Digital Commons Network^™

Epigenetics: A Novel Therapeutic Approach For The Treatment Of Alzheimer's Disease, Lina Adwan, Nasser H. Zawia

Biomedical and Pharmaceutical Sciences Faculty Publications

Alzheimer's disease (AD) is the most common type of dementia in the elderly. It is characterized by the deposition of two forms of aggregates within the brain, the amyloid β plaques and tau neurofibrillary tangles. Currently, no disease-modifying agent is approved for the treatment of AD. Approved pharmacotherapies target the peripheral symptoms but they do not prevent or slow down the progression of the disease. Although several disease-modifying immunotherapeutic agents are in clinical development, many have failed due to the lack of efficacy or serious adverse events. Epigenetic changes including DNA methylation and histone modifications are involved in learning and …

Division Of Research And Economic Development Annual Report For Fy2013, Uri Division Of Research And Economic Development

Reports (Research and Economic Development)

Annual report for the Division of Research and Economic Development of the University of Rhode Island for the year 2012-2013.

Includes statistics of project proposals, expenditures, URI Foundation Awards, previous annual report summaries and awards received by individual academic and administrative departments.

Division Of Research And Economic Development Monthly Report For January 2013, Uri Division Of Research And Economic Development

Reports (Research and Economic Development)

The monthly reports include statistics for project proposals and awards received by individual academic and administrative departments at the University of Rhode Island.

Division Of Research And Economic Development Monthly Report For May 2013, Uri Division Of Research And Economic Development

Reports (Research and Economic Development)

The monthly reports include statistics for project proposals and awards received by individual academic and administrative departments at the University of Rhode Island.

Division Of Research And Economic Development Monthly Report For December 2013, Uri Division Of Research And Economic Development

Reports (Research and Economic Development)

The monthly reports include statistics for project proposals and awards received by individual academic and administrative departments at the University of Rhode Island.

Application Of Igg-Derived Natural Treg Epitopes (Igg Tregitopes) To Antigen-Specific Tolerance Induction In A Murine Model Of Type 1 Diabetes, Leslie P. Cousens, Yan Su, Elizabeth Mcclaine, Xin Li, Frances Terry, Robert Smith, Jinhee Lee, William Martin, David W. Scott, Anne S. De Groot

Institute for Immunology and Informatics Faculty Publications

HLA class II-restricted regulatory T cell (Treg) epitopes in IgG (also called “Tregitopes”) have been reported to suppress immune responses to coadministered antigens by stimulating the expansion of natural Tregs (nTregs). Here we evaluate their impact on human immune responses to islet cell antigens ex vivo and on the modulation of type 1 diabetes (T1D) in a murine model in vivo. Co-administration of Tregitopes and T1D antigens delayed development of hyperglycemia and reduced the incidence of diabetes in NOD mice. Suppression of diabetes could be observed even following onset of disease. To measure the impact of Tregitope treatment on …

Epitope Recognition In Hla-Dr3 Transgenic Mice Immunized To Tsh-R Protein Or Peptides, Hidefumi Inaba, Leonard Moise, William Martin, Anne S. De Groot, Joe Desrosiers, Ryan Tassone, George Buchman, Takashi Akamizu, Leslie J. De Groot

Institute for Immunology and Informatics Faculty Publications

Development of Graves' disease is related to HLA-DR3. The extracellular domain (ECD) of human TSH receptor (hTSH-R) is a crucial antigen in Graves' disease. hTSH-R peptide 37 (amino acids 78–94) is an important immunogenic peptide in DR3 transgenic mice immunized to hTSH-R. This study examined the epitope recognition in DR3 transgenic mice immunized to hTSH-R protein and evaluated the ability of a mutant hTSH-R peptide to attenuate the immunogenicity of hTSH-R peptide 37. DR3 transgenic mice were immunized to recombinant hTSH-R-ECD protein or peptides. A mutant hTSH-R 37 peptide (ISRIYVSIDATLSQLES: 37m), in which DR3 binding motif position 5 was mutated …

Identification Of Borrelia Burgdorferi Ospc Genotypes In Canine Tissue Following Tick Infestation: Implications For Lyme Disease Vaccine And Diagnostic Assay Design, D. V.L. Rhodes, C. G. Earnhart, Thomas N. Mather, P. F.M. Meeus, R. T. Marconi

Plant Sciences and Entomology Faculty Publications

In endemic regions, Lyme disease is a potential health threat to dogs. Canine Lyme disease manifests with arthritis-induced lameness, anorexia, fever, lethargy, lymphadenopathy and, in some cases, fatal glomerulonephritis. A recent study revealed that the regional mean for the percentage of seropositive dogs in the north-east of the USA is 11.6%. The outer surface protein C (OspC) of Lyme disease spirochetes is an important virulence factor required for the establishment of infection in mammals. It is a leading candidate in human and canine Lyme disease vaccine development efforts. Over 30 distinct ospC phyletic types have been defined. It has been …

Research & Innovation For 2012-2013, University Of Rhode Island

Publications (Research and Economic Development)

The 2012-2013 issue of Research & Innovation, a periodical focused on research at the University of Rhode Island.

Hitting The Right Target: Taxonomic Challenges For, And Of, Plant Invasions, Peter Pyšek, Philip E. Hulme, Laura A. Meyerson, Gideon F. Smith, James S. Boatwright, Neil R. Crouch, Estrela Figueiredo, Llewellyn C. Foxcroft, Vojtěch Jarošik, David M. Richardson, Jan Suda, John R. U. Wilson

Natural Resources Science Faculty Publications

This paper explores how a lack of taxonomic expertise, and by implication a dearth of taxonomic products such as identification tools, has hindered progress in understanding and managing biological invasions. It also explores how the taxonomic endeavour could benefit from studies of invasive species. We review the literature on the current situation in taxonomy with a focus on the challenges of identifying alien plant species and explore how this has affected the study of biological invasions. Biosecurity strategies, legislation dealing with invasive species, quarantine, weed surveillance and monitoring all depend on accurate and rapid identification of non-native taxa. However, such …

Beyond Humanization And De-Immunization: Tolerization As A Method For Reducing The Immunogenicity Of Biologics, Anne S. De Groot, Frances Terry, Leslie Cousens, William Martin

Institute for Immunology and Informatics Faculty Publications

Immune responses to some monoclonal antibodies (mAbs) and biologic proteins interfere with their efficacy due to the development of anti-drug antibodies (ADA). In the case of mAbs, most ADA target ‘foreign’ sequences present in the complementarity determining regions (CDRs). Humanization of the mAb sequence is one approach that has been used to render biologics less foreign to the human immune system. However, fully human mAbs can also drive immunogenicity. De-immunization (removing epitopes) has been used to reduce biologic protein immunogenicity. Here, we discuss a third approach to reducing the immunogenicity of biologics: introduction of Treg epitopes that stimulate …

Tregitope Peptides: The Active Pharmaceutical Ingredient Of Ivig?, Anne S. De Groot, Leslie Cousens, Federico Mingozzi, William Martin

Institute for Immunology and Informatics Faculty Publications

Five years ago, we reported the identification and characterization of several regulatory T-cell epitopes (now called Tregitopes) that were discovered in the heavy and light chains of IgG (De Groot et al. Blood, 2008). When added ex vivo to human PBMCs, these Tregitopes activated regulatory T cells (Tregs), increased expression of the transcription factor FoxP3, and induced IL- 10 expression in CD4+ T cells. We have now shown that coadministration of the Tregitopes in vivo, in a number of different murine models of autoimmune disease, can suppress immune responses to antigen in an antigen-specific manner, and that this response is …

Report From The Field - Overview Of The Sixth Annual Vaccine Renaissance Conference, Denice Spero, Lauren Levitz, Anne S. De Groot

Institute for Immunology and Informatics Faculty Publications

The Sixth Annual Vaccine Renaissance Conference, hosted by the Institute for Immunology and Informatics (iCubed) at the University of Rhode Island (URI), took place on October 15–17, 2012. This conference provides a forum for the review of current progress in the discovery and development of vaccines, and creates an environment for the exchange of ideas. Dr. Joel McCleary opened the conference with a warning about the importance of preparing for well-defined biowarfare threats, including tularemia and Staphylococcal enterotoxin B. Following the keynote address, sessions explored biodefense and preparation for pandemic and biowarfare threats; vaccines for emerging and re-emerging neglected …

Low Immunogenicity Predicted For Emerging Avian-Origin H7n9, Anne S. De Groot, Matthew Ardito, Frances Terry, Lauren Levitz, Ted Ross, Leonard Moise, William Martin

Institute for Immunology and Informatics Faculty Publications

A new avian-origin influenza virus emerged near Shanghai in February 2013, and by the beginning of May it had caused over 130 human infections and 36 deaths. Human-to-human transmission of avian-origin H7N9 influenza A has been limited to a few family clusters, but the high mortality rate (27%) associated with human infection has raised concern about the potential for this virus to become a significant human pathogen. European, American, and Asian vaccine companies have already initiated the process of cloning H7 antigens such as hemagglutinin (HA) into standardized vaccine production vehicles. Unfortunately, previous H7 HA-containing vaccines have been poorly immunogenic. …

An Escherichia Coli Nissle 1917 Missense Mutant Colonizes The Streptomycin-Treated Mouse Intestine Better Than The Wild Type But Is Not A Better Probiotic, Jimmy Adediran, Mary P. Leatham-Jensen, Matthew E. Mokszycki, Jakob Frimodt-Møller, Karen A. Krogfelt, Krystyna Kazmierczak, Linda J. Kenney, Tyrrell Conway, Paul S. Cohen

Cell and Molecular Biology Faculty Publications

Previously we reported that the streptomycin-treated mouse intestine selected for two different Escherichia coli MG1655 mutants with improved colonizing ability: nonmotile E. coli MG1655 flhDC deletion mutants that grew 15% faster in vitro in mouse cecal mucus and motile E. coli MG1655 envZ missense mutants that grew slower in vitro in mouse cecal mucus yet were able to cocolonize with the faster-growing flhDC mutants. The E. coli MG1655 envZ gene encodes a histidine kinase that is a member of the envZ-ompR two-component signal transduction system, which regulates outer membrane protein profiles. In the present investigation, the envZ _P41L gene was …

A Comparative Study Of Hollow Copper Sulfide Nanoparticles And Hollow Gold Nanospheres On Degradability And Toxicity, Laingran Guo, Irene Panderi, Daisy D. Yan, Kevin Szulak, Yajuan Li, Yi-Tzai Chen, Hang Ma, Daniel B. Niesen, Navindra P. Seeram, Aftab Ahmed, Bingfang Yan, Dionysios Pantazatos, Wei Lu

Biomedical and Pharmaceutical Sciences Faculty Publications

Gold and copper nanoparticles have been widely investigated for photothermal therapy of cancer. However, degradability and toxicity of these nanoparticles remain concerns. Here, we compare hollow CuS nanoparticles (HCuSNPs) with hollow gold nanospheres (HAuNS) in similar particle sizes and morphology following intravenous administration to mice. The injected pegylated HCuSNPs (PEG-HCuSNPs) are eliminated through both hepatobiliary (67 percentage of injected dose, %ID) and renal (23 %ID) excretion within one month postinjection. By contrast, 3.98 %ID of Au is excreted from liver and kidney within one month after iv injection of pegylated HAuNS (PEG-HAuNS). Comparatively, PEG-HAuNS are almost nonmetabolizable, while PEG-HCuSNPs are …

Caloric Restriction-Mediated Induction Of Lipid Metabolism Gene Expression In Liver Is Enhanced By Keap1-Knockdown, Supriya R. Kullkarni, Laura E. Armstrong, Angela L. Slitt

Biomedical and Pharmaceutical Sciences Faculty Publications

Purpose: CR increases fatty acid oxidation to decrease tissue lipid content. The Nuclear factor E2-related factor 2 (Nrf2)-Kelch like ECH associated Protein 1 (Keap1) pathway is an antioxidant gene regulatory pathway that has been previously investigated in weight gain. However, limited interaction of Nrf2/Keap1 and CR exists. The purpose of this study was to determine how Keap1 knockdown (Keap1-KD), which is known to increase Nrf2 activity, affects the CR response, such as weight loss, hepatic lipid decrease, and induction of fatty acid oxidation gene expression.

Methods: C57BL/6 and Keap1-KD mice were maintained on 40% CR or fed ad libitum for …

Effect Of Caloric Restriction And Ampk Activation On Hepatic Nuclear Receptor, Biotransformation Enzyme, And Transporter Expression In Lean And Obese Mice, Supriya R. Kulkarni, Jialin Xu, Ajay C. Donepudi, Wei Wei, Angela L. Slitt

Biomedical and Pharmaceutical Sciences Faculty Publications

Purpose: Fatty liver alters liver transporter expression. Caloric restriction (CR), the recommended therapy to reverse fatty liver, increases Sirtuin1 deacetylase activity in liver. This study evaluated whether CR and CR mimetics reversed obesity-induced transporter expression in liver and hepatocytes.

Methods: mRNA and protein expression was determined in adult lean (lean) and leptin-deficient obese (OB) mice fed ad libitum or placed on 40% (kCal) reduced diet. Hepatocytes were isolated from lean and OB mice, treated with AMP Kinase activators, and gene expression was determined.

Results: CR decreased Oatp1a1, Oatp1b2, and Abcb11 mRNA expression in lean, but not OB mice. CR increased …

Keap1 Knockdown Increases Markers Of Metabolic Syndrome After Long-Term High Fat Diet Feeding, Vijay R. More, Jialin Xu, Prajakta C. Shimpi, Clyde Belgrave, James P. Luyendyk, Masayuki Yamamoto, Angela L. Slitt

Biomedical and Pharmaceutical Sciences Faculty Publications

The nuclear factor E2-related factor 2 (Nrf2)–Kelch-like ECH-associated protein 1 (Keap1) pathway upregulates antioxidant and biotransformation enzyme expression to counter cellular oxidative stress. The contributions of Nrf2 to other cellular functions, such as lipid homeostasis, are emerging. This study was conducted to determine how enhanced Nrf2 activity influences the progression of metabolic syndrome with long-term high-fat diet (HFD) feeding. C57BL/6 and Keap1-knockdown (Keap1-KD) mice, which exhibit enhanced Nrf2 activity, were fed a HFD for 24 weeks. Keap1-KD mice had higher body weight and white adipose tissue mass compared to C57BL/6 mice on HFD, along with increased inflammation and lipogenic gene …

Short-Term Treatment With Tolfenamic Acid Improves Cognitive Functions In Alzheimer's Disease Mice, Gehad M. Subaiea, Lina I. Adwan, Aseef H. Ahmed, Karen E. Stevens, Nasser H. Zawia

Biomedical and Pharmaceutical Sciences Faculty Publications

Tolfenamic acid lowers the levels of the amyloid precursor protein (APP) and amyloid beta (Aβ) when administered to C57BL/6 mice by lowering their transcriptional regulator specificity protein 1 (SP1). To determine whether changes upstream in the amyloidogenic pathway that forms Aβ plaques would improve cognitive outcomes, we administered tolfenamic acid for 34 days to hemizygous R1.40 transgenic mice. After the characterization of cognitive deficits in these mice, assessment of spatial learning and memory functions revealed that treatment with tolfenamic acid attenuated long-term memory and working memory deficits, determined using Morris water maze and the Y-maze. These improvements occurred within a …

Urinformed April 2013, Urinformed

URInformed: The URI Employees' Newsletter

No abstract provided.

Mechanistic Insights Into Isoform-Dependent And Species-Specific Regulation Of Bile Salt Export Pump By Farnesoid X Receptor, Xiulong Song, Yuan Chen, Leila Valanejad, Rajani Kaimal, Bingfang Yan, Matthew Stoner, Ruitang Deng

Biomedical and Pharmaceutical Sciences Faculty Publications

Expression of bile salt export pump (BSEP) is regulated by the bile acid/farnesoid X receptor (FXR) signaling pathway. Two FXR isoforms, FXRα1 and FXRα2, are predominantly expressed in human liver. We previously showed that human BSEP was isoform-dependently regulated by FXR and diminished with altered expression of FXRα1 and FXRα2 in patients with hepatocellular carcinoma. In this study, we demonstrate that FXRα1 and FXRα2 regulate human BSEP through two distinct FXR responsive elements (FXRE): IR1a and IR1b. As the predominant regulator, FXRα2 potently transactivated human BSEP through IR1a, while FXRα1 weakly transactivated human BSEP through a newly identified IR1b. Relative …

Effects Of Developmental Deltamethrin Exposure On White Adipose Tissue Gene Expression, Laura E. Armstrong, Maureen V. Driscoll, Vijay R. More, Ajay C. Donepudi, Jialin Xu, Angela Baker, Lauren M. Aleksunes, Jason R. Richardson, Angela Slitt

Biomedical and Pharmaceutical Sciences Faculty Publications

Deltamethrin, a type II pyrethroid, is a widely used insecticide. The purpose of this study was to determine whether perinatal deltamethrin exposure altered the expression of adipogenic and lipogenic genes in white adipose tissue (WAT) in adult pups. C57BL/6 pregnant mice were administered 0, 1, or 3 mg/kg of deltamethrin orally every 3 days throughout gestation and lactation. Offspring were weaned on postnatal day 25, and WAT was collected from 5‐month‐old male mice. Perinatal deltamethrin exposure decreased the mRNA expression of adipogenesis‐related transcription factors Pparγ, Cebpα, and lipogenic genes Srebp1c, Acc‐1, Cd36, Lpl, Scd‐1; along with Nrf2 and target genes …

Bile Salt Export Pump Is Dysregulated With Altered Farnesoid X Receptor Isoform Expression In Patients With Hepatocellular Carcinoma, Yuan Chen, Xiulong Song, Leila Valanejad, Alexander Vasilenko, Vijay More, Xi Qiu, Weikang Chen, Yurong Lai, Angela L. Slitt, Matthew Stoner, Bingfang Yan, Ruitang Deng

Biomedical and Pharmaceutical Sciences Faculty Publications

As a canalicular bile acid effluxer, the bile salt export pump (BSEP) plays a vital role in maintaining bile acid homeostasis. BSEP deficiency leads to severe cholestasis and hepatocellular carcinoma (HCC) in young children. Regardless of the etiology, chronic inflammation is the common pathological process for HCC development. Clinical studies have shown that bile acid homeostasis is disrupted in HCC patients with elevated serum bile acid level as a proposed marker for HCC. However, the underlying mechanisms remain largely unknown. In this study, we found that BSEP expression was severely diminished in HCC tissues and markedly reduced in adjacent nontumor …

Carboxylesterase-2 Is A Highly Sensitive Target Of The Antiobesity Agent Orlistat With Profound Implications In The Activation Of Anticancer Prodrugs, Da Xiao, Deshi Shi, Dongfang Yang, Benjamin Barthel, Tad H. Koch, Bingfang Yan

Biomedical and Pharmaceutical Sciences Faculty Publications

Orlistat has been the most used anti-obesity drug and the mechanism of its action is to reduce lipid absorption by inhibiting gastrointestinal lipases. These enzymes, like carboxylesterases (CESs), structurally belong to the α/β hydrolase fold superfamily. Lipases and CESs are functionally related as well. Some CESs (e.g., human CES1) have been shown to hydrolyze lipids. This study was designed to test the hypothesis that orlistat inhibits CESs with higher potency toward CES1 than CES2, a carboxylesterase with little lipase activity. Liver microsomes and recombinant CESs were tested for the inhibition of the hydrolysis of standard substrates and the anticancer prodrugs …

Impairment Of Trkb-Psd-95 Signaling In Angelman Syndrome, Cong Cao, Mengia S. Rioult-Pedotti, Paolo Migani, Crystal J. Yu, Rakesh Tiwari, Keykavous Parang, Mark R. Spaller, Dennis J. Goebel, John Marshall

Biomedical and Pharmaceutical Sciences Faculty Publications

Angelman syndrome (AS) is a neurodevelopment disorder characterized by severe cognitive impairment and a high rate of autism. AS is caused by disrupted neuronal expression of the maternally inherited Ube3A ubiquitin protein ligase, required for the proteasomal degradation of proteins implicated in synaptic plasticity, such as the activity-regulated cytoskeletalassociated protein (Arc/Arg3.1). Mice deficient in maternal Ube3A express elevated levels of Arc in response to synaptic activity, which coincides with severely impaired long-term potentiation (LTP) in the hippocampus and deficits in learning behaviors. In this study, we sought to test whether elevated levels of Arc interfere with brain-derived neurotrophic factor (BDNF) …

Ventilation Rates And Activity Levels Of Juvenile Jumbo Squid Under Metabolic Suppression In The Oxygen Minimum Zone, Katja Trübenbach, Maria R. Pegado, Brad A. Seibel, Rui Rosa

Biological Sciences Faculty Publications

The Humboldt (jumbo) squid, Dosidicus gigas, is a part-time resident of the permanent oxygen minimum zone (OMZ) in the Eastern Tropical Pacific and, thereby, it encounters oxygen levels below its critical oxygen partial pressure. To better understand the ventilatory mechanisms that accompany the process of metabolic suppression in these top oceanic predators, we exposed juvenile D. gigas to the oxygen levels found in the OMZ (1% O₂, 1 kPa, 10°C) and measured metabolic rate, activity cycling patterns, swimming mode, escape jet (burst) frequency, mantle contraction frequency and strength, stroke volume and oxygen extraction efficiency. In normoxia, metabolic …

Colony Growth Of Corals Transplanted For Restoration Depends On Their Site Of Origin And Environmental Factors, Graham E. Forrester, Kerianne Taylor, Stephanie Schofield, Amy Maynard

Natural Resources Science Faculty Publications

We determined that growth differences among coral fragments transplanted for restoration were influenced by both source population and environmental factors. In two common garden experiments, storm-generated fragments of Acropora palmata were transplanted from two source populations in the British Virgin Islands to a restoration site (a “common garden”) that lacked A. palmata. In the first experiment, colonies from different sources grew at different rates in the first year after transplanting, suggesting either genetic differences among source populations or enduring acclimation to conditions at the source site. No differences in growth among source populations were detected in the second common garden …

Multiple Environmental Chemical Exposures To Lead, Mercury And Polychlorinated Biphenyls Among Childbearing-Aged Women (Nhanes 1999–2004): Body Burden And Risk Factors, Marcella Remer Thompson, Kim Boekelheide

College of Nursing Faculty Publications

Background: Lead, mercury and polychlorinated biphenyls (PCBs) are neurotoxicants with intergenerational health consequences from maternal body burden and gestational exposures. Little is known about multiple chemical exposures among childbearing-aged women.

Objectives: To determine the percentage of women aged 16–49 of diverse races and ethnicities whose body burdens for all three xenobiotics were at or above the median; to identify mixed exposures; and to describe those women disproportionately burdened by two or more of these chemicals based on susceptibility- and exposure-related attributes, socioeconomic factors and race-ethnicity.

Methods: Secondary data analysis of National Health and Nutrition Examination Survey (1999–2004).

Results: The best-fit …

Price Discount Perception: Consumers' Numeric Interpretation Of Semantic Price Claims, Albert J. Della Bitta, Patricia A. Norberg

College of Business Faculty Publications

Behavioral pricing research includes a considerable amount of focus on the effects of semantic cues (phrases) used to label reference and offer prices in price promotions, but a related type of semantic claim also frequently used in price promotions has continued to escape research attention - claims that attempt to encourage purchases by describing the consequences of buying at the discounted price (e.g. Super Savings). Using a variety of methods and conceptual foundations, the present research is the first to comprehensively study consumers' discount and value associations of these semantic claims. In a series of three studies, we find evidence …