@article {804, title = {The mechanistic functional landscape of retinitis pigmentosa: a machine learning-driven approach to therapeutic target discovery.}, journal = {J Transl Med}, volume = {22}, year = {2024}, month = {2024 Feb 06}, pages = {139}, abstract = {

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

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

RESULTS: A mechanistic functional map of Retinitis Pigmentosa was constructed resulting in 226 functional circuits belonging to 40 KEGG signaling pathways. The method predicted 109 targets of approved drugs in use with a potential effect over circuits corresponding to nine hallmarks identified. Five of those targets were selected and experimentally validated in rd10 mice: Gabre, Gabra1 (GABARĪ±1 protein), Slc12a5 (KCC2 protein), Grin1 (NR1 protein) and Glr2a. As a result, we provide a resource to evaluate the potential impact of drug target genes in Retinitis Pigmentosa.

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

}, keywords = {Animals, Mice, Retinitis pigmentosa, Signal Transduction}, issn = {1479-5876}, doi = {10.1186/s12967-024-04911-7}, author = {Esteban-Medina, Marina and Loucera, Carlos and Rian, Kinza and Velasco, Sheyla and Olivares-Gonz{\'a}lez, Lorena and Rodrigo, Regina and Dopazo, Joaquin and Pe{\~n}a-Chilet, Maria} } @article {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 {775, title = {microRNAs-mediated regulation of insulin signaling in white adipose tissue during aging: Role of caloric restriction.}, journal = {Aging Cell}, year = {2023}, month = {2023 Jul 04}, pages = {e13919}, abstract = {

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

}, issn = {1474-9726}, doi = {10.1111/acel.13919}, author = {Corrales, Patricia and Martin-Taboada, Marina and Vivas-Garc{\'\i}a, Yurena and Torres, Lucia and Ramirez-Jimenez, Laura and Lopez, Yamila and Horrillo, Daniel and Vila-Bedmar, Rocio and Barber-Cano, Eloisa and Izquierdo-Lahuerta, Adriana and Pe{\~n}a-Chilet, Maria and Mart{\'\i}nez, Carmen and Dopazo, Joaquin and Ros, Manuel and Medina-Gomez, Gema} } @article {747, title = {Mapping the human genetic architecture of COVID-19.}, journal = {Nature}, volume = {600}, year = {2021}, month = {2021 Dec}, pages = {472-477}, abstract = {

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

}, issn = {1476-4687}, doi = {10.1038/s41586-021-03767-x} } @article {711, title = {Mechanistic modeling of the SARS-CoV-2 disease map.}, journal = {BioData Min}, volume = {14}, year = {2021}, month = {2021 Jan 21}, pages = {5}, abstract = {

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

}, issn = {1756-0381}, doi = {10.1186/s13040-021-00234-1}, author = {Rian, Kinza and Esteban-Medina, Marina and Hidalgo, Marta R and Cubuk, Cankut and Falco, Matias M and Loucera, Carlos and Gunyel, Devrim and Ostaszewski, Marek and Pe{\~n}a-Chilet, Maria and Dopazo, Joaquin} } @article {741, title = {Mutational Characterization of Cutaneous Melanoma Supports Divergent Pathways Model for Melanoma Development.}, journal = {Cancers (Basel)}, volume = {13}, year = {2021}, month = {2021 Oct 18}, abstract = {

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

}, issn = {2072-6694}, doi = {10.3390/cancers13205219}, author = {Mill{\'a}n-Esteban, David and Pe{\~n}a-Chilet, Maria and Garc{\'\i}a-Casado, Zaida and Manrique-Silva, Esperanza and Requena, Celia and Ba{\~n}uls, Jos{\'e} and Lopez-Guerrero, Jose Antonio and Rodr{\'\i}guez-Hern{\'a}ndez, Aranzazu and Traves, V{\'\i}ctor and Dopazo, Joaquin and Vir{\'o}s, Amaya and Kumar, Rajiv and Nagore, Eduardo} } @article {702, title = {Mechanistic models of signaling pathways deconvolute the glioblastoma single-cell functional landscapeAbstract}, journal = {NAR Cancer}, volume = {2}, year = {2020}, month = {Jan-06-2020}, doi = {10.1093/narcan/zcaa011}, url = {https://academic.oup.com/narcancer/article/doi/10.1093/narcan/zcaa011/5862620http://academic.oup.com/narcancer/article-pdf/2/2/zcaa011/33428092/zcaa011.pdfhttp://academic.oup.com/narcancer/article-pdf/2/2/zcaa011/33428092/zcaa011.pdf}, author = {Falco, Matias M and Pe{\~n}a-Chilet, Maria and Loucera, Carlos and Hidalgo, Marta R and Dopazo, Joaquin} } @article {695, title = {Mechanistic Models of Signaling Pathways Reveal the Drug Action Mechanisms behind Gender-Specific Gene Expression for Cancer Treatments.}, journal = {Cells}, volume = {9}, year = {2020}, month = {2020 06 29}, abstract = {

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

}, keywords = {Female, Gene Expression Regulation, Neoplastic, Humans, Male, Neoplasms, Signal Transduction}, issn = {2073-4409}, doi = {10.3390/cells9071579}, author = {Cubuk, Cankut and Can, Fatma E and Pe{\~n}a-Chilet, Maria and Dopazo, Joaquin} } @article {404, title = {Models of cell signaling uncover molecular mechanisms of high-risk neuroblastoma and predict disease outcome.}, journal = {Biol Direct}, volume = {13}, year = {2018}, month = {2018 08 22}, pages = {16}, abstract = {

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

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

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

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

}, keywords = {Computational Biology, Gene Expression Regulation, Neoplastic, Humans, JNK Mitogen-Activated Protein Kinases, Models, Theoretical, Neuroblastoma, Signal Transduction}, issn = {1745-6150}, doi = {10.1186/s13062-018-0219-4}, author = {Hidalgo, Marta R and Amadoz, Alicia and Cubuk, Cankut and Carbonell-Caballero, Jos{\'e} and Dopazo, Joaquin} } @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 {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 {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 {1046, title = {Molecular interactions between sugar beet and Polymyxa betae during its life cycle}, journal = {Annals of Applied Biology}, volume = {164}, number = {2}, year = {2014}, pages = {244{\textendash}256}, abstract = {Polymyxa betae is a biotrophic obligate sugar beet parasite that belongs to plasmodiophorids. The infection of sugar beet roots by this parasite is asymptomatic, except when it transmits Beet necrotic yellow vein virus (BNYVV), the causal agent of rhizomania. To date, there has been little work on P. betae{\textendash}sugar beet molecular interactions, mainly because of the obligate nature of the parasite and also because research on rhizomania has tended to focus on the virus. In this study, we investigated these interactions through differential transcript analysis, using suppressive subtractive hybridization. The analysis included 76 P. betae and 120 sugar beet expressed sequence tags (ESTs). The expression of selected ESTs from both organisms was monitored during the protist life cycle, revealing a potential role of two P. betae proteins, profilin and a Von Willebrand factor domain-containing protein, in the early phase of infection. This study also revealed an over-expression of some sugar beet genes involved in defence, such as those encoding PR proteins, stress resistance proteins or lectins, especially during the plasmodial stage of the P. betae life cycle. In addition to providing new information on the molecular aspects of P. betae{\textendash}sugar beet interactions, this study also enabled previously unknown ESTs of P. betae to be sequenced, thus enhancing our knowledge of the genome of this protist.}, doi = {10.1111/aab.12095}, url = {http://onlinelibrary.wiley.com/doi/10.1111/aab.12095/abstract}, author = {N. Desoignies and Carbonell, J. and J.-S. Moreau and A. Conesa and Dopazo, J. and A. Legr{\`e}ve} } @article {505, title = {Mammosphere formation in breast carcinoma cell lines depends upon expression of E-cadherin.}, journal = {PLoS One}, volume = {8}, year = {2013}, month = {2013}, pages = {e77281}, abstract = {

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

}, keywords = {Breast Neoplasms, Cadherins, Cell Line, Tumor, Cell Proliferation, Cluster Analysis, Female, gene expression, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Gene Knockdown Techniques, Humans, MCF-7 Cells, Neoplastic Stem Cells, Spheroids, Cellular, Tumor Cells, Cultured}, issn = {1932-6203}, doi = {10.1371/journal.pone.0077281}, author = {Manuel Iglesias, Juan and Beloqui, Izaskun and Garcia-Garcia, Francisco and Leis, Olatz and Vazquez-Martin, Alejandro and Eguiara, Arrate and Cufi, Silvia and Pavon, Andres and Menendez, Javier A and Dopazo, Joaquin and Martin, Angel G} } @article {1022, title = {Mammosphere Formation in Breast Carcinoma Cell Lines Depends upon Expression of E-cadherin}, journal = {PLoS ONE}, volume = {8}, year = {2013}, month = {2013/10/04}, pages = {e77281 -}, publisher = {Public Library of Science}, abstract = {

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

}, url = {http://dx.doi.org/10.1371\%2Fjournal.pone.0077281}, author = {Manuel Iglesias, Juan and Beloqui, Izaskun and Garcia-Garcia, Francisco and Leis, Olatz and Vazquez-Martin, Alejandro and Eguiara, Arrate and Cufi, Silvia and Pavon, Andres and Menendez, Javier A. and Dopazo, Joaquin and Martin, Angel G.} } @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 {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 {896, title = {Microarray analysis of Etrog citron (Citrus medica L.) reveals changes in chloroplast, cell wall, peroxidase and symporter activities in response to viroid infection.}, journal = {Molecular plant pathology}, year = {2012}, month = {2012 Mar 15}, abstract = {Viroids are small (246-401 nucleotides), single-stranded, circular RNA molecules that infect several crop plants and can cause diseases of economic importance. Citrus are the hosts in which the largest number of viroids have been identified. Citrus exocortis viroid (CEVd), the causal agent of citrus exocortis disease, induces considerable losses in citrus crops. Changes in the gene expression profile during the early (pre-symptomatic) and late (post-symptomatic) stages of Etrog citron infected with CEVd were investigated using a citrus cDNA microarray. MaSigPro analysis was performed and, on the basis of gene expression profiles as a function of the time after infection, the differentially expressed genes were classified into five clusters. FatiScan analysis revealed significant enrichment of functional categories for each cluster, indicating that viroid infection triggers important changes in chloroplast, cell wall, peroxidase and symporter activities.}, issn = {1364-3703}, doi = {10.1111/j.1364-3703.2012.00794.x}, author = {Rizza, Serena and Ana Conesa and Juarez, Jos{\'e} and Catara, Antonino and Navarro, Luis and Duran-Vila, Nuria and Ancillo, Gema} } @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 {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 {543, 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 = {Jan-08-2010}, pages = {827 - 838}, issn = {1087-0156}, doi = {10.1038/nbt.1665}, url = {http://www.nature.com/articles/nbt.1665http://www.nature.com/articles/nbt.1665.pdfhttp://www.nature.com/articles/nbt.1665.pdfhttp://www.nature.com/articles/nbt.1665} } @article {574, title = {Multidimensional gene set analysis of genomic data.}, journal = {PLoS One}, volume = {5}, year = {2010}, month = {2010 Apr 27}, pages = {e10348}, abstract = {

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

}, keywords = {Databases, Genetic, Gene Expression Profiling, Gene Regulatory Networks, Genome, Human, Genomics, Humans, Models, Statistical}, issn = {1932-6203}, doi = {10.1371/journal.pone.0010348}, author = {Montaner, David and Dopazo, Joaquin} } @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 {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 {17873908, title = {Molecular profiling related to poor prognosis in thyroid carcinoma. Combining gene expression data and biological information}, journal = {Oncogene}, volume = {27}, number = {11}, year = {2008}, note = {

Montero-Conde, C Martin-Campos, J M Lerma, E Gimenez, G Martinez-Guitarte, J L Combalia, N Montaner, D Matias-Guiu, X Dopazo, J de Leiva, A Robledo, M Mauricio, D Research Support, Non-U.S. Gov{\textquoteright}t England Oncogene Oncogene. 2008 Mar 6;27(11):1554-61. Epub 2007 Sep 17.

}, pages = {1554-61}, abstract = {

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

}, keywords = {Adenoma/genetics/metabolism/pathology Adolescent Adult Aged Carcinoma/genetics/metabolism/pathology Carcinoma, Biological/*genetics/metabolism, Neoplasm/genetics/metabolism Reverse Transcriptase Polymerase Chain Reaction Signal Transduction Thyroid Neoplasms/classification/*genetics/metabolism Tumor Markers, Neoplastic Humans Male Middle Aged *Oligonucleotide Array Sequence Analysis Prognosis RNA, Papillary/genetics/metabolism/pathology Cell Differentiation Female *Gene Expression Profiling *Gene Expression Regulation}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=17873908}, author = {Montero-Conde, C. and Martin-Campos, J. M. and Lerma, E. and Gimenez, G. and Martinez-Guitarte, J. L. and Combalia, N. and Montaner, D. and Matias-Guiu, X. and Dopazo, J. and de Leiva, A. and M. Robledo and Mauricio, D.} } @article {597, title = {Molecular profiling related to poor prognosis in thyroid carcinoma. Combining gene expression data and biological information.}, journal = {Oncogene}, volume = {27}, year = {2008}, month = {2008 Mar 06}, pages = {1554-61}, abstract = {

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

}, keywords = {Adenoma, Adolescent, Adult, Aged, Biomarkers, Tumor, Carcinoma, Carcinoma, Papillary, Cell Differentiation, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Male, Middle Aged, Oligonucleotide Array Sequence Analysis, Prognosis, Reverse Transcriptase Polymerase Chain Reaction, RNA, Neoplasm, Signal Transduction, Thyroid Neoplasms}, issn = {1476-5594}, doi = {10.1038/sj.onc.1210792}, author = {Montero-Conde, C and Mart{\'\i}n-Campos, J M and Lerma, E and Gimenez, G and Mart{\'\i}nez-Guitarte, J L and Combal{\'\i}a, N and Montaner, D and Mat{\'\i}as-Guiu, X and Dopazo, J and de Leiva, A and Robledo, M and Mauricio, D} } @inbook {475, title = {Microarray Technology in Agricultural Research}, booktitle = {Microarray Technology Through Applications}, year = {2007}, pages = {173-209}, publisher = {F. Falciani. Publisher: Taylor and Francis Group}, organization = {F. Falciani. Publisher: Taylor and Francis Group}, keywords = {babelomics}, issn = {0-4153-7853-2}, author = {A. Conesa and J. Forment and J. Gadea and van Dijk, J.} } @article {16481333, title = {maSigPro: a method to identify significantly differential expression profiles in time-course microarray experiments}, journal = {Bioinformatics}, volume = {22}, number = {9}, year = {2006}, note = {Conesa, Ana Nueda, Maria Jose Ferrer, Alberto Talon, Manuel England Bioinformatics (Oxford, England) Bioinformatics. 2006 May 1;22(9):1096-102. Epub 2006 Feb 15.}, pages = {1096-102}, abstract = {MOTIVATION: Multi-series time-course microarray experiments are useful approaches for exploring biological processes. In this type of experiments, the researcher is frequently interested in studying gene expression changes along time and in evaluating trend differences between the various experimental groups. The large amount of data, multiplicity of experimental conditions and the dynamic nature of the experiments poses great challenges to data analysis. RESULTS: In this work, we propose a statistical procedure to identify genes that show different gene expression profiles across analytical groups in time-course experiments. The method is a two-regression step approach where the experimental groups are identified by dummy variables. The procedure first adjusts a global regression model with all the defined variables to identify differentially expressed genes, and in second a variable selection strategy is applied to study differences between groups and to find statistically significant different profiles. The methodology is illustrated on both a real and a simulated microarray dataset.}, keywords = {*Algorithms Computer Simulation Gene Expression/*physiology Gene Expression Profiling/*methods *Models, Genetic Models, Statistical Oligonucleotide Array Sequence Analysis/*methods *Software Time Factors}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=16481333}, author = {A. Conesa and Nueda, M. J. and Ferrer, A. and Talon, M.} } @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 {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 {12597115, title = {A model for the emergence of adaptive subsystems}, journal = {Bull Math Biol}, volume = {65}, number = {1}, year = {2003}, note = {Dopazo, H Gordon, M B Perazzo, R Risau-Gusman, S Research Support, Non-U.S. Gov{\textquoteright}t United States Bulletin of mathematical biology Bull Math Biol. 2003 Jan;65(1):27-56.}, pages = {27-56}, abstract = {We investigate the interaction of learning and evolution in a changing environment. A stable learning capability is regarded as an emergent adaptive system evolved by natural selection of genetic variants. We consider the evolution of an asexual population. Each genotype can have {\textquoteright}fixed{\textquoteright} and {\textquoteright}flexible{\textquoteright} alleles. The former express themselves as synaptic connections that remain unchanged during ontogeny and the latter as synapses that can be adjusted through a learning algorithm. Evolution is modelled using genetic algorithms and the changing environment is represented by two optimal synaptic patterns that alternate a fixed number of times during the {\textquoteright}life{\textquoteright} of the individuals. The amplitude of the change is related to the Hamming distance between the two optimal patterns and the rate of change to the frequency with which both exchange roles. This model is an extension of that of Hinton and Nowlan in which the fitness is given by a probabilistic measure of the Hamming distance to the optimum. We find that two types of evolutionary pathways are possible depending upon how difficult (costly) it is to cope with the changes of the environment. In one case the population loses the learning ability, and the individuals inherit fixed synapses that are optimal in only one of the environmental states. In the other case a flexible subsystem emerges that allows the individuals to adapt to the changes of the environment. The model helps us to understand how an adaptive subsystem can emerge as the result of the tradeoff between the exploitation of a congenital structure and the exploration of the adaptive capabilities practised by learning.}, keywords = {*Adaptation, Biological Algorithms Alleles Animals Evolution Genotype Humans *Learning *Models, Genetic Models, Statistical Neural Networks (Computer) Phenotype Synapses/genetics}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=12597115}, author = {H. Dopazo and Gordon, M. B. and Perazzo, R. and Risau-Gusman, S.} } @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.} } @book {557, title = {Methods of Microarray Data Analysis IISupervised Neural Networks for Clustering Conditions in DNA Array Data After Reducing Noise by Clustering Gene Expression Profiles}, year = {2002}, pages = {91 - 103}, publisher = {Kluwer Academic Publishers}, organization = {Kluwer Academic Publishers}, address = {Boston}, doi = {10.1007/b11298210.1007/0-306-47598-7_7}, url = {http://www.springerlink.com/index/10.1007/b112982http://link.springer.com/10.1007/0-306-47598-7_7http://www.springerlink.com/index/pdf/10.1007/0-306-47598-7_7}, author = {Mateos, Alvaro and Herrero, Javier and Tamames, Javier and Dopazo, Joaquin}, editor = {Lin, Simon M. and Johnson, Kimberly F.} } @inbook {494, title = {Microarray Data Processing And Analysis}, booktitle = {Microarray data analysis II}, year = {2002}, pages = {43-63}, publisher = {Kluwer Academic}, organization = {Kluwer Academic}, author = {Dopazo, J.} } @article {11251224, title = {Methods and approaches in the analysis of gene expression data}, journal = {J Immunol Methods}, volume = {250}, number = {1-2}, year = {2001}, note = {

Dopazo, J Zanders, E Dragoni, I Amphlett, G Falciani, F Comparative Study Review Netherlands Journal of immunological methods J Immunol Methods. 2001 Apr;250(1-2):93-112.

}, pages = {93-112}, abstract = {

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

}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=11251224}, author = {Dopazo, J. and Zanders, E. and Dragoni, I. and Amphlett, G. and Falciani, F.} } @article {11146879, title = {A model for the interaction of learning and evolution}, journal = {Bull Math Biol}, volume = {63}, number = {1}, year = {2001}, note = {Dopazo, H Gordon, M B Perazzo, R Risau-Gusman, S Comparative Study Research Support, Non-U.S. Gov{\textquoteright}t United States Bulletin of mathematical biology Bull Math Biol. 2001 Jan;63(1):117-34.}, pages = {117-34}, abstract = {We present a simple model in order to discuss the interaction of the genetic and behavioral systems throughout evolution. This considers a set of adaptive perceptrons in which some of their synapses can be updated through a learning process. This framework provides an extension of the well-known Hinton and Nowlan model by blending together some learning capability and other (rigid) genetic effects that contribute to the fitness. We find a halting effect in the evolutionary dynamics, in which the transcription of environmental data into genetic information is hindered by learning, instead of stimulated as is usually understood by the so-called Baldwin effect. The present results are discussed and compared with those reported in the literature. An interpretation is provided of the halting effect.}, keywords = {Algorithms Alleles Animals *Evolution Genotype Humans *Learning *Neural Networks (Computer) Numerical Analysis, Computer-Assisted Phenotype Synapses/genetics}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=11146879}, author = {H. Dopazo and Gordon, M. B. and Perazzo, R. and Risau-Gusman, S.} }