bluuebunny/crossref_metadata_2025_split huggingface dataset:
SARS-CoV-2 Breakthrough Infections in Fully Vaccinated Individuals
Authors: Ramirez Esteban , Wilkes Rebecca P. , Carpi Giovanna , Dorman Jack , Bowen Craig , Smith Lisa 
Published: June 2021

AbstractImportanceWhile COVID-19 vaccines are highly effective against disease, breakthrough infections may occur in the context of rising variants of concern.ObjectiveWe paired random and passive surveillance nucleic acid testing with analysis of viral whole genomic sequences to detect and describe breakthrough infections, focusing in a university community.DesignAnterior nasal swabs were collected from individuals for a nucleic acid amplification test (NAAT) for detection of SARS-CoV-2. A subset of NAAT positive samples was sequenced to determine variants associated with infections. Included in the testing and sequencing protocol were individuals that were fully vaccinated.SettingThis study was performed as part of a surveillance program for SARS-CoV-2 on a university campus with 49,700 students and employees.ParticipantsSurveillance testing was random and included approximately 10% of the population each week. Additionally, individuals self-identified with COVID-19 related symptoms or those that had close contact with SARS-CoV-2 positive individuals were also tested.
Predicting age from 100,000 one week-long 100Hz wrist accelerometer records of physical activity
Authors: Le Goallec Alan , Collin Sasha , Jabri M’Hamed , Diai Samuel , Vincent Théo , Patel Chirag J. 
Published: June 2021

AbstractPhysical activity improves quality of life, physical health and mental health, and is also an important protective factor against highly prevalent age-related diseases such as cardiovascular diseases, diabetes, cancer and mental health. With age, physical activity tends to decrease, leading down a vicious cycle that increases vulnerability to disease in the elderly. In the following, we trained neural network architectures to predict age from 115,456 one week-long 100Hz wrist accelerometer recordings from the UK Biobank (R-Squared=63.5±2.4%; root mean squared error=4.7±0.1 years). We achieved this performance by preprocessing the raw data as 2,271 scalar features, 113 time series and four images. We also considered the raw signal at different time scales (weekly activity patterns vs. gait). We then defined accelerated aging for a participant as being predicted older than one’s actual age and aimed to characterize these participants. We performed a genome wide association on the accelerated aging phenotypes to estimate its heritability (h_g2=12.3±0.9%) and identified nine single nucleotide polymorphisms in seven genes associated with it (e.g HIST1H4L, involved in chromatin organization). Similarly, we identified biomarkers (e.g blood pressure), clinical phenotypes (e.g chest pain), diseases (e.g hypertension), environmental (e.g smoking) and socioeconomic (e.g income and education) variables associated with accelerated aging. We conclude that physical activity-derived biological age is a complex phenotype with both genetic and non-genetic factors.
Population disruption: estimating changes in population distribution of the UK during the COVID-19 pandemic
Authors: Gibbs Hamish , Waterlow Naomi R , Cheshire James , Danon Leon , Liu Yang , Grundy Chris , Kucharski Adam J. ,   LSHTM CMMID COVID-19 Working Group, Eggo Rosalind M. 
Published: June 2021

AbstractMobility data have demonstrated major changes in human movement patterns in response to COVID-19 and associated interventions in many countries. This can involve sub-national redistribution, short-term relocations as well as international migration. In this paper, we combine detailed location data from Facebook measuring the location of approximately 6 million daily active Facebook users in 5km2 tiles in the UK with census-derived population estimates to measure population mobility and redistribution. We provide time-varying population estimates and assess spatial population changes with respect to population density and four key reference dates in 2020 (First lockdown, End of term, Beginning of term, Christmas). We also show how population estimates derived from the distribution of Facebook users vary compared to mid-2020 small area population estimates by the UK national statistics agencies. We estimate that between March 2020 and March 2021, the total population of the UK declined and we identify important spatial variations in this population change, showing that low-density areas have experienced lower population decreases than urban areas. We estimate that, for the top 10% highest population tiles, the population has decreased by 6.6%. Further, we provide evidence that geographic redistributions of population within the UK coincide with dates of non-pharmaceutical interventions including lockdowns and movement restrictions, as well as seasonal patterns of migration around holiday dates. The methods used in this study reveal significant changes in population distribution at high spatial and temporal resolutions that have not previously been quantified by available demographic surveys in the UK. We found early indicators of potential longer-term changes in the population distribution of the UK although it is not clear if these changes may persist after the COVID-19 pandemic.
Diversity ofTreponema denticolaand other oral treponeme lineages in subjects with periodontitis and gingivitis
Authors: Zeng Huihui , Chan Yuki , Gao Wenling , Leung W. Keung , Watt Rory M. 
Published: June 2021

AbstractMore than 75 species/species-level phylotypes of taxa belonging to the genusTreponemainhabit the human oral cavity.Treponema denticolais commonly associated with periodontal disease, but the etiological roles and ecological distributions of other oral treponemes remain more obscure. Here, we compared the clinical distributions of phylogroup 1 and 2 oral treponemes in subgingival plaque sampled from Chinese subjects with periodontitis (n=10) and gingivitis (n=8), via the sequence analysis of the highly-conservedpyrH‘housekeeping’ gene. Two PCR primer sets that respectively targeted oral phylogroup 1 and 2 treponemepyrHgenes were used to construct plasmid clone-amplicon libraries for each subject, which were sequenced for bioinformatic analysis. 1,204 quality-filtered, full-lengthpyrHgene sequences were obtained from the cohort (median: 61.5; range: 59-83 of clonedpyrHsequences per subject), which were assigned to 34 ‘pyrHgenotypes’ (pyrH001-pyrH034; 97% sequence-identity cut-off). 18pyrHgenotypes (536pyrHsequences) corresponded to phylogroup 1 treponeme taxa (includingTreponema vincentii, Treponema medium). 16 pyrH genotypes (668pyrHsequences) corresponded toT. denticolaand other phylogroup 2 treponemes. Periodontitis subjects contained a greater diversity of phylogroup 2pyrHgenotypes, compared to gingivitis subjects (Mann-Whitney U-test). OneT. denticola pyrHgenotype (pyrH001) was highly prevalent: detected in 10/10 periodontitis and 6/8 gingivitis subjects. Several subjects harboured multipleT. denticola pyrHgenotypes. Non-metric multidimensional scaling and PERMANOVA tests revealed no significant differences in overallpyrHgenotype compositions between periodontitis and gingivitis subjects. In conclusion, our results clearly show that subjects with periodontitis and gingivitis commonly harbour highly-diverse oral treponeme communities.
Drug repurposing based on a Quantum-Inspired method versus classical fingerprinting uncovers potential antivirals against SARS-CoV-2 including vitamin B12
Authors: Jimenez-Guardeño Jose M. , Ortega-Prieto Ana Maria , Moreno Borja Menendez , Maguire Thomas J.A. , Richardson Adam , Diaz-Hernandez Juan Ignacio , Perez Javier Diez , Zuckerman Mark , Playa Albert Mercadal , Deline Carlos Cordero , Malim Michael H. , Martinez-Nunez Rocio T 
Published: June 2021

AbstractThe COVID-19 pandemic has accelerated the need to identify new therapeutics at pace, including through drug repurposing. We employed a Quadratic Unbounded Binary Optimization (QUBO) model, to search for compounds similar to Remdesivir (RDV), the only antiviral against SARS-CoV-2 currently approved for human use, using a quantum-inspired device. We modelled RDV and compounds present in the DrugBank database as graphs, established the optimal parameters in our algorithm and resolved the Maximum Weighted Independent Set problem within the conflict graph generated. We also employed a traditional Tanimoto fingerprint model. The two methods yielded different lists of compounds, with some overlap. While GS-6620 was the top compound predicted by both models, the QUBO model predicted BMS-986094 as second best. The Tanimoto model predicted different forms of cobalamin, also known as vitamin B12. We then determined the half maximal inhibitory concentration (IC50) values in cell culture models of SARS-CoV-2 infection and assessed cytotoxicity. Lastly, we demonstrated efficacy against several variants including SARS-CoV-2 Strain England 2 (England 02/2020/407073), B.1.1.7 (Alpha), B.1.351 (Beta) and B.1.617.2 (Delta). Our data reveal that BMS-986094 and different forms of vitamin B12 are effective at inhibiting replication of all these variants of SARS-CoV-2. While BMS-986094 can cause secondary effects in humans as established by phase II trials, these findings suggest that vitamin B12 deserves consideration as a SARS-CoV-2 antiviral, particularly given its extended use and lack of toxicity in humans, and its availability and affordability. Our screening method can be employed in future searches for novel pharmacologic inhibitors, thus providing an approach for accelerating drug deployment.
Intrinsic and extrinsic regulation of human fetal bone marrow haematopoiesis and perturbations in Down syndrome
Authors: Jardine Laura , Webb Simone , Goh Issac , Londoño Mariana Quiroga , Reynolds Gary , Mather Michael , Olabi Bayanne , Stephenson Emily , Botting Rachel A. , Horsfall Dave , Engelbert Justin , Maunder Daniel , Mende Nicole , Murnane Caitlin , Dann Emma , McGrath Jim , King Hamish , Kucinski Iwo , Queen Rachel , Carey Christopher D , Shrubsole Caroline , Poyner Elizabeth , Acres Meghan , Jones Claire , Ness Thomas , Coulthard Rowan , Elliott Natalina , O’Byrne Sorcha , Haltalli Myriam L. R. , Lawrence John E , Lisgo Steven , Balogh Petra , Meyer Kerstin B , Prigmore Elena , Ambridge Kirsty , Jain Mika Sarkin , Efremova Mirjana , Pickard Keir , Creasey Thomas , Bacardit Jaume , Henderson Deborah , Coxhead Jonathan , Filby Andrew , Hussain Rafiqul , Dixon David , McDonald David , Popescu Dorin-Mirel , Kowalczyk Monika S. , Li Bo , Ashenberg Orr , Tabaka Marcin , Dionne Danielle , Tickle Timothy L. , Slyper Michal , Rozenblatt-Rosen Orit , Regev Aviv , Behjati Sam , Laurenti Elisa , Wilson Nicola K. , Roy Anindita , Göttgens Berthold , Roberts Irene , Teichmann Sarah A. , Haniffa Muzlifah 
Published: June 2021

AbstractThroughout postnatal life, haematopoiesis in the bone marrow (BM) maintains blood and immune cell production. Haematopoiesis first emerges in human BM at 12 post conception weeks while fetal liver (FL) haematopoiesis is still expanding. Yet, almost nothing is known about how fetal BM evolves to meet the highly specialised needs of the fetus and newborn infant. Here, we detail the development of fetal BM including stroma using single cell RNA-sequencing. We find that the full blood and immune cell repertoire is established in fetal BM in a short time window of 6-7 weeks early in the second trimester. Fetal BM promotes rapid and extensive diversification of myeloid cells, with granulocytes, eosinophils and dendritic cell (DC) subsets emerging for the first time. B-lymphocyte expansion occurs, in contrast with erythroid predominance in FL at the same gestational age. We identify transcriptional and functional differences that underlie tissue-specific identity and cellular diversification in fetal BM and FL. Finally, we reveal selective disruption of B-lymphocyte, erythroid and myeloid development due to cell intrinsic differentiation bias as well as extrinsic regulation through an altered microenvironment in the fetal BM from constitutional chromosome anomaly Down syndrome during this crucial developmental time window.
RNAseq analysis reveals dynamic metaboloepigenetic profiles of human, mouse and bovine pre-implantation embryos
Authors: Milazzotto Marcella Pecora , Noonan Michael James , de Almeida Monteiro Melo Ferraz Marcia 
Published: June 2021

SummaryMetaboloepigenetic regulation (metabolites regulating the cellular epigenome inducing long-term changes), has been reported in stem cells, germ cells and tumor cells. Embryonic metaboloepigenetics, however, have just begun to be described. Here we analyzed RNAseq data to characterize the metaboloepigenetic profiles of human, mouse and bovine pre-implantation embryos. In embryos, metaboloepigenetic reprogramming is species specific, varies with the developmental stage and is disrupted with in vitro culture. Although the idea that the in vitro environment may influence embryo development is not new, there has been little progress on improving pregnancy rates after more than 43 years using in vitro fertilization. Hence, the present data on embryonic metaboloepigenetic will contribute to understanding how the in vitro manipulation affects the metaboloepigenetic status of early embryos, which can be used to establish culture strategies aimed at improving the in vitro environment and, consequently, pregnancy rates and offspring health.
Patterns of and processes shaping population structure and introgression among recently differentiatedDrosophila melanogasterpopulations
Authors: Coughlan J.M. , Dagilis A.J. , Serrato-Capuchina A. , Elias H. , Peede D. , Isbell K. , Castillo D.M. , Cooper B.S. , Matute D.R. 
Published: June 2021

ABSTRACTDespite a century of genetic analysis, the evolutionary history underlying patterns of exceptional genetic and phenotypic variation in the model organismDrosophila melanogasterremains poorly understood. How genetic and phenotypic variation is partitioned across the range ofD. melanogaster, particularly in its putative ancestral range in Subtropical Africa, remains unresolved. Here, we assess patterns of population genetic structure, admixture, mate preference, and genetic incompatibility across a global sample, including 174 new accessions from remote regions within Subtropical Africa. While almost all Out of Africa genomes correspond to a single genetic ancestry, different geographic regions within Africa contain multiple ancestries, with substantial cryptic diversity in Subtropical Africa. Admixture between distinct lineages is prevalent across the range, but admixture rates vary between lineages. Female mate choice within Subtropical Africa is highly polymorphic and behavioral types are not monophyletic. The genetic architecture of mate choice is highly polygenic, including loci associated with neurological development, behavior, olfactory perception, and learning. Finally, we discovered that many segregating putative incompatibilities likely evolved during or after expansion out of Africa. This work contributes to our understanding of the evolutionary history of a key model system, and provides insight into the distribution of polymorphic reproductive barriers.
Mutations in PIKFYVE cause autosomal dominant congenital cataract
Authors: Mei Shaoyi , Wu Yi , Wang Yan , Cui Yubo , Zhang Miao , Zhang Tong , Huang Xiaosheng , Yu Sejie , Yu Tao , Zhao Jun 
Published: June 2021

AbstractCongenital cataract, an ocular disease predominantly occurring within the first decade of life, is one of the leading causes of blindness in children. Through whole exome sequencing of a Chinese family with congenital cataract, we identified a disease-causing mutation (p.G1943E) in PIKFYVE, which affecting the PIP kinase domain of the PIKfyve protein. We demonstrated that heterozygous/homozygous disruption of PIKfyve kinase domain, instead of overexpression of PIKFYVEG1943E in zebrafish mimicked the cataract defect in human patients, suggesting that haploinsufficiency, rather than dominant-negative inhibition of PIKfyve activity caused the disease. Phenotypical analysis of pikfyve zebrafish mutants revealed that loss of Pikfyve caused aberrant vacuolation (accumulation of Rab7+Lc3+ amphisomes) in lens cells, which was significantly alleviated by treatment with the V-ATPase inhibitor bafilomycin A1 (Baf-A1). Collectively, we identified PIKFYVE as a novel causative gene for congenital cataract and demonstrated the potential application of Baf-A1 in treatment of congenital cataract.
SARS-CoV-2 Variants are Selecting for Spike Protein Mutations that Increase Protein Stability
Authors: Shorthouse David , Hall Benjamin. A. 
Published: June 2021

ABSTRACTThe emergence of SARS-CoV-2 in 2019 has caused severe disruption and a huge number of human deaths across the globe. As the pandemic spreads, a natural result is the emergence of variants with a variety of amino acid mutations. Variants of SARS-CoV-2 with mutations in their spike protein may result in an increased infectivity, increased lethality, or immune escape, and whilst many of these properties can be explained through changes to binding affinity or changes to post-translational modification, many mutations have no known biophysical impact on the structure of protein. The Gibbs free energy of a protein represents a measure of protein stability, with an increased stability resulting in a protein that is more thermodynamically stable, and more robust to changes in external environment.Here we show that mutations in the spike proteins of SARS-CoV-2 are selecting for amino acid changes that result in a more stable protein than expected by chance. We calculate all possible mutations in the SARS-CoV-2 spike protein, and show that many variants are more stable than expected when compared to the background, indicating that protein stability is an important consideration for the understanding of SARS-CoV-2 evolution. Variants exhibit a range of stabilities, and we further suggest that some stabilising mutations may be acting as a “counterbalance” to destabilising mutations that have other properties, such as increasing binding site affinity for the human ACE2 receptor. We suggest that protein folding calculations offer a useful tool for early identification of advantageous mutations.
Circulating multimeric immune complexes drive immunopathology in COVID-19
Authors: Ankerhold Jakob , Giese Sebastian , Kolb Philipp , Maul-Pavicic Andrea , Voll Reinhard E. , Göppert Nathalie , Ciminski Kevin , Kreutz Clemens , Lother Achim , Salzer Ulrich , Bildl Wolfgang , Welsink Tim , Morgenthaler Nils G. , Grawitz Andrea Busse , Huzly Daniela , Schwemmle Martin , Hengel Hartmut , Falcone Valeria 
Published: June 2021

AbstractA dysregulated immune response with high levels of SARS-CoV-2 specific IgG antibodies characterizes patients with severe or critical COVID-19. Although a robust IgG response is traditionally considered to be protective, excessive triggering of activating Fc-gamma-receptors (FcγRs) could be detrimental and cause immunopathology. Here, we document that patients who develop soluble circulating IgG immune complexes (sICs) during infection are subject to enhanced immunopathology driven by FcγR activation. Utilizing cell-based reporter systems we provide evidence that sICs are predominantly formed prior to a specific humoral response against SARS-CoV-2. sIC formation, together with increased afucosylation of SARS-CoV-2 specific IgG eventually leads to an enhanced CD16 (FcγRIII) activation of immune cells reaching activation levels comparable active systemic lupus erythematosus (SLE) disease. Our data suggest a vicious cycle of escalating immunopathology driven by an early formation of sICs in predisposed patients. These findings reconcile the seemingly paradoxical findings of high antiviral IgG responses and systemic immune dysregulation in severe COVID-19.Clinical implicationsThe identification of sICs as drivers of an escalating immunopathology in predisposed patients opens new avenues regarding intervention strategies to alleviate critical COVID-19 progression.Graphical abstractA vicious cycle of immunopathology in COVID-19 patients is driven by soluble multimeric immune complexes (sICs). SARS-CoV-2 infection triggers sIC formation in prone individuals. Activation of FcγRIII/CD16 expressing immune cells by sICs precedes a humoral response to SARS-CoV2 infection. sICs and infection add to IgG afucosylation, further enhancing FcγRIII/CD16 activation by opsonized targets. High inflammation induces further sIC mediated immune cell activation ultimately leading to an escalating immunopathology.
Persistence of SARS CoV-2 S1 Protein in CD16+ Monocytes in Post-Acute Sequelae of COVID-19 (PASC) Up to 15 Months Post-Infection
Authors: Patterson Bruce K. , Francisco Edgar B. , Yogendra Ram , Long Emily , Pise Amruta , Rodrigues Hallison , Hall Eric , Herrara Monica , Parikh Purvi , Guevara-Coto Jose , Triche Timothy J. , Scott Paul , Hekmati Saboor , Maglinte Dennis , Chang Xaiolan , Mora-Rodríguez Rodrigo A , Mora Javier 
Published: June 2021

ABSTRACTThe recent COVID-19 pandemic is a treatment challenge in the acute infection stage but the recognition of chronic COVID-19 symptoms termed post-acute sequelae SARS-CoV-2 infection (PASC) may affect up to 30% of all infected individuals. The underlying mechanism and source of this distinct immunologic condition three months or more after initial infection remains elusive. Here, we investigated the presence of SARS-CoV-2 S1 protein in 46 individuals. We analyzed T-cell, B-cell, and monocytic subsets in both severe COVID-19 patients and in patients with post-acute sequelae of COVID-19 (PASC). The levels of both intermediate (CD14+, CD16+) and non-classical monocyte (CD14Lo, CD16+) were significantly elevated in PASC patients up to 15 months post-acute infection compared to healthy controls (P=0.002 and P=0.01, respectively). A statistically significant number of non-classical monocytes contained SARS-CoV-2 S1 protein in both severe (P=0.004) and PASC patients (P=0.02) out to 15 months post-infection. Non-classical monocytes were sorted from PASC patients using flow cytometric sorting and the SARS-CoV-2 S1 protein was confirmed by mass spectrometry. Cells from 4 out of 11 severe COVID-19 patients and 1 out of 26 PASC patients contained ddPCR+ peripheral blood mononuclear cells, however, only fragmented SARS-CoV-2 RNA was found in PASC patients. No full length sequences were identified, and no sequences that could account for the observed S1 protein were identified in any patient. Non-classical monocytes are capable of causing inflammation throughout the body in response to fractalkine/CX3CL1 and RANTES/CCR5.