Medicine and Health Sciences Commons^™

A Large-Scale Genome-Wide Association Study Meta-Analysis Of Cannabis Use Disorder, Emma C Johnson, Alexander S Hatoum, June He, Kathleen K Bucholz, Louis Fox, Sarah M Hartz, John P Rice, Nancy L Saccone, Laura J Bierut, Richard A Grucza, Andrew C Heath, Pamela A F Madden, Elliot C Nelson, Arpana Agrawal, Et Al.

2020-Current year OA Pubs

BACKGROUND: Variation in liability to cannabis use disorder has a strong genetic component (estimated twin and family heritability about 50-70%) and is associated with negative outcomes, including increased risk of psychopathology. The aim of the study was to conduct a large genome-wide association study (GWAS) to identify novel genetic variants associated with cannabis use disorder.

METHODS: To conduct this GWAS meta-analysis of cannabis use disorder and identify associations with genetic loci, we used samples from the Psychiatric Genomics Consortium Substance Use Disorders working group, iPSYCH, and deCODE (20 916 case samples, 363 116 control samples in total), contrasting cannabis use …

Lower Survival After Coronary Artery Bypass In Patients Who Had Atrial Fibrillation Missed By Widely Used Definitions, Giovanni Filardo, Benjamin D Pollock, Briget Da Graca, Danielle M Sass, Teresa K Phan, Debbie E Montenegro, Gorav Ailawadi, Vinod H Thourani, Ralph J Damiano Jr

2020-Current year OA Pubs

OBJECTIVE: To investigate the impact of limiting the definition of post-coronary artery bypass graft (CABG) atrial fibrillation (AF) to AF/flutter requiring treatment-as in the Society of Thoracic Surgeons' (STS) database- on the association with survival.

PATIENTS AND METHODS: We assessed in-hospital incidence of post-CABG AF in 7110 consecutive isolated patients with CABG without preoperative AF at 4 hospitals (January 1, 2004 to December 31, 2010). Patients with ≥1 episode of post-CABG AF detected via continuous in-hospital electrocardiogram (ECG)/telemetry monitoring documented by physicians were assigned to the following: Group 1, identified as having post-CABG AF in STS data and Group 2, …

Sequence Analysis In Bos Taurus Reveals Pervasiveness Of X-Y Arms Races In Mammalian Lineages, Jennifer F Hughes, Colin Kremitzki, Catrina Fronick, Tina A Graves-Lindsay, Lucinda Fulton, Wesley C Warren, Richard K Wilson, Et Al.

2020-Current year OA Pubs

Studies of Y Chromosome evolution have focused primarily on gene decay, a consequence of suppression of crossing-over with the X Chromosome. Here, we provide evidence that suppression of X-Y crossing-over unleashed a second dynamic: selfish X-Y arms races that reshaped the sex chromosomes in mammals as different as cattle, mice, and men. Using super-resolution sequencing, we explore the Y Chromosome of

The Impact Of Uncorrected Mild Aortic Insufficiency At The Time Of Left Ventricular Assist Device Implantation, Yuki Tanaka, Tomohiro Nakajima, Irene Fischer, Fei Wan, Kunal Kotkar, Marc R Moon, Ralph J Damiano Jr, Muhammad F Masood, Akinobu Itoh

2020-Current year OA Pubs

OBJECTIVE: The study objective was to investigate the progression of uncorrected mild aortic insufficiency and its impact on survival and functional status after left ventricular assist device implantation.

METHODS: We retrospectively reviewed 694 consecutive patients who underwent implantation of a continuous-flow left ventricular assist device between January 2006 and March 2018. Pre-left ventricular assist device transthoracic echocardiography identified 111 patients with mild aortic insufficiency and 493 patients with trace or no aortic insufficiency. To adjust for differences in preoperative factors, propensity score matching was used, resulting in 101 matched patients in each of the mild aortic insufficiency and no aortic …

A Randomized, Placebo-Controlled Trial Evaluating Effects Of Lebrikizumab On Airway Eosinophilic Inflammation And Remodelling In Uncontrolled Asthma (Clavier), Cary D Austin, Kaharu Sumino, Et Al.

2020-Current year OA Pubs

BACKGROUND: The anti-interleukin 13 (IL-13) monoclonal antibody lebrikizumab improves lung function in patients with moderate-to-severe uncontrolled asthma, but its effects on airway inflammation and remodelling are unknown. CLAVIER was designed to assess lebrikizumab's effect on eosinophilic inflammation and remodelling.

OBJECTIVE: To report safety and efficacy results from enrolled participants with available data from CLAVIER.

METHODS: We performed bronchoscopy on patients with uncontrolled asthma before and after 12 weeks of randomized double-blinded treatment with lebrikizumab (n = 31) or placebo (n = 33). The pre-specified primary end-point was relative change in airway subepithelial eosinophils per mm

RESULTS: There was a baseline …

Functional Genomic Analyses Uncover Apoe-Mediated Regulation Of Brain And Cerebrospinal Fluid Beta-Amyloid Levels In Parkinson Disease, Laura Ibanez, Jorge A Bahena, Chengran Yang, Umber Dube, Fabiana H G Farias, John P Budde, Kristy Bergmann, Carol Brenner-Webster, John C Morris, Richard J Perrin, Nigel J Cairns, John O'Donnell, Rebecca Miller, Albert A Davis, Paul Kotzbauer, Meghan C Campbell, Joel S Perlmutter, Oscar Harari, Carlos Cruchaga, Bruno A Benitez, Et Al.

2020-Current year OA Pubs

Alpha-synuclein is the main protein component of Lewy bodies, the pathological hallmark of Parkinson's disease. However, genetic modifiers of cerebrospinal fluid (CSF) alpha-synuclein levels remain unknown. The use of CSF levels of amyloid beta

Antimicrobial Resistance In Enteric Bacteria: Current State And Next-Generation Solutions, M J Wallace, S R S Fishbein, G Dantas

2020-Current year OA Pubs

Antimicrobial resistance is one of the largest threats to global health and imposes substantial burdens in terms of morbidity, mortality, and economic costs. The gut is a key conduit for the genesis and spread of antimicrobial resistance in enteric bacterial pathogens. Distinct bacterial species that cause enteric disease can exist as invasive enteropathogens that immediately evoke gastrointestinal distress, or pathobionts that can arise from established bacterial commensals to inflict dysbiosis and disease. Furthermore, various environmental reservoirs and stressors facilitate the evolution and transmission of resistance. In this review, we present a comprehensive discussion on circulating resistance profiles and gene mobilization …

Phosphodiesterase 5 (Pde5) Restricts Intracellular Cgmp Accumulation During Enterotoxigenic Escherichia Coli Infection, Jennifer Foulke-Abel, Huimin Yu, Laxmi Sunuwar, Ruxian Lin, James M Fleckenstein, James B Kaper, Mark Donowitz

2020-Current year OA Pubs

Diarrhea caused by enterotoxigenic

Macrophage-Associated Lipin-1 Promotes Β-Oxidation In Response To Proresolving Stimuli, Robert M Schilke, Cassidy M R Blackburn, Shashanka Rao, David M Krzywanski, Brian N Finck, Matthew D Woolard

2020-Current year OA Pubs

Macrophages reprogram their metabolism to promote appropriate responses. Proresolving macrophages primarily use fatty acid oxidation as an energy source. Metabolites generated during the catabolism of fatty acids aid in the resolution of inflammation and tissue repair, but the regulatory mechanisms that control lipid metabolism in macrophages are not fully elucidated. Lipin-1, a phosphatidic acid phosphatase that has transcriptional coregulator activity, regulates lipid metabolism in a variety of cells. In this current study, we show that lipin-1 is required for increased oxidative phosphorylation in IL-4 stimulated mouse (

Strategies For Effective Dissemination Of Research To United States Policymakers: A Systematic Review, Laura Ellen Ashcraft, Deirdre A Quinn, Ross C Brownson

2020-Current year OA Pubs

BACKGROUND: Research has the potential to influence US social policy; however, existing research in this area lacks a coherent message. The Model for Dissemination of Research provides a framework through which to synthesize lessons learned from research to date on the process of translating research to US policymakers.

METHODS: The peer-reviewed and grey literature was systematically reviewed to understand common strategies for disseminating social policy research to policymakers in the United States. We searched Academic Search Premier, PolicyFile, SocINDEX, Social Work Abstracts, and Web of Science from January 1980 through December 2019. Articles were independently reviewed and thematically analyzed by …

Safety And Immunogenicity Of Fc-Eda, A Recombinant Ectodysplasin A1 Replacement Protein, In Human Subjects, Iris Körber, Ophir D Klein, Patrick Morhart, Florian Faschingbauer, Dorothy K Grange, Angus Clarke, Christine Bodemer, Silvia Maitz, Kenneth Huttner, Neil Kirby, Caroline Durand, Holm Schneider

2020-Current year OA Pubs

In X-linked hypohidrotic ectodermal dysplasia, the most frequent ectodermal dysplasia, an inherited deficiency of the signalling protein ectodysplasin A1 (EDA1) impairs the development of the skin and its appendages, various eccrine glands, and dentition. The severe hypohidrosis common to X-linked hypohidrotic ectodermal dysplasia patients may lead to life-threatening hyperthermia, especially during hot weather or febrile illness. Fc-EDA, an EDA1 replacement protein known to prevent the disease in newborn animals, was tested in 2 clinical trials (human adults and neonates) and additionally administered under compassionate use to 3 infants in utero. The data support the safety of Fc-EDA and efficacy if …

Potential Missed Opportunities For Diagnosis Of Cryptococcosis And The Association With Mortality: A Cohort Study, Ana S. Salazar, Matthew R. Keller, Margaret A. Olsen, Katelin B. Nickel, Ige A. George, Lindsey Larson, William G. Powderly, Andrej Spec

2020-Current year OA Pubs

BACKGROUND: Cryptococcosis is one of the most common life-threatening opportunistic mycoses worldwide. Insidious presentation and slow onset of symptoms make it difficult to recognize, complicating the diagnostic process. Delays in diagnosis may lead to increased mortality. We aim to determine the frequency of missed opportunities for diagnosis of cryptococcosis and its effects on mortality.

METHODS: To estimate the proportion of individuals with a potentially missed diagnosis for cryptococcosis in hospitalized patients, we conducted a retrospective cohort study using the Healthcare Cost and Utilization Project State Inpatient Databases from 2005 to 2015 from eight states. All hospitalized adult patients diagnosed with …

Gadobutrol-Enhanced Cardiac Magnetic Resonance Imaging For Detection Of Coronary Artery Disease, Andrew E Arai, Pamela K Woodard, Et Al.

2020-Current year OA Pubs

BACKGROUND: Gadolinium-based contrast agents were not approved in the United States for detecting coronary artery disease (CAD) prior to the current studies.

OBJECTIVES: The purpose of this study was to determine the sensitivity and specificity of gadobutrol for detection of CAD by assessing myocardial perfusion and late gadolinium enhancement (LGE) imaging.

METHODS: Two international, single-vendor, phase 3 clinical trials of near identical design, "GadaCAD1" and "GadaCAD2," were performed. Cardiovascular magnetic resonance (CMR) included gadobutrol-enhanced first-pass vasodilator stress and rest perfusion followed by LGE imaging. CAD was defined by quantitative coronary angiography (QCA) but computed tomography coronary angiography could exclude significant …

Swell1 Regulates Skeletal Muscle Cell Size, Intracellular Signaling, Adiposity And Glucose Metabolism, Ashutosh Kumar, Litao Xie, Chau My Ta, Antentor O Hinton, Susheel K Gunasekar, Rachel A Minerath, Karen Shen, Joshua M Maurer, Chad E Grueter, E Dale Abel, Gretchen Meyer, Rajan Sah

2020-Current year OA Pubs

Maintenance of skeletal muscle is beneficial in obesity and Type 2 diabetes. Mechanical stimulation can regulate skeletal muscle differentiation, growth and metabolism; however, the molecular mechanosensor remains unknown. Here, we show that SWELL1 (

Growth, Detection, Quantification, And Inactivation Of Sars-Cov-2, James Brett Case, Adam L. Bailey, Arthur S. Kim, Rita E. Chen, Michael S. Diamond

2020-Current year OA Pubs

Severe acute respiratory syndrome coronavirus (SARS-CoV)-2 is the agent responsible for the coronavirus disease 2019 (COVID-19) global pandemic. SARS-CoV-2 is closely related to SARS-CoV, which caused the 2003 SARS outbreak. Although numerous reagents were developed to study SARS-CoV infections, few have been applicable to evaluating SARS-CoV-2 infection and immunity. Current limitations in studying SARS-CoV-2 include few validated assays with fully replication-competent wild-type virus. We have developed protocols to propagate, quantify, and work with infectious SARS-CoV-2. Here, we describe: (1) virus stock generation, (2) RT-qPCR quantification of SARS-CoV-2 RNA; (3) detection of SARS-CoV-2 antigen by flow cytometry, (4) quantification of infectious …

Improved Tolerability Of Neratinib In Patients With Her2-Positive Early-Stage Breast Cancer: The Control Trial, C H Barcenas, R Bose, Et Al.

2020-Current year OA Pubs

BACKGROUND: Neratinib is an irreversible pan-HER tyrosine kinase inhibitor approved for extended adjuvant treatment in early-stage HER2-positive breast cancer based on the phase III ExteNET study. In that trial, in which no antidiarrheal prophylaxis was mandated, grade 3 diarrhea was observed in 40% of patients and 17% discontinued due to diarrhea. The international, open-label, sequential-cohort, phase II CONTROL study is investigating several strategies to improve tolerability.

PATIENTS AND METHODS: Patients who completed trastuzumab-based adjuvant therapy received neratinib 240 mg/day for 1 year plus loperamide prophylaxis (days 1-28 or 1-56). Sequential cohorts evaluated additional budesonide or colestipol prophylaxis (days 1-28) and …

Aadc Deficiency From Infancy To Adulthood: Symptoms And Developmental Outcome In An International Cohort Of 63 Patients, Toni S Pearson, Laura Gilbert, Kathleen D Meeks, Et Al.

2020-Current year OA Pubs

Aromatic l-amino acid decarboxylase deficiency (AADCD) is a rare, autosomal recessive neurodevelopmental disorder characterized by impaired synthesis of dopamine, noradrenaline, adrenaline and serotonin, leading to a complex syndrome of motor, behavioral, and autonomic symptoms. This retrospective study assessed the symptoms and developmental outcome of a large international cohort of patients with AADCD via physician and/or caregiver responses to a detailed, standardized questionnaire. Sixty-three patients (60% female; ages 6 months-36 years, median 7 years; 58 living) from 23 individual countries participated. Common symptoms at onset (median age 3 months, range 0-12 months) were hypotonia, developmental delay, and/or oculogyric crises. Oculogyric crises …

Tonic Tcr Signaling Inversely Regulates The Basal Metabolism Of Cd4+ T Cells, Ashley A Viehmann Milam, Juliet M Bartleson, Michael D Buck, Chih-Hao Chang, Alexey Sergushichev, David L Donermeyer, Wing Y Lam, Erika L Pearce, Maxim N Artyomov, Paul M Allen

2020-Current year OA Pubs

The contribution of self-peptide-MHC signaling in CD4

De Novo And Bi-Allelic Pathogenic Variants In Nars1 Cause Neurodevelopmental Delay Due To Toxic Gain-Of-Function And Partial Loss-Of-Function Effects, Andreea Manole, Marwan Shinawi, Marisa V. Andrews, Dustin Baldridge, John F. Mantovani, Et Al.

2020-Current year OA Pubs

Aminoacyl-tRNA synthetases (ARSs) are ubiquitous, ancient enzymes that charge amino acids to cognate tRNA molecules, the essential first step of protein translation. Here, we describe 32 individuals from 21 families, presenting with microcephaly, neurodevelopmental delay, seizures, peripheral neuropathy, and ataxia, with de novo heterozygous and bi-allelic mutations in asparaginyl-tRNA synthetase (NARS1). We demonstrate a reduction in NARS1 mRNA expression as well as in NARS1 enzyme levels and activity in both individual fibroblasts and induced neural progenitor cells (iNPCs). Molecular modeling of the recessive c.1633C>T (p.Arg545Cys) variant shows weaker spatial positioning and tRNA selectivity. We conclude that de novo and …

Combinatorial Pharmacogenomic Algorithm Is Predictive Of Citalopram And Escitalopram Metabolism In Patients With Major Depressive Disorder, Richard C. Shelton, Charles R. Conway, Et Al.

2020-Current year OA Pubs

Pharmacogenomic tests used to guide clinical treatment for major depressive disorder (MDD) must be thoroughly validated. One important assessment of validity is the ability to predict medication blood levels, which reflect altered metabolism. Historically, the metabolic impact of individual genes has been evaluated; however, we now know that multiple genes are often involved in medication metabolism. Here, we evaluated the ability of individual pharmacokinetic genes (CYP2C19, CYP2D6, CYP3A4) and a combinatorial pharmacogenomic test (GeneSight Psychotropic®; weighted assessment of all three genes) to predict citalopram/escitalopram blood levels in patients with MDD. Patients from the Genomics Used to Improve DEpression Decisions (GUIDED) …

Towards Hcp-Style Macaque Connectomes: 24-Channel 3t Multi-Array Coil, Mri Sequences And Preprocessing, Joonas A. Autio, Matthew F. Glasser, Chad J. Donahue, Timothy S. Coalson, David C. Van Essen, Et Al.

2020-Current year OA Pubs

Macaque monkeys are an important animal model where invasive investigations can lead to a better understanding of the cortical organization of primates including humans. However, the tools and methods for noninvasive image acquisition (e.g. MRI RF coils and pulse sequence protocols) and image data preprocessing have lagged behind those developed for humans. To resolve the structural and functional characteristics of the smaller macaque brain, high spatial, temporal, and angular resolutions combined with high signal-to-noise ratio are required to ensure good image quality. To address these challenges, we developed a macaque 24-channel receive coil for 3-T MRI with parallel imaging capabilities. …

Portable, Field-Based Neuroimaging Using High-Density Diffuse Optical Tomography, Andrew K. Fishell, Ana María Arbeláez, Claudia P. Valdés, Tracy N. Burns-Yocum, Arefeh Sherafati, Edward J. Richter, Margarita Torres, Adam T. Eggebrecht, Christopher D. Smyser, Joseph P. Culver

2020-Current year OA Pubs

Behavioral and cognitive tests in individuals who were malnourished as children have revealed malnutrition-related deficits that persist throughout the lifespan. These findings have motivated recent neuroimaging investigations that use highly portable functional near-infrared spectroscopy (fNIRS) instruments to meet the demands of brain imaging experiments in low-resource environments and enable longitudinal investigations of brain function in the context of long-term malnutrition. However, recent studies in healthy subjects have demonstrated that high-density diffuse optical tomography (HD-DOT) can significantly improve image quality over that obtained with sparse fNIRS imaging arrays. In studies of both task activations and resting state functional connectivity, HD-DOT is …

Collaborative, Multidisciplinary Evaluation Of Cancer Variants Through Virtual Molecular Tumor Boards Informs Local Clinical Practices, Shruti Rao, Beth Pitel, Alex H Wagner, Simina M Boca, Matthew Mccoy, Ian King, Samir Gupta, Ben Ho Park, Jeremy L Warner, James Chen, Peter K Rogan, Debyani Chakravarty, Malachi Griffith, Obi L Griffith, Subha Madhavan

2020-Current year OA Pubs

PURPOSE: The cancer research community is constantly evolving to better understand tumor biology, disease etiology, risk stratification, and pathways to novel treatments. Yet the clinical cancer genomics field has been hindered by redundant efforts to meaningfully collect and interpret disparate data types from multiple high-throughput modalities and integrate into clinical care processes. Bespoke data models, knowledgebases, and one-off customized resources for data analysis often lack adequate governance and quality control needed for these resources to be clinical grade. Many informatics efforts focused on genomic interpretation resources for neoplasms are underway to support data collection, deposition, curation, harmonization, integration, and analytics …

Proteogenomic Characterization Reveals Therapeutic Vulnerabilities In Lung Adenocarcinoma, Michael A. Gillette, Song Cao, Yize Li, Wen-Wei Liang, Michael C Wendl, Ramaswamy Govindan, Et Al.

2020-Current year OA Pubs

To explore the biology of lung adenocarcinoma (LUAD) and identify new therapeutic opportunities, we performed comprehensive proteogenomic characterization of 110 tumors and 101 matched normal adjacent tissues (NATs) incorporating genomics, epigenomics, deep-scale proteomics, phosphoproteomics, and acetylproteomics. Multi-omics clustering revealed four subgroups defined by key driver mutations, country, and gender. Proteomic and phosphoproteomic data illuminated biology downstream of copy number aberrations, somatic mutations, and fusions and identified therapeutic vulnerabilities associated with driver events involving KRAS, EGFR, and ALK. Immune subtyping revealed a complex landscape, reinforced the association of STK11 with immune-cold behavior, and underscored a potential immunosuppressive role of neutrophil degranulation. …

Test-Retest Reliability Of Fmri-Measured Brain Activity During Decision Making Under Risk, Ozlem Korucuoglu, Michael P. Harms, Serguei V. Astafiev, James T. Kennedy, Semyon Golosheykin, Deanna M. Barch, Andrey P. Anokhin

2020-Current year OA Pubs

Neural correlates of decision making under risk are being increasingly utilized as biomarkers of risk for substance abuse and other psychiatric disorders, treatment outcomes, and brain development. This research relies on the basic assumption that fMRI measures of decision making represent stable, trait-like individual differences. However, reliability needs to be established for each individual construct. Here we assessed long-term test-retest reliability (TRR) of regional brain activations related to decision making under risk using the Balloon Analogue Risk Taking task (BART) and identified regions with good TRRs and familial influences, an important prerequisite for the use of fMRI measures in genetic …

Evaluation Of Mavacamten In Symptomatic Patients With Nonobstructive Hypertrophic Cardiomyopathy, Carolyn Y Ho, Richard G Bach, Et Al.

2020-Current year OA Pubs

BACKGROUND: Patients with nonobstructive hypertrophic cardiomyopathy (nHCM) often experience a high burden of symptoms; however, there are no proven pharmacological therapies. By altering the contractile mechanics of the cardiomyocyte, myosin inhibitors have the potential to modify pathophysiology and improve symptoms associated with HCM.

OBJECTIVES: MAVERICK-HCM (Mavacamten in Adults With Symptomatic Non-Obstructive Hypertrophic Cardiomyopathy) explored the safety and efficacy of mavacamten, a first-in-class reversible inhibitor of cardiac-specific myosin, in nHCM.

METHODS: The MAVERICK-HCM trial was a multicenter, double-blind, placebo-controlled, dose-ranging phase II study in adults with symptomatic nHCM (New York Heart Association functional class II/III), left ventricular ejection fraction (LVEF) ≥55%, …

Hypoglycaemia Is Reduced With Use Of Inhaled Technosphere ® Insulin Relative To Insulin Aspart In Type 1 Diabetes Mellitus, E R Seaquist, L Blonde, J B Mcgill, S R Heller, D M Kendall, J B Bumpass, F M Pompilio, M L Grant

2020-Current year OA Pubs

AIM: To evaluate the effect of final HbA

METHODS: In the randomized, phase 3, multicentre AFFINITY-1 study, adults (N = 375) who had type 1 diabetes for ≥ 12 months and an HbA

RESULTS: Participants treated with Technosphere Insulin experienced statistically significantly fewer level 1 and 2 hypoglycaemic events and a lower incidence of level 3 hypoglycaemia than participants treated with insulin aspart. The lower rate of hypoglycaemia with Technosphere Insulin was observed across the range of end-of-treatment HbA

CONCLUSIONS: Participants using Technosphere Insulin experienced clinically non-inferior glycaemic control and lower hypoglycaemia rates across a range of HbA

Neural Circuit Dynamics For Sensory Detection, Sruti Mallik, Srinath Nizampatnam, Anirban Nandi, Debajit Saha, Baranidharan Raman, Shinung Ching

2020-Current year OA Pubs

We consider the question of how sensory networks enable the detection of sensory stimuli in a combinatorial coding space. We are specifically interested in the olfactory system, wherein recent experimental studies have reported the existence of rich, enigmatic response patterns associated with stimulus onset and offset. This study aims to identify the functional relevance of such response patterns (i.e., what benefits does such neural activity provide in the context of detecting stimuli in a natural environment). We study this problem through the lens of normative, optimization-based modeling. Here, we define the notion of a low-dimensional latent representation of stimulus identity, …

Rna-Induced Conformational Switching And Clustering Of G3bp Drive Stress Granule Assembly By Condensation, Jordina Guillén-Boixet, Alex S. Holehouse, Rohit V. Pappu, Et Al.

2020-Current year OA Pubs

Stressed cells shut down translation, release mRNA molecules from polysomes, and form stress granules (SGs) via a network of interactions that involve G3BP. Here we focus on the mechanistic underpinnings of SG assembly. We show that, under non-stress conditions, G3BP adopts a compact auto-inhibited state stabilized by electrostatic intramolecular interactions between the intrinsically disordered acidic tracts and the positively charged arginine-rich region. Upon release from polysomes, unfolded mRNAs outcompete G3BP auto-inhibitory interactions, engendering a conformational transition that facilitates clustering of G3BP through protein-RNA interactions. Subsequent physical crosslinking of G3BP clusters drives RNA molecules into networked RNA/protein condensates. We show that …

Polr1b And Neural Crest Cell Anomalies In Treacher Collins Syndrome Type 4, Elodie Sanchez, Tomi L Toler, Walton Nephi, Marcia Willing, Et Al.

2020-Current year OA Pubs

PURPOSE: Treacher Collins syndrome (TCS) is a rare autosomal dominant mandibulofacial dysostosis, with a prevalence of 0.2-1/10,000. Features include bilateral and symmetrical malar and mandibular hypoplasia and facial abnormalities due to abnormal neural crest cell (NCC) migration and differentiation. To date, three genes have been identified: TCOF1, POLR1C, and POLR1D. Despite a large number of patients with a molecular diagnosis, some remain without a known genetic anomaly.

METHODS: We performed exome sequencing for four individuals with TCS but who were negative for pathogenic variants in the known causative genes. The effect of the pathogenic variants was investigated in zebrafish.

RESULTS: …