The Ras protein superfamily: Evolutionary tree and role of conserved amino acids

The Ras superfamily is a fascinating example of functional diversification in the context of a preserved structural framework and a prototypic GTP binding site. Thanks to the availability of complete genome sequences of species representing important evolutionary branch points, we have analyzed the composition and organization of this superfamily at a greater level than was previously possible. Phylogenetic analysis of gene families at the organism and sequence level revealed complex relationships between the evolution of this protein superfamily sequence and the acquisition of distinct cellular functions. Together with advances in computational methods and structural studies, the sequence information has helped to identify features important for the recognition of molecular partners and the functional specialization of different members of the Ras superfamily.This work was supported by two grants from the Spanish Ministerio de Ciencia e Innovación: BIO2007-66855-E.00408 and FIS PS09/02111.Peer reviewe

EVAcon: a protein contact prediction evaluation service

Here we introduce EVAcon, an automated web service that evaluates the performance of contact prediction servers. Currently, EVAcon is monitoring nine servers, four of which are specialized in contact prediction and five are general structure prediction servers. Results are compared for all newly determined experimental structures deposited into PDB (∼5–50 per week). EVAcon allows for a precise comparison of the results based on a system of common protein subsets and the commonly accepted evaluation criteria that are also used in the corresponding category of the CASP assessment. EVAcon is a new service added to the functionality of the EVA system for the continuous evaluation of protein structure prediction servers. The new service is accesible from any of the three EVA mirrors: PDG (CNB-CSIC, Madrid) (); CUBIC (Columbia University, NYC) (); and Sali Lab (UCSF, San Francisco) ()

SPOC: A widely distributed domain associated with cancer, apoptosis and transcription

BACKGROUND: The Split ends (Spen) family are large proteins characterised by N-terminal RNA recognition motifs (RRMs) and a conserved SPOC (Spen paralog and ortholog C-terminal) domain. The aim of this study is to characterize the family at the sequence level. RESULTS: We describe undetected members of the Spen family in other lineages (Plasmodium and Plants) and localise SPOC in a new domain context, in a family that is common to all eukaryotes using profile-based sequence searches and structural prediction methods. CONCLUSIONS: The widely distributed DIO (Death inducer-obliterator) family is related to cancer and apoptosis and offers new clues about SPOC domain functionality

MAX mutant small-cell lung cancers exhibit impaired activities of MGA-dependent noncanonical polycomb repressive complex

The MYC axis is disrupted in cancer, predominantly through activation of the MYC family oncogenes but also through inactivation of the MYC partner MAX or of the MAX partner MGA. MGA and MAX are also members of the polycomb repressive complex, ncPRC1.6. Here, we use genetically modified MAX-deficient small-cell lung cancer (SCLC) cells and carry out genome-wide and proteomics analyses to study the tumor suppressor function of MAX. We find that MAX mutant SCLCs have ASCL1 or NEUROD1 or combined ASCL1/NEUROD1 characteristics and lack MYC transcriptional activity. MAX restitution triggers prodifferentiation expression profiles that shift when MAX and oncogenic MYC are coexpressed. Although ncPRC1.6 can be formed, the lack of MAX restricts global MGA occupancy, selectively driving its recruitment toward E2F6-binding motifs. Conversely, MAX restitution enhances MGA occupancy to repress genes involved in different functions, including stem cell and DNA repair/replication. Collectively, these findings reveal that MAX mutant SCLCs have either ASCL1 or NEUROD1 or combined characteristics and are MYC independent and exhibit deficient ncPRC1.6-mediated gene repression.We thank Isabel Bartolessis for technical assistance, the confocal facility (Carmen Casals) and the RNA-sequencing genomic facility (Anna Esteve) for important services. Funding: This work was supported by Spanish grant SAF2017-82186-RAEI/FEDER (UE) (to MSC) from the MINECO and a grant from the Fundación Científica Asociación Española Contra el Cancer- GCB14142170MONT (to MSC). M Torres-Diz was supported by the FPI-fellowship: BES- 2012-054579, P Llabata by the FPI-fellowship: BES-2015-072204 and by the European Association for Cancer Research Travel fellowship and L Tomas-Daza by the FPI-fellowship (number PRE2019-088005). BMJ is funded by Spanish Ministry of Science, Innovation, and Universities (MICINN) project number RTI2018-094788-A-I00 and by La Caixa Banking Foundation Junior Leader project (LCF/BQ/PI19/11690001). The proteomics analyses were performed in the IJC Proteomics Unit. The IJC Proteomics Unit is part of the Spanish Platform of Molecular and Bioinformatics Resources (ProteoRed), Instituto de Salud Carlos III (PT13/0001). Competing Interests: All authors declare no competing financial interests.Peer Reviewed"Article signat per 12 autors/es: Paula Llabata, Manuel Torres-Diz, Antonio Gomez, Laureano Tomas-Daza, Octavio A. Romero, Joaquim Grego-Bessa, Pere Llinas-Arias, Alfonso Valencia, Manel Esteller, Biola M. Javierre, Xiaoyang Zhang, and Montse Sanchez-Cespedes"Postprint (author's final draft

TSEMA: interactive prediction of protein pairings between interacting families

An entire family of methodologies for predicting protein interactions is based on the observed fact that families of interacting proteins tend to have similar phylogenetic trees due to co-evolution. One application of this concept is the prediction of the mapping between the members of two interacting protein families (which protein within one family interacts with which protein within the other). The idea is that the real mapping would be the one maximizing the similarity between the trees. Since the exhaustive exploration of all possible mappings is not feasible for large families, current approaches use heuristic techniques which do not ensure the best solution to be found. This is why it is important to check the results proposed by heuristic techniques and to manually explore other solutions. Here we present TSEMA, the server for efficient mapping assessment. This system calculates an initial mapping between two families of proteins based on a Monte Carlo approach and allows the user to interactively modify it based on performance figures and/or specific biological knowledge. All the explored mappings are graphically shown over a representation of the phylogenetic trees. The system is freely available at . Standalone versions of the software behind the interface are available upon request from the authors

Computational analysis of sense-antisense chimeric transcripts reveals their potential regulatory features and the landscape of expression in human cells

Many human genes are transcribed from both strands and produce sense-antisense gene pairs. Sense-antisense (SAS) chimeric transcripts are produced upon the coalescing of exons/introns from both sense and antisense transcripts of the same gene. SAS chimera was first reported in prostate cancer cells. Subsequently, numerous SAS chimeras have been reported in the ChiTaRS-2.1 database. However, the landscape of their expression in human cells and functional aspects are still unknown. We found that longer palindromic sequences are a unique feature of SAS chimeras. Structural analysis indicates that a long hairpin-like structure formed by many consecutive Watson-Crick base pairs appears because of these long palindromic sequences, which possibly play a similar role as double-stranded RNA (dsRNA), interfering with gene expression. RNA–RNA interaction analysis suggested that SAS chimeras could significantly interact with their parental mRNAs, indicating their potential regulatory features. Here, 267 SAS chimeras were mapped in RNA-seq data from 16 healthy human tissues, revealing their expression in normal cells. Evolutionary analysis suggested the positive selection favoring sense-antisense fusions that significantly impacted the evolution of their function and structure. Overall, our study provides detailed insight into the expression landscape of SAS chimeras in human cells and identifies potential regulatory features.Israeli Council for Higher Education [PBC Fellowship for Outstanding Post-Doctoral Fellows, 2019-2021 to S.M.]; Israel Innovation Authority [66824, 2019–2021 to M.F-M.]; RSF [18–14-00240 to Y.A.M. (in part)].Peer ReviewedPostprint (published version

Can the intra-operative measurement of the diameter of the femoral head help surgeons to choose the best size of the acetabular cup?

Purpose: We hypothesized that the intra-operative measurement of the femoral head may increase the accuracy of the acetabular cup size optimal selection in total hip arthroplasty (THA). The purpose of this clinical research was to analyze the correlation between the estimated cup size from intra-operative measurement of the femoral head and the pre-operative templated cup size. Methods: A prospective observational single-center study was conducted from June 2019 to January 2020 including primary THA (n = 100). All cases were pre-operatively templated. The measurement of the anterior-posterior diameter of the femoral head was routinely intra-operatively performed. Any definitive implanted cup was considered as 'oversized' when the size was > 4 mm than the diameter of the native head. Results: The median (interquartile range) size of the implanted cup, pre-operative planned cup size, and diameter of the femoral head were measured 52 (50-54) mm, 50 (48-54) mm and 49 (45-51) mm, respectively. Pre-operative planned size cup accurately predicted the implanted cup or differed in only one size (2 mm) in 77 (78%) cases. Otherwise, intra-operative femoral head measurement method accurately predicted the implanted or differed in only one size (2 mm) in 51 (87%) cases (p = 0.097). Conclusion: The intra-operative femoral head measurement is a simple and reliable tool to help the surgeons choose the best size of the acetabular cup and is as reliable as the pre-operative templating in order to avoid cup oversizing in THA. Utmost caution is warranted whenever the cup reamer is > 4 mm than the anterior-posterior diameter of the native head

Genome sequences and great expectations

To assess how automatic function assignment will contribute to genome annotation in the next five years, we have performed an analysis of 31 available genome sequences. An emerging pattern is that function can be predicted for almost two-thirds of the 73,500 genes that were analyzed. Despite progress in computational biology, there will always be a great need for large-scale experimental determination of protein function

The biomedical abbreviation recognition and resolution (BARR) track: Benchmarking, evaluation and importance of abbreviation recognition systems applied to Spanish biomedical abstracts

Healthcare professionals are generating a substantial volume of clinical data in narrative form. As healthcare providers are confronted with serious time constraints, they frequently use telegraphic phrases, domain-specific abbreviations and shorthand notes. Efficient clinical text processing tools need to cope with the recognition and resolution of abbreviations, a task that has been extensively studied for English documents. Despite the outstanding number of clinical documents written worldwide in Spanish, only a marginal amount of studies has been published on this subject. In clinical texts, as opposed to the medical literature, abbreviations are generally used without their definitions or expanded forms. The aim of the first Biomedical Abbreviation Recognition and Resolution (BARR) track, posed at the IberEval 2017 evaluation campaign, was to assess and promote the development of systems for generating a sense inventory of medical abbreviations. The BARR track required the detection of mentions of abbreviations or short forms and their corresponding long forms or definitions from Spanish medical abstracts. For this track, the organizers provided the BARR medical document collection, the BARR corpus of manually annotated abstracts labelled by domain experts and the BARR-Markyt evaluation platform. A total of 7 teams submitted 25 runs for the two BARR subtasks: (a) the identification of mentions of abbreviations and their definitions and (b) the correct detection of short form-long form pairs. Here we describe the BARR track setting, the obtained results and the methodologies used by participating systems. The BARR task summary, corpus, resources and evaluation tool for testing systems beyond this campaign are available at: http://temu.inab.org .We acknowledge the Encomienda MINETAD-CNIO/OTG Sanidad Plan TL and Open-Minted (654021) H2020 project for funding.Postprint (published version

Mortality in Persons With Autism Spectrum Disorder or Attention-Deficit/Hyperactivity Disorder: A Systematic Review and Meta-analysis

Importance: Autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) are childhood-onset disorders that may persist into adulthood. Several studies have suggested that they may be associated with an increased risk of mortality; however, the results are inconsistent. Objective: To assess the risk of mortality among persons with ASD or ADHD and their first-degree relatives. Data sources: A search of MEDLINE, Embase, Scopus, Web of Science, and PsycINFO (published from inception to April 1, 2021) was supplemented by searching reference lists of the retrieved articles. Study selection: Cohort and case-control studies that reported mortality rate ratios (RRs) in persons with ASD or ADHD and/or their first-degree relatives compared with the general population or those without ASD/ADHD were included. Data extraction and synthesis: Screening, data extraction, and quality assessment were performed by at least 2 researchers independently. A random-effects model was used to meta-analyze individual studies and assessed heterogeneity (I2). Main outcomes and measures: All-cause mortality in association with ASD or ADHD. Secondary outcome was cause-specific mortality. Results: Twenty-seven studies were included, with a total of 642 260 individuals. All-cause mortality was found to be higher for persons with ASD (154 238 participants; 12 studies; RR, 2.37; 95% CI, 1.97-2.85; I2, 89%; moderate confidence) and persons with ADHD (396 488 participants; 8 studies; RR, 2.13; 95% CI, 1.13-4.02; I2, 98%; low confidence) than for the general population. Among persons with ASD, deaths from natural causes (4 studies; RR, 3.80; 95% CI, 2.06-7.01; I2, 96%; low confidence) and deaths from unnatural causes were increased (6 studies; RR, 2.50; 95% CI, 1.49-4.18; I2, 95%; low confidence). Among persons with ADHD, deaths from natural causes were not significantly increased (4 studies; RR, 1.62; 95% CI, 0.89-2.96; I2, 88%; low confidence), but deaths from unnatural causes were higher than expected (10 studies; RR, 2.81; 95% CI, 1.73-4.55; I2, 92%; low confidence). Conclusions and relevance: This systematic review and meta-analysis found that ASD and ADHD are associated with a significantly increased risk of mortality. Understanding the mechanisms of these associations may lead to targeted strategies to prevent avoidable deaths in high-risk groups. The substantial heterogeneity between studies should be explored further.This study was supported by the Institute of Health Carlos III and Generalitat Valenciana. Drs Catalá-López and Tabarés-Seisdedos received funding from the Centro de Investigación Biomédica en Red de Salud Mental, Institute of Health Carlos III, and Generalitat Valencia. Dr Page received support from an Australian Research Council Discovery Early Career Researcher Award. Dr Hutton received support from a new investigator award from the Canadian Institutes of Health Research and the Drug Safety and Effectiveness Network. Dr Ridao received support from the Spanish Health Services Research on Chronic Patients Network and Institute of Health Carlos III.S