Medical Sciences Commons^™

Improvement Of Memory Loss Through Dietary Intervention In The Assisted Living And Rehabilitative Settings, Alexander Swartz, Martin Forsberg

Rowan-Virtua Research Day

• The ketogenic diet is a popular, controversial diet that fuels the brain through beta-oxidation of fatty acids and production of ketone bodies, the most populous of which is betahydroxybutyrate (BHB).

• The ketogenic diet consists of 70-80% fats, 20-25% protein, and 5-10% carbohydrates.

• Medically, the ketogenic diet is utilized in patients with epilepsy and recommended by some physicians to improve general health through weight loss and insulin sensitivity.

• Key factors of neurodegeneration include glucose hypometabolism, oxidative damage, and neuroinflammation.

• Studies have shown that with ingestion of exogenous ketones alone, or endogenous ketonemia through a ketogenic diet, there is: …

Modeling The Role Of Cyclin C In Connecting Stress-Induced Mitochondrial Fission To Apoptosis, Steven J. Doyle, Randy Strich

Rowan-Virtua Research Day

For normal cell function, exogenous signals must be correctly interpreted, and the proper response executed. The mitochondria are key regulatory nodes of cellular fate. For example, mitochondria undergo fission and fusion cycles depending on the energetic needs of the cell. Additionally, regulated cell death pathways also function at the mitochondria. Cyclin C is a transcriptional regulator of stress response and growth control genes. Following stress, a portion of cyclin C translocates to the cytoplasm, where it interacts with both the mitochondrial fission and apoptotic machinery. Based on these findings, we hypothesize that Cyclin C represents a key mediator linking transcription …

Riluzole For Pediatric Patients With Treatment-Refractory Obsessive-Compulsive Disorder, Maheen Mohammad, Stuti Parikh

Rowan-Virtua Research Day

Obsessive-compulsive disorder (OCD) occurs in about 1-3% of the pediatric population, but many do not respond to standard therapies. Riluzole, a glutamate antagonist, has shown to be an effective treatment for refractory OCD in adults, however few trials have been conducted to show the effectiveness of Riluzole in children to treat refractory OCD. The study investigates the potential use of riluzole in children to treat refractory OCD.

Substrate-Specific Effect On Sirtuin Conformation And Oligomerization, Jie Yang, Shannon L. Dwyer, Nathan I. Nicely, Brian P. Weiser

Rowan-Virtua Research Day

Human sirtuins are a family of nicotinamide adenine dinucleotide (NAD +)-dependent enzymes that are responsible for removing acyl modifications from lysine residues. Sirtuins are involved in the formation and proliferation of cancers and are thought to regulate the progression of neurodegenerative diseases. Although sirtuins can be pharmacologically targeted by small molecules, it is not easy to modulate the substrate selectivity of sirtuins despite the chemical diversity of their substrates. Here, we report substrate-specific effects on sirtuin conformation and oligomerization that regulate enzyme deacylase activity. We used fluorescent acyl peptide probes to study substrate interactions with two sirtuin isoforms: SIRT2 and …

Ung2 And Rpa Activity On Ssdna-Dsdna Junctions, Kathy Chen, Sharon Greenwood, Brian P. Weiser

Rowan-Virtua Research Day

Uracil DNA glycosylase, or UNG2, is an enzyme that is involved in DNA repair. Its primary job is to eliminate harmful uracil bases from DNA strands. To do this, the enzyme is assisted by replication protein A (RPA). RPA helps UNG2 in the identification of uracil bases by targeting UNG2 activity near ssDNA-dsDNA junctions (1-3). The results from assays presented here agree with published findings that showed UNG2 is heavily targeted by RPA to uracil bases that are close to ssDNA-dsDNA junctions (for example, uracil located 9 bps from the junction as opposed to 33 bps) (1,2). However, these previous …

Effect Of Calcium Chloride And Isoflurane On Force Frequency Relationship In Canines, Harrison Patrizio, Lawrence Mulligan

Rowan-Virtua Research Day

Proper calcium cycling is critical for a optimally functioning heart.

Improper calcium cycling in humans can contribute to heart failure.

Human calcium cycling is difficult to study due to the risks of damaging the patient’s cardiac tissue.

Risk of further damaging cardiac tissue is substantially increased in a heart failure patient.

Past studies focus on studying the effects of changing calcium cycling in lab rats.

Current research shows limited alternative methods in studying relationships between calcium cycling and FFR in larger mammals.

This project analyzes data to determine the response of the canine force frequency relationship to calcium chloride and …

Plasmalogen Deficiency: A Risk Factor For Dementias And Potential Treatment Target, Mitchel A. Kling, Mallika Mendu, Rima F. Kaddurah-Daouk, Sheldon Jordan, Dayan B. Goodenowe

Rowan-Virtua Research Day

Altered lipid metabolism is implicated in the risk of sporadic Alzheimer’s disease (AD) and related dementias (ADRD); however, the precise mechanisms accounting for findings from observational studies remains to be fully elucidated.

Plasmalogens are a subclass of integral membrane phospholipids with unique properties that appear to play important roles relevant to the pathophysiology of AD and ADRD, including vesicle fusion necessary for synaptic neurotransmitter release, modulation of membrane fluidity and microdomain dynamics, membrane antioxidant functions, and neuroprotection. Like the more familiar phosphatides, plasmalogens are synthesized on a 3-carbon glycerol backbone; however, they differ from phosphatides by the presence of a …

Morphine-Induced Hyperactivity Is Attenuated By Intra-Accumbens Administration Of The Highly-Selective Dopamine D3 Receptor Antagonist Vk4-40, Mansi Patel, Desta M. Pulley, Daniel Manvich

Rowan-Virtua Research Day

Opioids exert their abuse-related effects by enhancing dopamine (DA) neurotransmission within the brain’s mesolimbic reward system, a neural projection involving DA neurons in the ventral tegmental area (VTA) that project to medium spiny neurons within the nucleus accumbens (NAc). Mu (MOR) are expressed by several populations of GABAergic neurons that tonically inhibit VTA DA neurons. By inhibiting these GABAergic neurons in a MOR-dependent manner, opioids indirectly enhance DA neurotransmission via disinhibition of DAergic neurons. Accumulating evidence indicates that selective pharmacological antagonism of the dopamine D3 receptor (D3R) attenuates the abuse-related effects of several opioids, but the neurobiological mechanisms mediating this …

A Suspected Case Of Vaccine Induced Thrombosis With Thrombocytopenia Following Sars Cov2 Vaccine, Maryam Soliman

Rowan-Virtua Research Day

With the new development of the SARS-CoV vaccine and the majority of the population receiving this vaccine, it is important to recognize some of the rare side effects associated with it.

VITT is a rare complication of the COVID vaccine

Diagnostic criteria: COVID vaccine 4-24 days prior to symptom onset, any venous or arterial thrombosis, thrombocytopenia < 150, positive PF4 HIT ELISA, markedly elevated D-dimer >4x ULN.

Vaccine Induced Thrombosis with Thrombocytopenia is a potentially life-threatening diagnosis that must be recognized and treated correctly to prevent poor outcomes.

Alternate Site Pacing And The Impact On Intracellular Calcium Handling During The Post-Extrasystolic Cardiac Cycle, Kent Ozcan, Lawrence Mulligan

Rowan-Virtua Research Day

Objective: Previous work has shown that alternate site (RV apex) results in myocardial dysfunction. With the development of tools to place endocardial pacing leads in locations that create physiological pacing activation, we sought to evaluate how ventricular trans-septal or left ventricular apical placement pacing differs from right atrial pacing. We will evaluate how these chronic pacing modes impact the PR and RF at baseline, 0, and 16 weeks in the canine heart.

Methods: Quantitative analysis will be performed on previously generated data. The data set includes pacing of 15 dogs total (8 with trans-septal leads & 7 with left ventricular …

Effect Of Uracil Dna Glycosylase Activity On The Efficacy Of Thymidylate Synthase Inhibitor/Hdac Inhibitor Combination Therapies In Colon Cancer, Rashmi Kulkarni, Brian P Weiser

Rowan-Virtua Research Day

Human uracil DNA glycosylase (UNG2) is responsible for removing uracil bases from DNA and initiates base excision repair pathways. Accumulation of uracil or its fluorinated analogs in DNA is one of the killing mechanisms of thymidylate synthase (TS) inhibitors in cancer cells, and depletion of UNG2 often enhances the toxicity of these anticancer drugs. We tested the effect of UNG2 KO on the efficacy of multiple TS inhibitors (5-fluorouracil, fluorodeoxyuridine, and pemetrexed) and we determined that, except for 5-fluorouracil, all other TS inhibitors were significantly more potent in UNG2 KO cells compared to wild-type HT29 cells. Interestingly, UNG2 protein levels …

Interaction Of Fluorescent Probes With Sirtuin Proteins, James Fusco, Brian P Weiser

Rowan-Virtua Research Day

Sirtuins are a class of proteins belonging to the Sir2 (Silencing information regulator 2) family of NAD+ dependent protein lysine deacylases. Different Isoforms (SIRT1-SIRT7) differ in their specific deacylase activity and cellular location. They have roles in DNA repair, glucose metabolism, and cellular proliferation which make them highly desirable targets for carcinoma therapeutics. We previously used 1-aminoanthracene’s (AMA) fluorescent properties when bound with SIRT2 (Kd of 37 μM) to develop a high-throughput screen to identify novel ligands that inhibit SIRT2’s enzymatic activities. We hope to reveal other potential probes for future high-throughput screening with all the sirtuin isotopes. 1-AMA’s fluorescence …

Investigating The Role Of The Basolateral Amygdala Plays In The Incubation Of Cue-Induced Cocaine Seeking Behavior, Claire Marie Corbett

Graduate School of Biomedical Sciences Theses and Dissertations

Cocaine use disorder is a chronic, relapsing brain disease. Sex and ovarian hormones are known to influence cocaine addiction liability and relapse vulnerability. However, little is known regarding the cellular and synaptic mechanisms contributing to sex differences in relapse vulnerability, including how these measures are influenced by hormonal fluctuations. To investigate sex differences in relapse vulnerability we use a rodent model of cocaine craving and relapse called the incubation model in which cue-induced seeking progressively increases or “incubates” during the first month of withdrawal from extended-access cocaine self-administration. Using this model, we have recently shown that females in the estrus …

Differentiating The Mechanistic Role And Chemotherapeutic Potential Of Src And Podoplanin In Oncogenic Transformation, Edward P. Retzbach

Graduate School of Biomedical Sciences Theses and Dissertations

There were an estimated 20 million new cancer cases worldwide in 2020, resulting in nearly 1000 deaths per hour [1]. Oral cancer exemplifies the difficulties of treating cancer patients. The first line for oral cancer treatment is surgery and radiation that can lead to patient disfigurement and decreased quality of life in cancer survivors [2-4]. Though there have been many developments in chemotherapy in the last 30 years, the 50% mortality rate associated with oral cancer has not changed [4, 5]. Longitudinal studies that track survival rates in oral cancer patients demonstrate a 3-fold reduction in patient deaths when patients …

Contact Normalization And The Role Of Maackia Amurensis Seed Lectin As A Novel Chemotherapeutic And Antiviral Agent, Stephanie A. Sheehan

Graduate School of Biomedical Sciences Theses and Dissertations

Cells communicate with each other to coordinate tissue function and homeostasis. Diseases including cancer, arthritis, and acute respiratory disease syndrome (ARDS) require a breakdown in this intercellular communication. For example, cancer progression is suppressed by junctional communication between nontransformed and transformed cells. This process is called contact normalization. Junctional communication must be disrupted to enable transformed cells to grow into malignancies. However, the junctions and mechanisms by which nontransformed cells normalize cell behavior have not been clearly defined. My project aimed to identify junctions and elucidate mechanisms underlying contact normalization. We discovered that cadherins, specifically N-cadherin, form junctions that enable …

Investigations In The Cellular And Molecular Biology Of Human Airway Mucociliary Tissue, Vincent Manna

Graduate School of Biomedical Sciences Theses and Dissertations

Our laboratory has integrated the use of a human-derived, in vitro model of airway mucociliary tissue. We isolate human nasal epithelial cells (HNECs) from the nasal mucociliary tissue of donors with a small brush and expand the airway progenitor cells in culture. The HNECs are then seeded onto semi-permeable transwell inserts. The inserts are in contact with the media in the lower chamber but don’t contain media in the upper chamber therefore the cells are exposed to the air while drawing nutrients from the media below, this is called the Air-Liquid Interface (ALI). HNECs cultured at the ALI initiate a …

Replication Protein A (Rpa) Targeting Of Uracil Dna Glycosylase (Ung2), Derek Chen, Brian P Weiser

Rowan-Virtua Research Day

Replication Protein A (RPA) is a single stranded DNA binding protein which stabilizes ssDNA for replication and repair. One function of RPA is to bind the DNA repair enzyme uracil DNA glycosylase (UNG2) and direct its activity towards ssDNA dsDNA junctions.

UNG2 removes uracil bases from DNA which can appear through dUMP misincorporation or through cytosine deamination. If uracil is present instead of a cytosine, then the original GC pair becomes a GU pair. The uracil will then base pair to adenine in the replicated daughter strand. This results in a GC → AT mutation that could contribute to cancer …

Novel Technology Enables Diagnostic Ultrasound Machine To Treat Hepatocellular Carcinoma In Mice, Ryan Morrison, Mrigendra B. Karmacharya, Chandra M. Sehgal

Rowan-Virtua Research Day

An off-the-shelf diagnostic transducer (ULTRASONIX C5-2) was modified with custom-built circuitry to enable the transducer to produce therapeutic ultrasound in order to ablate hepatocellular carcinomas grown in immunodeficient athymic nude mice (25-35 g; Charles River Laboratories, Wilmington, MA, USA). The therapeutic antivascular ultrasound (AVUS) produced by the off-the-shelf abdominal transducer was unfocused, continuous 2.8MHz ultrasound targeting contrast-enhancing perflutren lipid microbubbles within tumor vasculature. Previous research with a dedicated physiotherapy ultrasound machine (D150 Plus, Dynatronics Corp., Salt Lake City, UT, USA) targeting similar hepatocellular carcinomas showed disrupted tumor neovasculature and irreparable dilation of tumor capillaries with subsequent intercellular edema and hemorrhage.1-3 …

Substrate-Dependent Modulation Of Sirt2 By A Fluorescent Probe, 1-Aminoanthracene, David Bi, Prashit Parikh, Jie Yang, Brian P Weiser

Rowan-Virtua Research Day

Sirtuin isoform 2 (SIRT2) is an enzyme that catalyzes the removal of acyl groups from lysine residues. SIRT2’s catalytic domain has a hydrophobic tunnel where its substrate acyl groups bind. Here, we report that the fluorescent probe 1-aminoanthracene (AMA) binds within SIRT2’s hydrophobic tunnel in a substrate-dependent manner. AMA’s interaction with SIRT2 was characterized by its enhanced fluorescence upon protein binding (>10-fold). AMA interacted weakly with SIRT2 alone in solution (Kd = 37 μM). However, when SIRT2 was equilibrated with a decanoylated peptide substrate, AMA’s affinity for SIRT2 was enhanced ∼10-fold (Kd = 4μM). The peptide’s decanoyl chain and …

A Case Of Cocaine Toxicity From Body Stuffing, Justin Smith, James Lee, Alan Lucerna, James Espinosa

Rowan-Virtua Research Day

Body stuffing refers to the ingestion of an illegal substance in an effort to conceal it and avoid prosecution. This is distinct from, and more common than, the practice of body packing in which large amounts of an illegal substance are carefully packaged and ingested to be transported discreetly by smugglers [1]. While body packers tend to ingest much larger quantities of a drug, they are less prone to developing symptoms of drug toxicity due to the meticulous packaging methods used when compared with those who ingest packets of drugs in haste to avoid prosecution [2]. Many substances have been …

The Dopamine D3 Receptor Antagonist Vk4-40 Attenuates Morphine-Induced Hyperactivity But Not Cocaine-Induced Hyperactivity In Mice, Desta M. Pulley, Jessica J. Debski, Daniel Manvich

Rowan-Virtua Research Day

In light of the increasing rates of opioid abuse in the US, the search for viable medications to treat opioid abuse disorder (OUD) has become ever more urgent. Opioids exert their abuse-related effects in part by indirectly increasing dopamine (DA) neurotransmission in the mesolimbic system, a dopaminergic projection arising in the ventral tegmental area and terminating in the nucleus accumbens. The DA D3 receptor (D3R), which belongs to the D2 family of dopamine receptors (D2, D3 , D4 receptor subtypes), is highly expressed in these brain regions and has shown strong potential as a pharmacotherapeutic target for the treatment of …

Affiliative Social Interactions Activate Vasopressin-Responsive Neurons In The Mouse Dorsal Raphe, Tirth Patel, Hanna O. Caiola, Olivia Mallari, Benjamin D. Rood

Rowan-Virtua Research Day

Social behavior is inextricably linked to human health, shaping both our susceptibility and resilience to disease and stress. Positive interactions as simple as maternal contact or friendships among children and adults can protect against emotional distress and improve treatment outcomes, whereas negative interactions such as abuse, social isolation, or bullying can increase aggression and precipitate mood disorders. Discovering the structure and function of neural circuits underlying social behavior is critical to understanding the link between social interaction and health. The neuropeptide vasopressin has been implicated in the regulation of multiple social interactions including social memory, aggression, mating, pair-bonding, and parental …

Case Presentation: Lower Back Pain Or Chronic Acetaminophen Overdose?, Meghan Whitt, Christopher Schwartz, Bhumi Shah

Rowan-Virtua Research Day

Unintentional ingestions can pose a difficult challenge to diagnose in the setting of the Emergency Department. Many may present with vague symptoms that are not consistent with classic overdose prodromes. Many patients do not identify or disclose over the counter medications, such as analgesics, with which acute/chronic ingestion in large quantities can result in life threatening medical emergencies. Their underlying symptoms may also cloud their clinical picture, further complicating workup within the ED.

Identification Of The E3 Ligase That Directs The Degradation Of Proteins That Control Cell Fate Decisions In Yeast, Prasanna Tati, Stephen D Willis, Katrina F. Cooper

Rowan-Virtua Research Day

The ubiquitin–proteasome system (UPS) and autophagy pathways are distinct, highly conserved proteolytic systems that play important roles in maintaining cellular homeostasis in response to environmental cues [1]. The goal of this project is to identify the E3 ligase that mediates the degradation of cyclin C following nitrogen starvation in yeast using quantitative Western blot analysis of cyclin C-myc following nitrogen starvation in mutants of known Ubc4/5 interacting E3 ligases. No potential E3 ligases were identified as stable after 4 hours of nitrogen starvation, suggesting redundancy in function.

Lipoxin A 4 (Lxa 4 ) Promotes Reduction And Antibiotic Efficacy Against Pseudomonas Aeruginosa Biofilm, Julianne M. Thornton, Jean Walker, Prem Yugandhar Kadiyam Sundarasivarao, Bernd Spur, Ana Rodriguez, Kingsley Yin

Rowan-Virtua Research Day

Pseudomonas aeruginosa (P aeruginosa) is an opportunistic bacterium commonly found in wound infections and airways of cystic fibrosis patients P aeruginosa readily forms biofilms which can reduce the efficacy of antibiotics used to eradicate the pathogen We have previously shown that a Specialized Pro resolving Mediator ( Lipoxin A 4 (LxA 4 is a quorum sensing inhibitor which can reduce P aeruginosa virulence In this study, we examined the direct actions of LxA 4 and RvD 2 on P aeruginosa biofilm formation and virulence gene expression The influence of LxA 4 on antibiotic efficacy and the combined effects on biofilm …

Physiological Response And Tissue Damage Following Different Depths Of Impact In A Rodent Model Of Mild Traumatic Brain Injury, Haven K. Predale, Christopher P. Knapp, Barry D. Waterhouse, Rachel L. Navarra

Rowan-Virtua Research Day

Mild traumatic brain injury (mTBI) is a serious public health concern that can result in significant neurological and behavioral deficit. mTBI results from impact to the head and can be repetitive in nature, especially in sports and domestic violence cases. Our laboratory studies the effects of repetitive mTBI on risky choice behavior in rodents using a closed-head controlled cortical impact (CH-CCI) model of injury and a well-established probabilistic discounting task that assesses risk-based decision-making behavior. We have recently found that females, but not males, display transient increases in risky choice behavior following three CH-CI’s delivered at 5.5m/s velocity and 2.5 …

Cyclin C Determines Cell Fate In Response To Oxidative Stress And Proteasome Inhibition, David C. Stieg

Graduate School of Biomedical Sciences Theses and Dissertations

In response to various sources of cellular stress, the coordination of intracellular events is necessary to elicit the appropriate molecular response. In particular, the reprogramming of gene expression by stress-specific transcription factors drives the activation of signaling pathways, triggering either cell survival or regulated cell death pathways. The Cdk8 kinase module (CKM) is a highly conserved transcriptional regulatory complex with a role in this decision. The CKM is composed of Cdk8, its activating partner cyclin C, and two scaffold proteins, Med12 and Med13. The CKM is a detachable subunit of the Mediator complex, which interacts with RNA polymerase II to …

Long-Term Impacts Of Acute Stressor Exposure On Locus Coeruleus Function And Anxiety-Like Behavior In Rats, Olga Borodovitsyna

Graduate School of Biomedical Sciences Theses and Dissertations

Stress is a physiological state characterized by behavioral arousal that occurs during exposure to harmful or threatening stimuli, and usually facilitates an adaptive behavioral response. The persistence of stress sometimes causes it to become maladaptive, potentially contributing to disease development, including physiological complications with altered neuroendocrine signaling and impaired function of organ systems, and psychological conditions including depression and anxiety. Anxiety disorders in particular are associated with a history of stress and are the most common class of mental disorders, with a lifetime prevalence of 33.7% in the general population. The locus coeruleus (LC) is a major node in the …

A High-Throughput Approach To Characterizing Arv1 On The Regulation Of Lipid Homeostasis Uncovers A Novel Interaction With Epidermal Growth Factor Receptor, Nicholas Anthony Wachowski

Graduate School of Biomedical Sciences Theses and Dissertations

Acyl-CoA cholesterol acyl transferase related enzyme-2 required for viability 1 (ARV1) was first recognized in Saccharomyces cerevisiae in a study done in 2000 by Tinkelenberg et al. In yeast, the deletion of ARV1 results in numerous defects including abnormal sterol trafficking [1], the reduction of sphingolipid metabolism [2], synthesis of glycosylphosphatidylinositol (GPI) anchor [3], ER stress [4], and hypersensitivity of fatty acids leading to lipoapoptosis [5]. Arv1 germline deletion in mice displayed a lean phenotype with increased energy [6]. In humans, ARV1 mutations lead to epileptic encephalopathy [7].

Non-alcoholic fatty liver disease (NAFLD) consists of simple steatosis to non-alcoholic steatohepatitis …

Effect Of S100b Deletion On Membrane Properties And Localization Of Ncald And Hpca, Natasha Hesketh

Graduate School of Biomedical Sciences Theses and Dissertations

Calcium signaling is particularly important for neuronal function. Neurons utilize a wide range of calcium-binding proteins. Dysregulation of such proteins is linked to neurodegeneration. Neurocalcin delta (NCALD), hippocalcin (HPCA), and S100B are calcium sensors that are expressed in the hippocampus, a brain region essential to memory and severely damaged in Alzheimer’s disease (AD). Despite the potential importance of these proteins, we do not fully understand the physiological significance of their relationship. Because NCALD and HPCA are known to interact with S100B, we hypothesized that the loss of S100B affects NCALD and HPCA localization, and therefore electrical properties, of hippocampal neurons. …