Digital Commons Network^™

Cns Myelination And Remyelination Depend On Fatty Acid Synthesis By Oligodendrocytes, Penelope Dimas, Laura Montani, Jorge A. Pereira, Daniel Moreno, Martin Trötzmüller, Joanne Gerber, Clay F. Semenkovich, Harald C. Köfeler, Ueli Suter

Open Access Publications

Oligodendrocytes (OLs) support neurons and signal transmission in the central nervous system (CNS) by enwrapping axons with myelin, a lipid-rich membrane structure. We addressed the significance of fatty acid (FA) synthesis in OLs by depleting FA synthase (FASN) from OL progenitor cells (OPCs) in transgenic mice. While we detected no effects in proliferation and differentiation along the postnatal OL lineage, we found that FASN is essential for accurate myelination, including myelin growth. Increasing dietary lipid intake could partially compensate for the FASN deficiency. Furthermore, FASN contributes to correct myelin lipid composition and stability of myelinated axons. Moreover, we depleted FASN …

Cystine/Glutamate Antiporter (Xct) Is Required For Chief Cell Plasticity After Gastric Injury, Anne R Meyer, Amy C Engevik, Spencer G Willet, Janice A Williams, Yong Zou, Pierre P Massion, Jason C Mills, Eunyoung Choi, James R Goldenring

Open Access Publications

BACKGROUND & AIMS: Many differentiated epithelial cell types are able to reprogram in response to tissue damage. Although reprogramming represents an important physiological response to injury, the regulation of cellular plasticity is not well understood. Damage to the gastric epithelium initiates reprogramming of zymogenic chief cells into a metaplastic cell lineage known as spasmolytic polypeptide-expressing metaplasia (SPEM). The present study seeks to identify the role of xCT, a cystine/glutamate antiporter, in chief cell reprogramming after gastric injury. We hypothesize that xCT-dependent reactive oxygen species (ROS) detoxification is required for the reprogramming of chief cells into SPEM.

METHODS: Sulfasalazine (an xCT …

Comparison Of Opioid Prescribing By Dentists In The United States And England, Katie J. Suda, Michael J. Durkin, Gregory S. Calip, Walid F. Gellad, Hajwa Kim, Peter B. Lockhart, Susan A. Rowan, Martin H. Thornhill

Open Access Publications

Importance: The United States consumes most of the opioids worldwide despite representing a small portion of the world's population. Dentists are one of the most frequent US prescribers of opioids despite data suggesting that nonopioid analgesics are similarly effective for oral pain. While oral health and dentist use are generally similar between the United States and England, it is unclear how opioid prescribing by dentists varies between the 2 countries.

Objective: To compare opioid prescribing by dentists in the United States and England.

Design, Setting, and Participants: Cross-sectional study of prescriptions for opioids dispensed from outpatient pharmacies and health care …

Partial Adaptation To The Value Range In The Macaque Orbitofrontal Cortex, Katherine E. Conen, Camillo Padoa-Schioppa

Open Access Publications

Values available for choice in different behavioral contexts can vary immensely. To compensate for this variability, neuronal circuits underlying economic decisions undergo adaptation. In orbitofrontal cortex (OFC), neurons encode the subjective value of offered and chosen goods in a quasilinear way. Previous experiments found that the gain of the encoding is lower when the value range is wider. However, the parameters OFC neurons adapted to remained unclear. Furthermore, previous studies did not examine additive changes in neuronal responses. Computational considerations indicate that these factors can directly impact choice behavior. Here we investigated how OFC neurons adapt to changes in the …

Genome-Wide Association Study In Finnish Twins Highlights The Connection Between Nicotine Addiction And Neurotrophin Signaling Pathway, Jenni Hällfors, Teemu Palviainen, Ida Surakka, Richa Gupta, Jadwiga Buchwald, Anu Raevuori, Samuli Ripatti, Tellervo Korhonen, Pekka Jousilahti, Pamela A F Madden, Jaakko Kaprio, Anu Loukola

Open Access Publications

The heritability of nicotine dependence based on family studies is substantial. Nevertheless, knowledge of the underlying genetic architecture remains meager. Our aim was to identify novel genetic variants responsible for interindividual differences in smoking behavior. We performed a genome-wide association study on 1715 ever smokers ascertained from the population-based Finnish Twin Cohort enriched for heavy smoking. Data imputation used the 1000 Genomes Phase I reference panel together with a whole genome sequence-based Finnish reference panel. We analyzed three measures of nicotine addiction-smoking quantity, nicotine dependence and nicotine withdrawal. We annotated all genome-wide significant SNPs for their functional potential. First, we …

Threat Sensitivity Is Associated With The Healthcare Source Used Most Often: Doctor's Office, Emergency Room, Or None At All, Stephen Ristvedt, Kathryn Trinkaus, Erika Waters, Aimee James

Open Access Publications

A significant proportion of American adults do not have a regular source of healthcare and the reasons for this shortfall are not fully understood. The objective of this study was to examine the relationship between individual differences in threat sensitivity and healthcare utilization in a survey of 483 African American men. Demographics, psychological characteristics, and health behaviors were assessed. The primary outcomes were: 1) most frequent source of healthcare utilization (doctor's office or clinic vs. emergency room vs. no place), and 2) frequency of healthcare utilization (one or more vs. no healthcare visits in the previous year). Data were analyzed …

Reaching The End Of The Line: Urinary Tract Infections, Kevin O Tamadonfar, Natalie S Omattage, Caitlin N Spaulding, Scott J Hultgren

Open Access Publications

Urinary tract infections (UTIs) cause a substantial health care burden. UTIs (i) are most often caused by uropathogenic

Brain Tumors In Neurofibromatosis Type 1, Amanda De Andrade Costa, David H Gutmann

Open Access Publications

As a cancer predisposition syndrome, individuals with neurofibromatosis type 1 (NF1) are at increased risk for the development of both benign and malignant tumors. One of the most common locations for these cancers is the central nervous system, where low-grade gliomas predominate in children. During early childhood, gliomas affecting the optic pathway are most frequently encountered, whereas gliomas of the brainstem and other locations are observed in slightly older children. In contrast, the majority of gliomas arising in adults with NF1 are malignant cancers, typically glioblastoma, involving the cerebral hemispheres. Our understanding of the pathogenesis of NF1-associated gliomas has been …

Comparison Of Best Versus Worst Clinical Outcomes For Adult Cervical Deformity Surgery, Justin S Smith, Michael Kelly, Munish Gupta, Et Al.

Open Access Publications

Study Design: Retrospective cohort study.

Objective: Factors that predict outcomes for adult cervical spine deformity (ACSD) have not been well defined. To compare ACSD patients with best versus worst outcomes.

Methods: This study was based on a prospective, multicenter observational ACSD cohort. Best versus worst outcomes were compared based on Neck Disability Index (NDI), Neck Pain Numeric Rating Scale (NP-NRS), and modified Japanese Orthopaedic Association (mJOA) scores.

Results: Of 111 patients, 80 (72%) had minimum 1-year follow-up. For NDI, compared with best outcome patients (n = 28), worst outcome patients (n = 32) were more likely to have had a …

High-Density Diffuse Optical Tomography For Imaging Human Brain Function, Muriah D Wheelock, Joseph P Culver, Adam T Eggebrecht

Open Access Publications

This review describes the unique opportunities and challenges for noninvasive optical mapping of human brain function. Diffuse optical methods offer safe, portable, and radiation free alternatives to traditional technologies like positron emission tomography or functional magnetic resonance imaging (fMRI). Recent developments in high-density diffuse optical tomography (HD-DOT) have demonstrated capabilities for mapping human cortical brain function over an extended field of view with image quality approaching that of fMRI. In this review, we cover fundamental principles of the diffusion of near infrared light in biological tissue. We discuss the challenges involved in the HD-DOT system design and implementation that must …

Regulation Of Cilia Abundance In Multiciliated Cells, Rashmi Nanjundappa, Dong Kong, Kyuhwan Shim, Tim Stearns, Steven L. Brody, Jadranka Loncarek, Moe R. Mahjoub

Open Access Publications

Multiciliated cells (MCC) contain hundreds of motile cilia used to propel fluid over their surface. To template these cilia, each MCC produces between 100-600 centrioles by a process termed centriole amplification. Yet, how MCC regulate the precise number of centrioles and cilia remains unknown. Airway progenitor cells contain two parental centrioles (PC) and form structures called deuterosomes that nucleate centrioles during amplification. Using an ex vivo airway culture model, we show that ablation of PC does not perturb deuterosome formation and centriole amplification. In contrast, loss of PC caused an increase in deuterosome and centriole abundance, highlighting the presence of …

Mutant Huntingtin Enhances Activation Of Dendritic Kv4 K+ Channels In Striatal Spiny Projection Neurons, Luis Carrillo-Reid, Michelle Day, Zhong Xie, Alexandria E. Melendez, Jyothisri Kondapalli, Joshua L. Plotkin, David L. Wokosin, Yu Chen, Geraldine J. Kress, Michael Kaplitt, Ema Ilijic, Jaime N. Guzman, C Savio Chan, D James Surmeier

Open Access Publications

Huntington's disease (HD) is initially characterized by an inability to suppress unwanted movements, a deficit attributable to impaired synaptic activation of striatal indirect pathway spiny projection neurons (iSPNs). To better understand the mechanisms underlying this deficit, striatal neurons in ex vivo brain slices from mouse genetic models of HD were studied using electrophysiological, optical and biochemical approaches. Distal dendrites of iSPNs from symptomatic HD mice were hypoexcitable, a change that was attributable to increased association of dendritic Kv4 potassium channels with auxiliary KChIP subunits. This association was negatively modulated by TrkB receptor signaling. Dendritic excitability of HD iSPNs was rescued …

Systematic Sampling Of Adults As A Sensitive Means Of Detecting Persistence Of Lymphatic Filariasis Following Mass Drug Administration In Sri Lanka, Ramakrishna U. Rao, Sandhya D. Samarasekera, Kumara C. Nagodavithana, Manjula W. Punchihewa, Udaya S. B. Ranasinghe, Gary J. Weil

Open Access Publications

No abstract provided.

The Effect Of Bpifa1/Splunc1 Genetic Variation On Its Expression And Function In Asthmatic Airway Epithelium, Niccolette Schaefer, Mario Castro, Andrea M. Coverstone, Jonathan Boomer, Et Al

Open Access Publications

Bacterial permeability family member A1 (BPIFA1), also known as short palate, lung, and nasal epithelium clone 1 (SPLUNC1), is a protein involved in the antiinflammatory response. The goal of this study was to determine whether BPIFA1 expression in asthmatic airways is regulated by genetic variations, altering epithelial responses to type 2 cytokines (e.g., IL-13). Nasal epithelial cells from patients with mild to severe asthma were collected from the National Heart, Lung, and Blood Institute Severe Asthma Research Program centers, genotyped for rs750064, and measured for BPIFA1. To determine the function of rs750064, cells were cultured at air-liquid interface and treated …

Down Syndrome Mouse Models Have An Abnormal Enteric Nervous System, Ellen M Schill, Christina M Wright, Alisha Jamil, Jonathan M Lacombe, Randall J Roper, Robert O Heuckeroth

Open Access Publications

Children with trisomy 21 (Down syndrome [DS]) have a 130-fold increased incidence of Hirschsprung Disease (HSCR), a developmental defect where the enteric nervous system (ENS) is missing from distal bowel (i.e., distal bowel is aganglionic). Treatment for HSCR is surgical resection of aganglionic bowel, but many children have bowel problems after surgery. Post-surgical problems like enterocolitis and soiling are especially common in children with DS. To determine how trisomy 21 affects ENS development, we evaluated the ENS in two DS mouse models, Ts65Dn and Tc1. These mice are trisomic for many chromosome 21 homologous genes, including Dscam and Dyrk1a, which …

An Obligatory Role For Club Cells In Preventing Obliterative Bronchiolitis In Lung Transplants, Zhiyi Liu, Fuyi Liao, Davide Scozzi, Yuka Furuya, Kaitlyn N Pugh, Ramsey Hachem, Delphine L Chen, Marlene Cano, Jonathan M Green, Alexander S Krupnick, Daniel Kreisel, Anne Karina T Perl, Howard J Huang, Steven L Brody, Andrew E Gelman

Open Access Publications

Obliterative bronchiolitis (OB) is a poorly understood airway disease characterized by the generation of fibrotic bronchiolar occlusions. In the lung transplant setting, OB is a pathological manifestation of bronchiolitis obliterans syndrome (BOS), which is a major impediment to long-term recipient survival. Club cells play a key role in bronchiolar epithelial repair, but whether they promote lung transplant tolerance through preventing OB remains unclear. We determined if OB occurs in mouse orthotopic lung transplants following conditional transgene-targeted club cell depletion. In syngeneic lung transplants club cell depletion leads to transient epithelial injury followed by rapid club cell-mediated repair. In contrast, allogeneic …

Significance Of Her2 Protein Expression And Her2 Gene Amplification In Colorectal Adenocarcinomas, Xin-Yu Wang, Zhi-Xue Zheng, Yu Sun, Yan-Hua Bai, Yun-Fei Shi, Li-Xin Zhou, Yun-Feng Yao, Ai-Wen Wu, Deng-Feng Cao

Open Access Publications

BACKGROUND: Human epidermal growth factor receptor 2 (HER2) is an oncogenic driver, and a well-established therapeutic target in breast and gastric cancers. While the role of HER2 as a prognostic biomarker in colorectal adenocarcinomas (CRCs) remains uncertain, its relevance as a therapeutic target has been established. We undertook the present study to evaluate the frequency of HER2 expression in CRC and to correlate it with various clinicopathological variables.

AIM: To correlate HER2 protein expression and

METHODS: About 1195 consecutive surgically resected CRCs were analyzed by immunohistochemical staining (IHC) to assess HER2 protein expression, and 141 selected tumors were further evaluated …

Novel Parent-Of-Origin-Specific Differentially Methylated Loci On Chromosome 16, Katharina V Schulze, Przemyslaw Szafranski, Harry Lesmana, Robert J Hopkin, Aaron Hamvas, Jennifer A Wambach, Marwan Shinawi, Gladys Zapata, Claudia M B Carvalho, Qian Liu, Justyna A Karolak, James R Lupski, Neil A Hanchard, Paweł Stankiewicz

Open Access Publications

BACKGROUND: Congenital malformations associated with maternal uniparental disomy of chromosome 16, upd(16)mat, resemble those observed in newborns with the lethal developmental lung disease, alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV). Interestingly, ACDMPV-causative deletions, involving FOXF1 or its lung-specific upstream enhancer at 16q24.1, arise almost exclusively on the maternally inherited chromosome 16. Given the phenotypic similarities between upd(16)mat and ACDMPV, together with parental allelic bias in ACDMPV, we hypothesized that there may be unknown imprinted loci mapping to chromosome 16 that become functionally unmasked by chromosomal structural variants.

RESULTS: To identify parent-of-origin biased DNA methylation, we performed high-resolution bisulfite …

Detection Of Pediatric Upper Extremity Motor Activity And Deficits With Accelerometry, Catherine R. Hoyt, Andrew N. Van, Mario Ortega, Jonathan M. Koller, Elyse A. Everett, Annie L. Nguyen, Catherine E. Lang, Bradley L. Schlaggar, Nico U.F. Dosenbach

Open Access Publications

Importance: Affordable, quantitative methods to screen children for developmental delays are needed. Motor milestones can be an indicator of developmental delay and may be used to track developmental progress. Accelerometry offers a way to gather real-world information about pediatric motor behavior.

Objective: To develop a referent cohort of pediatric accelerometry from bilateral upper extremities (UEs) and determine whether movement can accurately distinguish those with and without motor deficits.

Design, Setting, and Participants: Children aged 0 to 17 years participated in a prospective cohort from December 8, 2014, to December 29, 2017. Children were recruited from Ranken Jordan Pediatric Bridge Hospital, …

A Survey Of Risk Tolerance To Multiple Sclerosis Therapies, Robert J Fox, Carol Cosenza, Lauren Cripps, Paul Ford, Marybeth Mercer, Sneha Natarajan, Amber Salter, Tuula Tyry, Stacey S Cofield

Open Access Publications

OBJECTIVE: To determine tolerance to various risk scenarios associated with current multiple sclerosis (MS) therapies.

METHODS: People with MS from the North American Research Committee on Multiple Sclerosis Registry's online cohort and the National Multiple Sclerosis Society were invited to complete a questionnaire on tolerance to real-world risks associated with a hypothetical therapy. Multiple risks levels were presented, including skin rash, infection, kidney injury, thyroid injury, liver injury, and progressive multifocal leukoencephalopathy (PML).

RESULTS: Both PML and kidney injury had the lowest risk tolerance (RT) at 1:1,000,000, and thyroid and infection risks had the highest tolerance at 1:1,000. Men, younger …

The Structure Of Cognition In 9 And 10 Year-Old Children And Associations With Problem Behaviors: Findings From The Abcd Study's Baseline Neurocognitive Battery, Wesley K Thompson, Deanna M Barch, James M Bjork, Raul Gonzalez, Bonnie J Nagel, Sara Jo Nixon, Monica Luciana

Open Access Publications

The Adolescent Brain Cognitive Development (ABCD) study is poised to be the largest single-cohort long-term longitudinal study of neurodevelopment and child health in the United States. Baseline data on N= 4521 children aged 9-10 were released for public access on November 2, 2018. In this paper we performed principal component analyses of the neurocognitive assessments administered to the baseline sample. The neurocognitive battery included seven measures from the NIH Toolbox as well as five other tasks. We implemented a Bayesian Probabilistic Principal Components Analysis (BPPCA) model that incorporated nesting of subjects within families and within data collection sites. We extracted …

A Mixture Of U.S. Food And Drug Administration-Approved Monoaminergic Drugs Protects The Retina From Light Damage In Diverse Models Of Night Blindness, Henri Leinonen, Elliot H. Choi, Anthony Gardella, Vladimir J. Kefalov, Krzysztof Palczewski

Open Access Publications

Purpose: The purpose of this study was to test the extent of light damage in different models of night blindness and apply these paradigms in testing the therapeutic efficacy of combination therapy by drugs acting on the Gi, Gs, and Gq protein-coupled receptors.

Methods: Acute bright light exposure was used to test susceptibility to light damage in mice lacking the following crucial phototransduction proteins: rod transducin (GNAT1), cone transducin (GNAT2), visual arrestin 1 (ARR1), and rhodopsin kinase 1 (GRK1). Mice were intraperitoneally injected with either vehicle or drug combination consisting of metoprolol (β1-receptor antagonist), bromocriptine (dopamine family-2 receptor agonist) and …

Abnormal Oxidative Metabolism In A Quiet Genomic Background Underlies Clear Cell Papillary Renal Cell Carcinoma, Jianing Xu, James J. Hsieh, Et Al

Open Access Publications

No abstract provided.

Five-Year Efficacy And Safety Of Asfotase Alfa Therapy For Adults And Adolescents With Hypophosphatasia, Priya S Kishnani, Cheryl Rockman-Greenberg, Frank Rauch, M Tariq Bhatti, Scott Moseley, Andrew E Denker, Eric Watsky, Michael P Whyte

Open Access Publications

Hypophosphatasia (HPP) features low tissue-nonspecific alkaline phosphatase (TNSALP) isoenzyme activity resulting in extracellular accumulation of its substrates including pyridoxal 5'-phosphate (PLP), the principal circulating form of vitamin B6, and inorganic pyrophosphate (PPi), a potent inhibitor of mineralization. Asfotase alfa is an enzyme replacement therapy developed to treat HPP. This multinational, randomized, open-label study (NCT01163149; EudraCT 2010-019850-42) evaluated the efficacy and safety of asfotase alfa in adults and adolescents 13-66 years of age with HPP. The study comprised a 6-month primary treatment period and a 4.5-year extension phase. In the primary treatment period, 19 patients were randomized to receive asfotase alfa …

Conditional Deletion Of Des1 In The Mouse Retina Does Not Impair The Visual Cycle In Cones, Philip D Kiser, Alexander V Kolesnikov, Jianying Z Kiser, Zhiqian Dong, Bhagirath Chaurasia, Liping Wang, Scott A Summers, Thanh Hoang, Seth Blackshaw, Neal S Peachey, Vladimir J Kefalov, Krzysztof Palczewski

Open Access Publications

Cone photoreceptors are essential for vision under moderate to high illuminance and allow color discrimination. Their fast dark adaptation rate and resistance to saturation are believed to depend in part on an intraretinal visual cycle that supplies 11- cis-retinaldehyde to cone opsins. Candidate enzymes of this pathway have been reported, but their physiologic contribution to cone photoresponses remains unknown. Here, we evaluate the role of a candidate retinol isomerase of this pathway, sphingolipid δ4 desaturase 1 (Des1). Single-cell RNA sequencing analysis revealed Des1 expression not only in Müller glia but also throughout the retina and in the retinal pigment epithelium. …

A Heteroscedastic Hidden Markov Mixture Model For Responses And Categorized Response Times, Dylan Molenaar, Sandor Rózsa, Maria Bolsinova

Open Access Publications

Various mixture modeling approaches have been proposed to identify within-subjects differences in the psychological processes underlying responses to psychometric tests. Although valuable, the existing mixture models are associated with at least one of the following three challenges: (1) A parametric distribution is assumed for the response times that-if violated-may bias the results; (2) the response processes are assumed to result in equal variances (homoscedasticity) in the response times, whereas some processes may produce more variability than others (heteroscedasticity); and (3) the different response processes are modeled as independent latent variables, whereas they may be related. Although each of these challenges …

Suppression Of Ilc2 Differentiation From Committed T Cell Precursors By E Protein Transcription Factors, Liangyue Qian, Sandra Bajana, Constantin Georgescu, Vincent Peng, Hong-Cheng Wang, Indra Adrianto, Marco Colonna, Jose Alberola-Ila, Jonathan D. Wren, Xiao-Hong Sun

Open Access Publications

Current models propose that group 2 innate lymphoid cells (ILC2s) are generated in the bone marrow. Here, we demonstrate that subsets of these cells can differentiate from multipotent progenitors and committed T cell precursors in the thymus, both in vivo and in vitro. These thymic ILC2s exit the thymus, circulate in the blood, and home to peripheral tissues. Ablation of E protein transcription factors greatly promotes the ILC fate while impairing B and T cell development. Consistently, a transcriptional network centered on the ZBTB16 transcription factor and IL-4 signaling pathway is highly up-regulated due to E protein deficiency. Our results …

Subsequent Event Risk In Individuals With Established Coronary Heart Disease, Riyaz S. Patel, Petra A. Lenzini, Sharon Cresci, Et Al

Open Access Publications

No abstract provided.

Sting-Mediated Disruption Of Calcium Homeostasis Chronically Activates Er Stress And Primes T Cell Death, Jianjun Wu, Yu-Ju Chen, Nicole Dobbs, Tomomi Sakai, Jen Liou, Jonathan J. Miner, Nan Yan

Open Access Publications

STING gain-of-function mutations cause lung disease and T cell cytopenia through unknown mechanisms. Here, we found that these mutants induce chronic activation of ER stress and unfolded protein response (UPR), leading to T cell death by apoptosis in the

Sex Differences In Functional Connectivity During Fetal Brain Development, M D Wheelock, J L Hect, E Hernandez-Andrade, S S Hassan, R Romero, A T Eggebrecht, M E Thomason

Open Access Publications

Sex-related differences in brain and behavior are apparent across the life course, but the exact set of processes that guide their emergence in utero remains a topic of vigorous scientific inquiry. Here, we evaluate sex and gestational age (GA)-related change in functional connectivity (FC) within and between brain wide networks. Using resting-state functional magnetic resonance imaging we examined FC in 118 human fetuses between 25.9 and 39.6 weeks GA (70 male; 48 female). Infomap was applied to the functional connectome to identify discrete prenatal brain networks in utero. A consensus procedure produced an optimal model comprised of 16 distinct fetal …