Digital Commons Network^™

Zika Virus Infection In The Developing Mouse Produces Dramatically Different Neuropathology Dependent On Viral Strain, Kevin K. Noguchi, Brant S. Swiney, Sasha L. Williams, Jacob N. Huffman, Katherine Lucas, Sophie H. Wang, Kayla M. Kapral, Amber Li, Krikor T. Dikranian

Open Access Publications

Zika virus (ZIKV) infection during pregnancy has been causally linked to a constellation of neurodevelopmental deformities in the fetus resulting in a disease termed congenital Zika syndrome (CZS). Here we detail how ZIKV infection produces extensive neuropathology in the developing mouse brain and spinal cord of both sexes. Surprisingly, neuropathology differs depending on viral strain with a French Polynesian isolate producing primarily excitotoxicity and a Brazilian isolate being almost exclusively apoptotic but occurring over a prolonged period that is more likely to produce severe hypoplasia. We also show exposure can produce a characteristic pattern of infection that mirrors neuropathology and …

Analysis Of Neurodegenerative Disease-Causing Genes In Dementia With Lewy Bodies, Tatiana Orme, Nigel J Cairns, John C Morris, Et Al

Open Access Publications

Dementia with Lewy bodies (DLB) is a clinically heterogeneous disorder with a substantial burden on healthcare. Despite this, the genetic basis of the disorder is not well defined and its boundaries with other neurodegenerative diseases are unclear. Here, we performed whole exome sequencing of a cohort of 1118 Caucasian DLB patients, and focused on genes causative of monogenic neurodegenerative diseases. We analyzed variants in 60 genes implicated in DLB, Alzheimer's disease, Parkinson's disease, frontotemporal dementia, and atypical parkinsonian or dementia disorders, in order to determine their frequency in DLB. We focused on variants that have previously been reported as pathogenic, …

Multicenter Evaluation Of The New Etest Gradient Diffusion Method For Piperacillin-Tazobactam Susceptibility Testing Of Enterobacterales, Pseudomonas Aeruginosa, And Acinetobacter Baumannii Complex, Sergio García-Fernández, Yohann Bala, Tom Armstrong, María García-Castillo, Carey-Ann D. Burnham, Meghan A Wallace, Dwight Hardy, Gilles Zambardi, Rafael Cantón

Open Access Publications

Piperacillin-tazobactam (P/T) is a β-lactam-β-lactamase inhibitor combination frequently used in the hospital setting. Etest is a gradient diffusion method that represents an alternative to broth microdilution (BMD) for performing antimicrobial susceptibility testing. We conducted a multicenter evaluation of the performance of the new P/T Etest compared to that of BMD following U.S. Food and Drug Administration (FDA) and International Standards Organization (ISO) standard ISO 20776-2 criteria using Clinical and Laboratory Standards Institute (CLSI)-FDA and European Committee on Antimicrobial Susceptibility Testing (EUCAST) interpretive breakpoints, respectively. A total of 977 isolates (775

Structural And Biophysical Analysis Of The Clca1 Vwa Domain Suggests Mode Of Tmem16a Engagement, Kayla N Berry, Tom J Brett

Open Access Publications

The secreted protein calcium-activated chloride channel regulator 1 (CLCA1) utilizes a von Willebrand factor type A (VWA) domain to bind to and potentiate the calcium-activated chloride channel TMEM16A. To gain insight into this unique potentiation mechanism, we determined the 2.0-Å crystal structure of human CLCA1 VWA bound to Ca

The Impact Of Due Process And Disruptions On Emergency Medicine Education In The United States, Al'ai Alvarez, Anne Messman, Melissa Platt, Megan Healy, Elaine B Josephson, Shawn London, Douglas Char

Open Access Publications

INTRODUCTION: Academic Emergency Medicine (EM) departments are not immune to natural disasters, economic or political forces that disrupt a training program's operations and educational mission. Due process concerns are closely intertwined with the challenges that program disruption brings. Due process is a protection whereby an individual will not lose rights without access to a fair procedural process. Effects of natural disasters similarly create disruptions in the physical structure of training programs that at times have led to the displacement of faculty and trainees. Variation exists in the implementation of transitions amongst training sites across the country, and its impact on …

Clinical Controversies In Anticoagulation Monitoring And Antithrombin Supplementation For Ecmo, Meghan M Chlebowski, Sirine Baltagi, Mel Carlson, Jerrold H Levy, Philip C Spinella

Open Access Publications

During extracorporeal membrane oxygenation (ECMO), a delicate balance is required to titrate systemic anticoagulation to prevent thrombotic complications within the circuit and prevent bleeding in the patient. Despite focused efforts to achieve this balance, the frequency of both thrombotic and bleeding events remains high. Anticoagulation is complicated to manage in this population due to the complexities of the hemostatic system that are compounded by age-related developmental hemostatic changes, variable effects of the etiology of critical illness on hemostasis, and blood-circuit interaction. Lack of high-quality data to guide anticoagulation management in ECMO patients results in marked practice variability among centers. One …

Lxrs Regulate Features Of Age-Related Macular Degeneration And May Be A Potential Therapeutic Target, Mayur Choudhary, Ebraheim N Ismail, Pei-Li Yao, Faryan Tayyari, Roxana A Radu, Steven Nusinowitz, Michael E Boulton, Rajendra S Apte, Jeffrey W Ruberti, James T Handa, Peter Tontonoz, Goldis Malek

Open Access Publications

Effective treatments and animal models for the most prevalent neurodegenerative form of blindness in elderly people, called age-related macular degeneration (AMD), are lacking. Genome-wide association studies have identified lipid metabolism and inflammation as AMD-associated pathogenic pathways. Given liver X receptors (LXRs), encoded by the nuclear receptor subfamily 1 group H members 2 and 3 (NR1H3 and NR1H2), are master regulators of these pathways, herein we investigated the role of LXR in human and mouse eyes as a function of age and disease and tested the therapeutic potential of targeting LXR. We identified immunopositive LXR fragments in human extracellular early dry …

Perfect Timing: Circadian Rhythms, Sleep, And Immunity - An Nih Workshop Summary, Jeffrey A Haspel, Andrew E Gelman, Brian S Kim, Et Al

Open Access Publications

Recent discoveries demonstrate a critical role for circadian rhythms and sleep in immune system homeostasis. Both innate and adaptive immune responses - ranging from leukocyte mobilization, trafficking, and chemotaxis to cytokine release and T cell differentiation -are mediated in a time of day-dependent manner. The National Institutes of Health (NIH) recently sponsored an interdisciplinary workshop, "Sleep Insufficiency, Circadian Misalignment, and the Immune Response," to highlight new research linking sleep and circadian biology to immune function and to identify areas of high translational potential. This Review summarizes topics discussed and highlights immediate opportunities for delineating clinically relevant connections among biological rhythms, …

Association Of Clinical Outcomes With Left Ventricular Assist Device Use By Bridge To Transplant Or Destination Therapy Intent: The Multicenter Study Of Maglev Technology In Patients Undergoing Mechanical Circulatory Support Therapy With Heartmate 3 (Momentum 3) Randomized Clinical Trial, Daniel J Goldstein, Akinobu Itoh, Et Al

Open Access Publications

Importance: Left ventricular assist devices (LVADs) are well established in the treatment of advanced heart failure, but it is unclear whether outcomes are different based on the intended goal of therapy in patients who are eligible vs ineligible for heart transplant.

Objective: To determine whether clinical outcomes in the Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy With HeartMate 3 (MOMENTUM 3) trial differed by preoperative categories of bridge to transplant (BTT) or bridge to transplant candidacy (BTC) vs destination therapy (DT).

Design, Setting, and Participants: This study was a prespecified secondary analysis of the MOMENTUM …

The Tip Of The Vgrg Spike Is Essential To Functional Type Vi Secretion System Assembly In Acinetobacter Baumannii, Juvenal Lopez, Pek Man Ly, Mario F Feldman

Open Access Publications

The type VI secretion system (T6SS) is a critical weapon in bacterial warfare between Gram-negative bacteria. Although invaluable for niche establishment, this machine represents an energetic burden to its host bacterium.

Wormbase: A Modern Model Organism Information Resource, Todd W. Harris, Tim Schedl, Et Al

Open Access Publications

WormBase (https://wormbase.org/) is a mature Model Organism Information Resource supporting researchers using the nematode Caenorhabditis elegans as a model system for studies across a broad range of basic biological processes. Toward this mission, WormBase efforts are arranged in three primary facets: curation, user interface and architecture. In this update, we describe progress in each of these three areas. In particular, we discuss the status of literature curation and recently added data, detail new features of the web interface and options for users wishing to conduct data mining workflows, and discuss our efforts to build a robust and scalable architecture by …

Mirdb: An Online Database For Prediction Of Functional Microrna Targets, Yuhao Chen, Xiaowei Wang

Open Access Publications

MicroRNAs (miRNAs) are small noncoding RNAs that act as master regulators in many biological processes. miRNAs function mainly by downregulating the expression of their gene targets. Thus, accurate prediction of miRNA targets is critical for characterization of miRNA functions. To this end, we have developed an online database, miRDB, for miRNA target prediction and functional annotations. Recently, we have performed major updates for miRDB. Specifically, by employing an improved algorithm for miRNA target prediction, we now present updated transcriptome-wide target prediction data in miRDB, including 3.5 million predicted targets regulated by 7000 miRNAs in five species. Further, we have implemented …

Are We Ready To Share Qualitative Research Data? Knowledge And Preparedness Among Qualitative Researchers, Irb Members, And Data Repository Curators, Jessica Mozersky, Heidi Walsh, Meredith Parsons, Tristan Mcintosh, Kari Baldwin, James M Dubois

Open Access Publications

Data sharing maximizes the value of data, which is time and resource intensive to collect. Major funding bodies in the United States (US), like the National Institutes of Health (NIH), require data sharing and researchers frequently share de-identified quantitative data. In contrast, qualitative data are rarely shared in the US but the increasing trend towards data sharing and open science suggest this may be required in future. Qualitative methods are often used to explore sensitive health topics raising unique ethical challenges regarding protecting confidentiality while maintaining enough contextual detail for secondary analyses. Here, we report findings from semi-structured in-depth interviews …

Structure Of The Vesicular Stomatitis Virus L Protein In Complex With Its Phosphoprotein Cofactor, Simon Jenni, Louis-Marie Bloyet, Ruben Diaz-Avalos, Bo Liang, Sean P J Whelan, Nikolaus Grigorieff, Stephen C Harrison

Open Access Publications

The large (L) proteins of non-segmented, negative-strand RNA viruses are multifunctional enzymes that produce capped, methylated, and polyadenylated mRNA and replicate the viral genome. A phosphoprotein (P), required for efficient RNA-dependent RNA polymerization from the viral ribonucleoprotein (RNP) template, regulates the function and conformation of the L protein. We report the structure of vesicular stomatitis virus L in complex with its P cofactor determined by electron cryomicroscopy at 3.0 Å resolution, enabling us to visualize bound segments of P. The contacts of three P segments with multiple L domains show how P induces a closed, compact, initiation-competent conformation. Binding of …

The Cap-Snatching Sftsv Endonuclease Domain Is An Antiviral Target, Wenjie Wang, Woo-Jin Shin, Bojie Zhang, Younho Choi, Ji-Seung Yoo, Maxwell I Zimmerman, Thomas E Frederick, Gregory R Bowman, Michael L Gross, Daisy W Leung, Jae U Jung, Gaya K Amarasinghe

Open Access Publications

Severe fever with thrombocytopenia syndrome virus (SFTSV) is a tick-borne virus with 12%-30% case mortality rates and is related to the Heartland virus (HRTV) identified in the United States. Together, SFTSV and HRTV are emerging segmented, negative-sense RNA viral (sNSV) pathogens with potential global health impact. Here, we characterize the amino-terminal cap-snatching endonuclease domain of SFTSV polymerase (L) and solve a 2.4-Å X-ray crystal structure. While the overall structure is similar to those of other cap-snatching sNSV endonucleases, differences near the C terminus of the SFTSV endonuclease suggest divergence in regulation. Influenza virus endonuclease inhibitors, including the US Food and …

Atomistic Basis Of Opening And Conduction In Mammalian Inward Rectifier Potassium (Kir2.2) Channels, Eva-Maria Zangerl-Plessl, Sun-Joo Lee, Grigory Maksaev, Harald Bernsteiner, Feifei Ren, Peng Yuan, Anna Stary-Weinzinger, Colin G. Nichols

Open Access Publications

Potassium ion conduction through open potassium channels is essential to control of membrane potentials in all cells. To elucidate the open conformation and hence the mechanism of K+ ion conduction in the classic inward rectifier Kir2.2, we introduced a negative charge (G178D) at the crossing point of the inner helix bundle, the location of ligand-dependent gating. This "forced open" mutation generated channels that were active even in the complete absence of phosphatidylinositol-4,5-bisphosphate (PIP2), an otherwise essential ligand for Kir channel opening. Crystal structures were obtained at a resolution of 3.6 Å without PIP2 bound, or 2.8 Å in complex with …

Splicing Factor Sf3b1 Promotes Endometrial Cancer Progression Via Regulating Ksr2 Rna Maturation, Pooja Popli, Megan M. Richters, Sangappa B. Chadchan, Tae Hoon Kim, Eric Tycksen, Obi Griffith, Premal H. Thaker, Malachi Griffith, Ramakrishna Kommagani

Open Access Publications

No abstract provided.

Epigenomic Differences In The Human And Chimpanzee Genomes Are Associated With Structural Variation, Xiaoyu Zhuo, Alan Y Du, Erica C Pehrsson, Daofeng Li, Ting Wang

Open Access Publications

Structural variation (SV), including insertions and deletions (indels), is a primary mechanism of genome evolution. However, the mechanism by which SV contributes to epigenome evolution is poorly understood. In this study, we characterized the association between lineage-specific indels and epigenome differences between human and chimpanzee to investigate how SVs might have shaped the epigenetic landscape. By intersecting medium-to-large human-chimpanzee indels (20bp-50kb) with putative promoters and enhancers in cranial neural crest cells (CNCC) and repressed regions in induced pluripotent cells (iPSC), we found that ~12% indels overlap putative regulatory and repressed regions (RRRs), and 15% of these indels are associated with …

Genome-Wide Association Study Of Opioid Cessation, Jiayi W Cox, Richard M Sherva, Kathryn L Lunetta, Emma C Johnson, Nicholas G Martin, Louisa Degenhardt, Arpana Agrawal, Elliot C Nelson, Henry R Kranzler, Joel Gelernter, Lindsay A Farrer

Open Access Publications

The United States is experiencing an epidemic of opioid use disorder (OUD) and overdose-related deaths. However, the genetic basis for the ability to discontinue opioid use has not been investigated. We performed a genome-wide association study (GWAS) of opioid cessation (defined as abstinence from illicit opioids for >1 year or <6 months before the interview date) in 1130 African American (AA) and 2919 European ancestry (EA) participants recruited for genetic studies of substance use disorders and who met lifetime Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) criteria for OUD. Association tests performed separately within each ethnic group were combined by meta-analysis with results obtained from the Comorbidity and Trauma Study. Although there were no genome-wide significant associations, we found suggestive associations with nine independent loci, including three which are biologically relevant: rs4740988 in

Design And Rationale Of The Hapin Study: A Multicountry Randomized Controlled Trial To Assess The Effect Of Liquefied Petroleum Gas Stove And Continuous Fuel Distribution, Thomas Clasen, Victor G. Davila-Roman, Et Al.

Open Access Publications

No abstract provided.

Cell Type-Specific In Vitro Gene Expression Profiling Of Stem Cell-Derived Neural Models, James A Gregory, Celeste M Karch, Et Al

Open Access Publications

Genetic and genomic studies of brain disease increasingly demonstrate disease-associated interactions between the cell types of the brain. Increasingly complex and more physiologically relevant human-induced pluripotent stem cell (hiPSC)-based models better explore the molecular mechanisms underlying disease but also challenge our ability to resolve cell type-specific perturbations. Here, we report an extension of the RiboTag system, first developed to achieve cell type-restricted expression of epitope-tagged ribosomal protein (RPL22) in mouse tissue, to a variety of in vitro applications, including immortalized cell lines, primary mouse astrocytes, and hiPSC-derived neurons. RiboTag expression enables depletion of up to 87 percent of off-target RNA …

Antiretroviral Therapy Does Not Reduce Tuberculosis Reactivation In A Tuberculosis-Hiv Coinfection Model, Shashank R Ganatra, Shabaana A Khader, Et Al

Open Access Publications

While the advent of combination antiretroviral therapy (ART) has significantly improved survival, tuberculosis (TB) remains the leading cause of death in the HIV-infected population. We used Mycobacterium tuberculosis/simian immunodeficiency virus-coinfected (M. tuberculosis/SIV-coinfected) macaques to model M. tuberculosis/HIV coinfection and study the impact of ART on TB reactivation due to HIV infection. Although ART significantly reduced viral loads and increased CD4+ T cell counts in blood and bronchoalveolar lavage (BAL) samples, it did not reduce the relative risk of SIV-induced TB reactivation in ART-treated macaques in the early phase of treatment. CD4+ T cells were poorly restored specifically in the lung …

Alternative Splicing Of Ucp1 By Non-Cell-Autonomous Action Of Pemt, Jordan M. Johnson, Anthony R.P. Verkerke, J. Alan Maschek, Patrick J. Ferrara, Chien-Te Lin, Kimberly A. Kew, P. Darrell Neufer, Irfan J. Lodhi, James E. Cox, Katsuhiko Funai

Open Access Publications

No abstract provided.

5-Fluorocytosine Resistance Is Associated With Hypermutation And Alterations In Capsule Biosynthesis In Cryptococcus, R. Blake Billmyre, Shelly Applen Clancey, Lucy X. Li, Tamara L. Doering, Joseph Heitman

Open Access Publications

No abstract provided.

Structure Of A Rabies Virus Polymerase Complex From Electron Cryo-Microscopy, Joshua A. Horwitz, Simon Jenni, Stephen C. Harrison, Sean P. J. Whelan

Open Access Publications

No abstract provided.

Tumor Infiltrating Neutrophils Are Enriched In Basal-Type Urothelial Bladder Cancer, Giulio Eugenio Mandelli, Francesco Missale, Debora Bresciani, Luisa Benerini Gatta, Patrizia Scapini, Elena Caveggion, Elisa Roca, Mattia Bugatti, Matilde Monti, Luca Cristinelli, Sandra Belotti, Claudio Simeone, Stefano Calza, Laura Melocchi, William Vermi

Open Access Publications

BACKGROUND: Urothelial bladder cancers (UBCs) are distinct in two main molecular subtypes, namely basal and luminal type. Subtypes are also diverse in term of immune contexture, providing a rationale for patient selection to immunotherapy.

METHODS: By digital microscopy analysis of a muscle-invasive BC (MIBC) cohort, we explored the density and clinical significance of CD66b

RESULTS: Basal type BC contained a significantly higher density of CD66b

CONCLUSIONS: TAN are recruited in basal type MIBC by pro-inflammatory CKs. This finding establishes a groundwork for a better understanding of the UBC immunity and its relevance.

Loss-Of-Function Mutations In Udp-Glucose 6-Dehydrogenase Cause Recessive Developmental Epileptic Encephalopathy, Holger Hengel, Marisa V. Andrews, Marcia C. Willing, Et Al.

Open Access Publications

No abstract provided.

L-Plastin Deficiency Produces Increased Trabecular Bone Due To Attenuation Of Sealing Ring Formation And Osteoclast Dysfunction, Meenakshi A. Chellaiah, Megan C. Moorer, Sunipa Majumdar, Hanan Aljohani, Sharon C. Morley, Vanessa Yingling, Joseph P. Stains

Open Access Publications

No abstract provided.

Confidential Genetic Testing And Electronic Health Records: A Survey Of Current Practices Among Huntington Disease Testing Centers, Celeste C Eno, Stacey K Barton, Naghmeh Dorrani, Stephen D Cederbaum, Joshua L Deignan, Wayne W Grody

Open Access Publications

BACKGROUND: Clinical care teams providing presymptomatic genetic testing often employ advanced confidentiality practices for documentation and result storage. However, patient requests for increased confidentiality may be in conflict with the legal obligations of medical providers to document patient care activities in the electronic health record (EHR). Huntington disease presents a representative case study for investigating the ways centers currently balance the requirements of EHRs with the privacy demands of patients seeking presymptomatic genetic testing.

METHODS: We surveyed 23 HD centers (53% response rate) regarding their use of the EHR for presymptomatic HD testing.

RESULTS: Our survey revealed that clinical care …

Protective Role Of Brain Derived Neurotrophic Factor (Bdnf) In Obstructive Sleep Apnea Syndrome (Osas) Patients, Krisstopher Richard Flores, Fausta Viccaro, Mauro Aquilini, Stefania Scarpino, Francesco Ronchetti, Rita Mancini, Arianna Di Napoli, Davide Scozzi, Alberto Ricci

Open Access Publications

Obstructive sleep apnea syndrome (OSAS) is a common disorder characterized by repeated episodes of upper airways collapse during the sleep. The following intermittent hypoxia triggers a state of chronic inflammation, which also interests the nervous system leading to neuronal damage and increased risk of cognitive impairment. Brain derived neurotrophic factor (BDNF) is a growth factor often associated with neuroplasticity and neuroprotection whose levels increase in several condition associated with neuronal damage. However, whether patients affected by OSAS have altered BDNF levels and whether such alteration may be reflective of their cognitive impairment is still controversial. Here we show that, when …