Digital Commons Network^™

Whole-Exome Sequencing And Hipsc Cardiomyocyte Models Identify Myrip, Trappc11, And Slc27a6 Of Potential Importance To Left Ventricular Hypertrophy In An African Ancestry Population, Marguerite R Irvin, Lisa De Las Fuentes, C Charles Gu, Karen Schwander, Dabeeru C Rao, Et Al

Open Access Publications

No abstract provided.

Peripheral Sensory Stimulation Elicits Global Slow Waves By Recruiting Somatosensory Cortex Bilaterally, Zachary P. Rosenthal, Ryan V. Raut, Ryan M. Bowen, Abraham Z. Snyder, Joseph P. Culver, Marcus E. Raichle, Jin-Moo Lee

Open Access Publications

No abstract provided.

A Two-Hit Model Of Alcoholic Liver Disease That Exhibits Rapid, Severe Fibrosis, Monideepa Sengupta, Suomia Abuirqeba, Amina Kameric, Aurore Cecile-Valfort, Arindam Chatterjee, Kristine Griffett, Thomas P. Burris, Colin A. Flaveny

Open Access Publications

Alcoholic liver disease (ALD) is responsible for an average of 50.4% and 44.2%of liver disease deaths among males and females respectively. Driven by alcohol misuse, ALD is often reversible by cessation of consumption. However, abstinence programs can have limited success at curtailing abuse, and the loss of life. ALD, therefore, remains a significant clinical challenge. There is a need for effective treatments that prevent or reverse alcohol-induced liver damage to complement or supplant behavioral interventions. Metabolic syndrome, which is disproportionally prevalent in ALD patients, accelerates the progression of ALD and increases liver disease mortality. Current rodent models of ALD unfortunately …

Mr-Guided Radiotherapy For Liver Malignancies, Luca Boldrini, Stefanie Corradini, Cihan Gani, Lauren Henke, Ali Hosni, Angela Romano, Laura Dawson

Open Access Publications

MR guided radiotherapy represents one of the most promising recent technological innovations in the field. The possibility to better visualize therapy volumes, coupled with the innovative online adaptive radiotherapy and motion management approaches, paves the way to more efficient treatment delivery and may be translated in better clinical outcomes both in terms of response and reduced toxicity. The aim of this review is to present the existing evidence about MRgRT applications for liver malignancies, discussing the potential clinical advantages and the current pitfalls of this new technology.

Noise Exposure Potentiates Exocytosis From Cochlear Inner Hair Cells, Luis E Boero, Shelby Payne, Maria Eugenia Gómez-Casati, Mark A Rutherford, Juan D Goutman

Open Access Publications

Noise-induced hearing loss has gained relevance as one of the most common forms of hearing impairment. The anatomical correlates of hearing loss, principally cell damage and/or death, are relatively well-understood histologically. However, much less is known about the physiological aspects of damaged, surviving cells. Here we addressed the functional consequences of noise exposure on the capacity of inner hair cells (IHCs) to release synaptic vesicles at synapses with spiral ganglion neurons (SGNs). Mice of either sex at postnatal day (P) 15-16 were exposed to 1-12 kHz noise at 120 dB sound pressure level (SPL), for 1 h. Exocytosis was measured …

Development And Validation Of A Deep Learning Model To Quantify Glomerulosclerosis In Kidney Biopsy Specimens, Jon N. Marsh, Ta-Chiang Liu, Parker C. Wilson, S. Joshua Swamidass, Joseph P. Gaut

Open Access Publications

Importance: A chronic shortage of donor kidneys is compounded by a high discard rate, and this rate is directly associated with biopsy specimen evaluation, which shows poor reproducibility among pathologists. A deep learning algorithm for measuring percent global glomerulosclerosis (an important predictor of outcome) on images of kidney biopsy specimens could enable pathologists to more reproducibly and accurately quantify percent global glomerulosclerosis, potentially saving organs that would have been discarded.

Objective: To compare the performances of pathologists with a deep learning model on quantification of percent global glomerulosclerosis in whole-slide images of donor kidney biopsy specimens, and to determine the …

Sex-Dimorphic Genetic Effects And Novel Loci For Fasting Glucose And Insulin Variability, Vasiliki Lagou, Ping An, Michael A. Province, Et Al.

Open Access Publications

No abstract provided.

Quantitative Evaluation Of Frequency Domain Measurements In High Density Diffuse Optical Tomography, Guy A. Perkins, Adam T. Eggebrecht, Hamid Dehghani

Open Access Publications

No abstract provided.

Dengue And The Lectin Pathway Of The Complement System, Romchat Kraivong, Nuntaya Punyadee, M Kathryn Liszewski, John P Atkinson, Panisadee Avirutnan

Open Access Publications

Dengue is a mosquito-borne viral disease causing significant health and economic burdens globally. The dengue virus (DENV) comprises four serotypes (DENV1-4). Usually, the primary infection is asymptomatic or causes mild dengue fever (DF), while secondary infections with a different serotype increase the risk of severe dengue disease (dengue hemorrhagic fever, DHF). Complement system activation induces inflammation and tissue injury, contributing to disease pathogenesis. However, in asymptomatic or primary infections, protective immunity largely results from the complement system's lectin pathway (LP), which is activated through foreign glycan recognition. Differences in N-glycans displayed on the DENV envelope membrane influence the lectin pattern …

Liver-Specific Deletion Of Mttp Versus Tm6sf2 Reveals Distinct Defects In Stepwise Vldl Assembly, Elizabeth P Newberry, Gregory W Strout, James A J Fitzpatrick, Nicholas O Davidson

Open Access Publications

No abstract provided.

Programmed Cell Death Recruits Macrophages Into The Developing Mouse Cochlea, Vikrant Borse, Tejbeer Kaur, Ashley Hinton, Kevin Ohlemiller, Mark E Warchol

Open Access Publications

Programmed cell death (PCD) plays a critical role in the development and maturation of the cochlea. Significant remodeling occurs among cells of the greater epithelial ridge (GER) of Kölliker's organ, leading to tissue regression and formation of the inner sulcus. In mice, this event normally occurs between postnatal days 5-15 (P5-15) and is regulated by thyroid hormone (T3). During this developmental time period, the cochlea also contains a large population of macrophages. Macrophages are frequently involved in the phagocytic clearance of dead cells, both during development and after injury, but the role of macrophages in the developing cochlea is unknown. …

Shifting Pathways Of Stimulant Use Among Individuals With Opioid Use Disorder: A Retrospective Analysis Of The Last Thirty Years, Matthew S Ellis, Zachary A Kasper, Stephen Scroggins

Open Access Publications

No abstract provided.

Follow The Metaplasia: Characteristics And Oncogenic Implications Of Metaplasia's Pattern Of Spread Throughout The Stomach, José B Sáenz

Open Access Publications

The human stomach functions as both a digestive and innate immune organ. Its main product, acid, rapidly breaks down ingested products and equally serves as a highly effective microbial filter. The gastric epithelium has evolved mechanisms to appropriately handle the myriad of injurious substances, both exogenous and endogenous, to maintain the epithelial barrier and restore homeostasis. The most significant chronic insult that the stomach must face is

Overlapping But Disparate Inflammatory And Immunosuppressive Responses To Sars-Cov-2 And Bacterial Sepsis: An Immunological Time Course Analysis, Tyler J Loftus, Ricardo Ungaro, Marvin Dirain, Philip A Efron, Monty B Mazer, Kenneth E Remy, Richard S Hotchkiss, Luer Zhong, Rhonda Bacher, Petr Starostik, Lyle L Moldawer, Scott C Brakenridge

Open Access Publications

Both severe SARS-CoV-2 infections and bacterial sepsis exhibit an immunological dyscrasia and propensity for secondary infections. The nature of the immunological dyscrasias for these differing etiologies and their time course remain unclear. In this study, thirty hospitalized patients with SARS-CoV-2 infection were compared with ten critically ill patients with bacterial sepsis over 21 days, as well as ten healthy control subjects. Blood was sampled between days 1 and 21 after admission for targeted plasma biomarker analysis, cellular phenotyping, and leukocyte functional analysis

Associations Between Education And Dementia In The Caribbean And The United States: An International Comparison, Jing Li, Jorge J Llibre-Guerra, Amal Harrati, Jordan Weiss, Ivonne Z Jiménez-Velázquez, Daisy Acosta, Juan De Jesús Llibre-Rodriguez, Mao-Mei Liu, William H Dow

Open Access Publications

Introduction: Despite high dementia prevalence in Hispanic populations globally, especially Caribbean Hispanics, no study has comparatively examined the association between education and dementia among Hispanics living in the Caribbean Islands and older adults in the United States.

Methods: We used data on 6107 respondents aged 65 and older in the baseline wave of the population-based and harmonized 10/66 survey from Cuba, the Dominican Republic, and Puerto Rico, collected between 2003 and 2008, and 11,032 respondents aged 65 and older from the U.S.-based Health and Retirement Study data in 2014, a total of 17,139 individuals. We estimated multivariable logistic regression models …

Harnessing The Potential Of Multiomics Studies For Precision Medicine In Infectious Disease, Rebecca A. Ward, Philip A. Mudd, Rachel M. Presti, Andrej Spec, Et Al

Open Access Publications

The field of infectious diseases currently takes a reactive approach and treats infections as they present in patients. Although certain populations are known to be at greater risk of developing infection (eg, immunocompromised), we lack a systems approach to define the true risk of future infection for a patient. Guided by impressive gains in "omics" technologies, future strategies to infectious diseases should take a precision approach to infection through identification of patients at intermediate and high-risk of infection and deploy targeted preventative measures (ie, prophylaxis). The advances of high-throughput immune profiling by multiomics approaches (ie, transcriptomics, epigenomics, metabolomics, proteomics) hold …

Evaluation Of Commercial Rapid Lateral Flow Tests, Alone Or In Combination, For Sars-Cov-2 Antibody Testing, Peter U Fischer, Kerstin Fischer, Kurt C Curtis, Yuefang Huang, Nicole Fetcho, Charles W Goss, Gary J Weil

Open Access Publications

Antibody tests can be tools for detecting current or past severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 [coronavirus disease 2019 (COVID-19)]) infections. Independent test evaluations are needed to document the performance with different sample sets. We evaluated six lateral flow assays (LFAs) and two laboratory-based tests (EUROIMMUN-SARS-CoV-2 ELISA and Abbott-Architect-SARS-CoV-2-IgG). We tested 210 plasma samples from 89 patients diagnosed with acute COVID-19. These samples were collected at different time points after the onset of symptoms. In addition, 80 convalescent plasma samples, and 168 pre-pandemic samples collected from adults in the United States and in Africa were tested. LFA performance varied …

Genome‑Wide Chromatin Accessibility Analyses Provide A Map For Enhancing Optic Nerve Regeneration, Wolfgang Pita-Thomas, Tassia Mangetti Gonçalves, Ajeet Kumar, Guoyan Zhao, Valeria Cavalli

Open Access Publications

No abstract provided.

Ron Signalling Promotes Therapeutic Resistance In Esr1 Mutant Breast Cancer, Derek Dustin, Shunqiang Li, Et Al

Open Access Publications

BACKGROUND: Oestrogen Receptor 1 (ESR1) mutations are frequently acquired in oestrogen receptor (ER)-positive metastatic breast cancer (MBC) patients who were treated with aromatase inhibitors (AI) in the metastatic setting. Acquired ESR1 mutations are associated with poor prognosis and there is a lack of effective therapies that selectively target these cancers.

METHODS: We performed a proteomic kinome analysis in ESR1 Y537S mutant cells to identify hyperactivated kinases in ESR1 mutant cells. We validated Recepteur d'Origine Nantais (RON) and PI3K hyperactivity through phospho-immunoblot analysis, organoid growth assays, and in an in vivo patient-derived xenograft (PDX) metastatic model.

RESULTS: We demonstrated that RON …

Tlr3 Controls Constitutive Ifn-Β Antiviral Immunity In Human Fibroblasts And Cortical Neurons, Daxing Gao, Michael S Diamond, Et Al

Open Access Publications

Human herpes simplex virus 1 (HSV-1) encephalitis can be caused by inborn errors of the TLR3 pathway, resulting in impairment of CNS cell-intrinsic antiviral immunity. Deficiencies of the TLR3 pathway impair cell-intrinsic immunity to vesicular stomatitis virus (VSV) and HSV-1 in fibroblasts, and to HSV-1 in cortical but not trigeminal neurons. The underlying molecular mechanism is thought to involve impaired IFN-α/β induction by the TLR3 recognition of dsRNA viral intermediates or by-products. However, we show here that human TLR3 controls constitutive levels of IFNB mRNA and secreted bioactive IFN-β protein, and thereby also controls constitutive mRNA levels for IFN-stimulated genes …

Cd11c+ Cd88+ Cd317+ Myeloid Cells Are Critical Mediators Of Persistent Cns Autoimmunity, Navid Manouchehri, Rehana Z. Hussain, Petra D. Cravens, Ekaterina Esaulova, Maxim N. Artyomov, Brian T. Edelson, Gregory F. Wu, Anne H. Cross, Richard Doelger, Nicolas Loof, Todd N. Eagar, Thomas G. Forsthuber, Laurent Calvier, Joachim Herz, Olaf Stüve

Open Access Publications

No abstract provided.

Monitoring The Variation In The Gut Microbiota Of Captive Woolly Monkeys Related To Changes In Diet During A Reintroduction Process, Camilo Quiroga-González, Luis Alberto Chica Cardenas, Mónica Ramírez, Alejandro Reyes, Camila González, Pablo R. Stevenson

Open Access Publications

No abstract provided.

Inflammatory Signaling Sensitizes Piezo1 Mechanotransduction In Articular Chondrocytes As A Pathogenic Feed-Forward Mechanism In Osteoarthritis, Whasil Lee, Robert J. Nims, Alireza Savadipour, Qiaojuan Zhang, Holly A. Leddy, Fang Liu, Amy L. Mcnulty, Yong Chen, Farshid Guilak, Wolfgang B. Liedtke

Open Access Publications

No abstract provided.

Long, Noncoding Rna Dysregulation In Glioblastoma, Patrick A Desouza, Xuan Qu, Hao Chen, Bhuvic Patel, Christopher A Maher, Albert H Kim

Open Access Publications

Transcription occurs across more than 70% of the human genome and more than half of currently annotated genes produce functional noncoding RNAs. Of these transcripts, the majority-long, noncoding RNAs (lncRNAs)-are greater than 200 nucleotides in length and are necessary for various roles in the cell. It is increasingly appreciated that these lncRNAs are relevant in both health and disease states, with the brain expressing the largest number of lncRNAs compared to other organs. Glioblastoma (GBM) is an aggressive, fatal brain tumor that demonstrates remarkable intratumoral heterogeneity, which has made the development of effective therapies challenging. The cooperation between genetic and …

Mechanical Dysfunction Of The Sarcomere Induced By A Pathogenic Mutation In Troponin T Drives Cellular Adaptation, Sarah R. Clippinger, Paige E. Cloonan, Wei Wang, Lina Greenberg, W. Tom Stump, Paweorn Angsutararux, Jeanne M. Nerbonne, Michael J. Greenberg

Open Access Publications

Familial hypertrophic cardiomyopathy (HCM), a leading cause of sudden cardiac death, is primarily caused by mutations in sarcomeric proteins. The pathogenesis of HCM is complex, with functional changes that span scales, from molecules to tissues. This makes it challenging to deconvolve the biophysical molecular defect that drives the disease pathogenesis from downstream changes in cellular function. In this study, we examine an HCM mutation in troponin T, R92Q, for which several models explaining its effects in disease have been put forward. We demonstrate that the primary molecular insult driving disease pathogenesis is mutation-induced alterations in tropomyosin positioning, which causes increased …

Variables Associated With Intravenous Rehydration And Hospitalization In Children With Acute Gastroenteritis: A Secondary Analysis Of 2 Randomized Clinical Trials, Naveen Poonai, Philip Tarr, Et Al

Open Access Publications

Importance: Despite guidelines endorsing oral rehydration therapy, intravenous fluids are commonly administered to children with acute gastroenteritis in high-income countries.

Objective: To identify factors associated with intravenous fluid administration and hospitalization in children with acute gastroenteritis.

Design, Setting, and Participants: This study is a planned secondary analysis of the Pediatric Emergency Research Canada (PERC) and Pediatric Emergency Care Applied Research Network (PECARN) probiotic trials. Participants include children aged 3 to 48 months with 3 or more watery stools in 24 hours between November 5, 2013, and April 7, 2017, for the PERC study and July 8, 2014, and June 23, …

Lysis Of Arterial Thrombi By Perfusion Of N,N'-Diacetyl-L-Cystine (Dinac), Dongjune Kim, Susan M. Shea, David N. Ku

Open Access Publications

The search persists for a safe and effective agent to lyse arterial thrombi in the event of acute heart attacks or strokes due to thrombotic occlusion. The culpable thrombi are composed either primarily of platelets and von Willebrand Factor (VWF), or polymerized fibrin, depending on the mechanism of formation. Current thrombolytics were designed to target red fibrin-rich clots, but may be not be efficacious on white VWF-platelet-rich arterial thrombi. We have developed an in vitro system to study the efficacy of known and proposed thrombolytic agents on white clots formed from whole blood in a stenosis with arterial conditions. The …

Cannabis-Induced Hypodopaminergic Anhedonia And Cognitive Decline In Humans: Embracing Putative Induction Of Dopamine Homeostasis, Kenneth Blum, Jag Khalsa, Jean Lud Cadet, David Baron, Abdalla Bowirrat, Brent Boyett, Lisa Lott, Raymond Brewer, Marjorie Gondré-Lewis, Gregory Bunt, Shan Kazmi, Mark S Gold

Open Access Publications

Over years, the regular use of cannabis has substantially increased among young adults, as indicated by the rise in cannabis use disorder (CUD), with an estimated prevalence of 8. 3% in the United States. Research shows that exposure to cannabis is associated with hypodopaminergic anhedonia (depression), cognitive decline, poor memory, inattention, impaired learning performance, reduced dopamine brain response-associated emotionality, and increased addiction severity in young adults. The addiction medicine community is increasing concern because of the high content of delta-9-tetrahydrocannabinol (THC) currently found in oral and vaping cannabis products, the cognitive effects of cannabis may become more pronounced in young …

Thermoneutrality Alters Gastrointestinal Antigen Passage Patterning And Predisposes To Oral Antigen Sensitization In Mice, Taeko K Noah, Jee-Boong Lee, Christopher A Brown, Amnah Yamani, Sunil Tomar, Varsha Ganesan, Rodney D Newberry, Gary B Huffnagle, Senad Divanovic, Simon P Hogan

Open Access Publications

Food allergy is an emerging epidemic, and the underlying mechanisms are not well defined partly due to the lack of robust adjuvant free experimental models of dietary antigen sensitization. As housing mice at thermoneutrality (Tn) - the temperature of metabolic homeostasis (26-30°C) - has been shown to improve modeling various human diseases involved in inflammation, we tested the impact of Tn housing on an experimental model of food sensitization. Here we demonstrate that WT BALB/c mice housed under standard temperature (18-20°C, Ts) conditions translocated the luminal antigens in the small intestine (SI) across the epithelium

The Dystonia Coalition: A Multicenter Network For Clinical And Translational Studies, Gamze Kilic-Berkmen, Laura J Wright, Joel S Perlmutter, Cynthia Comella, Mark Hallett, Jan Teller, Sarah Pirio Richardson, David A Peterson, Carlos Cruchaga, Codrin Lungu, H A Jinnah

Open Access Publications

Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal postures, repetitive movements, or both. Research in dystonia has been challenged by several factors. First, dystonia is uncommon. Dystonia is not a single disorder but a family of heterogenous disorders with varied clinical manifestations and different causes. The different subtypes may be seen by providers in different clinical specialties including neurology, ophthalmology, otolaryngology, and others. These issues have made it difficult for any single center to recruit large numbers of subjects with specific types of dystonia for research studies in a timely manner. The Dystonia Coalition …