Medical Sciences Commons^™

Effects Of Dimerization On The Deacylase Activities Of Human Sirt2., Jie Yang, Nathan I Nicely, Brian P Weiser

Rowan-Virtua School of Osteopathic Medicine Departmental Research

Human sirtuin isoform 2 (SIRT2) is an NAD+-dependent enzyme that functions as a lysine deacetylase and defatty-acylase. Here, we report that SIRT2 readily dimerizes in solution and in cells and that dimerization affects its ability to remove different acyl modifications from substrates. Dimerization of recombinant SIRT2 was revealed with analytical size exclusion chromatography and chemical cross-linking. Dimerized SIRT2 dissociates into monomers upon binding long fatty acylated substrates (decanoyl-, dodecanoyl-, and myristoyl-lysine). However, we did not observe dissociation of dimeric SIRT2 in the presence of acetyl-lysine. Analysis of X-ray crystal structures led us to discover a SIRT2 double mutant (Q142A/E340A) that …

Modeling Biphasic, Non-Sigmoidal Dose-Response Relationships: Comparison Of Brain- Cousens And Cedergreen Models For A Biochemical Dataset, Venkat D. Abbaraju, Tamaraty L. Robinson, Brian P. Weiser

Rowan-Virtua School of Osteopathic Medicine Departmental Research

Biphasic, non-sigmoidal dose-response relationships are frequently observed in biochemistry and pharmacology, but they are not always analyzed with appropriate statistical methods. Here, we examine curve fitting methods for “hormetic” dose-response relationships where low and high doses of an effector produce opposite responses. We provide the full dataset used for modeling, and we provide the code for analyzing the dataset in SAS using two established mathematical models of hormesis, the Brain-Cousens model and the Cedergreen model. We show how to obtain and interpret curve parameters such as the ED50 that arise from modeling, and we discuss how curve parameters might change …

Invited Review: Adrenocortical Function In Avian And Non-Avian Reptiles: Insights From Dispersed Adrenocortical Cells., Rocco V. Carsia, Patrick J. Mcilroy, Henry B John-Alder

Rowan-Virtua School of Osteopathic Medicine Departmental Research

Herein we review our work involving dispersed adrenocortical cells from several lizard species: the Eastern Fence Lizard (Sceloporus undulatus), Yarrow's Spiny Lizard (Sceloporus jarrovii), Striped Plateau Lizard (Sceloporus virgatus) and the Yucatán Banded Gecko (Coleonyx elegans). Early work demonstrated changes in steroidogenic function of adrenocortical cells derived from adult S. undulatus associated with seasonal interactions with sex. However, new information suggests that both sexes operate within the same steroidogenic budget over season. The observed sex effect was further explored in orchiectomized and ovariectomized lizards, some supported with exogenous testosterone. Overall, a suppressive effect of testosterone was evident, especially in cells …

Role Of Chronic Stress-Induced Neuroinflammation In Rodent Locus Coeruleus Physiology And Anxiety-Like Behaviors, Arthur Anthony Alfonso Reyes

Graduate School of Biomedical Sciences Theses and Dissertations

The locus coeruleus (LC), the primary site of brain norepinephrine (NE), is a key anatomical brain region implicated in the stress response. Stress is a neuroendocrine physiologic response to a stressor that promotes organism survival through adaptive change and restoration of homeostasis. The central stress response, which drives behavioral and physiological change, is primarily mediated by activating the hypothalamic-pituitary-adrenal (HPA) axis. While advantageous in the short term, chronic stress exposure can lead to HPA axis and LC dysregulation, which are thought to contribute to the etiology of anxiety disorders. Previous studies demonstrate the effects of acute stress in increasing LC …

Human Airway Mucociliary Tissue Cultures Chronically Exposed To E-Cigarette Vapors Exhibit Altered Cell Populations And Increased Secretion Of Immunomodulatory Cytokines, Vanessa Pizutelli, Vincent Manna, Shannon Dwyer, Salvatore Caradonna

Rowan-Virtua Research Day

Vape-pens or electronic cigarettes (e-cigarettes) are handheld battery powered devices that use a vape-liquid to produce a vapor that is inhaled by the user. The active ingredients in commercial vape-liquids are commonly nicotine, tetrahydrocannabinol or cannabidiol. A consequence of the rise in e-cigarette usage was the 2019 emergence of a vaping-induced respiratory disease denoted ‘e-cigarette or vaping use-associated lung injury’ (EVALI). One of the suspected causes of EVALI is Vitamin E Acetate (VEA), which was found to be a diluent in certain illicit tetrahydrocannabinol vape-pens, whereas nicotine is commonly diluted in equal parts propylene glycol and vegetable glycerin (PG:VG). The …

Comparative Analysis Of The Effects Of Actual Versus Assumed Opioid Experience On The Regulation Of Ventral Striatal Opioid Receptor Gene Expression, Indu Mithra Madhuranthakam, Martin Job

Rowan-Virtua Research Day

Rationale: We conducted experiments to assess the effect of prior opioid experience on gene expression changes. We compared the current experimenter-imposed short versus extended-access conditions of opioid self-administration and developed a new quantitative method to determine their effectiveness in identifying the role of opioid experience in regulating opioid receptor expression levels in the ventral striatum (VS) using an oxycodone self-administration/abstinence model.

Methods: In this study, male Sprague-Dawley rats (n=36) were trained for 20 days to self-administer oxycodone at 0.1 mg/kg/infusion under short access (n=15, or saline as controls n=3, for 3h/day) or extended access (n=15, or saline as controls n=3, …

The Role Of Food Accessibility In Weight Loss In A Rat Model Of Parkinson’S Disease, Anjali Kikkisetti, Nicole Charles, Francois Gould

Rowan-Virtua Research Day

Parkinson’s disease (PD) is a neurodegenerative disorder that causes a variety of motor and non-motor symptoms. The goal of this project was to understand whether the weight loss seen with Parkinson’s disease was due to the lack of being able to access the food because of the food placement or because of inability to chew the food due to degeneration of muscles required for chewing food. Both treatment groups, Adjusted Diet and Unadjusted Diet, lost weight after injections started, whereas control weights were stable throughout the experiment. There is no statistically significant difference in weight loss between adjusted and unadjusted …

Perioperative Ketamine Use For Post Mastectomy Pain, Alessia Cooney, Jaylyn Thompson, Naomi Watkins-Granville

Rowan-Virtua Research Day

PMPS is defined as chronic neuropathic pain following breast cancer procedures in the ipsilateral arm, chest wall, axilla or shoulder.1-3 Approximately 20 to 50% of post mastectomy patients suffer from Post Mastectomy Pain Syndrome (PMPS).1 With more than 3.8 million breast cancer survivors, due to advances in treatment, there is increased importance in findings ways to better manage the quality of life of breast cancer survivors.1,4 Ketamine induces analgesic effects through its non-competitive antagonism of NDMA receptors.5 Low doses of ketamine infusion (20–30 mg x h−1) have been shown to produce analgesia in neuropathic pain states with benefits lasting up …

Differential Degeneration Of Neurons In A Mouse Model Of Canavan Disease, Vibha Chauhan, Quy Nguyen, Jeremy Francis, Paola Leone

Rowan-Virtua Research Day

Canavan disease (CD) is an inherited leukodystrophy caused by inactivating mutations to the glial enzyme aspartoacylase (ASPA). ASPA catabolizes neuronal N-acetylaspartate (NAA) into free acetate and aspartate and loss of this function results in the chronic elevation of non-catabolized NAA and the failure of developmental myelination. Elevated NAA is thought to cause damage to myelin and myelin-producing cells (oligodendrocytes, but the viability of neurons in CD is relatively unexplored. We compare here the progressive degeneration of neurons in two regions of the CD mouse brain, the thalamus and the cortex, distinguished by differing degrees of vacuolation, and show that the …

The Correlation Between Serum C-Reactive Protein Level And Risk Of Future Cardiovascular Disease: A Neurodivergent Population Dilemma, Brandon Cunha, Andrea Iannuzzelli, Venkateswar Venkataraman

Rowan-Virtua Research Day

Extensive research on neurotypical (NT) populations has demonstrated that a chronically elevated level of serum C Reactive Protein (CRP) is a strong predictor of future cardiovascular disease (CVD). Interestingly, many neurodivergent (ND) populations experience chronically elevated CRP levels higher than NT controls. Current research is concerned with establishing the significance of this relationship to accurately predict CVD risk for potentially at risk ND patients. To contribute to this gap in knowledge, the Rowan-Virtua Regional Integrated Special Needs (RISN) Center patient population will be studied to identify trends in baseline serum CRP levels across a multitude of ND conditions. A clinical …

A 5-Year Clinical Course Of Phenocopy Syndrome Of Behavioral Variant Frontotemporal Dementia: Case Report And Literature Review, Joseph Melillo, Keyur Patel, Christian White

Rowan-Virtua Research Day

Frontotemporal dementia is a neurocognitive disease which affects language, behavior, or executive functioning. This disease includes a spectrum of presentations which includes multiple variants. The phenocopy syndrome of behavioral variant frontotemporal dementia is one which mimics the behavioral variant of frontotemporal dementia. Patients with this condition show a decline in personality, social conduct and cognitive ability but often display no signs of neurological imaging and exhibit slow progression. This case focuses on a now 70-year-old male who has shown signs of behavioral changes with a slowly progressive clinical course and minimal findings on PET scan, but moderate changes seen on …

Brash Syndrome Case Report And Brief Review, Kelly Schuitema

Rowan-Virtua Research Day

BRASH syndrome is an acronym that stands for bradycardia, renal failure, AV node blocker, shock and hyperkalemia. The syndrome is precipitated by synergism from AV nodal blocking agents and hyperkalemia. The combination of the AV nodal blockade and renal failure leads to a cycle of severe bradycardia and hyperkalemia. We will discuss a case of BRASH syndrome with a 68 year old female who presented with generalized weakness and was found to be hypotensive, bradycardia, in acute renal failure with hyperkalemia likely related to metoprolol and amlodipine use.

Identifying Co-Factors That Drive Tra-1 Activator Function, Jibran Imtiaz, Youngquan Shen, Ronald Ellis

Rowan-Virtua Research Day

Gli proteins are involved in cell fate determination, proliferation, and patterning in many species and are major effectors of Hedgehog (Hh) signaling. There are three Gli proteins in humans, and mutations or errors in their regulation lead to a variety of developmental disorders or cancer. However, the mechanisms by which they interact with co-factors are poorly understood. We are analyzing co-factors of Gli proteins using TRA-1 in Caenorhabditis nematodes. The TRA-1 zinc fingers are structurally like those of other Gli proteins, and TRA-1 can be cleaved like other Gli proteins to form a repressor. However, its function has changed during …

Mcl-1 Inhibition Modulates Erk-Mediated Resistance In Multiple Myeloma, Omar Al-Odat, Krishne Gowda, Shantu Amin, Tulin Budak-Alpdogan, Subash Jonnalagadda, Manoj Pandey

Rowan-Virtua Research Day

Novel multiple myeloma (MM) treatments have significantly improved over the previous several decades, primarily on account of targeting bone marrow microenvironment (BMM) pathways. However, drug resistance and patient relapse remain major clinical problems. The role of BMM in the upregulation of anti-apoptotic protein Mcl-1 is well documented. The Mcl-1 protein plays a critical role in the progression and acquired drug resistance in MM. The regulation of Mcl-1, a protein characterized by a short half-life, from transcription to degradation is crucial for understanding its role in cell survival. The GSK3β and Erk play important role in the stability of Mcl-1. Also, …

Orthologs Of The C. Elegans Heterochronic Genes Have Divergent Functions In C. Briggsae, Maria Ivanova, Eric G. Moss

Rowan-Virtua Research Day

The heterochronic genes of C. elegans comprise the best-studied pathway controlling the timing of tissue and organ formation in an animal. To begin to understand the evolution of this pathway, the significance of each factor, and the relationships among the components, we characterized 11 C. briggsae orthologs of C. elegans heterochronic genes. Using CRISPR/Cas9, we made a variety of alleles and found that several mutant phenotypes differ in significant ways from those of C. elegans. Although most orthologs displayed defects in developmental timing, those phenotypes could differ in which stages they controlled, the penetrance and expressivity of the phenotypes, or …

Extravasated Brain-Reactive Autoantibodies Perturb Neuronal Surface Protein Expression In Alzheimer's Pathology, Wardah Bajwa, Mary Kosciuk, Randel L. Swanson, Anuradha Krishnan, Venkat Venkataraman, Robert Nagele, Nimish Acharya

Rowan-Virtua Research Day

Background: Increased blood-brain barrier (BBB) permeability is reported in both the neuropathological and in vivo studies in both Alzheimer’s Disease (AD) and age matched cognitively normal, no cognitive impairment (NCI), subjects. Impaired BBB allows various vascular components such as immunoglobulin G (IgG) to extravasate into the brain and specifically bind to various neuronal surface proteins (NSP), also known as brain reactive autoantibodies (BrABs). This interaction is predicted to further enhance deposition of amyloid plaques.

Hypothesis: Interaction between extravasated BrABs and its cognate NSPs lower the expression of that NSPs in AD patients.

Methods: We selected Western blotting technique to study …

The Involvement Of Ubiquitin In Med13 Cyclin C Degradation Following Cellular Stress, Ayesha Gurnani, Brittany Friedson, Katrina Cooper

Rowan-Virtua Research Day

The Cdk8 Kinase Module is a dissociable regulator of cellular stress response genes, with degradation of its components Med13 and cyclin C eventually determining cell fate decisions such as engaging cell survival or cell death mechanisms. We aimed to explore the roles of ubiquitin in degradation of the Cdk8 Kinase Module following nitrogen starvation, with respect to the potential involvement of deubiquitinating enzyme Doa4, lysine linkage at position K63, and E2 ubiquitin conjugating enzymes Ubc4 and Ubc5. We utilized Western blot analysis to observe nitrogen starvation-induced degradation of Med13-HA in wild-type, doa4 mutant, and K63R yeast strains; degradation of cyclin …

Maackia Amurensis Seed Lectin (Masl) Increases Movement Velocity Of Mice With Tnfα Induced Rheumatoid Arthritis, Amanda A. Greenspan, Kelly L. Hamilton, Alan J. Shienbaum, Bradford Fischer, Andrea Bottaro, Gary S. Goldberg

Rowan-Virtua Research Day

Up to 70 million people around the world suffer from rheumatoid arthritis. Current treatment options have varied efficacy and can cause unwanted side effects. New approaches are needed to treat this condition. Sialic acid modifications on chondrocyte receptors have been associated with arthritic inflammation and joint destruction. The transmembrane mucin receptor protein podoplanin (PDPN) has been identified as a functionally relevant receptor that presents extracellular sialic acid motifs. PDPN signaling promotes inflammation and invasion associated with arthritis and, therefore, has emerged as a target that can be used to inhibit arthritic inflammation. Maackia amurensis seed lectin (MASL) can target PDPN …

Maldi-Tof Ms Based Proteomic Fingerprinting Of Total Serum Plasma For Somatic Pain Syndromes, Isaiah Pinkerton, Venkateswar Venkataraman

Rowan-Virtua Research Day

There are racial and ethnic disparities regarding pain management within the United States, and that disproportionately affects women of color. There is also a fundamental lack of information regarding the biological mechanism by which pain sensitization and perception occurs, and how it could be affected by both neurologic and somatic pain syndromes.

Methods: Research was performed on principal electronic scientific databases including Google Scholar, PubMed, and Embase with search terms “MALDI-TOF”, “ESI-MS”, “Pain”, and “Biomarkers”, as well as other modifiers to narrow the literature search.

Results: Studies on comparison between MALDI-TOF and other traditional analysis platforms, including Electrospray Ionization (ESI-MS), …

Is There A Role For Plant-Based “Meat” In Cardiovascular Disease Prevention?, Aziza Jadallah, Usmaan Al-Shehab, Adam Friedman

Rowan-Virtua Research Day

Diet is an established risk factor for cardiovascular disease. The American Heart Association recommends following a whole-food, minimally processed diet emphasizing fruit and vegetables to reduce cardiovascular mortality. Recently, processed plant-based meat substitutes, such as Beyond Meat® and Impossible™ foods have become easily accessible to consumers and are advertised as a healthful addition to a plant-based diet. However, these products are highly processed and contain high amounts of saturated fat and sodium. The purpose of this research is to investigate the effect of processed plant-based meat diets on adverse cardiovascular events compared to animal-based meat diets and minimally processed healthful …

Immunomodulatory Effects Of Resolvin D2 In A Model Of Infection, Prem Yugandhar Kadiyam Sundarasivarao

Graduate School of Biomedical Sciences Theses and Dissertations

Dysregulated hyperinflammatory host immune response to underlying bacterial infections is a characteristic of sepsis. In sepsis, bacteria often trigger abnormal hyperinflammatory responses which can cause multiple organ failure and if sustained can lead to an immunosuppressive phase where the host is susceptible to secondary infections caused by opportunistic bacteria like Pseudomonas aeruginosa (P. aeruginosa). In our studies, we used a 2-hit model of cecal ligation and puncture (CLP) followed by P. aeruginosa secondary lung infection to investigate cellular and molecular mechanisms in the beneficial action of resolvin D2 (RvD2). Resolvins of the D-series are a group of fatty acids known …

Long Term Neuroprotective Effects Of Human Adipose-Derived Stem Cells In Neonatal Rats Post Hypoxic Ischemic Encephalopathy, Melissa February, Md, Thomas N. Tulenko, Phd, Barry Weinberger, Md, Alla Kushnir, Md

Cooper Rowan Medical Journal

Background: Hypoxemic ischemic encephalopathy (HIE) is a major cause of morbidity and mortality in the neonatal population. Recent research has shown human adipose stem cells (hASCs) to have neuroprotective effects in animal models of HIE. This study tested the hypothesis that neurodevelopmental outcomes would be improved using hASC therapy in term neonatal HIE rat model.

Methods: Seven day old rats underwent left carotid artery ligation followed by 8% oxygen for 120 minutes, or carotid isolation in shams. Forty-eight hours after surgery half of the rats received hASCs and half normal saline (NS) intravenously. Rota-rod and cylinder tests were used to …

Med13 Degradation Defines A New Receptor-Mediated Autophagy Pathway Activated By Nutrient Deprivation, Sara E. Hanley

Graduate School of Biomedical Sciences Theses and Dissertations

Cells are exposed to an enormous amount of diverse extracellular cues but have a limited arsenal of weapons for protecting and maintaining homeostasis. To overcome these restrictions, nature has engineered proteins that have multiple functions. The pleiotropy of using one protein to carry out a variety of functions allows cells to rapidly execute tailored responses to a diverse set of signals. The Cdk8 kinase module (CKM) is a conserved detachable unit of the Mediator complex predominantly known for its role in transcriptional regulation. The CKM is composed of four proteins, the scaffolding proteins Med13 and Med12, as well as the …

The Effects Of Specialized Pro-Resolving Mediator Lipoxin A4 On Pseudomonas Aeruginosa Biofilms And Interactions With Monocytes, Julianne M. Thornton

Graduate School of Biomedical Sciences Theses and Dissertations

Pseudomonas aeruginosa (P. aeruginosa) is an opportunistic pathogen known as a major cause of hospital-acquired secondary infections, commonly causing chronic respiratory infections in immunocompromised individuals, especially those with cystic fibrosis, and often found in wound infections. P. aeruginosa uses the quorum sensing pathway to readily form protective biofilms, which reduce the efficacy of antibiotics and access by host immune cells to eradicate the pathogen. Specialized pro-resolving mediators (SPMs) are lipids endogenously produced by the host immune response to infection to aid in infection resolution. One SPM, Lipoxin A4 (LxA4), has been shown to be a robust quorum sensing inhibitor.

The …

Anterior And Posterior Tongue Regions And Taste Papillae: Distinct Roles And Regulatory Mechanisms With An Emphasis On Hedgehog Signaling And Antagonism., Archana Kumari, Charlotte M. Mistretta

Rowan-Virtua School of Osteopathic Medicine Departmental Research

Sensory receptors across the entire tongue are engaged during eating. However, the tongue has distinctive regions with taste (fungiform and circumvallate) and non-taste (filiform) organs that are composed of specialized epithelia, connective tissues, and innervation. The tissue regions and papillae are adapted in form and function for taste and somatosensation associated with eating. It follows that homeostasis and regeneration of distinctive papillae and taste buds with particular functional roles require tailored molecular pathways. Nonetheless, in the chemosensory field, generalizations are often made between mechanisms that regulate anterior tongue fungiform and posterior circumvallate taste papillae, without a clear distinction that highlights …

Investigating The Role Of Vasopressin Receptor 1a Expressing Neurons In Mouse Dorsal Raphe, Tirth Nimishbhai Patel

Theses and Dissertations

Human social interactions heavily impact our physical and mental wellbeing. Arginine-vasopressin (Avp) and serotonin have both been implicated in modulation of social behaviors ranging from affiliation to aggression. In male mice, Avp neurons in the bed nucleus of stria terminalis (BNST) show increased activity during prosocial behavior. BNST sends Avp afferents to the dorsal raphe (DR) in the midbrain, a home to a large portion of serotonin neurons in the mouse brain. Previous data suggests that DR is activated during male prosocial behavior with a female stimulus, and Avp indirectly excites serotonin neurons. We hypothesized that DR contains a population …