Medicine and Health Sciences Commons^™

Cellular Sources And Neuroprotective Roles Of Interleukin-10 In The Facial Motor Nucleus After Axotomy, Elizabeth M Runge, Deborah O Setter, Abhirami K Iyer, Eric J Regele, Felicia M Kennedy, Virginia M Sanders, Kathryn J Jones

2020-Current year OA Pubs

Facial motoneuron (FMN) survival is mediated by CD4+ T cells in an interleukin-10 (IL-10)-dependent manner after facial nerve axotomy (FNA), but CD4+ T cells themselves are not the source of this neuroprotective IL-10. The aims of this study were to (1) identify the temporal and cell-specific induction of IL-10 expression in the facial motor nucleus and (2) elucidate the neuroprotective capacity of this expression after axotomy. Immunohistochemistry revealed that FMN constitutively produced IL-10, whereas astrocytes were induced to make IL-10 after FNA.

Integrating A Patient Decision Aid Into The Electronic Health Record: A Case Report On The Implementation Of Breastchoice At 2 Sites, Clara N Lee, Janessa Sullivan, Randi Foraker, Terence M Myckatyn, Margaret A Olsen, Crystal Phommasathit, Jessica Boateng, Katelyn L Parrish, Milisa Rizer, Tim Huerta, Mary C Politi

2020-Current year OA Pubs

UNLABELLED: Patient decision aids can support shared decision making and improve decision quality. However, decision aids are not widely used in clinical practice due to multiple barriers. Integrating patient decision aids into the electronic health record (EHR) can increase their use by making them more clinically relevant, personalized, and actionable. In this article, we describe the procedures and considerations for integrating a patient decision aid into the EHR, based on the example of BREASTChoice, a decision aid for breast reconstruction after mastectomy. BREASTChoice's unique features include 1) personalized risk prediction using clinical data from the EHR, 2) clinician- and patient-facing …

Why Tic Severity Changes From Then To Now And From Here To There, Ann M Iverson, Kevin J. Black

2020-Current year OA Pubs

Much of the research regarding Tourette's syndrome (TS) has focused on why certain individuals develop tics while others do not. However, a separate line of research focuses on the momentary influences that cause tics to increase or decrease in patients who are already known to have TS or another chronic tic disorder (CTD). Environmental and internal variables such as fatigue, anxiety, and certain types of thoughts all have been shown to worsen tic severity and may even overcome the positive effects of treatment. Other influences such as stress, distraction, and being observed have had mixed effects in the various studies …

Multi-Trait Genome-Wide Association Study Of Opioid Addiction: Oprm1 And Beyond, Nathan Gaddis, Arpana Agrawal, Paul W Jeffries, Kathleen Bucholz, Elliot C Nelson, Laura Bierut, Et Al.

2020-Current year OA Pubs

Opioid addiction (OA) is moderately heritable, yet only rs1799971, the A118G variant in OPRM1, has been identified as a genome-wide significant association with OA and independently replicated. We applied genomic structural equation modeling to conduct a GWAS of the new Genetics of Opioid Addiction Consortium (GENOA) data together with published studies (Psychiatric Genomics Consortium, Million Veteran Program, and Partners Health), comprising 23,367 cases and effective sample size of 88,114 individuals of European ancestry. Genetic correlations among the various OA phenotypes were uniformly high (r

Spontaneous Activity Patterns In Human Motor Cortex Replay Evoked Activity Patterns For Hand Movements, Tomer Livne, Dohyun Kim, Nicholas V Metcalf, Lu Zhang, Lorenzo Pini, Gordon L Shulman, Maurizio Corbetta

2020-Current year OA Pubs

Spontaneous brain activity, measured with resting state fMRI (R-fMRI), is correlated among regions that are co-activated by behavioral tasks. It is unclear, however, whether spatial patterns of spontaneous activity within a cortical region correspond to spatial patterns of activity evoked by specific stimuli, actions, or mental states. The current study investigated the hypothesis that spontaneous activity in motor cortex represents motor patterns commonly occurring in daily life. To test this hypothesis 15 healthy participants were scanned while performing four different hand movements. Three movements (Grip, Extend, Pinch) were ecological involving grip and grasp hand movements; one control movement involving the …

A Bioresorbable Peripheral Nerve Stimulator For Electronic Pain Block, Geumbee Lee, Emily Ray, Sabrina Genovese, Ying Yan, Arman Odabas, Umang Khandpur, Wilson Z Ray, Matthew R Macewan, Et Al.

2020-Current year OA Pubs

Local electrical stimulation of peripheral nerves can block the propagation of action potentials, as an attractive alternative to pharmacological agents for the treatment of acute pain. Traditional hardware for such purposes, however, involves interfaces that can damage nerve tissue and, when used for temporary pain relief, that impose costs and risks due to requirements for surgical extraction after a period of need. Here, we introduce a bioresorbable nerve stimulator that enables electrical nerve block and associated pain mitigation without these drawbacks. This platform combines a collection of bioresorbable materials in architectures that support stable blocking with minimal adverse mechanical, electrical, …

Integrating Transcriptomics, Metabolomics, And Gwas Helps Reveal Molecular Mechanisms For Metabolite Levels And Disease Risk, Xianyong Yin, Adam E Locke, Nathan O Stitziel, Et Al.

2020-Current year OA Pubs

Transcriptomics data have been integrated with genome-wide association studies (GWASs) to help understand disease/trait molecular mechanisms. The utility of metabolomics, integrated with transcriptomics and disease GWASs, to understand molecular mechanisms for metabolite levels or diseases has not been thoroughly evaluated. We performed probabilistic transcriptome-wide association and locus-level colocalization analyses to integrate transcriptomics results for 49 tissues in 706 individuals from the GTEx project, metabolomics results for 1,391 plasma metabolites in 6,136 Finnish men from the METSIM study, and GWAS results for 2,861 disease traits in 260,405 Finnish individuals from the FinnGen study. We found that genetic variants that regulate metabolite …

Continuous Npwt Regulates Fibrosis In Murine Diabetic Wound Healing, Mengfan Wu, Dany Y Matar, Zhen Yu, Ziyu Chen, Samuel Knoedler, Brian Ng, Oliver A Darwish, Sadaf Sohrabi, Leigh Friedman, Valentin Haug, George F Murphy, Yuval Rinkevich, Dennis P Orgill, Adriana C Panayi

2020-Current year OA Pubs

Scarring is associated with significant morbidity. The mechanical signaling factor yes-associated protein (YAP) has been linked to Engrailed-1 (En1)-lineage positive fibroblasts (EPFs), a pro-scarring fibroblast lineage, establishing a connection between mechanotransduction and fibrosis. In this study, we investigate the impact of micromechanical forces exerted through negative pressure wound therapy (NPWT) on the pathophysiology of fibrosis. Full-thickness excisional dorsal skin wounds were created on diabetic (db/db) mice which were treated with occlusive covering (control) or NPWT (continuous, -125 mmHg, 7 days; NPWT). Analysis was performed on tissue harvested 10 days after wounding. NPWT was associated with increased YAP (

A Living Database Of Hiv Implementation Research (Live Project): Protocol For Rapid Living Reviews, Ingrid Eshun-Wilson, Nathan Ford, Noelle Le Tourneau, Stefan Baral, Sheree Schwartz, Christopher Kemp, Elvin Geng

2020-Current year OA Pubs

BACKGROUND: HIV implementation research evolves rapidly and is often complex and poorly characterized, which makes the synthesis of data on HIV implementation strategies inherently difficult. This is further compromised by prolonged data abstraction processes due to variable interventions, outcomes, and context, and delays in the publication of review findings; this can all result in outdated and irrelevant systematic reviews.

OBJECTIVE: The LIVE project (A Living Database of HIV Implementation Research) aims to overcome these challenges by applying an implementation science lens to the conduct of rapid living systematic reviews and meta-analyses to inform HIV service delivery priorities and guideline development. …

Unravelling The Reservoirs For Colonisation Of Infants With Campylobacter Spp. In Rural Ethiopia: Protocol For A Longitudinal Study During A Global Pandemic And Political Tensions, Arie H Havelaar, Mark J Manary, Et Al.

2020-Current year OA Pubs

INTRODUCTION: Undernutrition is an underlying cause of mortality in children under five (CU5) years of age. Animal-source foods have been shown to decrease malnutrition in CU5. Livestock are important reservoirs for

METHODS AND ANALYSIS: This longitudinal study involves 115 infants who are followed from birth to 12 months of age and are selected randomly from 10 kebeles of Haramaya woreda, East Hararghe zone, Oromia region, Ethiopia. Questionnaire-based information is obtained on demographics, livelihoods, wealth, health, nutrition and women empowerment; animal ownership/management and diseases; and water, sanitation and hygiene. Faecal samples are collected from infants, mothers, siblings and livestock, drinking water …

Antidepressant Use And Its Association With 28-Day Mortality In Inpatients With Sars-Cov-2: Support For The Fiasma Model Against Covid-19, Nicolas Hoertel, Angela M Reiersen, Eric J Lenze, Bradley A Fritz, Et Al.

2020-Current year OA Pubs

To reduce Coronavirus Disease 2019 (COVID-19)-related mortality and morbidity, widely available oral COVID-19 treatments are urgently needed. Certain antidepressants, such as fluvoxamine or fluoxetine, may be beneficial against COVID-19. We included 388,945 adult inpatients who tested positive for SARS-CoV-2 at 36 AP-HP (Assistance Publique-Hôpitaux de Paris) hospitals from 2 May 2020 to 2 November 2021. We compared the prevalence of antidepressant use at admission in a 1:1 ratio matched analytic sample with and without COVID-19 (N = 82,586), and assessed its association with 28-day all-cause mortality in a 1:1 ratio matched analytic sample of COVID-19 inpatients with and without antidepressant …

Pan-Cancer Analysis Reveals Recurrent Bcar4 Gene Fusions Across Solid Tumors, Andrew Nickless, Jin Zhang, Ghofran Othoum, Jace Webster, Matthew J Inkman, Emily Coonrod, Sherron Fontes, Emily B Rozycki, Christopher A Maher, Nicole M White

2020-Current year OA Pubs

UNLABELLED: Chromosomal rearrangements often result in active regulatory regions juxtaposed upstream of an oncogene to generate an expressed gene fusion. Repeated activation of a common downstream partner-with differing upstream regions across a patient cohort-suggests a conserved oncogenic role. Analysis of 9,638 patients across 32 solid tumor types revealed an annotated long noncoding RNA (lncRNA), Breast Cancer Anti-Estrogen Resistance 4 (BCAR4), was the most prevalent, uncharacterized, downstream gene fusion partner occurring in 11 cancers. Its oncogenic role was confirmed using multiple cell lines with endogenous BCAR4 gene fusions. Furthermore, overexpressing clinically prevalent BCAR4 gene fusions in untransformed cell lines was sufficient …

Global Longitudinal Strain And Biomarkers Of Cardiac Damage And Stress As Predictors Of Outcomes After Transcatheter Aortic Valve Implantation, Andrew S Perry, Nishath Quader, Alan Zajarias, Et Al.

2020-Current year OA Pubs

Background Global longitudinal strain (GLS) is a sensitive measure of left ventricular function and a risk marker in severe aortic stenosis. We sought to determine whether biomarkers of cardiac damage (cardiac troponin) and stress (NT-proBNP [N-terminal pro-B-type natriuretic peptide]) could complement GLS to identify patients with severe aortic stenosis at highest risk. Methods and Results From a multicenter prospective cohort of patients with symptomatic severe aortic stenosis who underwent transcatheter aortic valve implantation, we measured absolute GLS (aGLS), cardiac troponin, and NT-proBNP at baseline in 499 patients. Left ventricular ejection fraction <50% was observed in 19% and impaired GLS (aGLS <15%) in 38%. Elevations in cardiac troponin and NT-proBNP were present in 79% and 89% of those with impaired GLS, respectively, as compared with 63% and 60% of those with normal GLS, respectively (

A Non-Canonical Retina-Iprgcs-Scn-Pvt Visual Pathway For Mediating Contagious Itch Behavior, Fang Gao, Jun Ma, Yao-Qing Yu, Xiao-Fei Gao, Yang Bai, Yi Sun, Juan Liu, Xianyu Liu, Devin M Barry, Steven Wilhelm, Tyler Piccinni-Ash, Na Wang, Dongyang Liu, Yan Hao, Jin-Jing Jia, Qianyi Yang, Johan Van Nispen, Zhou-Feng Chen, Et Al.

2020-Current year OA Pubs

Contagious itch behavior informs conspecifics of adverse environment and is crucial for the survival of social animals. Gastrin-releasing peptide (GRP) and its receptor (GRPR) in the suprachiasmatic nucleus (SCN) of the hypothalamus mediates contagious itch behavior in mice. Here, we show that intrinsically photosensitive retina ganglion cells (ipRGCs) convey visual itch information, independently of melanopsin, from the retina to GRP neurons via PACAP-PAC1R signaling. Moreover, GRPR neurons relay itch information to the paraventricular nucleus of the thalamus (PVT). Surprisingly, neither the visual cortex nor superior colliculus is involved in contagious itch. In vivo calcium imaging and extracellular recordings reveal contagious …

Association Between The Affordable Care Act Medicaid Expansion And Receipt Of Cardiac Resynchronization Therapy By Race And Ethnicity, Hunter Mwansa, Ibrahim Barry, Shannon M Knapp, Sula Mazimba, Elizabeth Calhoun, Nancy K Sweitzer, Khadijah Breathett

2020-Current year OA Pubs

Background Black and Hispanic patients are less likely to receive cardiac resynchronization therapy (CRT) than White patients. Medicaid expansion has been associated with increased access to cardiovascular care among racial and ethnic groups with higher prevalence of underinsurance. It is unknown whether the Medicaid expansion was associated with increased receipt of CRT by race and ethnicity. Methods and Results Using Healthcare Cost and Utilization Project Data State Inpatient Databases from 19 states and Washington, DC, we analyzed 1061 patients from early-adopter states (Medicaid expansion by January 2014) and 745 patients from nonadopter states (no implementation 2013-2014). Estimates of change in …

The Transcription Factor Bach2 Negatively Regulates Murine Natural Killer Cell Maturation And Function, Shasha Li, Michael D Bern, Benpeng Miao, Changxu Fan, Xiaoyun Xing, Takeshi Inoue, Sytse J Piersma, Ting Wang, Marco Colonna, Tomohiro Kurosaki, Wayne M Yokoyama

2020-Current year OA Pubs

BTB domain And CNC Homolog 2 (Bach2) is a transcription repressor that actively participates in T and B lymphocyte development, but it is unknown if Bach2 is also involved in the development of innate immune cells, such as natural killer (NK) cells. Here, we followed the expression of Bach2 during murine NK cell development, finding that it peaked in immature CD27

Current Communication Practices Between Obstetrics And Gynecology Residency Applicants And Program Directors, Helen Kang Morgan, Abigail Ford Winkel, Karen George, Eric Strand, Erika Banks, Fiona Byrne, David Marzano, Maya M Hammoud

2020-Current year OA Pubs

Importance: In order to equitably improve the residency application process, it is essential to understand the problems we need to address.

Objective: To determine how obstetrics and gynecology (OBGYN) applicants and faculty communicate applicants' interest to residency programs, and how program directors report being influenced by these communications.

Design, Setting, and Participants: This survey study was conducted with email surveys of OBGYN application stakeholders in 2022. Included participants were OBGYN applicants, clerkship directors, and residency program directors in medical education associations' email listservs.

Exposures: Surveys sent by the American Association of Medical Colleges, Association of Professors of Gynecology and Obstetrics, …

Effectiveness Of The Ad26.Cov2.S (Johnson & Johnson) Coronavirus Disease 2019 (Covid-19) Vaccine For Preventing Covid-19 Hospitalizations And Progression To High Disease Severity In The United States, Nathaniel M Lewis, Hilary M Babcock, Jennie H Kwon, Et Al.

2020-Current year OA Pubs

Background . Adults in the United States (US) began receiving the adenovirus vector coronavirus disease 2019 (COVID-19) vaccine, Ad26.COV2.S (Johnson & Johnson [Janssen]), in February 2021. We evaluated Ad26.COV2.S vaccine effectiveness (VE) against COVID-19 hospitalization and high disease severity during the first 10 months of its use. Methods . In a multicenter case-control analysis of US adults (≥18 years) hospitalized 11 March to 15 December 2021, we estimated VE against susceptibility to COVID-19 hospitalization (VEs), comparing odds of prior vaccination with a single dose Ad26.COV2.S vaccine between hospitalized cases with COVID-19 and controls without COVID-19. Among hospitalized patients with COVID-19, …

Reprogramming Alveolar Macrophage Responses To Tgf-Β Reveals Ccr2+ Monocyte Activity That Promotes Bronchiolitis Obliterans Syndrome, Zhiyi Liu, Fuyi Liao, Jihong Zhu, Dequan Zhou, Gyu Seong Heo, Hannah P. Leuhmann, Davide Scozzi, Antanisha Parks, Ramsey Hachem, Derek E. Byers, Laneshia K. Tague, Hrishikesh S. Kulkarni, Marlene Cano, Brian W. Wong, Wenjun Li, Daniel Kreisel, Andrew E Gelman, Et Al.

2020-Current year OA Pubs

Bronchiolitis obliterans syndrome (BOS) is a major impediment to lung transplant survival and is generally resistant to medical therapy. Extracorporeal photophoresis (ECP) is an immunomodulatory therapy that shows promise in stabilizing BOS patients, but its mechanisms of action are unclear. In a mouse lung transplant model, we show that ECP blunts alloimmune responses and inhibits BOS through lowering airway TGF-β bioavailability without altering its expression. Surprisingly, ECP-treated leukocytes were primarily engulfed by alveolar macrophages (AMs), which were reprogrammed to become less responsive to TGF-β and reduce TGF-β bioavailability through secretion of the TGF-β antagonist decorin. In untreated recipients, high airway …

Entrectinib In Children And Young Adults With Solid Or Primary Cns Tumors Harboring Ntrk, Ros1, Or Alk Aberrations (Startrk-Ng), Ami V Desai, Karen Gauvain, Amy E Armstrong, Et Al.

2020-Current year OA Pubs

BACKGROUND: Entrectinib is a TRKA/B/C, ROS1, ALK tyrosine kinase inhibitor approved for the treatment of adults and children aged ≥12 years with NTRK fusion-positive solid tumors and adults with ROS1 fusion-positive non-small-cell lung cancer. We report an analysis of the STARTRK-NG trial, investigating the recommended phase 2 dose (RP2D) and activity of entrectinib in pediatric patients with solid tumors including primary central nervous system tumors.

METHODS: STARTRK-NG (NCT02650401) is a phase 1/2 trial. Phase 1, dose-escalation of oral, once-daily entrectinib, enrolled patients aged <22 years with solid tumors with/without target NTRK1/2/3, ROS1, or ALK fusions. Phase 2, basket trial at the RP2D, enrolled patients with intracranial or extracranial solid tumors harboring target fusions or neuroblastoma. Primary endpoints: phase 1, RP2D based on toxicity; phase 2, objective response rate (ORR) in patients harboring target fusions. Safety-evaluable patients: ≥1 dose of entrectinib; response-evaluable patients: measurable/evaluable baseline disease and ≥1 dose at RP2D.

RESULTS: At data cutoff, 43 patients, median age of 7 years, were response-evaluable. In phase 1, 4 …

Shared Brain And Genetic Architectures Between Mental Health And Physical Activity, Wei Zhang, Sarah E Paul, Anderson Winkler, Ryan Bogdan, Janine D Bijsterbosch

2020-Current year OA Pubs

Physical activity is correlated with, and effectively treats various forms of psychopathology. However, whether biological correlates of physical activity and psychopathology are shared remains unclear. Here, we examined the extent to which the neural and genetic architecture of physical activity and mental health are shared. Using data from the UK Biobank (N = 6389), we applied canonical correlation analysis to estimate associations between the amplitude and connectivity strength of subnetworks of three major neurocognitive networks (default mode, DMN; salience, SN; central executive networks, CEN) with accelerometer-derived measures of physical activity and self-reported mental health measures (primarily of depression, anxiety disorders, …

Targeting Pim2 By Jp11646 Results In Significant Antitumor Effects In Solid Tumors, Eriko Katsuta, Malgorzata Gil-Moore, Justine Moore, Mohamed Yousif, Alex A Adjei, Yi Ding, Justin Caserta, Carmen M Baldino, Kelvin P Lee, Irwin H Gelman, Kazuaki Takabe, Mateusz Opyrchal

2020-Current year OA Pubs

Proviral integration of Moloney virus 2 (PIM2) is a pro‑survival factor of cancer cells and a possible therapeutic target in hematological malignancies. However, the attempts at inhibiting PIM2 have yielded underwhelming results in early clinical trials on hematological malignancies. Recently, a novel pan‑PIM inhibitor, JP11646, was developed. The present study examined the utility of targeting PIM2 in multiple solid cancers and investigated the antitumor efficacy and the mechanisms of action of JP11646. When PIM2 expression was compared between normal and cancer tissues in publicly available datasets, PIM2 was found to be overexpressed in several types of solid cancers. PIM2 ectopic …

Paediatrician's Guide To Post-Operative Care For Functionally Univentricular Chd: A Review, Christina Ronai, Sarosh P Batlivala, Quang-Tuyen Nguyen, Markus S Renno, Lindsay Arthur, Julie Glickstein, Jonathan N Johnson, Jacob R Miller, Carolyn A Altman, Elif Seda Selamet Tierney

2020-Current year OA Pubs

IMPORTANCE: Single ventricle CHD affects about 5 out of 100,000 newborns, resulting in complex anatomy often requiring multiple, staged palliative surgeries. Paediatricians are an essential part of the team that cares for children with single ventricle CHD. These patients often encounter their paediatrician first when a complication arises, so it is critical to ensure the paediatrician is knowledgeable of these issues to provide optimal care.

OBSERVATIONS: We reviewed the subtypes of single ventricle heart disease and the various palliative surgeries these patients undergo. We then searched the literature to detail the general paediatrician's approach to single ventricle patients at different …

Phase Ib Study Of Eprenetapopt (Apr-246) In Combination With Pembrolizumab In Patients With Advanced Or Metastatic Solid Tumors, H Park, Et Al.

2020-Current year OA Pubs

BACKGROUND: We conducted a phase I, multicenter, open-label, dose-finding, and expansion study to determine the safety and preliminary efficacy of eprenetapopt (APR-246) combined with pembrolizumab in patients with advanced/metastatic solid tumors (ClinicalTrials.gov NCT04383938).

PATIENTS AND METHODS: For dose-finding, requirements were non-central nervous system primary solid tumor, intolerant to/progressed after ≥1 line of treatment, and eligible for pembrolizumab; for expansion: (i) gastric/gastroesophageal junction tumor, intolerant to/progressed after first-line treatment, and no prior anti-programmed cell death receptor-1 (PD-1)/programmed death-ligand 1 (PD-L1) therapy; (ii) bladder/urothelial tumor, intolerant to/progressed after first-line cisplatin-based chemotherapy, and no prior anti-PD-1/PD-L1 therapy; (iii) non-small-cell lung cancer (NSCLC) with …

Radiotherapy For Elderly Patients With Glioblastoma: An Assessment Of Hypofractionation And Modern Treatment Techniques, Jennifer K. Matsui, Jiayi Huang, Et Al.

2020-Current year OA Pubs

Glioblastoma (GBM) is a disease with a poor prognosis. For decades, radiotherapy has played a critical role in the management of GBM. The standard of care radiation prescription is 60 Gy in 30 fractions, but landmark trials have historically excluded patients older than 70 years. Currently, there is considerable variation in the management of elderly patients with GBM. Shortened radiation treatment (hypofractionated) regimens have been explored since conventional treatment schedules are lengthy and many elderly patients have functional, cognitive, and social limitations. Clinical trials have demonstrated the effectiveness of hypofractionated radiotherapy (40 Gy in 15 fractions) to treat elderly or …

Lung Allograft Standardized Histological Analysis (Lasha) Template: A Research Consensus Proposal, Fiorella Calabrese, Chieh-Yu Lin, Et Al.

2020-Current year OA Pubs

BACKGROUND: Routine monitoring of lung-transplanted patients is crucial for the identification of immunological and non-immunological complications. Determining the etiology of acute allograft dysfunction, particularly in alloimmune-mediated disorders, relies heavily on the lung biopsy with histopathologic analysis. Standardization of the pathologic diagnosis of rejection (e.g., cellular and antibody-mediated) is based on consensus statements and guidelines, indicating the importance of a multidisciplinary approach to achieve a definitive etiological diagnosis. In addition to these statements and guidelines, refinements and standardizations are feasible through systematic analysis morphological, immunophenotypic and molecular alterations observed in transbronchial biopsies. This study is to identify key morphologic features to …

Incisionless Targeted Adeno-Associated Viral Vector Delivery To The Brain By Focused Ultrasound-Mediated Intranasal Administration, Dezhuang Ye, Jinyun Yuan, Yaoheng Yang, Yimei Yue, Zhongtao Hu, Siaka Fadera, Hong Chen

2020-Current year OA Pubs

BACKGROUND: Adeno-associated viral (AAV) vectors are currently the leading platform for gene therapy with the potential to treat a variety of central nervous system (CNS) diseases. There are numerous methods for delivering AAVs to the CNS, such as direct intracranial injection (DI), intranasal delivery (IN), and intravenous injection with focused ultrasound-induced blood-brain barrier disruption (FUS-BBBD). However, non-invasive and efficient delivery of AAVs to the brain with minimal systemic toxicity remain the major challenge. This study aims to investigate the potential of focused ultrasound-mediated intranasal delivery (FUSIN) in AAV delivery to brain.

METHODS: Mice were intranasally administered with AAV5 encoding enhanced …

Acute Glycogen Synthase Kinase-3 Inhibition Modulates Human Cardiac Conduction, Gang Li, Brittany D Brumback, Lei Huang, David M Zhang, Tiankai Yin, Catherine E Lipovsky, Stephanie C Hicks, Jesus Jimenez, Patrick M Boyle, Stacey L Rentschler

2020-Current year OA Pubs

Glycogen synthase kinase 3 (GSK-3) inhibition has emerged as a potential therapeutic target for several diseases, including cancer. However, the role for GSK-3 regulation of human cardiac electrophysiology remains ill-defined. We demonstrate that SB216763, a GSK-3 inhibitor, can acutely reduce conduction velocity in human cardiac slices. Combined computational modeling and experimental approaches provided mechanistic insight into GSK-3 inhibition-mediated changes, revealing that decreased sodium-channel conductance and tissue conductivity may underlie the observed phenotypes. Our study demonstrates that GSK-3 inhibition in human myocardium alters electrophysiology and may predispose to an arrhythmogenic substrate; therefore, monitoring for adverse arrhythmogenic events could be considered.

Functional Characterization Of Enhancer Activity During A Long Terminal Repeat's Evolution, Alan Y Du, Xiaoyu Zhuo, Vasavi Sundaram, Nicholas O Jensen, Hemangi G Chaudhari, Nancy L Saccone, Barak A Cohen, Ting Wang

2020-Current year OA Pubs

Many transposable elements (TEs) contain transcription factor binding sites and are implicated as potential regulatory elements. However, TEs are rarely functionally tested for regulatory activity, which in turn limits our understanding of how TE regulatory activity has evolved. We systematically tested the human LTR18A subfamily for regulatory activity using massively parallel reporter assay (MPRA) and found AP-1- and CEBP-related binding motifs as drivers of enhancer activity. Functional analysis of evolutionarily reconstructed ancestral sequences revealed that LTR18A elements have generally lost regulatory activity over time through sequence changes, with the largest effects occurring owing to mutations in the AP-1 and CEBP …

Congenital Aneurysm Of The Muscular Interventricular Septum Associated With Bifascicular Block, Hoang H. Nguyen, Patrick Y. Jay

2020-Current year OA Pubs

Isolated congenital aneurysm of the muscular interventricular septum is rare. We present a patient with congenital aneurysm of the basal muscular ventricular septum, who also develops conduction abnormalities with first-degree heart block, right bundle branch block, and left posterior fascicular block. The case details the natural history of the aneurysm over a 10-year period follow-up during which the patient remained asymptomatic with evidence of regression of the aneurysm. Given the aneurysm's location close to the proximal right bundle and left posterior fascicle, we believe that the cause for the aneurysm also injured both fascicles resulting in bifascicular block. The diagnosis …