Deep learning predictions of TCR-epitope interactions reveal epitope-specific chains in dual alpha T cells.

T cells have the ability to eliminate infected and cancer cells and play an essential role in cancer immunotherapy. T cell activation is elicited by the binding of the T cell receptor (TCR) to epitopes displayed on MHC molecules, and the TCR specificity is determined by the sequence of its α and β chains. Here, we collect and curate a dataset of 17,715 αβTCRs interacting with dozens of class I and class II epitopes. We use this curated data to develop MixTCRpred, an epitope-specific TCR-epitope interaction predictor. MixTCRpred accurately predicts TCRs recognizing several viral and cancer epitopes. MixTCRpred further provides a useful quality control tool for multiplexed single-cell TCR sequencing assays of epitope-specific T cells and pinpoints a substantial fraction of putative contaminants in public databases. Analysis of epitope-specific dual α T cells demonstrates that MixTCRpred can identify α chains mediating epitope recognition. Applying MixTCRpred to TCR repertoires from COVID-19 patients reveals enrichment of clonotypes predicted to bind an immunodominant SARS-CoV-2 epitope. Overall, MixTCRpred provides a robust tool to predict TCRs interacting with specific epitopes and interpret TCR-sequencing data from both bulk and epitope-specific T cells

Extra-curricular physical activity and socioeconomic status in Italian adolescents

BACKGROUND: The relationship between physical activity and health status has been thoroughly investigated in several studies, while the relation between physical activity and socio-economic status (SES) is less investigated. The aim of this study was to measure the extra-curricular physical activity of adolescents related to the socio-economic status (SES) of their families. METHODS: The survey was carried out by submitting an anonymous questionnaire to junior high school students in the following Regions: Lazio, Abruzzo, Molise, Campania, Puglia, during the school year 2002–2003. Extra-curriculum physical activity was evaluated considering whether or not present and hours of activity weekly conducted. 2411 students agreed to participate in the study. RESULTS: Participants were 1121 males (46.5%) and 1290 females (53.5%), aged between 11 and 17 years (median age: 12 years). 71.1% of the students reported to practice extra-curricular physical activity. Parents' educational levels and work activities play an important role in predicting students' physical activity, with the more remunerative activities and higher educational levels being more predictive. CONCLUSION: The results confirm the relationship between adolescents' physical activity and their families' SES. In particular, a positive relationship between participation in extra-curricular physical activity and their families high SES was found. These data will be useful for school administrators and for politicians in order to reduce the gap between adolescents from the least and most disadvantaged families

Epigenetic targeting of Hedgehog pathway transcriptional output through BET bromodomain inhibition

Hedgehog signaling drives oncogenesis in several cancers and strategies targeting this pathway have been developed, most notably through inhibition of Smoothened. However, resistance to Smoothened inhibitors occurs via genetic changes of Smoothened or other downstream Hedgehog components. Here, we overcome these resistance mechanisms by modulating GLI transcription via inhibition of BET bromodomain proteins. We show the BET bromodomain protein, BRD4, regulates GLI transcription downstream of SMO and SUFU and chromatin immunoprecipitation studies reveal BRD4 directly occupies GLI1 and GLI2 promoters, with a substantial decrease in engagement of these sites upon treatment with JQ1, a small molecule inhibitor targeting BRD4. Globally, genes associated with medulloblastoma-specific GLI1 binding sites are downregulated in response to JQ1 treatment, supporting direct regulation of GLI activity by BRD4. Notably, patient- and GEMM-derived Hedgehog-driven tumors (basal cell carcinoma, medulloblastoma and atypical teratoid/rhabdoid tumor) respond to JQ1 even when harboring genetic lesions rendering them resistant to Smoothened antagonists

Meta-analysis in more than 17,900 cases of ischemic stroke reveals a novel association at 12q24.12

Results: In an overall analysis of 17,970 cases of ischemic stroke and 70,764 controls, we identified a novel association on chromosome 12q24 (rs10744777, odds ratio [OR] 1.10 [1.07-1.13], p 5 7.12 3 10-11) with ischemic stroke. The association was with all ischemic stroke rather than an individual stroke subtype, with similar effect sizes seen in different stroke subtypes. There was no association with intracerebral hemorrhage (OR 1.03 [0.90-1.17], p 5 0.695).Conclusion: Our results show, for the first time, a genetic risk locus associated with ischemic stroke as a whole, rather than in a subtype-specific manner. This finding was not associated with intracerebral hemorrhage.Methods: Using the Immunochip, we genotyped 3,420 ischemic stroke cases and 6,821 controls. After imputation we meta-analyzed the results with imputed GWAS data from 3,548 case

Fast relational learning using bottom clause propositionalization with artificial neural networks

Relational learning can be described as the task of learning first-order logic rules from examples. It has enabled a number of new machine learning applications, e.g. graph mining and link analysis. Inductive Logic Programming (ILP) performs relational learning either directly by manipulating first-order rules or through propositionalization, which translates the relational task into an attribute-value learning task by representing subsets of relations as features. In this paper, we introduce a fast method and system for relational learning based on a novel propositionalization called Bottom Clause Propositionalization (BCP). Bottom clauses are boundaries in the hypothesis search space used by ILP systems Progol and Aleph. Bottom clauses carry semantic meaning and can be mapped directly onto numerical vectors, simplifying the feature extraction process. We have integrated BCP with a well-known neural-symbolic system, C-IL2P, to perform learning from numerical vectors. C-IL2P uses background knowledge in the form of propositional logic programs to build a neural network. The integrated system, which we call CILP++, handles first-order logic knowledge and is available for download from Sourceforge. We have evaluated CILP++ on seven ILP datasets, comparing results with Aleph and a well-known propositionalization method, RSD. The results show that CILP++ can achieve accuracy comparable to Aleph, while being generally faster, BCP achieved statistically significant improvement in accuracy in comparison with RSD when running with a neural network, but BCP and RSD perform similarly when running with C4.5. We have also extended CILP++ to include a statistical feature selection method, mRMR, with preliminary results indicating that a reduction of more than 90 % of features can be achieved with a small loss of accuracy

Genetic Interactions with Age, Sex, Body Mass Index, and Hypertension in Relation to Atrial Fibrillation: The AFGen Consortium

It is unclear whether genetic markers interact with risk factors to influence atrial fibrillation (AF) risk. We performed genome-wide interaction analyses between genetic variants and age, sex, hypertension, and body mass index in the AFGen Consortium. Study-specific results were combined using meta-analysis (88,383 individuals of European descent, including 7,292 with AF). Variants with nominal interaction associations in the discovery analysis were tested for association in four independent studies (131,441 individuals, including 5,722 with AF). In the discovery analysis, the AF risk associated with the minor rs6817105 allele (at the PITX2 locus) was greater among subjects ≤ 65 years of age than among those > 65 years (interaction p-value = 4.0 × 10-5). The interaction p-value exceeded genome-wide significance in combined discovery and replication analyses (interaction p-value = 1.7 × 10-8). We observed one genome-wide significant interaction with body mass index and several suggestive interactions with age, sex, and body mass index in the discovery analysis. However, none was replicated in the independent sample. Our findings suggest that the pathogenesis of AF may differ according to age in individuals of European descent, but we did not observe evidence of statistically significant genetic interactions with sex, body mass index, or hypertension on AF risk

Reliability of morphological criteria for sexing of birds during ringing, assessed using molecular methods - a study of thirteen species of passerines and near-passerines

Understanding the ecology and conservation of bird species often requires accurate sex determination of individuals. Species with sexually dimorphic plumage can usually be sexed in the hand based on consistent and definitive differences in plumage between sexes, but there are often challenges related to (1) how sexual dimorphism develops with age, (2) individuals that show intermediate visible morphological traits, or (3) consistent but subtle trait differences that require considerable experience to use reliably. Species with sexually monomorphic plumage, which constitute over half of all avian species globally, pose a greater challenge and can often not be sexed in the hand. The aim of this study was to use molecular methods to identify definitively the sex of individuals of both monomorphic and dimorphic species caught at a ringing site in south-west Portugal, in order to evaluate the standard morphological sexing techniques for species showing sexual dimorphism in plumage, or in biometric measurements. Blood samples were collected from a range of species during ringing, and DNA was extracted. Molecular methods were successful in identifying the sex of 202 individuals across 13 species of birds (eight species with sexually dimorphic plumage, and five sexually monomorphic in plumage). Molecular methods were consistent with the morphological sexing in the field for six of the eight species with dimorphic plumage, but discrepancies between the two methods were identified for Pied Flycatcher Ficedula hypoleuca and Eurasian Hoopoe Upupa epops. Finally, biometric measurements taken in the field were used to assess whether species with monomorphic plumage could have been correctly sexed based on the biometric differences between males and females reported in literature