bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dysfunctional Senescent Herpes Simplex Virus Specific CD57+CD8+ T cells are Associated with Recurrent Symptomatic Herpes in Humans
Authors: Khan Arif A. , Srivastava Ruchi , Vahed Hawa , BenMohamed Lbachir 
Published: January 2022

ABSTRACTHerpes simplex virus (HSV)-specific CD8+ T cells protect mice from herpes infection and disease. However, the phenotype and function of HSV-specific CD8+ T cells that play a key role in the “natural” protection seen in HSV-1-seropositive healthy asymptomatic (ASYMP) individuals (who have never had clinical herpes disease) remain to be determined. We previously reported that symptomatic (SYMP) patients (who have frequent bouts of recurrent herpes disease) had more less-differentiated and dysfunctional HSV-specific CD8+ T cells. In contrast, healthy ASYMP individuals maintained a significantly higher proportion of differentiated polyfunctional CD8+ T cells. Here we report that, HSV-specific CD8+ T cells from SYMP patients, but not from ASYMP individuals, have phenotypic and functional characteristics of cellular senescence, including: (i) high frequency of senescent (CD57+) and exhausted (PD-1+) CD8+ T cells; (ii) late terminally differentiated (KLRG1+), non-proliferating CD8+ T cells; (iii) HSV-specific CD8+ T cells were declined overtime and were not maintained homeostatistically (CD127+CD8+ T cells); (iv) loss of co-stimulatory molecule (CD28) on HSV-specific CD8+ T cells; (v) decreased production of effector molecules (granzyme B and perforin) by HSV-specific CD8+ T cells. Our findings provide insights into the role of senescence in HSV-specific CD8+ T cells in susceptibility to recurrent herpes and have implications for T-cell-based immunotherapeutic strategies against recurrent herpes in humans.IMPORTANCEReactivation of herpes simplex virus 1 (HSV-1) from latency leads to recurrent herpetic disease in symptomatic (SYMP) individuals. A role of T cells in herpes immunity against recurrent herpetic disease is established. However, the phenotype and function of HSV-specific CD8+ T cells that play a key role in the “natural” protection seen in HSV-1-seropositive healthy asymptomatic (ASYMP) individuals (who have never had clinical herpes disease) remain to be determined. In the present study, we report that, HSV-specific CD8+ T cells from SYMP patients, but not from ASYMP individuals, have phenotypic and functional characteristics of cellular senescence. Our findings provide insights into the role of senescence in HSV-specific CD8+ T cells in susceptibility to recurrent herpes and have implications for T-cell-based immunotherapeutic strategies against recurrent herpes in humans.
A 2-Gene Host Signature for Improved Accuracy of COVID-19 Diagnosis Agnostic to Viral Variants
Authors: Albright Jack , Mick Eran , Sanchez-Guerrero Estella , Kamm Jack , Mitchell Anthea , Detweiler Angela M. , Neff Norma , Tsitsiklis Alexandra , Serpa Paula Hayakawa , Ratnasiri Kalani , Havlir Diane , Kistler Amy , DeRisi Joseph L. , Pisco Angela Oliveira , Langelier Charles R. 
Published: January 2022

AbstractThe continued emergence of SARS-CoV-2 variants is one of several factors that may cause false negative viral PCR test results. Such tests are also susceptible to false positive results due to trace contamination from high viral titer samples. Host immune response markers provide an orthogonal indication of infection that can mitigate these concerns when combined with direct viral detection. Here, we leverage nasopharyngeal swab RNA-seq data from patients with COVID-19, other viral acute respiratory illnesses and non-viral conditions (n=318) to develop support vector machine classifiers that rely on a parsimonious 2-gene host signature to predict COVID-19. Optimal classifiers achieve an area under the receiver operating characteristic curve (AUC) greater than 0.9 when evaluated on an independent RNA-seq cohort (n=553). We show that a classifier relying on a single interferon-stimulated gene, such as IFI6 or IFI44, measured in RT-qPCR assays (n=144) achieves AUC values as high as 0.88. Addition of a second gene, such as GBP5, significantly improves the specificity compared to other respiratory viruses. The performance of a clinically practical 2-gene RT-qPCR classifier is robust across common SARS-CoV-2 variants, including Omicron, and is unaffected by cross-contamination, demonstrating its utility for improving accuracy of COVID-19 diagnostics.
Evaluating Real-World COVID-19 Vaccine Effectiveness Using a Test-Negative Case-Control Design
Authors: Reynolds Matthew W , Secora Alex , Joules Alice , Albert Lisa , Brinkley Emma , Kwon Tom , Mack Christina , Toovey Stephen , Dreyer Nancy A. 
Published: January 2022

AbstractIt is important to assess the extent to which the real-world effectiveness of marketed vaccines is consistent with that observed in the clinical trials, and to characterize how well vaccines prevent COVID-19 symptoms. We conducted a modified test-negative design (TND) to evaluate the RW effectiveness of three COVID-19 vaccines by leveraging data from an on-going, US community-based registry. Vaccine effectiveness was examined in two ways: considering cases who (1) tested positive for COVID-19 (695 cases, 1,786 controls) and who (2) tested positive with at least one moderate/severe COVID-19 symptom (165 cases, 2,316 controls). Any vaccination (full or partial) was associated with a 95% reduction in the odds of having a positive COVID-19 test [adjusted odds ratio (aOR) = 0.05 (95% confidence interval (CI): 0.04, 0.06)]. Full vaccination was associated with an aOR of 0.03 (95% CI: 0.03, 0.05) while partial vaccination had an aOR of 0.08 (95% CI: 0.06, 0.12). Any vaccination was associated with a 71% reduction in the odds of testing positive and having at least one moderate/severe symptom (aOR=0.29 (95% CI: 0.20, 0.40)). High effectiveness was observed across all three vaccine manufacturers both for prevention of positive COVID-19 test results and prevention of moderate/severe COVID-19 symptoms.Clinicaltrials.govNCT04368065
Older adults mount less durable humoral responses to two doses of COVID-19 mRNA vaccine, but strong initial responses to a third dose
Authors: Mwimanzi Francis , Lapointe Hope R. , Cheung Peter K. , Sang Yurou , Yaseen Fatima , Umviligihozo Gisele , Kalikawe Rebecca , Datwani Sneha , Omondi F. Harrison , Burns Laura , Young Landon , Leung Victor , Agafitei Olga , Ennis Siobhan , Dong Winnie , Basra Simran , Lim Li Yi , Ng Kurtis , Pantophlet Ralph , Brumme Chanson J. , Montaner Julio S.G. , Prystajecky Natalie , Lowe Christopher F. , DeMarco Mari L. , Holmes Daniel T. , Simons Janet , Niikura Masahiro , Romney Marc G. , Brumme Zabrina L. , Brockman Mark A. 
Published: January 2022

ABSTRACTBackgroundThird COVID-19 vaccine doses are broadly recommended, but immunogenicity data remain limited, particularly in older adults.MethodsWe measured circulating antibodies against the SARS-CoV-2 spike protein receptor-binding domain, ACE2 displacement, and virus neutralization against ancestral and Omicron (BA.1) strains from pre-vaccine up to one month following the third dose, in 151 adults aged 24-98 years who received COVID-19 mRNA vaccines.ResultsFollowing two vaccine doses, humoral immunity was weaker, less functional and less durable in older adults, where a higher number of chronic health conditions was a key correlate of weaker responses and poorer durability. Third doses boosted antibody binding and function to higher levels than second-doses, and induced responses in older adults that were comparable in magnitude to those in younger adults. Humoral responses against Omicron were universally weaker than against the ancestral strain after both second and third doses; nevertheless, after three doses, anti-Omicron responses in older adults reached equivalence to those in younger adults. After three vaccine doses, the number of chronic health conditions, but not age per se, was the strongest consistent correlate of weaker humoral responses.ConclusionResults underscore the immune benefits of third COVID-19 vaccine doses, particularly in older adults.
Genome-wide analyses of 200,453 individuals yields new insights into the causes and consequences of clonal hematopoiesis
Authors: Kar Siddhartha P. , Quiros Pedro M. , Gu Muxin , Jiang Tao , Langdon Ryan , Iyer Vivek , Barcena Clea , Vijayabaskar M.S. , Fabre Margarete A. , Carter Paul , Burgess Stephen , Vassiliou George S. 
Published: January 2022

AbstractClonal hematopoiesis (CH) is one of the most extensively studied somatic mutational phenomena, yet its causes and consequences remain poorly understood. We identify 10,924 individuals with CH amongst 200,453 whole-exome sequenced UK Biobank participants and use their linked genome-wide DNA genotypes to map the landscape of inherited predisposition to CH. We increase the number of European-ancestry genome-wide significant (P<5×10−8) germline associations with CH from four to 14 and identify one new transcriptome-wide significant (P<3.2×10−6) association. Genes at new loci implicate DNA damage repair (PARP1, ATM, andCHEK2), hematopoietic stem cell migration/homing (CD164), and myeloid oncogenesis (SETBP1) in CH development. Several associations were CH-subtype specific and, strikingly, variants atTCL1AandCD164had opposite associations withDNMT3A-versusTET2-mutant CH, mirroring recently reported differences in lifelong behavior of these two most common CH subtypes and proposing important roles for these loci in CH pathogenesis. Using Mendelian randomization, we show, amongst other findings, that smoking and longer leukocyte telomere length are causal risk factors for CH and demonstrate that genetic predisposition to CH increases risks of myeloproliferative neoplasia, several non-hematological malignancies, atrial fibrillation, and blood epigenetic age acceleration.
Updated projections for COVID-19 omicron wave in Florida
Authors: Hladish Thomas J. , Pillai Alexander N. , Longini Ira M. 
Published: January 2022

AbstractIn this report, we use a detailed simulation model to assess and project the COVID-19 epidemic in Florida. The model is a data-driven, stochastic, discrete-time, agent based model with an explicit representation of people and places. Using the model, we find that the omicron variant wave in Florida is likely to cause many more infections than occurred during the delta variant wave. Due to testing limitations and often mild symptoms, however, we anticipate that omicron infections will be underreported compared to delta. We project that reported cases of COVID-19 will continue to grow significantly and peak in early January 2022, and that the number of reported COVID-19 deaths due to omicron may be 1/3 of the total caused by the delta wave.
A novel time-based surface EMG measure for quantifying hypertonia in paretic arm muscles during daily activities after hemiparetic stroke
Authors: Sohn M. Hongchul , Deol Jasjit , Dewald Julius P.A. 
Published: January 2022

ABSTRACTAfter stroke, paretic arm muscles are constantly exposed to abnormal neural drive from the injured brain. As such, hypertonia, broadly defined as an increase in muscle tone, is prevalent especially in distal muscles, which impairs daily function or in long-term leads to a flexed resting posture in the wrist and fingers. However, there currently is no quantitative measure that can reliably track how hypertonia is expressed on daily basis. In this study, we propose a novel time-based surface electromyography (sEMG) measure that can overcome the limitations of the coarse clinical scales often measured in functionally irrelevant context and the magnitude-based sEMG measures that suffer from signal non-stationarity. We postulated that the key to robust quantification of hypertonia is to capture the “true” baseline in sEMG for each measurement session, by which we can define the relative duration of activity over a short time segment continuously tracked in a sliding window fashion. We validate that the proposed measure of sEMG active duration is robust across parameter choices (e.g., sampling rate, window length, threshold criteria), robust against typical noise sources present in paretic muscles (e.g., low signal-to-noise ratio, sporadic motor unit action potentials), and reliable across measurements (e.g., sensors, trials, and days), while providing a continuum of scale over the full magnitude range for each session. Furthermore, sEMG active duration could well characterize the clinically observed differences in hypertonia expressed across different muscles and impairment levels. The proposed measure can be used for continuous and quantitative monitoring of hypertonia during activities of daily living while at home, which will allow for the study of the practical effect of pharmacological and/or physical interventions that try to combat its presence.
Modeling the USA Winter 2021 CoVID-19 Resurgence
Authors: Eng Genghmun 
Published: January 2022

AbstractThe current USA 2021 CoVID-19 Winter Resurgence is modeled here with the same function used for analyzing prior USA CoVID-19 waves:

Here, N(t) gives the total number of CoVID-19 cases above the previous baseline, and tR sets the initial tdbl = tR (ln 2) pandemic tdbl doubling time. Larger αS values indicate that uninfected people are improving their pandemic mitigation efforts, such as Social Distancing and vaccinations ; while δ0> 0 accelerates the post-peak tail-off, and is empirically associated with mask-wearing. The pandemic wave end is when N(t) no longer increases.The USA Summer 2021 resurgence results from our prior medrxiv.org preprints* were used as a baseline. By 11/15/2021, an additional cases above baseline were found, signaling the USA Winter 2021 resurgence. This CoVID-19 wave is still in its initial stages. Presently, our analysis indicates that this CoVID-19 wave can infect virtually all susceptible persons; just like the initial stage of the USA Summer 2021 resurgence. Data up through 12/30/2021 gives these paremeter values:

These values are identical to the prior 2020 USA Winter Resurgence results. Also, the and the values are similar. However, while the Winter 2020 Resurgence showed a significant mask-wearing effect , this initial USA Winter 2021 Resurgence shows practically no mask-wearing effects . If mask-wearing were to quickly rise to the Winter 2020 levels, it would give these projected totals:

More robust mask-wearing and enhanced Social Distancing measures could further reduce these values (with 3 Figures).
STREAMING-tag system reveals spatiotemporal relationships between transcriptional regulatory factors and transcriptional activity
Authors: Ohishi Hiroaki , Shimada Seiru , Uchino Satoshi , Li Jieru , Sato Yuko , Shintani Manabu , Owada Hitoshi , Ohkawa Yasuyuki , Pertsinidis Alexandros , Yamamoto Takashi , Kimura Hiroshi , Ochiai Hiroshi 
Published: January 2022

SummaryTranscription is a dynamic process that stochastically switches between the ON and OFF states. To detect the dynamic relationship among protein clusters of RNA polymerase II (RNAPII) and coactivators, gene loci, and transcriptional activity, we inserted an MS2 repeat, a TetO repeat, and inteins with a selection marker just downstream of the transcription start site (TSS). By optimizing the individual elements, we have developed the Spliced TetO REpeAt, MS2 repeat, and INtein sandwiched reporter Gene tag (STREAMING-tag) system. Clusters of RNAPII and BRD4 were observed proximally to the TSS ofNanogwhen the gene was transcribed in mouse embryonic stem cells. In contrast, clusters of MED19 and MED22 Mediator subunits were constitutively located near the TSS. Thus, the STREAMING-tag system revealed the spatiotemporal relationships between transcriptional activity and protein clusters near the gene. This powerful tool is useful for quantitatively understanding dynamic transcriptional regulation in living cells.
MethylScore, a pipeline for accurate and context-aware identification of differentially methylated regions from population-scale plant WGBS data
Authors: Hüther Patrick , Hagmann Jörg , Nunn Adam , Kakoulidou Ioanna , Pisupati Rahul , Langenberger David , Weigel Detlef , Johannes Frank , Schultheiss Sebastian J. , Becker Claude 
Published: January 2022

AbstractWhole-genome bisulfite sequencing (WGBS) is the standard method for profiling DNA methylation at single-nucleotide resolution. Many WGBS-based studies aim to identify biologically relevant loci that display differential methylation between genotypes, treatment groups, tissues, or developmental stages. Over the years, different tools have been developed to extract differentially methylated regions (DMRs) from whole-genome data. Often, such tools are built upon assumptions from mammalian data and do not consider the substantially more complex and variable nature of plant DNA methylation. Here, we present MethylScore, a pipeline to analyze WGBS data and to account for plant-specific DNA methylation properties. MethylScore processes data from genomic alignments to DMR output and is designed to be usable by novice and expert users alike. It uses an unsupervised machine learning approach to segment the genome by classification into states of high and low methylation, substantially reducing the number of necessary statistical tests while increasing the signal-to-noise ratio and the statistical power. We show how MethylScore can identify DMRs from hundreds of samples and how its data-driven approach can stratify associated samples without prior information. We identify DMRs in the A. thaliana 1001 Genomes dataset to unveil known and unknown genotype-epigenotype associations. MethylScore is an accessible pipeline for plant WGBS data, with unprecedented features for DMR calling in small- and large-scale datasets; it is built as a Nextflow pipeline and its source code is available at https://github.com/Computomics/MethylScore.
Reversion of Ebolavirus Disease from a Single Intramuscular Injection of a pan-Ebolavirus Immunotherapeutic
Authors: Kuang Erin , Cross Robert W. , McCavitt-Malvido Maria , Abelson Dafna M. , Borisevich Viktoriya , Agans Krystle N. , Mlakar Neil , Marimuthu Arumugapradeep , Deer Daniel J. , Shestowsky William S. , Kim Do , Geisbert Joan B. , Zeitlin Larry , Moyer Crystal L. , Roy Chad J. , Geisbert Thomas , Bornholdt Zachary A. 
Published: January 2022

AbstractIntravenous administration (IV) of antiviral monoclonal antibodies (mAbs) is challenging due to limited resources for performing infusions during an ongoing epidemic. An ebolavirus therapeutic administered via intramuscular (IM) injection would reduce these burdens and allow rapid treatment of exposed individuals during an outbreak. Here, we demonstrate how MBP134, a two mAb pan-ebolavirus cocktail, reverses the course of Sudan ebolavirus (SUDV/Gulu) disease with a single IV or IM dose in non-human primates (NHPs) as far as five days post-exposure. Furthermore, we investigated the utility of adding half-life extension mutations to the MBP134 mAbs, ultimately creating a half-life extended cocktail designated MBP431. MBP431 demonstrated an extended serum half-life in vivo and offered complete or significant protection with a single IM dose delivered as a post-exposure prophylactic (PEP) or therapeutic in NHPs challenged with EBOV. These results support the use of MBP431 as a rapidly deployable IM medical countermeasure against every known ebolavirus.
Random Compressed Coding with Neurons
Authors: Malerba Simone Blanco , Pieropan Mirko , Burak Yoram , Azeredo da Silveira Rava 
Published: January 2022

SummaryClassical models of efficient coding in neurons assume simple mean responses—‘tuning curves’—such as bellshaped or monotonic functions of a stimulus feature. Real neurons, however, can be more complex: grid cells, for example, exhibit periodic responses which impart the neural population code with high accuracy. But do highly accurate codes require fine tuning of the response properties? We address this question with the use of a benchmark model: a neural network with random synaptic weights which result in output cells with irregular tuning curves. Irregularity enhances the local resolution of the code but gives rise to catastrophic, global errors. For optimal smoothness of the tuning curves, when local and global errors balance out, the neural network compresses information from a high-dimensional representation to a low-dimensional one, and the resulting distributed code achieves exponential accuracy. An analysis of recordings from monkey motor cortex points to such ‘compressed efficient coding’. Efficient codes do not require a finely tuned design—they emerge robustly from irregularity or randomness.
Fibrin, Bone Marrow Cells and macrophages interactively modulate cardiomyoblast fate
Authors: Borrego Inês , Frobert Aurélien , Ajalbert Guillaume , Valentin Jérémy , Kaltenrieder Cyrielle , Fellay Benoît , Stumpe Michael , Cook Stéphane , Dengjel Joern , Giraud Marie-Noelle 
Published: January 2022

ABSTRACTInteractions between macrophages, cardiac cells and the extracellular matrix are crucial for cardiac repair following myocardial infarction (MI). The paracrine effects of cell-based treatments of MI might modulate these interactions and impact cardiac repair. The immunomodulatory capacity of the therapeutic cells is therefore of interest and could be modulated by the use of biomaterials. We first showed that bone marrow cells (BMC) associated with fibrin could treat MI. Then, we interrogated the influence of fibrin, as a biologically active scaffold, on the secretome of BMC and the impact of their association on macrophage fate and cardiomyoblast proliferation.MethodsIn vivo, two weeks post-MI, rats were treated with epicardial implantation of BMC and fibrin or sham-operated. High-resolution echocardiography was performed to evaluate the heart function and structure changes after 4 weeeks. Histology and immunostaining were performed on harvested hearts.In vitro, BMC were first primed with fibrin. Second, non-polarized macrophages were differentiated toward either pro-inflammatory or anti-inflammatory phenotypes and stimulated with the conditioned medium of fibrin-primed BMC (F-BMC). Proteomic, cytokine levels quantification, and RT-PCR were performed. EdU incorporation and real-time cell analysis assessed cell proliferation.ResultsThe epicardial implantation of fibrin and BMC reduced the loss of cardiac function induced by MI, increased wall thickness and prevented the fibrotic scar expansion. After 4 and 12 weeks, the infarct content of CD68+and CD206+was similar in control and treated animals. In vitro, we showed that fibrin profoundly influenced the gene expression and the secretome of BMC, simultaneously upregulating both pro- and anti-inflammatory mediators. Furthermore, the conditioned medium from F-BMC significantly increased the proliferation of macrophages in a subsets dependent manner and modulated their gene expression and cytokines secretion. For instance, F-BMC significantly downregulated the expression ofNos2,Il6andCcl2/Mcp1whileArg1,TgfbandIL10were upregulated. Interestingly, macrophages educated by F-BMC increased cardiomyoblast proliferation.In conclusion, our study provides evidence that BMC/fibrin-based treatment lowered the infarct extent and improved cardiac function. The macrophage content was unmodified when measured at a chronic stage. Nevertheless, acutely andin vitro, the F-BMC secretome promotes an anti-inflammatory response that stimulates cardiac cell growth. Finally, our study emphases the acute impact of F-BMC educated macrophages on cardiac cell fate.