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Lessons Learned for Identifying and Annotating Permissions in Clinical Consent Forms.

Appl Clin Inform 2021 May 23;12(3):429-435. Epub 2021 Jun 23.

Department of Systems, Populations and Leadership, University of Michigan School of Nursing, Ann Arbor, Michigan, United States.

Background:  The lack of machine-interpretable representations of consent permissions precludes development of tools that act upon permissions across information ecosystems, at scale.

Objectives:  To report the process, results, and lessons learned while annotating permissions in clinical consent forms.

Methods:  We conducted a retrospective analysis of clinical consent forms. Read More

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Machine learning-based genetic diagnosis models for hereditary hearing loss by the GJB2, SLC26A4 and MT-RNR1 variants.

EBioMedicine 2021 Jun 19;69:103322. Epub 2021 Jun 19.

Department of Otorhinolaryngology-Head and Neck Surgery, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China; Ear Institute, Shanghai Jiaotong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, Shanghai, China. Electronic address:

Background: Hereditary hearing loss (HHL) is the most common sensory deficit, which highly afflicts humans. With gene sequencing technology development, more variants will be identified and support genetic diagnoses, which is difficult for human experts to diagnose. This study aims to develop a machine learning-based genetic diagnosis model of HHL-related variants of GJB2, SLC26A4 and MT-RNR1. Read More

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Design, synthesis, and biological evaluation of hydroxamic acid-substituted 2,4-diaryl aminopyrimidines as potent EGFRT790M/L858R inhibitors for the treatment of NSCLC.

Bioorg Chem 2021 May 31;114:105045. Epub 2021 May 31.

School of Pharmaceutical Engineering, and Key Laboratory of Structure-Based Drug Design & Discovery (Ministry of Education), Shenyang Pharmaceutical University, Shenyang 110016, PR China. Electronic address:

A series of 2,4-diarylaminopyrimidine derivatives bearing hydrophilic hydroxamic acids were designed and synthesized as potent EGFR inhibitors. Among the derivatives synthesized, 10c (IC = 5.192 nM), 10j (IC = 10. Read More

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Si113-prodrugs selectively activated by plasmin against hepatocellular and ovarian carcinoma.

Eur J Med Chem 2021 Jun 17;223:113653. Epub 2021 Jun 17.

Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via Aldo Moro 2, 53100, Siena, Italy; Lead Discovery Siena S.r.l., Via Vittorio Alfieri 31, 53019, Castelnuovo Berardenga, Siena, Italy; Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology Temple University, BioLife Science Building, Suite 333, 1900 North 12th Street, Philadelphia, PA, 19122, United States.

Si113, a pyrazolo[3,4-d]pyrimidine derivative, gained more attention as an anticancer agent due to its potent anticancer activity on both in vitro and in vivo hepatocellular carcinomas (HCC) and ovarian carcinoma models. But the drawback is the low water solubility which prevents its further development. In this context, we successfully overcame this limitation by synthesizing two novel prodrugs introducing the amino acid sequence D-Ala-Leu-Lys (TP). Read More

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Long-term survivors of murine sepsis are predisposed to enhanced LPS-induced lung injury and pro-inflammatory immune reprogramming.

Am J Physiol Lung Cell Mol Physiol 2021 Jun 23. Epub 2021 Jun 23.

Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, grid.214458.eUniversity of Michigan Medical School, Ann Arbor, Michigan, United States.

Millions of people who survive sepsis each year are rehospitalized and die due to late pulmonary complications. In order to prevent and treat these complications, biomarkers and molecular mediators must be identified. Persistent immune reprogramming in the form of immunoparalysis and impaired host defense is proposed to mediate late pulmonary complications after sepsis, particularly new pulmonary infections. Read More

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Developmental Consequences of Defective ATG7-Mediated Autophagy in Humans.

N Engl J Med 2021 Jun;384(25):2406-2417

From the Wellcome Centre for Mitochondrial Research, (J.J.C., M.O., N.M.-L., A.M.S., A.P., R.M., R.W.T.), the Translational and Clinical Research Institute (J.J.C, M.O., T.M.P., A.M.S., A.P., R.M., R.W.T.), and the NHS Highly Specialised Service for Rare Mitochondrial Disorders of Adults and Children (A.M.S., R.M., R.W.T.), Newcastle University, Newcastle Upon Tyne, and the Institute of Child Health, Department of Molecular Neuroscience, University College London Institute of Neurology (D.Z., M.R.), the Division of Genetics and Molecular Medicine, Guy's Hospital, King's College London School of Medicine (I.A.B.), and the Clinical Genetics Unit, Guy's and St. Thomas' NHS Foundation Trust (C.D.), London - all in the United Kingdom; Institut Universitaire de Recherche Clinique and Laboratoire de Génétique Moléculaire, University of Montpellier and Centre Hospitalier Universitaire (CHU) de Montpellier (C.G., S.S., L.L., M.K.), Departments of Neuroradiology (N.L.) and Pediatric Neurology (P.M., F.R.) and Reference Center for Neuromuscular Diseases Atlantic-Occitania-Caribbean (AOC) (P.M., F.R.), CHU de Montpellier, and Laboratoire de Physiologie et Médecine Expérimentale du Cœur et des Muscles (PhyMedExp), INSERM, CNRS, University of Montpellier (P.M., F.R.), Montpellier, and the Institute for Integrative Biology of the Cell (I2BC), Université Paris-Saclay, Alternative Energies and Atomic Energy Commission (CEA), CNRS Gif-sur-Yvette (F.P.-P., A.D.) - all in France; the Translational Stem Cell Biology and Metabolism Program, Research Programs Unit, and the Department of Anatomy, Faculty of Medicine, University of Helsinki, Helsinki (F.S., T.G.M.); Radiation Oncology, Albert Einstein College of Medicine, New York (N.M.-L.); the Institute of Medical Genetics, University of Zurich, Zurich, Switzerland (A.B., S.A.-B., A.R.); Hertie Institute for Clinical Brain Research and Center of Neurology, and the German Center for Neurodegenerative Diseases, University of Tübingen, Tübingen, Germany (S.R., L.S., M.S.); the Departments of Genetics (H.S.A., F.S.A.) and Neuroscience (S.A.), King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia; and the Dr. John T. Macdonald Foundation, Department of Human Genetics, and John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami (S.Z.).

Background: Autophagy is the major intracellular degradation route in mammalian cells. Systemic ablation of core autophagy-related () genes in mice leads to embryonic or perinatal lethality, and conditional models show neurodegeneration. Impaired autophagy has been associated with a range of complex human diseases, yet congenital autophagy disorders are rare. Read More

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BHLHE40 modulates post-traumatic stress disorder behaviors with the involvement of the PI3K/AKT signaling pathway.

An Acad Bras Cienc 2021 16;93(3):e20201708. Epub 2021 Jun 16.

Department of Second Psychiatry, Mental Health Center of Xinjiang in China, Urumuqi 830001, Xinjiang, China.

Post-traumatic stress disorder (PTSD) is closely related to the exposure to traumatic events and results in the structural and functional changes of hippocampus. Human basic helix-loop-helix family member e40 (BHLHE40) was reported to be implicated with neuron maturity and neuronal differentiation. The present study aimed to reveal the role of BHLHE40 on single-prolonged stress (SPS) model of PTSD in mice. Read More

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Techniques of orthotopic renal transplantation. II. Size-matched porcine grafts in monkey recipients.

Acta Cir Bras 2021 18;36(5):e360503. Epub 2021 Jun 18.

PhD. Department of Kidney Regenerative Medicine - The Jikei University School of Medicine - Tokyo, Japan.

Purpose: As a classical xenotransplantation model, porcine kidneys have been transplanted into the lower abdomen of non-human primates. However, we have improved upon this model by using size-matched grafting in the orthotopic position. The beneficial aspects and surgical details of our method are reported herein. Read More

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The Science for Profit Model-How and why corporations influence science and the use of science in policy and practice.

PLoS One 2021 23;16(6):e0253272. Epub 2021 Jun 23.

Department for Health, Tobacco Control Research Group, University of Bath, Bath, United Kingdom.

Science has been at the centre of attempts by major industries, including tobacco, chemical, and pharmaceutical, to delay progress in tackling threats to human and planetary health by, inter alia, obscuring industry harms, and opposing regulation. Some aspects of this influence are well documented, others remain poorly understood, and similarities between industries remain underexplored. This study, therefore, aims to synthesise the literature to develop an evidence-based typology and model of corporate influence on science in order to provide an overview of this multi-faceted phenomenon. Read More

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X-linked neonatal-onset epileptic encephalopathy associated with a gain-of-function variant p.R660T in GRIA3.

PLoS Genet 2021 Jun 23;17(6):e1009608. Epub 2021 Jun 23.

Ministry of Education Key Laboratory of Model Animal for Disease Study, Department of Neurology, Affiliated Drum Tower Hospital, Medical School, Nanjing University, Nanjing, China.

The X-linked GRIA3 gene encodes the GLUA3 subunit of AMPA-type glutamate receptors. Pathogenic variants in this gene were previously reported in neurodevelopmental diseases, mostly in male patients but rarely in females. Here we report a de novo pathogenic missense variant in GRIA3 (c. Read More

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Behavioral correlates of cortical semantic representations modeled by word vectors.

PLoS Comput Biol 2021 Jun 23;17(6):e1009138. Epub 2021 Jun 23.

Center for Information and Neural Networks (CiNet), National Institute of Information and Communications Technology (NICT), Suita, Osaka, Japan.

The quantitative modeling of semantic representations in the brain plays a key role in understanding the neural basis of semantic processing. Previous studies have demonstrated that word vectors, which were originally developed for use in the field of natural language processing, provide a powerful tool for such quantitative modeling. However, whether semantic representations in the brain revealed by the word vector-based models actually capture our perception of semantic information remains unclear, as there has been no study explicitly examining the behavioral correlates of the modeled brain semantic representations. Read More

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Localized chondro-ossification underlies joint dysfunction and motor deficits in the mouse model of osteogenesis imperfecta.

Proc Natl Acad Sci U S A 2021 Jun;118(25)

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030;

Osteogenesis imperfecta (OI) is a genetic disorder that features wide-ranging defects in both skeletal and nonskeletal tissues. Previously, we and others reported that loss-of-function mutations in FK506 Binding Protein 10 () lead to skeletal deformities in conjunction with joint contractures. However, the pathogenic mechanisms underlying joint dysfunction in OI are poorly understood. Read More

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Interleukin-6 is an activator of pituitary stem cells upon local damage, a competence quenched in the aging gland.

Proc Natl Acad Sci U S A 2021 Jun;118(25)

Laboratory of Tissue Plasticity in Health and Disease, Cluster of Stem Cell and Developmental Biology, Department of Development and Regeneration, Leuven Stem Cell Institute, Katholieke Universiteit Leuven, 3000 Leuven, Belgium;

Stem cells in the adult pituitary are quiescent yet show acute activation upon tissue injury. The molecular mechanisms underlying this reaction are completely unknown. We applied single-cell transcriptomics to start unraveling the acute pituitary stem cell activation process as occurring upon targeted endocrine cell-ablation damage. Read More

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Attention, awareness, and the right temporoparietal junction.

Proc Natl Acad Sci U S A 2021 Jun;118(25)

Department of Psychology, Princeton University, Princeton, NJ 08544;

The attention schema theory posits a specific relationship between subjective awareness and attention, in which awareness is the control model that the brain uses to aid in the endogenous control of attention. In previous experiments, we developed a behavioral paradigm in human subjects to manipulate awareness and attention. The paradigm involved a visual cue that could be used to guide attention to a target stimulus. Read More

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Validating model-based Bayesian integration using prior-cost metamers.

Proc Natl Acad Sci U S A 2021 Jun;118(25)

McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, MA 02139;

There are two competing views on how humans make decisions under uncertainty. Bayesian decision theory posits that humans optimize their behavior by establishing and integrating internal models of past sensory experiences (priors) and decision outcomes (cost functions). An alternative hypothesis posits that decisions are optimized through trial and error without explicit internal models for priors and cost functions. Read More

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's historical journey through Siberia and the Americas.

Proc Natl Acad Sci U S A 2021 Jun;118(25)

Warwick Medical School, University of Warwick, Coventry CV4 7AL, United Kingdom.

The gastric bacterium shares a coevolutionary history with humans that predates the out-of-Africa diaspora, and the geographical specificities of populations reflect multiple well-known human migrations. We extensively sampled from 16 ethnically diverse human populations across Siberia to help resolve whether ancient northern Eurasian populations persisted at high latitudes through the last glacial maximum and the relationships between present-day Siberians and Native Americans. A total of 556 strains were cultivated and genotyped by multilocus sequence typing, and 54 representative draft genomes were sequenced. Read More

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A Finite Element Analysis and Circuit Modelling Methodology for Studying Electrical Impedance Myography of Human Limbs.

IEEE Trans Biomed Eng 2021 Jun 23;PP. Epub 2021 Jun 23.

Objective: Electrical impedance myography (EIM) measures bioimpedance over muscles. This paper proposes a circuit-based modelling methodology originated from finite element analysis (FEA), to emulate tissues and effects from anthropometric variations, and electrode placements, on EIM measurements. The proposed methodology is demonstrated on the upper arms and lower legs. Read More

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Multiple pathways of toxicity induced by dipeptide repeat aggregates and GC RNA in a cellular model.

Elife 2021 Jun 23;10. Epub 2021 Jun 23.

Max Planck Institute of Biochemistry, Martinsried, Germany.

The most frequent genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia is a GC repeat expansion in the gene. This expansion gives rise to translation of aggregating dipeptide repeat (DPR) proteins, including poly-GA as the most abundant species. However, gain of toxic function effects have been attributed to either the DPRs or the pathological GC RNA. Read More

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Legionnaires' disease in dental offices: quantifying aerosol risks to dental workers and patients.

J Occup Environ Hyg 2021 Jun 23:1-21. Epub 2021 Jun 23.

Southern Nevada Water Authority, P.O. Box 99954, Las Vegas, NV 89193.

is an opportunistic bacterial respiratory pathogen that is the leading causes of drinking water outbreaks in the United States. Dental offices pose a potential risk for inhalation or aspiration of due to the high surface area to volume ratio of dental unit water lines-a feature that is conducive to biofilm growth. This is coupled with the use of high-pressure water devices (e. Read More

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Protective Role of Dietary Capsanthin in a Mouse Model of Nonalcoholic Fatty Liver Disease.

J Med Food 2021 Jun;24(6):635-644

Research Institute for Medical Sciences, College of Medicine, Chungnam National University, Daejeon, Korea.

Capsanthin is the main carotenoid compound in red paprika ( L.). However, little is known about the beneficial effects of capsanthin in nonalcoholic fatty liver disease (NAFLD). Read More

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QM/MM Study of Human Transketolase: Thiamine Diphosphate Activation Mechanism and Complete Catalytic Cycle.

J Chem Inf Model 2021 Jun 23. Epub 2021 Jun 23.

Université Clermont Auvergne, CNRS, Clermont Auvergne INP, ICCF, F-63000 Clermont-Ferrand, France.

A computational model for human transketolase was proposed, showing that thiamine diphosphate activation was based on His110 in place of His481 reported in yeast transketolase. In addition, a complete catalytic reaction pathway was investigated using d-xylulose-5-phosphate and d-ribose-5-phosphate as substrates, showing at every step a perfect superimposition of our model with high-resolution crystallographic structures 3MOS, 4KXV, and 4KXX. This study shows that H2N4' of the active thiamine diphosphate "V form" no longer has a self-activating role but allows self-stabilization of the cofactor and of the Breslow intermediate. Read More

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Product Inhibition and the Catalytic Destruction of a Nerve Agent Simulant by Zirconium-Based Metal-Organic Frameworks.

ACS Appl Mater Interfaces 2021 Jun 23. Epub 2021 Jun 23.

Department of Chemistry, Northwestern University, 2145 Sheridan Road, Evanston, Illinois 60208, United States.

Rapid degradation/destruction of chemical warfare agents, especially ones containing a phosphorous-fluorine bond, is of notable interest due to their extreme toxicity and typically rapid rate of human incapacitation. Recent studies of the hydrolytic destruction of a key nerve agent simulant, dimethyl 4-nitrophenylphosphate (DMNP), catalyzed by Zr-based metal-organic frameworks (MOFs), have suggested deactivation of the active sites due to inhibition by the products as the reaction progresses. In this study, the interactions of two MOFs, NU-1000 and MOF-808, and two hydrolysis products, dimethyl phosphate (DMP) and ethyl methyl phosphonate (EMP), from the hydrolysis of the simulant (DMNP) and nerve agent ethyl methylphosphonofluoridate (EMPF), resembling the hydrolysis degradation product of the G-series nerve agent, Sarin (GB), have been investigated to deconvolute the effect of product inhibition from other effects on catalytic activity. Read More

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Glutathione Reductase-Sensitive Polymeric Micelles for Controlled Drug Delivery on Arthritic Diseases.

ACS Biomater Sci Eng 2021 Jun 23. Epub 2021 Jun 23.

3B's Research Group, I3Bs - Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark, Parque de Ciência e Tecnologia, Zona Industrial da Gandra, Barco 4805-017, Guimarães, Portugal.

Inflammation plays an essential role in arthritis development and progression. Despite the advances in the pharmaceutical field, current treatments still present low efficacy and severe side effects. Considering the high activity of the glutathione reductase (GR) enzyme in inflamed joints, a distinctive drug delivery system sensitive to the GR enzyme was designed for efficient drug delivery on arthritic diseases. Read More

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A Magnetically Powered Stem Cell-Based Microrobot for Minimally Invasive Stem Cell Delivery via the Intranasal Pathway in a Mouse Brain.

Adv Healthc Mater 2021 Jun 23:e2100801. Epub 2021 Jun 23.

Department of Robotics Engineering, DGIST-ETH Microrobotics Research Center, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu, 42988, Republic of Korea.

Targeted stem cell delivery with microrobots has emerged as a potential alternative therapeutic strategy in regenerative medicine, and intranasal administration is an effective approach for minimally invasive delivery of therapeutic agents into the brain. In this study, a magnetically powered stem cell-based microrobot ("Cellbot") is used for minimally invasive targeted stem cell delivery to the brain through the intranasal passage. The Cellbot is developed by internalizing superparamagnetic iron oxide nanoparticles (SPIONs) into human nasal turbinate stem cells. Read More

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Early manifestation of gait alterations in the Tg2576 mouse model of Alzheimer's disease.

Geroscience 2021 Jun 23. Epub 2021 Jun 23.

Vascular Cognitive Impairment and Neurodegeneration Program, Oklahoma Center for Geroscience and Healthy Brain Aging, Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, 975 N. E. 10th Street - BRC 1303, Oklahoma City, OK, 73104, USA.

There is strong clinical evidence that multifaceted gait abnormalities may be manifested at early stages of Alzheimer's disease (AD), are related to cognitive decline, and can be used as an early biomarker to identify patients at risk of progressing to full-blown dementia. Despite their importance, gait abnormalities have not been investigated in mouse models of AD, which replicate important aspects of the human disease. The Tg2576 is frequently used in AD research to test therapeutic interventions targeting cellular mechanisms contributing to the genesis of AD. Read More

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In vitro and in vitro toxicity study of diesel exhaust particles using BEAS-2B cell line and the nematode Caenorhabditis elegans as biological models.

Environ Sci Pollut Res Int 2021 Jun 23. Epub 2021 Jun 23.

The Second Affiliated High School of East China Normal University, Shanghai, 201203, China.

It is well accepted that diesel exhaust particles (DEPs) are highly associated with improper function of organ systems. In this study, DEP toxicity was performed by using in vitro human BEAS-2B cell line and in vivo animal model, namely, Caenorhabditis elegans (C. elegans). Read More

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T-cell responses and combined immunotherapy against human carbonic anhydrase 9-expressing mouse renal cell carcinoma.

Cancer Immunol Immunother 2021 Jun 23. Epub 2021 Jun 23.

Department of Urology, Kindai University Faculty of Medicine, Osaka, Japan.

Renal cell carcinoma (RCC) is known to respond to immune checkpoint blockade (ICB) therapy, whereas there has been limited analysis of T-cell responses to RCC. In this study, we utilized human carbonic anhydrase 9 (hCA9) as a model neoantigen of mouse RENCA RCC. hCA9-expressing RENCA RCC (RENCA/hCA9) cells were rejected in young mice but grew in aged mice. Read More

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LSTM-PHV: prediction of human-virus protein-protein interactions by LSTM with word2vec.

Brief Bioinform 2021 Jun 23. Epub 2021 Jun 23.

Department of Bioscience and Bioinformatics in the Kyushu Institute of Technology, Japan.

Viral infection involves a large number of protein-protein interactions (PPIs) between human and virus. The PPIs range from the initial binding of viral coat proteins to host membrane receptors to the hijacking of host transcription machinery. However, few interspecies PPIs have been identified, because experimental methods including mass spectrometry are time-consuming and expensive, and molecular dynamic simulation is limited only to the proteins whose 3D structures are solved. Read More

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Fibrosis-4 Index vs Nonalcoholic Fatty Liver Disease Fibrosis Score in Identifying Advanced Fibrosis in Subjects With Nonalcoholic Fatty Liver Disease: A Meta-Analysis.

Am J Gastroenterol 2021 Jun 10. Epub 2021 Jun 10.

National Institute of Gastroenterology "Saverio de Bellis," Research Hospital, Castellana Grotte, Bari, Italy.

Introduction: In subjects with nonalcoholic fatty liver disease (NAFLD), advanced fibrosis (AF) carries the highest risk of adverse liver-related events. To reduce the number of unnecessary biopsies, several noninvasive tools (NITs) for the risk stratification of fibrosis have been developed. We conducted this meta-analysis to assess the performance of the fibrosis-4 index (FIB-4) and NAFLD fibrosis scores (NFS), the 2 most common NITs, for the appropriate selection of subjects with AF for biopsy. Read More

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Structural basis of covalent inhibitory mechanism of TMPRSS2-related serine proteases by camostat.

J Virol 2021 Jun 23:JVI0086121. Epub 2021 Jun 23.

College of Chemistry, Fuzhou University, Fuzhou, Fujian, 350116, P.R. China.

SARS-CoV-2 is the viral pathogen causing the COVID19 global pandemic. No effective treatment for COVID-19 has been established yet. TMPRSS2 is essential for viral spread and pathogenicity by facilitating the entry of SARS-CoV-2 onto host cells. Read More

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