Digital Commons Network^™

Investigating Rare Pathogenic/Likely Pathogenic Exonic Variation In Bipolar Disorder, Xiaoming Jia, Fernando S Goes, Adam E Locke, Duncan Palmer, Weiqing Wang, Et Al

Open Access Publications

Bipolar disorder (BD) is a serious mental illness with substantial common variant heritability. However, the role of rare coding variation in BD is not well established. We examined the protein-coding (exonic) sequences of 3,987 unrelated individuals with BD and 5,322 controls of predominantly European ancestry across four cohorts from the Bipolar Sequencing Consortium (BSC). We assessed the burden of rare, protein-altering, single nucleotide variants classified as pathogenic or likely pathogenic (P-LP) both exome-wide and within several groups of genes with phenotypic or biologic plausibility in BD. While we observed an increased burden of rare coding P-LP variants within 165 genes …

Genomic Characterization Of Emerging Bacterial Uropathogen Neisseria Meningitidis, Which Was Misidentified As Neisseria Gonorrhoeae By Nucleic Acid Amplification Testing, Kimberley V Sukhum, Sophonie Jean, Meghan Wallace, Neil Anderson, C A Burnham, Gautam Dantas

Open Access Publications

No abstract provided.

Nanoparticle T-Cell Engagers As A Modular Platform For Cancer Immunotherapy, Kinan Alhallak, Jennifer Sun, Katherine Wasden, Nicole Guenthner, Julie O'Neal, Barbara Muz, Justin King, Daniel Kohnen, Ravi Vij, Samuel Achilefu, John F Dipersio, Abdel Kareem Azab

Open Access Publications

T-cell-based immunotherapy, such as CAR-T cells and bispecific T-cell engagers (BiTEs), has shown promising clinical outcomes in many cancers; however, these therapies have significant limitations, such as poor pharmacokinetics and the ability to target only one antigen on the cancer cells. In multiclonal diseases, these therapies confer the development of antigen-less clones, causing tumor escape and relapse. In this study, we developed nanoparticle-based bispecific T-cell engagers (nanoBiTEs), which are liposomes decorated with anti-CD3 monoclonal antibodies (mAbs) targeting T cells, and mAbs targeting the cancer antigen. We also developed a nanoparticle that targets multiple cancer antigens by conjugating multiple mAbs against …

Central Venous Catheter Adverse Events Are Not Associated With Crowding Indicators, Daniel L Theodoro, Niraj Vyas, Enyo Ablordeppey, Brian Bausano, Stephanie Charshafian, Phillip Asaro, Richard T Griffey

Open Access Publications

OBJECTIVE: Crowding in the emergency department (ED) impacts a number of important quality and safety metrics. We studied ED crowding measures associated with adverse events (AE) resulting from central venous catheters (CVC) inserted in the ED, as well as the relationship between crowding and the frequency of CVC insertions in an ED cohort admitted to the intensive care unit (ICU).

METHODS: We conducted a retrospective observational study from 2008-2010 in an academic tertiary care center. Participants undergoing CVC in the ED or admitted to an ICU were categorized by quartile based on the following: National Emergency Department Overcrowding Scale (NEDOCS); …

Short-Term Effects Of Appropriate Empirical Antimicrobial Treatment With Ceftolozane/Tazobactam In A Swine Model Of Nosocomial Pneumonia, Ana Motos, Marin Kollef, Et Al

Open Access Publications

The rising frequency of multidrug-resistant and extensively drug-resistant (MDR/XDR) pathogens is making more frequent the inappropriate empirical antimicrobial therapy (IEAT) in nosocomial pneumonia, which is associated with increased mortality. We aim to determine the short-term benefits of appropriate empirical antimicrobial treatment (AEAT) with ceftolozane/tazobactam (C/T) compared with IEAT with piperacillin/tazobactam (TZP) in MDR

Naturalistic Language Input Is Associated With Resting-State Functional Connectivity In Infancy, Lucy S. King, M. Catalina Camacho, David F. Montez, Kathryn L. Humphreys, Ian H. Gotlib

Open Access Publications

The quantity and quality of the language input that infants receive from their caregivers affects their future language abilities; however, it is unclear how variation in this input relates to preverbal brain circuitry. The current study investigated the relation between naturalistic language input and the functional connectivity (FC) of language networks in human infancy using resting-state functional magnetic resonance imaging (rsfMRI). We recorded the naturalistic language environments of five- to eight-month-old male and female infants using the Linguistic ENvironment Analysis (LENA) system and measured the quantity and consistency of their exposure to adult words (AWs) and adult-infant conversational turns (CTs). …

Sars-Cov-2 Infection Severity Is Linked To Superior Humoral Immunity Against The Spike, Jenna J Guthmiller, Ya-Nan Dai, Christopher A Nelson, Paige D Hall, Daved H Fremont, Et Al

Open Access Publications

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is currently causing a global pandemic. The antigen specificity of the antibody response mounted against this novel virus is not understood in detail. Here, we report that subjects with a more severe SARS-CoV-2 infection exhibit a larger antibody response against the spike and nucleocapsid protein and epitope spreading to subdominant viral antigens, such as open reading frame 8 and nonstructural proteins. Subjects with a greater antibody response mounted a larger memory B cell response against the spike, but not the nucleocapsid protein. Additionally, we revealed that antibodies against the spike are still capable …

Coxsackievirus B3 Infection Early In Pregnancy Induces Congenital Heart Defects Through Suppression Of Fetal Cardiomyocyte Proliferation, Vipul Sharma, Lisa S Goessling, Anoop K Brar, Chetanchandra S Joshi, Indira U Mysorekar, Pirooz Eghtesady

Open Access Publications

Background Coxsackievirus B (CVB) is the most common cause of viral myocarditis. It targets cardiomyocytes through coxsackie and adenovirus receptor, which is highly expressed in the fetal heart. We hypothesized CVB3 can precipitate congenital heart defects when fetal infection occurs during critical window of gestation. Methods and Results We infected C57Bl/6 pregnant mice with CVB3 during time points in early gestation (embryonic day [E] 5, E7, E9, and E11). We used different viral titers to examine possible dose-response relationship and assessed viral loads in various fetal organs. Provided viral exposure occurred between E7 and E9, we observed characteristic features of …

Death And Myocardial Infarction Following Initial Revascularization Versus Optimal Medical Therapy In Chronic Coronary Syndromes With Myocardial Ischemia: A Systematic Review And Meta-Analysis Of Contemporary Randomized Controlled Trials, Andrea Soares, William E Boden, Whady Hueb, Maria M Brooks, Helen E A Vlachos, Kevin O'Fee, Angela Hardi, David L Brown

Open Access Publications

Background In chronic coronary syndromes, myocardial ischemia is associated with a greater risk of death and nonfatal myocardial infarction (MI). We sought to compare the effect of initial revascularization with percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) plus optimal medical therapy (OMT) with OMT alone in patients with chronic coronary syndrome and myocardial ischemia on long-term death and nonfatal MI. Methods and Results Ovid Medline, Embase, Scopus, and Cochrane Library databases were searched for randomized controlled trials of PCI or CABG plus OMT versus OMT alone for patients with chronic coronary syndromes. Studies were screened and data …

Designing And Undertaking Randomised Implementation Trials: Guide For Researchers, Luke Wolfenden, Robbie Foy, Justin Presseau, Jeremy Grimshaw, Noah Ivers, Byron Powell, Monica Taljaard, John Wiggers, Rachel Sutherland, Nicole Nathan, Christopher Williams, Melanie Kingsland, Andrew Milat, Rebecca Hodder, Sze Lin Yoong

Open Access Publications

No abstract provided.

Hypoxia Enhances Ilc3 Responses Through Hif-1Α-Dependent Mechanism, J L Fachi, L P Pral, J A C Dos Santos, A C Codo, S De Oliveira, J S Felipe, F F F Zambom, N O S Câmara, P M M M Vieira, M Colonna, M A R Vinolo

Open Access Publications

Group 3 innate lymphoid cells (ILC3) have a prominent role in the maintenance of intestine mucosa homeostasis. The hypoxia-inducible factor (HIF) is an important modulator of immune cell activation and a key mechanism for cellular adaptation to oxygen deprivation. However, its role on ILC3 is not well known. In this study, we investigated how a hypoxic environment modulates ILC3 response and the subsequent participation of HIF-1 signaling in this process. We found increased proliferation and activation of intestinal ILC3 at low oxygen levels, a response that was phenocopied when HIF-1α was chemically stabilized and was reversed when HIF-1 was blocked. …

Randomized Controlled Trial Of Oral Vancomycin Treatment In Clostridioides Difficile-Colonized Patients, Skye R S Fishbein, Tiffany Hink, Kimberly A Reske, Candice Cass, Emily Struttmann, Zainab Hassan Iqbal, Sondra Seiler, Jennie H Kwon, C A Burnham, Gautam Dantas, Erik R Dubberke

Open Access Publications

No abstract provided.

Dynamic Shifts In The Composition Of Resident And Recruited Macrophages Influence Tissue Remodeling In Nash, Sabine Daemen, Anastasiia Gainullina, Gowri Kalugotla, Li He, Mandy M Chan, Joseph W Beals, Kim H Liss, Samuel Klein, Ariel E Feldstein, Brian N Finck, Maxim N Artyomov, Joel D Schilling

Open Access Publications

Macrophage-mediated inflammation is critical in the pathogenesis of non-alcoholic steatohepatitis (NASH). Here, we describe that, with high-fat, high-sucrose-diet feeding, mature TIM4

Developmental Stage-Specific Changes In Protein Synthesis Differentially Sensitize Hematopoietic Stem Cells And Erythroid Progenitors To Impaired Ribosome Biogenesis, Jeffrey A Magee, Robert A J Signer

Open Access Publications

Adult hematopoietic stem cell (HSC) self-renewal requires precise control of protein synthesis, but fetal and adult HSCs have distinct self-renewal mechanisms and lineage outputs. This raises the question of whether protein synthesis rates change with age. Here, we show that protein synthesis rates decline during HSC ontogeny, yet erythroid protein synthesis rates increase. A ribosomal mutation that impairs ribosome biogenesis (Rpl24

Zika Virus Oncolytic Activity Requires Cd8+ T Cells And Is Boosted By Immune Checkpoint Blockade, Sharmila Nair, Luciano Mazzoccoli, Arijita Jash, Jennifer Govero, Sachendra S Bais, Tong Hu, Camila R Fontes-Garfias, Chao Shan, Hideho Okada, Sujan Shresta, Jeremy N Rich, Pei-Yong Shi, Michael S Diamond, Milan G Chheda

Open Access Publications

Glioblastoma multiforme (GBM) is a fatal human cancer in part because GBM stem cells are resistant to therapy and recurrence is inevitable. Previously, we demonstrated Zika virus (ZIKV) targets GBM stem cells and prevents death of mice with gliomas. Here, we evaluated the immunological basis of ZIKV-mediated protection against GBM. Introduction of ZIKV into the brain tumor increased recruitment of CD8+ T and myeloid cells to the tumor microenvironment. CD8+ T cells were required for ZIKV-dependent tumor clearance because survival benefits were lost with CD8+ T cell depletion. Moreover, while anti-PD-1 antibody monotherapy moderately improved tumor survival, when coadministered with …

The Dark Kinase Knowledgebase: An Online Compendium Of Knowledge And Experimental Results Of Understudied Kinases, Matthew E. Berginski, Nienke Moret, Changchang Liu, Dennis Goldfarb, Peter K. Sorger, Shawn M. Gomez

Open Access Publications

Kinases form the backbone of numerous cell signaling pathways, with their dysfunction similarly implicated in multiple pathologies. Further facilitated by their druggability, kinases are a major focus of therapeutic development efforts in diseases such as cancer, infectious disease and autoimmune disorders. While their importance is clear, the role or biological function of nearly one-third of kinases is largely unknown. Here, we describe a data resource, the Dark Kinase Knowledgebase (DKK; https://darkkinome.org), that is specifically focused on providing data and reagents for these understudied kinases to the broader research community. Supported through NIH's Illuminating the Druggable Genome (IDG) Program, the DKK …

Small Molecule Sarm1 Inhibitors Recapitulate The Sarm1 -/- Phenotype And Allow Recovery Of A Metastable Pool Of Axons Fated To Degenerate, Robert O Hughes, Todd Bosanac, Xianrong Mao, Thomas M Engber, Aaron Diantonio, Jeffrey Milbrandt, Rajesh Devraj, Raul Krauss

Open Access Publications

Axonal degeneration is responsible for disease progression and accumulation of disability in many neurodegenerative conditions. The axonal degenerative process can generate a metastable pool of damaged axons that remain structurally and functionally viable but fated to degenerate in the absence of external intervention. SARM1, an NADase that depletes axonal energy stores upon activation, is the central driver of an evolutionarily conserved program of axonal degeneration. We identify a potent and selective small molecule isoquinoline inhibitor of SARM1 NADase that recapitulates the SARM1

Function Of Mammalian M-Cones Depends On The Level Of Cralbp In Müller Cells, Alexander V. Kolesnikov, Philip D. Kiser, Krzysztof Palczewski, Vladimir J. Kefalov

Open Access Publications

Cone photoreceptors mediate daytime vision in vertebrates. The rapid and efficient regeneration of their visual pigments following photoactivation is critical for the cones to remain photoresponsive in bright and rapidly changing light conditions. Cone pigment regeneration depends on the recycling of visual chromophore, which takes place via the canonical visual cycle in the retinal pigment epithelium (RPE) and the Müller cell-driven intraretinal visual cycle. The molecular mechanisms that enable the neural retina to regenerate visual chromophore for cones have not been fully elucidated. However, one known component of the two visual cycles is the cellular retinaldehyde-binding protein (CRALBP), which is …

Oct4 Cooperates With Distinct Atp-Dependent Chromatin Remodelers In Naïve And Primed Pluripotent States In Human, Xin Huang, Kyoung-Mi Park, Paul Gontarz, Bo Zhang, Laura A. Fischer, Chen Dong, Sabine Dietmann, Xiaoyun Xing, Shafqat A. Khan, Nick Jensen, Ting Wang, Thorold W. Theunissen, Et Al

Open Access Publications

No abstract provided.

Improving Hindlimb Locomotor Function By Non-Invasive Aav-Mediated Manipulations Of Propriospinal Neurons In Mice With Complete Spinal Cord Injury, Benedikt Brommer, Miao He, Zicong Zhang, Zhiyun Yang, Jessica C. Page, Junfeng Su, Yu Zhang, Junjie Zhu, Emilia Gouy, Jing Tang, Philip Williams, Wei Dai, Qi Wang, Ryan Solinsky, Bo Chen, Zhigang He

Open Access Publications

No abstract provided.

Effect And Correction Of Optode Coupling Errors In Breast Imaging Using Diffuse Optical Tomography, Shuying Li, Kexin Huang, Menghao Zhang, K. M. Shihab Uddin, Quing Zhu

Open Access Publications

No abstract provided.

A Synthetic Mechanogenetic Gene Circuit For Autonomous Drug Delivery In Engineered Tissues, Robert J Nims, Lara Pferdehirt, Noelani B Ho, Alireza Savadipour, Jeremiah Lorentz, Sima Sohi, Jordan Kassab, Alison K Ross, Christopher J O'Conor, Wolfgang B Liedtke, Bo Zhang, Amy L Mcnulty, Farshid Guilak

Open Access Publications

Mechanobiologic signals regulate cellular responses under physiologic and pathologic conditions. Using synthetic biology and tissue engineering, we developed a mechanically responsive bioartificial tissue that responds to mechanical loading to produce a preprogrammed therapeutic biologic drug. By deconstructing the signaling networks induced by activation of the mechanically sensitive ion channel transient receptor potential vanilloid 4 (TRPV4), we created synthetic TRPV4-responsive genetic circuits in chondrocytes. We engineered these cells into living tissues that respond to mechanical loading by producing the anti-inflammatory biologic drug interleukin-1 receptor antagonist. Chondrocyte TRPV4 is activated by osmotic loading and not by direct cellular deformation, suggesting that tissue …

Type 2 Diabetes Prevention Focused On Normalization Of Glycemia: A Two-Year Pilot Study, Amy L Mckenzie, Shaminie J Athinarayanan, Jackson J Mccue, Rebecca N Adams, Monica Keyes, James P Mccarter, Jeff S Volek, Stephen D Phinney, Sarah J Hallberg

Open Access Publications

The purpose of this study is to assess the effects of an alternative approach to type 2 diabetes prevention. Ninety-six patients with prediabetes (age 52 (10) years; 80% female; BMI 39.2 (7.1) kg/m

Optimal Method For Fetal Brain Age Prediction Using Multiplanar Slices From Structural Magnetic Resonance Imaging, Jinwoo Hong, Hyuk Jin Yun, Gilsoon Park, Seonggyu Kim, Yangming Ou, Lana Vasung, Caitlin K Rollins, Cynthia M Ortinau, Emiko Takeoka, Shizuko Akiyama, Tomo Tarui, Judy A Estroff, Patricia Ellen Grant, Jong-Min Lee, Kiho Im

Open Access Publications

The accurate prediction of fetal brain age using magnetic resonance imaging (MRI) may contribute to the identification of brain abnormalities and the risk of adverse developmental outcomes. This study aimed to propose a method for predicting fetal brain age using MRIs from 220 healthy fetuses between 15.9 and 38.7 weeks of gestational age (GA). We built a 2D single-channel convolutional neural network (CNN) with multiplanar MRI slices in different orthogonal planes without correction for interslice motion. In each fetus, multiple age predictions from different slices were generated, and the brain age was obtained using the mode that determined the most …

Association Of Pet-Based Estradiol-Challenge Test For Breast Cancer Progesterone Receptors With Response To Endocrine Therapy, Farrokh Dehdashti, Ningying Wu, Cynthia X. Ma, Michael J. Naughton, John A. Katzenellenbogen, Barry A. Siegel

Open Access Publications

No abstract provided.

Odontoblast Trpc5 Channels Signal Cold Pain In Teeth, Laura Bernal, Allen Sclaroff, John D Pfeifer, Et Al

Open Access Publications

Teeth are composed of many tissues, covered by an inflexible and obdurate enamel. Unlike most other tissues, teeth become extremely cold sensitive when inflamed. The mechanisms of this cold sensation are not understood. Here, we clarify the molecular and cellular components of the dental cold sensing system and show that sensory transduction of cold stimuli in teeth requires odontoblasts. TRPC5 is a cold sensor in healthy teeth and, with TRPA1, is sufficient for cold sensing. The odontoblast appears as the direct site of TRPC5 cold transduction and provides a mechanism for prolonged cold sensing via TRPC5's relative sensitivity to intracellular …

Disrupted Association Of Sensory Neurons With Enveloping Satellite Glial Cells In Fragile X Mouse Model, Oshri Avraham, Pan-Yue Deng, Dario Maschi, Vitaly A Klyachko, Valeria Cavalli

Open Access Publications

Among most prevalent deficits in individuals with Fragile X syndrome (FXS) is hypersensitivity to sensory stimuli and somatosensory alterations. Whether dysfunction in peripheral sensory system contributes to these deficits remains poorly understood. Satellite glial cells (SGCs), which envelop sensory neuron soma, play critical roles in regulating neuronal function and excitability. The potential contributions of SGCs to sensory deficits in FXS remain unexplored. Here we found major structural defects in sensory neuron-SGC association in the dorsal root ganglia (DRG), manifested by aberrant covering of the neuron and gaps between SGCs and the neuron along their contact surface. Single-cell RNAseq analyses demonstrated …

Apobec1 Complementation Factor Overexpression Promotes Hepatic Steatosis, Fibrosis, And Hepatocellular Cancer, Valerie Blanc, Jesse D Riordan, Saeed Soleymanjahi, Joseph H Nadeau, Ilke Nalbantoglu, Yan Xie, Elizabeth A Molitor, Blair B Madison, Elizabeth M Brunt, Jason C Mills, Deborah C Rubin, Irene O Ng, Yeonjung Ha, Lewis R Roberts, Nicholas O Davidson

Open Access Publications

The RNA-binding protein Apobec1 complementation factor (A1CF) regulates posttranscriptional ApoB mRNA editing, but the range of RNA targets and the long-term effect of altered A1CF expression on liver function are unknown. Here we studied hepatocyte-specific A1cf-transgenic (A1cf+/Tg), A1cf+/Tg Apobec1-/-, and A1cf-/- mice fed chow or high-fat/high-fructose diets using RNA-Seq, RNA CLIP-Seq, and tissue microarrays from human hepatocellular cancer (HCC). A1cf+/Tg mice exhibited increased hepatic proliferation and steatosis, with increased lipogenic gene expression (Mogat1, Mogat2, Cidea, Cd36) associated with shifts in polysomal RNA distribution. Aged A1cf+/Tg mice developed spontaneous fibrosis, dysplasia, and HCC, and this development was accelerated on a high-fat/high-fructose …

Parental Factors Associated With The Decision To Participate In A Neonatal Clinical Trial, Elliott Mark Weiss, Rakesh Rao, Et Al

Open Access Publications

Importance: It remains poorly understood how parents decide whether to enroll a child in a neonatal clinical trial. This is particularly true for parents from racial or ethnic minority populations. Understanding factors associated with enrollment decisions may improve recruitment processes for families, increase enrollment rates, and decrease disparities in research participation.

Objective: To assess differences in parental factors between parents who enrolled their infant and those who declined enrollment for a neonatal randomized clinical trial.

Design, Setting, and Participants: This survey study conducted from July 2017 to October 2019 in 12 US level 3 and 4 neonatal intensive care units …

An Open Label, Randomized Clinical Trial To Compare The Tolerability And Efficacy Of Ivermectin Plus Diethylcarbamazine And Albendazole Vs. Diethylcarbamazine Plus Albendazole For Treatment Of Brugian Filariasis In Indonesia, Taniawati Supali, Yenny Djuardi, Michael Christian, Elisa Iskandar, Rahmat Alfian, Roospita Maylasari, Yossi Destani, Adriani Lomiga, Dominikus Minggu, Daphne Lew, Joshua Bogus, Gary J Weil, Peter U. Fischer

Open Access Publications

No abstract provided.