PredIG: a predictor of T-cell immunogenicity

The identification of immunogenic epitopes (such as fragments of proteins, in particular peptides, that can trigger an immune response) is a fundamental need for immune-based therapies. A computational tool that could predict such immunogenic epitopes would have vast potential applications in biomedicine ranging, from vaccine design against viruses or bacteria to therapeutic vaccination of cancer patients. While there are several methods that predict whether a peptide will be shown to the immune system via the Human Leukocyte Antigen (HLA) proteins of a patient, most of them cannot predict whether such presentation will indeed trigger an immune response. Additionally, T-cell immunogenicity is determined by multiple cellular processes, some of which are often overlooked by the current state-of-the-art immunogenicity predictors. The aim of this project is to build PredIG, an immunogenicity predictor that discriminates immunogenic from non-immunogenic T-cell epitopes given the peptide sequence and the HLA typing. After a careful study of the drivers of antigen processing and presentation on HLA class I molecules and an assessment of the physicochemical factors influencing epitope recognition by T-cell receptors (TCRs), we have used a selection of publicly available tools and in-house developed algorithms to identify the most relevant features that determine epitope immunogenicity. We then used these features to build an immunogenicity predictor (PredIG) modelled by XGBoost against immunogenically validated epitopes by the ImmunoEpitope DataBase (IEDB)(1), the PRIME dataset(2) and the TANTIGEN database(3). Pondering the feature importance in the model, the in-house developed softwares, NOAH for HLA Binding Affinity and NetCleave for Proteasomal Processing were identified as the major contributors to the performance of the model. Once PredIG was developed, we benchmarked the capacity to predict the immunogenicity of validated T-cell epitopes versus a set of state-of-the-art methods (Fig.1). Relevantly, PredIG showed a greater performance than the Immunogenicity predictors from Prime(2) and IEDB(4). Additionally, our results confirm that predicting T-cell immunogenicity based on data from T-cell assays is more accurate than using HLA Binding assays, the method mostly used in the field. An AUC value of 0.67 and an enrichment factor in the TOP10 epitopes of 90% outperforms the predictive performance of the available methods. In the context of the immune response against cancers, Tcell immunogenicity of tumoral mutations has been described as a response biomarker for immunotherapies such as immune checkpoint inhibitors. Similarly, the presence of immune infiltrate in a tumor has been related to a better prognosis for many cancer types. What is missing is the link between T-cell immunogenicity of tumoral mutations and the capacity of a tumor to attract immune cells. For this reason, we correlated the PredIG immunogenicity score obtained in a dataset of the The Cancer Genome Atlas (TCGA) against the tumor infiltrate in such tumors demonstrating that rather the total number of mutations a tumor accumulates, the tumor mutation burden (TMB), it is the number of immunogenic mutations what should be accounted for as biomarker of response

Fichas de las especies

Sittasomus griseicapillus, Xiphorhynchus flavigaster, Myiopagis viridicata, Mitrephanes phaeocercus, Empidonax difficilis / occidentalis, Myiarchus tuberculifer, Myiarchus cinerascens, Myiarchus nuttingi, Myiarchus tyrannulus, Pitangus sulphuratus, Myiozetetes similis, Myiodynastes luteiventris, Pachyramphus aglaiae, Vireo brevipennis, Vireo bellii, Vireo nelsoni, Vireo hypochryseus, Vireo gilvus, Vireo flavoviridis, Thryothorus sinaloa, Thryothorus felix, Troglodytes brunneicollis, Troglodytes aedon, Henicorhina leucophrys, Polioptila caerulea, Myadestes occidentalis, Catharus aurantiirostris, Catharus occidentalis, Catharus frantzii, Catharus ustulatus, Turdus assimilis, Turdus rufopalliatus, Melanotis caerulescens, Vermivora celata, Vermivora ruficapilla, Vermivora crissalis, Parula superciliosa, Parula pitiayumi, Dendroica petechia, Dendroica coronata, Dendroica nigrescens, Dendroica townsendi, Dendroica graciae, Mniotilta varia, Seiurus aurocapilla, Seiurus noveboracensis, Seiurus motacilla, Oporornis tolmiei, Geothlypis trichas, Geothlypis poliocephala, Wilsonia pusilla, Cardellina rubrifrons, Myioborus miniatus, Basileuterus belli, Icteria virens, Granatellus venustus Piranga erythrocephala, Volatinia jacarina, Diglossa baritula, Atlapetes pileatus, Arremon virenticeps Arremonops rufivirgatus, Melozone kieneri, Pipilo ocai, Aimophila ruficauda, Melospiza lincolnii Saltator coerulescens, Pheucticus melanocephalus, Cyanocompsa parellina, Passerina leclancherii, Passerina versicolor, Passerina ciris, Icterus cucullatus, Icterus pustulatus, Icterus graduacauda Carduelis notat

Resultados generales

Aspecto externo Morfometría esquelética y masa Morfometría alar y caudal Tamaño Estructuras sexuales externas Determinación del sexo Neumatización craneal Muda Datación mediante variables semicuantitativas Ciclos vitale

Computer-aided laccase engineering: toward biological oxidation of arylamines

Oxidation of arylamines, such as aniline, is of high industrial interest and laccases have been proposed as biocata-lysts to replace harsh chemical oxidants. However, the reaction is hampered by the redox potential of the substrate at acid pH and enzyme engineering is required to improve the oxidation. In this work, instead of trying to improve the redox potential of the en-zyme, we aim towards the (transient) substrate’s one and propose this as a more reliable strategy. We have successfully combined a computational approach with experimental validation to rationally design an improved biocatalyst. The in silico protocol combines classical and quantum mechanics to deliver atomic and electronic level detail on the two main processes involved: substrate binding and electron transfer. After mutant expression and comparison to the parent type, kinetic results show that the protocol accurately predicts aniline’s improved oxidation (2-fold kcat increase) in the engineered variant for biocatalyzed polyaniline production.This study was supported by the INDOX (KBBE-2013-7-613549) EU-project, and the NOESIS (BI0201456388-R) and OxiDesign (CTQ2013-48287-R) Spanish project. GS thanks an FPI grant of the Spanish Ministry of Competitiveness.Peer ReviewedPostprint (author's final draft

Harms in Systematic Reviews Paper 2: Methods used to assess harms are neglected in systematic reviews of gabapentin

Objective: We compared methods used with current recommendations for synthesizing harms in systematic reviews and meta-analyses (SRMAs) of gabapentin. Study Design & Setting: We followed recommended systematic review practices. We selected reliable SRMAs of gabapentin (i.e., met a pre-defined list of methodological criteria) that assessed at least one harm. We extracted and compared methods in four areas: pre-specification, searching, analysis, and reporting. Whereas our focus in this paper is on the methods used, Part 2 examines the results for harms across reviews. Results: We screened 4320 records and identified 157 SRMAs of gabapentin, 70 of which were reliable. Most reliable reviews (51/70; 73%) reported following a general guideline for SRMA conduct or reporting, but none reported following recommendations specifically for synthesizing harms. Across all domains assessed, review methods were designed to address questions of benefit and rarely included the additional methods that are recommended for evaluating harms. Conclusion: Approaches to assessing harms in SRMAs we examined are tokenistic and unlikely to produce valid summaries of harms to guide decisions. A paradigm shift is needed. At a minimal, reviewers should describe any limitations to their assessment of harms and provide clearer descriptions of methods for synthesizing harms

Harms in Systematic Reviews Paper 3: Given the same data sources, systematic reviews of gabapentin have different results for harms

Objective: In this methodologic study (Part 2 of 2), we examined the overlap in sources of evidence and the corresponding results for harms in systematic reviews for gabapentin. Study Design & Setting: We extracted all citations referenced as sources of evidence for harms of gabapentin from 70 systematic reviews, as well as the harms assessed and numerical results. We assessed consistency of harms between pairs of reviews with a high degree of overlap in sources of evidence (>50%) as determined by corrected covered area (CCA). Results: We found 514 reports cited across 70 included reviews. Most reports (244/514, 48%) were not cited in more than one review. Among 18 pairs of reviews, we found reviews had differences in which harms were assessed and their choice to meta-analyze estimates or present descriptive summaries. When a specific harm was meta-analyzed in a pair of reviews, we found similar effect estimates. Conclusion: Differences in harms results across reviews can occur because the choice of harms is driven by reviewer preferences, rather than standardized approaches to selecting harms for assessment. A paradigm shift is needed in the current approach to synthesizing harms

The Southern European Atlantic Diet is associated with lower concentrations of markers of coronary risk

Objective: The Southern European Atlantic Diet (SEAD) is the traditional diet of Northern Portugal and Galicia, a region in northwest Spain. The SEAD has been associated with a lower risk of non-fatal acute myocardial infarction, but the mechanisms of this association have not yet been investigated. Thus, we examined the association between the SEAD and numerous biomarkers of coronary risk, blood pressure and anthropometrics. Methods: Cross-sectional study conducted in 2008–2010 among 10,231 individuals representative of the population aged 18 years and older in Spain. Diet was assessed with a validated computerized diet history. SEAD adherence was measured with an index including 9 food components (fresh fish, cod, red meat and pork products, dairy products, legumes and vegetables, vegetable soup, potatoes, whole-grain bread, and wine), which ranges from 0 (lowest adherence) to 9 (highest adherence). C-reactive protein, uric acid, total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides, glucose, glycated hemoglobin, insulin, leptin, fibrinogen, were determined in 12-h fasting blood samples, while creatinine and urine albumin were determined in urine. Results: Mean SEAD score was 2.9 points (inter-quartile range 2–4 points). Higher SEAD adherence was associated with a lower level of plasma C-reactive protein (adjusted difference in geometric means between the highest and lowest SEAD quartiles −0.2 mg/l; p for trend <0.001), plasma triglycerides (−3.4 mg/dl; p for trend 0.012), insulin (−0.5 mU/l; p for trend <0.001), HOMA-IR (−0.12; p for trend <0.001), urine albumin (−0.8 mg/l; p for trend <0.001), urine albumin-creatinine ratio (−0.3 mg/g creatinine; p for trend <0.034), and systolic blood pressure (−1.6 mm Hg; p for trend <0.001). Conclusions: This study identifies possible mediators of the effect of SEAD on myocardial infarction, because SEAD is associated with a lower concentration of markers of inflammation and with reduced triglycerides, insulin, insulin resistance, and systolic blood pressure

Association of cooking patterns with inflammatory and cardio-metabolic risk biomarkers

Diet has been clearly associated with cardiovascular disease, but few studies focus on the influence of cooking and food preservation methods on health. The aim of this study was to describe cooking and food preservation patterns, as well as to examine their association with inflammatory and cardio-metabolic biomarkers in the Spanish adult population. A cross-sectional study of 10, 010 individuals, representative of the Spanish population, aged 18 years or over was performed using data from the ENRICA study. Food consumption data were collected through a face-to-face dietary history. Cooking and food preservation patterns were identified by factor analysis with varimax rotation. Linear regression models adjusted for main confounders were built. Four cooking and food preservation patterns were identified. The Spanish traditional pattern (positively correlated with boiling and sautéing, brining, and light frying) tends to be cardio-metabolically beneficial (with a reduction in C-reactive protein (-7.69%)), except for high density lipoprotein cholesterol (HDL-c), insulin levels, and anthropometrics. The health-conscious pattern (negatively correlated with battering, frying, and stewing) tends to improve renal function (with a reduction in urine albumin (-9.60%) and the urine albumin/creatinine ratio (-4.82%)). The youth-style pattern (positively correlated with soft drinks and distilled alcoholic drinks and negatively with raw food consumption) tends to be associated with good cardio-metabolic health except, for lower HDL-c (-6.12%), higher insulin (+6.35%), and higher urine albumin (+27.8%) levels. The social business pattern (positively correlated with the consumption of fermented alcoholic drinks, food cured with salt or smoke, and cured cheese) tends to be detrimental for the lipid profile (except HDL-c), renal function (urine albumin +8.04%), diastolic blood pressure (+2.48%), and anthropometrics. Cooking and food preservation patterns showed a relationship with inflammatory and cardio-metabolic health biomarkers. The Spanish traditional pattern and the health-conscious pattern were associated with beneficial effects on health and should be promoted. The youth-style pattern calls attention to some concerns, and the social business pattern was the most detrimental one. These findings support the influence of cooking and preservation patterns on health

Serum-Based Oxylipins Are Associated with Outcomes in Primary Prevention Implantable Cardioverter Defibrillator Patients

Analytical BioScience