bluuebunny/crossref_metadata_2025_split huggingface dataset:
Accuracy of automated computer aided-risk scoring systems to estimate the risk of COVID-19 and in-hospital mortality: a retrospective cohort study
Authors: Faisal Muhammad , Mohammed Mohammed A , Richardson Donald , Fiori Massimo , Beatson Kevin 
Published: December 2020

AbstractObjectivesAlthough a set of computer-aided risk scoring systems (CARSS), that use the National Early Warning Score and routine blood tests results, have been validated for predicting in-hospital mortality and sepsis in unplanned admission to hospital, little is known about their performance for COVID-19 patients. We compare the performance of CARSS in unplanned admissions with COVID-19 during the first phase of the pandemic.Designa retrospective cross-sectional studySettingTwo acute hospitals (Scarborough and York) are combined into a single dataset and analysed collectively.ParticipantsAdult (>=18 years) non-elective admissions discharged between 11-March-2020 to 13-June-2020 with an index NEWS electronically recorded within ±24 hours. We assessed the performance of all four risk score (for sepsis: CARS_N, CARS_NB; for mortality: CARM_N, CARM_NB) according to discrimination (c-statistic) and calibration (graphically) in predicting the risk of COVID-19 and in-hospital mortality.ResultsThe risk of in-hospital mortality following emergency medical admission was 8.4% (500/6444) and 9.6% (620/6444) had a diagnosis of COVID-19. For predicting COVID-19 admissions, the CARS_N model had the highest discrimination 0.73 (0.71 to 0.75) and calibration slope 0.81 (0.72 to 0.89). For predicting in-hospital mortality, the CARM_NB model had the highest discrimination 0.84 (0.82 to 0.75) and calibration slope 0.89 (0.81 to 0.98).ConclusionsTwo of the computer-aided risk scores (CARS_N and CARM_NB) are reasonably accurate for predicting the risk of COVID-19 and in-hospital mortality, respectively. They may be clinically useful as an early warning system at the time of admission especially to triage large numbers of unplanned hospital admissions because they are automated and require no additional data collection.Article SummaryIn this study, we found that two of the automated computer-aided risk scores are reasonably accurate for predicting the risk of COVID-19 and in-hospital mortality, respectively.They may be clinically useful as an early warning system at the time of admission especially to triage large numbers of unplanned hospital admissions because they are automated and require no additional data collection.Although we focused on in-hospital mortality (because we aimed to aid clinical decision making in the hospital), the impact of this selection bias needs to be assessed by capturing out-of-hospital mortality by linking death certification data and hospital data.We identified COVID-19 based on ICD-10 code ‘U071’ which was determined by COVID-19 swab test results (hospital or community) and clinical judgment and so our findings are constrained by the accuracy of these methods
Biliverdin reductase bridges focal adhesion kinase to Src to modulate synaptic signaling
Authors: Vasavda Chirag , Semenza Evan R. , Liew Jason , Kothari Ruchita , Dhindsa Ryan S. , Shanmukha Shruthi , Ricco Cristina , Tokhunts Robert , Snowman Adele M. , Albacarys Lauren , Paul Bindu D. , Snyder Solomon H. 
Published: December 2020

ABSTRACTSynapses are complex bridges that connect discrete neurons into vast networks that send, receive, and encode diverse forms of information. However, they must remain dynamic in order to adapt to changing inputs. Here, we report that the enzyme biliverdin reductase (BVR) physically links together key molecules in focal adhesion signaling at the synapse. In challenging mice with a battery of neurocognitive tasks, we first discover that BVR null (BVR-/-) mice exhibit profound deficits in learning and memory. We uncover that these deficits may be explained by a loss of focal adhesion signaling that is both transcriptionally and biochemically disrupted in BVR-/-hippocampi. We learn that BVR mediates focal adhesion signaling by physically bridging the initiatory kinases FAK/Pyk2 to the effector kinase Src. Activated Src normally promotes synaptic plasticity by phosphorylating the N-methyl-D-aspartate (NMDA) receptor, but FAK/Pyk2 are unable to bind and stimulate Src without BVR. Src itself is a molecular hub upon which many signaling pathways converge in order to stimulate NMDA neurotransmission, positioning BVR at a prominent intersection of synaptic signaling.
Convolutional neural networks for automated CMR image segmentation in rats with myocardial infarcts
Authors: Gondova Andrea , Zurek Magdalena , Karlsson Johan , Hultin Leif , Noeske Tobias , Watson Edmund 
Published: December 2020

AbstractIn translational cardiovascular research, delineation of left ventricle (LV) in magnetic resonance images is a crucial step in assessing heart’s function. Performed manually, this task is time-consuming and prone to inter- and intra-reader variability. Here we report first AI-based tool for segmentation of rat cardiovascular MRI. The method is an ensemble of fully convolutional networks and can quantify clinically relevant measures: end-diastolic volume (EDV), end-systolic volume (ESV), and ejection fraction (EF) automatically.Overall, our method reaches Dice score of 0.93 on the independent test set. The mean absolute difference of segmented volumes between automated and manual segmentation is 22.5μL for EDV, 13.6μL for ESV, and for EF 2.9%. Our work demonstrates the value of AI in development of tools that will significantly reduce time spent on repetitive work and result in increased efficiency of reporting data to project teams.
Development of an Antiseizure Drug Screening Platform for Dravet Syndrome at the NINDS contract site for the Epilepsy Therapy Screening Program
Authors: Pernici Chelsea D. , Mensah Jeffrey A. , Dahle Elizabeth J. , Johnson Kristina J. , Handy Laura , Buxton Lauren , Smith Misty D. , West Peter J. , Metcalf Cameron S. , Wilcox Karen S. 
Published: December 2020

SummaryObjectiveDravet syndrome (DS) is a rare, but catastrophic genetic epilepsy, with 80% of patients with carrying a mutation in the SCN1A gene. Currently, no anti-seizure drug (ASD) exists that adequately controls seizures. Patients with DS often present clinically with a febrile seizure and generalized tonic-clonic seizures that continue throughout life. To facilitate the development of ASDs for DS, the contract site of the NINDS Epilepsy Therapy Screening Program (ETSP) has evaluated a mouse model of DS using the conditional knock-inScn1aA1783V/WTmouse.MethodsSurvival rates and temperature thresholds forScn1aA1783V/WTwere determined. Prototype ASDs were administered via intraperitoneal injections at the time-to-peak effect, which was previously determined, prior to the induction of hyperthermia-induced seizures. Protection was determined if ASDs significantly increased the temperature at whichScn1aA1783V/WTmice seized.ResultsApproximately 50% ofScn1aA1783V/WTsurvive to adulthood and all have hyperthermia-induce seizures. The results suggest that hyperthermia-induced seizures in this model of DS are highly refractory to a battery of ASDs. Exceptions were clobazam, tiagabine, and the combination of clobazam and valproic acid with add-on stiripentol, which elevated seizure thresholdsSignificanceOverall, the data demonstrate the proposed model for DS is suitable for screening novel compounds for the ability to block hyperthermia-induced seizures and heterozygous mice can be evaluated repeatedly over the course of several weeks, allowing for higher throughput screening.Key PointsScn1aA1783V/WTmice have a 50% survival rate and all have hyperthermia-induced seizures.Common DS treatments such as CLB and combinatorial therapy of CLB, VPA, and STP increase temperature thresholds inScn1aA1783V/WTmice.Sodium channel blockers, such as CBZ and LTG, decrease temperature thresholds ofScn1aA1783V/WTmice as predicted.Scn1aA1783V/WTmice are highly pharmacoresitant to common ASDsTheScn1aA1783V/WTmay be a useful preclinical drug screening platform for the treatment of DS.
RTN3 inhibits RIGI-I-mediated antiviral responses by impairing TRIM25-mediated K63-linked polyubiquitination
Authors: Yang Ziwei , Wang Jun , He Bailin , Zhang Xiaolin , Li Xiaojuan , Kuang Ersheng 
Published: December 2020

AbstractUpon viral RNA recognition, the RIG-I signalosome continuously generates IFNs and cytokines, leading to neutrophil recruitment and inflammation. Thus, attenuation of excessive immune and inflammatory responses is crucial to restore immune homeostasis and prevent unwarranted damage, yet few proresolving mediators have been identified. In the present study, we demonstrated that RTN3 is strongly upregulated during RNA viral infection and acts as an inflammation-resolving regulator. Increased RTN3 aggregates on the endoplasmic reticulum and interacts with both TRIM25 and RIG-I, subsequently impairing K63-linked polyubiquitination and resulting in both IRF3 and NF-κB inhibition. Rtn3 overexpression in mice causes an obvious inflammation resolving phenomenon when challenged with VSV, Rtn3-overexpressing mice display significantly decreased neutrophil numbers and inflammatory cell infiltration, which is accompanied by reduced tissue edema in the liver and thinner alveolar interstitium. Taken together, our findings identify RTN3 as a conserved proresolving mediator of immune and inflammatory responses and provide insights into the negative feedback that maintains immune and inflammatory homeostasis.SummaryRTN3 is upregulated upon RNA viral infection due to inflammation and ER stress, in turn suppresses antiviral responses by impairing TRIM25-mediated RIG-I K63-linked polyubiquitination and consequently decreases neutrophil populations and inflammatory infiltration, representing a novel mechanism of negative inflammatory resolution.
Repurposing the Ebola and Marburg Virus Inhibitors Tilorone, Quinacrine and Pyronaridine: In vitro Activity Against SARS-CoV-2 and Potential Mechanisms
Authors: Puhl Ana C. , Fritch Ethan James , Lane Thomas R. , Tse Longping V. , Yount Boyd L. , Sacramento Carol Queiroz , Tavella Tatyana Almeida , Costa Fabio Trindade Maranhão , Weston Stuart , Logue James , Frieman Matthew , Premkumar Lakshmanane , Pearce Kenneth H. , Hurst Brett L. , Andrade Carolina Horta , Levi James A. , Johnson Nicole J. , Kisthardt Samantha C. , Scholle Frank , Souza Thiago Moreno L. , Moorman Nathaniel John , Baric Ralph S. , Madrid Peter , Ekins Sean 
Published: December 2020

AbstractSARS-CoV-2 is a newly identified virus that has resulted in over 1.3 M deaths globally and over 59 M cases globally to date. Small molecule inhibitors that reverse disease severity have proven difficult to discover. One of the key approaches that has been widely applied in an effort to speed up the translation of drugs is drug repurposing. A few drugs have shownin vitroactivity against Ebola virus and demonstrated activity against SARS-CoV-2in vivo. Most notably the RNA polymerase targeting remdesivir demonstrated activityin vitroand efficacy in the early stage of the disease in humans. Testing other small molecule drugs that are active against Ebola virus would seem a reasonable strategy to evaluate their potential for SARS-CoV-2. We have previously repurposed pyronaridine, tilorone and quinacrine (from malaria, influenza, and antiprotozoal uses, respectively) as inhibitors of Ebola and Marburg virusin vitroin HeLa cells and of mouse adapted Ebola virus in mousein vivo. We have now tested these three drugs in various cell lines (VeroE6, Vero76, Caco-2, Calu-3, A549-ACE2, HUH-7 and monocytes) infected with SARS-CoV-2 as well as other viruses (including MHV and HCoV 229E). The compilation of these results indicated considerable variability in antiviral activity observed across cell lines. We found that tilorone and pyronaridine inhibited the virus replication in A549-ACE2 cells with IC50values of 180 nM and IC50198 nM, respectively. We have also tested them in a pseudovirus assay and used microscale thermophoresis to test the binding of these molecules to the spike protein. They bind to spike RBD protein with Kdvalues of 339 nM and 647 nM, respectively. Human Cmaxfor pyronaridine and quinacrine is greater than the IC50hence justifyingin vivoevaluation. We also provide novel insights into their mechanism which is likely lysosomotropic.
Bivalent chromatin protects reversibly repressed genes from irreversible silencing
Authors: Kumar Dhirendra , Jothi Raja 
Published: December 2020

ABSTRACTBivalent chromatin is characterized by the simultaneous presence of H3K4me3 and H3K27me3, histone modifications generally associated with transcriptionally active and repressed chromatin, respectively. Prevalent in embryonic stem cells, bivalency is postulated to poise lineage-controlling developmental genes for rapid activation during embryogenesis while maintaining a transcriptionally repressed state in the absence of activation cues, but its function in development and disease remains a mystery. Here we show that bivalency does not poise genes for rapid activation but protects reversibly repressed genes from irreversible silencing. We find that H3K4me3 at bivalent gene promoters—a product of the underlying DNA sequence—persists in nearly all cell types irrespective of gene expression and confers protection fromde novoDNA methylation. Accordingly, loss of H3K4me3 at bivalent promoters is strongly associated with aberrant hypermethylation and irreversible silencing in adult human cancers. Bivalency may thus represent a distinct regulatory mechanism for maintaining epigenetic plasticity.HIGHLIGHTSBivalent chromatin does not poise genes for rapid activationH3K4me3 at bivalent promoters is not instructive for transcription activationH3K4me3 at bivalent promoters protects reversibly repressed genes fromde novoDNA methylationLoss of H3K4me3/bivalency is associated with aberrant DNA hypermethylation in cancer
A time-course study of actively stained mouse brains: DTI parameter and connectomic stability over one year
Authors: Xiao Jaclyn , Hornburg Kathryn J. , Cofer Gary , Cook James J. , Qi Yi , Johnson G Allan 
Published: December 2020

ABSTRACTWhile the application of diffusion tensor imaging (DTI), tractography, and connectomics to fixed ex-vivo tissue is a common practice today, there have been limited studies examining the effects of fixation on brain microstructure over extended periods. This time-course study reports the changes of regional brain volumes and diffusion scalar parameters, such as fractional anisotropy across twelve representative brain regions as measures of brain structural stability. The scalar DTI parameters and regional volumes were highly variable over the first two weeks after fixation. The same parameters were stable over a two to eight-week window after fixation which means confounds from tissue stability over that scanning window are minimal. Quantitative connectomes were analyzed over the same time period with extension out to one year. While there is some change in the scalar metrics at one year after fixation, these changes are sufficiently small, particularly in white matter to support reproducible connectomes over a period ranging from two weeks to one year post fixation. These findings delineate a stable scanning period during which brain volumes, diffusion scalar metrics and connectomes are remarkably stable.
FGF2 disruption enhances thermogenesis in brown and beige fat to protect against obesity and hepatic steatosis
Authors: Li Haifang , Zhang Xinzhi , Huang Cheng , Liu Huan , Liu Shuang , Zhang Qiang , Dong Mei , Hou Mengjie , Liu Yiming , Lin Hai 
Published: December 2020

ABSTRACTSince brown and beige fat expend energy in the form of heat via non-shivering thermogenesis, identifying key regulators of thermogenic functions represents a major goal for development of potential therapeutic avenues for obesity and associated disorders. Here, we identified fibroblast growth factor 2 (FGF2) as a novel thermogenic regulator. FGF2 gene disruption resulted in increased thermogenic capability in both brown and beige fat, which was supported by increased UCP1 expression, enhanced respiratory exchange ratio, and elevated thermogenic potential under cold challenge or β-adrenergic stimulation. Thus, deletion of FGF2 protected mice from high fat-induced obesity and hepatic steatosis. Mechanistically, FGF2 acts in autocrine/paracrine fashionsin vitro. Exogenous FGF2 supplementation inhibits both PGC-1α and PPARγ expression through ERK phosphorylation, thereby limiting PGC-1α/PPARγ interactions, and leading to suppression of UCP1 expression and thermogenic activity in brown and beige adipocytes. These findings suggest a viable potential strategy for use of FGF2-selective inhibitors in treatment of combating obesity and related disorders.
Effectivein-vitroinactivation of SARS-CoV-2 by commercially available mouthwashes
Authors: Davies Katherine , Buczkowski Hubert , Welch Stephen R , Green Nicole , Mawer Damian , Woodford Neil , Roberts Allen DG , Nixon Peter J , Seymour David W , Killip Marian J 
Published: December 2020

ABSTRACTInfectious SARS-CoV-2 can be recovered from the oral cavities and saliva of COVID-19 patients with potential implications for disease transmission. Reducing viral load in patient saliva using antiviral mouthwashes may therefore have a role as a control measure in limiting virus spread, particularly in dental settings. Here, the efficacy of SARS-CoV-2 inactivation by seven commercially available mouthwashes with a range of active ingredients were evaluatedin vitro. We demonstrate ≥4.1 to ≥5.5 log10reduction in SARS-CoV-2 titre following a one minute treatment with commercially available mouthwashes containing 0.01-0.02% stabilised hypochlorous acid or 0.58% povidone iodine, and non-specialist mouthwashes with both alcohol-based and alcohol-free formulations designed for home use. In contrast, products containing 1.5% hydrogen peroxide or 0.2% chlorhexidine gluconate were ineffective against SARS-CoV-2 in these tests. This study contributes to the growing body of evidence surrounding virucidal efficacy of mouthwashes/oral rinses against SARS-CoV-2, and has important applications in reducing risk associated with aerosol generating procedures in dentistry and potentially for infection control more widely.
A promiscuous archaeal cardiolipin synthase generating a variety of cardiolipins and phospholipids
Authors: Exterkate Marten , de Kok Niels A. W. , Andringa Ruben L. H. , Wolbert Niels H. J. , Minnaard Adriaan J. , Driessen Arnold J. M. 
Published: December 2020

AbstractCardiolipin (DPCL) biosynthesis has barely been explored in Archaeal isoprenoid-based ether lipid membranes. Here, we identified a cardiolipin synthase (MhCls) from the mesophilic anaerobic methanogenMethanospirillum hungatei.The enzyme was overexpressed inEscherichia coli,purified, and subsequently characterized by LC-MS. MhCls utilizes two archaetidylglycerol molecules in a transesterification reaction to synthesize archaeal di-phosphate cardiolipin (aDPCL) and glycerol. The enzyme is invariant to the stereochemistry of the glycerol-backbone and the nature of the lipid tail, as it also accepts phosphatidylglycerol to generate di-phosphate cardiolipin (DPCL). Remarkably, in the presence of archaetidylglycerol and phosphatidylglycerol, MhCls formed an archaeal-bacterial hybrid di-phosphate cardiolipin (hDPCL), that so far has not been observed in nature. Due to the reversibility of the transesterification, cardiolipin can be converted back in presence of glycerol into phosphatidylglycerol. In the presence of other compounds that contain primary hydroxyl groups (e.g. alcohols, water, sugars) various natural and unique artificial phospholipid species could be synthesized, including multiple di-phosphate cardiolipin species. Moreover, MhCls could utilize a glycolipid in the presence of phosphatidylglycerol to form a glycosyl-mono-phosphate cardiolipin, emphasizing the promiscuity of this cardiolipin synthase.
An Expanded Class of Histidine-Accepting Viral tRNA-like Structures
Authors: Langeberg Conner J. , Sherlock Madeline E. , MacFadden Andrea , Kieft Jeffrey S. 
Published: December 2020

ABSTRACTStructured RNA elements are common in the genomes of RNA viruses, often playing critical roles during viral infection. Some RNA elements use forms of tRNA mimicry, but the diverse ways this mimicry can be achieved are poorly understood. Histidine-accepting tRNA-like structures (TLSHis) are examples found at the 3′ termini of some positive-sense single-stranded RNA (+ssRNA) viruses where they interact with several host proteins, induce histidylation of the RNA genome, and facilitate several processes important for infection, to include replication. As only five TLSHisexamples had been reported, we explored the possible larger phylogenetic distribution and diversity of this TLS class using bioinformatic approaches. We identified many new examples of TLSHis, yielding a rigorous consensus sequence and secondary structure model that we validated by chemical probing of representative TLSHisRNAs. We confirmed new examples as authentic TLSHisby demonstrating their ability to be histidylatedin vitro, then used mutational analyses to verify a tertiary interaction that is likely analogous to the D- and T-loop interaction found in canonical tRNAs. These results expand our understanding of how diverse RNA sequences achieve tRNA-like structures and functions in the context of viral RNA genomes and lay the groundwork for high-resolution structural studies of tRNA mimicry by histidine-accepting TLSs.
Human spinal cord organoids exhibiting neural tube morphogenesis for a quantifiable drug screening system of neural tube defects
Authors: Lee Ju-Hyun , Shin Hyogeun , Shaker Mohammed R. , Kim Hyun Jung , Kim June Hoan , Lee Namwon , Kang Minjin , Cho Subin , Kwak Tae Hwan , Kim Jong Woon , Song Mi-Ryong , Kwon Seung-Hae , Han Dong Wook , Lee Sanghyuk , Choi Se-Young , Rhyu Im Joo , Kim Hyun , Geum Dongho , Cho Il-Joo , Sun Woong 
Published: December 2020

AbstractThe human spinal cord forms well-organized neural circuits for environment sensing and motor behavior. The three-dimensional (3D) induction of the spinal cord-like tissue from human pluripotent stem cells has been reported, but they often do not mimic morphological features of neurulation and their maturity is limited. Here, we report an advanced 3D culture system for the production of human spinal cord-like organoids (hSCOs) suitable for the scale-up and quantitative studies. The hSCOs exhibited many aspects of spinal cord development, including neurulation-like tube-forming morphogenesis, differentiation of the major spinal cord neurons and glial cells, and mature synaptic functional activities. We further demonstrated that hSCOs platform allowed quantitative and systematic high-throughput examination of the potential risk of neural tube defects induced by antiepileptic drugs. Thus, hSCOs can be used for understanding human spinal cord development, disease modeling, and toxicology screening.