bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic analysis of lung cancer reveals novel susceptibility loci and germline impact on somatic mutation burden
Authors: Gabriel Aurélie AG , Atkins Joshua R , Penha Ricardo CC , Smith-Byrne Karl , Gaborieau Valerie , Voegele Catherine , Abedi-Ardekani Behnoush , Milojevic Maja , Olaso Robert , Meyer Vincent , Boland Anne , François Deleuze Jean , Zaridze David , Mukeriya Anush , Swiatkowska Beata , Janout Vladimir , Schejbalová Miriam , Mates Dana , Stojšić Jelena , Ognjanovic Miodrag , Witte John S , Rashkin Sara R , Kachuri Linda , Hung Rayjean J , Kar Siddhartha , Brennan Paul , Sertier Anne-Sophie , Ferrari Anthony , Viari Alain , Johansson Mattias , Amos Christopher I , Foll Matthieu , McKay James D 
Published: April 2021

ABSTRACTGermline genetic variants are involved in lung cancer (LC) susceptibility. Previous genome-wide association studies (GWAS) have implicated genes involved in smoking propensity and DNA repair but further work is required to identify additional LC susceptibility variants and to investigate LC disease development dynamics.We have undertaken a family history-based genome-wide association (GWAx) study of LC, analysing 48,843 European cases with a parent/sibling with LC compared to 195,387 controls from the UK Biobank. This was meta-analysed with previously described LC GWAS results. We performed Polygenic Risk Scores (PRS) analyses and further evaluated the PRS influence on the somatic environment in exome (N=736) and genome sequencing (N=61) profiled cohorts.Eight novel loci were identified including DNA repair genes (CHEK1, MDM4), metabolic genes (CYP1A1) and variants that were also associated with smoking propensity, such as both subunits of the neuronal α4β2 nicotinic acetylcholine receptor (CHRNA4 and CHRNB2). PRS analysis demonstrated that variants related to eQTLs and/or smoking propensity are enriched for susceptibility variants, including variants below genome-wide significant threshold. PRS of LC variants related to smoking propensity were associated with somatic mutation burden in two case cohorts, with individuals with higher polygenic genetic risk having increased numbers of somatic mutations in their lung tumours.This study has expanded the number of susceptibility loci linked with LC and provided insights into the molecular mechanisms by which these susceptibility variants contribute to the development of lung cancer.
KLF3 and PAX6 are candidate driver genes in late-stage, MSI-hypermutated endometrioid endometrial carcinomas
Authors: Rudd Meghan L. , Hansen Nancy F. , Zhang Xiaolu , Urick Mary Ellen , Zhang Suiyuan , Merino Maria J. ,   National Institutes of Health Intramural Sequencing Center Comparative Sequencing Program, Mullikin James C. , Brody Lawrence C. , Bell Daphne W. 
Published: April 2021

AbstractEndometrioid endometrial carcinomas (EECs) are the most common histological subtype of uterine cancer. Late-stage disease is an adverse prognosticator for EEC. The purpose of this study was to analyze EEC exome mutation data to identify late-stage-specific statistically significantly mutated genes (SMGs), which represent candidate driver genes potentially associated with disease progression. We exome sequenced 15 late-stage (stage III or IV) non-ultramutated EECs and paired non-tumor DNAs; somatic variants were called using Strelka, Shimmer, Somatic Sniper and MuTect. Additionally, somatic mutation calls were extracted from The Cancer Genome Atlas (TCGA) data for 66 late-stage and 270 early-stage (stage I or II) non-ultramutated EECs. MutSigCV (v1.4) was used to annotate SMGs in the two late-stage cohorts and to derive p-values for all mutated genes in the early-stage cohort. To test whether late-stage SMGs are statistically significantly mutated in early-stage tumors, q-values for late-stage SMGs were re-calculated from the MutSigCV (v1.4) early-stage p-values, adjusting for the number of late-stage SMGs tested. We identified 14 SMGs in the combined late-stage EEC cohorts. When the 14 late-stage SMGs were examined in the TCGA early-stage data, only KLF3 and PAX6 failed to reach significance as early-stage SMGs, despite the inclusion of enough early-stage cases to ensure adequate statistical power. Within TCGA, nonsynonymous mutations in KLF3 and PAX6 were, respectively, exclusive or nearly exclusive to the microsatellite instability (MSI)-hypermutated molecular subgroup and were dominated by insertions-deletions at homopolymer tracts. In conclusion, our findings are hypothesis-generating and suggest that KLF3 and PAX6, which encode transcription factors, are MSI target genes and late-stage-specific SMGs in EEC.
Local emergence and decline of a SARS-CoV-2 variant with mutations L452R and N501Y in the spike protein
Authors: Mallm Jan-Philipp , Bundschuh Christian , Kim Heeyoung , Weidner Niklas , Steiger Simon , Lander Isabelle , Börner Kathleen , Bauer Katharina , Hübschmann Daniel , Benes Vladimir , Rausch Tobias , de Azevedo Nayara Trevisan Doimo , Telzerow Anja , Jost Katharina Laurence , Parthé Sylvia , Schnitzler Paul , Boutros Michael , Müller Barbara , Bartenschlager Ralf , Kräusslich Hans-Georg , Rippe Karsten 
Published: April 2021

SummaryVariants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are replacing the initial wild-type strain, jeopardizing current efforts to contain the pandemic. Amino acid exchanges in the spike protein are of particular concern as they can render the virus more transmissible or reduce vaccine efficacy. Here, we conducted whole genome sequencing of SARS-CoV-2 positive samples from the Rhine-Neckar district in Germany during January-March 2021. We detected a total of 166 samples positive for a variant with a distinct mutational pattern in the spike gene comprising L18F, L452R, N501Y, A653V, H655Y, D796Y and G1219V with a later gain of A222V. This variant was designated A.27.RN according to its phylogenetic clade classification. It emerged in parallel with the B.1.1.7 variant, increased to >50% of all SARS-CoV-2 variants by week five. Subsequently it decreased to <10% of all variants by calendar week eight when B.1.1.7 had become the dominant strain. Antibodies induced by BNT162b2 vaccination neutralized A.27.RN but with a two-to-threefold reduced efficacy as compared to the wild-type and B.1.1.7 strains. These observations strongly argue for continuous and comprehensive monitoring of SARS-CoV-2 evolution on a population level.
Pre-pandemic mental and physical health as predictors of COVID-19 vaccine hesitancy: evidence from a UK-wide cohort study
Authors: Batty G. David , Deary Ian J. , Altschul Drew 
Published: April 2021

AbstractImportanceAlthough several predictors of COVID-19 vaccine hesitancy have been identified, the role of physical health has not been well-examined, and the association with mental health is unknown.ObjectiveTo examine the association of pre-pandemic mental health, physical health, and shielding with vaccine hesitancy after the announcement of the successful testing of the Oxford University/AstraZeneca vaccine.Design, Setting, and ParticipantsWe used individual-level data from a pandemic-focused investigation (COVID Survey), a prospective cohort study nested within the UK Understanding Society (Main Survey) project. In the week immediately following the announcement of successful testing of the first efficacious inoculation (November/December 2020), data on vaccine intentionality were collected in 12,035 individuals aged 16-95 years. Pre-pandemic, study members had responded to enquiries about diagnoses of mental and physical health, completed the 12-item General Health Questionnaire for symptoms of psychological distress (anxiety and depression), and indicated whether they or someone in their household was shielding.Main outcome measuresSelf-reported intention to take up a vaccination for COVID-19. To summarise our results, we computed odds ratios with accompanying 95% confidence intervals for indices of health and shielding adjusted for selected covariates.ResultsIn an analytical sample of 11,955 people (6741 women), 15.4% indicated that they were vaccine hesitant. Relative to their disease-free counterparts, shielding was associated with a 24% lower risk of being hesitant (odds ratio; 95% confidence interval: 0.76; 0.59, 0.96), after adjustment for a range of covariates which included age, education, and ethnicity. Corresponding results for cardiometabolic disease were 22% (0.78; 0.64, 0.95), and for respiratory disease were 26% (0.74; 0.59, 0.93). Having a pre-pandemic diagnosis of anxiety or depression, or a high score on the distress symptom scale, were all unrelated to the willingness to take up a vaccine.Conclusions and relevancePeople who have been prioritised for COVID-19 vaccination owing to a physical condition are more likely to take it up. These effects were not apparent for indices of mental health.
Comprehensive genome-wide association study of different forms of hernia identifies more than 80 associated loci
Authors: Fadista João , Skotte Line , Karjalainen Juha , Abner Erik , Sørensen Erik , Ullum Henrik , Werge Thomas ,   iPSYCH-group, Esko Tõnu , Milani Lili , Palotie Aarno , Daly Mark ,   FinnGen, Melbye Mads , Feenstra Bjarke , Geller Frank 
Published: April 2021

AbstractHernias are characterized by protrusion of an organ or tissue through its surrounding cavity and often require surgical repair. We identified 65,492 cases for five hernia types in the UK Biobank and performed genome-wide association study scans for these five types and two combined groups. The results showed associated variants in all scans. Inguinal hernia had the most associations and we conducted a replication study with 23,803 additional cases from four study groups giving 84 independently associated variants. Identified variants from all scans were collapsed into 81 independent loci. Further testing showed that 26 loci were associated with more than one hernia type, suggesting substantial overlap between the underlying genetic mechanisms. Pathway analysis identified several genes with a strong link to collagen and/or elastin (ADAMTS6, ADAMTS16, ADAMTSL3, LOX, ELN) in the vicinity of associated loci for inguinal hernia, which substantiates an essential role of connective tissue morphology.
Evaluation of serological tests for detecting SARS-CoV-2 antibodies: implementation in assessing post vaccination status
Authors: Mahmoud Sally A. , Ganesan Subhashini , Naik Shivaraj , Bissar Safaa , Zamil Isra , Zaher Walid Abbas 
Published: April 2021

AbstractBackgroundThe anti-SARS-CoV-2 immunological assays have promising applications in the control and surveillance of the current COVID-19 pandemic. Therefore, large number of serological assays are developed in the commercial market to measure SARS-CoV-2 antibodies, which requires evaluation before their application in large scale.ObjectivesTo evaluate the performances of commercially available serological assays for detecting SARS-CoV-2 antibodies.MethodsThe study compared the performances of six different methods for detection of antibodies against SARS-CoV-2 which includes (i) Genscript SARS-CoV-2 surrogate virus neutralization test kit [Test A] (ii) Diasorin - SARS-CoV-2 S1/S2 IgG detection [Test B] (iii) Alinity SARS-CoV-2 IgG II [Test C] (iv) Diasorin – SARS-CoV-2 TrimericS IgG [Test D] (v) Roche Elecsys Anti-SARS-CoV-2 – cobas [Test E] (vi) AESKULISA (AESKU Enzyme Linked Immunosorbent Assay) [Test F] against the gold standard Plaque Reduction Neutralization Test (PRNT).ResultsTest E had the highest sensitivity and Test A had the highest specificity The ROC for tests A, C, D and E showed optimum cut-offs that differed from the manufacturer’s recommendation. Test D had the best performance considering all the performance indicators with the highest agreement with the PRNT results. Parallel testing of test A with test D and test B had the optimum performance.ConclusionSerological assays that are commercially available are very promising and show good agreement with the standard PRNT results. Studies on large samples for optimization of the assay cut-off values and cost-effective evaluations on parallel testing methods are needed to make recommendations on these commercial assays.ImportanceSerological assays that are commercially available are very promising and this paper adds new knowledge about the optimization of these kits for evaluating post vaccination antibodies status. It highlights the positive and negative aspects of each of these assays in terms of sensitivity, specificity, positive and negative predictive values, and the agreement of results with the standard neutralization test. When serological assays are being used to assess post-vaccine immune status, a balance of all parameters needs to be considered rather than emphasizing only on high specificity. This is particularly relevant in the current situation where vaccination is happening around the globe, high sensitivity assays will result in reporting a lower percentage of false negative reports and avoids panic about lack of vaccine response. It is important that we understand the strengths and limitations of commercially available serological assays for better application of these tests to understand immune response and the duration of protection post vaccination.
Age-varying genetic associations and implications for bias in Mendelian randomization
Authors: Labrecque Jeremy A , Swanson Sonja A 
Published: April 2021

AbstractEstimates from conventional Mendelian randomization (MR) analyses can be biased when the genetic variants proposed as instruments vary over age in their relationship with the exposure. For four exposures commonly studied using MR, we assessed the degree to which their relationship with genetic variants commonly used as instruments varies by age using flexible, spline-based models in UK Biobank data. Using these models, we then estimated how biased MR estimates would be due to age-varying relationships using plasmode simulations. We found that most genetic variants had age-varying relationships with the exposure for which they are a proposed instrument. Body mass index and LDL cholesterol had the most variation while alcohol consumption had very little. This variation over age led to small potential biases in some cases (e.g. alcohol consumption and C-reactive protein) and large potential biases for many proposed instruments for BMI and LDL.
Heterotypic Aβ interactions facilitate amyloid assembly and modify amyloid structure
Authors: Konstantoulea Katerina , Guerreiro Patricia , Ramakers Meine , Louros Nikolaos , Aubrey Liam , Houben Bert , Michiels Emiel , De Vleeschouwer Matthias , Lampi Yulia , Ribeiro Luís F. , de Wit Joris , Xue Wei-Feng , Schymkowitz Joost , Rousseau Frederic 
Published: April 2021

AbstractIt is still unclear why pathological amyloid deposition initiates in specific brain regions, nor why specific cells or tissues are more susceptible than others. Amyloid deposition is determined by the self-assembly of short protein segments called aggregation-prone regions (APRs) that favour cross-β structure. Here we investigated whether Aβ amyloid assembly can be modified by heterotypic interactions between Aβ APRs and short homologous segments in otherwise unrelated human proteins. We identified heterotypic interactions that accelerate Aβ assembly, modify fibril morphology and affect its pattern of depositionin vitro. Moreover, we found that co-expression of these proteins in an Aβ reporter cell line promotes Aβ amyloid aggregation. Importantly, reanalysis of proteomics data of Aβ plaques from AD patients revealed an enrichment in proteins that share homologous sequences to the Aβ APRs, suggesting heterotypic amyloid interactions may occur in patients. Strikingly, we did not find such a bias in plaques from overexpression models in mouse. Based on these data, we propose that heterotypic APR interactions may play a hitherto unrealised role in amyloid-deposition diseases.
No reproductive fitness benefits of dear enemy behaviour in a territorial songbird
Authors: Reichert Michael S. , Crane Jodie M.S. , Davidson Gabrielle L. , Dillane Eileen , Kulahci Ipek G. , O’Neill James , van Oers Kees , Sexton Ciara , Quinn John L. 
Published: April 2021

ABSTRACTTerritorial animals often respond less aggressively to neighbours than strangers. This ‘dear enemy’ effect is hypothesized to be adaptive by reducing unnecessary aggressive interactions with non-threatening individuals. A key prediction of this hypothesis, that individual fitness will be affected by variation in the speed and the extent to which individuals reduce their aggression towards neighbours relative to strangers, has never been tested. We used a series of song playbacks to measure the change in response of male great tits to a simulated establishment of a neighbour on an adjacent territory during early stages of breeding, as an assay of individuals’ tendencies to form dear enemy relationships. Males reduced their approach to the speaker and sang fewer songs on later playback repetitions. However, only some males exhibited dear enemy behaviour by responding more strongly to a subsequent stranger playback, and when the playback procedure was repeated on a subset of males, there was some indication for consistent differences among individuals in the expression of dear enemy behaviour. We monitored nests and analysed offspring paternity to determine male reproductive success. Individuals that exhibited dear enemy behaviour towards the simulated neighbour did not suffer any costs associated with loss of paternity, but there was also no evidence of reproductive benefits, and no net effect on reproductive fitness. The general ability to discriminate between neighbours and strangers is likely adaptive, but benefits are probably difficult to detect because of the indirect link between individual variation in dear enemy behaviour and reproductive fitness, and because of the complex range of mechanisms affecting relations with territorial neighbours.
An enveloped virus-like particle vaccine expressing a stabilized prefusion form of the SARS-CoV-2 spike protein elicits potent immunity after a single dose
Authors: Fluckiger Anne-Catherine , Ontsouka Barthelemy , Bozic Jasminka , Diress Abebaw , Ahmed Tanvir , Berthoud Tamara , Tran Anh , Duque Diane , Liao Mingmin , McCluskie Michael , Diaz-Mitoma Francisco , Anderson David E. , Soare Catalina 
Published: April 2021

AbstractDevelopment of efficacious single dose vaccines would substantially aid efforts to stop the uncontrolled spread of the COVID-19 pandemic. We evaluated enveloped virus-like particles (eVLPs) expressing various forms of the SARS-CoV-2 spike protein and several adjuvants in an effort to identify a COVID-19 vaccine candidate efficacious after a single dose. The eVLPs expressing a modified prefusion form of SARS-CoV-2 spike protein were selected as they induced the highest antibody binding titers and neutralizing activity after a single injection in mice. Formulation of SARS-CoV-2 S eVLPs with aluminum phosphate resulted in balanced induction of IgG2 and IgG1 isotypes and antibody binding and neutralization titers were undiminished for more than 3 months after a single immunization. A single dose of this candidate, VBI-2902a (prefusion S eVLPs formulated with aluminum phosphate), protected Syrian golden hamsters from challenge with SARS-CoV-2 and supports the on-going clinical evaluation of VBI-2902a as a potential single dose vaccine against COVID-19.HighlightsVBI-2902a is a VLP-based vaccine candidate against SARS-COV-2VBI-2902a contains VLPs pseudotyped with a modified prefusion SARS-COV-2 S in Alum.VBI-2902a induces robust neutralization antibody response against SARS-COV-2 SVBI-2902a protects hamsters from SARS-CoV-2 induced lung inflammationA single dose of VBI-2902a provides protective benefit in hamsters
Identification and correction of phase switches with Hi-C data in the Nanopore and HiFi chromosome-scale assemblies of the dikaryotic leaf rust fungusPuccinia triticina
Authors: Duan Hongyu , Jones Ashley W. , Hewitt Tim , Mackenzie Amy , Hu Yiheng , Sharp Anna , Lewis David , Mago Rohit , Upadhyaya Narayana M. , Rathjen John P. , Stone Eric A. , Schwessinger Benjamin , Figueroa Melania , Dodds Peter N. , Periyannan Sambasivam , Sperschneider Jana 
Published: April 2021

AbstractBackgroundMost animals and plants have more than one set of chromosomes and package these haplotypes into a single nucleus within each cell. In contrast, many fungal species carry multiple haploid nuclei per cell. Rust fungi are such species with two nuclei (karyons) that contain a full set of haploid chromosomes each. The physical separation of haplotypes in dikaryons means that, unlike in diploids, Hi-C chromatin contacts between haplotypes are false positive signals.ResultsWe generate the first chromosome-scale, fully-phased assembly for the dikaryotic leaf rust fungusPuccinia triticinaand compare Nanopore MinION and PacBio HiFi sequence-based assemblies. We show that false positive Hi-C contacts between haplotypes are predominantly caused by phase switches rather than by collapsed regions or Hi-C read mis-mappings. We introduce a method for phasing of dikaryotic genomes into the two haplotypes using Hi-C contact graphs, including a phase switch correction step. In the HiFi assembly, relatively few phase switches occur, and these are predominantly located at haplotig boundaries and can be readily corrected. In contrast, phase switches are widespread throughout the Nanopore assembly. We show that haploid genome read coverage of 30-40 times using HiFi sequencing is required for phasing of the leaf rust genome (~0.7% heterozygosity) and that HiFi sequencing resolves genomic regions with low heterozygosity that are otherwise collapsed in the Nanopore assembly.ConclusionsThis first Hi-C based phasing pipeline for dikaryons and comparison of long-read sequencing technologies will inform future genome assembly and haplotype phasing projects in other non-haploid organisms.
Copy-number alterations reshape the classification of diffuse intrinsic pontine gliomas. First exome sequencing results of the BIOMEDE trial
Authors: Kergrohen Thomas , Castel David , Le Teuff Gwenael , Tauziède-Espariat Arnault , Lechapt-Zalcman Emmanuèle , Nysom Karsten , Blomgren Klas , Leblond Pierre , Bertozzi Anne-Isabelle , De Carli Emilie , Faure-Conter Cécile , Chappe Celine , Entz-Werlé Natacha , Moussa Angokai , Ghermaoui Samia , Barret Emilie , Picot Stephanie , Sabourin-Cousin Marjorie , Beccaria Kevin , Vassal Gilles , Varlet Pascale , Puget Stephanie , Grill Jacques , Debily Marie-Anne 
Published: April 2021

AbstractDiffuse intrinsic pontine gliomas (DIPG) is an incurable neoplasm occurring mainly in children for which no progress was made in the last decades. The randomized phase II BIOMEDE trial compared three drugs (everolimus, dasatinib, erlotinib) combined with irradiation. The present report describes whole exome sequencing (WES) results for the first 100 patients randomized.Copy-number-Alteration (CNA) unsupervised clustering identified four groups with different outcomes and biology. This classification improved prognostication compared to models based on known biomarkers (Histone H3 and TP53 mutations). The cluster presenting complex genomic rearrangements was associated with significantly worse outcome and TP53 dysfunction. Mutation and CNA signatures confirmed the frequent alteration in DNA repair machinery. With respect to potential targetable pathways, PI3K/AKT/mTOR activation occurred in all the samples through multiples mechanisms. In conclusion, WES at diagnosis was feasible in most patients and provides a better patient stratification and theranostic information for precision medicine.