bluuebunny/crossref_metadata_2025_split huggingface dataset:
PT150 is a modulator of glucocorticoid and androgen receptors with antiviral activity against SARS-CoV-2
Authors: Theise Neil D. , Arment Anthony R. , Chakravarty Dimple , Gregg John M. H. , Jacobson Ira M. , Jung Kie Hoon , Nair Sujit S. , Tewari Ashutosh , Thurston Archie W. , Van Drie John , Westover Jonna B. 
Published: July 2020

AbstractPT150 is a clinical stage molecule, taken orally, with a strong safety profile having completed Phase 1 and Phase 2 clinical trials for its original use as an anti-depressant. It has an active IND for COVID-19. Antiviral activities have been found for PT150 and other members of its class in a variety of virus families; thus, it was now tested against SARS-CoV-2 in human bronchial epithelial lining cells and showed effective 90% inhibitory antiviral concentration (EC90) of 5.55 μM. PT150 is a member of an extended platform of novel glucocorticoid receptor (GR) and androgen receptor (AR) binding molecules. In vivo, their predominant net effect is one of systemic glucocorticoid antagonism, but they also show direct downregulation of AR and minor GR agonism at the cellular level. We hypothesize that anti-SARS-CoV-2 activity depends in part on this AR downregulation through diminished TMPRSS2 expression and modulation of ACE2 activity. Given that hypercortisolemia is now suggested to be a significant co-factor for COVID-19 progression, we also postulate an additive role for its potent immunomodulatory effects through systemic antagonism of cortisol.
Cold sensitivity of the SARS-CoV-2 spike ectodomain
Authors: Edwards Robert J , Mansouri Katayoun , Stalls Victoria , Manne Kartik , Watts Brian , Parks Rob , Janowska Katarzyna , Gobeil Sophie M. C. , Kopp Megan , Li Dapeng , Lu Xiaozhi , Mu Zekun , Deyton Margaret , Oguin Thomas H , Sprenz Jordan , Williams Wilton , Saunders Kevin , Montefiori David , Sempowski Gregory D. , Henderson Rory , Alam Munir , Haynes Barton F. , Acharya Priyamvada 
Published: July 2020

AbstractThe SARS-CoV-2 spike (S) protein, a primary target for COVID-19 vaccine development, presents its Receptor Binding Domain in two conformations: receptor-accessible “up” or receptor-inaccessible “down” conformations. Here, we report that the commonly used stabilized S ectodomain construct “2P” is sensitive to cold temperature, and that this cold sensitivity is resolved in a “down” state stabilized spike. Our results will impact structural, functional and vaccine studies that use the SARS-CoV-2 S ectodomain.
Reductions in 2020 US life expectancy due to COVID-19 and the disproportionate impact on the Black and Latino populations
Authors: Andrasfay Theresa , Goldman Noreen 
Published: July 2020

AbstractCOVID-19 has resulted in a staggering death toll in the US: over 180,000 by the end of August 2020, according to the National Center for Health Statistics. Black and Latino Americans have experienced a disproportionate burden of COVID-19 morbidity and mortality, reflecting persistent structural inequalities that increase risk of exposure to COVID-19 and mortality risk for those infected. We estimate life expectancy at birth and at age 65 for 2020, for the total US population and by race and ethnicity, using four scenarios of deaths – one in which the COVID-19 pandemic had not occurred and three including COVID-19 mortality projections produced by the Institute for Health Metrics and Evaluation. Our most likely estimate indicates a reduction in US life expectancy at birth of 1.41 years. This decline results in a life expectancy of 77.2 years, a value last observed in 2003. We also project a 1.08-year reduction in life expectancy at age 65. The Black and Latino populations are estimated to experience declines in life expectancy at birth of 2.69 and 3.66 years, respectively, both of which are several times the 0.84-year reduction for whites. These projections imply an increase of over 50% in the Black-white life expectancy gap, from 3.6 to 5.5 years, thereby eliminating twenty years of progress made in reducing this differential. Latinos, who have consistently experienced lower mortality than whites (a phenomenon known as the Latino or Hispanic paradox), would see their more than three-year survival advantage almost eliminated.
Efficacy of Chloroquine or Hydroxychloroquine in COVID-19 Patients: A Systematic Review and Meta-Analysis
Authors: Kashour Zakariya , Riaz Muhammad , Garbati Musa A. , AlDosary Oweida , Tlayjeh Haytham , Gerberi Dana , Murad M. Hassan , Sohail M. Rizwan , Kashour Tarek , Tleyjeh Imad M. 
Published: July 2020

BackgroundChloroquine (CQ) and hydroxychloroquine (HCQ) show anti-SARS-CoV-2 activity in vitro; however, clinical studies have reported conflicting results. We sought to systematically evaluate the effect of CQ and HCQ with or without azithromycin (AZ) on outcomes of COVID-19 patients.MethodsWe searched Medline, Embase, EBM Reviews, Scopus, Web of Science, preprints and grey literature up to July 7, 2020. We included studies that assessed COVID-19 patients treated with CQ or HCQ, with or without AZ. We pooled only adjusted effect estimates of mortality using a random effect model. We summarized the effect of CQ or HCQ on viral clearance and ICU admission/ mechanical ventilation.ResultsOut of 1463 citations screened for eligibility, five RCTs and 14 cohort studies were included (20,263 hospitalized patients). Thirteen studies (1 RCT and 12 cohorts) with 15,938 patients examined the effect of HCQ on short term mortality. The pooled adjusted OR was 1.05 (95% CI 0.96-1.15, I2=0 %, p=0.647). Six cohort studies examined the effect of HCQ and AZ combination among 14,016 patients. The pooled adjusted OR was 0.93 (95% CI 0.79-1.11, I2=59.3%, p=0.003). Two cohort studies and three RCTs found no significant effect of HCQ on viral clearance. One RCT with 48 patients demonstrated improved viral clearance in patients treated with CQ and HCQ. Three cohort studies found that HCQ with or without AZ had no significant effect on mechanical ventilation/ ICU admission.ConclusionModerate certainty evidence suggests that HCQ, with or without AZ, lacks efficacy in reducing short-term mortality in patients hospitalized with COVID-19.SummaryThis systematic review and meta-analysis showed that in-hospital treatment of COVID-19 patients with antimalarials medications failed to reduce short-term mortality and morbidity with potential harm if used in combination with azithromycin.
Novel surrogate virus neutralization test reveals low serum neutralizing anti-SARS-CoV-2-S antibodies levels in mildly affected COVID-19 convalescents
Authors: Bošnjak Berislav , Stein Saskia Catherina , Willenzon Stefanie , Cordes Anne Katrin , Puppe Wolfram , Bernhardt Günter , Ravens Inga , Ritter Christiane , Schultze-Florey Christian R. , Gödecke Nina , Martens Jörg , Kleine-Weber Hannah , Hoffmann Markus , Cossmann Anne , Yilmaz Mustafa , Pink Isabelle , Hoeper Marius M. , Behrens Georg M.N. , Pöhlmann Stefan , Blasczyk Rainer , Schulz Thomas F. , Förster Reinhold 
Published: July 2020

AbstractNeutralizing antibodies targeting the receptor-binding domain (RBD) of the SARS-CoV-2 spike (S) block severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry into cells using surface-expressed angiotensin-converting enzyme 2 (ACE2). We developed a surrogate neutralization test (sVNT) to assess at what degree serum antibodies interfere with the binding of SARS-CoV-2-S-RBD to ACE2. The sVNT revealed neutralizing anti-SARS-CoV-2-S antibodies in the sera of 90% of mildly and 100% of severely affected coronavirus-disease-2019 (COVID-19) convalescent patients. Importantly, sVNT results correlated strongly to the results from pseudotyped-vesicular stomatitis virus-vector-based neutralization assay and to levels of anti-SARS-CoV-2-S1 IgG and IgA antibodies. Moreover, levels of neutralizing antibodies also correlated to duration and severity of clinical symptoms, but not patient age or gender. These findings together with the sVNT will not only be important for evaluating the prevalence of neutralizing antibodies in a population but also for identifying promising plasma donors for successful passive antibody therapy.
Model-based reasoning methods for diagnosis in integrative medicine based on electronic medical records and natural language processing
Authors: Geng Wenye , Qin Xuanfeng , Wang Zhuo , Kong Qing , Tang Zihui , Jiang Lin 
Published: July 2020

AbstractBackgroundThis study aimed to investigate model-based reasoning (MBR) algorithms for the diagnosis of integrative medicine based on electronic medical records (EMRs) and natural language processing.MethodsA total of 14,075 medical records of clinical cases were extracted from the EMRs as the development dataset, and an external test dataset consisting of 1,000 medical records of clinical cases was extracted from independent EMRs. MBR methods based on word embedding, machine learning, and deep learning algorithms were developed for the automatic diagnosis of syndrome pattern in integrative medicine. MBR algorithms combining rule-based reasoning (RBR) were also developed. A standard evaluation metrics consisting of accuracy, precision, recall, and F1 score were used for the performance estimation of the methods. The association analyses were conducted on the sample size, number of syndrome pattern type, and diagnosis of lung diseases with the best algorithms.ResultsThe Word2Vec CNN MBR algorithms showed high performance (accuracy of 0.9586 in the test dataset) in the syndrome pattern diagnosis. The Word2Vec CNN MBR combined with RBR also showed high performance (accuracy of 0.9229 in the test dataset). The diagnosis of lung diseases could enhance the performance of the Word2Vec CNN MBR algorithms. Each group sample size and syndrome pattern type affected the performance of these algorithms.ConclusionThe MBR methods based on Word2Vec and CNN showed high performance in the syndrome pattern diagnosis in integrative medicine in lung diseases. The parameters of each group sample size, syndrome pattern type, and diagnosis of lung diseases were associated with the performance of the methods.Strengths and limitations of this studyA novel application of artificial intelligence – natural language processing approaches on diagnosis of integrative medicineA study of medical artificial intelligence based on real-world data of electronic medical recordsMultiple approaches on artificial intelligence to include traditional machine learning algorithms, neural network, and deep learning algorithmsRule-based combining model-based reasoning to be explored in this dataset
Assessing required SARS-CoV-2 blanket testing rates for possible control of the outbreak in the epicentre Lusaka province of Zambia with consideration for asymptomatic individuals: a simple mathematical modelling study
Authors: Sichone Joseph , Sinkala Musalula , Kikonko Mervis , Munsaka Sody M. , Simuunza Martin 
Published: July 2020

AbstractIntroductionThe novel Coronavirus disease (COVID-19), caused by the severe acute respiratory syndrome coronavirus - 2 (SARS-CoV-2), in Africa is characterised by a more substantial proportion of asymptomatic (or mildly symptomatic) individuals thought to be playing a role in the spread of the infection. The exact proportion and degree of infectiousness of asymptomatic individuals remains unclear. Studies however indicate that their management is crucial for control of SARS-CoV-2 transmission.MethodologyWe developed a simplified deterministic susceptible-exposed-infectious-removed (SEIR) mathematical model to assess the effect of active isolation of SARS-CoV-2 infected but asymptomatic individuals through blanket testing for control of the outbreak in Lusaka Province of Zambia. Here we modelled two scenarios; (1) assuming asymptomatic individuals comprised 70% of all COVID-19 cases and (2) asymptomatic individuals comprised only 50% of the cases. For contrast, the model was assessed first under the assumption that asymptomatic individuals are equally as infectious as symptomatic individuals and then secondly, and more likely, assuming asymptomatic individuals are only half as infectious as symptomatic individuals.ResultsFor the model assuming 70% asymptomatic cases, a minimum sustained blanket testing rate of ≥ 7911 tests/100000 population was sufficient to control the outbreak if asymptomatic individuals are only half as infectious while if equal infectiousness was assumed then a testing rate of ≥ 10028 tests/ 100000 population would be required. For 50% asymptomatic, minimum blanket testing rates of ≥ 4540 tests/ 100000 population was sufficient to control the outbreak at both assumed levels of infectiousness for asymptomatic individuals relative to symptomatic individuals.Discussion and conclusionOur model predicts that the current testing rates of ≈ 150/100,000 population are inadequate to control transmission of SARS-Cov-2 in Lusaka. Active isolation of COVID-19 cases including asymptomatic individuals through blanket testing can be used as a possible measure for control of the SARS-Cov-2 transmission in Lusaka, Zambia.
Integrating genetic dependencies and genomic alterations across pathways and cancer types
Authors: Park Tae Yoon , Leiserson Mark D.M. , Klau Gunnar W. , Raphael Benjamin J. 
Published: July 2020

AbstractRecent genome-wide CRISPR-Cas9 loss-of-function screens have identified genetic dependencies across many cancer cell lines. Associations between these dependencies and genomic alterations in the same cell lines reveal phenomena such as oncogene addiction and synthetic lethality. However, comprehensive characterization of such associations is complicated by complex interactions between genes across genetically heterogeneous cancer types. We introduce SuperDendrix, an algorithm to identify differential dependencies across cell lines and to find associations between differential dependencies and combinations of genetic alterations and cell-type-specific markers. Application of SuperDendrix to CRISPR-Cas9 loss-of-function screens from 554 cancer cell lines reveals a landscape of associations between differential dependencies and genomic alterations across multiple cancer pathways in different combinations of cancer types. We find that these associations respect the position and type of interactions within pathways with increased dependencies on downstream activators of pathways, such asNFE2L2and decreased dependencies on upstream activators of pathways, such asCDK6. SuperDendrix also reveals dozens of dependencies on lineage-specific transcription factors, identifies cancer-type-specific correlations between dependencies, and enables annotation of individual mutated residues.
Understanding site choice and competition through the adaptive dynamics of microbial settling strategy in a chemostat
Authors: Cai Yuhua , Geritz Stefan A. H. 
Published: July 2020

AbstractTo understand the choice and competition of sites in nature, we consider an ecological environment in a chemostat consisting of a polymorphic microbial population that can float in the fluid or settle down on the wall of the chemostat. For the transition of a microbe from its floating state to its settled state at a particular settling rate involving the choice and competition of sites on the wall, we consider three different mechanisms: (i)unimolecular-Bourgeois settling, i.e., floaters land freely on the wall, but in an occupied site, the owner keeps the site (Bourgeois behaviour); (ii)unimolecular-anti-Bourgeois settling, i.e., floaters land freely on the wall, but in an occupied site, the intruder gets the site (anti-Bourgeois behaviour); (iii)bimolecular settling, i.e., floaters land only on the vacant sites of the wall. Employing the framework of adaptive dynamics, we study the evolution of the settling rate with different settling mechanisms and investigate how physical operating conditions affect the evolutionary dynamics. Our results indicate that settling mechanisms and physical operating conditions have significant influences on the direction of evolution and the diversity of phenotypes. (1) For constant nutrient input, theoretical analysis shows that the population is always monomorphic during the long-term evolution. Notably, the direction of evolution depends on the settling mechanisms and physical operating conditions, which further determines the composition of the population. Moreover, we find two exciting transformations of types of Pairwise Invasibility Plots, which are thegradual transformationand thebang-bang transformation. (2) For periodic nutrient input, numerical analysis reveals that evolutionary coexistence is possible, and the population eventually maintains dimorphism. Remarkably, for all three settling mechanisms, the long-term evolution leads to one of the two coexisting species settle down totally on the wall if the input is low-frequency but float entirely in the fluid if the input becomes high-frequency.
Anti-SARS-CoV-2 IgG from severely ill COVID-19 patients promotes macrophage hyper-inflammatory responses
Authors: Hoepel Willianne , Chen Hung-Jen , Allahverdiyeva Sona , Manz Xue , Aman Jurjan ,   Amsterdam UMC COVID-19 Biobank, Bonta Peter , Brouwer Philip , de Taeye Steven , Caniels Tom , van der Straten Karlijn , Golebski Korneliusz , Griffith Guillermo , Jonkers René , Larsen Mads , Linty Federica , Neele Annette , Nouta Jan , van Baarle Frank , van Drunen Cornelis , Vlaar Alexander , de Bree Godelieve , Sanders Rogier , Willemsen Lisa , Wuhrer Manfred , Bogaard Harm Jan , van Gils Marit , Vidarsson Gestur , de Winther Menno , den Dunnen Jeroen 
Published: July 2020

AbstractFor yet unknown reasons, severely ill COVID-19 patients often become critically ill around the time of activation of adaptive immunity. Here, we show that anti-Spike IgG from serum of severely ill COVID-19 patients induces a hyper-inflammatory response by human macrophages, which subsequently breaks pulmonary endothelial barrier integrity and induces microvascular thrombosis. The excessive inflammatory capacity of this anti-Spike IgG is related to glycosylation changes in the IgG Fc tail. Moreover, the hyper-inflammatory response induced by anti-Spike IgG can be specifically counteracted in vitro by use of the active component of fostamatinib, an FDA- and EMA-approved therapeutic small molecule inhibitor of Syk.One sentence summaryAnti-Spike IgG promotes hyper-inflammation.
Unexpected diversity of CPR bacteria and nanoarchaea in the rare biosphere of rhizosphere-associated grassland soil
Authors: Nicolas Alexa M. , Jaffe Alexander L. , Nuccio Erin E. , Taga Michiko E. , Firestone Mary K. , Banfield Jillian F. 
Published: July 2020

AbstractCandidate Phyla Radiation (CPR) bacteria and nanoarchaea populate most ecosystems, but are rarely detected in soil. We concentrated particles less than 0.2μm from grassland soil, enabling targeted metagenomic analysis of these organisms, which are almost totally unexplored in soil. We recovered a diversity of CPR bacteria and some nanoarchaea sequences, but no sequences from other cellular organisms. The sampled sequences include Doudnabacteria (SM2F11) and Pacearchaeota, organisms not previously reported in soil, as well as Saccharibacteria, Parcubacteria and Microgenomates. CPR and DPANN (an acronym of the names of the first included archaea phyla) enrichments of 100-1000-fold were achieved compared to bulk soil, in which we estimate these organisms comprise about 1 to 100 cells per gram of soil. Like most CPR and DPANN sequenced to date, we predict these microorganisms live symbiotic, anaerobic lifestyles. However, Saccharibacteria, Parcubacteria, and Doudnabacteria genomes sampled here also encode ubiquinol oxidase operons that may have been acquired from other bacteria, likely during adaptation to aerobic soil environments. We posit that although present at low abundance, CPR bacteria and DPANN archaea could impact overall soil microbial community function by modulating host organism abundances and activity.
Hypothalamic dopamine neurons control sensorimotor behavior by modulating brainstem premotor nuclei
Authors: Barrios Joshua P. , Wang Wei-Chun , England Roman , Reifenberg Erica , Douglass Adam D. 
Published: July 2020

SummaryDopamine (DA)-producing neurons are critically involved in the production of motor behaviors in multiple circuits that are conserved from basal vertebrates to mammals. While there is increasing evidence that DA neurons in the hypothalamus play a locomotor role, their precise contributions to behavior and the circuit mechanisms by which they are achieved remain unclear. Here we demonstrate thattyrosine hydroxylase 2-expressing (th2+) DA neurons in the zebrafish hypothalamus fire phasic bursts of activity to acutely promote swimming and modulate audiomotor behaviors on fast timescales. Their anatomy and physiology reveal two distinct functional DA modules within the hypothalamus. The first comprises an interconnected set of cerebrospinal fluid-contacting DA nuclei surrounding the third ventricle, which lack distal projections outside of the hypothalamus and influence locomotion through unknown means. The second includes neurons in the preoptic nucleus, which send long-range projections to targets throughout the brain, including the mid- and hindbrain, where they activate premotor circuits involved in swimming and sensorimotor integration. These data suggest a broad regulation of motor behavior by DA neurons within multiple hypothalamic nuclei and elucidate a novel functional mechanism for the preoptic DA neurons in the initiation of movement.
A synthetic kinematic index of trunk displacement conveying the overall motor condition in Parkinson’s disease
Authors: Lopez Emahnuel Troisi , Minino Roberta , Sorrentino Pierpaolo , Rucco Rosaria , Carotenuto Anna , Agosti Valeria , Tafuri Domenico , Manzo Valentino , Liparoti Marianna , Sorrentino Giuseppe 
Published: July 2020

AbstractBACKGROUNDParkinson’s disease (PD) is characterized by motor impairment, affecting quality of life and increasing fall risk, due to ineffective postural control. To this day, the diagnosis remains based on clinical approach. Similarly, motor evaluation is based on heterogeneous, operator-dependent observational criteria. A synthetic, replicable index to quantify motor impairment is still lacking. In this paper, we build upon the idea that the trunk is crucial in balance control. Hence, we have designed a new measure of postural stability which assesses the trunk displacement in relation to the center of mass, that we named trunk displacement index (TDI).METHODSTwenty-three PD patients and twenty-three healthy controls underwent clinical (UPDRS-III) and motor examination (3D gait analysis). The TDI was extracted from kinematic measurements using a stereophotogrammetric system. A correlation analysis was performed to assess the relationship of TDI with typical gait parameters, to verify its biomechanical value, and UPDRS-III, to observe its clinical relevance. Finally, its sensitivity was measured, comparing pre- and post-L-DOPA subclinical intake.RESULTSThe TDI showed significant correlations with many gait parameters, including both velocity and stability characteristics of gait, and with the UPDRS-III. Finally, the TDI resulted capable in discriminating between off and on state in PD, whereas typical gait parameters failed two show any difference between those two conditions.CONCLUSIONSOur results suggest that the TDI may be considered a highly sensitive biomechanical index, reflecting the overall motor condition in PD, and provided of clinical relevance due to the correlation with the clinical evaluation.