bluuebunny/crossref_metadata_2025_split huggingface dataset:
A meta-analysis of the genome-wide association studies on two genetically correlated phenotypes (self-reported headache and self-reported migraine) identifies four new risk loci for headaches (N=397,385)
Authors: Meng Weihua , Reel Parminder S , Nangia Charvi , Rajendrakumar Aravind Lathika , Hebert Harry L , Adams Mark J , Zheng Hua , Lu Zen Haut ,   23andMe Research Team, Ray Debashree , Colvin Lesley A , Palmer Colin NA , McIntosh Andrew , Smith Blair H 
Published: September 2021

AbstractHeadache is one of the commonest complaints that doctors need to address in clinical settings. The genetic mechanisms of different types of headache are not well understood. In this study, we performed a meta-analysis of genome-wide association studies (GWAS) on the self-reported headache phenotype from the UK Biobank cohort and the self-reported migraine phenotype from the 23andMe resource using the metaUSAT for genetically correlated phenotypes (N=397,385). We identified 38 loci for headaches, of which 34 loci have been reported before and 4 loci were newly identified. The LRP1-STAT6-SDR9C7 region in chromosome 12 was the most significantly associated locus with a leading P value of 1.24 × 10−62 of rs11172113. The ONECUT2 gene locus in chromosome 18 was the strongest signal among the 4 new loci with a P value of 1.29 × 10−9 of rs673939. Our study demonstrated that the genetically correlated phenotypes of self-reported headache and self-reported migraine can be meta-analysed together in theory and in practice to boost study power to identify more new variants for headaches. This study has paved way for a large GWAS meta-analysis study involving cohorts of different, though genetically correlated headache phenotypes.
Absence of Excess Mortality in a Highly Vaccinated Population During the Initial Covid-19 Delta Period
Authors: Faust Jeremy Samuel , Du Chengan , Mayes Katherine Dickerson , Renton Benjamin , Li Shu-Xia , Lin Zhenqiu , Krumholz Harlan M. 
Published: September 2021

AbstractBackgroundAll-cause excess mortality (the number of deaths that exceed projections in any period) has been widely reported during the Covid-19 pandemic. Whether excess mortality has occurred during the Delta wave is less well understood.MethodsWe performed an observational study using data from the Massachusetts Department of Health. Five years of US Census population data and CDC mortality statistics were applied to a seasonal autoregressive integrated moving average (sARIMA) model to project the number of expected deaths for each week of the pandemic period, including the Delta period (starting in June 2021, extending through August 28th 2021, for which mortality data are >99% complete). Weekly Covid-19 cases, Covid-19-attributed deaths, and all-cause deaths are reported. County-level excess mortality during the vaccine campaign are also reported, with weekly rates of vaccination in each county that reported 100 or more all-cause deaths during any week included in the study period.ResultsAll-cause mortality was not observed after March 2021, by which time over 75% of persons over 65 years of age in Massachusetts had received a vaccination. Fewer deaths than expected (which we term ‘deficit mortality’) occurred both during the summer of 2020, the spring of 2021 and during the Delta wave (beginning June 13, 2021 when Delta isolates represented >10% of sequenced cases). After the initial wave in the spring of 2020, more Covid-19-attributed deaths were recorded that all-cause excess deaths, implying that Covid-19 was misattributed as the underlying cause, rather than a contributing cause of death in some cases.ConclusionIn a state with high vaccination rates, excess mortality has not been recorded during the Delta period. Deficit mortality has been recorded during this period.
Impact of prior SARS-CoV-2 infection on post-vaccination SARS-CoV-2 spike IgG antibodies in a longitudinal cohort of healthcare workers
Authors: Zhong Diana , Xiao Shaoming , Debes Amanda K. , Egbert Emily R. , Caturegli Patrizio , Colantuoni Elizabeth , Milstone Aaron M. 
Published: September 2021

AbstractWaning serum antibodies against SARS-CoV-2 have sparked discussions about long-term immunity and need for vaccine boosters. We examined SARS-CoV-2 spike IgG antibodies in a longitudinal cohort, comparing antibody decay in individuals who received an mRNA SARS-CoV-2 vaccine, with and without prior SARS-CoV-2 infection. We completed a longitudinal cohort of healthcare workers (HWs) between June 2020 and September 2021. HWs were included if they had a serum sample collected after SARS-CoV-2 infection and/or a serum sample collected ≥ 14 days after second dose of an mRNA SARS-CoV-2 vaccine. Linear regression models adjusting for vaccine type, age, and sex were used to compare post-vaccination antibody levels between 1) HWs with and without prior SARS-CoV-2 infection and 2) HWs with prior SARS-CoV-2 infection ≤ 90 days and > 90 days prior to first vaccine. Serum was collected from 98 HWs after SARS-CoV-2 infection and before vaccine, and 1960 HWs ≥ 14 days following second vaccine dose. Serum spike antibody levels were higher after vaccination than after natural infection. Compared to SARS-CoV-2 naïve individuals, those with prior infection maintained higher post-vaccination mean spike IgG values at 1, 3, and 6 months, after adjusting for age, sex, and vaccine type. Individuals with PCR-confirmed infection > 90 days before vaccination had higher post-vaccination antibody levels than individuals infected ≤ 90 days before vaccination. Individuals with three exposures to spike protein maintain the highest antibody levels particularly when first and second exposures were greater than 90 days apart. A booster dose provides a third exposure and may similarly induce a more durable antibody response.
Face mask fit modifications that improve source control performance
Authors: Blachere Francoise M. , Lemons Angela R. , Coyle Jayme P. , Derk Raymond C. , Lindsley William G. , Beezhold Donald H. , Woodfork Karen , Duling Matthew G. , Boutin Brenda , Boots Theresa , Harris James R. , Nurkiewicz Tim , Noti John D. 
Published: September 2021

BACKGROUNDDuring the COVID-19 pandemic, face masks are used as source control devices to reduce the expulsion of respiratory aerosols from infected people. Modifications such as mask braces, earloop straps, knotting and tucking, and double masking have been proposed to improve mask fit. However, the data on source control are limited.METHODSThe effectiveness of mask fit modifications was determined by conducting fit tests on human subjects and simulator manikins and by performing simulated coughs and exhalations using a source control measurement system.RESULTSMedical masks without modification blocked ≥56% of cough aerosols and ≥42% of exhaled aerosols. Modifying fit by crossing the earloops or placing a bracket under the mask did not increase performance, while using earloop toggles, an earloop strap, and knotting and tucking the mask increased performance. The most effective modifications for improving source control performance were double masking and using a mask brace. Placing a cloth mask over a medical mask blocked ≥85% of cough aerosols and ≥91% of exhaled aerosols. Placing a brace over a medical mask blocked ≥95% of cough aerosols and ≥99% of exhaled aerosols.CONCLUSIONFit modifications can greatly improve the performance of face masks as source control devices for respiratory aerosols.
How complete is the reporting of somatic sensory training interventions in individuals following a stroke? Protocol for a systematic review
Authors: Feller Daniel , Pedri Caterina , Gozzer Paolo , Innocenti Tiziano , Trentin Francesca 
Published: September 2021

ABSTRACTBackgroundTo implement intervention from research to clinical practice, treatments must be adequately described in randomized clinical trials. Specific reporting guidelines, such as the TIDieR checklist, have been developed to enhance the reporting of intervention in clinical trials.ObjectiveWe aim to evaluate the adherence to the TIDieR checklist in randomized controlled trials evaluating somatic sensory training interventions in individuals following a stroke.Material and MethodsWe will perform a systematic review of the literature, searching PubMed, CENTRAL, and PEDro for randomized controlled trials that evaluate the efficacy of any rehabilitative intervention on somatic sensation in patients with a history of stroke, independently form the comparator.Two authors independently will evaluate the completeness of the reporting of the intervention using the TIDieR checklist.A descriptive analysis of the total score and the individual items of the TIDieR will be produced.Ethics and disseminationA manuscript with results will be submitted for publication in a peer-reviewed journal in the rehabilitation field.
Identification and classification of cis-regulatory elements in the amphipod crustacean Parhyale hawaiensis
Authors: Sun Dennis A , Bredeson Jessen V , Bruce Heather S , Patel Nipam H 
Published: September 2021

AbstractEmerging research organisms enable the study of biology that cannot be addressed using classical “model” organisms. The development of new data resources can accelerate research in such animals. Here, we present new functional genomic resources for the amphipod crustacean Parhyale hawaiensis, facilitating the exploration of gene regulatory evolution using this emerging research organism. We use Omni-ATAC-Seq, an improved form of the Assay for Transposase-Accessible Chromatin coupled with next-generation sequencing (ATAC-Seq), to identify accessible chromatin genome-wide across a broad time course of Parhyale embryonic development. This time course encompasses many major morphological events, including segmentation, body regionalization, gut morphogenesis, and limb development. In addition, we use short- and long-read RNA-Seq to generate an improved Parhyale genome annotation, enabling deeper classification of identified regulatory elements. We discover differential accessibility, predict nucleosome positioning, infer transcription factor binding, cluster peaks based on accessibility dynamics, classify biological functions, and correlate gene expression with accessibility. Using a Minos transposase reporter system, we demonstrate the potential to identify novel regulatory elements using this approach, including distal regulatory elements. This work provides a platform for the identification of novel developmental regulatory elements in Parhyale, and offers a framework for performing such experiments in other emerging research organisms.Primary Findings–Omni-ATAC-Seq identifies cis-regulatory elements genome-wide during crustacean embryogenesis–Combined short- and long-read RNA-Seq improves the Parhyale genome annotation–ImpulseDE2 analysis identifies dynamically regulated candidate regulatory elements–NucleoATAC and HINT-ATAC enable inference of nucleosome occupancy and transcription factor binding–Fuzzy clustering reveals peaks with distinct accessibility and chromatin dynamics–Integration of accessibility and gene expression reveals possible enhancers and repressors–Omni-ATAC can identify known and novel regulatory elements
A flexible electronic strain sensor for the real-time monitoring of tumor progression
Authors: Abramson Alex , Chan Carmel T. , Khan Yasser , Mermin-Bunnell Alana , Matsuhisa Naoji , Fong Robyn , Shad Rohan , Hiesinger William , Mallick Parag , Gambhir Sanjiv Sam , Bao Zhenan 
Published: September 2021

AbstractHealthcare professionals and scientists utilize tumor shrinkage as a key metric to establish the efficacy of cancer treatments. However, current measurement tools such as CT scanners and calipers only provide brief snapshots of the dynamic geometric changes occurring in vivo, and they are unable to characterize the continuous micrometer-scale volumetric transformations transpiring at minute timescales. Here we present a stretchable electronic strain sensor, with a 10-micron scale resolution, capable of continuously monitoring tumor volume progression in real-time. In mouse models with subcutaneously implanted lung cancer or B-cell lymphoma tumors our sensors discerned a significant change in the tumor volumes of treated mice within 5 hours after small molecule therapy or immunotherapy initiation. Histology, caliper measurements, and luminescence imaging over a one-week treatment period validated the data from the continuous sensor. We anticipate that real-time tumor progression datasets could help expedite and automate the process of screening cancer therapies in vivo.
Epilepsy-causing KCNT1 variants increase KNa1.1 channel activity by disrupting the activation gate
Authors: Cole Bethan A. , Pilati Nadia , Lippiat Jonathan D. 
Published: September 2021

AbstractGain-of-function pathogenic missense KCNT1 variants are associated with several developmental and epileptic encephalopathies (DEE). With few exceptions, patients are heterozygous and there is a paucity of mechanistic information about how pathogenic variants increase KNa1.1 channel activity and the behaviour of heterotetrameric channels comprising both wild-type (WT) and variant subunits. To better understand these, we selected a range of variants across the DEE spectrum, involving mutations in different protein domains and studied their functional properties. Whole-cell electrophysiology was used to characterise homomeric and heteromeric KNa1.1 channel assemblies carrying DEE-causing variants in the presence and absence of 10 mM intracellular sodium. Voltage-dependent activation of homomeric variant KNa1.1 assemblies were more hyperpolarised than WT KNa1.1 and, unlike WT KNa1.1, exhibited voltage-dependent activation in the absence of intracellular sodium. Heteromeric channels formed by co-expression of WT and variant KNa1.1 had activation kinetics intermediate of homomeric WT and variant KNa1.1 channels, with residual sodium-independent activity. In general, WT and variant KNa1.1 activation followed a single exponential, with time constants unaffected by voltage or sodium. Mutating the threonine in the KNa1.1 selectivity filter disrupted voltage-dependent activation, but sodium-dependence remained intact. Our findings suggest that KNa1.1 gating involves a sodium-dependent activation gate that modulates a voltage-dependent selectivity filter gate. Collectively, all DEE-associated KNa1.1 mutations lowered the energetic barrier for sodium-dependent activation, but some also had direct effects on selectivity filter gating. Destabilisation of the inactivated unliganded channel conformation can explain how DEE-causing amino acid substitutions in diverse regions of the channel structure all cause gain-of-function.
Regulatory role of sphingolipid metabolites, sphingosine-1-phosphate and C16:0 ceramide, in immunogenic cell death of colon cancer cells induced by Bak/Bax-activation
Authors: Hengst Jeremy A. , Nduwumwami Asvelt J. , Yun Jong K. 
Published: September 2021

ABSTRACTWe have previously identified sphingolipid metabolism as a key intracellular process associated with immunogenic cell death (ICD) induced by mitoxantrone in colon cancer cells. Specifically, we have demonstrated that inhibition of the sphingosine kinases (SphKs) synergistically enhanced production of hallmarks of ICD including ectoCRT production. To better understand the mechanism associated with ICD enhanced by SphK1-inhibition, we focused on the ER stress-associated intracellular signaling pathways leading to ectoCRT production. It is known that ABT-263 and AZD-5991 (ABT/AZD) are inhibitors of Bcl-2/Bcl-XL and MCL-1, respectively, leading to activation of Bak/Bax. Herein, we now provide evidence that treatment of DLD-1 colon cancer cells with ABT/AZD results in the production of ectoCRT indicative of ICD. Additionally, our data show that ABT/AZD-induced ectoCRT production is significantly enhanced by combination treatment with the SphK1 inhibitor, PF-543. Mechanistically, we demonstrate that combined treatment of ABT/AZD+PF-543 induces ectoCRT exposure in a caspase 8-dependent manner. Accordingly, we have identified a Bak/Bax activation-dependent pathway that leads to activation of a pro-survival SphK1/sphingosine-1-phosphate (S1P) signaling that attenuates ectoCRT production. Additionally, we have identified a regulatory role of ceramide synthase 6 (CerS6)- C16:0 Cer in transporting of dimeric CRT to the cell surface (ectoCRT). Together, these results indicate that sphingolipid metabolites, such as S1P and C16:0 Cer, have a key regulatory role for survival/death decisions of cancer cells in response to ICD-inducing chemotherapeutic agents such as mitoxantrone and ABT/AZD. Hence, targeting SphKs may be an innovative means to enhance the efficacy of ICD-inducing chemotherapeutic agents promoting anti-tumor innate/adaptive immune response since SphK inhibition blocks the anti-ICD effects of S1P while simultaneously accumulating sphingosine (Sph) leading to pro-ICD C16:0 Cer synthesis.
Modeling the levels, trends, and connectivity of malaria transmission using genomic data from a health facility in Thiès, Senegal
Authors: Lee Albert , Ndiaye Yaye Die , Badiane Aida , Deme Awa , Daniels Rachel F. , Schaffner Stephen F. , Fall Fatou Ba , Ndiop Médoune , Gueye Alioune Badara , Diallo Ibrahima , Battle Katherine E. , Wenger Edward A. , Bever Caitlin A. , Sene Doudou , MacInnis Bronwyn , Wirth Dyann F. , Ndiaye Daouda , Hartl Daniel L. , Volkman Sarah K. , Proctor Joshua L. 
Published: September 2021

AbstractMolecular data and analysis outputs are being integrated into malaria surveillance efforts to provide valuable programmatic insights for national malaria control programs (NMCPs). A plethora of studies from diverse geographies have demonstrated that malaria parasite genetic data can be an important tool for drug resistance monitoring, species identification, outbreak analysis, and transmission characterization. Despite many successful research efforts, there are still important knowledge gaps hindering practical translation of each of these use cases for NMCPs. Here, we leverage epidemiological modeling and time-series data of 2035 genetic sequences collected in Thiès, Senegal from 2006-2018 to provide a quantitative and setting-specific assessment of the levels, trends, and connectivity of malaria transmission. We also identify the genetic features that are the most informative for inferring transmission in Thiès, such as the fraction of the population with multiple infections and the persistence of parasite lineages across multiple transmission seasons. The model fitting and uncertainty quantification framework also reveals a significant decrease in the level of malaria transmission around 2013. This difference coincides with a large-scale drought and bed net campaign by the NMCP and USAID and is independently corroborated by geo-spatial models of incidence in Thiès. We find that genetically identical samples are more likely to be geographically clustered even at the neighborhood scale; and moreover, these lineages propagate non-randomly around the city. Our approach and results provide quantitative guidance for the interpretation of malaria parasite genetic data from Thiès, Senegal and indicates the value of increased malaria genomic surveillance for NMCPs.
Public perception of organ donation and transplantation policies in Southern Spain
Authors: Díaz-Cobacho Gonzalo , Cruz-Piqueras Maite , Delgado Janet , Hortal-Carmona Joaquín , Martínez-López M. Victoria , Molina-Pérez Alberto , Padilla-Pozo Álvaro , Ranchal-Romero Julia , Rodríguez-Arias David 
Published: September 2021

AbstractBackgroundThis research explores how public awareness and attitudes towards donation and transplantation policies may contribute to Spain’s success in cadaveric organ donation.Materials and MethodsA representative sample of 813 people residing in Andalusia (Southern Spain) were surveyed by telephone or via Internet between October and December 2018.ResultsMost participants trust Spain’s donation and transplantation system (93%) and wish to donate their organs after death (76%). Among donors, a majority have expressed their consent (59%), while few non-donors have expressed their refusal (14%). Only a minority is aware of the presumed consent system in force (28%) and feel sufficiently informed regarding the requirements needed to be an organ donor (16%). Participants mainly consider that relatives should represent the deceased’s preferences and be consulted when the deceased’s wishes are unknown, as is the case in Spain.ConclusionsPublic trust in the transplant system may contribute to Spain’s high performance in organ donation. High levels of societal support towards organ donation and transplantation do not correspond in Spain with similar levels of public awareness of donation and transplantation policies.
Evaluation of evidence for pathogenicity demonstrates thatBLK, KLF11andPAX4should not be included in diagnostic testing for MODY
Authors: Laver Thomas W , Wakeling Matthew N , Knox Olivia , Colclough Kevin , Wright Caroline F , Ellard Sian , Hattersley Andrew T , Weedon Michael N , Patel Kashyap A 
Published: September 2021

AbstractMaturity Onset Diabetes of the Young (MODY) is an autosomal dominant form of monogenic diabetes, reported to be caused by variants in 16 genes. Concern has been raised about whether variants inBLK(MODY11),KLF11(MODY7) andPAX4(MODY9) cause MODY. We examined variant-level genetic evidence (co-segregation with diabetes and frequency in population) for published putative pathogenic variants in these genes and used burden testing to test gene-level evidence in a MODY cohort (n=1227) compared to population control (UK Biobank, n=185,898). For comparison we analysed well-established causes of MODY,HNF1AandHNF4A. The published variants inBLK, KLF11andPAX4showed poor co-segregation with diabetes (combined LOD scores ≤1.2), compared toHNF1AandHNF4A(LOD scores >9), and are all too common to cause MODY (minor allele frequency >4.95×10−5). Ultra-rare missense and protein-truncating variants (PTVs) were not enriched in a MODY cohort compared to the UK Biobank (PTVsP>0.05, missenseP>0.1 for all three genes) whileHNF1AandHNF4Awere enriched (P<10−6). Sensitivity analyses using different population cohorts supported our results. Variant and gene-level genetic evidence does not supportBLK, KLF11orPAX4as causes of MODY. They should not be included in MODY diagnostic genetic testing.
CanIsoNet: A Database to Study the Functional Impact of Isoform Switching Events in Diseases
Authors: Karakulak Tülay , Szklarczyk Damian , Saylan Cemil Can , Moch Holger , von Mering Christian , Kahraman Abdullah 
Published: September 2021

AbstractMotivationAlternative splicing, as an essential regulatory mechanism in normal mammalian cells, is frequently disturbed in cancer and other diseases. Switches in the expression of most dominant alternative isoforms can alter protein interaction networks of associated genes giving rise to a disease or disease progression. Here, we present CanIsoNet (disease-specific isoform interaction network), a database to view, browse and search these isoform switching events. CanIsoNet is the first webserver that incorporates isoform expression data with STRING interaction networks and ClinVar annotations to predict the pathogenic impact of isoform switching events in various diseases.ResultsData in CanIsoNet can be browsed by disease or searched by genes or isoforms in annotation-rich data tables. Various annotations for 11,072 isoforms and 13,531 unique isoform switching events across 28 different tissue types are provided. The network density score for each disease-specific isoform, PFAM domain IDs of disrupted interactions, domain structure visualization of transcripts and expression data of switched isoforms for each sample are given. Additionally, the genes annotated in ClinVar are highlighted in the interactive interaction network.AvailabilityCanIsoNet is freely available at https://caniso.net. The source codes can be found under a Creative Common License at https://github.com/kahramanlab/CanIsoNet_Web.Supplementary InformationSupplementary data are available at Bioinformatics online.