bluuebunny/crossref_metadata_2025_split huggingface dataset:
Quantifying SARS-CoV-2 spread in Switzerland based on genomic sequencing data
Authors: Nadeau Sarah , Beckmann Christiane , Topolsky Ivan , Vaughan Timothy , Hodcroft Emma , Schär Tobias , Nissen Ina , Santacroce Natascha , Burcklen Elodie , Ferreira Pedro , Jablonski Kim Philipp , Posada-Céspedes Susana , Capece Vincenzo , Seidel Sophie , de Souza Noemi Santamaria , Martinez-Gomez Julia M. , Cheng Phil , Bosshard Philipp P. , Levesque Mitchell P. , Kufner Verena , Schmutz Stefan , Zaheri Maryam , Huber Michael , Trkola Alexandra , Cordey Samuel , Laubscher Florian , Gonçalves Ana Rita , Leuzinger Karoline , Stange Madlen , Mari Alfredo , Roloff Tim , Seth-Smith Helena , Hirsch Hans H. , Egli Adrian , Redondo Maurice , Kobel Olivier , Noppen Christoph , Beerenwinkel Niko , Neher Richard A. , Beisel Christian , Stadler Tanja 
Published: October 2020

AbstractPathogen genomes provide insights into their evolution and epidemic spread. We sequenced 1,439 SARS-CoV-2 genomes from Switzerland, representing 3-7% of all confirmed cases per week. Using these data, we demonstrate that no one lineage became dominant, pointing against evolution towards general lower virulence. On an epidemiological level, we report no evidence of cryptic transmission before the first confirmed case. We find many early viral introductions from Germany, France, and Italy and many recent introductions from Germany and France. Over the summer, we quantify the number of non-traceable infections stemming from introductions, quantify the effective reproductive number, and estimate the degree of undersampling. Our framework can be applied to quantify evolution and epidemiology in other locations or for other pathogens based on genomic data.One Sentence SummaryWe quantify SARS-CoV-2 spread in Switzerland based on genome sequences from our nation-wide sequencing effort.
A universal framework for detecting cis-regulatory diversity in DNA regulatory regions
Authors: Biswas Anushua , Narlikar Leelavati 
Published: October 2020

AbstractHigh-throughput sequencing-based assays measure different biochemical activities pertaining to gene regulation, genome-wide. These activities include protein-DNA binding, enhancer-activity, open chromatin, and more. A major goal is to understand underlying sequence components, or motifs, that can explain the measured activity. It is usually not one motif, but a combination of motifs bound by cooperatively acting proteins that confers activity to such regions. Furthermore, although having a single type of activity, the regions can still be diverse, governed by different combinations of proteins/motifs. Current approaches do not take into account this issue of combinatorial diversity. We present a new statistical frameworkcisDiversity, which models regions as diverse modules characterized by combinations of motifs, while simultaneously learning the motifs themselves. We show that ChIP-seq data for the CTCF protein in fly contains diverse sequence structures, with most direct CTCF-binding sites situated far from promoters, giving insights into its co-factors and potential role in looping. Human CTCF-bound regions, on the other hand, have a different architecture. BecausecisDiversitydoes not rely on knowledge of motifs, modules, cell-type, or organism, it is general enough to be applied to regions reported by most high-throughput assays. Indeed, enhancer predictions resulting from different assays—GRO-cap, STARR-seq, and those measuring chromatin structure—show distinct modules and combinations of TF binding sites, some specific to the assay. No module occurs universally in all enhancer-assays. Finally, analysis of accessible chromatin suggests that regions open in one cell-state encode information about future states, with certain modules staying open and others closing down later. The code is freely available athttps://github.com/NarlikarLab/cisDIVERSITY.
Harnessing multivariate, penalized regression methods for genomic prediction and QTL detection to cope with climate change affecting grapevine
Authors: Brault Charlotte , Doligez Agnès , le Cunff Loïc , Coupel-Ledru Aude , Simonneau Thierry , Chiquet Julien , This Patrice , Flutre Timothée 
Published: October 2020

ABSTRACTViticulture has to cope with climate change and decrease pesticide inputs, while maintaining yield and wine quality. Breeding is a potential key to meet this challenge, and genomic prediction is a promising tool to accelerate breeding programs, multivariate methods being potentially more accurate than univariate ones. Moreover, some prediction methods also provide marker selection, thus allowing quantitative trait loci (QTLs) detection and allowing the identification of positional candidate genes. We applied several methods, interval mapping as well as univariate and multivariate penalized regression, in a bi-parental grapevine progeny, in order to compare their ability to predict genotypic values and detect QTLs. We used a new denser genetic map, simulated two traits under four QTL configurations, and re-analyzed 14 traits measured in semi-controlled conditions under different watering conditions. Using simulations, we recommend the penalized regression method Elastic Net (EN) as a default for genomic prediction, and controlling the marginal False Discovery Rate on EN selected markers to prioritize the QTLs. Indeed, penalized methods were more powerful than interval mapping for QTL detection across various genetic architectures. Multivariate prediction did not perform better than its univariate counterpart, despite strong genetic correlation between traits. Using experimental data, penalized regression methods proved as very efficient for intra-population prediction whatever the genetic architecture of the trait, with accuracies reaching 0.68. These methods applied on the denser map found new QTLs controlling traits linked to drought tolerance and provided relevant candidate genes. These methods can be applied to other traits and species.
Tumorigenic epithelial clusters are less sensitive to moderate osmotic stresses due to low amounts of junctional E-cadherin
Authors: Mohammed Danahe , Chan Park Young , Fredberg Jeffrey J. , Weitz David A. 
Published: October 2020

AbstractThe migration of tumorigenic epithelial cells is a critical step for metastatic breast cancer progression. Although the role of the extracellular matrix in breast cancer cell migration has been extensively described, the effect of osmotic stress on the migration of tumor breast epithelial cohorts remains unclear. Most of our understanding on the effect of osmotic stresses on cell migration comes from studies at the level of the single cell in isolation and does not take into account cell-cell interactions. Here, we study the impact of moderate osmotic stress on the migration of epithelial clusters composed of either non-tumorigenic or tumorigenic epithelial cells. We observe a decrease in migration distance and speed for non-tumorigenic epithelial cells but not for tumorigenic ones. To explain these differences, we investigate how osmotic stress impacts the mechanical properties of cell clusters and affects cell volumes. After application of osmotic stress renal epithelial cells become stiffer whereas non-tumorigenic and tumorigenic breast epithelial cells do not. In addition, tumorigenic cells are shown to be less sensitive to osmotic stress than non-tumorigenic cells, and this difference is associated with lower levels of E-cadherin expression. Using EGTA treatments, we confirm that the establishment of cell-cell adhesive interactions is a key component of the behavior of epithelial clusters in response to osmotic stress. This study provides evidence on the low sensitivity of tumorigenic epithelial clusters to moderate osmotic stress and highlights the importance of cadherin-based junctions in response to osmotic stress.
Poxviruses capture host genes by LINE-1 retrotransposition
Authors: Fixsen Sarah M. , Cone Kelsey R. , Goldstein Stephen A. , Sasani Thomas A. , Quinlan Aaron R. , Rothenburg Stefan , Elde Nels C. 
Published: October 2020

AbstractHorizontal gene transfer (HGT) provides a major source of genetic variation. Many viruses, including poxviruses, encode genes with crucial functions directly gained by gene transfer from hosts. The mechanism of transfer to poxvirus genomes is unknown. Using genome analysis and experimental screens of infected cells, we discovered a central role for Long Interspersed Nuclear Element-1 (LINE-1) retrotransposition in HGT to virus genomes. The process recapitulates processed pseudogene generation, but with host messenger RNA directed into virus genomes. Intriguingly, hallmark features of retrotransposition appear to favor virus adaption through rapid duplication of captured host genes on arrival. Our study reveals a previously unrecognized conduit of genetic traffic with fundamental implications for the evolution of many virus classes and their hosts.SummaryActive selfish genetic elements in infected cells aid virus adaptation by catalyzing transfer of host genes to virus genomes.
Optimal COVID-19 quarantine and testing strategies
Authors: Wells Chad R. , Townsend Jeffrey P. , Pandey Abhishek , Moghadas Seyed M. , Krieger Gary , Singer Burton , McDonald Robert H. , Fitzpatrick Meagan C. , Galvani Alison P. 
Published: October 2020

AbstractAs economic woes of the COVID-19 pandemic deepen, strategies are being formulated to avoid the need for prolonged stay-at-home orders, while implementing risk-based quarantine, testing, contact tracing and surveillance protocols. Given limited resources and the significant economic, public health, and operational challenges of the current 14-day quarantine recommendation, it is vital to understand if shorter but equally effective quarantine and testing strategies can be deployed. To quantify the probability of post-quarantine transmission upon isolation of a positive test, we developed a mathematical model in which we varied quarantine duration and the timing of molecular tests for three scenarios of entry into quarantine. Specifically, we consider travel quarantine, quarantine of traced contacts with an unknown time if infection, and quarantine of cases with a known time of exposure. With a one-day delay between test and result, we found that testing on exit (or entry and exit) can reduce the duration of a 14-day quarantine by 50%, while testing on entry shortened quarantine by at most one day. Testing on exit more effectively reduces post-quarantine transmission than testing upon entry. Furthermore, we identified the optimal testing date within quarantines of varying duration, finding that testing on exit was most effective for quarantines lasting up to seven days. As a real-world validation of these principles, we analyzed the results of 4,040 SARS CoV-2 RT-PCR tests administered to offshore oil rig employees. Among the 47 positives obtained with a testing on entry and exit strategy, 16 cases that previously tested negative at entry were identified, with no further cases detected among employees following quarantine exit. Moreover, this strategy successfully prevented an expected nine offshore transmission events stemming from cases who had tested negative on the entry test, each one a serious concern for initiating rapid spread and a disabling outbreak in the close quarters of an offshore rig. This successful outcome highlights that appropriately timed testing can make shorter quarantines more effective, thereby minimizing economic impacts, disruptions to operational integrity, and COVID-related public health risks.
Modelling trachoma post 2020: Opportunities for mitigating the impact of COVID-19 and accelerating progress towards elimination
Authors: Borlase Anna , Blumberg Seth , Callahan E Kelly , Deiner Michael S , Nash Scott D , Porco Travis C , Solomon Anthony W , Lietman Thomas M , Prada Joaquin M , Hollingsworth T. Dèirdre 
Published: October 2020

AbstractBackgroundThe COVID-19 pandemic has disrupted planned annual antibiotic mass drug administration (MDA) activities which have formed the cornerstone of the largely successful global efforts to eliminate trachoma as a public health problem.MethodsUsing a mathematical model we investigate the impact of interruption to MDA in trachoma-endemic settings. We evaluate potential measures to mitigate this impact and consider alternative strategies for accelerating progress in those areas where the trachoma elimination targets may not be achievable otherwise.ResultsWe demonstrate that for districts which were hyperendemic at baseline, or where the trachoma elimination thresholds have not already been achieved after 3 rounds of MDA, the interruption to planned MDA could lead to a delay greater than the duration of interruption. We also show that an additional round of MDA in the year following MDA resumption could effectively mitigate this delay. For districts where probability of elimination under annual MDA was already very low, we demonstrate that more intensive MDA schedules are needed to achieve agreed targets.ConclusionThrough appropriate use of additional MDA, the impact of COVID-19 in terms of delay to reaching trachoma elimination targets can be effectively mitigated. Additionally, more frequent MDA may accelerate progress towards 2030 goals.
Evaluation of the Abbott Architect, Roche Elecsys and Virtus S1 SARS-CoV-2 antibody tests in community-managed COVID-19 cases
Authors: Johnston Sebastian L. , McKay Paul F , Kebadze Tatiana , Hu Kai , Samnuan Karnyart , Aniscenko Juliya , Cameron Aoife , Patel Neeta , Randell Paul , Shattock Robin J , Edwards Michael R 
Published: October 2020

AbstractBackgroundAntibody testing can help define how protective immunity to SARS-CoV-2 is and how long this immunity lasts. Many antibody tests have been evaluated in hospitalised rather than community based COVID-19 cases. Virtus Respiratory Research Ltd (Virtus) has developed its own quantitative IgM and IgG SARS CoV-2 antibody assay. We report its validation and performance characteristics and compare its performance with the Abbott Architect and Roche Elecsys assays in community COVID cases.MethodsWe developed a quantitative antibody test to detect IgM and IgG to the SARS-CoV-2 S1 spike protein (the Virtus test) and validated this test in 107 “true positive” sera from 106 community-managed and 1 hospitalised COVID-19 cases and 208 “true negative” serum samples. We validated the Virtus test against a neutralising antibody test. We determined sensitivities of the Abbott test in the 107 true positive samples and the Roche test in a subset of 75 true positive samples.ResultsThe Virtus quantitative test was positive in 93 of 107 (87%) community cases of COVID-19 and both IgM and IgG levels correlated strongly with neutralising antibody titres (r=0.75 for IgM, r=0.71 for IgG, P<0.0001 for both antibodies). The specificity of the Virtus test was 98.6% for low level antibody positives, 99.5% for moderate positives and 100% for high or very high positives. The Abbott test had a sensitivity of 68%. In the 75 sample subset, the Virtus test was positive in 91%, the Roche test in 69%.ConclusionsThe Abbott and Roche tests had sensitives of 68% and 69% respectively in this community set of COVID-19 sera, while the Virtus test had sensitivities of 87% and 91% in the same sample sets. The strong positive correlation with virus neutralization suggests a positive Virtus quantitative antibody test is likely predictive of protective against recurrent COVID-19.FundingThe development of the Virtus test and sample testing with all antibody tests was funded by Virtus Respiratory Research Ltd. The research studies providing 111 of the 208 of the “true negative” samples was supported by MRC Grant numbers MR/M025330/1 and G1100238 and by the National Institute of Health Research (NIHR) Imperial Biomedical Research Centre (BRC), SLJ is a NIHR Emeritus Senior Investigator and is funded in part by European Research Council Advanced Grant 788575 and the Asthma UK Clinical Chair (grant CH11SJ). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care.
The neural circuitry underlying the “rhythm effect” in stuttering
Authors: Frankford Saul A. , Heller Murray Elizabeth S. , Masapollo Matthew , Cai Shanqing , Tourville Jason A. , Nieto-Castañón Alfonso , Guenther Frank H. 
Published: October 2020

AbstractPurposeStuttering is characterized by intermittent speech disfluencies which are dramatically reduced when speakers synchronize their speech with a steady beat. The goal of this study was to characterize the neural underpinnings of this phenomenon using functional magnetic resonance imaging.MethodData were collected from 17 adults who stutter and 17 adults who do not stutter while they read sentences aloud either in a normal, self-paced fashion or paced by the beat of a series of isochronous tones (“rhythmic”). Task activation and task-based functional connectivity analyses were carried out to compare neural responses between speaking conditions and groups.ResultsAdults who stutter produced fewer disfluent trials in the rhythmic condition than in the normal condition. While adults who do not stutter had greater activation in the rhythmic condition compared to the normal condition in regions associated with speech planning, auditory feedback control, and timing perception, adults who stutter did not have any significant changes. However, adults who stutter demonstrated increased functional connectivity between bilateral inferior cerebellum and bilateral orbitofrontal cortex as well as increased connectivity among cerebellar regions during rhythmic speech as compared to normal speech.ConclusionModulation of connectivity in the cerebellum and prefrontal cortex during rhythmic speech suggests that this fluency-inducing technique activates a compensatory timing system in the cerebellum and potentially modulates top-down motor control and attentional systems. These findings corroborate previous work associating the cerebellum with fluency in adults who stutter and indicate that the cerebellum may be targeted to enhance future therapeutic interventions.
Epitranscriptomic editing of the RNA N6-methyladenosine modification by dCasRx conjugated methyltransferase and demethylase
Authors: Xia Zhen , Tang Min , Zhang Hongyan , Gimple Ryan C. , Prager Briana C. , Tang Hongzhen , Sun Chongran , Liu Fuyi , Lin Peng , Mei Yutang , Du Ruoxin , Rich Jeremy N. , Xie Qi 
Published: October 2020

AbstractN6-methyladenosine (m6A) is the most common modification on endogenous RNA transcripts in mammalian cells. Currently, the lack of precise single-nucleotide RNA modification tools makes it challenging to understand the relationship between site-specific RNA methylation and the corresponding phenotypic outcomes. Here, we developed a bidirectional dCasRx epitranscriptome editing platform composed of a nucleus-localized dCasRx conjugated with either a methyltransferase, METTL3, or a demethylase, ALKBH5, to manipulate methylation events at targeted m6A sites in HEK293T and glioma stem cells. This platform specifically and efficiently edited m6A modifications at targeted sites, modulating both gene expression and cell proliferation. We then employed the dCasRx epitranscriptomic editor to further elucidate the molecular function of m6A-binding proteins YTH (DF1, DF2, DF3) family and found that the YTH paralogs act together to mediate RNA degradation. These findings collectively demonstrate that the dCasRx epitranscriptome perturbation platform reported in this study can be employed as site-specific m6A editors for delineating the functional roles of individual m6A modifications in the mammalian epitranscriptome.
BrainGENIE: The Brain Gene Expression and Network Imputation Engine
Authors: Hess Jonathan L. , Quinn Thomas P. , Zhang Chunling , Hearn Gentry C. , Chen Samuel ,   Neuropsychiatric Consortium for Analysis and Sharing of Transcriptomes, Kong Sek Won , Cairns Murray J. , Tsuang Ming T. , Faraone Stephen V. , Glatt Stephen J. 
Published: October 2020

AbstractIn vivoexperimental analysis of human brain tissue poses substantial challenges and ethical concerns. We developed a novel method called the Brain Gene Expression and Network Imputation Engine (BrainGENIE) that uses peripheral-blood transcriptomes to predict brain-tissue-specific gene-expression levels.BrainGENIEreliably predicted brain-tissue-specific expression levels for 1,733 – 11,569 genes (false-discovery rate-adjustedp<0.05), including many transcripts that cannot be predicted reliably by a transcriptome imputation method such asPrediXcan. We tested the generalizability ofBrainGENIEin external within-individual data fromex vivoperipheral blood andpostmortembrain samples from the Religious Orders Study and Memory and Aging Project, wherein we validated 39% of predicted gene expression levels as concordant with observed expression levels in dorsolateral prefrontal cortex and 23% in caudate.BrainGENIErecapitulated diagnosis-related gene expression changes in brain better than direct correlations from blood and predictions fromPrediXcan. BrainGENIEcomplements and, in some ways, outperforms existing transcriptome-imputation tools, providing biologically meaningful predictions and opening new research avenues.
Negative durotaxis: cell movement toward softer environments
Authors: Isomursu Aleksi , Park Keun-Young , Hou Jay , Cheng Bo , Shamsan Ghaidan , Fuller Benjamin , Kasim Jesse , Mahmoodi M. Mohsen , Lu Tian Jian , Genin Guy M. , Xu Feng , Lin Min , Distefano Mark , Ivaska Johanna , Odde David J. 
Published: October 2020

AbstractDurotaxis – the ability of cells to sense and migrate along stiffness gradients – is important for embryonic development and has been implicated in pathologies including fibrosis and cancer. Although cellular processes can sometimes turn toward softer environments, durotaxis at the level of cells has thus far been observed exclusively as migration from soft to stiff regions. The molecular basis of durotaxis, especially the factors that contribute to different durotactic behaviors in various cell types, are still inadequately understood. With the recent discovery of ‘optimal stiffness’, where cells generate maximal traction forces on substrates in an intermediate stiffness range, we hypothesized that some migratory cells may be capable of moving away from stiff environments and toward matrix on which they can generate more traction. Combining hydrogel-based stiffness gradients, live-cell imaging, genetic manipulations, and computational modeling, we found that cells move preferentially toward their stiffness optimum for maximal force transmission. Importantly, we directly observed biased migration toward softer environments, i.e. ‘negative durotaxis’, in human glioblastoma cells. This directional migration did not coincide with changes in FAK, ERK or YAP signaling, or with altered actomyosin contractility. Instead, integrin-mediated adhesion and motor-clutch dynamics alone are sufficient to generate asymmetric traction to drive both positive and negative durotaxis. We verified this mechanistically by applying a motor-clutch-based model to explain negative durotaxis in the glioblastoma cells and in neurites, and experimentally by switching breast cancer cells from positive to negative durotaxis via talin downregulation. Our results identify the likely molecular mechanisms of durotaxis, with a cell’s contractile and adhesive machinery dictating its capacity to exert traction on mechanically distinct substrates, directing cell migration.