bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of SARS-CoV-2 spike mutations on animal ACE2 usage and in vitro neutralization sensitivity
Authors: Yao Weitong , Ma Danting , Wang Haimin , Tang Xiaojuan , Du Chengzhi , Pan Hong , Li Chao , Lin Hua , Farzan Michael , Zhao Jincun , Li Yujun , Zhong Guocai 
Published: January 2021

AbstractThe emergence of SARS-CoV-2 variants poses greater challenges to the control of COVID-19 pandemic. Here, we parallelly investigated three important characteristics of seven SARS-CoV-2 variants, including two mink-associated variants, the B.1.617.1 variant, and the four WHO-designated variants of concerns (B.1.1.7, B.1.351, P.1, and B.1.617.2). We first investigated the ability of these variants to bind and use animal ACE2 orthologs as entry receptor. We found that, in contrast to a prototype variant, the B.1.1.7, B.1.351, and P.1 variants had significantly enhanced affinities to cattle, pig, and mouse ACE2 proteins, suggesting increased susceptibility of these species to these SARS-CoV-2 variants. We then evaluated in vitro neutralization sensitivity of these variants to four monoclonal antibodies in clinical use. We observed that all the variants were partially or completely resistant against at least one of the four tested antibodies, with B.1.351 and P.1 showing significant resistance to three of them. As ACE2-Ig is a broad-spectrum anti-SARS-CoV-2 drug candidate, we then evaluated in vitro neutralization sensitivity of these variants to eight ACE2-Ig constructs previously described in three different studies. All the SARS-CoV-2 variants were efficiently neutralized by these ACE2-Ig constructs. Interestingly, compared to the prototype variant, most tested variants including the variants of concern B.1.1.7, B.1.351, P.1, and B.1.617.2 showed significantly increased (up to ∼15-fold) neutralization sensitivity to ACE2-Ig constructs that are not heavily mutated in the spike-binding interface of the soluble ACE2 domain, suggesting that SARS-CoV-2 evolves toward better utilizing ACE2, and that ACE2-Ig is an attractive drug candidate for coping with SARS-CoV-2 mutations.
The successful use of volunteers to enhance NHS Test and Trace contact tracing of in-patients with Covid-19: a Pilot Study
Authors: Foster Rachel , Jones Bing , Carey Ian , Duda Andzelika , Reynolds Abigail , Czauderna Jack , Westran Alex ,   Consultant in Infectious Diseases Sheffield Teaching Hospital Foundation Trust
Published: January 2021

AbstractContact tracing in the UK for Covid-19 is performed by NHS Test and Trace (NHSTT) via telephone or email. This study estimates how many patients who have been admitted to hospital are not reached by NHSTT and the number of their contacts who were not advised to self-isolate.Medical Student volunteers conducted face to face interviews with patients diagnosed with Covid-19 on an infectious diseases ward. Data on their close contacts were sent to NHSTT.20 cases were enrolled. 13(65%) did not engage with NHSTT, 4(20%) because they had no positive PCR, 9(45%) because of severity of illness, language or intellectual difficulties. 49 close contacts were identified of whom 33(67%) were from cases who had not engaged with NHSTT. “Backwards” contacts tracing information was collected from 11(55%) cases and 8(40%) gave detailed information.These data suggest that NHSTT fails to engage nearly two thirds of Covid-19 in-patients and fails to advise two thirds of their close contacts to self isolate.Volunteers used face to face interviews to overcome false negative tests, illness and communication problems to identify both close contacts and data on sources of infection.
Ownership and COVID-19 in care homes for older people: A living systematic review of outbreaks, infections, and mortalities
Authors: Bach-Mortensen Anders Malthe , Verboom Ben , Movsisyan Ani , Esposti Michelle Degli 
Published: January 2021

AbstractBackgroundThe adult social care sector is increasingly outsourced to for-profit providers, who constitute the largest provider of care homes in many developed countries. During the COVID-19 pandemic, for-profit providers have been accused of failing their residents by prioritising profits over care, prevention, and caution, which has been reported to result in a higher prevalence of COVID-19 infections and deaths in for-profit care homes. Although many of these reports are anecdotal or based on news reports, there is a growing body of academic research investigating ownership variation across COVID-19 outcomes, which has not been systematically appraised and synthesised.ObjectivesTo identify, appraise, and synthesise the available research on ownership variation in COVID-19 outcomes (outbreaks, infections, deaths, shortage of personal protective equipment (PPE) and staff) across for-profit, public, and non-profit care homes for older people, and to update our findings as new research becomes available.DesignLiving systematic review.MethodsThis review was prospectively registered with Prospero (CRD42020218673). We searched 17 databases and performed forward and backward citation tracking of all included studies. Search results were screened and reviewed in duplicate. Risk of bias (RoB) was assessed in duplicate according to the COSMOS-E guidance. Data was extracted by ABM and independently validated. The results were synthesised by country, RoB, and model adjustments, and visualised using harvest plots.ResultsTwenty-nine studies across five countries were included, with 75% of included studies conducted in the Unites States. For-profit ownership was not consistently associated with a higher probability of a COVID-19 outbreak. However, there was compelling evidence of worse COVID-19 outcomes following an outbreak, with for-profit care homes having higher rates of accumulative infections and deaths. For-profit providers were also associated with shortages in PPE, which may have contributed to the higher incidence of infections and deaths in the early stages of the pandemic. Chain affiliation was often correlated with an increased risk of outbreak but was usually not reported to be associated with higher rates of deaths and infections.ConclusionFor-profit ownership was a consistent risk factor for higher cumulative COVID-19 infections and deaths in the first wave of the pandemic. Thus, ownership and the characteristics associated with FP care home providers may present key regulatable factors that can be addressed to improve health outcomes in vulnerable populations and reduce health disparities. This review will be updated as new research becomes published, which may change the conclusion of our synthesis.
UK osteopathic practice in 2019: a retrospective analysis of practice data
Authors: Plunkett Austin , Fawkes Carol , Carnes Dawn 
Published: January 2021

AbstractBackgroundThis study describes osteopathic activity, scope of practice and the osteopathic patient profile in order to understand the role osteopathy plays within the UK health system a decade after our previous survey.MethodWe used a retrospective questionnaire survey design to ask about osteopathic practice and audit patient case notes. All UK registered osteopaths were invited to participate in the survey.The survey was conducted using a web-based system. Each participating osteopath was asked about themselves, their practice and asked to randomly select and extract data from up to 8 random new patient health records during 2018. All patient related data were anonymised.ResultsThe survey response rate was 500 osteopaths (9.4% of the profession) who provided information about 395 patients and 2,215 consultations.Most osteopaths were self-employed (81.1%; 344/424 responses) working alone either exclusively or often (63.9%; 237/371) and were able to offer 48.6% of patients an appointment within 3 days (184/379).Patient ages ranged from 1 month to 96 years (mean 44.7 years, Std Dev. 21.5), of these 58.4% (227/389) were female. Infants <1 years old represented 4.8% (18/379) of patients.The majority of patients presented with musculoskeletal complaints (81.0%; 306/378). Persistent complaints (present for more than 12 weeks before appointment) were the most common (67.9%; 256/377) and 41.7% (156/374) of patients had co-existing medical conditions. The most common treatment approaches used at the first appointment were soft-tissue techniques (73.9%; 292/395), articulatory techniques (69.4%; 274/395) and high velocity low amplitude thrust (34.4%; 136/395). The mean number of treatments per patient was 7 (mode 4).ConclusionTo better understand the role of osteopathy in UK health service delivery, the profession needs to do more research with patients in order to understand their needs and their expected outcomes of care, and for this to inform osteopathic practice and education.
Differential contribution of two organelles of endosymbiotic origin to iron-sulfur cluster synthesis and overall fitness in Toxoplasma
Authors: Pamukcu Sarah , Cerutti Aude , Bordat Yann , Hem Sonia , Rofidal Valerie , Besteiro Sebastien 
Published: January 2021

AbstractIron-sulfur (Fe-S) clusters are one of the most ancient and ubiquitous prosthetic groups, and they are required by a variety of proteins involved in important metabolic processes. Apicomplexan parasites have inherited different plastidic and mitochondrial Fe-S clusters biosynthesis pathways through endosymbiosis. We have investigated the relative contributions of these pathways to the fitness ofToxoplasma gondii, an apicomplexan parasite causing disease in humans, by generating specific mutants. Phenotypic analysis and quantitative proteomics allowed us to highlight notable differences in these mutants. Both Fe-S cluster synthesis pathways are necessary for optimal parasite growth in vitro, but their disruption leads to markedly different fates: impairment of the plastidic pathway leads to a loss of the organelle and to parasite death, while disruption of the mitochondrial pathway trigger differentiation into a stress resistance stage. This highlights that otherwise similar biochemical pathways hosted by different sub-cellular compartments can have very different contributions to the biology of the parasites, which is something to consider when exploring novel strategies for therapeutic intervention.Author summaryToxoplasma gondiiis a ubiquitous unicellular parasite that harbours two organelles of endosymbiotic origin: the mitochondrion, and a relict plastid named the apicoplast. Each one of these organelles contains its own machinery for synthesizing iron-sulfur clusters, which are important protein co- factors. In this study, we show that interfering with either the mitochondrial or the plastidic iron- sulfur cluster synthesizing machinery has a profound impact on parasite growth. However, while disrupting the plastidic pathway led to an irreversible loss of the organelle and subsequent death of the parasite, disrupting the mitochondrial pathway led to conversion of the parasites into a stress resistance form. We used a comparative quantitative proteomic analysis of the mutants, combined with experimental validation, to provide mechanistic clues into these different phenotypic outcomes. Although the consequences of disrupting each pathway were manifold, our data highlighted distinct changes at the metabolic level. For instance, the plastidic iron-sulfur cluster synthesis pathway is likely important for maintaining the lipid homeostasis of the parasites, while the mitochondrial pathway is clearly crucial for maintaining their respiratory capacity. Interestingly, we have discovered that other mutants severely impacted for mitochondrial function, in particular the respiratory chain, are able to survive and initiate conversion to the stress resistance form. This illustrates a different capacity forT. gondiito adapt for survival in response to distinct metabolic dysregulations.
Lasting effects of a single psilocybin dose on resting-state functional connectivity in healthy individuals
Authors: McCulloch Drummond E-Wen , Madsen Martin Korsbak , Stenbæk Dea Siggard , Kristiansen Sara , Ozenne Brice , Jensen Peter Steen , Knudsen Gitte Moos , Fisher Patrick MacDonald 
Published: January 2021

ABSTRACTBackgroundPsilocybin is a psychedelic drug that has shown lasting positive effects on clinical symptoms and self-reported well-being following a single dose. There has been little research into the long-term effects of psilocybin on brain connectivity in humans.AimsEvaluate changes in resting-state functional connectivity (RSFC) at one-week and three-months after one psilocybin dose in 10 healthy psychedelic-naïve volunteers and explore associations between change in RSFC and related measures.MethodsParticipants received 0.2-0.3 mg/kg psilocybin in a controlled setting. Participants completed resting-state fMRI scans at baseline, one-week and three-months post-administration and [11C]Cimbi-36 PET scans at baseline and one-week. We examined changes in within-network, between-network and region-to-region RSFC. We explored associations between changes in RSFC and psilocybin-induced phenomenology as well as changes in psychological measures and neocortex serotonin 2A receptor binding.ResultsPsilocybin was well tolerated and produced positive changes in well-being. At one-week only, executive control network (ECN) RSFC was significantly decreased (Cohen’s d=-1.73, pFWE=0.010). We observed no other significant changes in RSFC at one-week or three-months, nor changes in region-to-region RSFC. Exploratory analyses indicated that decreased ECN RSFC at one-week predicted increased mindfulness at three-months (r =-0.65).ConclusionsThese findings in a small cohort indicate that psilocybin affects ECN function within the psychedelic “afterglow” period. Our findings implicate ECN modulation as mediating psilocybin-induced, long-lasting increases in mindfulness. Although our findings implicate a neural pathway mediating lasting psilocybin effects, it is notable that changes in neuroimaging measures at three-months, when personality changes are observed, remain to be identified.
A quick and versatile protocol for the 3D visualization of transgene expression across the whole body of larvalDrosophila
Authors: Kobler Oliver , Weiglein Aliće , Hartung Kathrin , Chen Yi-chun , Gerber Bertram , Thomas Ulrich 
Published: January 2021

AbstractLarvalDrosophilaare used as a genetically accessible study case in many areas of biological research. Here we report a fast, robust and user-friendly procedure for the whole-body multifluorescence imaging ofDrosophilalarvae; the protocol has been optimized specifically for larvae by systematically tackling the pitfalls associated with clearing this small but cuticularized organism. Tests on various fluorescent proteins reveal that the recently introduced monomeric infrared fluorescent protein (mIFP) is particularly suitable for our approach. This approach comprises an effective, low-cost clearing protocol with minimal handling time and reduced toxicity in the reagents employed. It combines a success rate high enough to allow for small-scale screening approaches and a resolution sufficient for cellular-resolution analyses with light sheet and confocal microscopy. Given that publications and database documentations typically specify expression patterns of transgenic driver lines only within a given organ system of interest, the present procedure should be versatile enough to extend such documentation systematically to the whole body. As examples, the expression patterns of transgenic driver lines covering the majority of neurons, or subsets of chemosensory, central brain or motor neurons, are documented in the context of whole larval body volumes (using nsyb-Gal4, IR76b-Gal4, APL-Gal4 and mushroom body Kenyon cells, or OK371-Gal4, respectively). Notably, the presented protocol allows for triple-color fluorescence imaging with near-infrared, red and yellow fluorescent proteins.
Sex-dependent gene regulation of human atherosclerotic plaques by DNA methylation and transcriptome integration points to smooth muscle cell involvement in women
Authors: Hartman Robin J. G. , Siemelink Marten A. , Haitjema Saskia , Dekkers Koen F. , Slenders Lotte , Boltjes Arjan , Mokry Michal , Timmerman Nathalie , de Borst Gert J. , Heijmans Bastiaan T. , Asselbergs Folkert W. , Pasterkamp Gerard , van der Laan Sander W. , den Ruijter Hester M. 
Published: January 2021

AbstractSex differences are evident in the clinical presentation and underlying histology of atherosclerotic disease with women developing more stable atherosclerotic lesions than men. It is unknown whether this is explained by sex differences in gene regulation in cellular compartments of atherosclerotic plaques. To study sex differences in gene regulation we performed genome-wide DNA methylation and transcriptomics analysis on plaques of 485 carotid endarterectomy patients (31% female). Sex-differential DNA methylation at 4,848 sites in the autosome was enriched for cell-fate commitment and developmental processes, and its deconvolution predicted more smooth muscle cells in females, as compared to more immune cells in males. RNA-sequencing of the same plaques corroborated the sex differences in DNA methylation predicted cell-types, in which genes that were higher expressed in females were enriched for TGF-beta signaling and extracellular matrix biology. In addition, female-biased genes were enriched for targeting by regulatory loci based on sex differential methylation. Lastly, by using single-cell RNA sequencing we showed that these female-biased genes are mostly expressed in smooth muscle cells, and higher expressed in smooth muscle cells from female (predominantly stable) plaques as compared to male (relatively unstable) plaques. Our approach identified female-biased genes in smooth muscle cells in fibrous atherosclerotic plaques. This points towards new mechanisms in smooth muscle cell biology of stable atherosclerotic plaques and offers new directions for research to develop new sex-specific therapeutics for atherosclerotic disease.
Interpretable prioritization of splice variants in diagnostic next-generation sequencing
Authors: Danis Daniel , Jacobsen Julius O.B. , Carmody Leigh , Gargano Michael , McMurry Julie A , Hegde Ayushi , Haendel Melissa A , Valentini Giorgio , Smedley Damian , Robinson Peter N 
Published: January 2021

ABSTRACTA critical challenge in genetic diagnostics is the computational assessment of candidate splice variants, specifically the interpretation of nucleotide changes located outside of the highly conserved dinucleotide sequences at the 5′ and 3′ ends of introns. To address this gap, we developed the Super Quick Informationcontent Random-forest Learning of Splice variants (SQUIRLS) algorithm. SQUIRLS generates a small set of interpretable features for machine learning by calculating the information-content (IC) of wildtype and variant sequences of canonical and cryptic splice sites, assessing changes in candidate splicing regulatory sequences, and incorporating characteristics of the sequence such as exon length, disruptions of the AG exclusion zone, and conservation. We curated a comprehensive collection of disease-associated splicealtering variants at positions outside of the highly conserved AG/GT dinucleotides at the termini of introns. SQUIRLS trains two random-forest classifiers for the donor and for the acceptor and combines their outputs by logistic regression to yield a final score. We show that SQUIRLS transcends previous state of the art accuracy in classifying splice variants as assessed by rank analysis in simulated exomes and is significantly faster than competing methods. SQUIRLS provides tabular output files for incorporation into diagnostic pipelines for exome and genome analysis, as well as visualizations that contextualize predicted effects of variants on splicing to make it easier to interpret splice variants in diagnostic settings
Strobemers: an alternative to k-mers for sequence comparison
Authors: Sahlin Kristoffer 
Published: January 2021

K-mer-based methods are widely used in bioinformatics for various types of sequence comparison. However, a single mutation will mutatekconsecutive k-mers and makes most k-mer based applications for sequence comparison sensitive to variable mutation rates. Many techniques have been studied to overcome this sensitivity,e.g., spaced k-mers and k-mer permutation techniques, but these techniques do not handle indels well. For indels, pairs or groups of small k-mers are commonly used, but these methods first produce k-mer matches, and only in a second step, a pairing or grouping of k-mers is performed. Such techniques produce many redundant k-mer matches due to the size ofk.Here, we proposestrobemersas an alternative to k-mers for sequence comparison. Intuitively, strobemers consist of linked minimizers. We use simulated data to show that strobemers provide more evenly distributed sequence matches and are less sensitive to different mutation rates than k-mers and spaced k-mers. Strobemers also produce a higher match coverage across sequences. We further implement a proof-of-concept sequence matching tool StrobeMap, and use synthetic and biological Oxford Nanopore sequencing data to show the utility of using strobemers for sequence comparison in different contexts such as sequence clustering and alignment scenarios. A reference implementation of our tool StrobeMap together with code for analyses is available athttps://github.com/ksahlin/strobemers.
Organelle bottlenecks facilitate evolvability by traversing heteroplasmic fitness valleys
Authors: Radzvilavicius Arunas L. , Johnston Iain G. 
Published: January 2021

AbstractBioenergetic organelles – mitochondria and plastids – retain their own genomes, and these organelle DNA (oDNA) molecules are vital for eukaryotic life. Like all genomes, oDNA must be able to evolve to suit new environmental challenges. However, mixed oDNA populations can challenge cellular bioenergetics, providing a penalty to the appearance and adaptation of new mutations. Here we show that organelle ‘bottlenecks’, mechanisms increasing cell-to-cell oDNA variability during development, can overcome this mixture penalty and facilitate the adaptation of beneficial mutations. We show that oDNA heteroplasmy and bottlenecks naturally emerge in evolutionary simulations subjected to fluctuating environments, demonstrating that this evolvability is itself evolvable. Usually thought of as a mechanism to clear damaging mutations, organelle bottlenecks therefore also resolve the tension between intracellular selection for pure oDNA populations and the ‘bet-hedging’ need for evolvability and adaptation to new environments. This general theory suggests a reason for the maintenance of organelle heteroplasmy in cells, and may explain some of the observed diversity in organelle maintenance and inheritance across taxa.
Network Pharmacology Analysis of the active components and anticancer targets of Rhubarb
Authors: Junrui Hu , Yongqiang Duan , Gongning Cui , Qiang Luo , Shanshan Xi , Rui Huang , Jun Ma , Min Bai , Hongyan Wu 
Published: January 2021

AbstractTo investigate the mechanisms and active components governing the anticancer activity of rhubarb.The TCMSP database was screened to identify the active components of rhubarb and Swiss target predictions were generated to predict their cellular targets. TTD and OMIM databases were used to predict tumor-related target genes. "Cytoscape" was used to construct drug targets. PPI network analysis, GO enrichment analysis and KEGG pathway analysis of the key targets were investigated using String and David databases. A total of 33 components and 116 corresponding targets were screened. Amongst them, the key active compounds in rhubarb included emodin, aloe emodin, β-sitosterol, emodin methyl ether and rhein, which were predicted to target TP53, AKT1, STAT3, PIK3CA, HRAS, and VEGFA. GO analysis revealed that the cellular targets clustered into 159 biological processes, including those involved in cellular composition (n=24) and molecular functions (n=42, P<0.01). KEGG pathway analysis revealed 85 (P < 0.01) pathways related to cancer. The active compounds in rhubarb target TP53, AKT1 and PIK3CA. Rhubarb therefore regulates cancer development through an array of biological pathways.