily member 1a (TNFR1a), and c-fos were performed to confirm their protein regulation and expression pattern in naive and injured retinas. These analyses demonstrated that for these genes, protein regulation followed transcriptional regulation and that these pro-apoptotic proteins were expressed by retinal ganglion cells (RGCs). MetaCore-based death-signaling maps show that several apoptotic cascades were regulated in the retina following optic nerve injury and highlight the similarities and differences between IONT and IONC in cell death profiling. CONCLUSIONS: This comprehensive time course retinal transcriptome study comparing IONT and IONC lesions provides a unique valuable tool to understand the molecular mechanisms underlying optic nerve injury and to design neuroprotective protocols.}, keywords = {Animals Cell Death Cluster Analysis Female *Gene Expression Profiling Gene Expression Regulation *Nerve Crush Optic Nerve/*metabolism/*pathology Optic Nerve Injuries/*genetics Rats Rats, Sprague-Dawley Reproducibility of Results Retina/*metabolism/*pathology Time Factors}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=18552980}, author = {Agudo, M. and Perez-Marin, M. C. and Lonngren, U. and Sobrado, P. and A. Conesa and Canovas, I. and Salinas-Navarro, M. and Miralles-Imperial, J. and Hallbook, F. and Vidal-Sanz, M.} } @article {18848557, title = {Transcriptional profiling of mRNA expression in the mouse distal colon}, journal = {Gastroenterology}, volume = {135}, number = {6}, year = {2008}, note = {Hoogerwerf, Willemijntje A Sinha, Mala Conesa, Ana Luxon, Bruce A Shahinian, Vahakn B Cornelissen, Germaine Halberg, Franz Bostwick, Jonathon Timm, John Cassone, Vincent M R21 DK074477-01A1/DK/NIDDK NIH HHS/United States Comparative Study Research Support, N.I.H., Extramural United States Gastroenterology Gastroenterology. 2008 Dec;135(6):2019-29. Epub 2008 Sep 3.}, pages = {2019-29}, abstract = {BACKGROUND \& AIMS: Intestinal epithelial cells and the myenteric plexus of the mouse gastrointestinal tract contain a circadian clock-based intrinsic time-keeping system. Because disruption of the biological clock has been associated with increased susceptibility to colon cancer and gastrointestinal symptoms, we aimed to identify rhythmically expressed genes in the mouse distal colon. METHODS: Microarray analysis was used to identify genes that were rhythmically expressed over a 24-hour light/dark cycle. The transcripts were then classified according to expression pattern, function, and association with physiologic and pathophysiologic processes of the colon. RESULTS: A circadian gene expression pattern was detected in approximately 3.7\% of distal colonic genes. A large percentage of these genes were involved in cell signaling, differentiation, and proliferation and cell death. Of all the rhythmically expressed genes in the mouse colon, approximately 7\% (64/906) have been associated with colorectal cancer formation (eg, B-cell leukemia/lymphoma-2 [Bcl2]) and 1.8\% (18/906) with various colonic functions such as motility and secretion (eg, vasoactive intestinal polypeptide, cystic fibrosis transmembrane conductance regulator). CONCLUSIONS: A subset of genes in the murine colon follows a rhythmic expression pattern. These findings may have significant implications for colonic physiology and pathophysiology.}, keywords = {Animals Blotting, Genetic, Inbred C57BL Microarray Analysis Proteins/*genetics/metabolism RNA, Messenger/biosynthesis/*genetics Reverse Transcriptase Polymerase Chain Reaction *Transcription, Western Cell Proliferation Circadian Rhythm/*genetics Colon/cytology/*metabolism Male Mice Mice}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=18848557}, author = {Hoogerwerf, W. A. and Sinha, M. and A. Conesa and Luxon, B. A. and Shahinian, V. B. and Cornelissen, G. and Halberg, F. and Bostwick, J. and Timm, J. and Cassone, V. M.} } @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 {17570147, title = {The AnnoLite and AnnoLyze programs for comparative annotation of protein structures}, journal = {BMC Bioinformatics}, volume = {8 Suppl 4}, year = {2007}, note = {Marti-Renom, Marc A Rossi, Andrea Al-Shahrour, Fatima Davis, Fred P Pieper, Ursula Dopazo, Joaquin Sali, Andrej Research Support, Non-U.S. Gov{\textquoteright}t England BMC bioinformatics BMC Bioinformatics. 2007 May 22;8 Suppl 4:S4.}, pages = {S4}, abstract = {BACKGROUND: Advances in structural biology, including structural genomics, have resulted in a rapid increase in the number of experimentally determined protein structures. However, about half of the structures deposited by the structural genomics consortia have little or no information about their biological function. Therefore, there is a need for tools for automatically and comprehensively annotating the function of protein structures. We aim to provide such tools by applying comparative protein structure annotation that relies on detectable relationships between protein structures to transfer functional annotations. Here we introduce two programs, AnnoLite and AnnoLyze, which use the structural alignments deposited in the DBAli database. DESCRIPTION: AnnoLite predicts the SCOP, CATH, EC, InterPro, PfamA, and GO terms with an average sensitivity of 90\% and average precision of 80\%. AnnoLyze predicts ligand binding site and domain interaction patches with an average sensitivity of 70\% and average precision of 30\%, correctly localizing binding sites for small molecules in 95\% of its predictions. CONCLUSION: The AnnoLite and AnnoLyze programs for comparative annotation of protein structures can reliably and automatically annotate new protein structures. The programs are fully accessible via the Internet as part of the DBAli suite of tools at http://salilab.org/DBAli/.}, keywords = {*Algorithms Amino Acid Sequence Confidence Intervals Data Interpretation, Amino Acid *Software Structure-Activity Relationship, Protein Information Storage and Retrieval/methods Molecular Sequence Data Proteins/*chemistry/classification/*metabolism Sensitivity and Specificity Sequence Alignment/*methods Sequence Analysis, Protein/*methods Sequence Homology, Statistical *Databases}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=17570147}, author = {M. A. Marti-Renom and Rossi, A. and Fatima Al-Shahrour and Davis, F. P. and Pieper, U. and Dopazo, J. and Sali, A.} } @article {17909067, title = {Association study of 69 genes in the ret pathway identifies low-penetrance loci in sporadic medullary thyroid carcinoma}, journal = {Cancer Res}, volume = {67}, number = {19}, year = {2007}, note = {Ruiz-Llorente, Sergio Montero-Conde, Cristina Milne, Roger L Moya, Christian M Cebrian, Arancha Leton, Rocio Cascon, Alberto Mercadillo, Fatima Landa, Inigo Borrego, Salud Perez de Nanclares, Guiomar Alvarez-Escola, Cristina Diaz-Perez, Jose Angel Carracedo, Angel Urioste, Miguel Gonzalez-Neira, Anna Benitez, Javier Santisteban, Pilar Dopazo, Joaquin Ponder, Bruce A Robledo, Mercedes Medullary Thyroid Carcinoma Clinical Group Research Support, Non-U.S. Gov{\textquoteright}t United States Cancer research Cancer Res. 2007 Oct 1;67(19):9561-7.}, pages = {9561-7}, abstract = {To date, few association studies have been done to better understand the genetic basis for the development of sporadic medullary thyroid carcinoma (sMTC). To identify additional low-penetrance genes, we have done a two-stage case-control study in two European populations using high-throughput genotyping. We selected 417 single nucleotide polymorphisms (SNP) belonging to 69 genes either related to RET signaling pathway/functions or involved in key processes for cancer development. TagSNPs and functional variants were included where possible. These SNPs were initially studied in the largest known series of sMTC cases (n = 266) and controls (n = 422), all of Spanish origin. In stage II, an independent British series of 155 sMTC patients and 531 controls was included to validate the previous results. Associations were assessed by an exhaustive analysis of individual SNPs but also considering gene- and linkage disequilibrium-based haplotypes. This strategy allowed us to identify seven low-penetrance genes, six of them (STAT1, AURKA, BCL2, CDKN2B, CDK6, and COMT) consistently associated with sMTC risk in the two case-control series and a seventh (HRAS) with individual SNPs and haplotypes associated with sMTC in the Spanish data set. The potential role of CDKN2B was confirmed by a functional assay showing a role of a SNP (rs7044859) in the promoter region in altering the binding of the transcription factor HNF1. These results highlight the utility of association studies using homogeneous series of cases for better understanding complex diseases.}, keywords = {80 and over Carcinoma, Adolescent Adult Aged Aged, Genetic, Genetic Proto-Oncogene Proteins c-ret/*genetics/metabolism Signal Transduction Thyroid Neoplasms/*genetics/metabolism Transcription, Medullary/*genetics/metabolism Case-Control Studies Cyclin-Dependent Kinase Inhibitor p15/biosynthesis/genetics Female Genetic Predisposition to Disease Germ-Line Mutation Haplotypes Humans Male Middle Aged Penetrance Polymorphism, Single Nucleotide Promoter Regions}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=17909067}, author = {Ruiz-Llorente, S. and Montero-Conde, C. and Milne, R. L. and Moya, C. M. and Cebrian, A. and Leton, R. and Cascon, A. and Mercadillo, F. and Landa, I. and Borrego, S. and Perez de Nanclares, G. and Alvarez-Escola, C. and Diaz-Perez, J. A. and Carracedo, A. and Urioste, M. and Gonzalez-Neira, A. and Benitez, J. and Santisteban, P. and Dopazo, J. and Ponder, B. A. and M. Robledo} } @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 {17478513, title = {DBAli tools: mining the protein structure space}, journal = {Nucleic Acids Res}, volume = {35}, number = {Web Server issue}, year = {2007}, note = {Marti-Renom, Marc A Pieper, Ursula Madhusudhan, M S Rossi, Andrea Eswar, Narayanan Davis, Fred P Al-Shahrour, Fatima Dopazo, Joaquin Sali, Andrej GM 62529/GM/NIGMS NIH HHS/United States GM074929/GM/NIGMS NIH HHS/United States GM54762/GM/NIGMS NIH HHS/United States GM71790/GM/NIGMS NIH HHS/United States Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov{\textquoteright}t England Nucleic acids research Nucleic Acids Res. 2007 Jul;35(Web Server issue):W393-7. Epub 2007 May 3.}, pages = {W393-7}, abstract = {The DBAli tools use a comprehensive set of structural alignments in the DBAli database to leverage the structural information deposited in the Protein Data Bank (PDB). These tools include (i) the DBAlit program that allows users to input the 3D coordinates of a protein structure for comparison by MAMMOTH against all chains in the PDB; (ii) the AnnoLite and AnnoLyze programs that annotate a target structure based on its stored relationships to other structures; (iii) the ModClus program that clusters structures by sequence and structure similarities; (iv) the ModDom program that identifies domains as recurrent structural fragments and (v) an implementation of the COMPARER method in the SALIGN command in MODELLER that creates a multiple structure alignment for a set of related protein structures. Thus, the DBAli tools, which are freely accessible via the World Wide Web at http://salilab.org/DBAli/, allow users to mine the protein structure space by establishing relationships between protein structures and their functions.}, keywords = {*Algorithms Amino Acid Sequence Computational Biology/*methods Data Interpretation, Amino Acid *Software Structure-Activity Relationship, Protein Internet Molecular Sequence Data Protein Conformation Proteins/*chemistry/classification/*metabolism Pseudomonas aeruginosa/*metabolism Sequence Alignment/*methods Sequence Analysis, Protein/*methods Sequence Homology, Statistical *Databases}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=17478513}, author = {M. A. Marti-Renom and Pieper, U. and Madhusudhan, M. S. and Rossi, A. and Eswar, N. and Davis, F. P. and Fatima Al-Shahrour and Dopazo, J. and Sali, A.} } @article {603, title = {DBAli tools: mining the protein structure space.}, journal = {Nucleic Acids Res}, volume = {35}, year = {2007}, month = {2007 Jul}, pages = {W393-7}, abstract = {

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

}, keywords = {Algorithms, Amino Acid Sequence, Computational Biology, Data Interpretation, Statistical, Databases, Protein, Internet, Molecular Sequence Data, Protein Conformation, Proteins, Pseudomonas aeruginosa, Sequence Alignment, Sequence Analysis, Protein, Sequence Homology, Amino Acid, Software, Structure-Activity Relationship}, issn = {1362-4962}, doi = {10.1093/nar/gkm236}, author = {Marti-Renom, Marc A and Pieper, Ursula and Madhusudhan, M S and Rossi, Andrea and Eswar, Narayanan and Davis, Fred P and Al-Shahrour, F{\'a}tima and Dopazo, Joaquin and Sali, Andrej} } @article {17519250, title = {Discovering gene expression patterns in time course microarray experiments by ANOVA-SCA}, journal = {Bioinformatics}, volume = {23}, number = {14}, year = {2007}, note = {Nueda, Maria Jose Conesa, Ana Westerhuis, Johan A Hoefsloot, Huub C J Smilde, Age K Talon, Manuel Ferrer, Alberto Research Support, Non-U.S. Gov{\textquoteright}t England Bioinformatics (Oxford, England) Bioinformatics. 2007 Jul 15;23(14):1792-800. Epub 2007 May 22.}, pages = {1792-800}, abstract = {MOTIVATION: Designed microarray experiments are used to investigate the effects that controlled experimental factors have on gene expression and learn about the transcriptional responses associated with external variables. In these datasets, signals of interest coexist with varying sources of unwanted noise in a framework of (co)relation among the measured variables and with the different levels of the studied factors. Discovering experimentally relevant transcriptional changes require methodologies that take all these elements into account. RESULTS: In this work, we develop the application of the Analysis of variance-simultaneous component analysis (ANOVA-SCA) Smilde et al. Bioinformatics, (2005) to the analysis of multiple series time course microarray data as an example of multifactorial gene expression profiling experiments. We denoted this implementation as ASCA-genes. We show how the combination of ANOVA-modeling and a dimension reduction technique is effective in extracting targeted signals from data by-passing structural noise. The methodology is valuable for identifying main and secondary responses associated with the experimental factors and spotting relevant experimental conditions. We additionally propose a novel approach for gene selection in the context of the relation of individual transcriptional patterns to global gene expression signals. We demonstrate the methodology on both real and synthetic datasets. AVAILABILITY: ASCA-genes has been implemented in the statistical language R and is available at http://www.ivia.es/centrodegenomica/bioinformatics.htm. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.}, keywords = {Algorithms *Analysis of Variance Computational Biology/*methods Computer Simulation Data Interpretation, Genetic, Genetic Models, Statistical Gene Expression Profiling/*methods Models, Statistical Oligonucleotide Array Sequence Analysis/*methods Principal Component Analysis Time Factors Transcription}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=17519250}, author = {Nueda, M. J. and A. Conesa and Westerhuis, J. A. and Hoefsloot, H. C. and Smilde, A. K. and Talon, M. and Ferrer, A.} } @article {17135190, title = {PeroxisomeDB: a database for the peroxisomal proteome, functional genomics and disease}, journal = {Nucleic Acids Res}, volume = {35}, number = {Database issue}, year = {2007}, note = {Schluter, Agatha Fourcade, Stephane Domenech-Estevez, Enric Gabaldon, Toni Huerta-Cepas, Jaime Berthommier, Guillaume Ripp, Raymond Wanders, Ronald J A Poch, Olivier Pujol, Aurora Research Support, Non-U.S. Gov{\textquoteright}t England Nucleic acids research Nucleic Acids Res. 2007 Jan;35(Database issue):D815-22. Epub 2006 Nov 28.}, pages = {D815-22}, abstract = {Peroxisomes are essential organelles of eukaryotic origin, ubiquitously distributed in cells and organisms, playing key roles in lipid and antioxidant metabolism. Loss or malfunction of peroxisomes causes more than 20 fatal inherited conditions. We have created a peroxisomal database (http://www.peroxisomeDB.org) that includes the complete peroxisomal proteome of Homo sapiens and Saccharomyces cerevisiae, by gathering, updating and integrating the available genetic and functional information on peroxisomal genes. PeroxisomeDB is structured in interrelated sections {\textquoteright}Genes{\textquoteright}, {\textquoteright}Functions{\textquoteright}, {\textquoteright}Metabolic pathways{\textquoteright} and {\textquoteright}Diseases{\textquoteright}, that include hyperlinks to selected features of NCBI, ENSEMBL and UCSC databases. We have designed graphical depictions of the main peroxisomal metabolic routes and have included updated flow charts for diagnosis. Precomputed BLAST, PSI-BLAST, multiple sequence alignment (MUSCLE) and phylogenetic trees are provided to assist in direct multispecies comparison to study evolutionary conserved functions and pathways. Highlights of the PeroxisomeDB include new tools developed for facilitating (i) identification of novel peroxisomal proteins, by means of identifying proteins carrying peroxisome targeting signal (PTS) motifs, (ii) detection of peroxisomes in silico, particularly useful for screening the deluge of newly sequenced genomes. PeroxisomeDB should contribute to the systematic characterization of the peroxisomal proteome and facilitate system biology approaches on the organelle.}, keywords = {Animals *Databases, Protein Genomics Humans Internet Mice Peroxisomal Disorders/*genetics Peroxisomes/*metabolism Protein Sorting Signals Proteome/chemistry/*genetics/*physiology Rats Saccharomyces cerevisiae Proteins/genetics/physiology Software User-Computer Interface}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=17135190}, author = {Schluter, A. and Fourcade, S. and Domenech-Estevez, E. and Gabald{\'o}n, T. and Huerta-Cepas, J. and Berthommier, G. and Ripp, R. and Wanders, R. J. and Poch, O. and Pujol, A.} } @article {17884042, title = {Protein translocation into peroxisomes by ring-shaped import receptors}, journal = {FEBS Lett}, volume = {581}, number = {25}, year = {2007}, note = {Stanley, Will A Fodor, Krisztian Marti-Renom, Marc A Schliebs, Wolfgang Wilmanns, Matthias Review Netherlands FEBS letters FEBS Lett. 2007 Oct 16;581(25):4795-802. Epub 2007 Sep 11.}, pages = {4795-802}, abstract = {Folded and functional proteins destined for translocation from the cytosol into the peroxisomal matrix are recognized by two different peroxisomal import receptors, Pex5p and Pex7p. Both cargo-loaded receptors dock on the same translocon components, followed by cargo release and receptor recycling, as part of the complete translocation process. Recent structural and functional evidence on the Pex5p receptor has provided insight on the molecular requirements of specific cargo recognition, while the remaining processes still remain largely elusive. Comparison of experimental structures of Pex5p and a structural model of Pex7p reveal that both receptors are built by ring-like arrangements with cargo binding sites, central to the respective structures. Although, molecular insight into the complete peroxisomal translocon still remains to be determined, emerging data allow to deduce common molecular principles that may hold for other translocation systems as well.}, keywords = {Amino Acid Sequence Binding Sites Humans Molecular Sequence Data Peroxisomes/*metabolism Protein Structure, Cytoplasmic and Nuclear/*chemistry, Tertiary Protein Transport Receptors}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=17884042}, author = {Stanley, W. A. and Fodor, K. and M. A. Marti-Renom and Schliebs, W. and Wilmanns, M.} } @article {16823138, title = {Blast2GO goes grid: developing a grid-enabled prototype for functional genomics analysis}, journal = {Stud Health Technol Inform}, volume = {120}, year = {2006}, note = {

Aparicio, G Gotz, S Conesa, A Segrelles, D Blanquer, I Garcia, J M Hernandez, V Robles, M Talon, M Netherlands Studies in health technology and informatics Stud Health Technol Inform. 2006;120:194-204.

}, pages = {194-204}, abstract = {

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

}, keywords = {babelomics}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=16823138}, author = {Aparicio, G. and Gotz, S. and A. Conesa and Segrelles, D. and Blanquer, I. and Garcia, J. M. and Hernandez, V. and Robles, M. and Talon, M.} } @article {18428767, title = {Comparative protein structure modeling using Modeller}, journal = {Curr Protoc Bioinformatics}, volume = {Chapter 5}, year = {2006}, note = {Eswar, Narayanan Webb, Ben Marti-Renom, Marc A Madhusudhan, M S Eramian, David Shen, Min-Yi Pieper, Ursula Sali, Andrej P01 A135707/PHS HHS/United States P01 GM71790/GM/NIGMS NIH HHS/United States R01 GM54762/GM/NIGMS NIH HHS/United States U54 GM62529/GM/NIGMS NIH HHS/United States Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov{\textquoteright}t United States Current protocols in bioinformatics / editoral board, Andreas D. Baxevanis ... [et al.] Curr Protoc Bioinformatics. 2006 Oct;Chapter 5:Unit 5.6.}, pages = {Unit 5 6}, abstract = {Functional characterization of a protein sequence is one of the most frequent problems in biology. This task is usually facilitated by accurate three-dimensional (3-D) structure of the studied protein. In the absence of an experimentally determined structure, comparative or homology modeling can sometimes provide a useful 3-D model for a protein that is related to at least one known protein structure. Comparative modeling predicts the 3-D structure of a given protein sequence (target) based primarily on its alignment to one or more proteins of known structure (templates). The prediction process consists of fold assignment, target-template alignment, model building, and model evaluation. This unit describes how to calculate comparative models using the program MODELLER and discusses all four steps of comparative modeling, frequently observed errors, and some applications. Modeling lactate dehydrogenase from Trichomonas vaginalis (TvLDH) is described as an example. The download and installation of the MODELLER software is also described.}, keywords = {Algorithms Amino Acid Sequence Computer Simulation Crystallography/*methods *Models, Chemical *Models, Molecular Molecular Sequence Data Protein Conformation Protein Folding Proteins/*chemistry/*ultrastructure Sequence Analysis, Protein/*methods *Software}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=18428767}, author = {Eswar, N. and Webb, B. and M. A. Marti-Renom and Madhusudhan, M. S. and Eramian, D. and Shen, M. Y. and Pieper, U. and Sali, A.} } @article {16751606, title = {A composite score for predicting errors in protein structure models}, journal = {Protein Sci}, volume = {15}, number = {7}, year = {2006}, note = {Eramian, David Shen, Min-yi Devos, Damien Melo, Francisco Sali, Andrej Marti-Renom, Marc A GM 08284/GM/NIGMS NIH HHS/United States R01 GM54762/GM/NIGMS NIH HHS/United States Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov{\textquoteright}t Research Support, U.S. Gov{\textquoteright}t, Non-P.H.S. United States Protein science : a publication of the Protein Society Protein Sci. 2006 Jul;15(7):1653-66. Epub 2006 Jun 2.}, pages = {1653-66}, abstract = {Reliable prediction of model accuracy is an important unsolved problem in protein structure modeling. To address this problem, we studied 24 individual assessment scores, including physics-based energy functions, statistical potentials, and machine learning-based scoring functions. Individual scores were also used to construct approximately 85,000 composite scoring functions using support vector machine (SVM) regression. The scores were tested for their abilities to identify the most native-like models from a set of 6000 comparative models of 20 representative protein structures. Each of the 20 targets was modeled using a template of <30\% sequence identity, corresponding to challenging comparative modeling cases. The best SVM score outperformed all individual scores by decreasing the average RMSD difference between the model identified as the best of the set and the model with the lowest RMSD (DeltaRMSD) from 0.63 A to 0.45 A, while having a higher Pearson correlation coefficient to RMSD (r=0.87) than any other tested score. The most accurate score is based on a combination of the DOPE non-hydrogen atom statistical potential; surface, contact, and combined statistical potentials from MODPIPE; and two PSIPRED/DSSP scores. It was implemented in the SVMod program, which can now be applied to select the final model in various modeling problems, including fold assignment, target-template alignment, and loop modeling.}, keywords = {*Models, Molecular Models, Theoretical Proteins/*chemistry}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=16751606}, author = {Eramian, D. and Shen, M. Y. and Devos, D. and Melo, F. and Sali, A. and M. A. Marti-Renom} } @article {17120584, title = {Development of the GENIPOL European flounder (Platichthys flesus) microarray and determination of temporal transcriptional responses to cadmium at low dose}, journal = {Environ Sci Technol}, volume = {40}, number = {20}, year = {2006}, note = {Williams, Tim D Diab, Amer M George, Stephen G Godfrey, Rita E Sabine, Victoria Conesa, Ana Minchin, Steven D Watts, Phil C Chipman, James K Research Support, Non-U.S. Gov{\textquoteright}t United States Environmental science \& technology Environ Sci Technol. 2006 Oct 15;40(20):6479-88.}, pages = {6479-88}, abstract = {We have constructed a high density, 13 270-clone cDNA array for the sentinel fish species European flounder (Platichthys flesus), combining clones from suppressive subtractive hybridization and a liver cDNA library; DNA sequences of 5211 clones were determined. Fish were treated by single intraperitoneal injection with 50 micrograms cadmium chloride per kilogram body weight, a dose relevant to environmental exposures, and hepatic gene expression changes were determined at 1, 2, 4, 8, and 16 days postinjection in comparison to saline-treated controls. Gene expression responses were confirmed by real-time reverse transcription polymerase chain reaction (RT-PCR). Blast2GO gene ontology analysis highlighted a general induction of the unfolded protein response, response to oxidative stress, protein synthesis, transport, and degradation pathways, while apoptosis, cell cycle, cytoskeleton, and cytokine genes were also affected. Transcript levels of cytochrome P450 1A (CYP1A) were repressed and vitellogenin altered, real-time PCR showed induction of metallothionein. We thus describe the establishment of a useful resource for ecotoxicogenomics and the determination of the temporal molecular responses to cadmium, a prototypical heavy metal pollutant.}, keywords = {Animals Cadmium Chloride/administration \& dosage/*pharmacology Dose-Response Relationship, Developmental/drug effects Liver/drug effects/growth \& development/metabolism Oligonucleotide Array Sequence Analysis/*methods Reverse Transcriptase Polymerase Chain Reaction Transcription, Drug Environmental Monitoring/methods Flounder/*genetics/growth \& development Gene Expression Profiling Gene Expression Regulation, Genetic/*drug effects}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=17120584}, author = {Williams, T. D. and Diab, A. M. and George, S. G. and Godfrey, R. E. and Sabine, V. and A. Conesa and Minchin, S. D. and Watts, P. C. and Chipman, J. K.} } @article {17018596, title = {ERCC4 associated with breast cancer risk: a two-stage case-control study using high-throughput genotyping}, journal = {Cancer Res}, volume = {66}, number = {19}, year = {2006}, note = {Milne, Roger Laughlin Ribas, Gloria Gonzalez-Neira, Anna Fagerholm, Rainer Salas, Antonio Gonzalez, Emilio Dopazo, Joaquin Nevanlinna, Heli Robledo, Mercedes Benitez, Javier Comparative Study Multicenter Study Research Support, Non-U.S. Gov{\textquoteright}t United States Cancer research Cancer Res. 2006 Oct 1;66(19):9420-7.}, pages = {9420-7}, abstract = {The failure of linkage studies to identify further high-penetrance susceptibility genes for breast cancer points to a polygenic model, with more common variants having modest effects on risk, as the most likely candidate. We have carried out a two-stage case-control study in two European populations to identify low-penetrance genes for breast cancer using high-throughput genotyping. Single-nucleotide polymorphisms (SNPs) were selected across preselected cancer-related genes, choosing tagSNPs and functional variants where possible. In stage 1, genotype frequencies for 640 SNPs in 111 genes were compared between 864 breast cancer cases and 845 controls from the Spanish population. In stage 2, candidate SNPs identified in stage 1 (nominal P < 0.01) were tested in a Finnish series of 884 cases and 1,104 controls. Of the 10 candidate SNPs in seven genes identified in stage 1, one (rs744154) on intron 1 of ERCC4, a gene belonging to the nucleotide excision repair pathway, was associated with recessive protection from breast cancer after adjustment for multiple testing in stage 2 (odds ratio, 0.57; Bonferroni-adjusted P = 0.04). After considering potential functional SNPs in the region of high linkage disequilibrium that extends across the entire gene and upstream into the promoter region, we concluded that rs744154 itself could be causal. Although intronic, it is located on the first intron, in a region that is highly conserved across species, and could therefore be functionally important. This study suggests that common intronic variation in ERCC4 is associated with protection from breast cancer.}, keywords = {80 and over Breast Neoplasms/epidemiology/*genetics/pathology Case-Control Studies DNA-Binding Proteins/genetics/*physiology Female Finland/epidemiology Genes, Adult Aged Aged, Recessive Genetic Predisposition to Disease Genotype Humans Introns/genetics Linkage Disequilibrium Middle Aged Neoplasm Proteins/genetics/*physiology Neoplasm Staging *Polymorphism, Single Nucleotide Risk Spain/epidemiology}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=17018596}, author = {Milne, R. L. and Ribas, G. and Gonzalez-Neira, A. and Fagerholm, R. and Salas, A. and Gonzalez, E. and Dopazo, J. and Nevanlinna, H. and M. Robledo and Benitez, J.} } @article {16461302, title = {Identification of overexpressed genes in frequently gained/amplified chromosome regions in multiple myeloma}, journal = {Haematologica}, volume = {91}, number = {2}, year = {2006}, note = {Largo, Cristina Alvarez, Sara Saez, Borja Blesa, David Martin-Subero, Jose I Gonzalez-Garcia, Ines Brieva, Jose A Dopazo, Joaquin Siebert, Reiner Calasanz, Maria J Cigudosa, Juan C Research Support, Non-U.S. Gov{\textquoteright}t Italy Haematologica Haematologica. 2006 Feb;91(2):184-91.}, pages = {184-91}, abstract = {BACKGROUND AND OBJECTIVES: Multiple myeloma (MM) is a malignancy characterized by clonal expansion of plasma cells. In 50\% of the cases, the neoplastic transformation begins with a chromosomal translocation that juxtaposes the IGH gene locus to an oncogene. Gene copy number changes are also frequent in MM but less characterized than in other neoplasias. We aimed to characterize genes that are amplified and overexpressed in human myeloma cell lines (HMCL) to provide putative molecular targets for MM therapy. DESIGN AND METHODS: Nine HMCL were characterized by fluorescent in situ hybridization, comparative genomic hybridization (CGH) and cDNA microarrays for gene expression profiling and copy number changes. RESULTS: After defining the IGH-translocations present in the cell lines, we conducted expression-profiling analysis. Supervised analysis identified 166 genes with significantly different expression among the cell lines harboring MMSET/FGFR3 (4p16), MAF (16q) and CCND1 (11q13) rearrangements. Array-CGH was then performed. Five chromosomes recurrently affected by gains/amplifications in primary samples and cell lines were analyzed in detail. Sixty amplified and overexpressed genes were found and 25 (42\%) of them were only overexpressed when amplified; moreover, six showed a significant association between overexpression and gain/amplification. We also found co-amplification and overexpression for genes located within the same amplicons, such as MALT1 and BCL2. INTERPRETATION AND CONCLUSIONS: Parallel analysis of gene copy numbers and expression levels by cDNA microarray in MM allowed efficient identification of genes whose expression levels are elevated because of increased copy number. This is the first time that MALT1 and BCL2 have been shown to be overexpressed and amplified in MM.}, keywords = {B-Cell, Caspases Cell Line, Human *Gene Amplification Gene Dosage Gene Expression Profiling *Gene Expression Regulation, Marginal Zone/genetics Multiple Myeloma/*genetics Neoplasm Proteins/genetics Proto-Oncogene Proteins c-bcl-2/genetics, Neoplasm Humans Immunoglobulin Heavy Chains/genetics Lymphoma, Neoplastic Gene Rearrangement *Genes, Tumor *Chromosomes}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=16461302}, author = {Largo, C. and Alvarez, S. and Saez, B. and Blesa, D. and Martin-Subero, J. I. and Gonzalez-Garcia, I. and Brieva, J. A. and Dopazo, J. and Siebert, R. and Calasanz, M. J. and Cigudosa, J. C.} } @article {16963645, title = {Localization of binding sites in protein structures by optimization of a composite scoring function}, journal = {Protein Sci}, volume = {15}, number = {10}, year = {2006}, note = {Rossi, Andrea Marti-Renom, Marc A Sali, Andrej P01 AI035707/AI/NIAID NIH HHS/United States R01 GM54762/GM/NIGMS NIH HHS/United States Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov{\textquoteright}t United States Protein science : a publication of the Protein Society Protein Sci. 2006 Oct;15(10):2366-80. Epub 2006 Sep 8.}, pages = {2366-80}, abstract = {The rise in the number of functionally uncharacterized protein structures is increasing the demand for structure-based methods for functional annotation. Here, we describe a method for predicting the location of a binding site of a given type on a target protein structure. The method begins by constructing a scoring function, followed by a Monte Carlo optimization, to find a good scoring patch on the protein surface. The scoring function is a weighted linear combination of the z-scores of various properties of protein structure and sequence, including amino acid residue conservation, compactness, protrusion, convexity, rigidity, hydrophobicity, and charge density; the weights are calculated from a set of previously identified instances of the binding-site type on known protein structures. The scoring function can easily incorporate different types of information useful in localization, thus increasing the applicability and accuracy of the approach. To test the method, 1008 known protein structures were split into 20 different groups according to the type of the bound ligand. For nonsugar ligands, such as various nucleotides, binding sites were correctly identified in 55\%-73\% of the cases. The method is completely automated (http://salilab.org/patcher) and can be applied on a large scale in a structural genomics setting.}, keywords = {Amino Acid Sequence Binding Sites Biomechanics Hydrophobicity Ligands *Monte Carlo Method Protein Conformation Proteins/*chemistry Static Electricity}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=16963645}, author = {Rossi, A. and M. A. Marti-Renom and Sali, A.} } @article {16381869, title = {MODBASE: a database of annotated comparative protein structure models and associated resources}, journal = {Nucleic Acids Res}, volume = {34}, number = {Database issue}, year = {2006}, note = {Pieper, Ursula Eswar, Narayanan Davis, Fred P Braberg, Hannes Madhusudhan, M S Rossi, Andrea Marti-Renom, Marc Karchin, Rachel Webb, Ben M Eramian, David Shen, Min-Yi Kelly, Libusha Melo, Francisco Sali, Andrej GM 08284/GM/NIGMS NIH HHS/United States P50 GM62529/GM/NIGMS NIH HHS/United States R01 GM 54762/GM/NIGMS NIH HHS/United States R33 CA84699/CA/NCI 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 England Nucleic acids research Nucleic Acids Res. 2006 Jan 1;34(Database issue):D291-5.}, pages = {D291-5}, abstract = {MODBASE (http://salilab.org/modbase) is a database of annotated comparative protein structure models for all available protein sequences that can be matched to at least one known protein structure. The models are calculated by MODPIPE, an automated modeling pipeline that relies on MODELLER for fold assignment, sequence-structure alignment, model building and model assessment (http:/salilab.org/modeller). MODBASE is updated regularly to reflect the growth in protein sequence and structure databases, and improvements in the software for calculating the models. MODBASE currently contains 3 094 524 reliable models for domains in 1 094 750 out of 1 817 889 unique protein sequences in the UniProt database (July 5, 2005); only models based on statistically significant alignments and models assessed to have the correct fold despite insignificant alignments are included. MODBASE also allows users to generate comparative models for proteins of interest with the automated modeling server MODWEB (http://salilab.org/modweb). Our other resources integrated with MODBASE include comprehensive databases of multiple protein structure alignments (DBAli, http://salilab.org/dbali), structurally defined ligand binding sites and structurally defined binary domain interfaces (PIBASE, http://salilab.org/pibase) as well as predictions of ligand binding sites, interactions between yeast proteins, and functional consequences of human nsSNPs (LS-SNP, http://salilab.org/LS-SNP).}, keywords = {Binding Sites *Databases, Molecular Polymorphism, Protein Humans Internet Ligands *Models, Protein Systems Integration User-Computer Interface, Single Nucleotide Protein Structure, Tertiary Proteins/*chemistry/genetics/metabolism Software *Structural Homology}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=16381869}, author = {Pieper, U. and Eswar, N. and Davis, F. P. and Braberg, H. and Madhusudhan, M. S. and Rossi, A. and M. A. Marti-Renom and Karchin, R. and Webb, B. M. and Eramian, D. and Shen, M. Y. and Kelly, L. and Melo, F. and Sali, A.} } @article {16556314, title = {Origin and evolution of the peroxisomal proteome}, journal = {Biol Direct}, volume = {1}, year = {2006}, note = {Gabaldon, Toni Snel, Berend van Zimmeren, Frank Hemrika, Wieger Tabak, Henk Huynen, Martijn A England Biology direct Biol Direct. 2006 Mar 23;1:8.}, pages = {8}, abstract = {BACKGROUND: Peroxisomes are ubiquitous eukaryotic organelles involved in various oxidative reactions. Their enzymatic content varies between species, but the presence of common protein import and organelle biogenesis systems support a single evolutionary origin. The precise scenario for this origin remains however to be established. The ability of peroxisomes to divide and import proteins post-translationally, just like mitochondria and chloroplasts, supports an endosymbiotic origin. However, this view has been challenged by recent discoveries that mutant, peroxisome-less cells restore peroxisomes upon introduction of the wild-type gene, and that peroxisomes are formed from the Endoplasmic Reticulum. The lack of a peroxisomal genome precludes the use of classical analyses, as those performed with mitochondria or chloroplasts, to settle the debate. We therefore conducted large-scale phylogenetic analyses of the yeast and rat peroxisomal proteomes. RESULTS : Our results show that most peroxisomal proteins (39-58\%) are of eukaryotic origin, comprising all proteins involved in organelle biogenesis or maintenance. A significant fraction (13-18\%), consisting mainly of enzymes, has an alpha-proteobacterial origin and appears to be the result of the recruitment of proteins originally targeted to mitochondria. Consistent with the findings that peroxisomes are formed in the Endoplasmic Reticulum, we find that the most universally conserved Peroxisome biogenesis and maintenance proteins are homologous to proteins from the Endoplasmic Reticulum Assisted Decay pathway. CONCLUSION: Altogether our results indicate that the peroxisome does not have an endosymbiotic origin and that its proteins were recruited from pools existing within the primitive eukaryote. Moreover the reconstruction of primitive peroxisomal proteomes suggests that ontogenetically as well as phylogenetically, peroxisomes stem from the Endoplasmic Reticulum. REVIEWERS: This article was reviewed by Arcady Mushegian, Gaspar Jekely and John Logsdon. OPEN PEER REVIEW: Reviewed by Arcady Mushegian, Gaspar Jekely and John Logsdon. For the full reviews, please go to the Reviewers{\textquoteright} comments section.}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=16556314}, author = {Gabald{\'o}n, T. and B. Snel and van Zimmeren, F. and Hemrika, W. and Tabak, H. and M. A. Huynen} } @article {16845085, title = {PupaSuite: finding functional single nucleotide polymorphisms for large-scale genotyping purposes}, journal = {Nucleic Acids Res}, volume = {34}, number = {Web Server issue}, year = {2006}, note = {

Conde, Lucia Vaquerizas, Juan M Dopazo, Hernan Arbiza, Leonardo Reumers, Joke Rousseau, Frederic Schymkowitz, Joost Dopazo, Joaquin Research Support, Non-U.S. Gov{\textquoteright}t England Nucleic acids research Nucleic Acids Res. 2006 Jul 1;34(Web Server issue):W621-5.

}, pages = {W621-5}, abstract = {

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

}, keywords = {Algorithms Computer Graphics Databases, Molecular Genotype Haplotypes Internet Linkage Disequilibrium *Polymorphism, Nucleic Acid Evolution, Single Nucleotide *Software User-Computer Interface}, url = {http://nar.oxfordjournals.org/cgi/content/full/34/suppl_2/W621}, author = {L. Conde and Vaquerizas, J. M. and H. Dopazo and Arbiza, L. and Reumers, J. and Rousseau, F. and Schymkowitz, J. and Dopazo, J.} } @article {16490207, title = {Refinement of protein structures by iterative comparative modeling and CryoEM density fitting}, journal = {J Mol Biol}, volume = {357}, number = {5}, year = {2006}, note = {Topf, Maya Baker, Matthew L Marti-Renom, Marc A Chiu, Wah Sali, Andrej 2 PN2 EY016525-02/EY/NEI NIH HHS/United States P20RR020647/RR/NCRR NIH HHS/United States P41RR02250/RR/NCRR NIH HHS/United States R01 GM54762/GM/NIGMS NIH HHS/United States Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov{\textquoteright}t Research Support, U.S. Gov{\textquoteright}t, Non-P.H.S. England Journal of molecular biology J Mol Biol. 2006 Apr 14;357(5):1655-68. Epub 2006 Feb 2.}, pages = {1655-68}, abstract = {We developed a method for structure characterization of assembly components by iterative comparative protein structure modeling and fitting into cryo-electron microscopy (cryoEM) density maps. Specifically, we calculate a comparative model of a given component by considering many alternative alignments between the target sequence and a related template structure while optimizing the fit of a model into the corresponding density map. The method relies on the previously developed Moulder protocol that iterates over alignment, model building, and model assessment. The protocol was benchmarked using 20 varied target-template pairs of known structures with less than 30\% sequence identity and corresponding simulated density maps at resolutions from 5A to 25A. Relative to the models based on the best existing sequence profile alignment methods, the percentage of C(alpha) atoms that are within 5A of the corresponding C(alpha) atoms in the superposed native structure increases on average from 52\% to 66\%, which is half-way between the starting models and the models from the best possible alignments (82\%). The test also reveals that despite the improvements in the accuracy of the fitness function, this function is still the bottleneck in reducing the remaining errors. To demonstrate the usefulness of the protocol, we applied it to the upper domain of the P8 capsid protein of rice dwarf virus that has been studied by cryoEM at 6.8A. The C(alpha) root-mean-square deviation of the model based on the remotely related template, bluetongue virus VP7, improved from 8.7A to 6.0A, while the best possible model has a C(alpha) RMSD value of 5.3A. Moreover, the resulting model fits better into the cryoEM density map than the initial template structure. The method is being implemented in our program MODELLER for protein structure modeling by satisfaction of spatial restraints and will be applicable to the rapidly increasing number of cryoEM density maps of macromolecular assemblies.}, keywords = {Amino Acid Sequence Cryoelectron Microscopy *Models, Molecular Molecular Sequence Data Plant Viruses/chemistry *Protein Conformation Software Viral Proteins/*chemistry/genetics}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=16490207}, author = {Topf, M. and Baker, M. L. and M. A. Marti-Renom and Chiu, W. and Sali, A.} } @inbook {481, title = {Reliable and specific protein function prediction by combining homology with genomic(s) context}, booktitle = {Discovery of biomolecular mechanisms with theoretical data analyses}, year = {2006}, publisher = {F. Eisenhaber, Landes Bioscience}, organization = {F. Eisenhaber, Landes Bioscience}, issn = {0-387-34527}, url = {http://www.landesbioscience.com/iu/output.php?id=479}, author = {M. A. Huynen and B. Snel and Gabald{\'o}n T} } @article {16423846, title = {Variable gap penalty for protein sequence-structure alignment}, journal = {Protein Eng Des Sel}, volume = {19}, number = {3}, year = {2006}, note = {Madhusudhan, M S Marti-Renom, Marc A Sanchez, Roberto Sali, Andrej DE016274/DE/NIDCR NIH HHS/United States GM54762/GM/NIGMS NIH HHS/United States GM62529/GM/NIGMS NIH HHS/United States Comparative Study Research Support, N.I.H., Extramural England Protein engineering, design \& selection : PEDS Protein Eng Des Sel. 2006 Mar;19(3):129-33. Epub 2006 Jan 19.}, pages = {129-33}, abstract = {The penalty for inserting gaps into an alignment between two protein sequences is a major determinant of the alignment accuracy. Here, we present an algorithm for finding a globally optimal alignment by dynamic programming that can use a variable gap penalty (VGP) function of any form. We also describe a specific function that depends on the structural context of an insertion or deletion. It penalizes gaps that are introduced within regions of regular secondary structure, buried regions, straight segments and also between two spatially distant residues. The parameters of the penalty function were optimized on a set of 240 sequence pairs of known structure, spanning the sequence identity range of 20-40\%. We then tested the algorithm on another set of 238 sequence pairs of known structures. The use of the VGP function increases the number of correctly aligned residues from 81.0 to 84.5\% in comparison with the optimized affine gap penalty function; this difference is statistically significant according to Student{\textquoteright}s t-test. We estimate that the new algorithm allows us to produce comparative models with an additional approximately 7 million accurately modeled residues in the approximately 1.1 million proteins that are detectably related to a known structure.}, keywords = {Algorithms Amino Acid Sequence Models, Amino Acid *Software, Molecular Molecular Sequence Data Proteins/*chemistry Sequence Alignment/*methods Sequence Analysis, Protein/*methods *Sequence Homology}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=16423846}, author = {Madhusudhan, M. S. and M. A. Marti-Renom and Sanchez, R. and Sali, A.} } @article {15670813, title = {Combining data from genomes, Y2H and 3D structure indicates that BolA is a reductase interacting with a glutaredoxin}, journal = {FEBS Lett}, volume = {579}, number = {3}, year = {2005}, note = {Huynen, Martijn A Spronk, Chris A E M Gabaldon, Toni Snel, Berend Research Support, Non-U.S. Gov{\textquoteright}t Netherlands FEBS letters FEBS Lett. 2005 Jan 31;579(3):591-6.}, pages = {591-6}, abstract = {Genomes, functional genomics data and 3D structure reflect different aspects of protein function. Here, we combine these data to predict that BolA, a widely distributed protein family with unknown function, is a reductase that interacts with a glutaredoxin. Comparisons at the 3D structure level as well as at the sequence profile level indicate homology between BolA and OsmC, an enzyme that reduces organic peroxides. Complementary to this, comparative analyses of genomes and genomics data provide strong evidence of an interaction between BolA and the mono-thiol glutaredoxin family. The interaction between BolA and a mono-thiol glutaredoxin is of particular interest because BolA does not, in contrast to its homolog OsmC, have evolutionarily conserved cysteines to provide it with reducing equivalents. We propose that BolA uses the mono-thiol glutaredoxin as the source for these.}, keywords = {*Genome Glutaredoxins Models, Molecular Oxidoreductases/chemistry/*metabolism Phylogeny Protein Conformation}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=15670813}, author = {M. A. Huynen and Spronk, C. A. and Gabald{\'o}n, T. and B. Snel} } @article {16170324, title = {The C-type lectin fold as an evolutionary solution for massive sequence variation}, journal = {Nat Struct Mol Biol}, volume = {12}, number = {10}, year = {2005}, note = {McMahon, Stephen A Miller, Jason L Lawton, Jeffrey A Kerkow, Donald E Hodes, Asher Marti-Renom, Marc A Doulatov, Sergei Narayanan, Eswar Sali, Andrej Miller, Jeff F Ghosh, Partho F31AI061840/AI/NIAID NIH HHS/United States F32AI49695/AI/NIAID NIH HHS/United States T32GM008326/GM/NIGMS NIH HHS/United States 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 Nature structural \& molecular biology Nat Struct Mol Biol. 2005 Oct;12(10):886-92. Epub 2005 Sep 18.}, pages = {886-92}, abstract = {Only few instances are known of protein folds that tolerate massive sequence variation for the sake of binding diversity. The most extensively characterized is the immunoglobulin fold. We now add to this the C-type lectin (CLec) fold, as found in the major tropism determinant (Mtd), a retroelement-encoded receptor-binding protein of Bordetella bacteriophage. Variation in Mtd, with its approximately 10(13) possible sequences, enables phage adaptation to Bordetella spp. Mtd is an intertwined, pyramid-shaped trimer, with variable residues organized by its CLec fold into discrete receptor-binding sites. The CLec fold provides a highly static scaffold for combinatorial display of variable residues, probably reflecting a different evolutionary solution for balancing diversity against stability from that in the immunoglobulin fold. Mtd variants are biased toward the receptor pertactin, and there is evidence that the CLec fold is used broadly for sequence variation by related retroelements.}, keywords = {Amino Acid Sequence Bacterial Outer Membrane Proteins/*chemistry Bacteriophages/*metabolism Bordetella/*virology Evolution, Bordetella/*chemistry, C-Type/*chemistry Molecular Sequence Data Protein Conformation Protein Folding Viral Proteins/*chemistry/*genetics Virulence Factors, Molecular Genetic Variation Genome, Viral Lectins}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=16170324}, author = {McMahon, S. A. and Miller, J. L. and Lawton, J. A. and Kerkow, D. E. and Hodes, A. and M. A. Marti-Renom and Doulatov, S. and Narayanan, E. and Sali, A. and Miller, J. F. and Ghosh, P.} } @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 {15830128, title = {Development of a citrus genome-wide EST collection and cDNA microarray as resources for genomic studies}, journal = {Plant Mol Biol}, volume = {57}, number = {3}, year = {2005}, note = {Forment, J Gadea, J Huerta, L Abizanda, L Agusti, J Alamar, S Alos, E Andres, F Arribas, R Beltran, J P Berbel, A Blazquez, M A Brumos, J Canas, L A Cercos, M Colmenero-Flores, J M Conesa, A Estables, B Gandia, M Garcia-Martinez, J L Gimeno, J Gisbert, A Gomez, G Gonzalez-Candelas, L Granell, A Guerri, J Lafuente, M T Madueno, F Marcos, J F Marques, M C Martinez, F Martinez-Godoy, M A Miralles, S Moreno, P Navarro, L Pallas, V Perez-Amador, M A Perez-Valle, J Pons, C Rodrigo, I Rodriguez, P L Royo, C Serrano, R Soler, G Tadeo, F Talon, M Terol, J Trenor, M Vaello, L Vicente, O Vidal, Ch Zacarias, L Conejero, V Comparative Study Research Support, U.S. Gov{\textquoteright}t, Non-P.H.S. Netherlands Plant molecular biology Plant Mol Biol. 2005 Feb;57(3):375-91.}, pages = {375-91}, abstract = {A functional genomics project has been initiated to approach the molecular characterization of the main biological and agronomical traits of citrus. As a key part of this project, a citrus EST collection has been generated from 25 cDNA libraries covering different tissues, developmental stages and stress conditions. The collection includes a total of 22,635 high-quality ESTs, grouped in 11,836 putative unigenes, which represent at least one third of the estimated number of genes in the citrus genome. Functional annotation of unigenes which have Arabidopsis orthologues (68\% of all unigenes) revealed gene representation in every major functional category, suggesting that a genome-wide EST collection was obtained. A Citrus clementina Hort. ex Tan. cv. Clemenules genomic library, that will contribute to further characterization of relevant genes, has also been constructed. To initiate the analysis of citrus transcriptome, we have developed a cDNA microarray containing 12,672 probes corresponding to 6875 putative unigenes of the collection. Technical characterization of the microarray showed high intra- and inter-array reproducibility, as well as a good range of sensitivity. We have also validated gene expression data achieved with this microarray through an independent technique such as RNA gel blot analysis.}, keywords = {Citrus/*genetics DNA, Complementary/chemistry/genetics *Expressed Sequence Tags Gene Expression Profiling Gene Library *Genome, DNA, Plant Genomics/*methods Molecular Sequence Data Oligonucleotide Array Sequence Analysis/*methods RNA, Plant/genetics/metabolism Reproducibility of Results Sequence Analysis}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=15830128}, author = {J. Forment and J. Gadea and Huerta, L. and Abizanda, L. and Agusti, J. and Alamar, S. and Alos, E. and Andres, F. and Arribas, R. and Beltran, J. P. and Berbel, A. and Blazquez, M. A. and Brumos, J. and Canas, L. A. and Cercos, M. and Colmenero-Flores, J. M. and A. Conesa and Estables, B. and Gandia, M. and Garcia-Martinez, J. L. and Gimeno, J. and Gisbert, A. and Gomez, G. and Gonzalez-Candelas, L. and Granell, A. and Guerri, J. and Lafuente, M. T. and Madueno, F. and Marcos, J. F. and Marques, M. C. and Martinez, F. and Martinez-Godoy, M. A. and Miralles, S. and Moreno, P. and Navarro, L. and Pallas, V. and Perez-Amador, M. A. and Perez-Valle, J. and Pons, C. and Rodrigo, I. and Rodriguez, P. L. and Royo, C. and Serrano, R. and Soler, G. and Tadeo, F. and Talon, M. and Terol, J. and Trenor, M. and Vaello, L. and Vicente, O. and Vidal, Ch and Zacarias, L. and Conejero, V.} } @article {15591357, title = {Highly specific and accurate selection of siRNAs for high-throughput functional assays}, journal = {Bioinformatics}, volume = {21}, number = {8}, year = {2005}, note = {Santoyo, Javier Vaquerizas, Juan M Dopazo, Joaquin Comparative Study Evaluation Studies Research Support, Non-U.S. Gov{\textquoteright}t England Bioinformatics (Oxford, England) Bioinformatics. 2005 Apr 15;21(8):1376-82. Epub 2004 Dec 10.}, pages = {1376-82}, abstract = {MOTIVATION: Small interfering RNA (siRNA) is widely used in functional genomics to silence genes by decreasing their expression to study the resulting phenotypes. The possibility of performing large-scale functional assays by gene silencing accentuates the necessity of a software capable of the high-throughput design of highly specific siRNA. The main objective sought was the design of a large number of siRNAs with appropriate thermodynamic properties and, especially, high specificity. Since all the available procedures require, to some extent, manual processing of the results to guarantee specific results, specificity constitutes to date, the major obstacle to the complete automation of all the steps necessary for the selection of optimal candidate siRNAs. RESULT: Here, we present a program that for the first time completely automates the search for siRNAs. In SiDE, the most complete set of rules for the selection of siRNA candidates (including G+C content, nucleotides at determined positions, thermodynamic properties, propensity to form internal hairpins, etc.) is implemented and moreover, specificity is achieved by a conceptually new method. After selecting possible siRNA candidates with the optimal functional properties, putative unspecific matches, which can cause cross-hybridization, are checked in databases containing a unique entry for each gene. These truly non-redundant databases are constructed from the genome annotations (Ensembl). Also intron/exon boundaries, presence of polymorphisms (single nucleotide polymorphisms) specificity for either gene or transcript, and other features can be selected to be considered in the design of siRNAs. AVAILABILITY: The program is available as a web server at http://side.bioinfo.cnio.es. The program was written under the GPL license. CONTACT: jdopazo@cnio.es.}, keywords = {*Algorithms Base Sequence *Gene Silencing Molecular Sequence Data RNA, RNA/*methods *Software *User-Computer Interface, Small Interfering/*genetics Sequence Alignment/*methods Sequence Analysis}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=15591357}, author = {J. Santoyo and Vaquerizas, J. M. and Dopazo, J.} } @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.} } @inbook {486, title = {Salinibacter ruber: genomics and biogeography}, booktitle = {Adaptation to life in high salt concentrations in Archaea, Bacteria and Eukarya}, volume = {9}, year = {2005}, pages = {257-266}, publisher = {Nina Gunde-Cimerman, Ana Plemenitas, and Aharon Oren. Kluwer Academic Publishers}, organization = {Nina Gunde-Cimerman, Ana Plemenitas, and Aharon Oren. Kluwer Academic Publishers}, address = {Dordrecht, Netherlands}, author = {Ant{\'o}n, J and Pe{\~n}a, A and Valens, M and Santos, F and Gl{\"o}ckner, F.O and Bauer, M and Dopazo, J. and Herrero, J. and Rossell{\'o}-Mora, R and Amann, R} } @article {15763561, title = {Variation and evolution of biomolecular systems: searching for functional relevance}, journal = {FEBS Lett}, volume = {579}, number = {8}, year = {2005}, note = {Huynen, Martijn A Gabaldon, Toni Snel, Berend Review Netherlands FEBS letters FEBS Lett. 2005 Mar 21;579(8):1839-45.}, pages = {1839-45}, abstract = {The availability of genome sequences and functional genomics data from multiple species enables us to compare the composition of biomolecular systems like biochemical pathways and protein complexes between species. Here, we review small- and large-scale, "genomics-based" approaches to biomolecular systems variation. In general, caution is required when comparing the results of bioinformatics analyses of genomes or of functional genomics data between species. Limitations to the sensitivity of sequence analysis tools and the noisy nature of genomics data tend to lead to systematic overestimates of the amount of variation. Nevertheless, the results from detailed manual analyses, and of large-scale analyses that filter out systematic biases, point to a large amount of variation in the composition of biomolecular systems. Such observations challenge our understanding of the function of the systems and their individual components and can potentially facilitate the identification and functional characterization of sub-systems within a system. Mapping the inter-species variation of complex biomolecular systems on a phylogenetic species tree allows one to reconstruct their evolution.}, keywords = {*Evolution, Molecular Genetic Variation Multiprotein Complexes/*genetics Phylogeny Protein Binding/genetics}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=15763561}, author = {M. A. Huynen and Gabald{\'o}n, T. and B. Snel} } @article {15044736, title = {Alignment of protein sequences by their profiles}, journal = {Protein Sci}, volume = {13}, number = {4}, year = {2004}, note = {Marti-Renom, Marc A Madhusudhan, M S Sali, Andrej P50 GM62529/GM/NIGMS NIH HHS/United States R01 GM54762/GM/NIGMS NIH HHS/United States Research Support, Non-U.S. Gov{\textquoteright}t Research Support, U.S. Gov{\textquoteright}t, P.H.S. United States Protein science : a publication of the Protein Society Protein Sci. 2004 Apr;13(4):1071-87.}, pages = {1071-87}, abstract = {The accuracy of an alignment between two protein sequences can be improved by including other detectably related sequences in the comparison. We optimize and benchmark such an approach that relies on aligning two multiple sequence alignments, each one including one of the two protein sequences. Thirteen different protocols for creating and comparing profiles corresponding to the multiple sequence alignments are implemented in the SALIGN command of MODELLER. A test set of 200 pairwise, structure-based alignments with sequence identities below 40\% is used to benchmark the 13 protocols as well as a number of previously described sequence alignment methods, including heuristic pairwise sequence alignment by BLAST, pairwise sequence alignment by global dynamic programming with an affine gap penalty function by the ALIGN command of MODELLER, sequence-profile alignment by PSI-BLAST, Hidden Markov Model methods implemented in SAM and LOBSTER, pairwise sequence alignment relying on predicted local structure by SEA, and multiple sequence alignment by CLUSTALW and COMPASS. The alignment accuracies of the best new protocols were significantly better than those of the other tested methods. For example, the fraction of the correctly aligned residues relative to the structure-based alignment by the best protocol is 56\%, which can be compared with the accuracies of 26\%, 42\%, 43\%, 48\%, 50\%, 49\%, 43\%, and 43\% for the other methods, respectively. The new method is currently applied to large-scale comparative protein structure modeling of all known sequences.}, keywords = {*Algorithms Amino Acid Sequence Computational Biology Databases, Protein Markov Chains Molecular Sequence Data *Protein Folding Protein Structure, Tertiary Proteins/*chemistry *Sequence Alignment Sequence Homology *Software}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=15044736}, author = {M. A. Marti-Renom and Madhusudhan, M. S. and Sali, A.} } @article {14681398, title = {MODBASE, a database of annotated comparative protein structure models, and associated resources}, journal = {Nucleic Acids Res}, volume = {32}, number = {Database issue}, year = {2004}, note = {Pieper, Ursula Eswar, Narayanan Braberg, Hannes Madhusudhan, M S Davis, Fred P Stuart, Ashley C Mirkovic, Nebojsa Rossi, Andrea Marti-Renom, Marc A Fiser, Andras Webb, Ben Greenblatt, Daniel Huang, Conrad C Ferrin, Thomas E Sali, Andrej P41 RR01081/RR/NCRR NIH HHS/United States P50 GM62529/GM/NIGMS NIH HHS/United States R01 GM 54762/GM/NIGMS NIH HHS/United States R33 CA84699/CA/NCI NIH HHS/United States Research Support, Non-U.S. Gov{\textquoteright}t Research Support, U.S. Gov{\textquoteright}t, P.H.S. England Nucleic acids research Nucleic Acids Res. 2004 Jan 1;32(Database issue):D217-22.}, pages = {D217-22}, abstract = {MODBASE (http://salilab.org/modbase) is a relational database of annotated comparative protein structure models for all available protein sequences matched to at least one known protein structure. The models are calculated by MODPIPE, an automated modeling pipeline that relies on the MODELLER package for fold assignment, sequence-structure alignment, model building and model assessment (http:/salilab.org/modeller). MODBASE uses the MySQL relational database management system for flexible querying and CHIMERA for viewing the sequences and structures (http://www.cgl.ucsf.edu/chimera/). MODBASE is updated regularly to reflect the growth in protein sequence and structure databases, as well as improvements in the software for calculating the models. For ease of access, MODBASE is organized into different data sets. The largest data set contains 1,26,629 models for domains in 659,495 out of 1,182,126 unique protein sequences in the complete Swiss-Prot/TrEMBL database (August 25, 2003); only models based on alignments with significant similarity scores and models assessed to have the correct fold despite insignificant alignments are included. Another model data set supports target selection and structure-based annotation by the New York Structural Genomics Research Consortium; e.g. the 53 new structures produced by the consortium allowed us to characterize structurally 24,113 sequences. MODBASE also contains binding site predictions for small ligands and a set of predicted interactions between pairs of modeled sequences from the same genome. Our other resources associated with MODBASE include a comprehensive database of multiple protein structure alignments (DBALI, http://salilab.org/dbali) as well as web servers for automated comparative modeling with MODPIPE (MODWEB, http://salilab. org/modweb), modeling of loops in protein structures (MODLOOP, http://salilab.org/modloop) and predicting functional consequences of single nucleotide polymorphisms (SNPWEB, http://salilab. org/snpweb).}, keywords = {Amino Acid Sequence Animals Binding Sites *Computational Biology *Databases, Molecular Molecular Sequence Data Polymorphism, Protein Genomics Humans Internet Ligands Models, Single Nucleotide Protein Binding Protein Conformation Proteins/*chemistry/genetics Sequence Alignment Software User-Computer Interface}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=14681398}, author = {Pieper, U. and Eswar, N. and Braberg, H. and Madhusudhan, M. S. and Davis, F. P. and Stuart, A. C. and Mirkovic, N. and Rossi, A. and M. A. Marti-Renom and Fiser, A. and Webb, B. and Greenblatt, D. and Huang, C. C. and Ferrin, T. E. and Sali, A.} } @article {15262789, title = {Phylogenomics and the number of characters required for obtaining an accurate phylogeny of eukaryote model species}, journal = {Bioinformatics}, volume = {20 Suppl 1}, year = {2004}, note = {

Dopazo, Hernan Santoyo, Javier Dopazo, Joaquin Research Support, Non-U.S. Gov{\textquoteright}t England Bioinformatics (Oxford, England) Bioinformatics. 2004 Aug 4;20 Suppl 1:i116-21.

}, pages = {i116-21}, abstract = {

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

}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=15262789}, author = {H. Dopazo and J. Santoyo and Dopazo, J.} } @article {15215388, title = {PupaSNP Finder: a web tool for finding SNPs with putative effect at transcriptional level}, journal = {Nucleic Acids Res}, volume = {32}, number = {Web Server issue}, year = {2004}, note = {Conde, Lucia Vaquerizas, Juan M Santoyo, Javier Al-Shahrour, Fatima Ruiz-Llorente, Sergio Robledo, Mercedes Dopazo, Joaquin England Nucleic acids research Nucleic Acids Res. 2004 Jul 1;32(Web Server issue):W242-8.}, pages = {W242-8}, abstract = {We have developed a web tool, PupaSNP Finder (PupaSNP for short), for high-throughput searching for single nucleotide polymorphisms (SNPs) with potential phenotypic effect. PupaSNP takes as its input lists of genes (or generates them from chromosomal coordinates) and retrieves SNPs that could affect the conserved regions that the cellular machinery uses for the correct processing of genes (intron/exon boundaries or exonic splicing enhancers), predicted transcription factor binding sites (TFBS) and changes in amino acids in the proteins. The program uses the mapping of SNPs in the genome provided by Ensembl. Additionally, user-defined SNPs (not yet mapped in the genome) can be easily provided to the program. Also, additional functional information from Gene Ontology, OMIM and homologies in other model organisms is provided. In contrast to other programs already available, which focus only on SNPs with possible effect in the protein, PupaSNP includes SNPs with possible transcriptional effect. PupaSNP will be of significant help in studies of multifactorial disorders, where the use of functional SNPs will increase the sensitivity of identification of the genes responsible for the disease. The PupaSNP web interface is accessible through http://pupasnp.bioinfo.cnio.es.}, keywords = {Amino Acid Substitution Binding Sites Humans Internet Phenotype *Polymorphism, Genetic, Single Nucleotide RNA Splicing *Software Transcription Factors/metabolism *Transcription}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=15215388}, author = {L. Conde and Vaquerizas, J. M. and J. Santoyo and Fatima Al-Shahrour and Ruiz-Llorente, S. and M. Robledo and Dopazo, J.} } @article {15172985, title = {Structure-based assessment of missense mutations in human BRCA1: implications for breast and ovarian cancer predisposition}, journal = {Cancer Res}, volume = {64}, number = {11}, year = {2004}, note = {Mirkovic, Nebojsa Marti-Renom, Marc A Weber, Barbara L Sali, Andrej Monteiro, Alvaro N A CA92309/CA/NCI NIH HHS/United States GM54762/GM/NIGMS NIH HHS/United States GM61390/GM/NIGMS NIH HHS/United States Research Support, Non-U.S. Gov{\textquoteright}t Research Support, U.S. Gov{\textquoteright}t, Non-P.H.S. Research Support, U.S. Gov{\textquoteright}t, P.H.S. United States Cancer research Cancer Res. 2004 Jun 1;64(11):3790-7.}, pages = {3790-7}, abstract = {The BRCA1 gene from individuals at risk of breast and ovarian cancers can be screened for the presence of mutations. However, the cancer association of most alleles carrying missense mutations is unknown, thus creating significant problems for genetic counseling. To increase our ability to identify cancer-associated mutations in BRCA1, we set out to use the principles of protein three-dimensional structure as well as the correlation between the cancer-associated mutations and those that abolish transcriptional activation. Thirty-one of 37 missense mutations of known impact on the transcriptional activation function of BRCA1 are readily rationalized in structural terms. Loss-of-function mutations involve nonconservative changes in the core of the BRCA1 C-terminus (BRCT) fold or are localized in a groove that presumably forms a binding site involved in the transcriptional activation by BRCA1; mutations that do not abolish transcriptional activation are either conservative changes in the core or are on the surface outside of the putative binding site. Next, structure-based rules for predicting functional consequences of a given missense mutation were applied to 57 germ-line BRCA1 variants of unknown cancer association. Such a structure-based approach may be helpful in an integrated effort to identify mutations that predispose individuals to cancer.}, keywords = {BRCA1 Genetic Predisposition to Disease Humans *Mutation, BRCA1 Protein/*chemistry/genetics Breast Neoplasms/*genetics Female *Genes, Missense Ovarian Neoplasms/*genetics Pedigree Protein Conformation Structure-Activity Relationship Transcriptional Activation}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=15172985}, author = {Mirkovic, N. and M. A. Marti-Renom and Weber, B. L. and Sali, A. and Monteiro, A. N.} } @article {12824315, title = {EVA: Evaluation of protein structure prediction servers}, journal = {Nucleic Acids Res}, volume = {31}, number = {13}, year = {2003}, note = {Koh, Ingrid Y Y Eyrich, Volker A Marti-Renom, Marc A Przybylski, Dariusz Madhusudhan, Mallur S Eswar, Narayanan Grana, Osvaldo Pazos, Florencio Valencia, Alfonso Sali, Andrej Rost, Burkhard 1-P50-GM62413-01/GM/NIGMS NIH HHS/United States 5-P20-LM7276/LM/NLM NIH HHS/United States P50 GM62529/GM/NIGMS NIH HHS/United States R01 GM54762/GM/NIGMS NIH HHS/United States R01-GM63029-01/GM/NIGMS NIH HHS/United States Research Support, Non-U.S. Gov{\textquoteright}t Research Support, U.S. Gov{\textquoteright}t, Non-P.H.S. Research Support, U.S. Gov{\textquoteright}t, P.H.S. England Nucleic acids research Nucleic Acids Res. 2003 Jul 1;31(13):3311-5.}, pages = {3311-5}, abstract = {EVA (http://cubic.bioc.columbia.edu/eva/) is a web server for evaluation of the accuracy of automated protein structure prediction methods. The evaluation is updated automatically each week, to cope with the large number of existing prediction servers and the constant changes in the prediction methods. EVA currently assesses servers for secondary structure prediction, contact prediction, comparative protein structure modelling and threading/fold recognition. Every day, sequences of newly available protein structures in the Protein Data Bank (PDB) are sent to the servers and their predictions are collected. The predictions are then compared to the experimental structures once a week; the results are published on the EVA web pages. Over time, EVA has accumulated prediction results for a large number of proteins, ranging from hundreds to thousands, depending on the prediction method. This large sample assures that methods are compared reliably. As a result, EVA provides useful information to developers as well as users of prediction methods.}, keywords = {Automation Databases, Protein, Protein Internet *Protein Conformation Protein Folding Protein Structure, Protein Structural Homology, Secondary Proteins/chemistry Reproducibility of Results *Sequence Analysis}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=12824315}, author = {Koh, I. Y. and Eyrich, V. A. and M. A. Marti-Renom and Przybylski, D. and Madhusudhan, M. S. and Eswar, N. and Grana, O. and Pazos, F. and Valencia, A. and Sali, A. and Rost, B.} } @article {12824345, title = {GEPAS: A web-based resource for microarray gene expression data analysis}, journal = {Nucleic Acids Res}, volume = {31}, number = {13}, year = {2003}, note = {

Herrero, Javier Al-Shahrour, Fatima Diaz-Uriarte, Ramon Mateos, Alvaro Vaquerizas, Juan M Santoyo, Javier Dopazo, Joaquin Research Support, Non-U.S. Gov{\textquoteright}t England Nucleic acids research Nucleic Acids Res. 2003 Jul 1;31(13):3461-7.

}, pages = {3461-7}, abstract = {

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

}, keywords = {gepas, microarray data analysis}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=12824345}, author = {Herrero, J. and Fatima Al-Shahrour and Diaz-Uriarte, R. and A. Mateos and Vaquerizas, J. M. and J. Santoyo and Dopazo, J.} } @article {12499313, title = {ModView, visualization of multiple protein sequences and structures}, journal = {Bioinformatics}, volume = {19}, number = {1}, year = {2003}, note = {Ilyin, Valentin A Pieper, Ursula Stuart, Ashley C Marti-Renom, Marc A McMahan, Linda Sali, Andrej P50-GM62529/GM/NIGMS NIH HHS/United States Research Support, Non-U.S. Gov{\textquoteright}t Research Support, U.S. Gov{\textquoteright}t, P.H.S. England Bioinformatics (Oxford, England) Bioinformatics. 2003 Jan;19(1):165-6.}, pages = {165-6}, abstract = {SUMMARY: We describe ModView, a web application for visualization of multiple protein sequences and structures. ModView integrates a multiple structure viewer, a multiple sequence alignment editor, and a database querying engine. It is possible to interactively manipulate hundreds of proteins, to visualize conservative and variable residues, active and binding sites, fragments, and domains in protein families, as well as to display large macromolecular complexes such as ribosomes or viruses. As a Netscape plug-in, ModView can be included in HTML pages along with text and figures, which makes it useful for teaching and presentations. ModView is also suitable as a graphical interface to various databases because it can be controlled through JavaScript commands and called from CGI scripts. AVAILABILITY: ModView is available at http://guitar.rockefeller.edu/modview.}, keywords = {*Database Management Systems Documentation/methods Imaging, Protein/*methods *User-Computer Interface, Three-Dimensional/methods Protein Conformation Proteins/*chemistry/genetics Sequence Alignment/*methods Sequence Analysis}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=12499313}, author = {Ilyin, V. A. and Pieper, U. and Stuart, A. C. and M. A. Marti-Renom and McMahan, L. and Sali, A.} } @article {12824331, title = {Tools for comparative protein structure modeling and analysis}, journal = {Nucleic Acids Res}, volume = {31}, number = {13}, year = {2003}, note = {Eswar, Narayanan John, Bino Mirkovic, Nebojsa Fiser, Andras Ilyin, Valentin A Pieper, Ursula Stuart, Ashley C Marti-Renom, Marc A Madhusudhan, M S Yerkovich, Bozidar Sali, Andrej P50 GM62529/GM/NIGMS NIH HHS/United States R01 GM 54762/GM/NIGMS NIH HHS/United States R33 CA84699/CA/NCI NIH HHS/United States Research Support, Non-U.S. Gov{\textquoteright}t Research Support, U.S. Gov{\textquoteright}t, P.H.S. England Nucleic acids research Nucleic Acids Res. 2003 Jul 1;31(13):3375-80.}, pages = {3375-80}, abstract = {The following resources for comparative protein structure modeling and analysis are described (http://salilab.org): MODELLER, a program for comparative modeling by satisfaction of spatial restraints; MODWEB, a web server for automated comparative modeling that relies on PSI-BLAST, IMPALA and MODELLER; MODLOOP, a web server for automated loop modeling that relies on MODELLER; MOULDER, a CPU intensive protocol of MODWEB for building comparative models based on distant known structures; MODBASE, a comprehensive database of annotated comparative models for all sequences detectably related to a known structure; MODVIEW, a Netscape plugin for Linux that integrates viewing of multiple sequences and structures; and SNPWEB, a web server for structure-based prediction of the functional impact of a single amino acid substitution.}, keywords = {Amino Acid *Software *Structural Homology, Internet Models, Molecular Protein Folding Proteins/chemistry Reproducibility of Results Sequence Alignment Sequence Homology, Protein Systems Integration}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=12824331}, author = {Eswar, N. and John, B. and Mirkovic, N. and Fiser, A. and Ilyin, V. A. and Pieper, U. and Stuart, A. C. and M. A. Marti-Renom and Madhusudhan, M. S. and Yerkovich, B. and Sali, A.} } @inbook {492, title = {Using Gene Ontology on genome-scale studies to find significant associations of biologically relevant terms to group of genes}, booktitle = {Neural Networks for Signal Processing XIII}, year = {2003}, pages = {43-52}, publisher = {IEEE Press}, organization = {IEEE Press}, address = {New York, USA}, keywords = {babelomics}, author = {Fatima Al-Shahrour and Herrero, J. and A. Mateos and J. Santoyo and D{\'\i}az-Uriarte, R and Dopazo, J.} } @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 {12005441, title = {Reliability of assessment of protein structure prediction methods}, journal = {Structure}, volume = {10}, number = {3}, year = {2002}, note = {

Marti-Renom, Marc A Madhusudhan, M S Fiser, Andras Rost, Burkhard Sali, Andrej GM 54762/GM/NIGMS NIH HHS/United States GM62413/GM/NIGMS NIH HHS/United States Comparative Study Research Support, Non-U.S. Gov{\textquoteright}t Research Support, U.S. Gov{\textquoteright}t, P.H.S. United States Structure (London, England : 1993) Structure. 2002 Mar;10(3):435-40.

}, pages = {435-40}, abstract = {

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

}, keywords = {*Computer Simulation Humans *Models, Molecular *Protein Conformation Proteins/*chemistry Reproducibility of Results}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=12005441}, author = {M. A. Marti-Renom and Madhusudhan, M. S. and Fiser, A. and Rost, B. and Sali, A.} } @article {12421757, title = {Systematic learning of gene functional classes from DNA array expression data by using multilayer perceptrons}, journal = {Genome Res}, volume = {12}, number = {11}, year = {2002}, note = {Mateos, Alvaro Dopazo, Joaquin Jansen, Ronald Tu, Yuhai Gerstein, Mark Stolovitzky, Gustavo Research Support, Non-U.S. Gov{\textquoteright}t Validation Studies United States Genome research Genome Res. 2002 Nov;12(11):1703-15.}, pages = {1703-15}, abstract = {Recent advances in microarray technology have opened new ways for functional annotation of previously uncharacterised genes on a genomic scale. This has been demonstrated by unsupervised clustering of co-expressed genes and, more importantly, by supervised learning algorithms. Using prior knowledge, these algorithms can assign functional annotations based on more complex expression signatures found in existing functional classes. Previously, support vector machines (SVMs) and other machine-learning methods have been applied to a limited number of functional classes for this purpose. Here we present, for the first time, the comprehensive application of supervised neural networks (SNNs) for functional annotation. Our study is novel in that we report systematic results for 100 classes in the Munich Information Center for Protein Sequences (MIPS) functional catalog. We found that only 10\% of these are learnable (based on the rate of false negatives). A closer analysis reveals that false positives (and negatives) in a machine-learning context are not necessarily "false" in a biological sense. We show that the high degree of interconnections among functional classes confounds the signatures that ought to be learned for a unique class. We term this the "Borges effect" and introduce two new numerical indices for its quantification. Our analysis indicates that classification systems with a lower Borges effect are better suitable for machine learning. Furthermore, we introduce a learning procedure for combining false positives with the original class. We show that in a few iterations this process converges to a gene set that is learnable with considerably low rates of false positives and negatives and contains genes that are biologically related to the original class, allowing for a coarse reconstruction of the interactions between associated biological pathways. We exemplify this methodology using the well-studied tricarboxylic acid cycle.}, keywords = {Algorithms Artificial Intelligence Citric Acid Cycle/genetics Cluster Analysis Computational Biology/methods Gene Expression Profiling/*methods/statistics \& numerical data Genes/*physiology Genetic Heterogeneity Neural Networks (Computer) Oligonucleotide}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=12421757}, author = {A. Mateos and Dopazo, J. and Jansen, R. and Tu, Y. and Gerstein, M. and Stolovitzky, G.} } @article {12471146, title = {Use of single point mutations in domain I of beta 2-glycoprotein I to determine fine antigenic specificity of antiphospholipid autoantibodies}, journal = {J Immunol}, volume = {169}, number = {12}, year = {2002}, note = {Iverson, G Michael Reddel, Stephen Victoria, Edward J Cockerill, Keith A Wang, Ying-Xia Marti-Renom, Marc A Sali, Andrej Marquis, David M Krilis, Steven A Linnik, Matthew D GM54762/GM/NIGMS NIH HHS/United States Research Support, Non-U.S. Gov{\textquoteright}t Research Support, U.S. Gov{\textquoteright}t, P.H.S. United States Journal of immunology (Baltimore, Md. : 1950) J Immunol. 2002 Dec 15;169(12):7097-103.}, pages = {7097-103}, abstract = {Autoantibodies against beta(2)-glycoprotein I (beta(2)GPI) appear to be a critical feature of the antiphospholipid syndrome (APS). As determined using domain deletion mutants, human autoantibodies bind to the first of five domains present in beta(2)GPI. In this study the fine detail of the domain I epitope has been examined using 10 selected mutants of whole beta(2)GPI containing single point mutations in the first domain. The binding to beta(2)GPI was significantly affected by a number of single point mutations in domain I, particularly by mutations in the region of aa 40-43. Molecular modeling predicted these mutations to affect the surface shape and electrostatic charge of a facet of domain I. Mutation K19E also had an effect, albeit one less severe and involving fewer patients. Similar results were obtained in two different laboratories using affinity-purified anti-beta(2)GPI in a competitive inhibition ELISA and with whole serum in a direct binding ELISA. This study confirms that anti-beta(2)GPI autoantibodies bind to domain I, and that the charged surface patch defined by residues 40-43 contributes to a dominant target epitope.}, keywords = {Amino Acid Substitution/genetics Antibodies, Antibody/genetics Binding, Antiphospholipid/blood/*metabolism Antibodies, Competitive/genetics/immunology Enzyme-Linked Immunosorbent Assay/methods Epitopes/analysis/*immunology/metabolism Glycine/genetics Glycoproteins/biosynthesis/*genetics/*immunology/isolation \& purification/metabolism Humans Models, Molecular Peptide Fragments/genetics/immunology/isolation \& purification/metabolism *Point Mutation Protein Structure, Monoclonal/blood/metabolism Antiphospholipid Syndrome/immunology Arginine/genetics *Binding Sites, Tertiary/genetics Recombinant Proteins/biosynthesis/immunology/isolation \& purification/metabolism Static Electricity beta 2-Glycoprotein I}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=12471146}, author = {Iverson, G. M. and Reddel, S. and Victoria, E. J. and Cockerill, K. A. and Wang, Y. X. and M. A. Marti-Renom and Sali, A. and Marquis, D. M. and Krilis, S. A. and Linnik, M. D.} } @article {11524379, title = {DBAli: a database of protein structure alignments}, journal = {Bioinformatics}, volume = {17}, number = {8}, year = {2001}, note = {Marti-Renom, M A Ilyin, V A Sali, A Research Support, Non-U.S. Gov{\textquoteright}t Research Support, U.S. Gov{\textquoteright}t, P.H.S. England Bioinformatics (Oxford, England) Bioinformatics. 2001 Aug;17(8):746-7.}, pages = {746-7}, abstract = {SUMMARY: The DBAli database includes approximately 35000 alignments of pairs of protein structures from SCOP (Lo Conte et al., Nucleic Acids Res., 28, 257-259, 2000) and CE (Shindyalov and Bourne, Protein Eng., 11, 739-747, 1998). DBAli is linked to several resources, including Compare3D (Shindyalov and Bourne, http://www.sdsc.edu/pb/software.htm, 1999) and ModView (Ilyin and Sali, http://guitar.rockefeller.edu/ModView/, 2001) for visualizing sequence alignments and structure superpositions. A flexible search of DBAli by protein sequence and structure properties allows construction of subsets of alignments suitable for a number of applications, such as benchmarking of sequence-sequence and sequence-structure alignment methods under a variety of conditions. AVAILABILITY: http://guitar.rockefeller.edu/DBAli/}, keywords = {Computational Biology *Databases, Protein Proteins/*chemistry/*genetics Sequence Alignment/*statistics \& numerical data Software Software Design}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=11524379}, author = {M. A. Marti-Renom and Ilyin, V. A. and Sali, A.} } @article {11751240, title = {EVA: continuous automatic evaluation of protein structure prediction servers}, journal = {Bioinformatics}, volume = {17}, number = {12}, year = {2001}, note = {Eyrich, V A Marti-Renom, M A Przybylski, D Madhusudhan, M S Fiser, A Pazos, F Valencia, A Sali, A Rost, B England Bioinformatics (Oxford, England) Bioinformatics. 2001 Dec;17(12):1242-3.}, pages = {1242-3}, abstract = {Evaluation of protein structure prediction methods is difficult and time-consuming. Here, we describe EVA, a web server for assessing protein structure prediction methods, in an automated, continuous and large-scale fashion. Currently, EVA evaluates the performance of a variety of prediction methods available through the internet. Every week, the sequences of the latest experimentally determined protein structures are sent to prediction servers, results are collected, performance is evaluated, and a summary is published on the web. EVA has so far collected data for more than 3000 protein chains. These results may provide valuable insight to both developers and users of prediction methods. AVAILABILITY: http://cubic.bioc.columbia.edu/eva. CONTACT: eva@cubic.bioc.columbia.edu}, keywords = {Automation Internet *Protein Conformation Proteins/*analysis *Software}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=11751240}, author = {Eyrich, V. A. and M. A. Marti-Renom and Przybylski, D. and Madhusudhan, M. S. and Fiser, A. and Pazos, F. and Valencia, A. and Sali, A. and Rost, B.} } @article {11278701, title = {Expression of the Caldariomyces fumago chloroperoxidase in Aspergillus niger and characterization of the recombinant enzyme}, journal = {J Biol Chem}, volume = {276}, number = {21}, year = {2001}, note = {Conesa, A van De Velde, F van Rantwijk, F Sheldon, R A van Den Hondel, C A Punt, P J Research Support, Non-U.S. Gov{\textquoteright}t United States The Journal of biological chemistry J Biol Chem. 2001 May 25;276(21):17635-40. Epub 2001 Feb 22.}, pages = {17635-40}, abstract = {The Caldariomyces fumago chloroperoxidase was successfully expressed in Aspergillus niger. The recombinant enzyme was produced in the culture medium as an active protein and could be purified by a three-step purification procedure. The catalytic behavior of recombinant chloroperoxidase (rCPO) was studied and compared with that of native CPO. The specific chlorination activity (47 units/nmol) of rCPO and its pH optimum (pH 2.75) were very similar to those of native CPO. rCPO catalyzes the oxidation of various substrates in comparable yields and selectivities to native CPO. Indole was oxidized to 2-oxindole with 99\% selectivity and thioanisole to the corresponding R-sulfoxide (enantiomeric excess >98\%). Incorporation of (18)O from labeled H(2)18O(2) into the oxidized products was 100\% in both cases.}, keywords = {Aspergillus niger/enzymology/genetics Catalysis Chloride Peroxidase/biosynthesis/*genetics Fungal Proteins/biosynthesis/*genetics Recombinant Proteins/biosynthesis/genetics Substrate Specificity}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=11278701}, author = {A. Conesa and van De Velde, F. and van Rantwijk, F. and Sheldon, R. A. and van den Hondel, C. A. and Punt, P. J.} } @article {11254175, title = {Identification of optimal regions for phylogenetic studies on VP1 gene of foot-and-mouth disease virus: analysis of types A and O Argentinean viruses}, journal = {Vet Res}, volume = {32}, number = {1}, year = {2001}, note = {Nunez, J I Martin, M J Piccone, M E Carrillo, E Palma, E L Dopazo, J Sobrino, F Research Support, Non-U.S. Gov{\textquoteright}t France Veterinary research Vet Res. 2001 Jan-Feb;32(1):31-45.}, pages = {31-45}, abstract = {An analysis of the informative content of sequence stretches on the foot-and-mouth disease virus (FMDV) VPI gene was applied to two important viral serotypes: A and O. Several sequence regions were identified to allow the reconstruction of phylogenetic trees equivalent to those derived from the whole VPI gene. The optimal informative regions for sequence windows of 150 to 250 nt were predicted between positions 250 and 550 of the gene. The sequences spanning the 250 nt of the 3{\textquoteright} end (positions 400 to 650), extensively used for FMDV phylogenetic analyses, showed a lower informative content. In spite of this, the use of sequences from this region allowed the derivation of phylogenetic trees for type A and type O FMDVs which showed topologies similar to those previously reported for the whole VP1 gene. When the sequences determined for viruses isolated in Argentina, between 1990 and 1993, were included in these analyses, the results obtained revealed features of the circulation of type A and type O viruses in the field, in the months that preceded the eradication of the disease in this country. Type A viruses were closely related to an Argentinean vaccine strain, and defined an independent cluster within this serotype. Among the type O viruses analysed, two groups were distinguished; one was closely related to the South American vaccine strains, while the other was grouped with viruses of the O3 subtype. In addition, a detailed phylogeny for type A FMDV is presented.}, keywords = {Amino Acid Sequence Animals Aphthovirus/classification/*genetics Base Sequence Capsid/chemistry/*genetics Capsid Proteins DNA, Complementary/chemistry Molecular Sequence Data *Phylogeny Polymerase Chain Reaction RNA, Viral/chemistry/genetics Serotyping Viral Proteins/analysis/*genetics}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=11254175}, author = {Nunez, J. I. and Martin, M. J. and Piccone, M. E. and Carrillo, E. and Palma, E. L. and Dopazo, J. and Sobrino, F.} }