bluuebunny/crossref_metadata_2025_split huggingface dataset:
Chansu Injection Improves the Respiratory Function of Severe COVID-19 Patients
Authors: Hu Fen , Chen Jiao , Chen Hao , Zhu Jin , Wang Chen , Ni Haibin , Cheng Jianming , Cao Peng , Hu Xingxing 
Published: May 2020

AbstractChansu and its major active constituent of bufalin have been reported to have broad-spectrum antiviral effects. This study aims to assess the efficacy of Chansu injection in treating patients with severe COVID-19. The patients diagnosed as severe or critical COVID-19 in The First People’s Hospital of Jiangxia District, Wuhan, China from February 5 to March 5, 2020 were randomly allocated in a 1:1 ratio to receive general treatment plus Chansu injection or only general treatment as the control group. The treatment course was 7 days. The changes of PaO2/FiO2 and ROX index indicating respiratory function, the white blood cell (WBC) count, peripheral blood mononuclear lymphocyte (PBML) count, respiratory support step-down time (RSST), and safety indicators for the 7th day were retrospectively analyzed. After 7 days treatment, the oxygenation index was improved in 20 of 21 patients (95.2%) in the treatment group, as compared with 13 of 19 patients (68.4%) in the control group. The PaO2/FiO2 and ROX indices in the treatment group (mean, 226.27±67.35 and 14.01±3.99 respectively) were significantly higher than the control group (mean, 143.23±51.29 and 9.64±5.54 respectively). The RSST was 1 day shorter in the treatment group than the control group. Multivariate regression analysis suggested that Chansu injection contributed the most to the outcome of PaO2/FiO2. No obvious adverse effects were observed. Preliminary data showed that Chansu injection had apparent efficacy in treating patients with severe COVID-19.Significance StatementPatients with severe COVID-19 usually have dyspnea and/or hypoxemia one week after the onset of symptoms, and can quickly progress to acute respiratory distress syndrome, septic shock, metabolic acidosis that is difficult to correct, coagulation dysfunction and multiple organs failure. Chansu injection, a widely used drug in clinical cancer and chronic hepatitis B therapy in China, can improve the respiratory function and shorten the respiratory support step-down time with 1 day in patients with severe COVID-19. These preliminary findings raise the possibility that Chansu injection may be helpful in the treatment of patients with severe COVID-19.
Ledidi: Designing genomic edits that induce functional activity
Authors: Schreiber Jacob , Lu Yang Young , Noble William Stafford 
Published: May 2020

AbstractThe development of modern genome editing tools has enabled researchers to make edits with high precision, but has left unsolved the problem of designing these edits. We propose Ledidi, an approach that treats the design of genomic edits as an optimization problem where the goal is to produce the desired output from a predictive model. The discrete nature of biological sequences makes direct optimization challenging, but we overcome this by using the Gumbel-Softmax reparameterization trick. We validate Ledidi by pairing it with the Basenji model, which makes predictions for thousands of functional profiles, and designing edits that affect CTCF binding and induce cell type-specific binding of JUND.
Expanding Covid-19 Testing: Mathematical Guidelines for the Optimal Sample Pool Size Given Positive Test Rate
Authors: Adams Kayleigh 
Published: May 2020

AbstractWidespread testing is essential to the mitigation of the spread of any virus, and is particularly central to the discussion on transitioning out of national quarantine. Sample pooling is a method that aims to multiply testing capability by using one testing kit for multiple samples, but will only be successful under certain conditions. This paper gives precise guidelines on those conditions for success: for any proposed sample pool size, explicit bounds on the positive infection rate are given that are informed by both discrete and statistical modeling.
Investigational treatments for COVID-19 may increase ventricular arrhythmia risk through drug interactions
Authors: Varshneya Meera , Irurzun-Arana Itziar , Campana Chiara , Dariolli Rafael , Gutierrez Amy , Pullinger Taylor K. , Sobie Eric A. 
Published: May 2020

ABSTRACTMany drugs that have been proposed for treatment of COVID-19 are reported to cause cardiac adverse events, including ventricular arrhythmias. In order to properly weigh risks against potential benefits, particularly when decisions must be made quickly, mathematical modeling of both drug disposition and drug action can be useful for predicting patient response and making informed decisions. Here we explored the potential effects on cardiac electrophysiology of 4 drugs proposed to treat COVID-19: lopinavir, ritonavir, chloroquine, and azithromycin, as well as combination therapy involving these drugs. Our study combined simulations of pharmacokinetics (PK) with quantitative systems pharmacology (QSP) modeling of ventricular myocytes to predict potential cardiac adverse events caused by these treatments. Simulation results predicted that drug combinations can lead to greater cellular action potential prolongation, analogous to QT prolongation, compared with drugs given in isolation. The combination effect can result from both pharmacokinetic and pharmacodynamic drug interactions. Importantly, simulations of different patient groups predicted that females with pre-existing heart disease are especially susceptible to drug-induced arrhythmias, compared males with disease or healthy individuals of either sex. Overall, the results illustrate how PK and QSP modeling may be combined to more precisely predict cardiac risks of COVID-19 therapies.
Personalizedin-silicodrug response prediction based on the genetic landscape of muscle-invasive bladder cancer
Authors: Krentel Friedemann , Singer Franziska , Lourdes Rosano-Gonzalez María , Gibb Ewan A. , Liu Yang , Davicioni Elai , Keller Nicola , Stekhoven Daniel , Kruithof-de Julio Marianna , Seiler Roland 
Published: May 2020

AbstractIn bladder cancer (BLCA) there are, to date, no reliable diagnostics available to predict the potential benefit of a therapeutic approach. The extraordinarily high molecular heterogeneity of BLCA might explain its wide range of therapy responses to empiric treatments. To better stratify patients for treatment response, we present a highly automated workflow forin-silicodrug response prediction based on a tumor’s individual multi-omic profile. Within the TCGA-BLCA cohort, the algorithm identified a panel of 21 genes and 72 drugs, that suggested personalized treatment for 94,7% of patients - including five genes not yet reported as biomarkers for clinical testing in BLCA. The automated predictions were complemented by manually curated data, thus allowing for accurate sensitivity- or resistance-directed drug response predictions. Manual curation revealed pitfalls of current, and potential of future drug-gene interaction databases. Functional testing in patient derived models and/or clinical trials are next steps to validate ourin-silicodrug predictions.
Late adolescence mortality in mice with brain-specific deletion of the volume-regulated anion channel subunit LRRC8A
Authors: Wilson Corinne S. , Dohare Preeti , Orbeta Shaina , Nalwalk Julia W. , Huang Yunfei , Ferland Russell J. , Sah Rajan , Scimemi Annalisa , Mongin Alexander A. 
Published: May 2020

AbstractThe leucine-rich repeat-containing family 8 member A (LRRC8A) is an essential subunit of the volume-regulated anion channel (VRAC). VRAC is critical for cell volume control, but its broader physiological functions remain under investigation. Recent studies in the field indicate thatLrrc8adisruption in brain astrocytes reduces neuronal excitability, impairs synaptic plasticity and memory, and protects against cerebral ischemia. In the present work, we generated the brain-wide conditional LRRC8A knock-out mice (LRRC8A bKO) usingNestinCre-drivenLrrc8aflox/floxexcision in neurons, astrocytes, and oligodendroglia. LRRC8A bKO animals were born close to the expected Mendelian ratio and developed without overt histological abnormalities, but, surprisingly, all died between 5 and 9 weeks of age with a seizure phenotype, which was confirmed by video and EEG recordings. Brain slice electrophysiology detected changes in the excitability of pyramidal cells and modified GABAergic inputs in the hippocampal CA1 region of LRRC8A bKO. LRRC8A-null hippocampi showed increased immunoreactivity of the astrocytic marker GFAP, indicating reactive astrogliosis. We also found decreased whole-brain protein levels of the GABA transporter GAT-1, the glutamate transporter GLT-1, and the astrocytic enzyme glutamine synthetase. Complementary HPLC assays identified reduction in the tissue levels of the glutamate and GABA precursor glutamine. Together, these findings suggest that VRAC provides vital control of brain excitability in mouse adolescence. VRAC deletion leads to a lethal phenotype involving progressive astrogliosis and dysregulation of astrocytic uptake and supply of amino acid neurotransmitters and their precursors.
Quantitative modeling of the effect of antigen dosage on B-cell affinity distributions in maturating germinal centers
Authors: Molari Marco , Eyer Klaus , Baudry Jean , Cocco Simona , Monasson Rémi 
Published: May 2020

AbstractAffinity maturation is a complex dynamical process allowing the immune system to generate antibodies capable of recognizing antigens. We introduce a model for the evolution of the distribution of affinities across the antibody population in germinal centers. The model is amenable to detailed mathematical analysis, and gives insight on the mechanisms through which antigen availability controls the rate of maturation and the expansion of the antibody population. It is also capable, upon maximum-likelihood inference of the parameters, to reproduce accurately the distributions of affinities of IgG-secreting cells we measure in mice immunized against Tetanus Toxoid under largely varying conditions (antigen dosage, delay between injections). Both model and experiments show that the average population affinity depends non-monotonically on the antigen dosage. We show that combining quantitative modelling and statistical inference is a concrete way to investigate biological processes underlying affinity maturation (such as selection permissiveness), hardly accessible through measurements.
A transfer-learning approach for first-year developmental infant brain segmentation using deep neural networks
Authors: Wang Yun , Haghpanah Fateme Sadat , Aw Natalie , Laine Andrew , Posner Jonathan 
Published: May 2020

AbstractThe months between birth and age 2 are increasingly recognized as a period critical for neuro-development, with potentially life-long implications for cognitive functioning. However, little is known about the growth trajectories of brain structure and function across this time period. This is in large part because of insufficient approaches to analyze infant MRI scans at different months, especially brain segmentation. Addressing technical gaps in infant brain segmentation would significantly improve our capacity to efficiently measure and identify relevant infant brain structures and connectivity, and their role in long-term development. In this paper, we propose a transfer-learning approach based on convolutional neural network (CNN)-based image segmentation architecture, QuickNAT, to segment brain structures for newborns and 6-month infants separately. We pre-trained QuickNAT on auxiliary labels from a large-scale dataset, fine-tuned on manual labels, and then cross-validated the model’s performance on two separate datasets. Compared to other commonly used methods, our transfer-learning approach showed superior segmentation performance on both newborns and 6-month infants. Moreover, we demonstrated improved hippocampus segmentation performance via our approach in preterm infants.
Study of pre-synaptic internalisation in human schizophrenia brains
Authors: Tzioras Makis , Stevenson Anna J. , Boche Delphine , Spires-Jones Tara L. 
Published: May 2020

AbstractAimsEfficient synaptic communication is crucial to maintain healthy behavioural and cognitive processes. Individuals affected by schizophrenia present behavioural symptoms and alterations in decision-making, suggesting altered synaptic integrity as the support of the illness. It is currently unknown how this synaptic change is mediated in schizophrenia, but microglia have been proposed to act as the culprit, actively removing synapses pathologically. Here, we aimed to explore the interaction between microglia and synaptic uptake in human post-mortem tissue.MethodsWe assessed microglial activation and synaptic internalisation by microglia in a post-mortem human tissue of 10 control and 10 schizophrenia cases. Immunohistochemistry was performed to identify microglia (Iba1 and CD68) and the presynaptic terminals (synapsin I).ResultsWe found no difference in microglial expression, nor a difference in pre-synaptic protein level phagocyted by microglia between the two groups.ConclusionsOur findings are consistent with the brain imaging studies in schizophrenia implying that microglia play a role mainly during the early phases of the disease, by example in active synapse remodelling, which is not detected in the chronic stage of the illness.
A benchmark of online COVID-19 symptom checkers
Authors: Munsch Nicolas , Martin Alistair , Gruarin Stefanie , Nateqi Jama , Abdarahmane Isselmou , Weingartner-Ortner Rafael , Knapp Bernhard 
Published: May 2020

AbstractBackgroundA large number of online COVID-19 symptom checkers and chatbots have been developed but anecdotal evidence suggests that their conclusions are highly variable. To our knowledge, no study has evaluated the accuracy of COVID-19 symptom checkers in a statistically rigorous manner.MethodsIn this paper, we evaluate 10 different COVID-19 symptom checkers screening 50 COVID-19 case reports alongside 410 non-COVID-19 control cases.ResultsWe find that the number of correctly assessed cases varies considerably between different symptom checkers, with Symptoma (F1=0.92, MCC=0.85) showing the overall best performance followed by Infermedica (F1=0.80, MCC=0.61).
Analysis of Crowdsourced Metformin Tablets from Individuals Reveals Widespread Contamination with N-Nitrosodimethylamine (NDMA) and N,N-Dimethylformamide (DMF) in the United States
Authors: Wu Qian , Kvitko Evgenia , Hudspeth Amber , Williams Shannon , Costantino Ryan C. , Kucera Kaury , Light David 
Published: May 2020

AbstractReports of metformin drug products contaminated with unacceptable levels of the probable human carcinogen N-Nitrosodimethylamine (NDMA) prompted a national sampling of post-market metformin drug products in early 2020. To broadly sample the United States market and minimize supply chain bias, metformin medication samples were crowdsourced directly from individuals across many states. 155 samples were received, and liquid chromatography-high resolution mass spectrometry tests for a panel of nitrosamines and N,N-Dimethylformamide (DMF) revealed significant levels of NDMA and DMF that relate to formulation. 49% of all medication samples contained detectable levels of NDMA and, when scaled to maximum daily tablet dose, 16% of all medication samples contained NDMA levels exceeding the United States Food and Drug Administration acceptable daily intake (ADI) limit. The highest NDMA detection from the tested samples was 748 ng per 500 mg tablet, which, when scaled to a common 2000 mg per day dosage regimen, is 31 times the ADI limit. The presence of N,N-Dimethylformamide (DMF) across 74% of the sampled metformin products is concerning given its same carcinogenicity categorization as NDMA and proposed role in formation of NDMA. Results underscore the need for continued surveillance of product quality, recalls of tainted medications, and investigation of metformin manufacturing practices.
The p150 Isoform of ADAR1 Blocks Sustained RLR signaling and Apoptosis during Influenza Virus Infection
Authors: Vogel Olivia A. , Han Julianna , Liang Chieh-Yu , Manicassamy Santhakumar , Perez Jasmine T. , Manicassamy Balaji 
Published: May 2020

AbstractSignaling through retinoic acid inducible gene I (RIG-I) like receptors (RLRs) is tightly regulated, with activation occurring upon sensing of viral nucleic acids, and suppression mediated by negative regulators. Under homeostatic conditions aberrant activation of melanoma differentiation-associated protein-5 (MDA5) is prevented through editing of endogenous dsRNA by RNA editing enzyme Adenosine Deaminase Acting on RNA (ADAR1). In addition, ADAR1 is postulated to play proviral and antiviral roles during viral infections that are dependent or independent of RNA editing activity. Here, we investigated the importance of ADAR1 isoforms in modulating influenza A virus (IAV) replication and revealed the opposing roles for ADAR1 isoforms, with the nuclear p110 isoform restricting versus the cytoplasmic p150 isoform promoting IAV replication. Importantly, we demonstrate that p150 is critical for preventing sustained RIG-I signaling, as p150 deficient cells showed increased IFN-β expression and apoptosis during IAV infection, independent of RNA editing activity. Taken together, the p150 isoform of ADAR1 is important for preventing sustained RIG-I induced IFN-β expression and apoptosis during viral infection.
Osteoarthritis: articular chondrocyte inflammatory signaling leads to enhanced gene expression and function of mechanotransduction channel Piezo1 as a pathogenic feed-forward mechanism
Authors: Lee Whasil , Nims Robert J. , Savadipour Alireza , Leddy Holly , Liu Fang , McNulty Amy , Chen Yong , Guilak Farshid , Liedtke Wolfgang B. 
Published: May 2020

AbstractOsteoarthritis (OA) is a painful and debilitating condition of synovial joints without any disease-modifying therapies (1, 2). We previously identified mechanosensitive PIEZO channels, PIEZO1 and PIEZO2, both expressed in articular cartilage, to function in chondrocyte mechanotransduction in response to injury (3, 4). We therefore asked whether interleukin-1-mediated inflammatory signaling, as occurs in OA, influences Piezo gene expression and channel function, thus indicative of maladaptive reprogramming that can be rationally targeted. Primary porcine chondrocyte culture and human osteoarthritic cartilage tissue were studied.We found that interleukin-1α (IL-1α) upregulated Piezo1 in porcine chondrocytes. Piezo1 expression was significantly increased in human osteoarthritic cartilage. Increased Piezo1 expression in chondrocytes resulted in a feed-forward pathomechanism whereby increased function of Piezo1 induced excess intracellular Ca2+, at baseline and in response to mechanical deformation. Elevated resting state Ca2+in turn rarefied the F-actin cytoskeleton and amplified mechanically-induced deformation-microtrauma. As intracellular substrates of this novel OA-related inflammatory pathomechanism, in porcine articular chondrocytes exposed to IL-1α we discovered that enhanced Piezo1 expression depended on p38 MAP-kinase and transcription factors HNF4 and ATF2/CREBP1. CREBP1 directly bound to the proximalPIEZO1gene promoter.In ensemble, these signaling and genetic re-programming events represent a novel and detrimental Ca2+-driven feed-forward mechanism that can be rationally targeted to stem the progression of OA.Significance StatementOsteoarthritis affecting weight-bearing joints is a global health problem, causing loss of mobility and enormous healthcare costs. Disease-modifying approaches are lacking. Here, we report a new cellular mechanism of inflammatory signaling in chondrocytes, the cellular substrate of cartilage. We show how osteoarthritis-relevant levels of interleukin-1α reprogram articular chondrocytes so that they become more susceptible to mechanical trauma, which chondrocytes sense via Piezo1/2 mechanosensitive ion channels. We uncover that IL-1α enhances gene expression of Piezo1 in primary articular chondrocytes underlying Piezo1 gain-of-function. We elucidate the new signaling pathway, from membrane to nucleus, including transcription factors that enhance Piezo1-expression. We also define detrimental effects of gain-of-function of Piezo1, for mechanotransduction and at-rest, that suggest this new reprogramming mechanism to contribute to osteoarthritis pathogenesis.
SARS-CoV-2 IgG Antibody Responses in New York City
Authors: Reifer Josh , Hayum Nosson , Heszkel Benzion , Klagsbald Ikey , Streva Vincent A. 
Published: May 2020

ABSTRACTSevere Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a strain of coronavirus that causes coronavirus disease 2019 (Covid-19) and has been declared a global pandemic by the World Health Organization. Total cases of SARS-CoV-2 worldwide exceed 4.8 million, with over 320,000 deaths recorded. Little is known about the body’s immune response to SARS-CoV-2 infection. In this paper, we describe SARS-CoV-2 IgG antibody responses in 28,523 patients from the New York City metropolitan area and report a SARS-CoV-2 IgG positivity rate of 44%, indicating the widespread nature of the pandemic in the city and state of New York. Additionally, for a subset of patients, we report on the correlation between SARS-CoV-2 patient symptom severity and level of SARS-CoV-2 IgG antibody found in the patient sample.
Evaluation of ELISA tests for the qualitative determination of IgG, IgM and IgA to SARS-CoV-2
Authors: Francesca Colavita , Alessandra Brogi , Daniele Lapa , Licia Bordi , Giulia Matusali , Silvia Meschi , Patrizia Marsella , Giulia Tesi , Tommaso Bandini , Antonino Di Caro , Rosaria Capobianchi Maria , Concetta Castilletti 
Published: May 2020

AbstractSerological assays for anti-SARS-CoV-2 antibodies are now of critical importance to support diagnosis, guide epidemiological intervention, and understand immune response to natural infection and vaccine administration. We developed and validated new anti-SARS-CoV-2 IgG, IgM and IgA ELISA tests (ENZY-WELL SARS-CoV-2 ELISA, DIESSE Diagnostica Senese S.p.a.) based on whole-virus antigens. We used a total of 553 serum samples including samples from COVID-19 suspected and confirmed cases, healthy donors, and patients positive for other infections or autoimmune conditions. Overall, the assays showed good concordance with the indirect immunofluorescence reference test in terms of sensitivity and specificity. Especially for IgG and IgA, we observed high sensitivity (92.5 and 93.6%, respectively); specificity was high (>96%) for all antibody types ELISAs. In addition, sensitivity was linked to the days from symptoms onset (DSO) due to the seroconversion window, and for ENZY-WELL SARS-CoV-2 IgG and IgA ELISAs resulted 100% in those samples collected after 10 and 12 DSO, respectively. The results showed that ENZY-WELL SARS-CoV-2 ELISAs may represent a valid option for both diagnostic and epidemiological purposes, covering all different antibody types developed in SARS-CoV-2 immune response.
The spectrum of COVID-19-associated dermatologic manifestations: an international registry of 716 patients from 31 countries
Authors: Freeman Esther E. , McMahon Devon E. , Lipoff Jules B. , Rosenbach Misha , Kovarik Carrie , Desai Seemal R. , Harp Joanna , Takeshita Junko , French Lars E. , Lim Henry W. , Thiers Bruce H. , Hruza George J. , Fox Lindy P. 
Published: May 2020

Key PointsQuestionWhat are the cutaneous manifestations associated with COVID-19 and do they provide insight into the pathophysiology or prognosis?FindingsIn this international registry-based case series of 716 patients representing 31 countries, the most common dermatologic morphologies encountered in the 171 COVID-19 confirmed case included morbilliform, pernio-like, urticarial, macular erythema, vesicular, papulosquamous, and retiform purpura. Retiform purpura was seen exclusively in critically ill, hospitalized patients.MeaningCOVID-19 is associated with a spectrum of skin findings in affected patients. These cutaneous manifestations may vary depending on the severity of COVID-19.