Digital Commons Network^™

Phentolamine Mesylate Ophthalmic Solution Provides Lasting Pupil Modulation And Improves Near Visual Acuity In Presbyopic Glaucoma Patients In A Randomized Phase 2b Clinical Trial, Jay S Pepose, Et Al

Open Access Publications

Purpose: Phentolamine mesylate ophthalmic solution (PMOS), applied to the eye topically, was shown previously to have beneficial effects in patients with dim light vision disturbances (DLD), including decreased pupil diameter (PD), improved best-corrected distance visual acuity (BCDVA), as well as lower intraocular pressure (IOP). The ORION-1 trial evaluated the long-term safety and efficacy of PMOS in a glaucomatous, presbyopic population.

Patients and Methods: In this randomized, double-masked, multi-center, placebo-controlled, multiple-dose Phase 2b trial, 39 patients with elevated IOP were randomized to receive one evening dose of study medication or placebo for 14 days. The primary outcome measure was mean change …

Development And Testing Of A Spray-Dried Tuberculosis Vaccine Candidate In A Mouse Model, Mellissa Gomez, Mushtaq Ahmed, Shibali Das, Leah Mellett, Rosemary Swanson, Ananya Gupta, Shabaana A Khader, Et Al

Open Access Publications

Converting a vaccine into a thermostable dry powder is advantageous as it reduces the resource burden linked with the cold chain and provides flexibility in dosage and administration through different routes. Such a dry powder presentation may be especially useful in the development of a vaccine towards the respiratory infectious disease tuberculosis (TB). This study assesses the immunogenicity and protective efficacy of spray-dried ID93+GLA-SE, a promising TB vaccine candidate, against

Hyperexcitability Of Sensory Neurons In Fragile X Mouse Model, Pan-Yue Deng, Oshri Avraham, Valeria Cavalli, Vitaly A Klyachko

Open Access Publications

Sensory hypersensitivity and somatosensory deficits represent the core symptoms of Fragile X syndrome (FXS). These alterations are believed to arise from changes in cortical sensory processing, while potential deficits in the function of peripheral sensory neurons residing in dorsal root ganglia remain unexplored. We found that peripheral sensory neurons exhibit pronounced hyperexcitability in

Dynamics Of Oddball Sound Processing: Trial-By-Trial Modeling Of Ecog Signals, Françoise Lecaignard, Raphaëlle Bertrand, Peter Brunner, Anne Caclin, Gerwin Schalk, Jérémie Mattout

Open Access Publications

Recent computational models of perception conceptualize auditory oddball responses as signatures of a (Bayesian) learning process, in line with the influential view of the mismatch negativity (MMN) as a prediction error signal. Novel MMN experimental paradigms have put an emphasis on neurophysiological effects of manipulating regularity and predictability in sound sequences. This raises the question of the contextual adaptation of the learning process itself, which on the computational side speaks to the mechanisms of gain-modulated (or precision-weighted) prediction error. In this study using electrocorticographic (ECoG) signals, we manipulated the predictability of oddball sound sequences with two objectives: (i) Uncovering the …

Druggable Lipid Binding Sites In Pentameric Ligand-Gated Ion Channels And Transient Receptor Potential Channels, Wayland W L Cheng, Mark J Arcario, John T Petroff

Open Access Publications

Lipids modulate the function of many ion channels, possibly through direct lipid-protein interactions. The recent outpouring of ion channel structures by cryo-EM has revealed many lipid binding sites. Whether these sites mediate lipid modulation of ion channel function is not firmly established in most cases. However, it is intriguing that many of these lipid binding sites are also known sites for other allosteric modulators or drugs, supporting the notion that lipids act as endogenous allosteric modulators through these sites. Here, we review such lipid-drug binding sites, focusing on pentameric ligand-gated ion channels and transient receptor potential channels. Notable examples include …

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.

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 …

Endocannabinoid System Unlocks The Puzzle Of Autism Treatment, Tangfeng Su, Yu Yan, Qiang Li, Jiacai Ye, Lei Pei

Open Access Publications

Autism spectrum disorder (ASD) is a serious neurodevelopmental disorder and characterized by early childhood-onset impairments in social interaction and communication, restricted and repetitive patterns of behavior or interests. So far there is no effective treatment for ASD, and the pathogenesis of ASD remains unclear. Genetic and epigenetic factors have been considered to be the main cause of ASD. It is known that endocannabinoid and its receptors are widely distributed in the central nervous system, and provide a positive and irreversible change toward a more physiological neurodevelopment. Recently, the endocannabinoid system (ECS) has been found to participate in the regulation of …

Consensus Guidelines For Improving Quality Of Assessment And Training For Neuromuscular Diseases, Tina Duong, Kristin J Krosschell, Meredith K James, Leslie Nelson, Lindsay N Alfano, Katy Eichinger, Elena Mazzone, Kristy Rose, Linda P Lowes, Anna Mayhew, Julaine Florence, Wendy King, Claudia R Senesac, Michelle Eagle

Open Access Publications

Critical components of successful evaluation of clinical outcome assessments (COAs) in multisite clinical trials and clinical practice are standardized training, administration, and documented reliability of scoring. Experiences of evaluators, alongside patient differences from regional standards of care, may contribute to heterogeneity in clinical center's expertise. Achieving low variability and high reliability of COA is fundamental to clinical research and to give confidence in our ability to draw rational, interpretable conclusions from the data collected. The objective of this manuscript is to provide a framework to guide the learning process for COAs for use in clinics and clinical trials to maximize …

High Affinity Associations With Α-Snap Enable Calcium Entry Via Orai1 Channels, Ramanagouda Ramanagoudr-Bhojappa, Yong Miao, Monika Vig

Open Access Publications

Molecular steps that activate store-operated calcium entry (SOCE) via Orai channel supramolecular complex remain incompletely defined. We have earlier shown that α-SNAP regulates the on-site functional assembly and calcium selectivity of Orai1 channels. Here we investigate the molecular basis of its association with Orai, Stim and find that the affinity of α-SNAP for Orai and Stim is substantially higher than previously reported affinities between Stim and Orai sub-domains. α-SNAP binds the coiled-coil 3 (CC3) sub-domain of Stim1. Mutations of Tryptophan 430 in Stim1-CC3 disrupted α-SNAP association and SOCE, demonstrating a novel α-SNAP dependent function for this crucial subdomain. Further, α-SNAP …

Type Iii Interferons: Emerging Roles In Autoimmunity, Sindhu Manivasagam, Robyn S Klein

Open Access Publications

Type III interferons (IFNs) or the lambda IFNs (IFNLs or IFN-λs) are antimicrobial cytokines that play key roles in immune host defense at endothelial and epithelial barriers. IFNLs signal

Metformin Downregulates Pd-L1 Expression In Esophageal Squamous Cell Catrcinoma By Inhibiting Il-6 Signaling Pathway, Yao Lu, Dao Xin, Lulu Guan, Mengli Xu, Yalan Yang, Yu Chen, Yuanyuan Yang, Andrea Wang-Gillam, Li Wang, Shanggang Zong, Feng Wang

Open Access Publications

Purpose: To characterize the mechanism by which metformin inhibits PD-L1 expression in esophageal squamous cell carcinoma (ESCC) and to evaluate the effect of metformin on the antitumor immune response.

Methods: The Cancer Genome Atlas (TCGA) database was used to analyze the correlations between IL-6 and prognosis and between IL-6 and PD-L1 gene expression in esophageal cancer. Reverse transcription-quantitative polymerase chain reaction (RT-PCR), Western blotting and immunofluorescence were used to study the mechanism by which metformin affects PD-L1 expression. Additionally, T cell function was assessed in a coculture system containing ESCC cells and peripheral blood mononuclear cells (PBMCs) treated with metformin …

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 …

Sensory Percepts Elicited By Chronic Macro-Sieve Electrode Stimulation Of The Rat Sciatic Nerve, Nikhil S Chandra, Weston M Mccarron, Ying Yan, Luis C Ruiz, Eric G Sallinger, Nathan K Birenbaum, Harold Burton, Leonard Green, Daniel W Moran, Wilson Z Ray, Matthew R Macewan

Open Access Publications

No abstract provided.

Continuous Renal Replacement Therapy For Two Neonates With Hyperammonemia, Christopher Markham, Caroline Williams, Cory Miller, Dorothy K Grange, T Keefe Davis, Kenneth E Remy

Open Access Publications

No abstract provided.

Noninvasive Immuno-Pet Imaging Of Cd8 + T Cell Behavior In Influenza A Virus-Infected Mice, Paul W Rothlauf, Zeyang Li, Novalia Pishesha, Yushu Joy Xie, Andrew W Woodham, Djenet Bousbaine, Stephen C Kolifrath, Vincent L Verschoor, Hidde L Ploegh

Open Access Publications

Immuno-positron emission tomography (immuno-PET) is a noninvasive imaging method that enables tracking of immune cells in living animals. We used a nanobody that recognizes mouse CD8α and labeled it with

Transcript Assembly Improves Expression Quantification Of Transposable Elements In Single-Cell Rna-Seq Data, Wanqing Shao, Ting Wang

Open Access Publications

Transposable elements (TEs) are an integral part of the host transcriptome. TE-containing noncoding RNAs (ncRNAs) show considerable tissue specificity and play important roles during development, including stem cell maintenance and cell differentiation. Recent advances in single-cell RNA-seq (scRNA-seq) revolutionized cell type-specific gene expression analysis. However, effective scRNA-seq quantification tools tailored for TEs are lacking, limiting our ability to dissect TE expression dynamics at single-cell resolution. To address this issue, we established a TE expression quantification pipeline that is compatible with scRNA-seq data generated across multiple technology platforms. We constructed TE-containing ncRNA references using bulk RNA-seq data and showed that quantifying …

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.

Association Of Immunosuppression And Viral Load With Subcortical Brain Volume In An International Sample Of People Living With Hiv, Talia M. Nir, Beau M. Ances, Et Al

Open Access Publications

Importance: Despite more widely accessible combination antiretroviral therapy (cART), HIV-1 infection remains a global public health challenge. Even in treated patients with chronic HIV infection, neurocognitive impairment often persists, affecting quality of life. Identifying the neuroanatomical pathways associated with infection in vivo may delineate the neuropathologic processes underlying these deficits. However, published neuroimaging findings from relatively small, heterogeneous cohorts are inconsistent, limiting the generalizability of the conclusions drawn to date.

Objective: To examine structural brain associations with the most commonly collected clinical assessments of HIV burden (CD4+ T-cell count and viral load), which are generalizable across demographically and clinically diverse …

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 …

Increased Utilization Of Total Joint Arthroplasty After Medicaid Expansion, Christopher J Dy, Amber Salter, Abigail Barker, Derek Brown, Matthew Keller, Margaret A Olsen

Open Access Publications

BACKGROUND: The expansion of state Medicaid programs under the U.S. Affordable Care Act has led to a dramatic increase in the number of Americans with health insurance coverage. Prior analyses of a limited number of states have suggested that greater utilization of total hip arthroplasty (THA) and total knee arthroplasty (TKA) should be expected after Medicaid expansion. The purpose of our study was to examine whether increased utilization of THA and TKA occurred across a broader range of states after Medicaid expansion.

METHODS: We analyzed administrative data from the Healthcare Cost and Utilization Project from 9 states (Arkansas, Arizona, Colorado, …

Epcam (Cd326) Regulates Intestinal Epithelial Integrity And Stem Cells Via Rho-Associated Kinase, Takeshi Ouchi, Sohshi Morimura, Lukas E Dow, Hiroyuki Miyoshi, Mark C Udey

Open Access Publications

Humans with biallelic inactivating mutations in Epithelial Cell Adhesion Molecule (EpCAM) develop congenital tufting enteropathy (CTE). To gain mechanistic insights regarding EpCAM function in this disorder, we prepared intestinal epithelial cell (IEC) organoids and spheroids. IEC organoids and spheroids were generated from

Killing The Invaders: Nk Cell Impact In Tumors And Anti-Tumor Therapy, Martina Molgora, Victor S Cortez, Marco Colonna

Open Access Publications

Natural Killer cells belong to group 1 innate lymphoid cells, which also includes ILC1s. NK/ILC1s are highly heterogeneous cell types showing distinct phenotypes across tissues and conditions. NK cells have long been described as innate lymphocytes able to directly and rapidly kill tumor cells without antigen-restriction. Different mechanisms were shown to modulate NK cell activation and tumor resistance, mainly based on cytokine stimulation and receptor-ligand interactions, and several strategies have been developed to target NK cells in tumor immunotherapy to promote NK cell function and overcome tumor evasion. The characterization of ILC1 distinct phenotype and function and the specific role …

The Association Of Polygenic Risk For Schizophrenia, Bipolar Disorder, And Depression With Neural Connectivity In Adolescents And Young Adults: Examining Developmental And Sex Differences, J.L. Meyers, E.C. Johnson, A. Agrawal, A. Anokhin, M.H. Plawecki, Et Al.

Open Access Publications

No abstract provided.

Von Willebrand Disease: Proposing Definitions For Future Research, Nathan T. Connell, Jorge Di Paola, Et Al.

Open Access Publications

No abstract provided.

Adipose Saturation Reduces Lipotoxic Systemic Inflammation And Explains The Obesity Paradox, Biswajit Khatua, Bara El-Kurdi, Krutika Patel, Christopher Rood, Pawan Noel, Michael Crowell, Jordan R Yaron, Sergiy Kostenko, Andre Guerra, Douglas O Faigel, Mark Lowe, Vijay P Singh

Open Access Publications

Obesity sometimes seems protective in disease. This obesity paradox is predominantly described in reports from the Western Hemisphere during acute illnesses. Since adipose triglyceride composition corresponds to long-term dietary patterns, we performed a meta-analysis modeling the effect of obesity on severity of acute pancreatitis, in the context of dietary patterns of the countries from which the studies originated. Increased severity was noted in leaner populations with a higher proportion of unsaturated fat intake. In mice, greater hydrolysis of unsaturated visceral triglyceride caused worse organ failure during pancreatitis, even when the mice were leaner than those having saturated triglyceride. Saturation interfered …

Chemoprevention Agents To Reduce Mammographic Breast Density In Premenopausal Women: A Systematic Review Of Clinical Trials, Ana S. Salazar, Malika Rakhmankulova, Laura E. Simon, Adetunji T. Toriola

Open Access Publications

Background: Higher mammographic breast density (MBD) is associated with an increased risk of breast cancer when compared with lower MBD, especially in premenopausal women. However, little is known about the effectiveness of chemoprevention agents in reducing MBD in premenopausal women without a history of breast cancer. Findings from this review should provide insight on how to target MBD in breast cancer prevention in premenopausal women with dense breasts.

Methods: We searched 9 electronic databases for clinical trials in English, Spanish, French, or German published until January 2020. Articles evaluating the association of pharmacological agents and MBD were included. Data were …

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.

Cerebrospinal Fluid Ncam-1 Concentration Is Associated With Neurodevelopmental Outcome In Post-Hemorrhagic Hydrocephalus Of Prematurity, David D. Limbrick, Diego M. Morales, Et Al.

Open Access Publications

OBJECTIVE: Efforts directed at mitigating neurological disability in preterm infants with intraventricular hemorrhage (IVH) and post hemorrhagic hydrocephalus (PHH) are limited by a dearth of quantifiable metrics capable of predicting long-term outcome. The objective of this study was to examine the relationships between candidate cerebrospinal fluid (CSF) biomarkers of PHH and neurodevelopmental outcomes in infants undergoing neurosurgical treatment for PHH.

STUDY DESIGN: Preterm infants with PHH were enrolled across the Hydrocephalus Clinical Research Network. CSF samples were collected at the time of temporizing neurosurgical procedure (n = 98). Amyloid precursor protein (APP), L1CAM, NCAM-1, and total protein (TP) were compared …

Are Fc Gamma Receptor Polymorphisms Important In Hiv-1 Infection Outcomes And Latent Reservoir Size?, Helena Lamptey, Evelyn Y Bonney, Bright Adu, George B Kyei

Open Access Publications

Fc gamma receptors (FcγR) are cell surface glycoproteins which trigger specific effector-cell responses when cross-linked with the Fc portions of immunoglobulin (IgG) antibodies. During HIV-1 infection, the course of disease progression, ART response, and viral reservoir size vary in different individuals. Several factors may account for these differences; however, Fc gamma receptor gene polymorphisms, which influence receptor binding to IgG antibodies, are likely to play a key role. FcγRIIa (CD32) was recently reported as a potential marker for latent HIV reservoir, however, this assertion is still inconclusive. Whether FcγR polymorphisms influence the size of the viral reservoir, remains an important …