bluuebunny/crossref_metadata_2025_split huggingface dataset:
Background and concurrent factors predicting non-adherence to public health preventive measures during the chronic phase of the COVID-19 pandemic
Authors: Pollak Yehuda , Shoham Rachel , Dayan Haym , Seri Ortal Gabrieli , Berger Itai 
Published: October 2020

AbstractTo determine factors that predict non-adherence to preventive measures for COVID-19 during the chronic phase of the pandemic, a cross-sectional, general population survey was conducted in Israel. Sociodemographic, health-related, behavioral, and COVID-19-related characteristics were collected. Among 2055 participants, non-adherence was associated with male gender, young age, bachelorhood, being employed, lower decrease in income, low physical activity, psychological distress, ADHD symptoms, past risk-taking and anti-social behavior, low pro-sociality, perceived social norms favoring non-adherence, low perceived risk of COVID-19, low perceived efficacy of the preventive measures, and high perceived costs of adherence to the preventive measures. There appears to be a need for setting out and communicating preventive measures to specifically targeted at-risk populations.
Genome-wide association study identifies five risk loci for pernicious anemia and implicates the role of HLA-DR15 haplotype
Authors: Laisk Triin , Lepamets Maarja , Mägi Reedik 
Published: October 2020

AbstractPernicious anemia is a rare condition characterized by vitamin B12 deficiency anemia due to lack of intrinsic factor, often caused by autoimmune gastritis. Patients with pernicious anemia have a higher incidence of other autoimmune disorders, such as type 1 diabetes, vitiligo and autoimmune thyroid issues. Therefore, the disease has a clear autoimmune basis, although the genetic susceptibility factors have thus far remained poorly studied. We conducted a genome-wide association study meta-analysis in 2,166 cases and 659,516 European controls from population-based biobanks and identified genome-wide significant signals in or near thePTPN22 (rs6679677, p=1.91 ⨯ 10−24, OR=1.63), PNPT1(rs12616502, p=3.14 ⨯ 10−8, OR=1.70),HLA-DQB1(rs28414666, p=1.40 ⨯ 10−16, OR=1.38),IL2RA(rs2476491, p=1.90 ⨯ 10−8, OR=1.22) andAIRE(rs74203920, p=2.33 ⨯ 10−9, OR=1.83) genes, thus providing the first robust associations between pernicious anemia and genetic risk factors. We further mapped the susceptibility in the HLA region to the HLA-DR15 haplotype. Analysis of associated diagnoses and disease trajectories confirm the association between pernicious anemia and thyroid issues, vitiligo, gastritis, stomach cancer, osteoporosis and other diagnoses.
Identification of drugs associated with reduced severity of COVID-19: A case-control study in a large population
Authors: Israel Ariel , Schäffer Alejandro A. , Cicurel Assi , Feldhamer Ilan , Tal Ameer , Cheng Kuoyuan , Sinha Sanju , Schiff Eyal , Lavie Gil , Ruppin Eytan 
Published: October 2020

AbstractBackgroundUntil COVID-19 drugs specifically developed to treat COVID-19 become more widely accessible, it is crucial to identify whether existing medications have a protective effect against severe disease. Towards this objective, we conducted a large population study in Clalit Health Services (CHS), the largest healthcare provider in Israel, insuring over 4.7 million members.MethodsTwo case-control matched cohorts were assembled to assess which medications, acquired in the last month, decreased the risk of COVID-19 hospitalization. Case patients were adults aged 18-95 hospitalized for COVID-19. In the first cohort, five control patients, from the general population, were matched to each case (n=6202); in the second cohort, two non-hospitalized SARS-CoV-2 positive control patients were matched to each case (n=6919). The outcome measures for a medication were: odds ratio (OR) for hospitalization, 95% confidence interval (CI), and the p-value, using Fisher’s exact test. False discovery rate was used to adjust for multiple testing.ResultsMedications associated with most significantly reduced odds for COVID-19 hospitalization include: ubiquinone (OR=0.185, 95% CI (0.058 to 0.458), p<0.001), ezetimibe (OR=0.488, 95% CI ((0.377 to 0.622)), p<0.001), rosuvastatin (OR=0.673, 95% CI (0.596 to 0.758), p<0.001), flecainide (OR=0.301, 95% CI (0.118 to 0.641), p<0.001), and vitamin D (OR=0.869, 95% CI (0.792 to 0.954), p<0.003). Remarkably, acquisition of artificial tears, eye care wipes, and several ophthalmological products were also associated with decreased risk for hospitalization.ConclusionsUbiquinone, ezetimibe and rosuvastatin, all related to the cholesterol synthesis pathway were associated with reduced hospitalization risk. These findings point to a promising protective effect which should be further investigated in controlled, prospective studies.FundingThis research was supported in part by the Intramural Research Program of the National Institutes of Health, NCI.
A Highly Generalizable Natural Language Processing Algorithm for the Diagnosis of Pulmonary Embolism from Radiology Reports
Authors: Johnson Jacob , Qiu Grace , Lamoureux Christine , Ngo Jennifer , Ngo Lawrence 
Published: October 2020

AbstractThough sophisticated algorithms have been developed for the classification of free-text radiology reports for pulmonary embolism (PE), their overall generalizability remains unvalidated given limitations in sample size and data homogeneity. We developed and validated a highly generalizable deep-learning based NLP algorithm for this purpose with data sourced from over 2,000 hospital sites and 500 radiologists. The algorithm achieved an AUCROC of 0.995 on chest angiography studies and 0.994 on non-angiography studies for the presence or absence of PE. The high accuracy achieved on this large and heterogeneous dataset allows for the possibility of application in large multi-center radiology practices as well as for deployment at novel sites without significant degradation in performance.
Genetics of Low Polygenic Risk Score Type 1 Diabetes Patients: rare variants in 22 novel loci
Authors: Qu Jingchun , Qu Hui-Qi , Bradfield Jonathan , Glessner Joseph , Chang Xiao , Tian Lifeng , March Michael , Roizen Jeffrey D , Sleiman Patrick , Hakonarson Hakon 
Published: October 2020

AbstractWith polygenic risk score (PRS) for autoimmune type 1 diabetes (T1D), this study identified T1D cases with low T1D PRS and searched for susceptibility loci in these cases. Our hypothesis is that genetic effects (likely mediated by relatively rare genetic variants) of non-mainstream (or non-autoimmune) T1D might have been diluted in the previous studies on T1D cases in general. Two cohorts for the PRS modeling and testing respectively were included. The first cohort consisted of 3,356 T1D cases and 6,203 controls, and the independent second cohort consisted of 3,355 T1D cases and 6,203 controls. Cases with low T1D PRS were identified using PRSice-2 and compared to controls with low T1D PRS by genome-wide association (GWA) test. Twenty-six genetic loci with SNPs/SNVs associated with low PRS T1D at genome-wide significance (P≤5.0xE-08) were identified, including 4 established T1D loci, as well as 22 novel loci represented by rare SNVs. For the 22 novel loci, 12 regions have been reported of association with obesity related traits by previous GWA studies. Five loci encoding long intergenic non-protein coding RNAs (lncRNA), two loci involved in N-linked glycosylation, two loci encoding GTPase activators, and two ciliopathy genes, are also highlighted in this study.
A Neanderthal OAS1 isoform Protects Against COVID-19 Susceptibility and Severity: Results from Mendelian Randomization and Case-Control Studies
Authors: Zhou Sirui , Butler-Laporte Guillaume , Nakanishi Tomoko , Morrison David , Afilalo Jonathan , Afilalo Marc , Laurent Laetitia , Pietzner Maik , Kerrison Nicola , Zhao Kaiqiong , Brunet-Ratnasingham Elsa , Henry Danielle , Kimchi Nofar , Afrasiabi Zaman , Rezk Nardin , Bouab Meriem , Petitjean Louis , Guzman Charlotte , Xue Xiaoqing , Tselios Chris , Vulesevic Branka , Adeleye Olumide , Abdullah Tala , Almamlouk Noor , Chen Yiheng , Chassé Michaël , Durand Madeleine , Pollak Michael , Paterson Clare , Zeberg Hugo , Normark Johan , Frithiof Robert , Lipcsey Miklós , Hultström Michael , Greenwood Celia M T , Langenberg Claudia , Thysell Elin , Mooser Vincent , Forgetta Vincenzo , Kaufmann Daniel E. , Richards J Brent 
Published: October 2020

AbstractProteins detectable in peripheral blood may influence COVID-19 susceptibility or severity. However, understanding which circulating proteins are etiologically involved is difficult because their levels may be influenced by COVID-19 itself and are also subject to confounding factors. To identify circulating proteins influencing COVID-19 susceptibility and severity we undertook a large-scale two-sample Mendelian randomization (MR) study, since this study design can rapidly scan hundreds of circulating proteins and reduces bias due to reverse causation and confounding. We identified genetic determinants of 931 circulating proteins in 28,461 SARS-CoV-2 uninfected individuals, retaining only single nucleotide polymorphism near the gene encoding the circulating protein. We found that a standard deviation increase in OAS1 levels was associated with reduced COVID-19 death or ventilation (N = 4,336 cases / 623,902 controls; OR = 0.54, P = 7×10−8), COVID-19 hospitalization (N = 6,406 / 902,088; OR = 0.61, P = 8×10−8) and COVID-19 susceptibility (N = 14,134 / 1,284,876; OR = 0.78, P = 8×10−6). Results were consistent in multiple sensitivity analyses. We then measured OAS1 levels in 504 patients with repeated plasma samples (N=1039) with different COVID-19 outcomes and found that increased OAS1 levels in a non-infectious state were associated with protection against very severe COVID-19, hospitalization and susceptibility. Further analyses suggested that a Neanderthal isoform of OAS1 affords this protection. Thus, evidence from MR and a case-control study supported a protective role for OAS1 in COVID-19 outcomes. Available medicines, such as phosphodiesterase-12 inhibitors, increase OAS1 and could be explored for their effect on COVID-19 susceptibility and severity.
Pilot production of SARS-CoV-2 related proteins in plants: a proof of concept for rapid repurposing of indoors farms into biomanufacturing facilities
Authors: Diego-Martin Borja , González Beatriz , Vazquez-Vilar Marta , Selma Sara , Mateos-Fernández Rubén , Gianoglio Silvia , Fernández-del-Carmen Asun , Orzáez Diego 
Published: October 2020

ABSTRACTThe current CoVid-19 crisis is revealing the strengths and the weaknesses of the world’s capacity to respond to a global health crisis. A critical weakness has resulted from the excessive centralization of the current biomanufacturing capacities, a matter of great concern, if not a source of nationalistic tensions. On the positive side, scientific data and information have been shared at an unprecedented speed fuelled by the preprint phenomena, and this has considerably strengthened our ability to develop new technology-based solutions. In this work we explore how, in a context of rapid exchange of scientific information, plant biofactories can serve as a rapid and easily adaptable solution for local manufacturing of bioreagents, more specifically recombinant antibodies. For this purpose, we tested our ability to produce, in the framework of an academic lab and in a matter of weeks, milligram amounts of six different recombinant monoclonal antibodies against SARS-CoV-2 inNicotiana benthamiana.For the design of the antibodies we took advantage, among other data sources, of the DNA sequence information made rapidly available by other groups in preprint publications. mAbs were all engineered as single-chain fragments fused to a human gamma Fc and transiently expressed using a viral vector. In parallel, we also produced the recombinant SARS-CoV-2 N protein and its Receptor Binding Domain (RBD)in plantaand used them to test the binding specificity of the recombinant mAbs. Finally, for two of the antibodies we assayed a simple scale-up production protocol based on the extraction of apoplastic fluid. Our results indicate that gram amounts of anti-SARS-CoV-2 antibodies could be easily produced in little more than 6 weeks in repurposed greenhouses with little infrastructure requirements usingN. benthamianaas production platform. Similar procedures could be easily deployed to produce diagnostic reagents and, eventually, could be adapted for rapid therapeutic responses.
Sequential infection with influenza A virus followed by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) leads to more severe disease and encephalitis in a mouse model of COVID-19
Authors: Clark Jordan J. , Penrice-Randal Rebekah , Sharma Parul , Kipar Anja , Dong Xiaofeng , Pennington Shaun H. , Marriott Amy E. , Colombo Stefano , Davidson Andrew , Williamson Maia Kavanagh , Matthews David A. , Turtle Lance , Prince Tessa , Hughes Grant L. , Patterson Edward I. , Shawli Ghada , Mega Daniele F. , Subramaniam Krishanthi , Sharp Jo , McLaughlin Lynn , Zhou En-Min , Turner Joseph D. , Biagini Giancarlo , Owen Andrew , Hiscox Julian A. , Stewart James P. 
Published: October 2020

AbstractCOVID-19 is a spectrum of clinical symptoms in humans caused by infection with SARS-CoV-2, a recently emerged coronavirus that rapidly caused a pandemic. Coalescence of this virus with seasonal respiratory viruses, particularly influenza virus is a global health concern. To investigate this, transgenic mice expressing the human ACE2 receptor driven by the epithelial cell cytokeratin-18 gene promoter (K18-hACE2) were first infected with IAV followed by SARS-CoV-2. The host response and effect on virus biology was compared to K18-hACE2 mice infected with IAV or SARS-CoV-2 only. Infection of mice with each individual virus resulted in a disease phenotype compared to control mice. Although SARS-CoV-2 RNA synthesis appeared significantly reduced in the sequentially infected mice, they exhibited more rapid weight loss, more severe lung damage and a prolongation of the innate response compared to singly infected or control mice. The sequential infection also exacerbated the extrapulmonary encephalitic manifestations associated with SARS-CoV-2 infection. Conversely, prior infection with a commercially available, multivalent live-attenuated influenza vaccine (Fluenz tetra) elicited the same reduction in SARS-CoV-2 RNA synthesis albeit without the associated increase in disease severity. This suggests that the innate immune response stimulated by infection with IAV is responsible for the observed inhibition of SARS-CoV-2, however, infection with attenuated, apathogenic influenza vaccine does not result in an aberrant immune response and enhanced disease severity. Taken together, the data suggest that the concept of ‘twinfection’ is deleterious and mitigation steps should be instituted as part of a comprehensive public health response to the COVID-19 pandemic.
Evolution of Honey Resistance in Experimental Populations of Bacteria Depends on the Type of Honey, and Has no Major Side Effects for Antibiotic Susceptibility
Authors: Bischofberger Anna M. , Pfrunder Cardozo Katia R. , Baumgartner Michael , Hall Alex R. 
Published: October 2020

AbstractWith rising antibiotic resistance, alternative treatments for communicable diseases are increasingly relevant. One possible alternative for some types of infections is honey, used in wound care since before 2000 BCE and more recently in licensed, medical-grade products. However, it is unclear whether medical application of honey results in the evolution of bacterial honey resistance, and whether this has collateral effects on other bacterial traits such as antibiotic resistance. Here, we used single-step screening assays and serial transfer at increasing concentrations to isolate honey-resistant mutants ofEscherichia coli. We only detected bacteria with consistently increased resistance to the honey they evolved in with two of the four tested honey products, and the observed increases were small (maximum two-fold increase in IC90). Genomic sequencing and experiments with single-gene knockouts showed a key mechanism by which bacteria increased their honey resistance was by mutating genes involved in detoxifying methylglyoxal, which contributes to the antibacterial activity ofLeptospermumhoneys. Crucially, we found no evidence that honey adaptation conferred cross-resistance or collateral sensitivity against nine antibiotics from six different classes. These results reveal constraints on bacterial adaptation to different types of honey, improving our ability to predict downstream consequences of wider honey application in medicine.
Presence and Transmission of Mitochondrial Heteroplasmic Mutations in Human Populations of European and African Ancestry
Authors: Liu Chunyu , Fetterman Jessica L. , Qian Yong , Sun Xianbang , Yan Kaiyu , Blackwell Thomas , Pitsillides Achilleas , Cade Brian E. , Wang Heming , Raffield Laura M. , Lange Leslie A. , Anugu Pramod , Abecasis Goncalo , Cupples L Adrienne , Redline Susan , Correa Adolfo , Vasan Ramachandran S , Wilson James , Ding Jun , Levy Daniel ,   NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium
Published: October 2020

ABSTRACTWe investigated the concordance of mitochondrial DNA heteroplasmic mutations (heteroplasmies) in different types of maternal pairs (n=6,745 pairs) of European (EA, n=4,718 pairs) and African (AA, n=2,027 pairs) Americans with whole genome sequences (WGSs). The average concordance rate of heteroplasmies was highest between mother-offspring pairs, followed by sibling-sibling pairs and more distantly related maternal pairs in both EA and AA participants. The allele fractions of concordant heteroplasmies exhibited high correlation (R2=0.8) between paired individuals. Compared to concordant heteroplasmies, discordant ones were more likely to locate in coding regions, be nonsynonymous or nonsynonymous-deleterious (p<0.001). The average number of heteroplasmies per individual (i.e. heteroplasmic burden) was at a similar level until older age (70-80 years old) and increased significantly thereafter (p<0.01). The burden of deleterious heteroplasmies (combined annotation-dependent depletion score≥15), however, was significantly correlated with advancing age (20-44, 45-64, ≥65 years, p-trend=0.01). A genome-wide association analysis of the heteroplasmic burden identified many significant (P<5e-8) common variants (minor allele frequency>0.05) at 11p11.12. Many of the top SNPs act as strong long-range cis regulators of protein tyrosine phosphatase receptor type J. This study provides further evidence that mtDNA heteroplasmies may be inherited or somatic. Somatic heteroplasmic variants increase with advancing age and are more likely to have an adverse impact on mitochondrial function. Further studies are warranted for functional characterization of the deleterious heteroplasmies occurring with advancing age and the association of the 11p11.12 region of the nuclear genome with mtDNA heteroplasmy.
Genetic variation in heat tolerance of the coralPlatygyra daedaleaindicates potential for adaptation to ocean warming
Authors: Elder Holland , Weis Virginia , Montalvo-Proano Jose , Mocellin Veronique J.L , Baird Andrew H. , Meyer Eli , Bay Line K. 
Published: October 2020

AbstractClimate change induced increases in global ocean temperature represent the greatest threat to the persistence of reef ecosystems and most coral populations are projected to experience temperatures above their current bleaching thresholds annually by 2050. Adaptation to higher temperatures is necessary if corals are to persist in a warming future. While many aspects of heat stress have been well studied, few data are available for predicting the capacity for adaptive cross-generational responses in corals. Consistent sets of heat tolerant genomic markers that reliably predict thermal tolerance have yet to be identified. To address this knowledge gap, we quantified the heritability and genetic variation associated with heat tolerance inPlatygyra daedaleafrom the Great Barrier Reef. We tracked the survival of quantitative genetic crosses of larvae in a heat tolerance selection experiment. We also identified allelic shifts in heat-selected survivors compared with paired, non-selected controls. The narrow-sense heritability of survival under heat stress was 0.66 and a total of 1,069 single nucleotide polymorphisms (SNPs) were associated with different survival probabilities. While 148 SNPs were shared between several experimental crosses, no common SNPs were identified for all crosses suggesting that specific combinations of many markers are responsible for heat tolerance. However, we found two regions that overlap with previously identified loci associated with heat tolerance in Persian Gulf populations ofP. daedaleareinforcing the importance of these markers for heat tolerance. These results illustrate the importance of high heritability and the complexity of the genomic architecture underpinning host heat tolerance. These findings suggest that thisP. daedaleapopulation has the genetic prerequisites for adaptation to increasing temperatures. This study also provides knowledge for the development of high throughput genomic tools to screen for variation within and across populations to enhance adaptation through assisted gene flow and assisted migration.
Selective inhibition of histone deacetylase 1 and 3 improves motor phenotype and alleviates transcriptional dysregulation in Huntington’s disease mice
Authors: Hecklau Katharina , Mueller Susanne , Koch Stefan Paul , Mehkary Mustafa Hussain , Kilic Busra , Harms Christoph , Boehm-Sturm Philipp , Yildirim Ferah 
Published: October 2020

AbstractHuntington’s disease (HD) is an autosomal dominant neurodegenerative disease characterized by a late clinical onset of psychiatric, cognitive, and motor symptoms. Transcriptional dysregulation is an early and central disease mechanism which is accompanied by epigenetic alterations in HD. Previous studies demonstrated that targeting transcriptional changes by inhibition of histone deacetylases (HDACs), especially the class I HDACs, provides therapeutic effects. Yet, their exact mechanisms of action and the features of HD pathology, on which these inhibitors act remain to be elucidated. Here, using transcriptional profiling, we found that selective inhibition of HDAC1 and HDAC3 by RGFP109 repaired the expression of a number of genes, including the transcription factor genesNeurod2andNr4a2, and 43% of the gene sets that were dysregulated by mutant Huntingtin expression in the striatum and improved motor skill learning deficit in the R6/1 mouse model of HD. RGFP109-treated R6/1 mice showed improved coordination on the RotaRod over four consecutive trials, while vehicle-treated R6/1 animals displayed no improvement in coordination skills and fell 50 seconds earlier off the rod in the fourth trial. We also found, by volumetric MRI, a widespread brain atrophy in the R6/1 mice at the symptomatic disease stage, on which RGFP109 showed a modest effect. Collectively, our combined work presents new evidence for specific HDAC1 and HDAC3 inhibition as a therapeutic strategy for alleviating the phenotypic and molecular features of HD.