Digital Commons Network^™

Lithium Treatment Of Appswdi/Nos2−/− Mice Leads To Reduced Hyperphosphorylated Tau, Increased Amyloid Deposition And Altered Inflammatory Phenotype, Tiffany L. Sudduth, Joan G. Wilson, Angela Everhart, Carol A. Colton, Donna M. Wilcock

Sanders-Brown Center on Aging Faculty Publications

Lithium is an anti-psychotic that has been shown to prevent the hyperphosphorylation of tau protein through the inhibition of glycogen-synthase kinase 3-beta (GSK3β). We recently developed a mouse model that progresses from amyloid pathology to tau pathology and neurodegeneration due to the genetic deletion of NOS2 in an APP transgenic mouse; the APPSwDI/NOS2-/- mouse. Because this mouse develops tau pathology, amyloid pathology and neuronal loss we were interested in the effect anti-tau therapy would have on amyloid pathology, learning and memory. We administered lithium in the diets of APPSwDI/NOS2-/- mice for a period of eight months, followed by water maze …

Environmentally Realistic Exposure To The Herbicide Atrazine Alters Some Sexually Selected Traits In Male Guppies, Kausalya Shenoy

Biology Faculty Publications

Male mating signals, including ornaments and courtship displays, and other sexually selected traits, like male-male aggression, are largely controlled by sex hormones. Environmental pollutants, notably endocrine disrupting compounds, can interfere with the proper functioning of hormones, thereby impacting the expression of hormonally regulated traits. Atrazine, one of the most widely used herbicides, can alter sex hormone levels in exposed animals. I tested the effects of environmentally relevant atrazine exposures on mating signals and behaviors in male guppies, a sexually dimorphic freshwater fish. Prolonged atrazine exposure reduced the expression of two honest signals: the area of orange spots (ornaments) and the …

Decorin-Mediated Inhibition Of Colorectal Cancer Growth And Migration Is Associated With E-Cadherin In Vitro And In Mice., Xiuli Bi, Nicole M Pohl, Zhibin Qian, George R Yang, Yuan Gou, Grace Guzman, Andre Kajdacsy-Balla, Renato V Iozzo, Wancai Yang

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Previous studies have shown that decorin expression is significantly reduced in colorectal cancer tissues and cancer cells, and genetic deletion of the decorin gene is sufficient to cause intestinal tumor formation in mice, resulting from a downregulation of p21, p27(kip1) and E-cadherin and an upregulation of β-catenin signaling [Bi,X. et al. (2008) Genetic deficiency of decorin causes intestinal tumor formation through disruption of intestinal cell maturation. Carcinogenesis, 29, 1435-1440]. However, the regulation of E-cadherin by decorin and its implication in cancer formation and metastasis is largely unknown. Using a decorin knockout mouse model (Dcn(-/-) mice) and manipulated expression of decorin …

Pressure-Overload-Induced Subcellular Relocalization/Oxidation Of Soluble Guanylyl Cyclase In The Heart Modulates Enzyme Stimulation., Emily J Tsai, Yuchuan Liu, Norimichi Koitabashi, Djahida Bedja, Thomas Danner, Jean-Francois Jasmin, Michael P Lisanti, Andreas Friebe, Eiki Takimoto, David A Kass

Department of Stem Cell Biology and Regenerative Medicine Faculty Papers & Presentations

RATIONALE: Soluble guanylyl cyclase (sGC) generates cyclic guanosine monophophate (cGMP) upon activation by nitric oxide (NO). Cardiac NO-sGC-cGMP signaling blunts cardiac stress responses, including pressure-overload-induced hypertrophy. The latter itself depresses signaling through this pathway by reducing NO generation and enhancing cGMP hydrolysis.

OBJECTIVE: We tested the hypothesis that the sGC response to NO also declines with pressure-overload stress and assessed the role of heme-oxidation and altered intracellular compartmentation of sGC as potential mechanisms.

METHODS AND RESULTS: C57BL/6 mice subjected to transverse aortic constriction (TAC) developed cardiac hypertrophy and dysfunction. NO-stimulated sGC activity was markedly depressed, whereas NO- and heme-independent sGC …

Rna-Seq Based Transcriptional Map Of Bovine Respiratory Disease Pathogen "Histophilus Somni 2336"., Ranjit Kumar, Mark L. Lawrence, James Watt, Amanda M. Cooksey, Shane C. Burgess, Bindu Nanduri

CVM Publications

Genome structural annotation, i.e., identification and demarcation of the boundaries for all the functional elements in a genome (e.g., genes, non-coding RNAs, proteins and regulatory elements), is a prerequisite for systems level analysis. Current genome annotation programs do not identify all of the functional elements of the genome, especially small non-coding RNAs (sRNAs). Whole genome transcriptome analysis is a complementary method to identify "novel" genes, small RNAs, regulatory regions, and operon structures, thus improving the structural annotation in bacteria. In particular, the identification of non-coding RNAs has revealed their widespread occurrence and functional importance in gene regulation, stress and virulence. …

Orai1 Deficiency Leads To Heart Failure And Skeletal Myopathy In Zebrafish., Mirko Völkers, Nima Dolatabadi, Natalie Gude, Patrick Most, Mark A Sussman, David Hassel

Center for Translational Medicine Faculty Papers

Mutations in the store-operated Ca²⁺ entry pore protein ORAI1 have been reported to cause myopathies in human patients but the mechanism involved is not known. Cardiomyocytes express ORAI1 but its role in heart function is also unknown. Using reverse genetics in zebrafish, we demonstrated that inactivation of the highly conserved zebrafish orthologue of ORAI1 resulted in severe heart failure, reduced ventricular systolic function, bradycardia and skeletal muscle weakness. Electron microscopy of Orai1-deficient myocytes revealed progressive skeletal muscle instability with loss of myofiber integrity and ultrastructural abnormalities of the z-disc in both skeletal and cardiac muscle. Isolated Orai1-deficient cardiomyocytes showed loss …

Uterine Dysfunction In Biglycan And Decorin Deficient Mice Leads To Dystocia During Parturition., Zhiping Wu, Abraham W Aron, Elyse E Macksoud, Renato V Iozzo, Chi-Ming Hai, Beatrice E Lechner

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Cesarean birth rates are rising. Uterine dysfunction, the exact mechanism of which is unknown, is a common indication for Cesarean delivery. Biglycan and decorin are two small leucine-rich proteoglycans expressed in the extracellular matrix of reproductive tissues and muscle. Mice deficient in biglycan display a mild muscular dystrophy, and, along with mice deficient in decorin, are models of Ehlers-Danlos Syndrome, a connective tissue anomaly associated with uterine rupture. As a variant of Ehlers-Danlos Syndrome is caused by a genetic mutation resulting in abnormal biglycan and decorin secretion, we hypothesized that biglycan and decorin play a role in uterine function. Thus, …

A High Density Snp Array For The Domestic Horse And Extant Perissodactyla: Utility For Association Mapping, Genetic Diversity, And Phylogeny Studies, Molly E. Mccue, Danika L. Bannasch, Jessica L. Petersen, Jessica Gurr, Ernie Bailey, Matthew M. Binns, Ottmar Distl, Gérard Guérin, Telhisa Hasegawa, Emmeline W. Hill, Tosso Leeb, Gabriella Lindgren, M Cecilia T. Penedo, Knut H. Røed, Oliver A. Ryder, June E. Swinburne, Teruaki Tozaki, Stephanie J. Valberg, Mark Vaudin, Kerstin Lindblad-Toh, Claire M. Wade, James R. Mickelson

Veterinary Science Faculty Publications

An equine SNP genotyping array was developed and evaluated on a panel of samples representing 14 domestic horse breeds and 18 evolutionarily related species. More than 54,000 polymorphic SNPs provided an average inter-SNP spacing of ∼43 kb. The mean minor allele frequency across domestic horse breeds was 0.23, and the number of polymorphic SNPs within breeds ranged from 43,287 to 52,085. Genome-wide linkage disequilibrium (LD) in most breeds declined rapidly over the first 50-100 kb and reached background levels within 1-2 Mb. The extent of LD and the level of inbreeding were highest in the Thoroughbred and lowest in the …

Inflammatory Signaling Compromises Cell Responses To Interferon Alpha., W-C Huangfu, J Qian, C Liu, J Liu, A E Lokshin, D P Baker, H Rui, S Y Fuchs

Department of Cancer Biology Faculty Papers

Interferon alpha (IFNα) is widely used for treatment of melanoma and certain other malignancies. This cytokine as well as the related IFNβ exerts potent anti-tumorigenic effects; however, their efficacy in patients is often suboptimal. Here, we report that inflammatory signaling impedes the effects of IFNα/β. Melanoma cells can secrete pro-inflammatory cytokines that inhibit cellular responses to IFNα/β via activating the ligand-independent pathway for the phosphorylation and subsequent ubiquitination and accelerated degradation of the IFNAR1 chain of type I IFN receptor. Catalytic activity of the p38 protein kinase was required for IFNAR1 downregulation and inhibition of IFNα/β signaling induced by proinflammatory …

Enteric Alpha Defensins In Norm And Pathology., Nikolai A Lisitsyn, Yulia A Bukurova, Inna G Nikitina, George S Krasnov, Yuri Sykulev, Sergey F Beresten

Kimmel Cancer Center Faculty Papers

ABSTRACT: Microbes living in the mammalian gut exist in constant contact with immunity system that prevents infection and maintains homeostasis. Enteric alpha defensins play an important role in regulation of bacterial colonization of the gut, as well as in activation of pro- and anti-inflammatory responses of the adaptive immune system cells in lamina propria. This review summarizes currently available data on functions of mammalian enteric alpha defensins in the immune defense and changes in their secretion in intestinal inflammatory diseases and cancer.

Usp8 Promotes Smoothened Signaling By Preventing Its Ubiquitination And Changing Its Subcellular Localization, Ruohan Xia, Hongge Jia, Junkai Fan, Yajuan Liu, Jianhang Jia

Molecular and Cellular Biochemistry Faculty Publications

The seven transmembrane protein Smoothened (Smo) is a critical component of the Hedgehog (Hh) signaling pathway and is regulated by phosphorylation, dimerization, and cell-surface accumulation upon Hh stimulation. However, it is not clear how Hh regulates Smo accumulation on the cell surface or how Hh regulates the intracellular trafficking of Smo. In addition, little is known about whether ubiquitination is involved in Smo regulation. In this study, we demonstrate that Smo is multi-monoubiquitinated and that Smo ubiquitination is inhibited by Hh and by phosphorylation. Using an in vivo RNAi screen, we identified ubiquitin-specific protease 8 (USP8) as a deubiquitinase that …

Hiv-1 Tat Triggers Nuclear Localization Of Zo-1 Via Rho Signaling And Camp Response Element-Binding Protein Activation, Yu Zhong, Bei Zhang, Sung Yong Eum, Michal Toborek

Neurosurgery Faculty Publications

The human immunodeficiency virus (HIV)-specific protein trans-activator of transcription (Tat) can contribute to the dysfunction of brain endothelial cells and HIV trafficking into the brain by disrupting tight junction (TJ) integrity at the blood–brain barrier (BBB) level. Specific TJ proteins, such as zonula occludens (ZO) proteins, localize not only at the cell–cell borders but are also present in the nuclei. The objective of the present study was to evaluate the mechanisms and significance of Tat-induced nuclear localization of ZO-1. Treatment of a brain endothelial cell line (hCMEC/D3 cells) with Tat resulted in a decrease in total levels of ZO-1 but …

The Complete Mitochondrial Genome And Novel Gene Arrangement Of The Unique-Headed Bug Stenopirates Sp. (Hemiptera: Enicocephalidae), Hu Li, Hui Liu, Aimin Shi, Pavel Stys, Xuguo Zhou, Wanzhi Cai

Entomology Faculty Publications

Many of true bugs are important insect pests to cultivated crops and some are important vectors of human diseases, but few cladistic analyses have addressed relationships among the seven infraorders of Heteroptera. The Enicocephalomorpha and Nepomorpha are consider the basal groups of Heteroptera, but the basal-most lineage remains unresolved. Here we report the mitochondrial genome of the unique-headed bug Stenopirates sp., the first mitochondrial genome sequenced from Enicocephalomorpha. The Stenopirates sp. mitochondrial genome is a typical circular DNA molecule of 15, 384 bp in length, and contains 37 genes and a large non-coding fragment. The gene order differs substantially from …

Mapping Migratory Bird Prevalence Using Remote Sensing Data Fusion, Anu Swatantran, Ralph Dubayah, Scott Goetz, Michelle Hofton, Matthew G. Betts, Mindy Sun, Marc Simard, Richard Holmes

Dartmouth Scholarship

Background: Improved maps of species distributions are important for effective management of wildlife under increasing anthropogenic pressures. Recent advances in lidar and radar remote sensing have shown considerable potential for mapping forest structure and habitat characteristics across landscapes. However, their relative efficacies and integrated use in habitat mapping remain largely unexplored. We evaluated the use of lidar, radar and multispectral remote sensing data in predicting multi-year bird detections or prevalence for 8 migratory songbird species in the unfragmented temperate deciduous forests of New Hampshire, USA.

Methodology and Principal Findings: A set of 104 predictor variables describing vegetation vertical structure and …

Sociology And Anthrozoology: Symbolic Interactionist Contributions, Leslie Irvine

Human and Animal Bonding Collection

This essay examines the sociological contributions to anthrozoology, focusing on research from the United States that employs a symbolic interactionist perspective. In particular, the work of Arluke and Sanders highlights the importance of understanding the meanings that animals hold for people. Using a selective review of their research, this essay outlines how a focus on understanding meaning can inform anthrozoological research. Arluke’s research on animal abuse reveals how harm must be defined in context. Sanders’s research on canine–human relationships documents how people come to understand companion dogs as persons. Both bodies of work rely on careful observation and listening to …

Tropical Medicine Training In The Department Of Defense, Rodney L. Coldren, David Brett-Major, Patrick W. Hickey, Eric Garges, Peter J. Weina, Paula Corrigan, Gerald Quinnan

Journal Articles: Epidemiology

No abstract provided.

Creation Of A Natural History Information Database With Mobile Device Access For The Pace Campus In Pleasantville, Joshua J. Schwartz, Martina Blackwood

Cornerstone 3 Reports : Interdisciplinary Informatics

No abstract provided.

Testing Phylogenetic Hypotheses Of The Subgenera Of The Freshwater Crayfish Genus Cambarus (Decapoda: Cambaridae)., Jesse W Breinholt, Megan L Porter, Keith A Crandall

Computational Biology Institute

BACKGROUND: The genus Cambarus is one of three most species rich crayfish genera in the Northern Hemisphere. The genus has its center of diversity in the Southern Appalachians of the United States and has been divided into 12 subgenera. Using Cambarus we test the correspondence of subgeneric designations based on morphology used in traditional crayfish taxonomy to the underlying evolutionary history for these crayfish. We further test for significant correlation and explanatory power of geographic distance, taxonomic model, and a habitat model to estimated phylogenetic distance with multiple variable regression.

METHODOLOGY/PRINCIPAL FINDINGS: We use three mitochondrial and one nuclear gene …

Dimerization And Heme Binding Are Conserved In Amphibian And Starfish Homologues Of The Microrna Processing Protein Dgcr8., Rachel Senturia, Arthur Laganowsky, Ian Barr, Brooke D. Scheidemantle, Feng Guo

Natural Sciences and Mathematics | Faculty Scholarship

Human DiGeorge Critical Region 8 (DGCR8) is an essential microRNA (miRNA) processing factor that is activated via direct interaction with Fe(III) heme. In order for DGCR8 to bind heme, it must dimerize using a dimerization domain embedded within its heme-binding domain (HBD). We previously reported a crystal structure of the dimerization domain from human DGCR8, which demonstrated how dimerization results in the formation of a surface important for association with heme. Here, in an attempt to crystallize the HBD, we search for DGCR8 homologues and show that DGCR8 from Patiria miniata (bat star) also binds heme. The extinction coefficients (ε) …

Limitations Of The Rhesus Macaque Draft Genome Assembly And Annotation, Xiongfei Zhang, Joel Goodsell, Robert B. Norgren

Journal Articles: Genetics, Cell Biology & Anatomy

Finished genome sequences and assemblies are available for only a few vertebrates. Thus, investigators studying many species must rely on draft genomes. Using the rhesus macaque as an example, we document the effects of sequencing errors, gaps in sequence and misassemblies on one automated gene model pipeline, Gnomon. The combination of draft genome with automated gene finding software can result in spurious sequences. We estimate that approximately 50% of the rhesus gene models are missing, incomplete or incorrect. The problems identified in this work likely apply to all draft vertebrate genomes annotated with any automated gene model pipeline and thus …

Identification Of The Functional Binding Pocket For Compounds Targeting Small-Conductance Ca²⁺-Activated Potassium Channels., Miao Zhang, John M Pascal, Marcel Schumann, Roger S Armen, Ji-Fang Zhang

Department of Molecular Physiology and Biophysics Faculty Papers

Small- and intermediate-conductance Ca(2+)-activated potassium channels, activated by Ca(2+)-bound calmodulin, have an important role in regulating membrane excitability. These channels are also linked to clinical abnormalities. A tremendous amount of effort has been devoted to developing small molecule compounds targeting these channels. However, these compounds often suffer from low potency and lack of selectivity, hindering their potential for clinical use. A key contributing factor is the lack of knowledge of the binding site(s) for these compounds. Here we demonstrate by X-ray crystallography that the binding pocket for the compounds of the 1-ethyl-2-benzimidazolinone (1-EBIO) class is located at the calmodulin-channel interface. …

Aleuria Aurantia Lectin (Aal)-Reactive Immunoglobulin G Rapidly Appears In Sera Of Animals Following Antigen Exposure., Songming Chen, Chen Lu, Hongbo Gu, Anand Mehta, Jianwei Li, Patrick B Romano, David Horn, D Craig Hooper, Carthene R Bazemore-Walker, Timothy Block

Department of Cancer Biology Faculty Papers

We have discovered an Aleuria Aurantia Lectin (AAL)-reactive immunoglobulin G (IgG) that naturally occurs in the circulation of rabbits and mice, following immune responses induced by various foreign antigens. AAL can specifically bind to fucose moieties on glycoproteins. However, most serum IgGs are poorly bound by AAL unless they are denatured or treated with glycosidase. In this study, using an immunogen-independent AAL-antibody microarray assay that we developed, we detected AAL-reactive IgG in the sera of all animals that had been immunized 1-2 weeks previously with various immunogens with and without adjuvants and developed immunogen-specific responses. All of these animals subsequently …

Gentamicin Rapidly Inhibits Mitochondrial Metabolism In High-Frequency Cochlear Outer Hair Cells, Heather Jensen Smith, Richard Hallworth, Michael G. Nichols

Journal Articles: Eppley Institute

Aminoglycosides (AG), including gentamicin (GM), are the most frequently used antibiotics in the world and are proposed to cause irreversible cochlear damage and hearing loss (HL) in 1/4 of the patients receiving these life-saving drugs. Akin to the results of AG ototoxicity studies, high-frequency, basal turn outer hair cells (OHCs) preferentially succumb to multiple HL pathologies while inner hair cells (IHCs) are much more resilient. To determine if endogenous differences in IHC and OHC mitochondrial metabolism dictate differential sensitivities to AG-induced HL, IHC- and OHC-specific changes in mitochondrial reduced nicotinamide adenine dinucleotide (NADH) fluorescence during acute (1 h) GM treatment …

Methamphetamine Administration Targets Multiple Immune Subsets And Induces Phenotypic Alterations Suggestive Of Immunosuppression., Robert Z. Harms, Brenda M. Morsey, Craig W. Boyer, Howard S. Fox, Nora E. Sarvetnick

Journal Articles: Regenerative Medicine

Methamphetamine (Meth) is a widely abused stimulant and its users are at increased risk for multiple infectious diseases. To determine the impact of meth on the immune system, we utilized a murine model that simulates the process of meth consumption in a typical addict. Our phenotypic analysis of leukocytes from this dose escalation model revealed that meth affected key immune subsets. Meth administration led to a decrease in abundance of natural killer (NK) cells and the remaining NK cells possessed a phenotype suggesting reduced responsiveness. Dendritic cells (DCs) and Gr-1(high) monocytes/macrophages were also decreased in abundance while Gr-1(low) monocytes/macrophages appear …

Malaria And Related Outcomes In Patients With Intestinal Helminths: A Cross-Sectional Study, Abraham Degarege, Mengistu Legesse, Girmay Medhin, Abebe Animut, Berhanu Erko

Journal Articles: Epidemiology

BACKGROUND: The effects of helminth co-infection on malaria in humans remain uncertain. This study aimed to evaluate the nature of association of intestinal helminths with prevalence and clinical outcomes of Plasmodium infection.

METHODS: A cross-sectional study involving 1,065 malaria suspected febrile patients was conducted at Dore Bafeno Health Center, Southern Ethiopia, from December 2010 to February 2011. Plasmodium and intestinal helminth infections were diagnosed using Giemsa-stained blood films and Kato-Katz technique, respectively. Haemoglobin level was determined using a haemocue machine.

RESULTS: Among 1,065 malaria suspected febrile patients, 28.8% were positive for Plasmodium parasites (P. falciparum =13.0%, P. vivax =14.5%, P. …

Seg1 Controls Eisosome Assembly And Shape, Karen E. Moreira, Sebastian Schuck, Bianca Schrul, Florian Fröhlich, James B. Moseley

Dartmouth Scholarship

Eisosomes are stable domains at the plasma membrane of the budding yeast Saccharomyces cerevisiae and have been proposed to function in endocytosis. Eisosomes are composed of two main cytoplasmic proteins, Pil1 and Lsp1, that form a scaffold around furrow-like plasma membrane invaginations. We show here that the poorly characterized eisosome protein Seg1/Ymr086w is important for eisosome biogenesis and architecture. Seg1 was required for efficient incorporation of Pil1 into eisosomes and the generation of normal plasma membrane furrows. Seg1 preceded Pil1 during eisosome formation and established a platform for the assembly of other eisosome components. This platform was further shaped and …

Ceria-Engineered Nanomaterial Distribution In, And Clearance From, Blood: Size Matters, Mo Dan, Peng Wu, Eric A. Grulke, Uschi M. Graham, Jason M. Unrine, Robert A. Yokel

Pharmaceutical Sciences Faculty Publications

AIMS: Characterize different sized ceria-engineered nanomaterial (ENM) distribution in, and clearance from, blood (compared to the cerium ion) following intravenous infusion.

MATERIALS & METHODS: Cerium (Ce) was quantified in whole blood, serum and clot (the formed elements) up to 720 h.

RESULTS: Traditional pharmacokinetic modeling showed best fit for 5 nm ceria ENM and the cerium ion. Ceria ENMs larger than 5 nm were rapidly cleared from blood. After initially declining, whole blood 15 and 30 nm ceria increased (results that have not been well-described by traditional pharmacokinetic modeling). The cerium ion and 5 and 55 nm ceria did not …

Neuroangiogenesis: A Vascular Basis For Alzheimer's Disease And Cognitive Decline During Aging, Charles T. Ambrose

Microbiology, Immunology, and Molecular Genetics Faculty Publications

Angiogenesis directs development of the brain's microcirculation during antenatal and postnatal development, but its role later in life is less well recognized. I contend that during senescence a reduced cerebral capillary density accounts in part for the vascular cognitive impairment observed in many older persons and possibly for some forms of Alzheimer's disease. I propose that neuroangiogenesis is essential throughout adult life for maintaining the microcirculation of the cerebral cortex and elsewhere in the brain and that it commonly declines with old age. To support this hypothesis I have examined the neurological literature for relevant studies on cerebral capillary density …

It's Not All About The Animals: Veterinarians' Perspectives On Their Work, Nicole Owens

Electronic Theses and Dissertations

This study examines lived experiences of veterinarians. A common feature of being a veterinarian is curing and caring for nonhuman animals. It is the love and connection most veterinarians share for animals that ignite their journey to become an animal doctor. Data collected during semi-structured interviews with 17 veterinarians reveal that there are many more intricacies to the job than just animal medicine. These veterinarians suggest that they must treat animals as learning tools during veterinary training and once they complete school, they deal with people and business on a regular basis. Most veterinarians would like their jobs to be …

Prevalence Of Anguillicoloides Crassus And Growth Variation In Migrant Yellow-Phase American Eels Of The Upper Potomac River Drainage, Jl Zimmerman, Sa Welsh

Faculty & Staff Scholarship

No abstract provided.