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Superresolution Imaging Identifies That Conventional Trafficking Pathways Are Not Essential For Endoplasmic Reticulum To Outer Mitochondrial Membrane Protein Transport., Kyle Salka, Shivaprasad Bhuvanendran, Kassandra Wilson, Petros Bozidis, Mansi Mehta, Kristin Rainey, Hiromi Sesaki, George H Patterson, Jyoti K. Jaiswal, Anamaris M. Colberg-Poley 2017 George Washington University

Superresolution Imaging Identifies That Conventional Trafficking Pathways Are Not Essential For Endoplasmic Reticulum To Outer Mitochondrial Membrane Protein Transport., Kyle Salka, Shivaprasad Bhuvanendran, Kassandra Wilson, Petros Bozidis, Mansi Mehta, Kristin Rainey, Hiromi Sesaki, George H Patterson, Jyoti K. Jaiswal, Anamaris M. Colberg-Poley

Integrative Systems Biology Faculty Publications

Most nuclear-encoded mitochondrial proteins traffic from the cytosol to mitochondria. Some of these proteins localize at mitochondria-associated membranes (MAM), where mitochondria are closely apposed with the endoplasmic reticulum (ER). We have previously shown that the human cytomegalovirus signal-anchored protein known as viral mitochondria-localized inhibitor of apoptosis (vMIA) traffics from the ER to mitochondria and clusters at the outer mitochondrial membrane (OMM). Here, we have examined the host pathways by which vMIA traffics from the ER to mitochondria and clusters at the OMM. By disruption of phosphofurin acidic cluster sorting protein 2 (PACS-2), mitofusins (Mfn1/2), and dynamin related protein 1 ...


Epigenetics And Shared Molecular Processes In The Regeneration Of Complex Structures, Labib Rouhana, Junichi Tasaki 2017 Wright State University - Main Campus

Epigenetics And Shared Molecular Processes In The Regeneration Of Complex Structures, Labib Rouhana, Junichi Tasaki

Labib Rouhana

The ability to regenerate complex structures is broadly represented in both plant and animal kingdoms. Although regenerative abilities vary significantly amongst metazoans, cumulative studies have identified cellular events that are broadly observed during regenerative events. For example, structural damage is recognized and wound healing initiated upon injury, which is followed by programmed cell death in the vicinity of damaged tissue and a burst in proliferation of progenitor cells. Sustained proliferation and localization of progenitor cells to site of injury give rise to an assembly of differentiating cells known as the regeneration blastema, which fosters the development of new tissue. Finally ...


Cellular And Molecular Dissection Of Pluripotent Adult Somatic Stem Cells In Planarians, Norito Shibata, Labib Rouhana, Kiyokazu Agata 2017 Wright State University - Main Campus

Cellular And Molecular Dissection Of Pluripotent Adult Somatic Stem Cells In Planarians, Norito Shibata, Labib Rouhana, Kiyokazu Agata

Labib Rouhana

Freshwater planarians, Plathelminthes, have been an intriguing model animal of regeneration studies for more than 100 years. Their robust regenerative ability is one of asexual reproductive capacity, in which complete animals develop from tiny body fragments within a week. Pluripotent adult somatic stem cells, called neoblasts, assure this regenerative ability. Neoblasts give rise to not only all types of somatic cells, but also germline cells. During the last decade, several experimental techniques for the analysis of planarian neoblasts at the molecular level, such as in situ hybridization, RNAi and fluorescence activated cell sorting, have been established. Moreover, information about genes ...


Piwi Homologs Mediate Histone H4 Mrna Localization To Planarian Chromatoid Bodies, Labib Rouhana, Jennifer A. Weiss, Ryan S. King, Phillip A. Newmark 2017 Wright State University - Main Campus

Piwi Homologs Mediate Histone H4 Mrna Localization To Planarian Chromatoid Bodies, Labib Rouhana, Jennifer A. Weiss, Ryan S. King, Phillip A. Newmark

Labib Rouhana

The well-known regenerative abilities of planarian flatworms are attributed to a population of adult stem cells called neoblasts that proliferate and differentiate to produce all cell types. A characteristic feature of neoblasts is the presence of large cytoplasmic ribonucleoprotein granules named chromatoid bodies, the function of which has remained largely elusive. This study shows that histone mRNAs are a common component of chromatoid bodies. Our experiments also demonstrate that accumulation of histone mRNAs, which is typically restricted to the S phase of eukaryotic cells, is extended during the cell cycle of neoblasts. The planarian PIWI homologs SMEDWI-1 and SMEDWI-3 are ...


Time Of Day Regulates Subcellular Trafficking, Tripartite Synaptic Localization, And Polyadenylation Of The Astrocytic Fabp7 Mrna, Jason R. Gerstner, William M. Vanderheyden, Timothy LaVaute, Cara J. Westmark, Labib Rouhana, Allan I. Pack, Marvin Wickens, Charles F. Landry 2017 Wright State University - Main Campus

Time Of Day Regulates Subcellular Trafficking, Tripartite Synaptic Localization, And Polyadenylation Of The Astrocytic Fabp7 Mrna, Jason R. Gerstner, William M. Vanderheyden, Timothy Lavaute, Cara J. Westmark, Labib Rouhana, Allan I. Pack, Marvin Wickens, Charles F. Landry

Labib Rouhana

The astrocyte brain fatty acid binding protein (Fabp7) has previously been shown to have a coordinated diurnal regulation of mRNA and protein throughout mouse brain, and an age-dependent decline in protein expression within synaptoneurosomal fractions. Mechanisms that control time-of-day changes in expression and trafficking Fabp7 to the perisynaptic process are not known. In this study, we confirmed an enrichment of Fabp7 mRNA and protein in the astrocytic perisynaptic compartment, and observed a diurnal change in the intracellular distribution of Fabp7 mRNA in molecular layers of hippocampus. Northern blotting revealed a coordinated time-of-day-dependent oscillation for the Fabp7 mRNA poly(A) tail ...


Germline Defects Caused By Smed-Boule Rna-Interference Reveal That Egg Capsule Deposition Occurs Independently Of Fertilization, Ovulation, Mating, Or The Presence Of Gametes In Planarian Flatworms, Jessica Kathryne Steiner, Junichi Tasaki, Labib Rouhana 2017 Wright State University - Main Campus

Germline Defects Caused By Smed-Boule Rna-Interference Reveal That Egg Capsule Deposition Occurs Independently Of Fertilization, Ovulation, Mating, Or The Presence Of Gametes In Planarian Flatworms, Jessica Kathryne Steiner, Junichi Tasaki, Labib Rouhana

Labib Rouhana

Few animals are known to lay eggs in the absence of ovulation or copulation, as it is presumably energetically wasteful and subjected to negative selection. Characterization of Smed-boule, a member of the DAZ family of germline RNA-binding proteins, revealed that egg capsule (or capsule) production and deposition occurs independently of the presence of gametes in the planarian flatworm Schmidtea mediterranea. Reduction of Smed-boule expression by RNA-interference (RNAi) causes ablation of spermatogonial stem cells and the inability of ovarian germline stem cells to undergo oogenesis. Although animals subjected to Smed-boule RNAi lose their gametes and become sterile, they continue to lay ...


Prmt5 And The Role Of Symmetrical Dimethylarginine In Chromatoid Bodies Of Planarian Stem Cells, Labib Rouhana, Ana P. Vieira, Rachel H. Roberts-Galbraith, Phillip A. Newmark 2017 Wright State University - Main Campus

Prmt5 And The Role Of Symmetrical Dimethylarginine In Chromatoid Bodies Of Planarian Stem Cells, Labib Rouhana, Ana P. Vieira, Rachel H. Roberts-Galbraith, Phillip A. Newmark

Labib Rouhana

Planarian flatworms contain a population of adult stem cells (neoblasts) that proliferate and generate cells of all tissues during growth, regeneration and tissue homeostasis. A characteristic feature of neoblasts is the presence of chromatoid bodies, large cytoplasmic ribonucleoprotein (RNP) granules morphologically similar to structures present in the germline of many organisms. This study aims to reveal the function, and identify additional components, of planarian chromatoid bodies. We uncover the presence of symmetrical dimethylarginine (sDMA) on chromatoid body components and identify the ortholog of protein arginine methyltransferase PRMT5 as the enzyme responsible for sDMA modification in these proteins. RNA interference-mediated depletion ...


Vertebrate Gld2 Poly(A) Polymerases In The Germline And The Brain, Labib Rouhana, Liaoteng Wang, Natascha Buter, Jae Eun Kwak, Craig A. Schiltz, Tania Gonzalez, Ann E. Kelley, Charles F. Landry, Marvin Wickens 2017 Wright State University - Main Campus

Vertebrate Gld2 Poly(A) Polymerases In The Germline And The Brain, Labib Rouhana, Liaoteng Wang, Natascha Buter, Jae Eun Kwak, Craig A. Schiltz, Tania Gonzalez, Ann E. Kelley, Charles F. Landry, Marvin Wickens

Labib Rouhana

Cytoplasmic polyadenylation is important in the control of mRNA stability and translation, and for early animal development and synaptic plasticity. Here, we focus on vertebrate poly(A) polymerases that are members of the recently described GLD2 family. We identify and characterize two closely related GLD2 proteins in Xenopus oocytes, and show that they possess PAP activity in vivo and in vitro and that they bind known polyadenylation factors and mRNAs known to receive poly(A) during development. We propose that at least two distinct polyadenylation complexes exist in Xenopus oocytes, one of which contains GLD2; the other, maskin and Pumilio ...


De Novo Alignment Of Girardia Dorotocephala Transcriptome, Labib Rouhana, Eugene M. P. Almazan 2017 Wright State University - Main Campus

De Novo Alignment Of Girardia Dorotocephala Transcriptome, Labib Rouhana, Eugene M. P. Almazan

Labib Rouhana

De novo alignment of a Girardia dorotocephala (2n = 16) transcriptome using the Trinity platform.


Autoregulation Of Gld-2 Cytoplasmic Poly(A) Polymerase, Labib Rouhana, Marvin Wickens 2017 Wright State University - Main Campus

Autoregulation Of Gld-2 Cytoplasmic Poly(A) Polymerase, Labib Rouhana, Marvin Wickens

Labib Rouhana

Cytoplasmic polyadenylation regulates mRNA stability and translation and is required for early development and synaptic plasticity. The GLD-2 poly(A) polymerase catalyzes cytoplasmic polyadenylation in the germline of metazoa. Among vertebrates, the enzyme is encoded by two isoforms of mRNA that differ only in the length of their 3′-UTRs. Here we focus on regulation of vertebrateGLD-2 mRNA. We show that the 3′-UTR of GLD-2 mRNA elicits its own polyadenylation and translational activation during frog oocyte maturation. We identify the sequence elements responsible for repression and activation, and demonstrate that CPEB and PUF proteins likely mediate repression in ...


Revbayes: Bayesian Phylogenetic Inference Using Graphical Models And An Interactive Model-Specification Language, Sebastian Höhna, Michael J. Landis, Tracy A. Heath, Nicolas Lartillot, Brian R. Moore, John P. Huelsenbeck, Fredrik Ronquist 2017 University of California, Berkeley

Revbayes: Bayesian Phylogenetic Inference Using Graphical Models And An Interactive Model-Specification Language, Sebastian Höhna, Michael J. Landis, Tracy A. Heath, Nicolas Lartillot, Brian R. Moore, John P. Huelsenbeck, Fredrik Ronquist

Tracy Heath

Programs for Bayesian inference of phylogeny currently implement a unique and fixed suite of models. Consequently, users of these software packages are simultaneously forced to use a number of programs for a given study, while also lacking the freedom to explore models that have not been implemented by the developers of those programs. We developed a new open-source software package, RevBayes, to address these problems. RevBayes is entirely based on probabilistic graphical models, a powerful generic framework for specifying and analyzing statistical models. Phylogenetic-graphical models can be specified interactively in RevBayes, piece by piece, using a new succinct and intuitive ...


Total-Evidence Dating Under The Fossilized Birth–Death Process, Chi Zhang, Tanja Stadler, Serena Klopfstein, Tracy A. Heath, Fredrik Ronquist 2017 Swedish Museum of Natural History

Total-Evidence Dating Under The Fossilized Birth–Death Process, Chi Zhang, Tanja Stadler, Serena Klopfstein, Tracy A. Heath, Fredrik Ronquist

Tracy Heath

Bayesian total-evidence dating involves the simultaneous analysis of morphological data from the fossil record and morphological and sequence data from recent organisms, and it accommodates the uncertainty in the placement of fossils while dating the phylogenetic tree. Due to the flexibility of the Bayesian approach, total-evidence dating can also incorporate additional sources of information. Here, we take advantage of this and expand the analysis to include information about fossilization and sampling processes. Our work is based on the recently described fossilized birth–death (FBD) process, which has been used to model speciation, extinction, and fossilization rates that can vary over ...


Mitochondria Mediate Cell Membrane Repair And Contribute To Duchenne Muscular Dystrophy., Maria C Vila, Sree Rayavarapu, Marshall W Hogarth, Jack H Van der Meulen, Adam Horn, Aurelia Defour, Shin'ichi Takeda, Kristy J. Brown, Yetrib Hathout, Kanneboyina Nagaraju, Jyoti K. Jaiswal 2017 George Washington University

Mitochondria Mediate Cell Membrane Repair And Contribute To Duchenne Muscular Dystrophy., Maria C Vila, Sree Rayavarapu, Marshall W Hogarth, Jack H Van Der Meulen, Adam Horn, Aurelia Defour, Shin'ichi Takeda, Kristy J. Brown, Yetrib Hathout, Kanneboyina Nagaraju, Jyoti K. Jaiswal

Integrative Systems Biology Faculty Publications

Dystrophin deficiency is the genetic basis for Duchenne muscular dystrophy (DMD), but the cellular basis of progressive myofiber death in DMD is not fully understood. Using two dystrophin-deficient mdx mouse models, we find that the mitochondrial dysfunction is among the earliest cellular deficits of mdx muscles. Mitochondria in dystrophic myofibers also respond poorly to sarcolemmal injury. These mitochondrial deficits reduce the ability of dystrophic muscle cell membranes to repair and are associated with a compensatory increase in dysferlin-mediated membrane repair proteins. Dysferlin deficit in mdx mice further compromises myofiber cell membrane repair and enhances the muscle pathology at an asymptomatic ...


The Mayfly Newsletter, Donna J. Giberson 2017 The Permanent Committee of the International Conferences on Ephemeroptera

The Mayfly Newsletter, Donna J. Giberson

The Mayfly Newsletter

No abstract provided.


Vamorolone, A Dissociative Steroidal Compound, Reduces Pro-Inflammatory Cytokine Expression In Glioma Cells And Increases Activity And Survival In A Murine Model Of Cortical Tumor., Elizabeth Wells, Madhuri Kambhampati, Jesse M Damsker, Heather Gordish-Dressman, Sridevi Yadavilli, Oren J Becher, Jamila Gittens, Mojca Stampar, Roger J. Packer, Javad Nazarian 2016 George Washington University

Vamorolone, A Dissociative Steroidal Compound, Reduces Pro-Inflammatory Cytokine Expression In Glioma Cells And Increases Activity And Survival In A Murine Model Of Cortical Tumor., Elizabeth Wells, Madhuri Kambhampati, Jesse M Damsker, Heather Gordish-Dressman, Sridevi Yadavilli, Oren J Becher, Jamila Gittens, Mojca Stampar, Roger J. Packer, Javad Nazarian

Integrative Systems Biology Faculty Publications

Corticosteroids, such as dexamethasone, are routinely used as palliative care in neuro-oncology for their anti-inflammatory benefits, however many patients experience dose limiting side effects caused by glucocorticoid response element (GRE)-mediated transcription. The purpose of this study was to use a murine model to investigate a new steroid alternative, vamorolone, which promises to reduce side effects through dissociating GRE-mediated transcription and NF-κB -mediated anti-inflammatory actions. To compare vamorolone to dexamethasone in reducing pro-inflammatory signals in vitro, murine glioma cells were treated with dexamethasone, vamorolone or vehicle control. Changes in mRNA expression were assessed using the nanostring inflammatory platform. Furthermore, drug ...


Effect Of Arginine On Oligomerization And Stability Of N-Acetylglutamate Synthase., N Haskins, A Mumo, P H Brown, Mendel Tuchman, Hiroki Morizono, L Caldovic 2016 George Washington University

Effect Of Arginine On Oligomerization And Stability Of N-Acetylglutamate Synthase., N Haskins, A Mumo, P H Brown, Mendel Tuchman, Hiroki Morizono, L Caldovic

Integrative Systems Biology Faculty Publications

N-acetylglutamate synthase (NAGS; E.C.2.3.1.1) catalyzes the formation of N-acetylglutamate (NAG) from acetyl coenzyme A and glutamate. In microorganisms and plants, NAG is the first intermediate of the L-arginine biosynthesis; in animals, NAG is an allosteric activator of carbamylphosphate synthetase I and III. In some bacteria bifunctional N-acetylglutamate synthase-kinase (NAGS-K) catalyzes the first two steps of L-arginine biosynthesis. L-arginine inhibits NAGS in bacteria, fungi, and plants and activates NAGS in mammals. L-arginine increased thermal stability of the NAGS-K from Maricaulis maris (MmNAGS-K) while it destabilized the NAGS-K from Xanthomonas campestris (XcNAGS-K). Analytical gel chromatography and ultracentrifugation ...


Network Inference Driven Drug Discovery, Gergely Zahoránszky-Kőhalmi, Tudor I. Oprea MD, PhD, Cristian G. Bologa PhD, Subramani Mani MD, PhD, Oleg Ursu PhD 2016 University of New Mexico School of Medicine

Network Inference Driven Drug Discovery, Gergely Zahoránszky-Kőhalmi, Tudor I. Oprea Md, Phd, Cristian G. Bologa Phd, Subramani Mani Md, Phd, Oleg Ursu Phd

Biomedical Sciences ETDs

The application of rational drug design principles in the era of network-pharmacology requires the investigation of drug-target and target-target interactions in order to design new drugs. The presented research was aimed at developing novel computational methods that enable the efficient analysis of complex biomedical data and to promote the hypothesis generation in the context of translational research. The three chapters of the Dissertation relate to various segments of drug discovery and development process.

The first chapter introduces the integrated predictive drug discovery platform „SmartGraph”. The novel collaborative-filtering based algorithm „Target Based Recommender (TBR)” was developed in the framework of this ...


Crystal Structure Of The Dna Binding Domain Of The Transcription Factor T-Bet Suggests Simultaneous Recognition Of Distant Genome Sites, Ce Feng Liu, Gabriel S. Brandt, Quyen Q. Hoang, Natalia Naumova, Vanja Lazarevic, Eun Sook Hwang, Job Dekker, Laurie H. Glimcher, Dagmar Ringe, Gregory A. Petsko 2016 Weill Cornell Medical College

Crystal Structure Of The Dna Binding Domain Of The Transcription Factor T-Bet Suggests Simultaneous Recognition Of Distant Genome Sites, Ce Feng Liu, Gabriel S. Brandt, Quyen Q. Hoang, Natalia Naumova, Vanja Lazarevic, Eun Sook Hwang, Job Dekker, Laurie H. Glimcher, Dagmar Ringe, Gregory A. Petsko

Program in Systems Biology Publications and Presentations

The transcription factor T-bet (Tbox protein expressed in T cells) is one of the master regulators of both the innate and adaptive immune responses. It plays a central role in T-cell lineage commitment, where it controls the TH1 response, and in gene regulation in plasma B-cells and dendritic cells. T-bet is a member of the Tbox family of transcription factors; however, T-bet coordinately regulates the expression of many more genes than other Tbox proteins. A central unresolved question is how T-bet is able to simultaneously recognize distant Tbox binding sites, which may be located thousands of base pairs away. We ...


Single-Cell Transcriptional Analysis Reveals Novel Neuronal Phenotypes And Interaction Networks Involved In The Central Circadian Clock, James Park, Haisun Zhu, Sean O'Sullivan, Babatunde A. Ogunnaike, David R. Weaver, James S. Schwaber, Rajanikanth Vadigepalli 2016 Thomas Jefferson University

Single-Cell Transcriptional Analysis Reveals Novel Neuronal Phenotypes And Interaction Networks Involved In The Central Circadian Clock, James Park, Haisun Zhu, Sean O'Sullivan, Babatunde A. Ogunnaike, David R. Weaver, James S. Schwaber, Rajanikanth Vadigepalli

Neurobiology Publications and Presentations

Single-cell heterogeneity confounds efforts to understand how a population of cells organizes into cellular networks that underlie tissue-level function. This complexity is prominent in the mammalian suprachiasmatic nucleus (SCN). Here, individual neurons exhibit a remarkable amount of asynchronous behavior and transcriptional heterogeneity. However, SCN neurons are able to generate precisely coordinated synaptic and molecular outputs that synchronize the body to a common circadian cycle by organizing into cellular networks. To understand this emergent cellular network property, it is important to reconcile single-neuron heterogeneity with network organization. In light of recent studies suggesting that transcriptionally heterogeneous cells organize into distinct cellular ...


A Gene-Centered C. Elegans Protein-Dna Interaction Network Provides A Framework For Functional Predictions, Juan Fuxman Bass, Carles Pons, Lucie Kozlowski, John S. Reece-Hoyes, Shaleen Shrestha, Amy D. Holdorf, Akihiro Mori, Chad L. Myers, Albertha J. M. Walhout 2016 University of Massachusetts Medical School

A Gene-Centered C. Elegans Protein-Dna Interaction Network Provides A Framework For Functional Predictions, Juan Fuxman Bass, Carles Pons, Lucie Kozlowski, John S. Reece-Hoyes, Shaleen Shrestha, Amy D. Holdorf, Akihiro Mori, Chad L. Myers, Albertha J. M. Walhout

Open Access Articles

Transcription factors (TFs) play a central role in controlling spatiotemporal gene expression and the response to environmental cues. A comprehensive understanding of gene regulation requires integrating physical protein-DNA interactions (PDIs) with TF regulatory activity, expression patterns, and phenotypic data. Although great progress has been made in mapping PDIs using chromatin immunoprecipitation, these studies have only characterized ~10% of TFs in any metazoan species. The nematode C. elegans has been widely used to study gene regulation due to its compact genome with short regulatory sequences. Here, we delineated the largest gene-centered metazoan PDI network to date by examining interactions between 90 ...


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