bluuebunny/crossref_metadata_2025_split huggingface dataset:
Structure of the thin filament in native skeletal muscles reveals its interaction with nebulin and two distinct conformations of myosin
Authors: Wang Zhexin , Grange Michael , Pospich Sabrina , Wagner Thorsten , Kho Ay Lin , Gautel Mathias , Raunser Stefan 
Published: October 2021

AbstractNebulin is a major structural protein of skeletal sarcomeres and is essential for proper assembly and contraction of skeletal muscle1. It stabilises and regulates the length of thin filaments,2 but the structural mechanism remains nebulous. Using electron cryotomography and sub-tomogram averaging, we present the first structure of native nebulin bound to thin filaments within the A-band and I-band of intact sarcomeres. This in-situ reconstruction reveals unprecedented detail of interaction at pseudo-atomic resolution between nebulin and actin, providing the basis for understanding the structural and regulatory roles of nebulin. The position of nebulin on the thin filament indicates that there is no contact to tropomyosin or myosin, but an unexpected interaction with a troponin-T linker, possibly through two binding motifs on nebulin. In addition, our structure of myosin bound to the thin filaments reveals different conformations of the neck domain, both within the same sarcomere and when compared to purified structures, highlighting an inherent structural variability in muscle. We provide a complete description of cross-bridge formation on fully native, nebulin-containing thin filaments at near-atomic scale. Our structures establish the molecular basis for the role of nebulin as a thin filament “molecular ruler” and the impact of nemaline myopathies mutations that will aid future development of therapies.
Uncovering expression signatures of synergistic drug response using an ensemble of explainable AI models
Authors: Janizek Joseph D. , Dincer Ayse B. , Celik Safiye , Chen Hugh , Chen William , Naxerova Kamila , Lee Su-In 
Published: October 2021

AbstractComplex machine learning models are poised to revolutionize the treatment of diseases like acute myeloid leukemia (AML) by helping physicians choose optimal combinations of anti-cancer drugs based on molecular features. While accurate predictions are important, it is equally important to be able to learn about the underlying molecular basis of anti-cancer drug synergy. Explainable AI (XAI) offers a promising new route for data-driven cancer pharmacology, combining highly accurate models with interpretable insights into model decisions. Due to the highly correlated, high-dimensional nature of cancer transcriptomic data, however, we find that existing XAI approaches are suboptimal when applied naively to large transcriptomic datasets. We show how a novel approach based on model ensembling helps to increase the quality of explanations. We then use our method to demonstrate that a hematopoietic differentiation signature underlies synergy for a variety of anti-AML drug combinations.
Oxytocin regulation of social transmission of fear in zebrafish reveals its evolutionary conserved role in emotional contagion
Authors: Akinrinade Ibukun , Kareklas Kyriacos , Gliksberg Michael , Petri Giovanni , Levkowitz Gil , Oliveira Rui F. 
Published: October 2021

AbstractEmotional contagion is the most ancestral form of empathy that relies on simple perception-action mechanisms, on top of which more complex forms of empathic behaviors, such as consolation and helping, have evolved. Here we tested to what extent the proximate mechanisms of emotional contagion are evolutionary conserved by assessing the role of oxytocin, known to regulate empathic behaviors in mammals, in social fear contagion in zebrafish, which represents an evolutionary divergent line to that of tetrapods, within vertebrates. Using mutants for the ligand of the fish oxytocin nonapeptide and both of its receptors in zebrafish we showed that oxytocin is necessary for observer zebrafish to copy the distressed behavior of conspecific demonstrators. Exogeneous administration of oxytocin to the ligand mutant rescued the ability of observers to express social fear transmission, indicating that oxytocin is not only necessary but also sufficient for emotional contagion. The brain regions in the ventral telencephalon that are associated with emotional contagion in zebrafish are homologous to those known to be involved in the same process in rodents (e.g. striatum, lateral septum), and receive direct projections from oxytocinergic neurons located in the pre-optic area. Finally, we ruled out the hypothesis that social transmission of fear in zebrafish merely relies on behavior contagion by motor imitation, and we showed that it rather relies on emotion discrimination. Together our results support an evolutionary conserved role for oxytocin as a key regulator of basic empathic behaviors across vertebrates.One-Sentence SummaryOxytocin is necessary and sufficient for social fear contagion in zebrafish supporting an evolutionary conserved role for oxytocin in emotional contagion among vertebrates.
Arginine methylation sites on SepIVA help balance elongation and septation of the cell wall inMycobacterium smegmatis
Authors: Freeman Angela H , Tembiwa Karen , Brenner James R , Chase Michael R , Fortune Sarah M , Morita Yasu S , Boutte Cara C 
Published: October 2021

AbstractGrowth of mycobacterial cells requires successful coordination between elongation and septation of the cell wall. However, it is not clear which factors directly mediate this coordination. Here, we studied the function and post-translational modification of an essential division factor, SepIVA, inMycobacterium smegmatis. We find that SepIVA is arginine methylated, and that alteration of these methylation sites affects both septation and polar elongation ofMsmeg. Furthermore, we show that SepIVA regulates the localization of MurG, and that this regulation may impact polar elongation. Finally, we map SepIVA’s two regulatory functions to different sites on the protein: the N-terminus regulates elongation while the C-terminus regulates division. These results establish SepIVA as a regulator of both elongation and division and characterize a physiological role for protein arginine methylation sites for the first time in mycobacteria.
Patient attrition in Molecular Tumour Boards: A Review
Authors: Frost Hannah , Graham Donna M. , Carter Louise , O’Regan Paul , Landers Donal , Freitas Andre 
Published: October 2021

AbstractMolecular Tumour Boards (MTBs) were created with the purpose of supporting clinical decision making within precision medicine. Though these meetings are in use globally reporting often focuses on the small percentages of patients that receive treatment via this process and are less likely to report on, and assess, patients who do not receive treatment. A literature review was performed to understand patient attrition within MTBs and barriers to patients receiving treatment. A total of 54 papers were reviewed spanning a 6 year period from 11 different countries. 20% of patients received treatment through the MTB process. Of those that did not receive treatment the main reasons were no mutations identified (26%), no actionable mutations (22%) and clinical deterioration (15%). However, the data was often incomplete due to inconsistent reporting of MTBs with only 53% reporting on patients having no mutations, 48% reporting on presence of actionable mutations with no treatment options and 57% reporting on clinical deterioration. As patient attrition in MTBs is an issue which is very rarely alluded to in reporting, more transparent reporting is needed to understand barriers to treatment and integration of new technologies is required to process increasing omic and treatment data.
Characterizing the effective reproduction number during the COVID-19 epidemic: Insights from Qatar’s experience
Authors: Bsat Raghid , Chemaitelly Hiam , Coyle Peter , Tang Patrick , Hasan Mohammad R. , Al Kanaani Zaina , Al Kuwari Einas , Butt Adeel A. , Jeremijenko Andrew , Kaleeckal Anvar Hassan , Latif Ali Nizar , Shaik Riyazuddin Mohammad , Nasrallah Gheyath K. , Benslimane Fatiha M. , Al Khatib Hebah A. , Yassine Hadi M. , Al Kuwari Mohamed G. , Al Romaihi Hamad Eid , Al-Thani Mohamed H. , Al Khal Abdullatif , Bertollini Roberto , Abu-Raddad Laith J. , Ayoub Houssein H. 
Published: October 2021

AbstractBackgroundThe effective reproduction number,Rt, is a tool to track and understand epidemic dynamics. This investigation ofRtestimations was conducted to guide the national COVID-19 response in Qatar, from the onset of the epidemic until August 18, 2021.MethodsReal-time “empirical”was estimated using five methods, including the Robert Koch Institute, Cislaghi, Systrom-Bettencourt and Ribeiro, Wallinga and Teunis, and Cori et al. methods.Rwas also estimated using a transmission dynamics model. Uncertainty and sensitivity analyses were conducted. Agreements between differentRtestimates were assessed by calculating correlation coefficients.Resultscaptured the evolution of the epidemic through three waves, public health response landmarks, effects of major social events, transient fluctuations coinciding with significant clusters of infection, and introduction and expansion of the B.1.1.7 variant. The various estimation methods produced consistent and overall comparableestimates with generally large correlation coefficients. The Wallinga and Teunis method was the fastest at detecting changes in epidemic dynamics.estimates were consistent whether using time series of symptomatic PCR-confirmed cases, all PCR-confirmed cases, acute-care hospital admissions, or ICU-care hospital admissions, to proxy trends in true infection incidence.correlated strongly withand provided an average.ConclusionsRtestimations were robust and generated consistent results regardless of the data source or the method of estimation. Findings affirmed an influential role forRtestimations in guiding national responses to the COVID-19 pandemic, even in resource-limited settings.
Gut microbial communities modulate efficacy of albendazole-ivermectin against soil-transmitted helminthiases
Authors: Schneeberger Pierre H.H. , Gueuning Morgan , Welsche Sophie , Hürlimann Eveline , Dommann Julian , Häberli Cécile , Frey Jürg E. , Sayasone Somphou , Keiser Jennifer 
Published: October 2021

AbstractBackgroundSoil-transmitted helminth infections represent a large burden across the globe with over a quarter of the world’s population at risk. The outcome of available treatments is species-specific with a large proportion of unexplained treatment failure. Administration of albendazole is the standard of care, but because of low cure rates (CR) observed in treatingTrichuris trichiurainfections, a significantly more efficacious alternative therapy combining albendazole and ivermectin is being investigated.Methods80 patients from the village of Pak-Khan, in Laos, with confirmed STH infections (Trichuris trichiuraand hookworms), received either albendazole (400 mg) or albendazole (400 mg) and ivermectin (200 µg/kg) together. A pre-treatment stool sample was collected as well as daily post-treatment stool samples for up to 28 days to measure treatment efficacy. Taxonomic profiling of pre-treatment stool samples was conducted using 16S rRNA gene sequencing, target-specific and total bacteria qPCR, as well as shotgun sequencing.ResultsThree bacterial communities, or enterotypes (ET) 1-3, were identified. No association with pre-treatment enterotype and treatment outcome of bothTrichuris trichiuraand hookworm were found in the monotherapy arm with overall cure rates (CR) of 7.5% and 50%, respectively. Pre-treatment enterotype was strongly associated with efficacy of the combination therapy for both,T. trichiura(CRoverall= 33.3%; CRET1= 5.8%; CRET2= 16.6%; CRET3= 68.5%) and hookworm (CRoverall= 47.2%; CRET1= 31.2%; CRET2= 16.6%; CRET3= 78.5%) infections. Daily post-treatment egg per gram of stool counts recapitulated these observations and faster and increased egg reduction was observed in ET3 when compared to failure-associated ET1 and ET2. Species-level comparisons of these enterotypes highlighted a set of ten differentially enriched bacterial species.ConclusionTaxonomically distinct gut microbiota communities were found in this setting in terms of both, relative and absolute abundances, of specific bacterial taxa. Pre-treatment enterotype was relevant for treatment outcome of the combination therapy, albendazole and ivermectin, forT. trichiuraas well as for hookworm infections. These observations indicate that pre-treatment microbial composition of stool samples should be monitored to ensure evidence-based administration of albendazole-ivermectin to treat these diseases.
Protection Across Age Groups of BNT162b2 Vaccine Booster against Covid-19
Authors: Bar-On Yinon M. , Goldberg Yair , Mandel Micha , Bodenheimer Omri , Freedman Laurence , Alroy-Preis Sharon , Ash Nachman , Huppert Amit , Milo Ron 
Published: October 2021

AbstractBACKGROUNDFollowing administration to persons 60+ years of age, the booster vaccination campaign in Israel was gradually expanded to younger age groups who received a second dose >5 months earlier. We study the booster effect on COVID-19 outcomes.METHODSWe extracted data for the period July 30, 2021 to October 6, 2021 from the Israeli Ministry of Health database regarding 4,621,836 persons. We compared confirmed Covid-19 infections, severe illness, and death of those who received a booster ≥12 days earlier (booster group) with a nonbooster group. In a secondary analysis, we compared the rates 3-7 days with ≥12 days after receiving the booster dose. We used Poisson regressions to estimate rate ratios after adjusting for possible confounding factors.RESULTSConfirmed infection rates were ≈10-fold lower in the booster versus nonbooster group (ranging 8.8-17.6 across five age groups) and 4.8-11.2 fold lower in the secondary analysis. Severe illness rates in the primary and secondary analysis were 18.7-fold (95% CI, 15.7-22.4) and 6.5-fold (95% CI, 5.1-8.3) lower for ages 60+, and 22.0-fold (95% CI, 10.3-47.0) and 3.2-fold (95% CI, 1.1-9.6) lower for ages 40-60. For ages 60+, COVID-19 associated death rates were 14.7-fold (95% CI, 9.4-23.1) lower in the primary analysis and 4.8-fold (95% CI, 2.8-8.2) lower in the secondary analysis.CONCLUSIONSAcross all age groups, rates of confirmed infection and severe illness were substantially lower among those who received a booster dose of the BNT162b2 vaccine.
Rhesus negative males have an enhanced IFNγ-mediated immune response to influenza A virus
Authors: Sugrue Jamie A. , Smith Megan , Posseme Celine , Charbit Bruno ,   Milieu Interieur Consortium, Bourke Nollaig M. , Duffy Darragh , O’Farrelly Cliona 
Published: October 2021

AbstractThe Rhesus D antigen (RhD) has been associated with susceptibility to several viral infections. Reports suggest that RhD-negative individuals are better protected against infectious diseases and have overall better health. However, potential mechanisms contributing to these associations have not yet been defined. Here, we used transcriptomic and genomic data from theMilieu Interieurcohort of 1000 healthy individuals to explore the effect of RhD on immune responses. We used the rs590787 SNP in the RHD gene to classify the 1000 donors as either RhD-positive or -negative. Whole blood was stimulated with LPS, polyIC, and the live influenza A virus and the NanoString human immunology panel of 560 genes used to assess donor immune response and to investigate sex specific effects. Using regression analysis, we observed no significant differences in responses to polyIC or LPS between RhD-positive and - negative individuals. However, upon sex-specific analysis, we observed over 30 differentially expressed genes (DEGs) between RhD-positive (n=401) and RhD-negative males (n=78). Interestingly these Rhesus-associated differences were not seen in females. Further investigation, using gene set enrichment analysis, revealed enhanced IFNγ signalling in RhD-negative males. This amplified IFNγ signalling axis may explain the increased viral resistance previously described in RhD-negative individuals.
The consequences of a year of the COVID-19 pandemic for the mental health of young adult twins in England and Wales
Authors: Rimfeld Kaili , Malanchini Margherita , Arathimos Ryan , Gidziela Agnieszka , Pain Oliver , McMillan Andrew , Ogden Rachel , Webster Louise , Packer Amy E. , Shakeshaft Nicholas G. , Schofield Kerry L. , Pingault Jean-Baptiste , Allegrini Andrea G. , Stringaris Argyris , von Stumm Sophie , Lewis Cathryn M. , Plomin Robert 
Published: October 2021

AbstractThe COVID-19 pandemic has impacted all our lives, not only through the infection itself, but also through the measures taken to control the virus’s spread (e.g., lockdown). Here we investigated how the COVID-19 pandemic and unprecedented lockdown affected the mental health of young adults in England and Wales. We compared the mental health symptoms of up to 4,000 twins in their mid-twenties in 2018 prior to the COVID-19 pandemic (T1) to those in a four-wave longitudinal data collection during the pandemic in April, July, and October 2020, and in March 2021 (T2-T5). The average changes in mental health were small-to-medium and mainly occurred from 2018 (T1) to March 2020 (T2, one month following the start of lockdown; average Cohen d=0.14). Despite the expectation of catastrophic effects on the pandemic on mental health of our young adults, we did not observe trends in worsening mental health during the pandemic (T3-T5). Young people with pre-existing mental health problems were adversely affected at the beginning of the pandemic, but their increased problems largely subsided as the pandemic persisted. Twin analyses indicated that the aetiology of individual differences did not change during the lockdown. The average heritability of mental health symptoms was 33% across 5 waves of assessment, and the average genetic correlation between T1 and T2-T5 was .95, indicating that genetic effects before the pandemic (T1) are substantially correlated with genetic effects up to a year later (T2-T5). We conclude that on average the mental health of young adults in England and Wales has been remarkably resilient to the effects of the pandemic and associated lockdown.
Age and body mass index affect fit of spirometry GLI references in schoolchildren
Authors: Mozun Rebeca , Ardura-Garcia Cristina , Pedersen Eva S. L. , Usemann Jakob , Singer Florian , Latzin Philipp , Moeller Alexander , Kuehni Claudia E. 
Published: October 2021

AbstractBackgroundReferences from the Global Lung Function Initiative (GLI) are widely used to interpret children’s spirometry results. We assessed fit for healthy schoolchildren.MethodsLuftiBus in the school (LUIS) is a population-based cross-sectional study done from 2013-2016 in the canton of Zurich, Switzerland. Parents and children aged 6-17 years answered questionnaires about respiratory symptoms and lifestyle. Children underwent spirometry in a mobile lung function lab. We calculated GLI-based z-scores for FEV1, FVC, FEV1/FVC, and FEF25-75for healthy White participants. We defined appropriate fit to GLI references by mean values ±0.5 z-scores. We assessed if fit varied by age, body mass index, height, and sex using linear regression models.ResultsWe analysed data from 2036 children with valid FEV1measurements of which 1762 also had valid FVC measurements. The median age was 12.2 years. Fit was appropriate for children aged 6-11 years for all indices. In adolescents aged 12-17 years, fit was appropriate for FEV1/FVC (mean: -0.09; SD: 1.02) z-scores, but not for FEV1(mean: -0.62; SD: 0.98), FVC (mean: -0.60; SD: 0.98), and FEF25-75(mean: -0.54; SD: 1.02). FEV1, FVC, and FEF25-75z-scores fitted better in children considered overweight (means: -0.25, -0.13, -0.38) than normal weight (means: -0.55, -0.50, -0.55;p-trend: <0.001, 0.014, <0.001). FEV1, FVC, and FEF25-75z-scores depended on both age and height (pinteraction: 0.034, 0.019, <0.01).ConclusionGLI-based FEV1, FVC, and FEF25-75z-scores do not fit White Swiss adolescents well. This should be considered when using reference equations for clinical decision making, research and international comparison.Take home messageOur study suggests GLI-based FEV1, FVC, and FEF25-75z-scores over detect abnormal lung function in Swiss adolescents, and more so among slimmer adolescents, which has important implications for clinical care, research, and international comparisons.
A longitudinal analysis of pneumococcal vaccine serotypes in pneumonia patients in Germany
Authors: Bahrs Christina , Kesselmeier Miriam , Kolditz Martin , Ewig Santiago , Rohde Gernot , Barten-Neiner Grit , Rupp Jan , Witzenrath Martin , Welte Tobias , Pletz Mathias W. ,   for the CAPNETZ Study Group
Published: October 2021

AbstractRecently, a 15-valent (PCV15) and a 20-valent pneumococcal conjugate vaccine (PCV20) have been licensed by the US Food and Drug Administration and are under evaluation by the European Medicines Agency. PCV15 contains all serotypes of the 13-valent conjugate vaccine (PCV13) plus serotype 22F and 33F and PCV20 includes PCV13 serotypes plus serotypes 8, 10A, 11A, 12F, 15B, 22F, 33F. We investigated pneumococcal serotype distribution, secular trends and proportion of pneumonia caused by serotypes included in PCV13, PCV15, PCV20, and the 23-valent pneumococcal polysaccharide vaccine (PPV23) among adult patients with all-cause community-acquired pneumonia (CAP) between 2013 and 2019. We applied logistic mixed regression modelling to assess annual trends. Urine samples from adult patients with CAP treated in the community or hospital in Germany and included in the CAPNETZ study, a prospective multi-centre cohort study, were analysed by two serotype-specific multiplex urinary antigen detection assays (UAD1/UAD2) at Pfizer’s Vaccines Research and Development Laboratory. UAD1 detects serotypes in PCV13, UAD2 detects additional serotypes in PCV20 plus serotypes 2, 9N, 17F and 20. Out of 1,831 patients screened, urine samples with a valid UAD test result were available for 1,343 patients (73.3%). Among those patients, 829 patients (61.7%) were male, 792 patients (59.0%) were aged ≥60 years, 1038 patients (77.3%) had at least one comorbidity and 1,204 patients (89.7%) were treated in the hospital. The overall proportion of vaccine-type pneumonia among all-cause CAP for PCV13, PCV15, PCV20 and PPV23 was 7.7% (n=103), 9.1% (n=122), 12.3% (n=165) and 13.3% (n=178). Over the entire observation period, we did not observe evidence for significant annual trends in pneumococcal vaccine serotype coverage against pneumonia in adults (PCV13: OR 0.94, 95% CI 0.83-1.05; PCV15: OR 0.93, 95% CI 0.84-1.03; PCV20: OR 0.95, 95% CI 0.86-1.04; PPV23: OR 0.99, 95% CI 0.90-1.08). In conclusion, our data show i) no decline of PCV13 serotypes in all-cause CAP between 2013-2019 mainly due to a persistently high proportion of serotype 3 suggesting no meaningful effect of childhood PCV13 vaccination on PCV13 coverage in pneumonia in adults during this time period and ii) that the gap in the coverage between PCV20 and PPV23 was small and did not increase over the entire observation time.