bluuebunny/crossref_metadata_2025_split huggingface dataset:
COVID-19 induces a hyperactive phenotype in circulating platelets
Authors: Comer Shane P. , Cullivan Sarah , Szklanna Paulina B. , Weiss Luisa , Cullen Steven , Kelliher Sarah , Smolenski Albert , Moran Niamh , Murphy Claire , Altaie Haidar , Curran John , O’Reilly Katherine , Cotter Aoife G. , Marsh Brian , Gaine Sean , Mallon Patrick , McCullagh Brian , Ní Áinle Fionnuala , Kevane Barry , Maguire Patricia B. 
Published: July 2020

AbstractBackgroundCoronavirus disease 2019 (COVID-19), caused by novel coronavirus SARS-CoV-2, has to date affected over 13.3 million globally. Although high rates of venous thromboembolism and evidence of COVID-19-induced endothelial dysfunction have been reported, the precise aetiology of the increased thrombotic risk associated with COVID-19 infection remains to be fully elucidated.ObjectivesHere, we assessed clinical platelet parameters and circulating platelet activity in patients with severe and non-severe COVID-19.MethodsAn assessment of clinical blood parameters in patients with severe COVID-19 disease (requiring intensive care), patients with non-severe disease (not requiring intensive care), general medical in-patients without COVID-19 and healthy donors was undertaken. Platelet function and activity were also assessed by secretion and specific marker analysis.ResultsWe show that routine clinical blood parameters including increased MPV and decreased platelet:neutrophil ratio are associated with disease severity in COVID-19 upon hospitalisation and intensive care unit admission. Strikingly, agonist-induced ADP release was dramatically higher in COVID-19 patients compared with non-COVID-19 hospitalized patients and circulating levels of PF4, sP-selectin and TPO were also significantly elevated in COVID-19.ConclusionDistinct differences exist in routine full blood count and other clinical laboratory parameters between patients with severe and non-severe COVID-19. Moreover, we have determined that COVID-19 patients possess hyperactive circulating platelets. These data suggest that abnormal platelet reactivity may contribute to hypercoagulability in COVID-19. Further investigation of platelet function in COVID-19 may provide additional insights into the aetiology of thrombotic risk in this disease and may contribute to the optimisation of thrombosis prevention and treatment strategies.EssentialsRoutine platelet-related clinical blood parameters (MPV, PNR) are associated with disease severity in COVID-19.Agonist-induced ADP release is dramatically higher in COVID-19 patients compared with non-COVID-19 hospitalized patients.Circulating levels of PF4, sP-selectin levels and TPO are significantly elevated in COVID-19.Identification of a hyperactive platelet phenotype may warrant re-evaluation of current thrombotic prevention strategies in COVID-19 treatment.
Rapid generation of circulating and mucosal decoy ACE2 using mRNA nanotherapeutics for the potential treatment of SARS-CoV-2
Authors: Kim Jeonghwan , Mukherjee Anindit , Nelson Dylan , Jozic Antony , Sahay Gaurav 
Published: July 2020

ABSTRACTSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters through the airways and infects the lungs, causing lethal pulmonary damage in vulnerable patients. This virus contains spike proteins on its envelope that binds to human angiotensin-converting enzyme 2 (hACE2) expressed on the surface of airway cells, enabling entry of the virus for causing infection1,2. In severe cases, the virus enters the circulatory system, contributing to multiorgan failure. Soluble form of hACE2 binds to SARS-CoV-2 spike protein and prevents viral entry into target cells3. Moreover, soluble recombinant ACE2 ameliorates lung injury4but its short half-life limits its therapeutic utility5. Here, we engineered synthetic mRNA to encode a soluble form of hACE2 (hsACE2) to prevent viral infection. Novel lipid nanoparticles (LNPs) were used to package mRNA and transfect mammalian cells for enhanced production of secreted proteins. Intravenously administered LNP led to hepatic delivery of the mRNA. This elicited secretion of hsACE2 into the blood circulation within 2 h, and levels of circulating hsACE2 peaked at 6 h and gradually decreased over several days. Since the primary site of entry and pathogenesis for SARS-CoV-2 is the lungs, we instilled LNPs into the lungs and were able to detect hsACE2 in the bronchoalveolar lavage fluid within 24 h and lasted for 48 h. Through co-immunoprecipitation, we found that mRNA-generated hsACE2 was able to bind with the receptor binding domain of the SARS-CoV-2 spike protein. Furthermore, hsACE2 was able to strongly inhibit (over 90%) SARS-CoV-2 pseudovirus infection. Our proof of principle study shows that mRNA-based nanotherapeutics can be potentially deployed for pulmonary and extrapulmonary neutralization of SARS-CoV-2 and open new treatment opportunities for COVID-19.
Benchmarking challenging small variants with linked and long reads
Authors: Wagner Justin , Olson Nathan D , Harris Lindsay , McDaniel Jennifer , Khan Ziad , Farek Jesse , Mahmoud Medhat , Stankovic Ana , Kovacevic Vladimir , Yoo Byunggil , Miller Neil , Rosenfeld Jeffrey A. , Ni Bohan , Zarate Samantha , Kirsche Melanie , Aganezov Sergey , Schatz Michael , Narzisi Giuseppe , Byrska-Bishop Marta , Clarke Wayne , Evani Uday S. , Markello Charles , Shafin Kishwar , Zhou Xin , Sidow Arend , Bansal Vikas , Ebert Peter , Marschall Tobias , Lansdorp Peter , Hanlon Vincent , Mattsson Carl-Adam , Barrio Alvaro Martinez , Fiddes Ian T , Xiao Chunlin , Fungtammasan Arkarachai , Chin Chen-Shan , Wenger Aaron M , Rowell William J , Sedlazeck Fritz J , Carroll Andrew , Salit Marc , Zook Justin M 
Published: July 2020

SummaryGenome in a Bottle (GIAB) benchmarks have been widely used to help validate clinical sequencing pipelines and develop new variant calling and sequencing methods. Here, we use accurate linked reads and long reads to expand the prior benchmarks in 7 samples to include difficult-to-map regions and segmental duplications that are not readily accessible to short reads. Our new benchmark adds more than 300,000 SNVs, 50,000 indels, and 16 % new exonic variants, many in challenging, clinically relevant genes not previously covered (e.g.,PMS2). For HG002, we include 92% of the autosomal GRCh38 assembly, while excluding problematic regions for benchmarking small variants (e.g., copy number variants and reference errors) that should not have been in the previous version, which included 85% of GRCh38. By including difficult-to-map regions, this benchmark identifies eight times more false negatives in a short read variant call set relative to our previous benchmark.We have demonstrated the utility of this benchmark to reliably identify false positives and false negatives across technologies in more challenging regions, which enables continued technology and bioinformatics development.
NT3/TrkC pathway modulates the expression of UCP-1 and adipocyte size in human and murine adipose tissue
Authors: Bové María , Monto Fermi , Guillem-Llobat Paloma , Ivorra M Dolores , Noguera M Antonia , Zambrano Andrea , Sirerol-Piquer Ma Salome , Requena Ana Cristina , García-Alonso Mauricio , Tejerina Teresa , Real José T. , Fariñas Isabel , D’Ocon Pilar 
Published: July 2020

ABSTRACTNT3, through activation of its tropomyosin-related kinase receptor C (TrkC), modulates neuronal survival and neural stem cell differentiation. It is widely distributed in peripheral tissues (specially vessels and pancreas) and this ubiquitous pattern suggests a role for NT3, outside the nervous system and related to metabolic functions. The presence of the NT3/TrkC pathway in the adipose tissue (AT) has never been investigated. Present work studies in human and murine adipose tissue (AT) the presence of elements of the NT3/TrkC pathway and its role on lipolysis and adipocyte differentiation. qRT-PCR and immunoblot indicate that NT3 was present in human retroperitoneal AT and decreases with age. NT3 was also present in rat isolated adipocytes and retroperitoneal, interscapular, perivascular and perirenal AT. Histological analysis evidences that NT3 was mainly present in vessels irrigating AT close associated to sympathetic fibers. Similar mRNA levels of TrkC and β-adrenoceptors were found in all ATs assayed and in isolated adipocytes. NT3, through TrkC activation, exert a mild effect in lipolysis. Addition of NT3 during the differentiation process of human pre-adipocytes resulted in smaller adipocytes and increased uncoupling protein-1 (UCP-1) without changes in β-adrenoceptors. Similarly, transgenic mice with reduced expression of NT3 (Ntf3 knock-in lacZ reporter mice) or lacking endothelial NT3 expression (Ntf3flox1/flox2;Tie2-Cre+/0) displayed enlarged white and brown adipocytes and lower UCP-1 expression.ConclusionsNT3, mainly released by blood vessels, activates TrkC and regulates adipocyte differentiation and browning. Disruption of NT3/TrkC signaling conducts to hypertrophied white and brown adipocytes with reduced expression of the thermogenesis marker UCP-1
AD-linked R47H-TREM2mutation induces disease-enhancing proinflammatory microglial states in mice and humans
Authors: Sayed Faten A. , Kodama Lay , Udeochu Joe C. , Fan Li , Carling Gillian K. , Le David , Li Qingyun , Zhou Lu , Mathys Hansruedi , Wang Minghui , Niu Xiang , Mazutis Linas , Jiang Xueqiao , Wang Xueting , Wong Man Ying , Gao Fuying , Telpoukhovskaia Maria , Tracy Tara E. , Frost Georgia , Zhou Yungui , Li Yaqiao , Brendel Matthew , Qiu Yue , Cheng Zuolin , Yu Guoqiang , Hardy John , Coppola Giovanni , Gong Shiaoching , Wang Fei , DeTure Michael A. , Zhang Bin , Xie Lei , Dickson Dennis W. , Luo Wenjie , Gan Li 
Published: July 2020

ABSTRACTThe hemizygous R47H variant ofTREM2, a microglia-specific gene in the brain, increases risk for late-onset Alzheimer’s disease (AD). In this study, we identified a subpopulation of microglia with disease-enhancing proinflammatory signatures associated with the R47H mutation in human AD brains and tauopathy mouse brains. Using transcriptomic analysis at the single-nuclei level from AD patients with the R47H or the common variant (CV)-TREM2with matched sex, pathology andAPOEstatus, we found that the R47H mutation was associated with cell type- and sex-specific transcriptional changes in human AD brains, with microglia exhibiting the most robust alterations. Further characterization revealed that R47H-associated microglial subpopulations had enhanced inflammatory signatures including hyperactivation of Akt, one of the signaling pathways downstream of TREM2. In a newly-generated tauopathy knock-in mouse model expressing one allele of humanTREM2(hTREM2)with either the R47H mutation or CV, R47H induced and exacerbated tau-mediated spatial memory deficits in female mice. Single-cell transcriptomic analysis of microglia from these mice also revealed transcriptomic changes induced by R47H that had significant overlaps with R47H microglia in human AD brains, including robust increases in proinflammatory cytokines, activation of Syk-Akt-signaling, and elevation of a subset of disease-associated microglial signatures. Strikingly, pharmacological Akt inhibition largely reversed the enhanced inflammatory signatures induced by R47H in primary microglia treated with tau fibrils. By unraveling the disease-enhancing properties of the R47H mutation in mouse and human, our findings shed light on an immune-linked AD subtype and provide new directions for modulating microglial immune responses to treat AD.
Improving gene-network inference with graph-wavelets and making insights about ageing associated regulatory changes in lungs
Authors: Mishra Shreya , Srivastava Divyanshu , Kumar Vibhor 
Published: July 2020

AbstractUsing gene-regulatory-networks based approach for single-cell expression profiles can reveal un-precedented details about the effects of external and internal factors. However, noise and batch effect in sparse single-cell expression profiles can hamper correct estimation of dependencies among genes and regulatory changes. Here we devise a conceptually different method using graph-wavelet filters for improving gene-network (GWNet) based analysis of the transcriptome. Our approach improved the performance of several gene-network inference methods. Most Importantly, GWNet improved consistency in the prediction of generegulatory-network using single-cell transcriptome even in presence of batch effect. Consistency of predicted gene-network enabled reliable estimates of changes in the influence of genes not highlighted by differential-expression analysis. Applying GWNet on the single-cell transcriptome profile of lung cells, revealed biologically-relevant changes in the influence of pathways and master-regulators due to ageing. Surprisingly, the regulatory influence of ageing on pneumocytes type II cells showed noticeable similarity with patterns due to effect of novel coronavirus infection in Human Lung.
Corticotropin-Releasing Factor Neurons in the Bed Nucleus of the Stria Terminalis Differentially Influence Pain Processing and Modulation in Male and Female Mice
Authors: Yu Waylin , Stanhope Christina M. , Rivera Sanchez Natalia del R. , Moseley Garrett A. , Kash Thomas L. 
Published: July 2020

AbstractThe bed nucleus of the stria terminalis (BNST) plays an emerging yet understudied role in pain. Corticotropin-releasing factor (CRF) is an important source of pain modulation in the BNST, with local pharmacological inhibition of CRF receptors conditionally impacting the sensory and affective-motivational components of pain. Knowledge on how pain dynamically engages CRF neurons in the BNST and is influenced by intra-BNST production of CRF, however, remains unknown. In the present study, we utilizedin vivocalcium imaging to show robust and synchronized recruitment of BNSTCRF+neurons during acute exposure to noxious heat. Distinct patterns of recruitment were observed by sex, as the magnitude and timing of heat responsive activity in BNSTCRF+neurons differed for male and female mice. We then established the necessity of CRF for intact pain behaviors by genetically deletingCrfin the BNST, which reduced thermal and mechanical nociceptive sensitivity for both sexes, and increased paw attending in female mice, suggesting a divergent role for CRF with respect to active coping responses to pain. Together, these findings demonstrate that CRF in the BNST contributes to multiple facets of the pain experience and may play a key role in the sex-specific expression of pain-related behaviors.
Foraging gene and xenobiotic stresses relationships inDrosophila melanogaster
Authors: Marcel Amichot , Sophie Tarès 
Published: July 2020

AbstractIn several insect species, the foraging behaviour has been demonstrated to be controlled by theforaginggene (for) which encodes for a cGMP-dependent protein kinase (PKG). In wild Drosophila populations, rover and sitter individuals coexist and are characterized by high and low PKG activity levels respectively. Because of their increased foraging behaviour, we postulated that rover flies are more exposed to environmental stresses than sitter flies. Thus, we tested whether rover and sitter flies differ in their fitness by using insecticides as chemical stressors. We showed that their responses are different depending on the insecticide used and are linked to variations of cytochrome P450s activities. Furthermore, the expression of the insecticide metabolizing cytochrome P450Cyp6a2was shown to be under the control of theforgene. We evidence here a new physiological function for theforgene in Drosophila and we demonstrate its involvement in the adaptation to chemicals in the environment.
Analysis and modeling of cancer drug responses using cell cycle phase-specific rate effects
Authors: Gross Sean M. , Mohammadi Farnaz , Sanchez-Aguila Crystal , Zhan Paulina J. , Liby Tiera A. , Dane Mark A. , Meyer Aaron S. , Heiser Laura M. 
Published: July 2020

ABSTRACTIdentifying effective therapeutic strategies that can prevent tumor cell proliferation is a major challenge to improving outcomes for patients with breast cancer. Here we sought to deepen our understanding of how clinically relevant anti-cancer agents modulate cell cycle progression. We genetically engineered breast cancer cell lines to express a cell cycle reporter and then tracked drug-induced changes in cell number and cell cycle phase, which revealed drug-specific cell cycle effects that varied across time. This suggested that a computational model that could account for cell cycle phase durations would provide a framework to explore drug-induced changes in cell cycle changes. Toward that goal, we developed a linear chain trick (LCT) computational model, in which the cell cycle was partitioned into subphases that faithfully captured drug-induced dynamic responses. The model inferred drug effects and localized them to specific cell cycle phases, which we confirmed experimentally. We then used our LCT model to predict the effect of unseen drug combinations that target cells in different cell cycle phases. Experimental testing confirmed several model predictions and identified combination treatment strategies that may improve therapeutic response in breast cancer patients. Overall, this integrated experimental and modeling approach opens new avenues for assessing drug responses, predicting effective drug combinations, and identifying optimal drug sequencing strategies.
Brain geometry matters in Alzheimer’s disease progression: a simulation study
Authors: Hoore Masoud , Kelling Jeffrey , Sayadmanesh Mahsa , Mitra Tanmay , Schips Marta , Meyer-Hermann Michael 
Published: July 2020

AbstractThe Amyloid cascade hypothesis (ACH) for Alzheimer’s disease (AD) is modeled over the whole brain tissue with a set of partial differential equations. Our results show that the amyloid plaque formation is critically dependent on the secretion rate of amyloid β (Aβ), which is proportional to the product of neural density and neural activity. Neural atrophy is similarly related to the secretion rate of Aβ. Due to a heterogeneous distribution of neural density and brain activity throughout the brain, amyloid plaque formation and neural death occurs heterogeneously in the brain. The geometry of the brain and microglia migration in the parenchyma bring more complexity into the system and result in a diverse amyloidosis and dementia pattern of different brain regions. Although the pattern of amyloidosis in the brain cortex from in-silico results is similar to experimental autopsy findings, they mismatch at the central regions of the brain, suggesting that ACH is not able to explain the whole course of AD without considering other factors, such as tau-protein aggregation or neuroinflammation.
Human Beta Cell Mass Expansion In Vivo With A Harmine and Exendin-4 Combination: Quantification and Visualization By iDISCO+ 3D Imaging
Authors: Rosselot Carolina , Alvarsson Alexandra , Wang Peng , Li Yansui , Beliard Kara , Lu Geming , Li Rosemary , Liu Hongtao , Gillespie Virginia , Tzavaras Nikolaos , Kumar Kunal , DeVita Robert J. , Stewart Andrew F. , Stanley Sarah A. , Garcia-Ocaña Adolfo 
Published: July 2020

Abstract463 million people globally suffer from diabetes. The majority are deficient in insulin-producing pancreatic beta cells, although beta cells remain in most people with diabetes. Unfortunately, although many diabetes drugs exist, none is able to increase adult human beta cell numbers. Recently, small molecules that inhibit the kinase, DYRK1A, have been suggested to induce human beta cell replicationin vitroandin vivoas assessed using proliferation markers, and this is enhanced by drugs that stimulate the GLP1 receptor (GLP1R) on beta cells. DYRK1A inhibitors also enhance human beta cell differentiation and function. However, it is unknown whether any drug can actually increase human beta cell massin vivo, reflecting: 1) the intrinsic resistance of human beta cells to regeneration; and, 2) the current technical inability to accurately assess human beta cell massin vivo. Here, we demonstrate for the first time that combining a DYRK1A inhibitor with a GLP1R agonist increases actual human beta cell numbers and overall massin vivoby 400-700% in diabetic and non-diabetic mice over three months. We further describe a novel application of tissue-clearing and 3D imaging for quantification of human beta cell mass. These findings should be transformative for diabetes treatment.
Interneuron Specific Gamma Synchronization Indexes Cue Uncertainty and Prediction Errors in Lateral Prefrontal and Anterior Cingulate Cortex
Authors: Boroujeni Kianoush Banaie , Tiesinga Paul , Womelsdorf Thilo 
Published: July 2020

SummaryInhibitory interneurons are believed to realize critical gating functions in cortical circuits, but it has been difficult to ascertain the content of gated information for well characterized interneurons in primate cortex. Here, we address this question by characterizing putative interneurons in primate prefrontal and anterior cingulate cortex while monkeys engaged in attention demanding reversal learning. We find that subclasses of narrow spiking neurons have a relative suppressive effect on the local circuit indicating they are inhibitory interneurons. One of these interneuron subclasses showed prominent firing rate modulations and (35-45 Hz) gamma synchronous spiking during periods of uncertainty in both, lateral prefrontal cortex (LPFC) and in anterior cingulate cortex (ACC). In LPFC this interneuron subclass activated when the uncertainty of attention cues was resolved during flexible learning, whereas in ACC it fired and gamma-synchronized when outcomes were uncertain and prediction errors were high during learning. Computational modeling of this interneuron-specific gamma band activity in simple circuit motifs suggests it could reflect a soft winner-take-all gating of information having high degree of uncertainty. Together, these findings elucidate an electrophysiologically-characterized interneuron subclass in the primate, that forms gamma synchronous networks in two different areas when resolving uncertainty during adaptive goal-directed behavior.