bluuebunny/crossref_metadata_2025_split huggingface dataset:
Health-related quality of life of patients presenting to the emergency department with a musculoskeletal disorder
Authors: Gagnon Rose , Perreault Kadija , Robert-Guertin Jason , Berthelot Simon , Achou Bertrand , Hébert Luc J. 
Published: October 2020

AbstractObjectivesThe purpose of this study was to assess utility scores of patients presenting to the emergency department (ED) with a musculoskeletal disorder and to explore the influence of diverse factors on health-related quality of life.DesignSecondary analysis of data obtained before randomization during a pragmatic randomized controlled trialSettingAcademic ED in Quebec City (Canada)ParticipantsParticipants aged 18-80 years old presenting with a minor MSKD.Main Outcome MeasuresHealth-related quality of life (five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) and utility scores (0 – dead, 100 – perfect health), measured with the EQ-5D-5L, were compared between subgroups and with reference values using descriptive statistics (mean, median), rankFD ANOVAs, and χ2 tests.ResultsSixty-nine participants completed the EQ-5D-5L. Mean and median utility scores were respectively 0.536 (95% CI: 0.479-0.594) and 0.531 (IQR: 0.356-0.760). Participants with higher levels of pain (<4/10: 0.741; 4-7/10: 0.572; >7/10: 0.433) or pain interference on function (<4/10: 0.685; 4-7/10: 0.463; >7/10: 0.294) presented significantly lower utility scores. No significant differences were found for other socio-demographic characteristics. The mean overall VAS score was 58.1 (95% CI: 52.2-64.0).ConclusionsIn patients with MSKDs presenting to the ED, higher levels of pain and pain interference on function may influence perceived health-related QoL. These findings need to be confirmed on a larger scale.Trial RegistrationThis trial was registered at the US National Institutes of Health (ClinicalTrials.gov) #NCT04009369 on July 5, 2019
Global Absence and Targeting of Protective Immune States in Severe COVID-19
Authors: Combes Alexis J. , Courau Tristan , Kuhn Nicholas F. , Hu Kenneth H. , Ray Arja , Chen William S. , Cleary Simon J. , Chew Nayvin W. , Kushnoor Divyashree , Reeder Gabriella C. , Shen Alan , Tsui Jessica , Hiam-Galvez Kamir J. , Muñoz-Sandoval Priscila , Zhu Wandi S , Lee David S. , Sun Yang , You Ran , Magnen Mélia , Rodriguez Lauren , Leligdowicz Aleksandra , Zamecnik Colin R. , Loudermilk Rita P. , Wilson Michael R. , Ye Chun J. , Fragiadakis Gabriela K. , Looney Mark R. , Chan Vincent , Ward Alyssa , Carrillo Sidney ,   The UCSF COMET Consortium, Matthay Michael , Erle David J. , Woodruff Prescott G. , Langelier Charles , Kangelaris Kirsten , Hendrickson Carolyn M. , Calfee Carolyn , Rao Arjun Arkal , Krummel Matthew F. 
Published: October 2020

AbstractWhile SARS-CoV-2 infection has pleiotropic and systemic effects in some patients, many others experience milder symptoms. We sought a holistic understanding of the severe/mild distinction in COVID-19 pathology, and its origins. We performed a whole-blood preserving single-cell analysis protocol to integrate contributions from all major cell types including neutrophils, monocytes, platelets, lymphocytes and the contents of serum. Patients with mild COVID-19 disease display a coordinated pattern of interferon-stimulated gene (ISG) expression across every cell population and these cells are systemically absent in patients with severe disease. Severe COVID-19 patients also paradoxically produce very high anti-SARS-CoV-2 antibody titers and have lower viral load as compared to mild disease. Examination of the serum from severe patients demonstrates that they uniquely produce antibodies with multiple patterns of specificity against interferon-stimulated cells and that those antibodies functionally block the production of the mild disease-associated ISG-expressing cells. Overzealous and auto-directed antibody responses pit the immune system against itself in many COVID-19 patients and this defines targets for immunotherapies to allow immune systems to provide viral defense.One Sentence SummaryIn severe COVID-19 patients, the immune system fails to generate cells that define mild disease; antibodies in their serum actively prevents the successful production of those cells.
Analysis of the early Covid-19 epidemic curve in Germany by regression models with change points
Authors: Küchenhoff Helmut , Günther Felix , Höhle Michael , Bender Andreas 
Published: October 2020

AbstractWe analyze the Covid-19 epidemic curve from March to end of April 2020 in Germany. We use statistical models to estimate the number of cases with disease onset on a given day and use back-projection techniques to obtain the number of new infections per day. The respective time series are analyzed by a trend regression model with change points. The change points are estimated directly from the data. We carry out the analysis for the whole of Germany and the federal state of Bavaria, where we have more detailed data. Both analyses show a major change between March 9th and 13th for the time series of infections: from a strong increase to a decrease. Another change was found between March 25th and March 29th, where the decline intensified. Furthermore, we perform an analysis stratified by age. A main result is a delayed course of the epidemic for the age group 80+ resulting in a turning point at the end of March.Our results differ from those by other authors as we take into account the reporting delay, which turned out to be time dependent and therefore changes the structure of the epidemic curve compared to the curve of newly reported cases.
The COVID-19 Healthcare Personnel Study (CHPS): Overview, Methods and Preliminary Findings
Authors: DiMaggio Charles , Abramson David , Susser Ezra S. , Hoven Christina W. , Chen Qixuan , Andrews Howard F , Herman Daniel , Kreniske Jonah , Ryan Megan , Susser Ida , Thorpe Lorna E. , Li Guohua 
Published: October 2020

AbstractIntroductionThe onslaught of the COVID-19 pandemic has placed severe demands on US health systems and the health care workforce. In New York State (NYS) and New York City (NYC), the early American epicenter, hospitals ran the risk of exhausting supplies of ventilators, ICU beds, and personal protective equipment (PPE); the capacity of the healthcare workforce to meet the added demand was equally strained. The COVID-19 Healthcare Personnel Study (CHPS) was designed to assess adverse short and long-term physical and mental health impacts of the COVID-19 pandemic on New York’s physicians, nurse practitioners, and physician assistants.MethodsPopulation-based online survey of physicians, nurse practitioners and physician assistants registered with the New York State Department of Health. Survey-weighted descriptive results were analyzed using frequencies, proportions, and means, with 95% confidence intervals. Odds ratios were calculated for association using survey-weighted logistic regression.ResultsOver half (51.5%; 95% CI 49.1, 54.0) of respondents worked directly with COVID-19 patients. Among those tested, 27.3% (95% CI 22.5, 32.2) were positive. The majority (57.6%; 95% CI 55.2, 60.0) of respondents reported that the COVID-19 pandemic had a negative impact on their mental health. Negative mental health was associated with experiencing symptoms of COVID-19 (OR=1.7, 95% CI 1.3, 2.1) and redeployment to unfamiliar functions. (OR=1.3, 95% CI 1.1, 1.6).ConclusionsA majority of New York healthcare providers were involved in treating COVID-19 patients and reported that the pandemic had a negative impact on their mental health.
The FLI portion of EWS/FLI contributes a transcriptional regulatory function that is distinct and separable from its DNA-binding function in Ewing sarcoma
Authors: Boone Megann A. , Taslim Cenny , Crow Jesse C. , Selich-Anderson Julia , Showpnil Iftekhar A. , Sunkel Benjamin D. , Wang Meng , Stanton Benjamin Z. , Theisen Emily R. , Lessnick Stephen L. 
Published: October 2020

AbstractBackgroundEwing sarcoma is an aggressive bone cancer in children and young adults that contains a pathognomonic chromosomal translocation: t(11;22)(q24;q12). The encoded protein, EWS/FLI, fuses the low-complexity amino-terminal portion of EWS to the carboxyl-terminus of FLI. The FLI portion contains an ETS DNA-binding domain and adjacent amino- and carboxyl-regions. Early studies using non-Ewing sarcoma cellular models provided conflicting information on the role of these adjacent regions in the oncogenic function of EWS/FLI. We therefore sought to define the specific contributions of each FLI region to EWS/FLI activity in an appropriate Ewing model, and in doing so, to better understand Ewing sarcoma development mediated by the fusion protein.MethodsWe used a “knock-down/rescue” system to replace endogenous EWS/FLI expression with mutant forms of the protein in Ewing sarcoma cells and tested these for oncogenic transformation using soft-agar colony forming assays. These data were complemented by DNA-binding assays using fluorescence anisotropy, genomic localization assays using CUT&RUN, transcriptional regulation studies using luciferase reporter assays and RNA-sequencing, as well as chromatin accessibility assays using ATAC-sequencing.ResultsWe found that the DNA-binding domain and short flanking regions of FLI were required for oncogenic transformation, gene expression, genomic localization and chromatin accessibility when fused to the amino-terminal EWS-portion from EWS/FLI, but that the remaining regions of FLI were dispensable for these functions. Removal of a carboxyl-terminal alpha-helix from the short flanking regions of the DNA-binding domain of FLI created a hypomorphic EWS/FLI that retained normal DNA binding, genomic localization, and chromatin accessibility, but had significantly restricted transcriptional activity and a near total loss of oncogenic transformational capacity.ConclusionsThe DNA-binding domain and carboxyl-terminal short flanking region of FLI are the only portions of FLI required for EWS/FLI-mediated oncogenic transformation in a Ewing sarcoma cellular context. In addition to the well-defined DNA-binding function of FLI, this additional alpha-helix immediately downstream of the DNA-binding domain contributes a previously-undescribed function in gene regulation and oncogenic transformation. Understanding the function of this critical region could provide new therapeutic opportunities to target EWS/FLI in Ewing sarcoma.
Degenerated virulence and irregular development ofFusarium oxysporumf. sp.niveuminduced by successive subculture
Authors: Chang Tao-Ho , Lin Ying-Hong , Wan Yu-Ling , Chen Kan-Shu , Huang Jenn-Wen , Chang Pi-Fang Linda 
Published: October 2020

AbstractSuccessive cultivation of fungus has been reported to cause the sectorization, which leads to degeneration of developmental phenotype, and virulence.Fusarium oxysporumf. sp.niveum(Fon), the causal agent of watermelon Fusarium wilt, demonstrated that successive cultivation formed the degenerated sectors. In the present research, we demonstrated that subculture with aged mycelium increased the incidence of degenerations. To further investigate the differences between the Fon wild type (sporodochial type, ST) and variants (MT: mycelium type and PT: pionnotal type), developmental phenotypes and pathogenicity to watermelon were examined. Results have shown that degeneration variants (PT2, PT3, PT11 and MT6) were different from ST with mycelium growth, conidia production and chlamydospore formation. Virulence of degenerated variants on susceptible watermelon Grand Baby (GB) cultivar was determined after inoculated with Fon variants and Fon ST. In root dipping methods, all Fon variants showed slightly increased disease severity than ST. Conversely, all Fon variants showed a significant decrease in disease progression compared with ST through infested soil inoculation. The contrary results of two inoculation methods suggest that the changes of successive cultural degeneration may lead to the loss of pathogen virulence-related factors of the early stage of Fon infection process. Therefore, Cell wall-degrading enzymes (CWDEs; cellulase, pectinase, and xylanase) activities of different variants were analysed. All Fon degenerated variants demonstrated significantly decreased of CWDEs activities compared with ST. Additionally, transcripts level of 9 virulence-related genes (fmk1,fgb1,pacC,xlnR,pl1,rho1,gas1,wc1 and fow1) were assessed in normal state. The degenerated variants demonstrated a significantly low level of tested virulence-related genes transcripts except forfmk1,xlnRandfow1. In summary, the degeneration of Fon is triggered with successive subculture through aged mycelium. The degeneration showed significant impacts on virulence to watermelon, which caused by the reduction of CWDEs activities and declining expression of a set of virulence-related genes.
The adaptive benefit of evolved increases in hemoglobin-O2affinity is contingent on tissue O2diffusing capacity in high-altitude deer mice
Authors: Wearing Oliver H. , Ivy Catherine M. , Gutiérrez-Pinto Natalia , Velotta Jonathan P. , Campbell-Staton Shane C. , Natarajan Chandrasekhar , Cheviron Zachary A. , Storz Jay F. , Scott Graham R. 
Published: October 2020

AbstractBackgroundComplex organismal traits are often the result of multiple interacting genes and sub-organismal phenotypes, but how these interactions shape the evolutionary trajectories of adaptive traits is poorly understood. We examined how functional interactions between cardiorespiratory traits contribute to adaptive increases in the capacity for aerobic thermogenesis (maximal O2consumption, V◻O2max, during acute cold exposure) in high-altitude deer mice (Peromyscus maniculatus). We crossed highland and lowland deer mice to produce F2inter-population hybrids, which expressed genetically based variation in hemoglobin (Hb) O2affinity on a mixed genetic background. We then combined physiological experiments and mathematical modeling of the O2transport pathway to examine links between cardiorespiratory traits and V◻O2max.ResultsPhysiological experiments revealed that increases in Hb-O2affinity of red blood cells improved blood oxygenation in hypoxia, but were not associated with an enhancement in V◻O2max. Sensitivity analyses performed using mathematical modeling showed that the influence of Hb-O2affinity on V◻O2max in hypoxia was contingent on the capacity for O2diffusion in active tissues.ConclusionsThese results suggest that increases in Hb-O2affinity would only have adaptive value in hypoxic conditions if concurrent with or preceded by increases in tissue O2diffusing capacity. In high-altitude deer mice, the adaptive benefit of increasing Hb-O2affinity is contingent on the capacity to extract O2from the blood, which helps resolve controversies about the general role of hemoglobin function in hypoxia tolerance.
Early invasion of uropathogenicEscherichia coliinto the bladder wall by solitary bacteria that are protected from antibiotics and neutrophil swarms in an organoid model
Authors: Sharma Kunal , Thacker Vivek V. , Dhar Neeraj , Signorino-Gelo François , Cabrer Maria Clapés , Dubois Anaëlle , Mullenders Jasper , Knott Graham , Clevers Hans , McKinney John D. 
Published: October 2020

AbstractUropathogenicEscherichia coli(UPEC) is the most common cause of urinary tract infections (UTIs) requiring antibiotic therapy. Recurrent infections, which occur in a quarter of treated individuals, may arise from “quiescent intracellular reservoirs” of bacteria that invade deeper layers of the bladder wall following infection and exfoliation of superficial umbrella cells. Here, we present a novel bladder organoid model of UPEC infection that recapitulates the stratified bladder architecture within a small volume suitable for live-cell imaging of host-pathogen dynamics with high spatiotemporal resolution. We confirm that bacteria injected into the organoid lumen rapidly enter superficial cells that resemble umbrella cells and proliferate to generate tightly packed colonies that resemble intracellular bacterial communities (IBCs), a hallmark of UPEC pathogenesis. Unexpectedly, at early stages of infection we detect individual “solitary” bacteria that penetrate deeper layers of the organoid wall, where they evade killing by antibiotics and neutrophils. Volumetric serial block face scanning electron microscopy of infected organoids reveals that solitary bacteria can be found throughout the bladder wall and may be intracellular or pericellular (sandwiched between uroepithelial cells). Unlike bacteria within IBCs, which are coccoid-shaped and non-flagellated, solitary bacteria within the bladder wall are rod-shaped and flagellated. We conclude that early invasion of deeper layers of the bladder wall, independent of IBC formation, results in the establishment of reservoirs of solitary bacteria that resist elimination by antibiotics and the host innate immune response.
Boosting the MS1-only proteomics with machine learning allows 2000 protein identifications in 5-minute proteome analysis
Authors: Ivanov Mark V. , Bubis Julia A. , Gorshkov Vladimir , Abdrakhimov Daniil A. , Kjeldsen Frank , Gorshkov Mikhail V. 
Published: October 2020

ABSTRACTProteome-wide analyses most often rely on tandem mass spectrometry imposing considerable instrumental time consumption that is one of the main obstacles in a broader acceptance of proteomics in biomedical and clinical research. Recently, we presented a fast proteomic method termed DirectMS1 based on MS1-only mass spectra acquisition and data processing. The method allowed significant squeezing of the proteome-wide analysis to a few minute time frame at the depth of quantitative proteome coverage of 1000 proteins at 1% FDR. In this work, to further increase the capabilities of the DirectMS1 method, we explored the opportunities presented by the recent progress in the machine learning area and applied the LightGBM tree-based learning algorithm into the scoring of peptide-feature matches when processing MS1 spectra. Further, we integrated the peptide feature identification algorithm of DirectMS1 with the recently introduced peptide retention time prediction utility, DeepLC. Additional approaches to improve performance of the DirectMS1 method are discussed and demonstrated, such as FAIMS coupled to the Orbitrap mass analyzer. As a result of all improvements to DirectMS1, we succeeded in identifying more than 2000 proteins at 1% FDR from the HeLa cell line in a 5 minute LC-MS1 analysis.
DNA methylation directs nucleosome positioning in RNA-mediated transcriptional silencing
Authors: Rothi M. Hafiz , Sethuraman Shriya , Dolata Jakub , Boyle Alan P , Wierzbicki Andrzej T 
Published: October 2020

ABSTRACTRepressive chromatin modifications are instrumental in regulation of gene expression and transposon silencing. InArabidopsis thaliana, transcriptional silencing is performed by the RNA-directed DNA methylation (RdDM) pathway. In this process, two specialized RNA polymerases, Pol IV and Pol V, produce non-coding RNAs, which recruit several RNA-binding proteins and lead to the establishment of repressive chromatin marks. An important feature of chromatin is nucleosome positioning, which has also been implicated in RdDM. We show that RdDM affects nucleosomes via the SWI/SNF chromatin remodeling complex. This leads to the establishment of nucleosomes on methylated regions, which counteracts the general depletion of DNA methylation on nucleosomal regions. Nucleosome placement by RdDM has no detectable effects on the pattern of DNA methylation. Instead, DNA methylation by RdDM and other pathways affects nucleosome positioning. We propose a model where DNA methylation serves as one of the determinants of nucleosome positioning.
Sclerostin directly stimulates osteocyte synthesis of fibroblast growth factor-23
Authors: Ito Nobuaki , Prideaux Matthew , Wijenayaka Asiri R. , Yang Dongqing , Ormsby Renee T. , Bonewald Lynda F. , Atkins Gerald J. 
Published: October 2020

AbstractOsteocyte produced fibroblast growth factor 23 (FGF23) is the key regulator of serum phosphate (Pi) homeostasis. The interplay between parathyroid hormone (PTH), FGF23 and other proteins that regulate FGF23 production and serum Pi levels is complex and incompletely characterised. Evidence suggests that the protein product of theSOSTgene, sclerostin (SCL), also a PTH target and also produced by osteocytes, plays a role in FGF23 expression, however the mechanism for this effect is unclear. Part of the problem of understanding the interplay of these mediators is the complex multi-organ system that achieves Pi homeostasisin vivo. In the current study, we sought to address this using a unique cell line model of the osteocyte, IDG-SW3, known to express FGF23 at both the mRNA and protein levels. In cultures of differentiated IDG-SW3 cells, both PTH1-34and recombinant human (rh) SCL remarkably inducedFgf23mRNA expression dose-dependently within 3 hours. Both rhPTH1-34and rhSCL also strongly induced C-terminal FGF23 protein secretion. Secreted intact FGF23 levels remained unchanged, consistent with constitutive post-translational cleavage of FGF23 in this cell model. Both rhPTH1-34and rhSCL treatments significantly suppressed mRNA levels ofPhex, Dmp1andEnpp1mRNA, encoding putative negative regulators of FGF23 levels, and inducedGalnt3mRNA expression, encoding N-acetylgalactosaminyl-transferase 3 (GalNAc-T3), which protects FGF23 from furin-like proprotein convertase-mediated cleavage. The effect of both rhPTH1-34and rhSCL was antagonised by pre-treatment with the NF-κβ signalling inhibitors, BAY11 and TPCK. RhSCL also stimulatedFGF23mRNA expression inex vivocultures of human bone. These findings provide evidence for the direct regulation of FGF23 expression by sclerostin. Locally expressed sclerostin via the induction of FGF23 in osteocytes thus has the potential to contribute to the regulation of Pi homeostasis.
Ethanol’s interaction with BK channel α subunit residue K361 does not mediate behavioral responses to alcohol in mice
Authors: Okhuarobo Agbonlahor , Kreifeldt Max , Gandhi Pauravi J , Lopez Catherine , Martinez Briana , Bajo Michal , Bhattacharyya Pushpita , Dopico Alex M , Roberto Marisa , Roberts Amanda J , Homanics Gregg E , Contet Candice 
Published: October 2020

AbstractLarge conductance potassium (BK) channels are among the most sensitive molecular targets of ethanol and genetic variations in the channel-forming α subunit have been nominally associated with alcohol use disorders. However, whether the direct action of ethanol at BK α influences the motivation to drink alcohol remains to be determined. In the present study, we sought to investigate the behavioral relevance of this molecular interaction by introducing in the mouse genome a point mutation known to render BK channels insensitive to ethanol while preserving their physiological function. The BK α K361N substitution prevented ethanol from reducing spike threshold in medial habenula neurons. However, it did not alter acute responses to ethanolin vivo, including ataxia, sedation, hypothermia, analgesia, and conditioned place preference.Furthermore, the mutation did not have reproducible effects on alcohol consumption in limited, continuous, or intermittent access home cage two-bottle choice paradigms conducted in both males and females. Notably, in contrast to previous observations made in mice missing BK channel auxiliary β subunits, the BK α K361N substitution had no significant impact on ethanol intake escalation induced by chronic intermittent alcohol vapor inhalation. It also did not affect the metabolic and locomotor consequences of chronic alcohol exposure. Altogether, these data suggest that the direct interaction of ethanol with BK α does not mediate the alcohol-related phenotypes examined here in mice.