Digital Commons Network^™

Continuous Representations Of Speed By Striatal Medium Spiny Neurons, Wambura C. Fobbs, Sebastiano Bariselli, Julia A. Licholai, Nanami L. Miyazaki, Bridget A. Matikainen-Ankney, Meaghan C. Creed, Alexxai V. Kravitz

Open Access Publications

The striatum is critical for controlling motor output. However, it remains unclear how striatal output neurons encode and facilitate movement. A prominent theory suggests that striatal units encode movements in bursts of activity near specific events, such as the start or end of actions. These bursts are theorized to gate or permit specific motor actions, thereby encoding and facilitating complex sequences of actions. An alternative theory has suggested that striatal neurons encode continuous changes in sensory or motor information with graded changes in firing rate. Supporting this theory, many striatal neurons exhibit such graded changes without bursting near specific actions. …

Trpm3_Mir-204: A Complex Locus For Eye Development And Disease, Alan Shiels

Open Access Publications

First discovered in a light-sensitive retinal mutant of Drosophila, the transient receptor potential (TRP) superfamily of non-selective cation channels serve as polymodal cellular sensors that participate in diverse physiological processes across the animal kingdom including the perception of light, temperature, pressure, and pain. TRPM3 belongs to the melastatin sub-family of TRP channels and has been shown to function as a spontaneous calcium channel, with permeability to other cations influenced by alternative splicing and/or non-canonical channel activity. Activators of TRPM3 channels include the neurosteroid pregnenolone sulfate, calmodulin, phosphoinositides, and heat, whereas inhibitors include certain drugs, plant-derived metabolites, and G-protein subunits. Activation …

Clinical Care Recommendations For Cardiologists Treating Adults With Myotonic Dystrophy, Elizabeth M Mcnally, Douglas L Mann, Yigal Pinto, Deepak Bhakta, Gordon Tomaselli, Saman Nazarian, William J Groh, Takuhisa Tamura, Denis Duboc, Hideki Itoh, Leah Hellerstein, Pradeep P A Mammen

Open Access Publications

Myotonic dystrophy is an inherited systemic disorder affecting skeletal muscle and the heart. Genetic testing for myotonic dystrophy is diagnostic and identifies those at risk for cardiac complications. The 2 major genetic forms of myotonic dystrophy, type 1 and type 2, differ in genetic etiology yet share clinical features. The cardiac management of myotonic dystrophy should include surveillance for arrhythmias and left ventricular dysfunction, both of which occur in progressive manner and contribute to morbidity and mortality. To promote the development of care guidelines for myotonic dystrophy, the Myotonic Foundation solicited the input of care experts and organized the drafting …

Cryptococcus Neoformans Chitin Synthase 3 Plays A Critical Role In Dampening Host Inflammatory Responses, Camaron R Hole, Woei C Lam, Rajendra Upadhya, Jennifer K Lodge

Open Access Publications

No abstract provided.

Proof-Of-Concept Study Of The Efficacy Of A Microbiota-Directed Complementary Food Formulation (Mdcf) For Treating Moderate Acute Malnutrition, Ishita Mostafa, Naila Nurun Nahar, Md Munirul Islam, Sayeeda Huq, Mahfuz Mustafa, Michael Barratt, Jeffrey I Gordon, Tahmeed Ahmed

Open Access Publications

BACKGROUND: Childhood undernutrition remains a significant global health challenge accounting for over half of all under 5 child mortality. Moderate acute malnutrition (MAM), which leads to wasting [weight-for-length z-scores (WLZ) between - 2 and - 3], affects 33 million children under 5 globally and more than 2 million in Bangladesh alone. We have previously reported that acute malnutrition in this population is associated with gut microbiota immaturity, and in a small, 1-month pre-proof-of-concept (POC) study demonstrated that a microbiota-directed complementary food formulation (MDCF-2) was able to repair this immaturity, promote weight gain and increase plasma biomarkers and mediators of healthy …

Myocardial B Cells Are A Subset Of Circulating Lymphocytes With Delayed Transit Through The Heart, Luigi Adamo, Cibele Rocha-Resende, Chieh-Yu Lin, Sarah Evans, Jesse Williams, Hao Dun, Wenjun Li, Cedric Mpoy, Prabhakar S Andhey, Buck E Rogers, Kory Lavine, Daniel Kreisel, Maxim Artyomov, Gwendalyn J Randolph, Douglas L Mann

Open Access Publications

Current models of B lymphocyte biology posit that B cells continuously recirculate between lymphoid organs, without accumulating in peripheral healthy tissues. Nevertheless, B lymphocytes are one of the most prevalent leukocyte populations in the naive murine heart. To investigate this apparent inconsistency in the literature, we conducted a systematic analysis of myocardial B cell ontogeny, trafficking dynamics, histology, and gene expression patterns. We found that myocardial B cells represent a subpopulation of circulating B cells that make close contact with the microvascular endothelium of the heart and arrest their transit as they pass through the heart. The vast majority ( …

Dnmt3b Ablation Impairs Fracture Repair Through Upregulation Of Notch Pathway, Jun Ying, Taotao Xu, Cuicui Wang, Hongting Jin, Peijian Tong, Jianjun Guan, Yousef Abu-Amer, Regis O'Keefe, Jie Shen

Open Access Publications

We previously established that DNA methyltransferase 3b (Dnmt3b) is the sole Dnmt responsive to fracture repair and that Dnmt3b expression is induced in progenitor cells during fracture repair. In the current study, we confirmed that Dnmt3b ablation in mesenchymal progenitor cells (MPCs) resulted in impaired endochondral ossification, delayed fracture repair, and reduced mechanical strength of the newly formed bone in Prx1-Cre;Dnmt3bf/f (Dnmt3bPrx1) mice. Mechanistically, deletion of Dnmt3b in MPCs led to reduced chondrogenic and osteogenic differentiation in vitro. We further identified Rbpjκ as a downstream target of Dnmt3b in MPCs. In fact, we located 2 Dnmt3b binding sites in the …

Derivation Of Trophoblast Stem Cells From Naïve Human Pluripotent Stem Cells, Chen Dong, Mariana Beltcheva, Paul Gontarz, Bo Zhang, Pooja Popli, Laura A. Fischer, Shafqat A Khan, Kyoung-Mi Park, Eun-Ja Yoon, Xiaoyun Xing, Ramakrishna Kommagani, Ting Wang, Lilianna Solnica-Krezel, Thorold W. Theunissen

Open Access Publications

Naïve human pluripotent stem cells (hPSCs) provide a unique experimental platform of cell fate decisions during pre-implantation development, but their lineage potential remains incompletely characterized. As naïve hPSCs share transcriptional and epigenomic signatures with trophoblast cells, it has been proposed that the naïve state may have enhanced predisposition for differentiation along this extraembryonic lineage. Here we examined the trophoblast potential of isogenic naïve and primed hPSCs. We found that naïve hPSCs can directly give rise to human trophoblast stem cells (hTSCs) and undergo further differentiation into both extravillous and syncytiotrophoblast. In contrast, primed hPSCs do not support hTSC derivation, but …

Encephalitic Alphaviruses Exploit Caveola-Mediated Transcytosis At The Blood-Brain Barrier For Central Nervous System Entry, Hamid Salimi, Matthew D Cain, Xiaoping Jiang, Robyn A Roth, Wandy L Beatty, Chengqun Sun, William B Klimstra, Jianghui Hou, Robyn S Klein

Open Access Publications

Venezuelan and western equine encephalitis viruses (VEEV and WEEV, respectively) invade the central nervous system (CNS) early during infection, via neuronal and hematogenous routes. While viral replication mediates host shutoff, including expression of type I interferons (IFN), few studies have addressed how alphaviruses gain access to the CNS during established infection or the mechanisms of viral crossing at the blood-brain barrier (BBB). Here, we show that hematogenous dissemination of VEEV and WEEV into the CNS occurs via caveolin-1 (Cav-1)-mediated transcytosis (Cav-MT) across an intact BBB, which is impeded by IFN and inhibitors of RhoA GTPase. Use of reporter and nonreplicative …

A Qualitative Study Of Physician Perspectives On Adaptation To Electronic Health Records, Cynthia J Sieck, Nicole Pearl, Tiffani J Bright, Po-Yin Yen

Open Access Publications

BACKGROUND: Electronic Health Records (EHRs) have the potential to improve many aspects of care and their use has increased in the last decade. Because of this, acceptance and adoption of EHRs is less of a concern than adaptation to use. To understand this issue more deeply, we conducted a qualitative study of physician perspectives on EHR use to identify factors that facilitate adaptation.

METHODS: We conducted semi-structured interviews with 9 physicians across a range of inpatient disciplines at a large Academic Medical Center. Interviews were conducted by phone, lasting approximately 30 min, and were transcribed verbatim for analysis. We utilized …

Spatiotemporal Dynamics Of Multi-Vesicular Release Is Determined By Heterogeneity Of Release Sites Within Central Synapses, Dario Maschi, Vitaly A. Klyachko

Open Access Publications

A synaptic active zone (AZ) can release multiple vesicles in response to an action potential. This multi-vesicular release (MVR) occurs at most synapses, but its spatiotemporal properties are unknown. Nanoscale-resolution detection of individual release events in hippocampal synapses revealed unprecedented heterogeneity among vesicle release sites within a single AZ, with a gradient of release probability decreasing from AZ center to periphery. Parallel to this organization, MVR events preferentially overlap with uni-vesicular release (UVR) events at sites closer to an AZ center. Pairs of fusion events comprising MVR are also not perfectly synchronized, and the earlier event tends to occur closer …

Neuronal Activity In The Primate Amygdala During Economic Choice, Ahmad Jezzini, Camillo Padoa-Schioppa

Open Access Publications

Multiple lines of evidence link economic choices to the orbitofrontal cortex (OFC), but other brain regions may contribute to the computation and comparison of economic values. A particularly strong candidate is the basolateral amygdala (BLA). Amygdala lesions impair performance in reinforcer devaluation tasks, suggesting that the BLA contributes to value computation. Furthermore, previous studies of the BLA have found neuronal activity consistent with a value representation. Here, we recorded from the BLA of two male rhesus macaques choosing between different juices. Offered quantities varied from trial to trial, and relative values were inferred from choices. Approximately one-third of BLA cells …

Quantitative Trait Variation In Asd Probands And Toddler Sibling Outcomes At 24 Months, Jessica B Girault, Kelly N Botteron, John N Constantino, Et Al

Open Access Publications

BACKGROUND: Younger siblings of children with autism spectrum disorder (ASD) are at increased likelihood of receiving an ASD diagnosis and exhibiting other developmental concerns. It is unknown how quantitative variation in ASD traits and broader developmental domains in older siblings with ASD (probands) may inform outcomes in their younger siblings.

METHODS: Participants included 385 pairs of toddler siblings and probands from the Infant Brain Imaging Study. ASD probands (mean age 5.5 years, range 1.7 to 15.5 years) were phenotyped using the Autism Diagnostic Interview-Revised (ADI-R), the Social Communication Questionnaire (SCQ), and the Vineland Adaptive Behavior Scales, Second Edition (VABS-II). Siblings …

Prevalence And Family-Related Factors Associated With Suicidal Ideation, Suicide Attempts, And Self-Injury In Children Aged 9 To 10 Years, Danielle C. Deville, Diana Whalen, Florence J. Breslin, Amanda S. Morris, Sahib S. Khalsa, Martin P. Paulus, Deanna M. Barch

Open Access Publications

Importance: Although suicide is a leading cause of death for children in the United States, and the rate of suicide in childhood has steadily increased, little is known about suicidal ideation and behaviors in children.

Objective: To assess the overall prevalence of suicidal ideation, suicide attempts, and nonsuicidal self-injury, as well as family-related factors associated with suicidality and self-injury among preadolescent children.

Design, Setting, and Participants: Cross-sectional study using retrospective analysis of the baseline sample from the Adolescent Brain Cognitive Development (ABCD) study. This multicenter investigation used an epidemiologically informed school-based recruitment strategy, with consideration of the demographic composition of …

Mechanism Of Differential Zika And Dengue Virus Neutralization By A Public Antibody Lineage Targeting The Diii Lateral Ridge, Haiyan Zhao, Lily Xu, Robin Bombardi, Rachel Nargi, Zengqin Deng, John M. Errico, Christopher A. Nelson, Kimberly A. Dowd, Theodore C. Pierson, James E. Crowe, Michael S. Diamond, Daved H. Fremont

Open Access Publications

We previously generated a panel of human monoclonal antibodies (mAbs) against Zika virus (ZIKV) and identified one, ZIKV-116, that shares germline usage with mAbs identified in multiple donors. Here we show that ZIKV-116 interferes with ZIKV infection at a post-cellular attachment step by blocking viral fusion with host membranes. ZIKV-116 recognizes the lateral ridge of envelope protein domain III, with one critical residue varying between the Asian and African strains responsible for differential binding affinity and neutralization potency (E393D). ZIKV-116 also binds to and cross-neutralizes some dengue virus serotype 1 (DENV1) strains, with genotype-dependent inhibition explained by variation in a …

Inhibition Of Rev-Erbs Stimulates Microglial Amyloid-Beta Clearance And Reduces Amyloid Plaque Deposition In The 5xfad Mouse Model Of Alzheimer's Disease, Jiyeon Lee, Do Eon Kim, Percy Griffin, Patrick W Sheehan, Dong-Hou Kim, Erik S Musiek, Seung-Yong Yoon

Open Access Publications

A promising new therapeutic target for the treatment of Alzheimer's disease (AD) is the circadian system. Although patients with AD are known to have abnormal circadian rhythms and suffer sleep disturbances, the role of the molecular clock in regulating amyloid-beta (Aβ) pathology is still poorly understood. Here, we explored how the circadian repressors REV-ERBα and β affected Aβ clearance in mouse microglia. We discovered that, at Circadian time 4 (CT4), microglia expressed higher levels of the master clock protein BMAL1 and more rapidly phagocytosed fibrillary Aβ

Emerging Priorities For Hiv Service Delivery, Nathan Ford, Elvin Geng, Et Al.

Open Access Publications

Nathan Ford and co-authors discuss global priorities in the provision of HIV prevention and treatment services.

Comparison Of Symptomatic And Functional Responses To Vagus Nerve Stimulation In Anthem-Hf, Inovate-Hf, And Nectar-Hf, Inder S Anand, Marvin A Konstam, Helmut U Klein, Douglas L Mann, Jeffrey L Ardell, Douglas D Gregory, Joseph M Massaro, Imad Libbus, Lorenzo A Dicarlo, John James E Udelson, Javed Butler, John D Parker, John R Teerlink

Open Access Publications

AIMS: Clinical studies of vagal nerve stimulation (VNS) for heart failure with reduced ejection fraction have had mixed results to date. We sought to compare VNS delivery and associated changes in symptoms and function in autonomic regulation therapy via left or right cervical vagus nerve stimulation in patients with chronic heart failure (ANTHEM-HF), increase of vagal tone in heart failure (INOVATE-HF), and neural cardiac therapy for heart failure (NECTAR-HF) for hypothesis generation.

METHODS AND RESULTS: Descriptive statistics were used to analyse data from the public domain for differences in proportions using Pearson's chi-square test, differences in mean values using Student's …

Hardly Vacuous: The Parasitophorous Vacuolar Membrane Of Malaria Parasites, Daniel E Goldberg, Joshua Zimmerberg

Open Access Publications

When a malaria parasite invades a host erythrocyte it pushes itself in and invaginates a portion of the host membrane, thereby sealing itself inside and establishing itself in the resulting vacuole. The parasitophorous vacuolar membrane (PVM) that surrounds the parasite is modified by the parasite, using its secretory organelles. To survive within this enveloping membrane, the organism must take in nutrients, secrete wastes, export proteins into the host cell, and eventually egress. Here, we review current understanding of the unique solutions Plasmodium has evolved to these challenges and discuss the remaining questions.

Circulating Ceramide Ratios And Risk Of Vascular Brain Aging And Dementia, Emer R Mcgrath, Jayandra J Himali, Vanessa Xanthakis, Meredith S Duncan, Jean E Schaffer, Daniel S Ory, Linda R Peterson, Charles Decarli, Matthew P Pase, Claudia L Satizabal, Ramachandran S Vasan, Alexa S Beiser, Sudha Seshadri

Open Access Publications

BACKGROUND: We determined the association between ratios of plasma ceramide species of differing fatty-acyl chain lengths and incident dementia and Alzheimer's disease (AD) dementia in a large, community-based sample.

METHODS: We measured plasma ceramide levels in 1892 [54% women, mean age 70.1 (SD 6.9) yr.] dementia-free Framingham Offspring Study cohort participants between 2005 and 2008. We related ratios of very long-chain (C24:0, C22:0) to long-chain (C16:0) ceramides to subsequent risk of incident dementia and AD dementia. Structural MRI brain measures were included as secondary outcomes.

RESULTS: During a median 6.5 year follow-up, 81 participants developed dementia, of whom 60 were …

Mboat7 Down-Regulation By Hyper-Insulinemia Induces Fat Accumulation In Hepatocytes, Marica Meroni, Nicholas O Davidson, Et Al

Open Access Publications

BACKGROUND: Naturally occurring variation in Membrane-bound O-acyltransferase domain-containing 7 (MBOAT7), encoding for an enzyme involved in phosphatidylinositol acyl-chain remodelling, has been associated with fatty liver and hepatic disorders. Here, we examined the relationship between hepatic Mboat7 down-regulation and fat accumulation.

METHODS: Hepatic MBOAT7 expression was surveyed in 119 obese individuals and in experimental models. MBOAT7 was acutely silenced by antisense oligonucleotides in C57Bl/6 mice, and by CRISPR/Cas9 in HepG2 hepatocytes.

FINDINGS: In obese individuals, hepatic MBOAT7 mRNA decreased from normal liver to steatohepatitis, independently of diabetes, inflammation and MBOAT7 genotype. Hepatic MBOAT7 levels were reduced in murine models of fatty …

The Prevalence And Clinical Implications Of Comorbid Back Pain In Shoulder Instability: A Multicenter Orthopaedic Outcomes Network (Moon) Shoulder Instability Cohort Study, Kevin Cronin, Robert Brophy, Matthew Smith, Rick Wright, Et Al

Open Access Publications

Background: Understanding predictors of pain is critical, as recent literature shows that comorbid back pain is an independent risk factor for worse functional and patient-reported outcomes (PROs) as well as increased opioid dependence after total joint arthroplasty.

Purpose/Hypothesis: The purpose of this study was to evaluate whether comorbid back pain would be predictive of pain or self-reported instability symptoms at the time of stabilization surgery. We hypothesized that comorbid back pain will correlate with increased pain at the time of surgery as well as with worse scores on shoulder-related PRO measures.

Study Design: Cross-sectional study; Level of evidence, 3.

Methods: …

2019 Hrs/Ehra/Aphrs/Lahrs Expert Consensus Statement On Catheter Ablation Of Ventricular Arrhythmias: Executive Summary, Edmond M Cronin, Phillip Cuculich, Et Al

Open Access Publications

Ventricular arrhythmias are an important cause of morbidity and mortality and come in a variety of forms, from single premature ventricular complexes to sustained ventricular tachycardia and fibrillation. Rapid developments have taken place over the past decade in our understanding of these arrhythmias and in our ability to diagnose and treat them. The field of catheter ablation has progressed with the development of new methods and tools, and with the publication of large clinical trials. Therefore, global cardiac electrophysiology professional societies undertook to outline recommendations and best practices for these procedures in a document that will update and replace the …

Direct And Indirect Costs Of Infectious Conjunctivitis In A Commercially Insured Population In The United States, Jay S Pepose, Sujata P Sarda, Wendy Y Cheng, Nora Mccormick, Hoi Ching Cheung, Priyanka Bobbili, Corey Joseph, Mei Sheng Duh

Open Access Publications

PURPOSE: To assess the direct and indirect costs of infectious conjunctivitis and quantify medical costs due to conjunctivitis transmission in families.

METHODS: In this retrospective claims analysis from the OptumHealth Care Solutions, Inc. database (1998-2016), beneficiaries with or without at least one diagnosis of infectious conjunctivitis were identified. Direct and indirect costs (in 2016 US$) during the 60 days post conjunctivitis diagnosis (or imputed date for controls) were compared using cost differences in linear regressions. For transmission cost analysis, the total cost of each conjunctivitis episode was the sum of the primary episode (seed patient) and the secondary episode (infected …

Endoscopic Mucosal Resection Of A Gastric Perineurioma, Michael Weaver, Rehan Rais, Jon Ritter, Vladimir Kushnir

Open Access Publications

No abstract provided.

Hope On The Horizon: Novel Fungal Treatments In Development, Adriana M. Rauseo, Ariella Coler-Reilly, Lindsey Larson, Andrej Spec

Open Access Publications

The treatment of invasive fungal infections remains challenging due to limitations in currently available antifungal therapies including toxicity, interactions, restricted routes of administration, and drug resistance. This review focuses on novel therapies in clinical development, including drugs and a device. These drugs have novel mechanisms of action to overcome resistance, and some offer new formulations providing distinct advantages over current therapies to improve safety profiles and reduce interactions. Among agents that target the cell wall, 2 glucan synthesis inhibitors are discussed (rezafungin and ibrexafungerp), as well as fosmanogepix and nikkomycin Z. Agents that target the cell membrane include 3 fourth-generation …

Phase Ib/Ii Study Combining Tosedostat With Capecitabine In Patients With Advanced Pancreatic Adenocarcinoma, Patrick Grierson, Andrea Teague, Rama Suresh, Kian-Huat Lim, Manik Amin, Katrina Pedersen, Benjamin Tan, Jesse Huffman, Nick Boice, Lingling Du, Jingxia Liu, A. Craig Lockhart, Andrea Wang-Gillam

Open Access Publications

Background: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with limited therapeutic options. We evaluated the safety and efficacy of the aminopeptidase inhibitor tosedostat with capecitabine in advanced PDAC.

Methods: We conducted a phase Ib/II trial of tosedostat with capecitabine as second-line therapy for advanced PDAC. Planned enrollment was 36 patients. Eligible patients were treated with capecitabine 1,000 mg/m

Results: Sixteen patients were enrolled. Tosedostat 120 mg oral twice daily with capecitabine 1,000 mg/m

Conclusions: Tosedostat with capecitabine displayed tolerable toxicity, and prolonged disease control in a subset of patients. These data encourage further exploration of aminopeptidase inhibitors in pancreatic …

Perioperative Care Of The Geriatric Patient For Noncardiac Surgery, Jonathan D Wolfe, Natasha K Wolfe, Michael W Rich

Open Access Publications

Adults age 65 and over are the fastest growing segment of the population in the United States and around the world. As the size of this population expands, the number of older adults referred for surgical procedures will continue to increase. Due to the physiologic changes of aging and the increased frequency of comorbidities, older adults are at increased risk for adverse outcomes, and perioperative care is inherently more complex than in younger individuals. In this review, we discuss the physiologic changes of aging relevant to the surgical patient, comprehensive preoperative assessment, and postoperative management of common complications in older …

Parental Deployment And Distress, And Adolescent Disordered Eating In Prevention-Seeking Military Dependents, M K Higgins Neyland, Denise E Wilfley, Et Al

Open Access Publications

OBJECTIVE: Parental military deployment can lead to stress in the family system due to concerns about the deployed service-member's safety and increased responsibilities for those not deployed. Parent-related stress can impact adolescent disordered eating. Given the important role that stress plays in disordered eating and obesity, it is crucial to understand the impacts of unique stressors to which vulnerable populations are exposed.

METHOD: We studied 126 adolescent (14.3 ± 1.6 years; 59.5% girls; 44.4% non-Hispanic White; BMI-z, 1.91 ± .39) military dependents prior to entering an obesity and binge-eating disorder prevention trial. The Eating Disorder Examination was used to assess …

Targeting Refractory Sarcomas And Malignant Peripheral Nerve Sheath Tumors In A Phase I/Ii Study Of Sirolimus In Combination With Ganetespib (Sarc023), Aerang Kim, Brian A. Van Tine, Et Al

Open Access Publications

No abstract provided.