bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluation of saliva self-collection devices for SARS-CoV-2 diagnostics
Authors: Allicock Orchid M. , Petrone Mary E. , Yolda-Carr Devyn , Breban Mallery , Walsh Hannah , Watkins Anne E. , Rothman Jessica E. , Farhadian Shelli F. , Grubaugh Nathan D. , Wyllie Anne L. 
Published: February 2021

SummaryThere is an urgent need to expand testing for SARS-CoV-2 and other respiratory pathogens as the global community struggles to control the COVID-19 pandemic. Current diagnostic methods can be affected by supply chain bottlenecks and require the assistance of medical professionals, impeding the implementation of large-scale testing. Self-collection of saliva may solve these problems, as it can be completed without specialized training and uses generic materials. In this study, we observed thirty individuals who self-collected saliva using four different collection devices and analyzed their feedback. Two of these devices, a funnel and bulb pipette, were used to evaluate at-home saliva collection by 60 individuals. All devices enabled the safe, unsupervised self-collection of saliva. The quantity and quality of the samples received were acceptable for SARS-CoV-2 diagnostic testing, as determined by RNase P detection. Here, we demonstrate inexpensive, generic, buffer free collection devices suitable for unsupervised and home saliva self-collection.
PRINCIPLE trial demonstrates scope for in-pandemic improvement in primary care antibiotic stewardship
Authors: de Lusignan Simon , Joy Mark , Sherlock Julian , Tripathy Manasa , van Hecke Oliver , Gbinigie Oghenekome , Williams John , Butler Christopher , Hobbs FD Richard 
Published: February 2021

AbstractBackgroundThe Platform Randomised trial of INterventions against COVID-19 In older peoPLE (PRINCIPLE) trial has provided in-pandemic evidence of what does not work in the early primary care management of coronavirus-2019 disease (COVID-19). PRINCIPLE’s first finding was that azithromycin and doxycycline were not effective.AimTo explore the extent to which azithromycin and doxycycline were being used in-pandemic, and the scope for trial findings impacting on practice.Design and SettingWe compared crude rates of prescribing and respiratory tract infections (RTI) in 2020, the pandemic year, with 2019, using the Oxford-Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC).MethodsWe used a negative binomial model including age-band, gender, socioeconomic status, and NHS region to compare azithromycin and doxycycline lower respiratory tract infections (LRTI), upper respiratory tract infections (URTI), and influenza-like-illness (ILI) in 2020 with 2019; reporting incident rate ratios (IRR) between years and 95% confidence intervals (95%CI).ResultsAzithromycin prescriptions increased 7% in 2020 compared to 2019, whereas doxycycline decreased by 7%. Concurrently, LRTI and URTI incidence fell by over half (58.3% and 54.4% respectively) while ILI rose slightly (6.4%). The overall percentage of RTI prescribed azithromycin rose by 42.1% between 2019 and 2020, doxycycline increased by 33%.Our adjusted IRR showed azithromycin prescribing was 22% higher in 2020 (IRR=1.22, 95%CI:1.19-1.26, p<0.0001), for every unit rise in confirmed COVID there was an associated 3% rise in prescription (IRR=1.026, 95%CI 1.024-1.0285, p<0.0001); whereas these measures were static for doxycycline.ConclusionPRINCIPLE trial flags scope for improvement in antimicrobial stewardship.
Point-of-care evaluation of a rapid antigen test (CLINITEST® Rapid COVID-19 Antigen Test) for diagnosis of SARS-CoV-2 infection in symptomatic and asymptomatic individuals
Authors: Torres Ignacio , Poujois Sandrine , Albert Eliseo , Álvarez Gabriela , Colomina Javier , Navarro David 
Published: February 2021

AbstractRapid antigen assays (RAD) based on lateral flow immunochromatography (LFIC) technology have emerged as a valuable tool for the control of COVID-19 pandemic. Manufacturer□independent, real□world evaluation of these assays is crucial given the considerable heterogeneity reported in their clinical and analytical performances. Here, we report for the first time on the point-of-care performance of the CLINITEST® Rapid COVID-19 Antigen Test (Siemens, Healthineers, Erlangen, Germany) to detect SARS-CoV-2 infection in presumptive COVID-19 cases or asymptomatic close contacts of COVID-19 patients. When compared to RT-PCR, the overall sensitivity of the assay was 80.2 (95% CI, 70.9-87.1) for symptomatic patients sampled (nasopharyngeal specimens) within five days after the onset of symptoms and 60% (95% CI, 40.7-76.6%) for asymptomatic participants. The overall specificity was 100% in both population groups.
Role of Inflammation in Depression and Anxiety: Tests for Disorder Specificity, Linearity and Potential Causality of Association in the UK Biobank
Authors: Ye Zheng , Kappelmann Nils , Moser Sylvain , Smith George Davey , Burgess Stephen , Jones Peter B. , Khandaker Golam M. 
Published: February 2021

ABSTRACTBackgroundConcentrations of C-reactive protein (CRP), interleukin 6 (IL-6) and other inflammatory markers are elevated in people with depression and anxiety compared to controls, but evidence for disorder-specificity, linearity and potential causality is sparse.MethodsUsing data from up to 144,890 UK Biobank cohort participants, we tested associations of circulating CRP concentrations with depression and anxiety symptom scores and probable diagnosis, including tests for linearity, disorder-specificity and sex difference. We examined potential causality using 1-sample and 2-sample Mendelian randomisation (MR) analyses testing associations of genetically-predicted CRP concentration and IL-6 activity with depression and anxiety.FindingsCRP concentration was associated with depressive and anxiety symptom scores and with probable diagnoses of depression and generalised anxiety disorder (GAD) in a dose-response fashion. These associations were stronger for depression than for anxiety, and for women than for men although less consistently. MR analyses provided consistent results suggesting that genetically predicted higher IL-6 activity was associated with increased risk for depressive symptoms, while genetically-predicted higher CRP concentration was associated with decreased risks of depressive and anxiety symptoms.InterpretationAltered activity of the IL-6/IL-6R pathway could be causally linked to depression. The field now requires experimental studies of IL-6 modulation in humans and animal models to further examine causality, mechanisms and treatment potential. Such studies are also needed to elucidate mechanisms for divergent associations of genetically-predicted higher IL-6 activity (risk increasing) and higher CRP concentrations (protective) with depression/anxiety.FundingMQ (MQDS17/40); Wellcome Trust (201486/Z/16/Z).
The mutation profile of SARS-CoV-2 is primarily shaped by the host antiviral defense
Authors: Azgari Cem , Kilinc Zeynep , Turhan Berk , Circi Defne , Adebali Ogun 
Published: February 2021

AbstractUnderstanding SARS-CoV-2 evolution is a fundamental effort in coping with the COVID-19 pandemic. The virus genomes have been broadly evolving due to the high number of infected hosts world-wide. Mutagenesis and selection are the two inter-dependent mechanisms of virus diversification. However, which mechanisms contribute to the mutation profiles of SARS-CoV-2 remain under-explored. Here, we delineate the contribution of mutagenesis and selection to the genome diversity of SARS-CoV-2 isolates. We generated a comprehensive phylogenetic tree with representative genomes. Instead of counting mutations relative to the reference genome, we identified each mutation event at the nodes of the phylogenetic tree. With this approach, we obtained the mutation events that are independent of each other and generated the mutation profile of SARS-CoV-2 genomes. The results suggest that the heterogeneous mutation patterns are mainly reflections of host (i) antiviral mechanisms that are achieved through APOBEC, ADAR, and ZAP proteins and (ii) probable adaptation against reactive oxygen species.ImportanceSARS-CoV-2 genomes are evolving worldwide. Revealing the evolutionary characteristics of SARS-CoV-2 is essential to understand host-virus interactions. Here, we aim to understand whether mutagenesis or selection is the primary driver of SARS-CoV-2 evolution. This study provides an unbiased computational method for profiling and analyzing independently occurring SARS-CoV-2 mutations. The results point out three host antiviral mechanisms shaping the mutational profile of SARS-CoV-2 through APOBEC, ADAR, and ZAP proteins. Besides, reactive oxygen species might have an impact on the SARS-CoV-2 mutagenesis.
14-3-3ζ-depletion impairs mammary gland development in the mouse
Authors: Poltavets Valentina , Esmaeili Zahra , Boyle Sarah T. , Ramshaw Hayley S. , Lopez Angel F. , Kochetkova Marina , Samuel Michael S. 
Published: February 2021

AbstractThe 14-3-3 family of proteins have roles in regulating several key cellular processes. While their significant structural and functional homology had informed the idea that these proteins acted redundantly, it is now becoming clear that individual family members may have tissue and context specific functions, highlighting the need for a more nuanced understanding of these important proteins. Here, we demonstrate that mice deficient in 14-3-3ζ exhibit developmental defects of the mammary epithelium, associated with dysregulation of key transcription factors involved in the maintenance of mammary stem cell populations. We believe that this model will be prove useful for investigating the role of 14-3-3ζ in the maintenance of mammary stem cell populations and elucidating the transcriptional networks driving specification of the mammary epithelium.
Tig1 regulates proximo-distal identity during salamander limb regeneration
Authors: Oliveira Catarina R. , Knapp Dunja , Elewa Ahmed , Gerber Tobias , Gonzalez Malagon Sandra G. , Gates Phillip B. , Walters Hannah E. , Petzold Andreas , Arce Hernan , Cordoba Rodrigo C. , Subramanian Elaiyaraja , Chara Osvaldo , Tanaka Elly M. , Simon András , Yun Maximina H. 
Published: February 2021

AbstractSalamander limb regeneration is an accurate process which gives rise exclusively to the missing structures, irrespective of the amputation level. This suggests that cells in the stump have an awareness of their spatial location, a property termed ‘positional identity’. Little is known about how positional identity is encoded, in salamanders or other biological systems. Through single-cell RNAseq analysis, we identified Tig1/Rarres1 as a potential determinant of proximal identity. Tig1 encodes a conserved cell surface molecule, is regulated by retinoic acid and exhibits a graded expression along the proximo-distal axis of the limb. Its overexpression leads to regeneration defects in the distal elements and elicits proximal displacement of blastema cells, while its neutralisation blocks proximo-distal cell surface interactions. Critically, Tig1 reprogrammes distal cells to a proximal identity, upregulating Prod1 and inhibiting Hoxa13 and distal transcriptional networks. Thus, Tig1 is a central cell surface determinant of proximal identity in the salamander limb.
Allogeneic CAR-invariant Natural Killer T Cells Exert Potent Antitumor Effects Through Host CD8 T Cell Cross-Priming
Authors: Simonetta Federico , Lohmeyer Juliane K. , Hirai Toshihito , Maas-Bauer Kristina , Alvarez Maite , Wenokur Arielle S. , Baker Jeanette , Aalipour Amin , Ji Xuhuai , Haile Samuel , Mackall Crystal L. , Negrin Robert S. 
Published: February 2021

AbstractThe development of allogeneic chimeric antigen receptor (CAR) T cell therapies for off-the-shelf use is a major goal yet faces two main immunological challenges, namely the risk of graft-versus-host-disease (GvHD) induction by the transferred cells and the rejection by the host immune system limiting their persistence. We demonstrate that allogeneic CAR-engineered invariant natural killer T (iNKT) cells, a cell population without GvHD-induction potential that displays immunomodulatory properties, exerted potent direct and indirect antitumor activity in murine models of B-cell lymphoma when administered across major MHC-barriers. In addition to their known direct cytotoxic effect, allogeneic CAR iNKT cells induced tumor-specific antitumor immunity through host CD8 T cell cross-priming, resulting in a potent antitumor effect lasting longer than the physical persistence of the allogeneic cells. The utilization of off-the-shelf allogeneic CAR iNKT cells could meet significant unmet needs in the clinic.
A modular platform for engineering function of natural and synthetic biomolecular condensates
Authors: Lasker Keren , Boeynaems Steven , Lam Vinson , Stainton Emma , Jacquemyn Maarten , Daelemans Dirk , Villa Elizabeth , Holehouse Alex S. , Gitler Aaron D. , Shapiro Lucy 
Published: February 2021

AbstractPhase separation is emerging as a universal principle for how cells use dynamic subcompartmentalization to organize biochemical reactions in time and space1,2. Yet, whether the emergent physical properties of these biomolecular condensates are important for their biological function remains unclear. The intrinsically disordered protein PopZ forms membraneless condensates at the poles of the bacteriumCaulobacter crescentusand selectively sequesters kinase-signaling cascades to regulate asymmetric cell division3–5. By dissecting the molecular grammar underlying PopZ phase separation, we find that unlike many eukaryotic examples, where unstructured regions drive condensation6,7, a structured domain of PopZ drives condensation, while conserved repulsive features of the disordered region modulate material properties. By generating rationally designed PopZ mutants, we find that the exact material properties of PopZ condensates directly determine cellular fitness, providing direct evidence for the physiological importance of the emergent properties of biomolecular condensates. Our work codifies a clear set of design principles illuminating how sequence variation in a disordered domain alters the function of a widely conserved bacterial condensate. We used these insights to repurpose PopZ as a modular platform for generating synthetic condensates of tunable function in human cells.
Impact of the B.1.1.7 variant on neutralizing monoclonal antibodies recognizing diverse epitopes on SARS-CoV-2 Spike
Authors: Graham Carl , Seow Jeffrey , Huettner Isabella , Khan Hataf , Kouphou Neophytos , Acors Sam , Winstone Helena , Pickering Suzanne , Galao Rui Pedro , Lista Maria Jose , Jimenez-Guardeno Jose M , Laing Adam G. , Wu Yin , Joseph Magdalene , Muir Luke , Ng Weng M. , Duyvesteyn Helen M. E. , Zhao Yuguang , Bowden Thomas A. , Shankar-Hari Manu , Rosa Annachiara , Cherepanov Peter , McCoy Laura E. , Hayday Adrian C. , Neil Stuart J.D. , Malim Michael H. , Doores Katie J. 
Published: February 2021

AbstractThe interaction of the SARS-CoV-2 Spike receptor binding domain (RBD) with the ACE2 receptor on host cells is essential for viral entry. RBD is the dominant target for neutralizing antibodies and several neutralizing epitopes on RBD have been molecularly characterized. Analysis of circulating SARS-CoV-2 variants has revealed mutations arising in the RBD, the N-terminal domain (NTD) and S2 subunits of Spike. To fully understand how these mutations affect the antigenicity of Spike, we have isolated and characterized neutralizing antibodies targeting epitopes beyond the already identified RBD epitopes. Using recombinant Spike as a sorting bait, we isolated >100 Spike-reactive monoclonal antibodies from SARS-CoV-2 infected individuals. ~45% showed neutralizing activity of which ~20% were NTD-specific. None of the S2-specific antibodies showed neutralizing activity. Competition ELISA revealed that NTD-specific mAbs formed two distinct groups: the first group was highly potent against infectious virus, whereas the second was less potent and displayed glycan-dependant neutralization activity. Importantly, mutations present in B.1.1.7 Spike frequently conferred resistance to neutralization by the NTD-specific neutralizing antibodies. This work demonstrates that neutralizing antibodies targeting subdominant epitopes need to be considered when investigating antigenic drift in emerging variants.
Summix:A method for detecting and adjusting for population structure in genetic summary data
Authors: Arriaga-MacKenzie IS , Matesi G , Chen S , Ronco A , Marker KM , Hall JR , Scherenberg R , Khajeh-Sharafabadi M , Wu Y , Gignoux CR , Null M , Hendricks AE 
Published: February 2021

AbstractPublicly available genetic summary data have high utility in research and the clinic including prioritizing putative causal variants, polygenic scoring, and leveraging common controls. However, summarizing individual-level data can mask population structure resulting in confounding, reduced power, and incorrect prioritization of putative causal variants. This limits the utility of publicly available data, especially for understudied or admixed populations where additional research and resources are most needed. While several methods exist to estimate ancestry in individual-level data, methods to estimate ancestry proportions in summary data are lacking. Here, we present Summix, a method to efficiently deconvolute ancestry and provide ancestry-adjusted allele frequencies from summary data. Using continental reference ancestry, African (AFR), Non-Finnish European (EUR), East Asian (EAS), Indigenous American (IAM), South Asian (SAS), we obtain accurate and precise estimates (within 0.1%) for all simulation scenarios. We apply Summix to gnomAD v2.1 exome and genome groups and subgroups finding heterogeneous continental ancestry for several groups including African/African American (∼84% AFR, ∼14% EUR) and American/Latinx (∼4% AFR, ∼5% EAS, ∼43% EUR, ∼46% IAM). Compared to the unadjusted gnomAD AFs, Summix’s ancestry-adjusted AFs more closely match respective African and Latinx reference samples. Even on modern, dense panels of summary statistics, Summix yields results in seconds allowing for estimation of confidence intervals via block bootstrap. Given an accompanying R package, Summix increases the utility and equity of public genetic resources, empowering novel research opportunities.
Molecular dynamics simulation study reveals effects of key mutations on spike protein structure in SARS-CoV-2
Authors: Lon Jerome Rumdon , Xi Binbin , Zhong Bingxu , Zheng Yiyuan , Chen Zixi , Qiu Ruoran , Zhang Siqing , Guo Pei , Du Hongli 
Published: February 2021

SummarySARS-CoV-2 has been spreading rapidly since 2019 and has produced large-scale mutations in the genomes. The mutation in genes may lead to changes in protein structure, which would have a great impact on the epidemiological characteristics. In this study, we selected the key mutations of SARS-CoV-2 from a real-time monitoring tool, including D614G, A222V, N501Y, T716I, S982A, D1118H of spike (S) protein, and performed molecular dynamics (MD) simulations on single-site mutant D614G, double-site mutant D614G&A222V and penta-site mutant N501Y&D614G&T716I&S982A&D1118H to investigate their effects on protein structure and stability using molecular dynamics (MD) simulations. The results suggested that D614G improved the stability of S protein, while D614G&A222V and N501Y&D614G&T716I&S982A&D1118H showed an increased solvent accessible surface area and they might enhance the ability of protein to react with the outside environment. Our findings could complement the mechanistic link between genotype--phenotype--epidemiological characteristics in the study of SARS-CoV-2. We also found no significant difference between the antigenicity of S protein and the mutants through Ellipro, which may reference for vaccine development and application.
Bridging Between Material Properties Of Proteins And The Underlying Molecular Interactions
Authors: Song Guang 
Published: February 2021

AbstractIn this work, we develop a novel method that bridges between material properties of proteins, particularly the modulus of elasticity, and the underlying molecular interactions. To this end, we employ both an all-atom normal mode analysis (NMA) model with the CHARMM force field and an elastic solid model for proteins and protein interfaces. And the “bridge” between the two models is a common physical property that they both can predict: the magnitude of thermal vibrations. This connection allows one to calibrate the Young’s moduli of proteins and protein interface regions. We find that the elastic moduli of proteins are mostly in the range of a few Gpa to 10 Gpa, while the elastic moduli of the interface regions are about an order smaller. The work is significant as it represents the first attempt to systematically compute the moduli of elasticity of proteins from molecular interactions.
SamQL: A Structured Query Language and filtering tool for the SAM/BAM file format
Authors: Lee Christopher T , Maragkakis Manolis 
Published: February 2021

AbstractThe Sequence Alignment/Map Format Specification (SAM) is one of the most widely used file formats in computational biology today and several tools have been developed to process it and use it. It is a flexible file format, used by many bioinformaticians on a daily basis. Despite its flexibility, SAM encoded files can often be difficult to query and understand. As genomic data are rapidly growing, structured and efficient queries on data encoded in SAM/BAM files is becoming critical. Importantly, any new tools should be able to support existing large datasets without requiring any data transformations. Here we introduce SamQL, an SQL-like query language for the SAM format with intuitive syntax that supports complex and efficient queries on top of SAM/BAM files and that can replace commonly used Bash one-liners employed by many bioinformaticians. SamQL is a complete query language that we envision as a step to a structured database engine for genomics. SamQL is written in Go, taking advantage of modern multicore compute systems and is freely available as standalone program and as an open-source library released under an MIT license,https://github.com/maragkakislab/samql/.