Jnk And Nf-Κb Cell Signaling Pathways In Cardiovascular Disease Present Potential Targets For Curcumin Therapy, Mary Richfield

Senior Honors Theses

Curcumin (diferuloylmethane) is a compound derived from the rhizomes of Curcumin longa that has been long used for medicinal purposes. Curcumin alleviates the pathology of cardiovascular diseases, including atherosclerosis, aneurysm, and cardiomyopathy. The mechanism of curcumin therapy is under active research. The NF-κB and JNK pathways are two that curcumin interacts with to block inflammatory processes, apoptosis, and fibrotic tissue remodeling to prevent the pathologies of cardiovascular disease. While curcumin has demonstrated powerful mediation of cardiovascular disease, its bioavailability in body tissues is limited due to the instability and hydrophobicity of its structure. Further work is underway to stabilize …

Determining The Genomic Localization And Binding Partners Of Zinc Finger Protein 410, Mariko Locke

Senior Honors Theses

The results of a folate deficiency study affecting cognition in mice suggested the altered genes may be controlled by a transcription factor known as Zinc Finger Protein 410 (Zfp410). Due to a lack of literature on Zfp410’s interacting proteins and DNA-binding location, our study aims to further elucidate the role Zfp410 plays in affecting cognition. A custom antibody was used to determine the Zfp410 isoforms present in mouse and rat brains. Moreover, the antibody was used to determine the binding partners of Zfp410 in the brain and locate specific genomic regions/sequences with which it associates in vivo. These results may …

The Development Of Inhibitors For Sars-Cov-2 Orf8, My Thanh Thao Nguyen

CSB and SJU Distinguished Thesis

An unexpected outbreak of SARS-CoV-2 caused a worldwide pandemic in 2020. Many repurposed drugs were tested, but there are currently only three FDA approved antivirals (Merck’s antiviral Molnupiravir, Pfizer’s antiviral Paxlovid, and Remdisivir).1 Most of the antiviral drugs tested SARS-CoV-2 main protease and RNA-dependent RNA polymerase. However, it is important to explore different drug targets of SARS-CoV-2 to prepare for the virus mutations of the future. This research looks at an alternative approach in which SARSCoV- 2 Open Reading Frame 8 (ORF8), which has been shown to be a rapidly evolving hypervariable gene, was chosen to be the protein of …

Sars-Cov-2 Main Protease Inhibitors Repurposed For Hiv-1 Protease Binding, Jacob Minkkinen

CSB and SJU Distinguished Thesis

Severe acute respiratory syndrome (SARS-CoV-2) led to the COVID-19 global pandemic, with over 460 million cases of infection and over 6 million deaths since the start of the pandemic. SARS-CoV-2 is a retrovirus that utilizes a main protease (Mpro). Mpro is a catalytic cys/his protease. Several treatments were proposed to stop the pandemic including repurposing drugs to inhibit the Mpro. Another retrovirus that uses a protease is human immunodeficiency virus (HIV-1) which has been a global epidemic for 40 years and is a devastating disease that attacks the immune system. HIV-1 has infected 79.5 million people and has killed an …

Microplastics, The Environment, And Reproductive Health: How Is The Accumulation Of Microplastics In Our Environment And Bodies Impacting Reproductive Health?, Katherine Hayward

Independent Study Project (ISP) Collection

As global trends in both production and consumption of plastics continue to evolve, the bioaccumulation and biomagnification of microplastic particles in our everyday lives follow suit. This increasingly relevant problem has only recently been explored in the context of global health, and more specifically, reproductive health. Along with this steady increase in plastics and our exposure to them, researchers have separately observed adverse patterns in reproductive health. The chemicals involved throughout the microplastic life cycle may be playing a key role in these simultaneous patterns. With the aid of previous studies and publications on microplastics, exposure pathways, endocrine disruptors, and …

Geotemporospatial And Causal Inferential Epidemiological Overview And Survey Of Usa Cannabis, Cannabidiol And Cannabinoid Genotoxicity Expressed In Cancer Incidence 2003–2017: Part 2 – Categorical Bivariate Analysis And Attributable Fractions, Albert Stuart Reece, Gary Kenneth Hulse

Research outputs 2022 to 2026

Background: As the cannabis-cancer relationship remains an important open question epidemiological investigation is warranted to calculate key metrics including Rate Ratios (RR), Attributable Fractions in the Exposed (AFE) and Population Attributable Risks (PAR) to directly compare the implicated case burden between emerging cannabinoids and the established carcinogen tobacco. Methods: SEER*Stat software from Centres for Disease Control was used to access age-standardized state census incidence of 28 cancer types (including “All (non-skin) Cancer”) from National Cancer Institute in US states 2001–2017. Drug exposures taken from the National Survey of Drug Use and Health 2003–2017, response rate 74.1%. Federal seizure data provided …

Geotemporospatial And Causal Inferential Epidemiological Overview And Survey Of Usa Cannabis, Cannabidiol And Cannabinoid Genotoxicity Expressed In Cancer Incidence 2003–2017: Part 3 – Spatiotemporal, Multivariable And Causal Inferential Pathfinding And Exploratory Analyses Of Prostate And Ovarian Cancers, Albert Stuart Reece, Gary Kenneth Hulse

Research outputs 2022 to 2026

Background: The epidemiology of cannabinoid-related cancerogenesis has not been studied with cutting edge epidemiological techniques. Building on earlier bivariate papers in this series we aimed to conduct pathfinding studies to address this gap in two tumours of the reproductive tract, prostate and ovarian cancer. Methods: Age-standardized cancer incidence data for 28 tumour types (including “All (non-skin) Cancer”) was sourced from Centres for Disease Control and National Cancer Institute using SEER*Stat software across US states 2001–2017. Drug exposure was sourced from the nationally representative household survey National Survey of Drug Use and Health conducted annually by the Substance Abuse and Mental …

Geotemporospatial And Causal Inferential Epidemiological Overview And Survey Of Usa Cannabis, Cannabidiol And Cannabinoid Genotoxicity Expressed In Cancer Incidence 2003–2017: Part 1 - Continuous Bivariate Analysis, Albert Stuart Reece, Gary Kenneth Hulse

Research outputs 2022 to 2026

Background

The genotoxic and cancerogenic impacts of population-wide cannabinoid exposure remains an open but highly salient question. The present report examines these issues from a continuous bivariate perspective with subsequent reports continuing categorical and detailed analyses.

Methods

Age-standardized state census incidence of 28 cancer types (including “All (non-skin) Cancer”) was sourced using SEER*Stat software from Centres for Disease Control and National Cancer Institute across US states 2001–2017. It was joined with drug exposure data from the nationally representative National Survey of Drug Use and Health conducted annually by the Substance Abuse and Mental Health Services Administration 2003–2017, response rate 74.1%. …

Amphiphilic Cell-Penetrating Peptides Containing Natural And Unnatural Amino Acids As Drug Delivery Agents, David Salehi, Saghar Mozaffari, Khalid Zoghebi, Sandeep Lohan, Dindyal Mandal, Rakesh Tiwari, Keykavous Parang

Pharmacy Faculty Articles and Research

A series of cyclic peptides, [(DipR)(WR)₄], [(DipR)₂(WR)₃], [(DipR)₃(WR)₂], [(DipR)₄(WR)], and [DipR]₅, and their linear counterparts containing arginine (R) as positively charged residues and tryptophan (W) or diphenylalanine (Dip) as hydrophobic residues, were synthesized and evaluated for their molecular transporter efficiency. The in vitro cytotoxicity of the synthesized peptides was determined in human epithelial ovary adenocarcinoma cells (SK-OV-3), human lymphoblast peripheral blood cells (CCRF-CEM), human embryonic epithelial kidney healthy cells (HEK-293), human epithelial mammary gland adenocarcinoma cells (MDA-MB-468), pig epithelial kidney normal cells (LLC-PK1), and human epithelial …

Succinic Semialdehyde Dehydrogenase Deficiency (Ssadhd): Qualitative Needs Assessment For Patients With A Rare Neurological Disorder, Cassandra Bovee, Kayla Woodring

Annual Research Symposium

No abstract provided.

A Quantitative Analysis Of The Efficacy Of Various Essential Oils Against The Sars Cov-2 Virus, Elizabeth Wagstaff, Chandrelyn Kraczek, Jack Brandon Lopez

Annual Research Symposium

A poster presentation and abstract for the Roseman Symposium. The project focuses on testing 3 essential oil blends and two disinfectants containing an essential oil blend against SARS CoV-2 in response to the COVID-19 pandemic. The project procedure involves plaque assays, disinfection, and neutralization techniques.

Dissecting Mutational Allosteric Effects In Alkaline Phosphatases Associated With Different Hypophosphatasia Phenotypes: An Integrative Computational Investigation, Fei Xiao, Ziyun Zhou, Xingyu Song, Mi Gan, Jie Long, Gennady M. Verkhivker, Guang Hu

Mathematics, Physics, and Computer Science Faculty Articles and Research

Hypophosphatasia (HPP) is a rare inherited disorder characterized by defective bone mineralization and is highly variable in its clinical phenotype. The disease occurs due to various loss-of-function mutations in ALPL, the gene encoding tissue-nonspecific alkaline phosphatase (TNSALP). In this work, a data-driven and biophysics-based approach is proposed for the large-scale analysis of ALPL mutations-from nonpathogenic to severe HPPs. By using a pipeline of synergistic approaches including sequence-structure analysis, network modeling, elastic network models and atomistic simulations, we characterized allosteric signatures and effects of the ALPL mutations on protein dynamics and function. Statistical analysis of molecular features computed for the …

Antibacterial Activity, Structure-Activity Relationships, And Scale-Up Reaction Of 1,3,4-Oxadiazoles, Olivia Marie Smith

Undergraduate Honors Thesis Projects

Oxadiazoles are compounds in the field of organic chemistry that have been gathering interest in the medicinal chemistry and microbiology communities for their biological properties, which range from anti-inflammatory agents, to chemotherapy drugs, to antibiotics. The synthesis of oxadiazoles can be difficult due to the expensive and complex nature of the techniques used as well as the volatile reagents and elevated temperatures that are often required in organic synthesis. The Grote lab has recently developed a new method for the synthesis of 1,3,4-oxadiazoles under mild conditions. The goals of this thesis were thus twofold: to develop a viable scale-up procedure …

Combination Of Amphiphilic Cyclic Peptide [R4W4] And Levofloxacin Against Multidrug-Resistant Bacteria, Muhammad Imran Sajid, Sandeep Lohan, Shun Kato, Rakesh Kumar Tiwari

Pharmacy Faculty Articles and Research

Bacterial resistance is a growing global concern necessitating the discovery and development of antibiotics effective against the drug-resistant bacterial strain. Previously, we reported a cyclic antimicrobial peptide [R₄W₄] containing arginine (R) and tryptophan (W) with a MIC of 2.67 µg/mL (1.95 µM) against methicillin-resistant Staphylococcus aureus (MRSA). Herein, we investigated the cyclic peptides [R₄W₄] or linear (R₄W₄) and their conjugates (covalent or noncovalent) with levofloxacin (Levo) with the intent to improve their potency to target drug-resistant bacteria. The physical mixture of the Levo with the cyclic [R_{4 …}

Emerging Drug Targets And New Drugs In The Treatment Of Psoriatic Arthritis, Carmen Lariccia, Natalie Lennartz, Jessica Lewe, Jeffery Allison

Pharmacy and Wellness Review

Psoriasis is an autoimmune disease characterized by painful skin lesions. When joints and connective tissue also become involved, the condition is referred to as psoriatic arthritis (PsA). Current treatments for moderate to severe PsA include therapies used to treat rheumatoid arthritis (RA) despite differences in disease presentation which includes factors such as peripheral disease, sacroiliitis, stiffness, presence of rheumatoid factor and psoriasis. Treatment out-comes for PsA are measured by the American College of Rheumatology (ACR) Responder Index (ACR20) and the Dis-ease Activity Score for 28 joints (DAS28). First-line treatment includes disease-modifying antirheumatic drugs (DMARDs) such as methotrexate, sulfasalazine or leflunomide …

Management Of Hyperkalemia To Prevent Cardiac Arrest, Jennifer Harklerode, Amber Paul, Crystal Zheng, Olivia Vanscoy, Olivia Henton, Mark Olah

Pharmacy and Wellness Review

Hyperkalemia is a metabolic problem that may be life threatening if left untreated. Cardiac arrhythmias may develop with the potential to lead to cardiac arrest and death. Hyperkalemia can oftentimes be undiagnosed due to the lack of clear, specific symptoms and inconclusive variations in electrocardiogram (ECG) readings and lab values. Therefore, it is important to recognize risk factors that can potentially in-crease serum potassium levels. Screening for medications that increase serum potassium levels and educating patients are steps that both inpatient and outpatient health care professionals can take to increase early detection and prevention of a hyperkalemic episode. It is …

Daclizumab (Zinbryta®): An Emerging Therapy For The Treatment Of Relapsing-Remitting Multiple Sclerosis, Morgan Homan, Sunitha Jones, Michaela Louden, Molly Wheeler, Anh Dao Le, Lindsey Peters

Pharmacy and Wellness Review

Multiple sclerosis (MS) is an autoimmune disorder of the central nervous system characterized by the deterioration of the myelin sheath, causing axonal damage which leads to debilitating symptoms. Most therapies for the treatment of MS, including daclizumab, primarily target relapsing-remitting multiple sclerosis (RRMS), a form of MS where patients experience periods of exacerbated symptoms as well as intermittent periods of remission. Daclizumab is a humanized monoclonal antibody that is administered as a once monthly subcutaneous injection. The SELECT trilogy of trials have been instrumental in providing safety and efficacy data for daclizumab. The DECIDE study was the first randomized controlled …

Tackling Protein-Calorie Malnutrition During World Crises, Zahra Ali Padhani, Jai K. Das, Saeed Akhtar, Tariq Ismail, Zulfiqar Ahmed Bhutta

Woman and Child Health

Undernutrition is still highly prevalent in developing countries and leads to a multitude of problems as it weakens the immune system, which leads to increased risk of infections and diet-related diseases. COVID-19 has worsened the existing situation and has resulted in unprecedented health, social, and economic disruptions across the world. Before COVID-19, about 54% children under 5 years were moderately or seriously malnourished, and after the COVID-19 pandemic, early estimates suggest that an additional 2.6 million children were stunted; 9.3 million were wasted, with an addition of 2.1 million maternal anemia cases; 168,000 child deaths; and USD 29.7 billion in …

Structural And Computational Studies Of The Sars-Cov-2 Spike Protein Binding Mechanisms With Nanobodies: From Structure And Dynamics To Avidity-Driven Nanobody Engineering, Gennady M. Verkhivker

Mathematics, Physics, and Computer Science Faculty Articles and Research

Nanobodies provide important advantages over traditional antibodies, including their smaller size and robust biochemical properties such as high thermal stability, high solubility, and the ability to be bioengineered into novel multivalent, multi-specific, and high-affinity molecules, making them a class of emerging powerful therapies against SARS-CoV-2. Recent research efforts on the design, protein engineering, and structure-functional characterization of nanobodies and their binding with SARS-CoV-2 S proteins reflected a growing realization that nanobody combinations can exploit distinct binding epitopes and leverage the intrinsic plasticity of the conformational landscape for the SARS-CoV-2 S protein to produce efficient neutralizing and mutation resistant characteristics. Structural …

Hsp90 Inhibitors Modulate Sars-Cov-2 Spike Protein Subunit 1-Induced Human Pulmonary Microvascular Endothelial Activation And Barrier Dysfunction, Ruben Manuel Luciano Colunga Biancatelli, Pavel Solopov, Betsy W. Gregory, Yara Khodour, John D. Catravas

Bioelectrics Publications

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has caused more than 5 million deaths worldwide. Multiple reports indicate that the endothelium is involved during SARS-Cov-2-related disease (COVID-19). Indeed, COVID-19 patients display increased thrombophilia with arterial and venous embolism and lung microcapillary thrombotic disease as major determinants of deaths. The pathophysiology of endothelial dysfunction in COVID-19 is not completely understood. We have investigated the role of subunit 1 of the SARS-CoV-2 spike protein (S1SP) in eliciting endothelial barrier dysfunction, characterized dose and time relationships, and tested the hypothesis that heat shock protein 90 (HSP90) inhibitors would prevent and repair such injury. S1SP …

4,6-O-Phenylethylidene Acetal Protected D-Glucosamine Carbamate-Based Gelators And Their Applications For Multi-Component Gels, Pooja Sharma, Guijun Wang

Chemistry & Biochemistry Faculty Publications

The self-assembly of carbohydrate-based low molecular weight gelators has led to useful advanced soft materials. The interactions of the gelators with various cations and anions are important in creating novel molecular architectures and expanding the scope of the small molecular gelators. In this study, a series of thirteen new C-2 carbamates of the 4,6-O-phenylethylidene acetalprotected D-glucosamine derivatives has been synthesized and characterized. These compounds are rationally designed from a common sugar template. All carbamates synthesized were found to be efficient gelators and three compounds are also hydrogelators. The resulting gels were characterized using optical microscopy, atomic force microscopy, …

Syringe Pump, Sophie C. Moffatt, Nicholas R. Guillermo-Martinez, Lauren A. Martin

Biomedical Engineering

Our team was asked to design a syringe pump that would deliver fluid at a controlled flow rate to cells in a microfluidic device. The design process of our syringe pump proved to be a very dynamic one. The beginning research of both microfluidic devices and existing syringe pumps helped our team get an idea of ways we could implement existing aspects that work into our design. There were many existing devices that resembled the one that we were asked to make closely; however, due to our resources as students, we had to be a bit more creative in figuring …

Use Of Steroids In Covid-19 Patients: What Is Known?, Syed Muhammad Mustahsan, Marzia Tahir, Emaduddin Siddiqui

Department of Emergency Medicine

COVID-19 pandemic has exaggerated the role of steroids in the standard of care despite minimum direct evidence of their efficacy in COVID-19 patients and their well-known adverse effects. The literature abounds on the side effects of steroids affecting different organ systems of the body. COVID-19 patients, who are on long-term steroids, are more susceptible to their adverse effects. We, herein, briefly review the potential uses and the adverse effects of steroids on different organ systems of the body. Key Words: Steroids, COVID-19, Adverse effects.

Enhancing The Capabilities Of Fluid Bed Granulation Through Process Automation And Digitalisation, Marcus O'Mahony, Caroline Mccormack, Chris O'Callaghan, Ian Jones, Gavin Walker, Patrick Cronin

Level 3

This paper describes a PAT-enabled, digitalised, and automated fluid bed granulation system. A multichannel Near-Infrared (NIR) spectrophotometer and a direct imaging particle size and shape analyser in constant dialogue with the SmartX no-code/low-code platform provide a ground-breaking process automation toolset now located at the Bernal Institute in the University of Limerick. Two sets of results are presented for this study, from two iterations of the Advance Dynamic Process Control (ADPC) controller application. The results demonstrate the direct measurement and control of the product’s critical quality attributes through digitality enabled feedback control of processing setpoints and parameters. The platform controlled the …

Trends And Age-Related Characteristics Of Substance Use In The Hospitalized Homeless Population, Sung-Youn Chun, Ji W. Yoo, Hyeki Park, Jinwook Hwang, Pearl C. Kim, Seong Park, Jay J. Shen

School of Medicine Faculty Research

We aimed to examine trends and characteristics of substance use (opioid, cocaine, marijuana, and heroin) among hospitalized homeless patients in comparison with other hospitalized patients in 3 states. This was a cross-sectional study, based on the 2007 to 2015 State Inpatient Data of Arizona, Florida, and Washington (n= 32,162,939). Use of opioid, cocaine, marijuana, heroin, respectively, was identified by the International Classification of Diseases, 9th Revision. Multi-level multivariable regressions were performed to estimate relative risk (RR) and 95% confidence intervals (CI). Dependent variables were the use of substances (opioid, cocaine, marijuana, and heroin), respectively. The main independent variable was homeless …

Late-Stage Chemoenzymatic Installation Of Hydroxy-Bearing Allyl Moiety On The Indole Ring Of Tryptophan-Containing Peptides, Nagaraju Mupparapu, Lauren Brewster, Katrina F. Ostrom, Sherif I. Elshahawi

Pharmacy Faculty Articles and Research

The late-stage functionalization of indole- and tryptophan-containing compounds with reactive moieties facilitates downstream diversification and leads to changes in their biological properties. Here, the synthesis of two hydroxy-bearing allyl pyrophosphates is described. A chemoenzymatic method is demonstrated which uses a promiscuous indole prenyltransferase enzyme to install a dual reactive hydroxy-bearing allyl moiety directly on the indole ring of tryptophan-containing peptides. This is the first report of late-stage indole modifications with this reactive group.

Allosteric Determinants Of The Sars-Cov-2 Spike Protein Binding With Nanobodies: Examining Mechanisms Of Mutational Escape And Sensitivity Of The Omicron Variant, Gennady M. Verkhivker

Mathematics, Physics, and Computer Science Faculty Articles and Research

Structural and biochemical studies have recently revealed a range of rationally engineered nanobodies with efficient neutralizing capacity against the SARS-CoV-2 virus and resilience against mutational escape. In this study, we performed a comprehensive computational analysis of the SARS-CoV-2 spike trimer complexes with single nanobodies Nb6, VHH E, and complex with VHH E/VHH V nanobody combination. We combined coarse-grained and all-atom molecular simulations and collective dynamics analysis with binding free energy scanning, perturbation-response scanning, and network centrality analysis to examine mechanisms of nanobody-induced allosteric modulation and cooperativity in the SARS-CoV-2 spike trimer complexes with these nanobodies. By quantifying energetic and allosteric …

Escherichia Coli Alanyl-Trna Synthetase Maintains Proofreading Activity And Translational Accuracy Under Oxidative Stress, Arundhati Kavoor, Paul Kelly, Michael Ibba

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Aminoacyl-tRNA synthetases (aaRSs) are enzymes that synthesize aminoacyl-tRNAs to facilitate translation of the genetic code. Quality control by aaRS proofreading and other mechanisms maintains translational accuracy, which promotes cellular viability. Systematic disruption of proofreading, as recently demonstrated for alanyl-tRNA synthetase (AlaRS), leads to dysregulation of the proteome and reduced viability. Recent studies showed that environmental challenges such as exposure to reactive oxygen species can also alter aaRS synthetic and proofreading functions, prompting us to investigate if oxidation might positively or negatively affect AlaRS activity. We found that while oxidation leads to modification of several residues in Escherichia coli AlaRS, unlike …

A Case Of Diphenhydramine With Alcohol Induced Rhabdomyolysis, Adham Abdulamir, Kayla Szolek, Wahab Gbadamosi, Muhammad Awais

Advances in Clinical Medical Research and Healthcare Delivery

ABSTRACT

Rhabdomyolysis is muscle necrosis and the release of intracellular muscle components into circulation. Approximately 26,000 cases of rhabdomyolysis are reported annually in the United States. The severity varies greatly from asymptomatic individuals to individuals with life-threatening muscle enzyme elevations along with severe electrolyte abnormalities, acute other organ damage, and compartment syndrome. The mortality rates are as high as 59% in critically ill patients. There are multiple causes of rhabdomyolysis that can be classified as traumatic or non-traumatic. The traumatic cases are usually evident at presentation however, in a non-traumatic setting, the presentation may be misleading. In this specific case …

Cilia Proteins Are Biomarkers Of Altered Flow In The Vasculature, Ankan Gupta, Karthikeyan Thirugnanam, Madhan Thamilarasan, Ashraf M. Mohieldin, Hadeel T. Zedan, Shubhangi Prabhudesai, Meghan R. Griffin, Andrew D. Spearman, Amy Pan, Sean P. Palecek, Huseyin C. Yalcin, Surya M. Nauli, Kevin R. Rarick, Rahima Zennadi, Ramani Ramchandran

Pharmacy Faculty Articles and Research

Cilia, microtubule-based organelles that project from the apical luminal surface of endothelial cells (ECs), are widely regarded as low-flow sensors. Previous reports suggest that upon high shear stress, cilia on the EC surface are lost, and more recent evidence suggests that deciliation—the physical removal of cilia from the cell surface—is a predominant mechanism for cilia loss in mammalian cells. Thus, we hypothesized that EC deciliation facilitated by changes in shear stress would manifest in increased abundance of cilia-related proteins in circulation. To test this hypothesis, we performed shear stress experiments that mimicked flow conditions from low to high shear stress …