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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. …

Neurotransmitter Identity Is Acquired In A Lineage-Restricted Manner In The Drosophila Cns, Haluk Lacin, Hui-Min Chen, Xi Long, Robert H. Singer, Tzumin Lee, James W. Truman

Open Access Publications

The vast majority of the adult fly ventral nerve cord is composed of 34 hemilineages, which are clusters of lineally related neurons. Neurons in these hemilineages use one of the three fast-acting neurotransmitters (acetylcholine, GABA, or glutamate) for communication. We generated a comprehensive neurotransmitter usage map for the entire ventral nerve cord. We did not find any cases of neurons using more than one neurotransmitter, but found that the acetylcholine specific gene ChAT is transcribed in many glutamatergic and GABAergic neurons, but these transcripts typically do not leave the nucleus and are not translated. Importantly, our work uncovered a simple …

A Novel Pathogenic Variant In Osbpl2 Linked To Hereditary Late-Onset Deafness In A Mongolian Family, Ningjin Wu, Husile Husile, Liqing Yang, Yaning Cao, Xing Li, Wenyan Huo, Haihua Bai, Yangjian Liu, Qizhu Wu

Open Access Publications

BACKGROUND: To investigate the clinical features and the underlying causal gene of a family with hereditary late-onset deafness in Inner Mongolia of China, and to provide evidence for the early genetic screening and diagnosis of this disease.

METHODS: Family data were collected to draw a pedigree. Audiological testing and physical examination of the family members were conducted following questionnaire. Genomic DNA was extracted from peripheral blood of 5 family members (3 patients and 2 normal control) and subjected to whole genome sequencing for identifying deafness casual genes. The pathogenic variant in the deafness gene was further confirmed by Sanger sequencing. …

Network Meta-Analysis Of Randomised Trials Of Pharmacological, Psychotherapeutic, Exercise And Collaborative Care Interventions For Depressive Symptoms In Patients With Coronary Artery Disease: Hybrid Systematic Review Of Systematic Reviews Protocol, Frank Doyle, Kenneth Freedland, Robert Carney, Peter De Jonge, Chris Dickens, Susanne Pedersen, Jan Sorensen, Martin Dempster

Open Access Publications

BACKGROUND: Depression is common in patients with coronary artery disease (CAD) and is associated with poorer outcomes and higher costs. Several randomised controlled trials (RCTs) targeting depression, of various modalities (including pharmacological, psychotherapeutic and other approaches), have been conducted and summarised in pairwise meta-analytic reviews. However, no study has considered the cumulative evidence within a network, which can provide valuable indirect comparisons and information about the relative efficacy of interventions. Therefore, we will adopt a review of review methodology to develop a network meta-analysis (NMA) of depression interventions for depression in CAD.

METHODS: We will search relevant databases from inception …

Homozygous Frameshift Mutations In Fat1 Cause A Syndrome Characterized By Colobomatous-Microphthalmia, Ptosis, Nephropathy And Syndactyly., Najim Lahrouchi, Aman George, Ilham Ratbi, Ronen Schneider, Siham C Elalaoui, Shahida Moosa, Sanita Bharti, Ruchi Sharma, Mones Abu-Asab, Felix Onojafe, Najlae Adadi, Elisabeth M Lodder, Fatima-Zahra Laarabi, Yassine Lamsyah, Hamza Elorch, Imane Chebbar, Alex V Postma, Vassilios Lougaris, Alessandro Plebani, Janine Altmueller, Henriette Kyrieleis, Vardiella Meiner, Helen Mcneill, Kapil Bharti, Stanislas Lyonnet, Bernd Wollnik, Alexandra Henrion-Caude, Amina Berraho, Friedhelm Hildebrandt, Connie R Bezzina, Brian P Brooks, Abdelaziz Sefiani

Open Access Publications

A failure in optic fissure fusion during development can lead to blinding malformations of the eye. Here, we report a syndrome characterized by facial dysmorphism, colobomatous microphthalmia, ptosis and syndactyly with or without nephropathy, associated with homozygous frameshift mutations in FAT1. We show that Fat1 knockout mice and zebrafish embryos homozygous for truncating fat1a mutations exhibit completely penetrant coloboma, recapitulating the most consistent developmental defect observed in affected individuals. In human retinal pigment epithelium (RPE) cells, the primary site for the fusion of optic fissure margins, FAT1 is localized at earliest cell-cell junctions, consistent with a role in facilitating optic …

Temperoammonic Stimulation Depotentiates Schaffer Collateral Ltp Via P38 Mapk Downstream Of Adenosine A1 Receptors, Yukitoshi Izumi, Charles F. Zorumski

Open Access Publications

We previously found that low-frequency stimulation of direct temperoammonic (TA) inputs to hippocampal area CA1 depotentiates previously established long-term potentiation in the Schaffer collateral (SC) pathway through complex signaling involving dopamine, endocannabinoids, neuregulin-1, GABA, and adenosine, with adenosine being the most distal modulator identified to date. In the present studies, we examined mechanisms contributing to the effects of adenosine in hippocampal slices from male albino rats. We found that extracellular conversion of ATP to adenosine via an ectonucleotidase contributes significantly to TA-mediated SC depotentiation and the depotentiation resulting from block of adenosine transport. Adenosine-mediated SC depotentiation does not involve activation …

Association Of The Infant Gut Microbiome With Early Childhood Neurodevelopmental Outcomes: An Ancillary Study To The Vdaart Randomized Clinical Trial, Joanne E. Sordillo, Susan Korrick, Nancy Laranjo, Vincent Carey, George M. Weinstock, Diane R. Gold, George O'Connor, Megan Sandel, Leonard B. Bacharier, Avraham Beigelman, Robert Zeiger, Augusto A. Litonjua, Scott T. Weiss

Open Access Publications

Importance: In animal models, the early life gut microbiome influences later neurodevelopment. Corresponding data in human populations are lacking.

Objective: To study associations between the gut microbiome in infants and development at preschool age measured by the Ages and Stages Questionnaire, third edition (ASQ-3).

Design, Setting, and Participants: This ancillary cohort study of the Vitamin D Antenatal Asthma Reduction Trial (VDAART) used data from 715 participants who had development assessed at 3 years of age by the ASQ-3, which included scores in 5 domains (gross motor skills, fine motor skills, problem solving, communication, and personal and social skills). A total …

Staying Awake To Stay Alive: A Circuit Controlling Starvation-Induced Waking, Krishna Melnattur, Paul Shaw

Open Access Publications

The balance of sleep and wake is plastic and changes to meet environmental demands. Mechanisms that allow an animal to suppress sleep and maintain waking in potentially adverse situations could serve adaptive functions in evolution. The fruit fly, Drosophila melanogaster, is well poised as a system in which to explore these questions. The environment changes sleep and wake in flies, e.g., starvation induces waking in Drosophila as it does in many animals. Further, the sophisticated neurobiological toolkit available to Drosophila researchers gives the fly a great advantage as a system to investigate the precise neurobiological mechanisms underlying these adaptive changes. …

Genetics Of Group A Streptococci, Kyu Hong Cho, Gary C Port, Michael Caparon

Open Access Publications

No abstract provided.

Comprehensive Gene Expression Meta-Analysis Identifies Signature Genes That Distinguish Microglia From Peripheral Monocytes/Macrophages In Health And Glioma, Verena Haage, Marcus Semtner, Ramon Oliveira Vidal, Daniel Perez Hernandez, Winnie W Pong, Zhihong Chen, Dolores Hambardzumyan, Vincent Magrini, Amy Ly, Jason Walker, Elaine Mardis, Philipp Mertins, Sascha Sauer, Helmut Kettenmann, David H Gutmann

Open Access Publications

Monocytes/macrophages have begun to emerge as key cellular modulators of brain homeostasis and central nervous system (CNS) disease. In the healthy brain, resident microglia are the predominant macrophage cell population; however, under conditions of blood-brain barrier leakage, peripheral monocytes/macrophages can infiltrate the brain and participate in CNS disease pathogenesis. Distinguishing these two populations is often challenging, owing to a paucity of universally accepted and reliable markers. To identify discriminatory marker sets for microglia and peripheral monocytes/macrophages, we employed a large meta-analytic approach using five published murine transcriptional datasets. Following hierarchical clustering, we filtered the top differentially expressed genes (DEGs) through …

Ilc2s Are The Predominant Source Of Intestinal Ilc-Derived Il-10, Jennifer K Bando, Susan Gilfillan, Blanda Di Luccia, José L Fachi, Cristiane Sécca, Marina Cella, Marco Colonna

Open Access Publications

Although innate lymphoid cells (ILCs) functionally analogous to T helper type 1 (Th1), Th2, and Th17 cells are well characterized, an ILC subset strictly equivalent to IL-10-secreting regulatory T cells has only recently been proposed. Here, we report the absence of an intestinal regulatory ILC population distinct from group 1 ILCs (ILC1s), ILC2s, and ILC3s in (1) mice bred in our animal facility; (2) mice from The Jackson Laboratory, Taconic Biosciences, and Charles River Laboratories; and (3) mice subjected to intestinal inflammation. Instead, a low percentage of intestinal ILC2s produced IL-10 at steady state. A screen for putative IL-10 elicitors …

Gene Therapy Targeting Sarm1 Blocks Pathological Axon Degeneration In Mice, Stefanie Geisler, Shay X. Huang, Amy Strickland, Ryan A. Doan, Daniel W. Summers, Xianrong Mao, Jiwoong Park, Aaron Diantonio, Jeffrey Milbrandt

Open Access Publications

Axonal degeneration (AxD) following nerve injury, chemotherapy, and in several neurological disorders is an active process driven by SARM1, an injury-activated NADase. Axons of SARM1-null mice exhibit greatly delayed AxD after transection and in models of neurological disease, suggesting that inhibiting SARM1 is a promising strategy to reduce pathological AxD. Unfortunately, no drugs exist to target SARM1. We, therefore, developed SARM1 dominant-negatives that potently block AxD in cellular models of axotomy and neuropathy. To assess efficacy in vivo, we used adeno-associated virus-mediated expression of the most potent SARM1 dominant-negative and nerve transection as a model of severe AxD. While axons …

Comprehensive Behavioral And Biochemical Outcomes Of Novel Murine Models Of Gm1-Gangliosidosis And Morquio Syndrome Type B, Michael J Przybilla, Li Ou, Alexandru-Flaviu Tăbăran, Xuntian Jiang, Rohini Sidhu, Pamela J Kell, Daniel S Ory, M Gerard O'Sullivan, Chester B Whitley

Open Access Publications

Deficiencies in the lysosomal hydrolase β-galactosidase (β-gal) lead to two distinct diseases: the skeletal disease Morquio syndrome type B, and the neurodegenerative disease GM1-gangliosidosis. Utilizing CRISPR-Cas9 genome editing, the mouse β-gal encoding gene, Glb1, was targeted to generate both models of β-gal deficiency in a single experiment. For Morquio syndrome type B, the common human missense mutation W273L (position 274 in mice) was introduced into the Glb1 gene (Glb1

Mitochondrial Fusion Supports Increased Oxidative Phosphorylation During Cell Proliferation, Cong-Hui Yao, Rencheng Wang, Yahui Wang, Che-Pei Kung, Jason D. Weber, Gary J. Patti

Open Access Publications

Proliferating cells often have increased glucose consumption and lactate excretion relative to the same cells in the quiescent state, a phenomenon known as the Warburg effect. Despite an increase in glycolysis, however, here we show that non-transformed mouse fibroblasts also increase oxidative phosphorylation (OXPHOS) by nearly two-fold and mitochondrial coupling efficiency by ~30% during proliferation. Both increases are supported by mitochondrial fusion. Impairing mitochondrial fusion by knocking down mitofusion-2 (Mfn2) was sufficient to attenuate proliferation, while overexpressing Mfn2 increased proliferation. Interestingly, impairing mitochondrial fusion decreased OXPHOS but did not deplete ATP levels. Instead, inhibition caused cells to transition from excreting …

Apo-Opsin Exists In Equilibrium Between A Predominant Inactive And A Rare Highly Active State, Shinya Sato, Beata Jastrzebska, Andreas Engel, Krzysztof Palczewski, Vladimir J. Kefalov

Open Access Publications

Bleaching adaptation in rod photoreceptors is mediated by apo-opsin, which activates phototransduction with effective activity 10

Inducible Down-Regulation Of Mhc Class I Results In Natural Killer Cell Tolerance, Michael D. Bern, Bijal A. Parikh, Liping Yang, Diana L. Beckman, Jennifer Poursine-Laurent, Wayne M. Yokoyama

Open Access Publications

Natural killer (NK) cells are innate lymphocytes that are thought to kill cells that down-regulate MHC class I (MHC-I) through "missing-self" recognition. NK cells from

The Transcriptional Regulator Snon Promotes The Proliferation Of Cerebellar Granule Neuron Precursors In The Postnatal Mouse Brain, Xiaoying Chen, Ayan Chanda, Yoshiho Ikeuchi, Xiaoqing Zhang, Jared V. Goodman, Naveen C. Reddy, Shahriyar P. Majidi, Dennis Y. Wu, Sarah E. Smith, Abigail Godec, Anna Oldenborg, Harrison W. Gabel, Guoyan Zhao, Shirin Bonni, Azad Bonni

Open Access Publications

Control of neuronal precursor cell proliferation is essential for normal brain development, and deregulation of this fundamental developmental event contributes to brain diseases. Typically, neuronal precursor cell proliferation extends over long periods of time during brain development. However, how neuronal precursor proliferation is regulated in a temporally specific manner remains to be elucidated. Here, we report that conditional KO of the transcriptional regulator SnoN in cerebellar granule neuron precursors robustly inhibits the proliferation of these cells and promotes their cell cycle exit at later stages of cerebellar development in the postnatal male and female mouse brain. In laser capture microdissection …

Voltage-Independent Sk-Channel Dysfunction Causes Neuronal Hyperexcitability In The Hippocampus Of Fmr1 Knock-Out Mice, Pan-Yue Deng, Dan Carlin, Young Mi Oh, Leila K. Myrick, Stephen T. Warren, Valeria Cavalli, Vitaly A. Klyachko

Open Access Publications

Neuronal hyperexcitability is one of the major characteristics of fragile X syndrome (FXS), yet the molecular mechanisms of this critical dysfunction remain poorly understood. Here we report a major role of voltage-independent potassium (K

A Hox-Tale Regulatory Circuit For Neural Crest Patterning Is Conserved Across Vertebrates, Hugo J. Parker, Bony De Kumar, Stephen A. Green, Karin D. Prummel, Christopher Hess, Charles K. Kaufman, Christian Mosimann, Leanne M. Wiedemann, Marianne E. Bronner, Robb Krumlauf

Open Access Publications

No abstract provided.

Clinical Characterization Of Host Response To Simian Hemorrhagic Fever Virus Infection In Permissive And Refractory Hosts: A Model For Determining Mechanisms Of Vhf Pathogenesis, Adam L. Bailey, Et Al

Open Access Publications

No abstract provided.

Aav-Mediated Taz Gene Replacement Restores Mitochondrial And Cardioskeletal Function In Barth Syndrome, Silveli Suzuki-Hatano, Madhurima Saha, Skylar A. Rizzo, Rachael L. Witko, Bennett J. Gosiker, Manashwi Ramanathan, Meghan S. Soustek, Michael D. Jones, Peter B. Kang, Barry J. Byrne, W. Todd Cade, Christina A. Pacak

Open Access Publications

No abstract provided.

Imaging Of Her2 With [89zr]Pertuzumab In Response To T-Dm1 Therapy, Adriana V.F. Massicano, Supum Lee, Bryant K. Crenshaw, Tolulope A. Aweda, Retta El Sayed, Ian Super, Ron Bose, Bernadette V. Marquez-Nostra, Suzanne E. Lapi

Open Access Publications

No abstract provided.

Phosphatidylcholine Synthesis Through Cholinephosphate Cytidylyltransferase Is Dispensable In Leishmania Major, Samrat Moitra, Mattie C. Pawlowic, Fong-Fu Hsu, Kai Zhang

Open Access Publications

No abstract provided.

Mild Chronic Perturbation Of Inhibition Severely Alters Hippocampal Function, Min-Yu Sun, Luke Ziolkowski, Peter Lambert, Hong-Jin Shu, Micah Keiser, Nicholas Rensing, Natasha Warikoo, Monika Martinek, Carson Platnick, Ann Benz, John Bracamontes, Gustav Akk, Joe Henry Steinbach, Charles F. Zorumski, Michael Wong, Steven Mennerick

Open Access Publications

No abstract provided.

A Short Translational Ramp Determines The Efficiency Of Protein Synthesis, Manasvi Verma, Junhong Choi, Kyle A. Cottrell, Zeno Lavagnino, Erica N. Thomas, Slavica Pavlovic-Djuranovic, Pawel Szczesny, David W. Piston, Hani S. Zaher, Joseph D. Puglisi, Sergej Djuranovic

Open Access Publications

No abstract provided.

Deficiency Of Dietary Fiber In Slc5a8-Null Mice Promotes Bacterial Dysbiosis And Alters Colonic Epithelial Transcriptome Towards Proinflammatory Milieu, Sathish Sivaprakasam, Pramodh K. Ganapathy, Mohd Omar Faruk Sikder, Moamen Elmassry, Sabarish Ramachandran, Kameswara Rao Kottapalli, Vadivel Ganapathy

Open Access Publications

No abstract provided.

Reduction Of Leukocyte Microvascular Adherence And Preservation Of Blood-Brain Barrier Function By Superoxide-Lowering Therapies In A Piglet Model Of Neonatal Asphyxia, Jacob B. Ruden, Kevin L. Quick, Ernesto R. Gonzales, Aarti R. Shah, T. S. Park, Nan Kennedy, Laura L. Dugan, Jeffrey M. Gidday

Open Access Publications

No abstract provided.

Crispr/Cas9 Mediated Generation Of An Ovine Model For Infantile Neuronal Ceroid Lipofuscinosis (Cln1 Disease), S. L. Eaton, C. Proudfoot, S. G. Lillico, P. Skehel, R. A. Kline, K. Hamer, N. M. Rzechorzek, E. Clutton, R. Gregson, T. King, C. A. O'Neill, J. D. Cooper, G. Thompson, C. B. Whitelaw, T. M. Wishart

Open Access Publications

No abstract provided.

Promising Recent Strategies With Potential Clinical Translational Value To Combat Antibacterial Resistant Surge, Partha Karmakar, Vishwanath Gaitonde

Open Access Publications

No abstract provided.

Ether-A-Go-Go Related Gene-1a Potassium Channel Abundance Varies Within Specific Skeletal Muscle Fiber Type, Luke B. Anderson, Chase D. Latour, Omar Khader, Bryce H. Massey, Brittan Cobb, Amber L. Pond

Open Access Publications

No abstract provided.