bluuebunny/crossref_metadata_2025_split huggingface dataset:
The peripheral T cell population is associated with pneumonia severity in cynomolgus monkeys experimentally infected with severe acute respiratory syndrome coronavirus 2
Authors: Nagata Noriyo , Iwata-Yoshikawa Naoko , Sano Kaori , Ainai Akira , Shiwa Nozomi , Shirakura Masayuki , Kishida Noriko , Arita Tomoko , Suzuki Yasushi , Harada Toshihiko , Kawai Yasuhiro , Ami Yasushi , Iida Shun , Katano Harutaka , Fujisaki Seiichiro , Sekizuka Tsuyoshi , Shimizu Hiroyuki , Suzuki Tadaki , Hasegawa Hideki 
Published: January 2021

AbstractThe coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global pandemic that began in December 2019. Lymphopenia is a common feature in severe cases of COVID-19; however, the role of T cell responses during infection is unclear. Here, we inoculated six cynomolgus monkeys, divided into two groups according to the CD3+ T cell population in peripheral blood, with two clinical isolates of SARS-CoV-2: one of East Asian lineage and one of European lineage. After initial infection with the isolate of East Asian lineage, all three monkeys in the CD3+ low group showed clinical symptoms, including loss of appetite, lethargy, and transient severe anemia with/without short-term fever, within 14 days post-infection (p.i.). By contrast, all three monkeys in the CD3+ high group showed mild clinical symptoms such as mild fever and loss of appetite within 4 days p.i. and then recovered. After a second inoculation with the isolate of European lineage, three of four animals in both groups showed mild clinical symptoms but recovered quickly. Hematological, immunological, and serological tests suggested that the CD3+ high and low groups mounted different immune responses during the initial and second infection stages. In both groups, anti-viral and innate immune responses were activated during the early phase of infection and re-infection. However, in the CD3+ low group, inflammatory responses, such as increased production of monocytes and neutrophils, were stronger than those in the CD3+ high group, leading to more severe immunopathology and failure to eliminate the virus. Taken together, the data suggest that the peripheral T lymphocyte population is associated with pneumonia severity in cynomolgus monkeys experimentally infected with SARS-CoV-2.Author summarySARS-CoV-2 infection causes an illness with clinical manifestations that vary from asymptomatic or mild to severe; examples include severe pneumonia and acute respiratory distress syndrome. Lymphopenia, which is common in severe COVID-19 cases, is characterized by markedly reduced numbers of CD4+ T cells, CD8+ T cells, B cells, and natural killer cells. Here, we showed that cynomolgus monkeys selected according to the T cell populations in peripheral blood have different outcomes after experimental infection with SARS-CoV-2. These findings will increase our understanding of disease pathogenesis and may facilitate the development of animal models for vaccine evaluation.
Engineering the thermotolerant industrial yeastKluyveromyces marxianusfor anaerobic growth
Authors: Dekker Wijbrand J. C. , Ortiz-Merino Raúl A. , Kaljouw Astrid , Battjes Julius , Wiering Frank W. , Mooiman Christiaan , de la Torre Pilar , Pronk Jack T. 
Published: January 2021

AbstractCurrent large-scale, anaerobic industrial processes for ethanol production from renewable carbohydrates predominantly rely on the mesophilic yeastSaccharomyces cerevisiae. Use of thermotolerant, facultatively fermentative yeasts such asKluyveromyces marxianuscould confer significant economic benefits. However, in contrast toS. cerevisiae, these yeasts cannot grow in the absence of oxygen. Response ofK. marxianusandS. cerevisiaeto different oxygen-limitation regimes were analyzed in chemostats. Genome and transcriptome analysis, physiological responses to sterol supplementation and sterol-uptake measurements identified absence of a functional sterol-uptake mechanism as a key factor underlying the oxygen requirement ofK. marxianus. Heterologous expression of a squalene-tetrahymanol cyclase enabled oxygen-independent synthesis of the sterol surrogate tetrahymanol inK. marxianus. After a brief adaptation under oxygen-limited conditions, tetrahymanol-expressingK. marxianusstrains grew anaerobically on glucose at temperatures of up to 45 °C. These results open up new directions in the development of thermotolerant yeast strains for anaerobic industrial applications.
Neutralization of N501Y mutant SARS-CoV-2 by BNT162b2 vaccine-elicited sera
Authors: Xie Xuping , Zou Jing , Fontes-Garfias Camila R. , Xia Hongjie , Swanson Kena A. , Cutler Mark , Cooper David , Menachery Vineet D. , Weaver Scott , Dormitzer Philip R. , Shi Pei-Yong 
Published: January 2021

AbstractRapidly spreading variants of SARS-CoV-2 that have arisen in the United Kingdom and South Africa share the spike N501Y substitution, which is of particular concern because it is located in the viral receptor binding site for cell entry and increases binding to the receptor (angiotensin converting enzyme 2). We generated isogenic N501 and Y501 SARS-CoV-2. Sera of 20 participants in a previously reported trial of the mRNA-based COVID-19 vaccine BNT162b2 had equivalent neutralizing titers to the N501 and Y501 viruses.
GC-1 spg cells are most similar to Leydig cells, a testis somatic cell-type, and not germ cells
Authors: Norman Andrew R. , Byrnes Lauren , Reiter Jeremy F. 
Published: January 2021

AbstractGC-1 spg is an immortalized cell line derived from an adult mouse testis and reported to be most similar to spermatocytes, a male germ cell-type. However, immunofluorescence indicates that GC-1 spg cells express WT1, a marker of testis somatic cells, and do not express markers of germ cells. Transcriptomic profiling indicate GC-1 cells are most similar to Leydig cells. Therefore, we conclude that GC-1 spg cells are most similar to testis somatic cells.
Synthetic gene networks recapitulate dynamic signal decoding and differential gene expression
Authors: Benzinger Dirk , Ovinnikov Serguei , Khammash Mustafa 
Published: January 2021

AbstractCells live in constantly changing environments and employ dynamic signaling pathways to transduce information about the signals they encounter. However, the mechanisms by which dynamic signals are decoded into appropriate gene expression patterns remain poorly understood. Here, we devise networked optogenetic pathways that achieve novel dynamic signal processing functions that recapitulate cellular information processing. Exploiting light-responsive transcriptional regulators with differing response kinetics, we build a falling-edge pulse-detector and show that this circuit can be employed to demultiplex dynamically encoded signals. We combine this demultiplexer with dCas9-based gene networks to construct pulsatile-signal filters and decoders. Applying information theory, we show that dynamic multiplexing significantly increases the information transmission capacity from signal to gene expression state. Finally, we use dynamic multiplexing for precise multidimensional regulation of a heterologous metabolic pathway. Our results elucidate design principles of dynamic information processing and provide original synthetic systems capable of decoding complex signals for biotechnological applications.
Intracellular softening and fluidification reveals a mechanical switch of cytoskeletal material contributions during division
Authors: Hurst Sebastian , Vos Bart E. , Betz Timo 
Published: January 2021

AbstractThe life and death of an organism depends largely on correct cell division. While the overall biochemical signaling and morphological processes during mitosis are well understood, the importance of mechanical forces and material properties is only just starting to be discovered. Recent studies of global cell stiffening during cell division may imply an understanding of the cytosol mechanics that is mistaken. Here we show that in contrast to the stiffening process in the cell cortex, the interior of the cell undergoes a softening and fluidification that is accompanied by a decrease of active forces driving particle mobility. Using optical tweezers-based microrheology we capture the complex active and passive material state of the cytoplasm using only six relevant parameters. We demonstrate that the softening occurs because of a surprising role switch between microtubules and actin, where the intracellular, actin-based mechanics is largely controlled by a formin-mediated network.
Effects of Emodin, a Plant-Derived Anthraquinone, on TGF-β1-Induced Cardiac Fibroblast Activation and Function
Authors: Carver Wayne , Fix Ethan , Fix Charity , Fan Daping , Chakrabarti Mrinmay , Azhar Mohamad 
Published: January 2021

AbstractCardiac fibrosis accompanies a number of pathological conditions and results in altered myocardial structure, biomechanical properties and function. The signaling networks leading to fibrosis are complex, contributing to the general lack of progress in identifying effective therapeutic approaches to prevent or reverse this condition. Several studies have shown protective effects of emodin, a plant-derived anthraquinone, in animal models of fibrosis. A number of questions remain regarding the mechanisms whereby emodin impacts fibrosis. TGF-β1 is a potent stimulus of fibrosis and fibroblast activation. In the present study, experiments were performed to evaluate the effects of emodin on activation and function of cardiac fibroblasts following treatment with TGF-β1. We demonstrate that emodin attenuates TGF-β1-induced fibroblast activation and collagen accumulation in vitro. Emodin also inhibits activation of several canonical (SMAD2/3) and non-canonical (Erk1/2) TGF-β signaling pathways, while activating the p38 pathway. These results suggest that emodin may provide an effective therapeutic agent for fibrosis that functions via specific TGF-β signaling pathways.
Atomistic Dynamics of a Viral Infection Process: Release of Membrane Lytic Peptides from a Non-Enveloped Virus
Authors: Jana Asis K. , May Eric R. 
Published: January 2021

AbstractMolecular simulations have played an instrumental role in uncovering the structural dynamics and physical properties of virus capsids. In this work we move beyond equilibrium physicochemical characterization of a virus system to study a stage of the infection process which is required for viral proliferation. Despite many biochemical and functional studies, the molecular mechanism of host cell entry by non-enveloped viruses remains largely unresolved. Flock House Virus (FHV) is model system for non-enveloped viruses and is the subject of the current study. FHV infects through the acid-dependent endocytic pathway, where low pH triggers externalization of membrane disrupting (γ) peptides from the capsid interior. Employing all-atom equilibrium and enhanced sampling simulations, the mechanism and energetics of γ peptide liberation and the effect of pH on this process is investigated. Our computations agree with experimental findings and reveal nanoscopic details regarding the pH control mechanism which are not readily accessible in experiments.
Gradual differentiation uncoupled from cell cycle exit generates heterogeneity in the epidermal stem cell layer
Authors: Cockburn Katie , Annusver Karl , Ganesan Smirthy , Mesa Kailin R. , Kawaguchi Kyogo , Kasper Maria , Greco Valentina 
Published: January 2021

AbstractHigh turnover tissues continually lose specialized cells that are replaced by stem cell activity. In the adult mammalian epidermis, it is unclear how molecularly heterogenous stem/progenitor cell populations fit into the complete trajectory of epidermal differentiation. We show that differentiation, from commitment to exit from the stem cell layer, is a multi-day process wherein cells transit through a continuum of transcriptional changes. Differentiation-committed cells remain capable of dividing to produce daughter cells fated to further differentiate, demonstrating that differentiation is uncoupled from cell cycle exit. These cell divisions are not required as part of an obligate transit amplifying program but instead protect density in the stem cell layer. Thus, instead of distinct contributions from multiple progenitors, a continuous gradual differentiation process fuels homeostatic epidermal turnover.One sentence summaryHeterogeneity in the epidermal stem cell layer reflects a gradual differentiation program that is uncoupled from the loss of proliferative capacity.
Ischemic tolerance and cardiac repair in the African spiny mouse
Authors: Koopmans Tim , van Beijnum Henriette , Roovers Elke F. , Malhotra Divyanshu , Tomasso Antonio , Boeter Jochem , Versteeg Danielle , van Rooij Eva , Bartscherer Kerstin 
Published: January 2021

AbstractIschemic heart disease and by extension myocardial infarction is the primary cause of death worldwide, necessitating regenerative therapies to restore heart function. Current models of heart regeneration are restricted in that they are not of adult mammalian origin, precluding the study of class-specific traits that have emerged throughout evolution, and reducing translatability of research findings to humans. Here, we overcome those restrictions by introducing the African spiny mouse (Acomys spp.), a murid rodent that has recently been found to exhibitbona fideregeneration of the back skin and ear pinna. We show that spiny mice exhibit tolerance to myocardial infarction through superior survivability, improved ventricular conduction, smaller scar size, and near-absence of cardiac remodeling. Critically, spiny mice display increased vascularization and cardiomyocyte expansion, with an associated improvement in heart function. These findings present new avenues for mammalian heart research by leveraging unique tissue properties of the spiny mouse.
Microglial Neuropilin-1 trans-regulates oligodendrocyte expansion during development and remyelination
Authors: Sherafat Amin , Pfeiffer Friederike , Reiss Alexander M. , Wood William M. , Nishiyama Akiko 
Published: January 2021

SUMMARYNG2 glia or oligodendrocyte precursor cells (OPCs) are distributed throughout the gray and white matter and generate myelinating cells. OPCs in white matter proliferate more than those in gray matter in response to platelet-derived growth factor AA (PDGF AA), despite similar levels of its alpha receptor (PDGFRα) on their surface. Here we show that the type 1 integral membrane protein Neuropilin-1 (Nrp1) is expressed not on OPCs but on amoeboid and activated microglia in white but not gray matter in an age- and activity-dependent manner. Microglia-specific deletion of Nrp1 compromised developmental OPC proliferation in white matter as well as OPC expansion and subsequent myelin repair after acute demyelination. Exogenous Nrp1 increased PDGF AA-induced OPC proliferation and PDGFRα phosphorylation on dissociated OPCs, most prominently in the presence of suboptimum concentrations of PDGF AA. These findings uncover a novel mechanism of regulating oligodendrocyte lineage cell density that involves trans-activation of PDGFRα on OPCs via Nrp1 expressed by adjacent microglia.
A high throughput lipidomics method usingscheduledmultiple reaction monitoring
Authors: Bhaskar Akash Kumar , Naushin Salwa , Ray Arjun , Pradhan Shalini , Adlakha Khushboo , Siddiqua Towfida Jahan , Malakar Dipankar , Sengupta Shantanu 
Published: January 2021

AbstractLipid compositions of cells, tissues and bio-fluids are complex, with varying concentrations and structural diversity, which makes their identification challenging. Newer methods for comprehensive analysis of lipids are thus necessary. Herein, we propose a targeted-mass spectrometry based method for large-scale lipidomics using a combination of variable retention time window and relative dwell time weightage. Using this, we detected more than 1000 lipid species, including structural isomers. The limit of detection varied from femtomolar to nanomolar range and the coefficient of variance <30% for 849 lipid species. We used this method to identify lipids altered due to Vitamin B12deficiency and found that the levels of lipids with ω-3 fatty acid chains decreased while those with ω-6 increased. This method enables identification of by far the largest number of lipid species with structural isomers in a single experiment and would significantly advance our understanding of the role of lipids in biological processes.
What is the risk of missing orbital cellulitis in children?
Authors: Ibrahim Laila F , Babl Franz E , Hopper Sandy M , Bryant Penelope A 
Published: January 2021

BackgroundPreseptal cellulitis can be difficult to distinguish from orbital cellulitis in children. The majority of patients with periorbital infections are admitted for intravenous antibiotics. This study aimed to investigate the risk of missing orbital cellulitis and the outcomes of missed patients.MethodsA prospective cohort study of children aged 3 months to 18 years diagnosed with preseptal cellulitis over 5 years. Data were collected prospectively, including demographics, clinical features and outcomes.ResultsThere were 216 children diagnosed with preseptal cellulitis. 75 (35%) were treated with oral antibiotics and 141 (65%) with intravenous antibiotics. 5 (2%) children who were hospitalised were subsequently determined to have orbital cellulitis. All 5 children were either a young infant with difficult eye examination, or had headache or vomiting.ConclusionThe risk of missing orbital cellulitis is low. Young infants with difficult eye examination or the presence of headache or vomiting should increase suspicion of orbital cellulitis.
Group-led creative writing and behavioural health in cancer: a randomised clinical trial
Authors: Nesterova Darya , Zhu Junjia , Kramer Courtney , Vasekar Monali , Truica Cristina , Joshi Aditya , Hayes Michael , Kessler Jolene , Saunders Erika F H , Drabick Joseph J , Joshi Monika 
Published: January 2021

BackgroundCancer diagnosis can adversely affect mental well-being and overall clinical outcome. We evaluated the efficacy of a group-led creative writing workshop (CWW) on mood in patients with cancer prospectively.MethodsWe conducted a single-institution phase II study. Sixty adult patients with cancer (any type or stage) were randomised 2:1 to CWW (4×CWW sessions, bimonthly over 8 weeks) versus active control (AC) (independent writing at home with the help of a book, four sessions, bimonthly over 8 weeks). The total study duration was 6 months with a follow-up of up to 3 months. Primary objective: changes in overall mood, depression and anxiety symptoms before and after intervention in both arms. Emotional Thermometer Scale (ETS) was used to assess changes in patients’ mood. Additionally, the Patient Health Questionnaire (PHQ)-9 and General Anxiety Disorder Scale (GAD)-7 were used to evaluate depression and anxiety symptoms.ResultsOf 50 evaluable patients (CWW 34, AC 17), 26 patients in the CWW arm attended at least one class and 19 attended at least four classes. Patients in CWW had significant immediate improvement in the overall ETS (post vs preclass scores; p<0.0001, 95% CI −4.31 to −2.47). Four of the five subscale ETS scores were significantly lower for the CWW arm: distress (p=0.0346, 95% CI −2.6 to −0.1), anxiety (p=0.0366, 95% CI −4.1 to −0.2), depression (p=0.0441, 95% CI −3.9 to −0.1) and anger (p=0.0494, 95% CI −3.3 to 0). No significant differences were seen in the AC arm. No significant differences were observed in the PHQ-9 or the GAD-7 scores.ConclusionCWW had a positive effect on mood based on ETS scores, suggesting a potential therapeutic benefit among patients with cancer.
Survival and risk of recurrence of takotsubo syndrome
Authors: Lau Christopher , Chiu Sarah , Nayak Rohith , Lin Bryan , Lee Ming-Sum 
Published: January 2021

ObjectiveThe goal of this study is to evaluate the long-term outcomes of patients with takotsubo syndrome and assess factors associated with death or recurrence.MethodsThis is a retrospective population-based cohort study of consecutive patients who presented to an integrated health system in Southern California with takotsubo syndrome between 2006 and 2016. Medical records were manually reviewed to confirm diagnosis and to identify predisposing factors, medication treatment and long-term outcomes. Factors associated with death or recurrent takotsubo syndrome were tested using Cox regression models.ResultsBetween 2006 and 2016, there were 519 patients with a confirmed diagnosis of takotsubo syndrome. Patients were followed for 5.2 years (IQR 3.0–7.2). During the follow-up period, 39 (7.5%) had recurrent takotsubo syndrome and 84 (16.2%) died. In multivariate modelling, factors associated with higher risk of recurrence or death were age (HR 1.56 per 10-year increase, 95% CI 1.29 to 1.87), male sex (HR 2.52, 95% CI 1.38 to 4.60), diabetes (HR 1.6, 95% CI 1.06 to 2.43), pulmonary disease (HR 2.0, 95% CI 1.37 to 2.91) and chronic kidney disease (HR 1.58, 95% CI 1.01 to 2.47). Treatment with beta-blockers were associated with lower risk of recurrence or death (HR 0.46, 95% CI 0.29 to 0.72). No association was observed between treatment with ACE inhibitors or angiotensin-receptor blockers and recurrence or death (HR 0.92, 95% CI 0.59 to 1.42).ConclusionsRecurrent takotsubo syndrome occurred in a minor subset of patients. Treatment with beta-blocker was associated with higher event-free survival.
Cultivating not gatekeeping: a key leadership role in the creative process
Authors: Katz Joshua H , Herman Geoffrey L , Johnson Mark A , Loewenstein Jeffrey 
Published: January 2021

BackgroundCreativity and innovation are frequent features in healthcare discussions and proposals. A burgeoning area of research shows that evaluating proposals is a crucial juncture in the creative process. Leadership can make a substantial difference in how well the evaluation process does.ResultOrganisational leaders want creativity, yet often inadvertently act as gatekeepers and disproportionately reject creative proposals. We review research to provide guidance for leaders on how to cultivate creativity through improvements in the process of evaluating proposals.
Chr15q25 genetic variant (rs16969968) independently confers risk of lung cancer, COPD and smoking intensity in a prospective study of high-risk smokers
Authors: Hopkins Raewyn J , Duan Fenghai , Gamble Greg D , Chiles Caroline , Cavadino Alana , Billings Paul , Aberle Denise , Young Robert P 
Published: January 2021

ImportanceWhile cholinergic receptor nicotinic alpha 5 (CHRNA5) variants have been linked to lung cancer, chronic obstructive pulmonary disease (COPD) and smoking addiction in case–controls studies, their corelationship is not well understood and requires retesting in a cohort study.ObjectiveTo re-examine the association between the CHRNA5 variant (rs16969968 AA genotype) and the development of lung cancer, relative to its association with COPD and smoking.MethodsIn 9270 Non-Hispanic white subjects from the National Lung Screening Trial, a substudy of high-risk smokers were followed for an average of 6.4 years. We compared CHRNA5 genotype according to baseline smoking exposure, lung function and COPD status. We also compared the lung cancer incidence rate, and used multiple logistic regression and mediation analysis to examine the role of the AA genotype of theCHRNA5variant in smoking exposure, COPD and lung cancer.ResultsAs previously reported, we found the AA high-risk genotype was associated with lower lung function (p=0.005), greater smoking intensity (p<0.001), the presence of COPD (OR 1.28 (95% CI 1.10 to 1.49) p=0.0015) and the development of lung cancer (HR 1.41, (95% CI 1.03 to 1.93) p=0.03). In a mediation analyses, the AA genotype was independently associated with smoking intensity (OR 1.42 (95% CI 1.25 to 1.60, p<0.0001), COPD (OR 1.25, (95% CI 1.66 to 2.53), p=0.0015) and developing lung cancer (OR 1.37, (95% CI 1.03 to 1.82) p=0.03).ConclusionIn this large-prospective study, we found the CHRNA5 rs 16 969 968 AA genotype to be independently associated with smoking exposure, COPD and lung cancer (triple whammy effect).