bluuebunny/crossref_metadata_2025_split huggingface dataset:
Machine Learning to Predict Mortality and Critical Events in COVID-19 Positive New York City Patients
Authors: Vaid Akhil , Somani Sulaiman , Russak Adam J , De Freitas Jessica K , Chaudhry Fayzan F , Paranjpe Ishan , Johnson Kipp W , Lee Samuel J , Miotto Riccardo , Zhao Shan , Beckmann Noam D , Naik Nidhi , Arfer Kodi , Kia Arash , Timsina Prem , Lala Anuradha , Paranjpe Manish , Glowe Patricia , Golden Eddye , Danieletto Matteo , Singh Manbir , Meyer Dara , O’Reilly Paul F , Huckins Laura H , Kovatch Patricia , Finkelstein Joseph , Freeman Robert M , Argulian Edgar , Kasarskis Andrew , Percha Bethany , Aberg Judith A , Bagiella Emilia , Horowitz Carol R , Murphy Barbara , Nestler Eric J , Schadt Eric E , Cho Judy H , Cordon-Cardo Carlos , Fuster Valentin , Charney Dennis S , Reich David L , Bottinger Erwin P , Levin Matthew A , Narula Jagat , Fayad Zahi A , Just Allan C , Charney Alexander W , Nadkarni Girish N , Glicksberg Benjamin S 
Published: April 2020

AbstractCoronavirus 2019 (COVID-19), caused by the SARS-CoV-2 virus, has become the deadliest pandemic in modern history, reaching nearly every country worldwide and overwhelming healthcare institutions. As of April 20, there have been more than 2.4 million confirmed cases with over 160,000 deaths. Extreme case surges coupled with challenges in forecasting the clinical course of affected patients have necessitated thoughtful resource allocation and early identification of high-risk patients. However, effective methods for achieving this are lacking. In this paper, we use electronic health records from over 3,055 New York City confirmed COVID-19 positive patients across five hospitals in the Mount Sinai Health System and present a decision tree-based machine learning model for predicting in-hospital mortality and critical events. This model is first trained on patients from a single hospital and then externally validated on patients from four other hospitals. We achieve strong performance, notably predicting mortality at 1 week with an AUC-ROC of 0.84. Finally, we establish model interpretability by calculating SHAP scores to identify decisive features, including age, inflammatory markers (procalcitonin and LDH), and coagulation parameters (PT, PTT, D-Dimer). To our knowledge, this is one of the first models with external validation to both predict outcomes in COVID-19 patients with strong validation performance and identify key contributors in outcome prediction that may assist clinicians in making effective patient management decisions.One-Sentence SummaryWe identify clinical features that robustly predict mortality and critical events in a large cohort of COVID-19 positive patients in New York City.
Heterozygous RELA mutations cause early-onset systemic lupus erythematosus by hijacking the NF-κB pathway towards transcriptional activation of type-I Interferon genes
Authors: Barnabei Laura , Lamrini Hicham , Castela Mathieu , Jeremiah Nadia , Stolzenberg Marie-Claude , Chentout Loïc , Jacques Sidonie , Bouafia Amine , Magérus-Chatinet Aude , Moncan Matthieu , Mirshahvalad Sajedeh , Pellé Olivier , Bondet Vincent , Duffy Darragh , Parisot Mélanie , Bras Marc , Uggenti Carolina , Salomon Rémi , Bodemer Christine , Rabant Marion , Cavazzana Marina , Miner J.J. , Belot Alexandre , Hié Miguel , Picard Capucine , Bader-Meunier Brigitte , Kracker Sven , Rieux-Laucat Frédéric 
Published: April 2020

AbstractSystemic Lupus Erythematosus (SLE) is an autoimmune and inflammatory disease characterized by uncontrolled production of autoantibodies and inflammatory cytokines such as the type-I interferons. Due to the lack of precise pathophysiological mechanisms, treatments are based on broad unspecific immunossupression. To identify genetic factors associated with SLE we performed whole exome sequencing and identified twoRELAheterozygous activating mutations in 3 early-onset and familial SLE cases. The corresponding RELA/p65 mutant were abundant in the nucleus but poorly activate transcription of genes controlled by NF-κB consensus sequences. The co-expression of the mutant and wild-type RELA/p65 strongly activated the expression of genes controlled by the IFNα-consensus sequences. These molecular mechanisms lead to the overproduction of type-I IFN in the patients’ cells. Our findings highlight a novel mechanism of autoimmunity where these new RELA mutants are transactivating the type-I IFN genes and are thus promoting type-I interferon production and early-onset SLE, thereby paving the way to the identification of new and specific therapeutic targets.SummaryHeterozygous RELA mutations are associated with Systemic Lupus Erythematosus, with increased expression of genes controlled by the IFNα-consensus sequences.
Sympathetic axonal sprouting induces changes in macrophage populations and protects against pancreatic cancer
Authors: Guillot Jérémy , Dominici Chloé , Lucchesi Adrien , Nguyen Thi Trang Huyen , Nigri Jérémy , Guillaumond Fabienne , Bigonnet Martin , Dusetti Nelson , Etzerodt Anders , Lawrence Toby , Pudlo Pierre , Hubert Florence , Scoazec Jean-Yves , van de Pavert Serge A. , Tomasini Richard , Chauvet Sophie , Mann Fanny 
Published: April 2020

AbstractRecent evidence has highlighted the presence of neuronal nerve processes in the tumor microenvironment. However, the origin of intra-tumoral nerves remains poorly known, in part because of technical difficulties in tracing nerve fibers via regular histological preparations. Here, we employed three-dimensional (3D) imaging of cleared tissues for a comprehensive analysis of sympathetic innervation in pancreatic ductal adenocarcinoma (PDAC). The results support two independent, but coexisting, mechanisms: passive engulfment of pre-existing nerves within tumors and active, localized sprouting of nerve terminals into non-neoplastic lesions and tumor periphery. Nerve ablation revealed an inverse correlation between sympathetic innervation and tumor growth and spread. Furthermore, sympathectomy increased CD163+macrophage levels, which contributed to worse outcomes. Altogether, our findings revealed protective properties of the sympathetic nervous system in PDAC immunity and progression that could pave the way for new treatments.
Mapping the molecular and structural specialization of the skin basement membrane for inter-tissue interactions
Authors: Tsutsui Ko , Machida Hiroki , Morita Ritsuko , Nakagawa Asako , Sekiguchi Kiyotoshi , Miner Jeffrey H. , Fujiwara Hironobu 
Published: April 2020

AbstractInter-tissue interaction is fundamental to multicellularity. Although the basement membrane (BM) is located at tissue interfaces, its mode of action in inter-tissue interactions remains poorly understood, mainly because the molecular and structural details of the BM at distinct inter-tissue interfaces remain unclear. By combining quantitative transcriptomics and immunohistochemistry, we systematically identify the cellular origin, molecular identity and tissue distribution of extracellular matrix molecules in mouse hair follicles, and reveal that BM composition and architecture are exquisitely specialized for distinct inter-tissue interactions, including epidermal–fibroblast, epidermal–muscle and epidermal–nerve interactions. The epidermal–fibroblast interface, namely, hair germ–dermal papilla interface, makes asymmetrically organized side-specific heterogeneity in BM, defined by the newly characterized interface, hook and mesh BMs. One component of these BMs, laminin α5, is required for the topological and functional integrity of hair germ–dermal papilla interactions. Our study highlights the significance of BM heterogeneity in distinct inter-tissue interactions.
Disparate temperature-dependent virus – host dynamics for SARS-CoV-2 and SARS-CoV in the human respiratory epithelium
Authors: V’kovski Philip , Gultom Mitra , Kelly Jenna , Steiner Silvio , Russeil Julie , Mangeat Bastien , Cora Elisa , Pezoldt Joern , Holwerda Melle , Kratzel Annika , Laloli Laura , Wider Manon , Portmann Jasmine , Tran Thao , Ebert Nadine , Stalder Hanspeter , Hartmann Rune , Gardeux Vincent , Alpern Daniel , Deplancke Bart , Thiel Volker , Dijkman Ronald 
Published: April 2020

AbstractSince its emergence in December 2019, SARS-CoV-2 has spread globally and become a major public health burden. Despite its close phylogenetic relationship to SARS-CoV, SARS-CoV-2 exhibits increased human-to-human transmission dynamics, likely due to efficient early replication in the upper respiratory epithelium of infected individuals. Since different temperatures encountered in the human respiratory tract have been shown to affect the replication kinetics of several viruses, as well as host immune response dynamics, we investigated the impact of temperatures during SARS-CoV-2 and SARS-CoV infection in the human airway epithelial cell culture model. SARS-CoV-2, in contrast to SARS-CoV, replicated more efficiently at temperatures encountered in the upper respiratory tract, and displayed higher sensitivity to type I and type III IFNs. Time-resolved transcriptome analysis highlighted a temperature-dependent and virus-specific induction of the IFN-mediated antiviral response. These data reflect clinical features of SARS-CoV-2 and SARS-CoV, as well as their associated transmission efficiencies, and provide crucial insight on pivotal virus - host interaction dynamics.
Adiposome Targeting and Enzymatic Activity of Lipid Droplet-Specific Proteins
Authors: Ma Xuejing , Zhi Zelun , Zhang Shuyan , Zhou Chang , Mechler Adam , Liu Pingsheng 
Published: April 2020

SUMMARYNew strategies to decode the specific protein targeting mechanism on lipid droplet (LD) are urgently needed. Using adiposome, the LD binding of perilipin 2 (PLIN2), perilipin 3 (PLIN3), and adipose triglyceride lipase (ATGL) were studied. Scatchard analysis found that the binding of PLIN2 to the adiposome surface was saturable, pointing to a specific membrane binding partner. Phosphatidylinositol (PI) was found to inhibit PLIN2 binding while it did not impede PLIN3. Structural analysis combined with mutagenesis revealed that the 73rdglutamic acid of PLIN2 is significant for the effect of PI on the protein binding. The presence of PI significantly stimulated the activity of ATGLin vitro. The phosphorylation site mutants of ATGL were found reducing the lipase activity in the adiposome system. Our study demonstrates the utility of adiposome as a powerful, manipulatable model system for the characterization of LD binding and enzymatic activity of LD proteinsin vitro.
Optogenetic control of the Bone Morphogenetic Protein signalling pathway through engineered blue light-sensitive receptors
Authors: Humphreys Paul A. , Woods Steven , Smith Christopher A. , Cain Stuart A. , Lucas Robert , Kimber Susan J. 
Published: April 2020

AbstractBone Morphogenetic Proteins (BMPs) are members of the Transforming Growth Factor β (TGFβ) superfamily and have crucial roles during development; including mesodermal patterning and specification of renal, hepatic and skeletal tissues.In vitrodevelopmental models currently rely upon costly and unreliable recombinant BMP proteins that do not enable dynamic or precise perturbation of the BMP signalling pathway. Here, we develop a novel optogenetic BMP signalling system (optoBMP) that enables rapid induction of the canonical BMP signalling pathway through illumination with blue light. We demonstrate the utility of the optoBMP system in multiple human cell lines to initiate signal transduction through phosphorylation and nuclear translocation of SMAD1/5, leading to upregulation of BMP target genes includingInhibitors of DNA binding ID2andID4. Furthermore, we demonstrate how the optoBMP system can be used to fine-tune activation of the BMP signalling pathway through variable light stimulation. Optogenetic control of BMP signalling will enable dynamic and high-throughput intervention across a variety of applications in cellular and developmental systems.
Withania somniferashowed neuroprotective effect and increase longevity inDrosophilaAlzheimer’s disease model
Authors: Halim Mardani Abdul , Rosli Izzah Madihah , Jaafar Siti Shafika Muhamad , Ooi Hoi-Min , Leong Pui-Wei , Shamsuddin Shaharum , Najimudin Nazalan , Azzam Ghows 
Published: April 2020

AbstractAlzheimer’s disease is a complex neurodegenerative disease and is only unique to human. The disease is defined in human brain by the accumulation of amyloid beta in the parenchyma of the brain. Withania somnifera, commonly known as Ashwagandha is an Indian Ayurvedic medicine that has been used for centuries to treat countless range of human health problem. The active compound of Ashwagandha was shown to be beneficial in treating many neurodegenerative diseases including Alzheimer’s disease (AD). In this study,Drosophilamelanogaster AD model was used to study the effect of Ashwagandha on the toxicity of beta amyloid and also the longevity effect of the compound. We found that 20 mg/mL of Ashwagandha was shown to be effective in rescuing the “rough eye phenotype” of ADDrosophila. Furthermore, Ashwagandha also promotes longevity in AD as well as wild-typeDrosophila. The results above showed that Ashwagandha could potentially be a potent drug to treat AD as well as maintaining the wellbeing of cells.
Neurodegeneration-related beta-amyloid as autocatabolism-attenuator in amicro-in vivosystem
Authors: Balazs Evelin , Galik-Olah Zita , Galik Bence , Bozso Zsolt , Kalman Janos , Datki Zsolt 
Published: April 2020

AbstractInvestigation of human neurodegeneration-related aggregates of beta-amyloid 1-42 (Aβ42) on bdelloid rotifers is a novel interdisciplinary approach in life sciences. We reapplied an organ size-basedin vivomonitoring system, exploring the autocatabolism-related alterations evoked by Aβ42, in a glucose-supplemented starvation model. The experientially easy-to-follow size reduction of the bilateral reproductive organ (germovitellaria) in fasted rotifers was rescued by Aβ42, serving as a nutrient source- and peptide sequence-specific attenuator of the organ shrinkage phase and enhancer of the regenerative one including egg reproduction. Recovery of the germovitellaria was significant in comparison with the greatly shrunken form. In contrast to the well-known neurotoxic Aβ42 (except the bdelloids) with specific regulatory roles, the artificially designed scrambled version (random order of amino acids) was inefficient in autocatabolism attenuation, behaving as negative control. This native Aβ42-related modulation of the ‘functionally reversible organ shrinkage’ can be a potential experiential and supramolecular marker of autocatabolismin vivo.
Association of 4 epigenetic clocks with measures of functional health, cognition, and all-cause mortality in The Irish Longitudinal Study on Ageing (TILDA)
Authors: McCrory Cathal , Fiorito Giovanni , Hernandez Belinda , Polidoro Silvia , O’Halloran Aisling M. , Hever Ann , Cheallaigh Cliona Ni , Lu Ake T. , Horvath Steve , Vineis Paolo , Kenny Rose Anne 
Published: April 2020

ABSTRACTThe aging process is characterized by the presence of high interindividual variation between individuals of the same chronical age prompting a search for biomarkers that capture this heterogeneity. The present study examines the associations of four epigenetic clocks - Horvath, Hannum, PhenoAge, GrimAge - with a wide range of clinical phenotypes, and with all-cause mortality at up to 10-year follow-up in a sample of 490 participants in the Irish Longitudinal Study on Ageing. Results indicate that the GrimAge clock represents a step-improvement in the predictive utility of the epigenetic clocks for identifying age-related decline in an array of clinical phenotypes.
Loss of CNOT9 begets impairment in gastrulation leading to embryonic lethality
Authors: Sarmah Hemanta , Ito Kentaro , Kaneko Mari , Abe Takaya , Yamamoto Tadashi 
Published: April 2020

AbstractThe multi-subunit eukaryotic CCR4-NOT complex imparts gene expression control primarily via messenger RNA (mRNA) decay. Here, we present the role of subunit CNOT9 in target mRNA decay during embryonic development. CNOT9 null mice appear normal by the onset of gastrulation (E7.0), however, exhibit growth and differentiation defects accompanied by extensive cell death by embryonic day 9.5 (E9.5). Sox-2 Cre conditional CNOT9 knockout mice show almost identical phenotype with brief delay in onset and progression, suggesting defects to be epiblast-dominant. Among various identified targets, we show thatLefty2mRNA expression is post-transcriptionally regulated by CNOT9.Lefty2 3’-UTRcontaining mRNA has significantly higher stability in cells expressing mutant form of CNOT9, relative to cells expressing wild-type CNOT9. In addition, CNOT9 primarily localizes within the cytoplasm and bridges interactions between the CCR4-NOT complex and miRNA-RISC complex in gastrulating embryos.
Osteogenic differentiation potential and marker gene expression of different porcine bone marrow mesenchymal stem cell subpopulations selected in different basal media
Authors: Kannan Sangeetha , Ghosh Jyotirmoy , Dhara Sujoy K. 
Published: April 2020

AbstractMultipotent porcine mesenchymal stem cells (pMSC) are indispensable for research and therapeutic use. Derivation and culture media might affect the selection of MSC subpopulation and thus the differentiation potential of cells. In this study we evaluated the effects of αMEM, aDMEM, M199, αMEM/M199, aDMEM/M199 and αMEM/aDMEM media on porcine bone marrow MSC derivation; pre-differentiation expression of ALP, COL1A1, SPP1 and BGLAP osteogenic marker genes at passage 5 and 10 pMSC; and differentiation potential of passage 5 pMSC. Morphological changes and matrix formation in osteogenic cells were evaluated by microscopical examination and calcium deposit in osteocytes was confirmed by Alizarin Red S staining. Results indicated media independent selection of different bone marrow MSC subpopulations with different surface marker gene expressions. Many pMSC subpopulations in different media had CD14+ expressing cells. We also observed basal media dependent changes in osteogenic markers expression and differentiation potential of pMSC. The αMEM/aDMEM media grown pMSC showed best osteogenic differentiation potential. We thus recommended the testing of αMEM/aDMEM mixed media in other species for pre-differentiation MSC culture that are intended for better osteogenic differentiation.SummaryPre-differentiation basal media influence osteogenic differentiation potential of mesenchymal stem cells (MSC). Among the tested media, αMEM/aDMEM was the best for pre-differentiation porcine MSC culture intending to use in osteogenesis.
Perturbed structural dynamics underlie inhibition and altered specificity of the multidrug efflux pump AcrB
Authors: Reading Eamonn , Ahdash Zainab , Fais Chiara , Ricci Vito , Kan Xuan Wang , Grimsey Elizabeth , Stone Jack , Malloci Giuliano , Lau Andy M. , Findlay Heather , Konijnenberg Albert , Booth Paula J. , Ruggerone Paolo , Vargiu Attilio V. , Piddock Laura J. V. , Politis Argyris 
Published: April 2020

AbstractResistance-nodulation-division (RND) efflux pumps play a key role in inherent and evolved multidrug-resistance (MDR) in bacteria. AcrB is the prototypical member of the RND family and acts to recognise and export a wide range of chemically distinct molecules out of bacteria, conferring resistance to a variety of antibiotics. Although high resolution structures exist for AcrB, its conformational fluctuations and their putative role in function are largely unknown, preventing a complete mechanistic understanding of efflux and inhibition. Here, we determine these structural dynamics in the presence of AcrB substrates using hydrogen/deuterium exchange mass spectrometry, complemented by molecular modelling, drug binding and bacterial susceptibility studies. We show that the well-studied efflux pump inhibitor phenylalanine-arginine-β-naphthylamide (PAβN) potentiates antibiotic activity by restraining drug-binding pocket dynamics, rather than preventing antibiotic binding. We also reveal that a drug-binding pocket substitution discovered within an MDR clinical isolate, AcrBG288D, modifies the plasticity of the transport pathway, which could explain its altered substrate specificity. Our results provide molecular insight into drug export and inhibition of a major MDR-conferring efflux pump and the important directive role of its dynamics.
Ropinirole, a dopamine agonist with high D3 affinity, reduces proactive inhibition: a double-blind, placebo-controlled study in healthy adults
Authors: Rawji Vishal , Rocchi Lorenzo , Foltynie Tom , Rothwell John C. , Jahanshahi Marjan 
Published: April 2020

AbstractResponse inhibition describes the cognitive processes mediating the suppression of unwanted actions. A network involving the basal ganglia mediates two forms of response inhibition: reactive and proactive inhibition. Reactive inhibition serves to abruptly stop motor activity, whereas proactive inhibition is goal-orientated and results in slowing of motor activity in anticipation of stopping. Due to its impairment in several psychiatric disorders, the neurochemistry of response inhibition has become of recent interest. Dopamine has been posed as a candidate mediator of response inhibition due to its role in functioning of the basal ganglia and the observation that patients with Parkinson’s disease on dopamine agonists develop impulse control disorders. Although the effects of dopamine on reactive inhibition have been studied, substantial literature on the role of dopamine on proactive inhibition is lacking. To fill this gap, we devised a double-blind, placebo-controlled study of 1 mg ropinirole (a dopamine agonist) on response inhibition in healthy volunteers. We found that whilst reactive inhibition was unchanged, proactive inhibition was impaired when participants were on ropinirole relative to when on placebo. To investigate how ropinirole mediated this effect on proactive inhibition, we used hierarchical drift-diffusion modelling. We found that ropinirole impaired the ability to raise the decision threshold when proactive inhibition was called upon. Our results provide novel evidence that an acute dose of ropinirole selectively reduces proactive inhibition in healthy participants. These results may help explain how ropinirole induces impulse control disorders in susceptible patients with Parkinson’s disease.
ToxoplasmaFER1 is a versatile and dynamic mediator of differential microneme trafficking and microneme exocytosis
Authors: Tagoe Daniel N.A. , Ribeiro E Silva Adeline , Drozda Allison A. , Coppens Isabelle , Coleman Bradley I. , Gubbels Marc-Jan 
Published: April 2020

AbstractToxoplasma gondiiis a polarized cell concentrating several secretory organelles at the apical pole. The secretory micronemes come in two sub-populations differentiated by dependence on the Rab5A/C in their biogenesis. Calcium-dependent exocytosis of micronemes occurs at the very apical tip and is critical for parasite egress from its host cell, adhesion and invasion of the next cell. Ferlins represent a protein family with roles in exocytosis containing multiple Ca2+-sensing C2 domains. We determined thatT. gondii’s ferlin 1 (FER1) localized dynamically to the parasite’s secretory pathway. FER1 function was dissected by dominant negative overexpression strategies. We demonstrated that FER1 traffics microneme organelles along the following trajectories:1. From thetrans-Golgi-endosomes network to the subpellicular cortex; 2. Along the cortex to the apical end; 3. To the apical tip for fusion with the plasma membrane; 4. Retrograde transport allowing microneme recycling from mother to daughter; 5. Differential microneme sub-population traffic. Finally, FER1 overexpression triggers a microneme exocytosis burst, supporting the notion that the radially organized micronemes at the apical tip comprise a readily-releasable microneme pool. In summary, FER1 is pivotal for dynamic microneme trafficking, acts differently on the two microneme subpopulations, and acts on the plasma membrane fusion step during microneme exocytosis.