Digital Commons Network^™

Conservation Of Inner Nuclear Membrane Targeting Sequences In Mammalian Pom121 And Yeast Heh2 Membrane Proteins., Annemarie Kralt, Noorjahan B Jagalur, Vincent Van Den Boom, Ravi K Lokareddy, Anton Steen, Gino Cingolani, Maarten Fornerod, Liesbeth M Veenhoff

Department of Biochemistry and Molecular Biology Faculty Papers

Endoplasmic reticulum-synthesized membrane proteins traffic through the nuclear pore complex (NPC) en route to the inner nuclear membrane (INM). Although many membrane proteins pass the NPC by simple diffusion, two yeast proteins, ScSrc1/ScHeh1 and ScHeh2, are actively imported. In these proteins, a nuclear localization signal (NLS) and an intrinsically disordered linker encode the sorting signal for recruiting the transport factors for FG-Nup and RanGTP-dependent transport through the NPC. Here we address whether a similar import mechanism applies in metazoans. We show that the (putative) NLSs of metazoan HsSun2, MmLem2, HsLBR, and HsLap2β are not sufficient to drive nuclear accumulation of …

Week Of September 14, 2015, New York Medical College

InTouch

• Dean Miller Hosts School of Medicine Retreat
• Adam D. Hammerman Named VP for Financial Operations
• NYMC Joins the Good Food Farmers Network

High Throughput Sequencing Identifies Micrornas Mediating Α-Synuclein Toxicity By Targeting Neuroactive-Ligand Receptor Interaction Pathway In Early Stage Of Drosophila Parkinson's Disease Model., Yan Kong, Xijun Liang, Lin Liu, Dongdong Zhang, Chao Wan, Zhenji Gan, Liudi Yuan, Bing-Hua Jiang

Department of Medicine Faculty Papers

Parkinson's disease (PD) is a prevalent neurodegenerative disorder with pathological features including death of dopaminergic neurons in the substantia nigra and intraneuronal accumulations of Lewy bodies. As the main component of Lewy bodies, α-synuclein is implicated in PD pathogenesis by aggregation into insoluble filaments. However, the detailed mechanisms underlying α-synuclein induced neurotoxicity in PD are still elusive. MicroRNAs are ~20nt small RNA molecules that fine-tune gene expression at posttranscriptional level. A plethora of miRNAs have been found to be dysregulated in the brain and blood cells of PD patients. Nevertheless, the detailed mechanisms and their in vivo functions in PD …

Differential Expression Of Mrna Encoding Cytokines And Chemokines In The Reproductive Tract After Infection Of Mice With Chlamydia Trachomatis, Katheryn L. Cerny, Maranda Van Fleet, Anatoly Slepenkin, Ellena M. Peterson, Phillip J. Bridges

Animal and Food Sciences Faculty Publications

Infection with Chlamydia trachomatis targets epithelial cells within the genital tract which respond by secreting chemokines and cytokines. Persistent inflammation can lead to fibrosis, tubal infertility and/or ectopic pregnancy; many infections are asymptomatic. Most studies have investigated the inflammatory response in the initial stages of infection, less is known about the later stages of infection, especially with a low, potentially asymptomatic, bacterial load. Our objective was to determine the inflammatory mediators involved in clearance of low-grade infection and the potential involvement in chronic inflammation. Six to eight week old C3H/HeJ mice were pretreated with 2.5 mg medroxyprogesterone acetate on day …

Novel Approaches Reveal That Toxoplasma Gondii Bradyzoites Within Tissue Cysts Are Dynamic And Replicating Entities In Vivo, Elizabeth Watts, Yihua Zhao, Animesh Dhara, Becca Eller, Abhijit R. Patwardhan, Anthony P. Sinai

Microbiology, Immunology, and Molecular Genetics Faculty Publications

Despite their critical role in chronic toxoplasmosis, the biology of Toxoplasma gondii bradyzoites is poorly understood. In an attempt to address this gap, we optimized approaches to purify tissue cysts and analyzed the replicative potential of bradyzoites within these cysts. In order to quantify individual bradyzoites within tissue cysts, we have developed imaging software, BradyCount 1.0, that allows the rapid establishment of bradyzoite burdens within imaged optical sections of purified tissue cysts. While in general larger tissue cysts contain more bradyzoites, their relative "occupancy" was typically lower than that of smaller cysts, resulting in a lower packing density. The packing …

The Role Of Perlecan And Endorepellin In The Control Of Tumor Angiogenesis And Endothelial Cell Autophagy., Stephen Douglass, Atul Goyal, Renato V. Iozzo

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

During tumor growth and angiogenesis there is a dynamic remodeling of tissue architecture often accompanied by the release of extracellular matrix constituents full of biological activity. One of the key constituents of the tumor microenvironment is the large heparan sulfate proteoglycan perlecan. This proteoglycan, strategically located at cell surfaces and within basement membranes, is a well-defined pro-angiogenic molecule when intact. However, when partially processed by proteases released during cancer remodeling and invasion, the C-terminal fragment of perlecan, known as endorepellin, has opposite effects than its parent molecule. Endorepellin is a potent inhibitor of angiogenesis by exerting a dual receptor antagonism …

Jan Van Der Noordaa (1934-2015); A Virologist Pur Sang., Ben Berkhout, Michael Bukrinsky

Microbiology, Immunology, and Tropical Medicine Faculty Publications

No abstract provided.

The Tri-State Experience: Outcome Analysis Of Patients With Triple Negative Breast Cancer Treated At Marshall University, Laurie Matt Md, Mph, Mohammad Mozayen Md, Todd W. Gress Md, Maria Tria Tirona Md

Internal Medicine

Breast cancer is the most frequently diagnosed malignancy in women in the United States. It is the second most common malignancy to cause death, with approximately 39,000 women dying of breast cancer in the United States in 2013. Triple negative breast cancer is defined as the absence of estrogen, progesterone and human epidermal growth factor receptor 2 receptors. It has been associated with a higher incidence in African American women, a younger age and a more advanced stage at diagnosis, and an inferior overall survival. To recognize the differences of our West Virginia community population when compared to the national …

The Conserved G-Protein Coupled Receptor Fshr-1 Regulates Protective Host Responses To Infection And Oxidative Stress, Elizabeth V. Miller, Leah N. Grandi, Jennifer A. Giannini, Joseph D. Robinson, Jennifer R. Powell

Biology Faculty Publications

The innate immune system’s ability to sense an infection is critical so that it can rapidly respond if pathogenic microorganisms threaten the host, but otherwise maintain a quiescent baseline state to avoid causing damage to the host or to commensal microorganisms. One important mechanism for discriminating between pathogenic and non-pathogenic bacteria is the recognition of cellular damage caused by a pathogen during the course of infection. InCaenorhabditis elegans, the conserved G-protein coupled receptor FSHR-1 is an important constituent of the innate immune response. FSHR-1 activates the expression of antimicrobial infection response genes in infected worms and delays accumulation …

Impact Of Dietary Components On Nk And Treg Cell Function For Cancer Prevention, Young S. Kim, Thomas J. Sayers, Nancy H. Colburn, John A. Milner, Howard A. Young

United States Public Health Resources

An important characteristic of cancer is that the disease can overcome the surveillance of the immune system. A possible explanation for this resistance arises from the ability of tumor cells to block the tumoricidal activity of host immune cells such as natural killer (NK) cells by inducing the localized accumulation of regulatory T (Treg) cells. Evidence exists that components in commonly consumed foods including vitamins A, D, and E, water-soluble constituents of mushrooms, polyphenolics in fruits and vegetables, and n-3 fatty acids in fish oil can modulate NK cell activities, Treg cell properties, and the interactions between those two cell …

Method And System For Diagnosis Of Lawsonia Intracellularis, Harold F. Stills Jr., David W. Horohov, Allen E. Page

Microbiology, Immunology and Molecular Genetics Faculty Patents

A method, system, and kit are provided for diagnosing L. intracellularis infection or exposure in a subject. The method includes purifying whole L. intracellularis from host cells and host debris produced in or on a suitable medium and adhering the purified whole L. intracellularis on a suitable material to form an antigen substrate for determining whether a subject produces L. intracellularis-specific antibodies against the antigen to thereby indicate L. intracellularis exposure or infection in the subject. The kit includes purified whole L. intracellularis produced from host cells and host debris adhered to a suitable material to form an antigen …

Trim21 Regulates Nmi-Ifi35 Complex-Mediated Inhibition Of Innate Antiviral Response, Anshuman Das, Phat X. Dinh, Asit K. Pattnaik

School of Veterinary and Biomedical Sciences: Faculty Publications

In this study, using an immunoprecipitation coupled with mass spectrometry approach, we have identified the E3 ubiquitin ligase Trim21 as an interacting partner of IFI35 and Nmi. We found that this interaction leads to K63-linked ubiquitination on K22 residue of Nmi, but not IFI35. Using domain deletion analysis, we found that the interaction is mediated via the coiled-coil domain of Nmi and the carboxyl-terminal SPRY domain of Trim21. Furthermore, we show that depletion of Trim21 leads to significantly reduced interaction of Nmi with IFI35, which results in the abrogation of the negative regulatory function of the Nmi-IFI35 complex on innate …

Rna-Seq Analysis Of Differential Splice Junction Usage And Intron Retentions By Dexseq, Yafang Li, Xiayu Rao, William W. Mattox, Christopher I. Amos, Bin Liu

Dartmouth Scholarship

Alternative splicing is an important biological process in the generation of multiple functional transcripts from the same genomic sequences. Differential analysis of splice junctions (SJs) and intron retentions (IRs) is helpful in the detection of alternative splicing events. In this study, we conducted differential analysis of SJs and IRs by use of DEXSeq, a Bioconductor package originally designed for differential exon usage analysis in RNA-seq data analysis. We set up an analysis pipeline including mapping of RNA-seq reads, the preparation of count tables of SJs and IRs as the input files, and the differential analysis in DEXSeq. We analyzed the …

Intracellular Na+ Concentration ([Na+]I) Is Elevated In Diabetic Hearts Due To Enhanced Na+–Glucose Cotransport, Rebekah Lambert, Sarah Srodulski, Xiaoli Peng, Kenneth B. Margulies, Florin Despa, Sanda Despa

Pharmacology and Nutritional Sciences Faculty Publications

BACKGROUND: Intracellular Na⁺ concentration ([Na⁺]i) regulates Ca²⁺ cycling, contractility, metabolism, and electrical stability of the heart. [Na⁺]i is elevated in heart failure, leading to arrhythmias and oxidative stress. We hypothesized that myocyte [Na⁺]i is also increased in type 2 diabetes (T2D) due to enhanced activity of the Na⁺-glucose cotransporter.

METHODS AND RESULTS: To test this hypothesis, we used myocardial tissue from humans with T2D and a rat model of late-onset T2D (HIP rat). Western blot analysis showed increased Na⁺-glucose cotransporter expression in failing hearts from T2D patients compared …

Novel Human Abcc9/Sur2 Brain-Expressed Transcripts And An Eqtl Relevant To Hippocampal Sclerosis Of Aging, Peter T. Nelson, Wang-Xia Wang, Bernard R. Wilfred, Angela Wei, James Dimayuga, Qingwei Huang, Eseosa T. Ighodaro, Sergey C. Artiushin, David W. Fardo

Sanders-Brown Center on Aging Faculty Publications

ABCC9 genetic polymorphisms are associated with increased risk for various human diseases including hippocampal sclerosis of aging. The main goals of this study were 1 > to detect the ABCC9 variants and define the specific 3′ untranslated region (3′UTR) for each variant in human brain, and 2 > to determine whether a polymorphism (rs704180) associated with risk for hippocampal sclerosis of aging pathology is also associated with variation in ABCC9 transcript expression and/or splicing. Rapid amplification of ABCC9 cDNA ends (3′RACE) provided evidence of novel 3′ UTR portions of ABCC9 in human brain. In silico and experimental studies were performed focusing on …

Platelet-Activating Factor Receptor Affects Food Intake And Body Weight, Wei Li, Thomas M. Mcintyre

Biomedical Sciences

“Let’s Move!” is a comprehensive initiative, launched by the First Lady, Michelle Obama, dedicates to solving problems of obesity, which is growing in child. The life behaviors do affect obesity; however, the mechanistic insight in molecular level is still not clear. In this study, by continually monitoring mouse body weight under chow and high fat western diets as well as metabolic, physical activity and food intake behaviors assessed in a CLAMS Comprehensive Lab Animal Monitoring System, we demonstrated that the platelet-activating factor receptor (PTAFR) contributes to modification of life behaviors. PTAFR does not affect metabolism of ingested dietary fat and …

Dietary Intake And Bio-Activation Of Nitrite And Nitrate In Newborn Infants, Jesica Ann Jones

Loma Linda University Electronic Theses, Dissertations & Projects

Nitrate and nitrite are commonly thought of as inert end products of nitric oxide (NO) oxidation, possibly carcinogenic food additives, or well-water contaminants. However, recent studies have shown that nitrate and nitrite play an important role in cardiovascular and gastrointestinal homeostasis through conversion back into NO via a physiological system involving enterosalivary recirculation, bacterial nitrate reductases, and enzyme-catalyzed or acidic reduction of nitrite to NO. The diet is a key source of nitrate in adults; however, infants ingest significantly less nitrate due to low concentrations in breast milk. In the mouth, bacteria convert nitrate to nitrite, which has gastro-protective effects. …

Palmitic Acid Activation Of Dendritic Cells: Implications For Type 2 Diabetes, Dequina Angelina Nicholas

Loma Linda University Electronic Theses, Dissertations & Projects

Infiltration of immune cells into visceral adipose tissue is observed in type 2 diabetes development. Monocytes are recruited to obese visceral adipose tissue in large numbers and retain the ability to differentiate into dendritic cells, important antigen presenting cells in the immune system. Differentiation of monocytes into dendritic cells likely accounts for the increased number of dendritic cells observed in the adipose tissue of type 2 diabetic patients. We have demonstrated this differentiation process is regulated in part by a major reduction of linker histone proteins. In adipose tissue, dendritic cells are exposed to high levels of saturated fatty acids. …

Discovering Distinct Functional Modules Of Specific Cancer Types Using Protein-Protein Interaction Networks., Ru Shen, Xiaosheng Wang, Chittibabu Guda

Journal Articles: Genetics, Cell Biology & Anatomy

Background. The molecular profiles exhibited in different cancer types are very different; hence, discovering distinct functional modules associated with specific cancer types is very important to understand the distinct functions associated with them. Protein-protein interaction networks carry vital information about molecular interactions in cellular systems, and identification of functional modules (subgraphs) in these networks is one of the most important applications of biological network analysis. Results. In this study, we developed a new graph theory based method to identify distinct functional modules from nine different cancer protein-protein interaction networks. The method is composed of three major steps: (i) extracting modules …

Week Of August 31, 2015, New York Medical College

InTouch

• NYMC Achieves Top ACCME Accreditation
• CrisisManager Makes Campus Debut
• GSBMS Hosts Fourth Annual STAR Student Research Forum
• Karen Sanders, M.D. '77, deputy chief academic affiliations officer of the U.S. Department of Veterans Affairs, Visits NYMC
• NYMC Joins the Good Food Farmers Network
• High Schoolers Visit NYMC for Insider's View of Medicine

Mitochondrial Activity And Cyr1 Are Key Regulators Of Ras1 Activation Of C. Albicans Virulence Pathways, Nora Grahl, Elora G. Demers, Allia K. Lindsay, Colleen E. Harty, Sven D. Wilger, Amy E. Piispanen, Deborah A. Hogan

Dartmouth Scholarship

Candida albicans is both a major fungal pathogen and a member of the commensal human microflora. The morphological switch from yeast to hyphal growth is associated with disease and many environmental factors are known to influence the yeast-to-hyphae switch. The Ras1-Cyr1-PKA pathway is a major regulator of C. albicans morphogenesis as well as biofilm formation and white-opaque switching. Previous studies have shown that hyphal growth is strongly repressed by mitochondrial inhibitors. Here, we show that mitochondrial inhibitors strongly decreased Ras1 GTP-binding and activity in C. albicans and similar effects were observed in other Candida species. Consistent with there …

Gene Diversification Of An Emerging Pathogen: A Decade Of Mutation In A Novel Fish Viral Hemorrhagic Septicemia (Vhs) Substrain Since Its First Appearance In The Laurentian Great Lakes, Carol A. Stepien, Lindsey R. Pierce, Douglas W. Leaman, Megan D. Niner, Brian S. Shepherd

Biological Sciences Faculty Publications

Viral Hemorrhagic Septicemia virus (VHSv) is an RNA rhabdovirus, which causes one of the world's most serious fish diseases, infecting >80 freshwater and marine species across the Northern Hemisphere. A new, novel, and especially virulent substrain—VHSv-IVb—first appeared in the Laurentian Great Lakes about a decade ago, resulting in massive fish kills. It rapidly spread and has genetically diversified. This study analyzes temporal and spatial mutational patterns of VHSv-IVb across the Great Lakes for the novel non-virion (Nv) gene that is unique to this group of novirhabdoviruses, in relation to its glycoprotein (G), phosphoprotein (P), …

Macroecology Of North American Suckers (Catostomidae): Tests Of Bergmann's And Rapoport's Rules, Stephen J. Jacquemin, Jason C. Doll

Biological Sciences Faculty Publications

Discerning spatial macroecological patterns in freshwater fishes has broad implications for community assembly, ecosystem dynamics, management, and conservation. This study explores the potential interspecific covariation of geographic range (Rapoport's rule) and body size (Bergmann's rule) with latitude in North American sucker fishes (Cypriniformes: Catostomidae). While numerous tests of Rapoport's and Bergmann's rules are documented in the literature, comparatively few of these studies have specifically tested for these patterns, and none have incorporated information reflecting shared ancestry into analyses of North American freshwater fish through a hierarchical model. This study utilized a hierarchical modeling approach with Bayesian inference to evaluate the …

Week Of August 24, 2015, New York Medical College

InTouch

• School of Medicine Class of 2019 Embarks on their Journey to Medicine at the White Coat Ceremony
• NYMC Celebrates Walkway Ribbon Cutting
• NYMC Celebrates Faculty Authorship
• D.P.T. Class of 2015 Achieves 100 Percent First-Time Passing Rate on the National Licensure Exam
• GSBMS Welcomes New Cohort of Ph.D. Candidates

Atomic Structure Of Grk5 Reveals Distinct Structural Features Novel For G Protein-Coupled Receptor Kinases, Konstantin E. Komolov, Anshul Bhardwaj, Jeffrey L. Benovic

Department of Biochemistry and Molecular Biology Faculty Papers

G protein-coupled receptor kinases (GRKs) are members of the protein kinase A, G, and C families (AGC) and play a central role in mediating G protein-coupled receptor phosphorylation and desensitization. One member of the family, GRK5, has been implicated in several human pathologies, including heart failure, hypertension, cancer, diabetes, and Alzheimer disease. To gain mechanistic insight into GRK5 function, we determined a crystal structure of full-length human GRK5 at 1.8 Å resolution. GRK5 in complex with the ATP analog 5'-adenylyl β,γ-imidodiphosphate or the nucleoside sangivamycin crystallized as a monomer. The C-terminal tail (C-tail) of AGC kinase domains is a highly …

The C-Terminal Domain (Ctd) Of Human Dna Glycosylaseneil1 Is Required For Forming Berosome Repair Complex With Dna Replication Proteins At The Replicating Genome: Dominant Negative Function Of The Ctd, Pavana M. Hegde, Arijit Dutta, Shiladitya Sengupta, Joy Mitra, Sanjay Adhikari, Alan E. Tomkinson, Guo-Min Li, Istvan Boldogh, Tapas K. Hazra, Sankar Mitra, Muralidhar L. Hegde

Toxicology and Cancer Biology Faculty Publications

The human DNA glycosylase NEIL1 was recently demonstrated to initiate prereplicative base excision repair (BER) of oxidized bases in the replicating genome, thus preventing mutagenic replication. A significant fraction of NEIL1 in cells is present in large cellular complexes containing DNA replication and other repair proteins, as shown by gel filtration. However, how the interaction of NEIL1 affects its recruitment to the replication site for prereplicative repair was not investigated. Here, we show that NEIL1 binarily interacts with the proliferating cell nuclear antigen clamp loader replication factor C, DNA polymerase δ, and DNA ligase I in the absence of DNA …

The Role Of Glutaminase 1 In Hiv-1 Associated Neurocognitive Disorders And In Brain Development, Yi Wang

Theses & Dissertations

Glutaminase is the enzyme that converts glutamine into glutamate, which serves as a key excitatory neurotransmitter and one of the energy providers for cellular metabolism. Glutamate is essential for proper brain functioning but at excess levels, it is neurotoxic and has a key role in the pathogenesis of various neurodegenerative diseases, including HIV-1 associated neurocognitive disorders (HAND). However, the detailed mechanism of glutamate-mediated neurotoxicity remains unclear. In part I, we identified the regulation of glutaminase 1 (GLS1) in the central nervous system (CNS) of HAND animal models including HIV-Tat transgenic (Tg) mouse and HIVE-SCID mouse, since GLS1 is the dominant …

Investigation Of Behavioral And Cellular Changes In The Maternal Immune Activation Model Of Autism Spectrum Disorders, Shreya Roy

Theses & Dissertations

Maternal infection during pregnancy, which leads to maternal immune activation (MIA), is an environmental risk factor for autism spectrum disorders (ASD). MIA can be induced in mice and their offspring exhibit behaviors that model the core symptoms of ASD. One of the core behavioral symptoms in ASD patients is presence of increased repetitive behavior, which is modeled by an increase in marble burying in MIA mice. It has been shown that the deficits seen in MIA mice are associated with the dysregulation of cytokine levels in the developing brain, specifically an increase in pro-inflammatory cytokines. In this thesis, I tested …

Roles Of Serum Lycopene In The Prevalence And Mortality Of Metabolic Syndrome In The Adult Population, Guang-Ming Han

Theses & Dissertations

Metabolic syndrome (MetS) is a cluster of metabolic disorders, including increased fasting glucose, blood pressure, plasma triglyceride, reduced high-density lipoprotein cholesterol and abdominal obesity. It leads to an increased risk of cardiovascular disease and diabetes. The growing prevalence of MetS is strongly related to the increasing prevalence of overweight/obesity. As an antioxidant, lycopene can reduce the risk of MetS. However, it is unclear whether lycopene has similar effects among overweight/obese individuals and whether lycopene can reduce the risk of mortality among individuals with MetS. The purpose of this study was to explore the roles of lycopene in the prevalence and …

Disseminated Histiocytoses Biomarkers Beyond Brafv600e: Frequent Expression Of Pd-L1., Nurija Bilalovic, Juan P. Palazzo, Ryan P Bender, Jeffrey Swensen, Sherri Z Millis, Semir Vranic, Daniel Von Hoff, Robert J Arceci, Zoran Gatalica

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

The histiocytoses are rare tumors characterized by the primary accumulation and tissue infiltration of histiocytes and dendritic cells. Identification of the activating BRAFV600E mutation in Erdheim-Chester disease (ECD) and Langerhans cell histiocytosis (LCH) cases provided the basis for the treatment with BRAF and/or MEK inhibitors, but additional treatment options are needed. Twenty-four cases of neoplastic histiocytic diseases [11 extrapulmonary LCH, 4 ECD, 4 extranodal Rosai-Dorfman disease (RDD), 3 follicular dendritic cell sarcoma (FDCS), 1 histiocytic sarcoma (HS) and 1 blastic plasmacytoid dendritic cell neoplasm (BPDCN)] were analyzed using immunohistochemical and mutational analysis in search of biomarkers for targeted therapy. BRAF …