@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 {799, title = {Real-world evidence with a retrospective cohort of 15,968 COVID-19 hospitalized patients suggests 21 new effective treatments.}, journal = {Virol J}, volume = {20}, year = {2023}, month = {2023 Oct 06}, pages = {226}, abstract = {

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

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

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

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

}, issn = {1743-422X}, doi = {10.1186/s12985-023-02195-9}, author = {Loucera, Carlos and Carmona, Rosario and Esteban-Medina, Marina and Bostelmann, Gerrit and Mu{\~n}oyerro-Mu{\~n}iz, Dolores and Villegas, Rom{\'a}n and Pe{\~n}a-Chilet, Maria and Dopazo, Joaquin} } @article {745, title = {Real world evidence of calcifediol or vitamin D prescription and mortality rate of COVID-19 in a retrospective cohort of hospitalized Andalusian patients.}, journal = {Sci Rep}, volume = {11}, year = {2021}, month = {2021 12 03}, pages = {23380}, abstract = {

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

}, keywords = {Calcifediol, COVID-19, Female, Humans, Kaplan-Meier Estimate, Male, Retrospective Studies, Spain, Survival Analysis, Vitamin D}, issn = {2045-2322}, doi = {10.1038/s41598-021-02701-5}, author = {Loucera, Carlos and Pe{\~n}a-Chilet, Maria and Esteban-Medina, Marina and Mu{\~n}oyerro-Mu{\~n}iz, Dolores and Villegas, Rom{\'a}n and L{\'o}pez-Miranda, Jos{\'e} and Rodr{\'\i}guez-Ba{\~n}o, Jes{\'u}s and T{\'u}nez, Isaac and Bouillon, Roger and Dopazo, Joaquin and Quesada Gomez, Jose Manuel} } @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 {388, title = {Reference genome assessment from a population scale perspective: an accurate profile of variability and noise.}, journal = {Bioinformatics}, volume = {33}, year = {2017}, month = {2017 Nov 15}, pages = {3511-3517}, abstract = {

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

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

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

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

Supplementary information: Supplementary data are available at Bioinformatics online.

}, keywords = {Animals, Genetic Variation, Genome, Genomics, Genotype, Humans, Models, Statistical, Quality Control, Reproducibility of Results, Software}, issn = {1367-4811}, doi = {10.1093/bioinformatics/btx482}, url = {https://academic.oup.com/bioinformatics/article-lookup/doi/10.1093/bioinformatics/btx482}, author = {Carbonell-Caballero, Jos{\'e} and Amadoz, Alicia and Alonso, Roberto and Hidalgo, Marta R and Cubuk, Cankut and Conesa, David and L{\'o}pez-Qu{\'\i}lez, Antonio and Dopazo, Joaquin} } @article {467, title = {Re-evaluation casts doubt on the pathogenicity of homozygous USH2A p.C759F.}, journal = {Am J Med Genet A}, volume = {167}, year = {2015}, month = {2015 Jul}, pages = {1597-600}, abstract = {

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

}, keywords = {Base Sequence, Cyclic Nucleotide Phosphodiesterases, Type 6, Extracellular Matrix Proteins, Gene Library, Humans, Molecular Sequence Data, Mutation, Missense, Pedigree, Retinitis pigmentosa, Sequence Analysis, DNA, Spain}, issn = {1552-4833}, doi = {10.1002/ajmg.a.37003}, author = {Pozo, Mar{\'\i}a Gonz{\'a}lez-Del and Bravo-Gil, Nereida and M{\'e}ndez-Vidal, Cristina and Montero-de-Espinosa, Ignacio and Mill{\'a}n, Jos{\'e} M and Dopazo, Joaquin and Borrego, Salud and Anti{\v n}olo, Guillermo} } @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 {501, title = {Role of CPI-17 in restoring skin homoeostasis in cutaneous field of cancerization: effects of topical application of a film-forming medical device containing photolyase and UV filters.}, journal = {Exp Dermatol}, volume = {22}, year = {2013}, month = {2013 Jul}, pages = {494-6}, abstract = {

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

}, keywords = {Administration, Topical, Adult, Aged, Aged, 80 and over, Biopsy, Deoxyribodipyrimidine Photo-Lyase, Female, Gene Expression Profiling, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, Homeostasis, Humans, Inflammation, Intracellular Signaling Peptides and Proteins, Liposomes, Male, Middle Aged, Muscle Proteins, Phenotype, Phosphoprotein Phosphatases, Reactive Oxygen Species, Skin, Skin Neoplasms, Ultraviolet Rays}, issn = {1600-0625}, doi = {10.1111/exd.12177}, author = {Puig-Butille, Joan Anton and Malvehy, Josep and Potrony, Miriam and Trullas, Carles and Garcia-Garcia, Francisco and Dopazo, Joaquin and Puig, Susana} } @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 {18689811, title = {RNA structure alignment by a unit-vector approach}, journal = {Bioinformatics}, volume = {24}, number = {16}, year = {2008}, note = {Capriotti, Emidio Marti-Renom, Marc A Research Support, Non-U.S. Gov{\textquoteright}t England Bioinformatics (Oxford, England) Bioinformatics. 2008 Aug 15;24(16):i112-8.}, pages = {i112-8}, abstract = {MOTIVATION: The recent discovery of tiny RNA molecules such as microRNAs and small interfering RNA are transforming the view of RNA as a simple information transfer molecule. Similar to proteins, the native three-dimensional structure of RNA determines its biological activity. Therefore, classifying the current structural space is paramount for functionally annotating RNA molecules. The increasing numbers of RNA structures deposited in the PDB requires more accurate, automatic and benchmarked methods for RNA structure comparison. In this article, we introduce a new algorithm for RNA structure alignment based on a unit-vector approach. The algorithm has been implemented in the SARA program, which results in RNA structure pairwise alignments and their statistical significance. RESULTS: The SARA program has been implemented to be of general applicability even when no secondary structure can be calculated from the RNA structures. A benchmark against the ARTS program using a set of 1275 non-redundant pairwise structure alignments results in inverted approximately 6\% extra alignments with at least 50\% structurally superposed nucleotides and base pairs. A first attempt to perform RNA automatic functional annotation based on structure alignments indicates that SARA can correctly assign the deepest SCOR classification to >60\% of the query structures. AVAILABILITY: The SARA program is freely available through a World Wide Web server http://sgu.bioinfo.cipf.es/services/SARA/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.}, keywords = {Algorithms Base Sequence Computer Simulation *Models, Chemical *Models, Molecular Molecular Sequence Data Nucleic Acid Conformation RNA/*chemistry/*ultrastructure Sequence Alignment/*methods Sequence Analysis, RNA/*methods *Software}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=18689811}, author = {E. Capriotti and M. A. Marti-Renom} } @inbook {476, title = {Reconstruction of ancestral proteomes}, booktitle = {Ancestral Sequence Reconstruction}, year = {2007}, publisher = {D. Liberles}, organization = {D. Liberles}, address = {Oxford}, url = {http://www.us.oup.com/us/catalog/general/subject/LifeSciences/EvolutionaryBiology/?view=usa\&ci=9780199299188}, author = {Gabald{\'o}n, T. and M. A. Huynen} } @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 {12893934, title = {Reconstruction of the proto-mitochondrial metabolism}, journal = {Science}, volume = {301}, number = {5633}, year = {2003}, note = {Gabaldon, Toni Huynen, Martijn A Comparative Study Research Support, Non-U.S. Gov{\textquoteright}t United States Science (New York, N.Y.) Science. 2003 Aug 1;301(5633):609.}, pages = {609}, keywords = {Aerobiosis Algorithms Alphaproteobacteria/chemistry/genetics/*metabolism Amino Acids/metabolism Animals Bacterial Proteins/chemistry/*metabolism Genome Genome, Bacterial Glycerol/metabolism Humans Lipid Metabolism Mitochondria/chemistry/genetics/*metabolism Phylogeny *Proteome Symbiosis Yeasts/metabolism}, url = {http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve\&db=PubMed\&dopt=Citation\&list_uids=12893934}, author = {Gabald{\'o}n, T. and M. A. Huynen} } @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.} }