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Yes, Associated Protein plays differential roles in regeneration and scar formation

Robyn Allen | University of Kentucky | College of Arts and Sciences | Biology

Poster board #001

A fundamental question in regeneration is how cell proliferation is activated and sustained to appropriately restore lost tissue. The transcriptional coactivator, Yes associated protein (YAP), is a potent inducer of cell proliferation. Activation of YAP has been shown to induce or enhance regeneration in several tissues. The African spiny mouse (Acomys cahirinus), a mammal with the remarkable ability to regenerate complex tissues such as ear pinna and skin, maintains higher levels of YAP activity in its fibroblasts than the lab mouse (Mus musculus). In addition, inhibition of YAP delays ear pinna regeneration in the spiny mouse, suggesting that YAP plays an important role in spiny mouse regenerative ability. Using spiny mouse ear pinna regeneration, we investigated the role of YAP signaling at different stages. We show that ears treated with a YAP activator re-epithelialized and closed earlier than DMSO treated ears. However, YAP activation did not increase proliferative index or closure rate. Bulk RNA seq analysis shows that direct targets of YAP related to the inflammatory process are upregulated during early stages of spiny mouse regeneration, suggesting that rather than increasing proliferation, YAP activation causes early inflammatory resolution. Interestingly, YAP activation increases the amount of tissue restored following 4mm ear punch in lab mice but is not sufficient to close the defect. Together these data support that YAP plays a role in the early inflammatory stages of regeneration in highly regenerative spiny mice but may still induce proliferation in poorly regenerative lab mice.

Effects of human angiotensinogen and human renin in proximal tubule cells on development of atherosclerosis in hypercholesterolemic mice

Naofumi Amioka | University of Kentucky | College of Medicine | Department of Physiology

Poster board #002

Objective: This study determined whether angiotensinogen (AGT) interacted with renin in renal proximal tubule cells (PTCs) to promote atherosclerosis.

Approach and Results: We first determined whether hepatocyte-derived AGT interacts with renin in PTCs to promote atherosclerosis. Transgenic mice expressing human renin in PTCs driven by a kidney androgen-related protein promoter (KAP-hREN) in an LDLR -/- background were used. To induce the synthesis of human AGT in hepatocytes, AAV containing human AGT with a liver-specific promoter was injected intraperitoneally. Three groups of male littermates were administered testosterone to activate human renin expression in PTCs: (1) wild type mice administered null AAV, (2) KAP-hREN transgenic mice administered null AAV, and (3) KAP-hREN transgenic mice administered AAV containing human AGT. Two weeks after administration of testosterone and AAVs, mice were fed a Western diet for 6 weeks. Induction of human AGT in liver and human renin in PTCs did not increase atherosclerosis, comparing to the other two groups. Next, to evaluate the direct interaction of AGT and renin in PTCs for promoting atherosclerosis, KAP-human AGT (KAP-hAGT) and KAP-hREN double transgenic mice were fed a Western diet for 12 weeks. Although immunostaining confirmed the presence of human AGT and human renin in PTCs, double transgenic mice did not have increased percent atherosclerotic lesion area, comparing to either wild type or single transgenic littermate groups.

Conclusions: The presence of human AGT in liver or PTCs with the combination of human renin in PTCs did not augment Western diet-induced atherosclerosis in mice. "

Total Synthesis of Isohericerinol A and Its Analogs to Access Their Neurotrophic Effects

Chhabi Chaudhary | University of Kentucky | College of Pharmacy | Pharmaceutical Sciences

Poster board #003

An edible mushroom, Hericium erinaceus belonging to the Hericiaceae family, is broadly found in East Asian countries. It is commonly used in traditional medicines for the treatment of gastrointestinal diseases, dyspepsia, and enervation. The secondary metabolites from H. erinaceus, are reported to have neurotrophic and neuroprotective effects. A report showed that isohericerinol A (1), isolated from its fruiting parts has a strong capacity to increase the nerve growth factor (NGF) secretion in C6 glioma cells. This work describes the total synthesis of a 1 and a synthesis of its regioisomer 2 in a few steps with moderate overall yield (up to 29.9%) using easily accessible feedstocks, which include two different routes to 1 and a regiodivergent route for both 1 and 2. The obtained natural product 1, regioisomer 2, and their intermediates screened for neuroprotective effects in C6 glioma and N2a cells and observed potent neurotrophic activity in experimental concentrations. Thus, this diversity-oriented synthetic method has provided access to prepare derivatives to gain insights into the systematic structure−activity relationship study. The search for potential neuroprotective drug candidates using this scaffold is ongoing in our laboratory.

Conserved transcriptional mechanisms directing Nr2f1 expression in vertebrate atria

Ugo Coppola | Cincinnati Children's Research Foundation | Molecular Cardiovascular Biology Division and Heart Institute

Poster board #004

Nr2f transcription factors (TFs) display conserved requirements determining atrial chamber size via promoting atrial cardiomyocyte (AC) differentiation in vertebrates. However, the regulatory logic directing their expression in vertebrate ACs remains obscure. To identify conserved enhancers regulating Nr2f expression, we compared accessible chromatin surrounding 730 kb of the nr2f1a locus from ATAC-seq data of isolated zebrafish ACs to vertebrate Nr2f1 loci employing VISTA and manual alignments. Using transgenic reporters, we identified a conserved 280 base pair enhancer 3’ to nr2f1a, which we termed 3’reg1-nr2f1a, that drives expression in ACs. TF binding site analysis of 3’reg1 highlighted conserved sites for FoxF and Tcf TFs, which are involved in murine atrial differentiation. Mutating each of three FoxF sites reduced 3’reg1 atrial expression, while disrupting the single Tcf site caused 3’reg1 pan-cardiac expression, suggesting that these TFs respectively promote and repress expression of 3’reg1. Consistent with these observations, overexpression of murine Foxf1 mRNA and dominant negative-Foxf1 expanded and reduced 3’reg1 expression within the heart, respectively. Furthermore, abrogation of Tcf7l1a (Wnt repressor) and Wnt activation drove pan-cardiac 3’reg1 expansion, supporting that Wnt relieves Tcf7l1a-mediated repression. Overexpression of tcf7l1a prevented Foxf1 from activating 3’reg1, suggesting that Tcf7l1a limits Foxf1 function on this enhancer. Functionally, Foxf1 and Wnt signals both promote the differentiation of Nr2f1a+ ACs. However, the same manipulations did not augment AC number within nr2f1a-/- and 3’reg1-nr2f1a-/-, implying that Nr2f1a and 3’reg1-nr2f1a drive responsiveness to these signals in ACs. Together, our data support a model whereby proper atrial relies on a conserved Wnt/Foxf1/Nr2f1 regulatory cascade.

Computer Simulations of Stretch Responses Following Afterloaded Contractions

Poster board #005

Utku Gulbulak | University of Kentucky | College of Medicine | Physiology

Fast myocardial relaxation is important for cardiac function. Impaired relaxation compromises ventricular filling and leads to diastolic dysfunction. Prior work has shown that relaxation following an afterloaded contraction can be accelerated by a quick stretch. This is termed mechanical control of relaxation. To investigate the molecular mechanisms underpinning molecular control of relaxation, additional experiments measured the peak stress response to ramp stretches imposed on rat trabeculae. The force responses scaled with the prevailing tension at the initiation of the stretch and increased with both stretch velocity and amplitude. Force measured after recovery from a stretch was greater than that measured in a paired trial performed without a perturbation. The increased force resulting from stretches imposed early in relaxation could exceed the increase from a late diastolic stretch, which is dominated by passive viscoelastic components. This suggests that the muscle exhibited stretch activation. Simulations mimicking these experiments were performed using a Huxley-type model called MATMyoSim. Cross-bridges transitioned between a super-relaxed (SRX), a disordered relaxed (DRX), and a single attached state. The detachment rate of bound heads depended on the load and increased as the heads were pushed toward shortening. The simulations mimicked key aspects of the experimental data. The stretch responses increased with the prevailing tension and with stretch velocity and stretch amplitude. The model also exhibited stretch activation due to the quick stretches pulling bound heads to positions where they had lower detachment rates. These simulations suggest that cross-bridges can have a significant impact on diastolic function in the heart.

Regulatory Mechanisms of the LBD40 Transcription Factor in Arabidopsis Embryogenesis

Sanjay Joshi | University of Kentucky | College of Agriculture, Food and Environment | Kentucky Tobacco Research & Development Center

Poster board #006

Somatic Embryogenesis (SE) is a process by which an embryo is derived from a single somatic cell or group of somatic cells that are regulated by key transcription factors (TF), including AGAMOUS-like 15 (AGL15). SE is a valuable means to generate transgenic plants to meet food demands or test gene function but is poorly understood. One of the intriguing proteins with which AGL15 interacts in yeast 2-hybrid assays is LBD40. LBD40 encodes a LATERAL ORGAN BOUNDARIES (LOB)-domain TF that is unique to plants, is specifically expressed during seed development and has a role in supporting SE. In planta protein interaction of AGL15 and LBD40 has now been documented using co-immunoprecipitation. Siliques and SE tissue with epitope-tagged transgenes were used for Chromatin-Immunoprecipitation (ChIP) that allows one to determine where TFs bind to DNA in vivo, a step necessary to understanding genes directly controlled by a TF. More than four hundred binding regions for LBD40 were found genome-wide in three biological replications of ChIP-sequencing. RNA-seq results of 7-8 days old seeds from lbd40/41 mutant line compared to wild type seeds showed genes as significantly expressed and repressed targets. More than seven hundred genes had increased RNA (785 genes) in the mutant, while 2086 genes were downregulated (decreased RNA accumulation) in the mutant line compared to the wild type. The Gene Ontology (GO) enrichment analysis of these regulated genes showed an overrepresentation of biological processes that are associated with SE, further indicating the importance of LBD40 in SE.

Discovery and Optimization of Novel 2,4,5-Trisubstituted Benzamides as Orally Active Antileishmanial Agents.

Taraman Kadayat | University of Kentucky | College of Pharmacy | Pharmaceutical Sciences

Poster board #007

Leishmaniasis, an infectious disease endemic in tropical and subtropical regions of Asia, Africa, Southern Europe, and Americas is caused by Leishmania parasites and vectored between humans by the bites of infected sand flies. Roughly 1 billion people are at high risk of infection and there is an annual morbidity of 1 million new cases of leishmaniasis. Treatment options for leishmaniasis are very limited due to a historical low effort developing new drugs for leishmaniasis. Of the antileishmanial drugs only miltefosine is orally bioavailable and it shares severe toxicity and high cost. We addressed the pressing need for new therapies by pursuing a two-step phenotypic high throughput screen (HTS) of roughly 600,000 small molecules and discovered a novel and potent antileishmanial agent (compound 1). We further disclosed our efforts for the design and synthesis of optimized novel substituted benzamide analogs as novel orally bioavailable antileishmanial drugs. An extensive structure-activity relationship and structure-property relationship study resulted compound 82 with suitable potency, microsomal stability, and improved aqueous solubility with good in vivo pharmacokinetic data. Taken together, our drug discovery chemistry campaign has led to generation of optimized lead that may be directed towards the development of new orally available antileishmanial drugs.

Combination of oral metronomic chemotherapy and anti-PD-1 therapy modulates tumor specific immunity and establishes long-term immunity against colon cancer

Ruby Maharjan | University of Kentucky | College of Pharmacy | Pharmaceutics

Poster board #008

The concept of metronomic therapy (MCT) was introduced to overcome the toxic effects of conventional chemotherapy which uses maximum tolerated dose (MTD). Since the basis of metronomic chemotherapy is frequent administration, oral drugs are a good candidate for metronomic therapy. Thus, in this study oral formulation of intravenous drugs such as oxaliplatin (OXA) and pemetrexed (PMX) was developed by ionic conjugation with an intestinal permeability enhancer, Nα-deoxycholyl-l-lysyl-methylester (DCK), to formulate OXA/DCK nanoemulsion (OXA/DCK-NE) and PMX/DCK powder formulation (PMX/DCK-OP), respectively. The immune-modulating effect of metronomic treatment (MCT) of OXA/DCK-NE plus PMX/DCK-OP was studied in mouse colon cancer model. MCT boosted DC uptake, presentation, cross presentation, and activation. Effector T cell populations such as CD45+, CD8+, CD45+, macrophages as well as their functioning were upregulated by MCT compared to MTD. Furthermore, on combining MCT with αPD-1, the tumor suppression was more effective showing 97.8% decrease in tumor volume compared to that of control leading to tumor free mice (95% complete response). Mice that achieved complete antitumor response upon re-challenge, demonstrated that combination therapy of MCT and αPD-1 induced memory response by rejecting tumor growth which was further confirmed by 1.5-fold enhanced antigen specific memory response compared to αPD-1 only treated group as detected by secretion of INF-γ. In conclusion, MCT was more effective than MTD in tumor inhibition and could successfully elicit immunomodulatory effects establishing long-term immunity against colon cancer.

Development and optimization of liposomal Azithromycin formulation for healing broken hearts

Abdullah Masud | University of Kentucky | College of Pharmacy | Pharmaceutical sciences

Poster board #009

Myocardial infarction (MI) is a leading cause of morbidity and mortality worldwide. Poorly manageable inflammation that develops in the injured cardiomyocytes is highly detrimental to the healing process in post-MI. Interestingly, azithromycin (AZM), a widely known antibiotic, has recently shown to alleviate inflammatory responses in MI induced mice. However, dose-related toxicity due to off targeting of azithromycin seems to pose a serious concern to its therapeutic success as an effective anti-inflammatory agent. Nevertheless, our group found that encapsulating azithromycin in liposomes significantly improved its anti-inflammatory efficacy in post MI leading to a substantial reduction in dose-associated toxicity. Thus, optimizing the L-AZM formulation in the context of quality attributes along with the ability to manufacture the liposomes in a reproducible and high throughput manner are vital for its transition to clinic. Whereas our parent formulation contains an equimolar amount of DSPC, DSPG and cholesterol, its drug encapsulation efficiency (EE%) is moderate i.e., 30 – 50%, primarily because AZM is too heavy molecule (MW 785) to leak out of the liposomal bilayer membranes. To improve upon the retention of AZM in the bilayer membrane, we utilized an ion pairing approach between the cationic AZM and anionic lipids in a microfluidic channel. Optimizing multitude of parameters such as charge ratio of AZM to lipids, AZM concentration and the microfluidic factors, i.e., flow mixing rate, and mixing ratio, the lead formulation yields the EE% exceeding 90% along with the ability to slowly release the drug over the course of more than 24 hours. An optimized L-AZM formulation supported with positive pre-clinical data would make it a potential candidate for the clinic.

Transposon Sequencing Reveals Role of Multiple Pathways in Developing Resistance to Cathepsin-G in Group A Streptococcus

Tanmoy Mukherjee | University of Kentucky | College of Medicine | Department of Microbiology, Immunology and Molecular Genetics

Poster board #010

Group A Streptococcus (GAS) is a significant human pathogen which is associated with numerous diseases ranging from minor skin and throat infections to life-threatening diseases such as scarlet fever, streptococcal toxic syndrome, necrotizing fasciitis, cellulitis and erysipelas. Furthermore, repeated GAS infections can lead to acute rheumatic fever and subsequent rheumatic heart disease. The ability of GAS to cause infections is associated with its resistance to killing by the host immune defense mechanisms. The key components of innate immunity are cationic antimicrobial peptides (AMPs) that vary from 10 to 150 amino acids. Among the most potent AMP is Cathepsin-G(Cat-G). Cat-G is highly cationic, serine protease found in the azurophilic granules of neutrophils. Cat-G can regulate inflammatory responses and are responsible for the activation and mobilization of immune cells to the site of pathogen leading to clearance of pathogen from the site. Recent studies have shown that bacteria can disarm Cat-G using various mechanisms unique to the bacteria. To identify the genetic factors conferring resistance/susceptibility as fundamental determinants of Cat-G potency against GAS, we used genome wide screen using Transposon Sequencing (Tn-Seq). Tn-Seq analysis shows that GAS may take a multi-prong approach to develop resistance against Cat-G that includes capsule biosynthesis, fatty acid metabolism, Zinc uptake system, PTS system, peptidoglycan modification & cell separation machinery. In addition to that several non-coding regions including ncRNAs & intergenic regions were also found to be under selective pressure of CatG. We have also found genes that increases sensitivity of GAS to Cat-G.

The association of gabapentin initiation and neurocognitive changes in older adults with normal cognition

GYeon Oh | University of Kentucky | College of Medicine | Sanders-Brown Center on Aging

Poster board #011

This study aimed to examine the association of gabapentin use with neurocognitive changes in older adults. We conducted a retrospective cohort study using the National Alzheimer’s Coordinating Center Uniform Data Set (Sept 2005-March 2021), where participants are assessed approximately annually. From the eligible sample (≥age 65 years), we identified cognitively normal new-users of gabapentin and the visit they initiated gabapentin (i.e., index). To prevent immortal time bias, initiators were matched to randomly selected nonusers on year of enrollment and visit number from enrollment to index. Cognitive decline was defined using Clinical Dementia Rating global score (CDRGLOB) (any increase) and CDR sum of boxes (CDR-SB) (1-point increase). Functional status decline was defined using sum of the Functional Activities Questionnaire (FAQ) (3-point increase) and mean FAQ (0.3-point increase). Decline in motor function was defined as new clinician reports of gait disorder, falls, and slowness. All analyses were conducted comparing index to index+1 and index+2 visits. We included 480 initiators (mean age[SD]: 78.7[6.9]; male 34.4%) and 4,320 nonusers (78.3[7.0]; 34.4%). Gabapentin initiation was significantly associated with cognitive/functional status decline: worsening CDRGLOB at index+1 visit (odds ratio [95% confidence interval]: 1.55[1.07, 2.25]); CDR-SB at index+1 visit (1.94[1.22, 3.09]); and mean FAQ at index+2 visit (1.78[1.12, 2.83]). After excluding initiators with extant motor dysfunction, we identified 459 initiators (78.7[6.9]; 34.0%) and 4,131 nonusers (78.2[6.9]; 34.7%); in this sample, gabapentin initiation was associated with increased falls at index+2 visit (2.51[1.19, 5.31]). Given the significant association of gabapentin initiation with deleterious neurocognitive changes, further studies are needed to examine the risk/benefit of prescribing gabapentin in older adults.

Targeting the opioid epidemic: Developing an Improved Rescue Agent

Edem Onyameh | University of Kentucky | College of Pharmacy | Pharmaceutical Sciences

Poster board #012

In 2020, exacerbated by the COVID-19 pandemic, more than 69,000 deaths in the United States have been attributed to opioid overdose and 80% of these fatal deaths involves synthetics such as fentanyl (100 times more potent than morphine) and its analogs. Opioid induced fatalities result from respiratory depression that is the result of agonism at the mu opioid receptor. Currently, there are three opioid antagonists (naloxone, naltrexone and nalmefene) available clinically with the potential to reverse the effects of fentanyl. However, these antagonists are not optimal because of their short duration of action and weak potency compared to fentanyl. Thus, there is a need to develop higher potency and longer-acting opioid antagonists to reverse the respiratory depression of fentanyl and its analogues.Diprenorphine is an opioid partial agonist used in veterinary medicine for reversing the effects of super-potent opioid analgesics such as etorphine and carfentanil that are used for tranquilizing large animals. Due to its intriguing profile of reversing these highly potent opioid agonists, our laboratory has undertaken an optimization campaign to identify a diprenorphine analogue suitable for use in humans as an opioid rescue agent. Through a combination of multi-step organic synthesis and structure-activity relationships studies, we have identified MOR antagonists with enhanced potency compared to naloxone and greater antagonism than diprenorphine.

Protein glycosylation protects Streptococcus pyogenes from host innate immune defences

Mohammad Rahman | University of Kentucky | College of Medicine | Microbiology, Immunology and Molecular Genetics

Poster board #013

Bacterial protein glycosylation, a post-translational modification of proteins by sugar, plays major roles in biological processes including adhesion, immune evasion and host colonization. Glycosyltransferases (GTs) are the enzymes that specifically transfer sugar moieties to the proteins, resulting in protein glycosylation. In this study, using lectin affinity chromatography followed by proteomic analysis we discovered that in Streptococcus pyogenes (GAS), a human pathogen that causes around 500000 deaths annually worldwide, six membrane proteins are glycosylated at the Serine/Threonine residues with glucose (Glc) moiety, indicating the presence of O-linked glycosylation pathway. The identified glycoproteins participate in protein folding, Group A Carbohydrate biosynthesis, and peptidoglycan synthesis in GAS. Mutagenesis approach revealed the role of the GT-A type transferase Spy420 and GT-C type transferase Spy1862 in protein glycosylation. We found that Spy 420 catalyses the first step of protein glycosylation in the cytosol transferring UDP-glucose (UDP-Glc) to the lipid career, undecaprenyl phosphate (Und-P). We suggest that Spy 1862 transfer a Glc moiety from a glycolipid to the Serine/Threonine residues of acceptor membrane-proteins. In addition, we found that Spy 420 and Spy 1862 are crucial for GAS protection from antimicrobial proteins and peptides, cathepsin G and LL-37. These data suggest that O-linked protein glycosylation might contribute to GAS evasion of innate immune defenses.

Ability + Opportunity: Equitable Training Practices in Science and Medicine

Brittany Rice | University of Kentucky | College of Medicine | Behavioral Science

Poster board #014

Underrepresented racial/ethnic minorities and underserved persons make up a small fraction of scientists and leadership in cancer research. Much of this disparity is a result of structural racism and classism in our educational system that has led to dramatic inequities in terms of opportunities, proactive mentorship and advancement in science-based careers. In an effort to address the increased awareness of the need of divergent perspectives as well as inclusive and equitable training, research training paradigms nationwide have been engineered specifically for those that are marginalized. The objective of the Markey Science Training in Research, Oncology, Networking and professional Growth (STRONG) Scholars Program is to increase the number of individuals who are from underrepresented and underserved groups in cancer research. STRONG programming consists of research and clinical experiences, cancer education, personalized mentoring as well as personal and professional development. Throughout the program, STRONG participants successively demonstrated increased acquaintance with, understanding of, and motivation to pursue careers in cancer research in addition to the adoption of positive science identities bolstered by a sense of academic belonging.

Isolation and Identification of an Enzyme in Manduca sexta that Converts Monomeric TIAs into Dimeric Insecticidal Anhydrovinblastine

Lei Sha | University of Kentucky | College of Agriculture, Food and Environment | Kentucky Tobacco Research & Development Center (KTRDC)

Poster board #015

Catharanthus roseus produces almost 200 terpenoid indole alkaloids (TIAs). The precursors (catharanthine and vindoline) accumulate separately in different cellular compartments of C. roseus leaves, suggesting a compartmentalized “Timebomb” against herbivores, in which the precursors and enzymes related to the synthesis of primary defensive chemicals in plants are spatially separated. In planta, the condensation of vindoline and catharanthine initiates the synthesis of dimeric MIAs through the formation of anhydrovinblastine (AVLB) that displays cytotoxic properties. C. roseus leaves consumption resulted in a rapid death of M. sexta larvae that could be linked to the MIA dimerization observed in intestinal tracts. For feeding of M. sexta larvae on tobacco leaves, the mixture of vindoline and catharanthine showed higher dietary toxicity on M. sexta larvae than did either of the two individual compounds in our preliminary research. Acute toxicity was only found in the mixture rather than in the two individual compounds.

Neurotensin regulates mouse granulosa cells function during the ovulatory period

Ketan Shrestha | University of Kentucky | College of Medicine | OB/GYN-Endocrinology

Poster board #017

The release of a fertilizable egg/oocyte is an essential step that governs female fertility. In fact, the major cause of female infertility is related to ovulation problems or the inability to release a fertilizable egg. Hence, the mechanisms that control ovulation, including a more thorough understanding of the mediators during the ovulatory period, are extremely important to improve the quality of women’s reproductive health. Our laboratory has identified neurotensin (NTS), a small neuropeptide, as one of the most abundantly induced genes in mouse granulosa cells (mGCs) that surround the cumulus-oocyte complex within the ovulatory follicle. However, nothing is known about the regulation and function of NTS during the ovulatory period. We have found that Nts is regulated by human chorionic gonadotropin (hCG; LH-analog) and LH-induced epidermal growth factor in mGCs. Then, using Nts knockdown by small-interfering-RNA and RNA-seq approach, we found thousands of genes regulated by NTS. The most significant genes are RNA polymerase II 2, radical S-adenosyl methionine domain containing 2, and vacuolar protein sorting 37A. Moreover, silencing Nts increased cell metabolic activity. NTS treatment inhibited glucose uptake in mGCs. In summary, these data demonstrate that Nts is induced by hCG and NTS regulates mGCs function during the ovulatory period providing new insight into the potential role of NTS during the ovulatory period. Altogether, this study could aid in the understanding of the regulation of human fertility and could provide future opportunities to manipulate this key pathway to improve outcomes for infertile women.

Lung Cancer Prevention among Appalachian KY Women: A Community-Engaged Mixed Method Study

Jessica Thompson | University of Kentucky | College of Medicine | Community Impact Office, Markey Cancer Center

Poster board #018

Introduction: Central Appalachian Kentucky (KY) experiences the highest lung cancer rates in the US. Although lung cancer has declined steadily among men, such decreases have not been seen among women. Central Appalachian smoking rates are among the highest in the country; however, 20% of women with lung cancer are lifelong non-smokers. Thus, more insight is needed to increase primary and secondary preventive efforts. This study utilizes concept mapping, a community-engaged mixed method, to: 1) uncover perceived barriers and facilitators to lung cancer prevention and 2) identify community-driven intervention ideas among Appalachian KY women.

Methods: We are recruiting participants who identify as women in Appalachian KY (N=70) to participate in online concept mapping activities. We are using multidimensional scaling to create a point map representing perceived similarities and hierarchical cluster analysis to create cluster maps illustrating thematic categories. Through qualitative group discussions, we are utilizing the generated maps to explore lung cancer prevention interventions.

Results: In progress, the quantitative concept mapping elements identify perceived barriers and facilitators across individual, interpersonal, community, and environmental levels as well as relationships between items by importance and feasibility. The qualitative groups provide local insights on potential interventions to increase lung cancer prevention.

Discussion: This study develops novel understanding of local barriers, gender-specific risk factors, and community-driven intervention ideas. A community-engaged study, this work informs potential strategies to improve lung cancer prevention in the Appalachian KY counties. These findings provide a platform for future studies to understand gender-related lung cancer prevention needs in other communities globally.

“Everyone eats, so everyone poops!”: When Wastewater is the Path to More Equitable Healthcare and Predicting the Next Pandemic

Soroosh Torabi | University of Kentucky | College of Engineering | Mechanical Engineering

Poster board #019

Introduction: In early 2020, the first laboratory-confirmed case of COVID-19 was reported in the US. The whole world was facing an invisible and deadly threat that was difficult to track. Testing everyone was a logistical nightmare, and once a positive case was confirmed, it was already too late; hundreds of other people had already been infected in that community. Flashforward to 2022, the majority of the people are vaccinated and there are fewer mask mandates in public areas. Many people are using at-home test kits “but” are less likely to report their test results. Clinical cases may be low; however, the fire is still smoldering under the ashes!

Methods: Our good news is “everyone eats, so everyone poops!”. If you are infected with COVID-19, whether you have symptoms or not, your body sheds the virus in your stool. As a result, the presence of the virus can be tested in the wastewater from the communities, and the infection rate at a community level can be tracked or even predicted by a few days.

Results & Discussion: We have established wastewater surveillance for infectious diseases in Eastern Kentucky, tracking COVID infection trends in Appalachia. We have developed various technologies to simplify the wastewater sample processing for low-resource settings, and we are expanding to look for the spread of upcoming infectious diseases such as Monkeypox. This is particularly impactful in rural and low-resource areas across the globe where access to laboratory testing is limited, promoting equity in healthcare access among under-served populations.

Recovery of valuable metals using hydrophobic ternary deep eutectic solvents (DESs) from lithium-ion battery (LIB) cathode materials

Ahamed Ullah | University of Kentucky | College of Engineering | Biosystems and Agricultural Engineering

Poster board #020

The extensive usage of lithium-ion batteries (LIBs) in electronic devices and electric vehicles (EV) will produce a huge amount of waste from dead batteries in the future. Among various parts of LIBs, the cathode material is critical because it contains metals that are valuable and limited in quantity in nature. So, proper and efficient methods are needed to extract and recover these metal elements from the cathode materials of spent LIBs. Here, we designed and tested novel hydrophobic ternary deep eutectic solvents (htDESs) for effective metal extraction. Those htDESs made of naturally derived compounds such as menthol, thymol, and phenols showed great leaching efficiency and can mostly dissolve the LiCoO2 (LCO) powder under mild leaching conditions. The selected htDESs are being tested using the real black mass from spent batteries (mostly containing graphite, lithium, nickel, aluminum, cobalt, etc.). This study demonstrates the potential use of sustainable solvents for the recovery of critical metals from LIBs.

A MnSOD enhancer alleviates inflammation in immune cells from older individuals with obesity by promoting quiescence

Teresa Vezza | University of Kentucky | College of Medicine | Department of Pharmacology and Nutritional Sciences

Poster board #021

Obesity rates have risen dramatically in recent years with nearly 40% of the older adult population (60+yrs) in the US falling in the obesity category and ~70% in the overweight. Accumulating evidence suggest low-grade systemic inflammation and redox imbalance as key events in the onset and progression of both obesity and aging. Blood CD4+ T cells from older lean subjects show changes in mitochondrial bioenergetics and redox system and less mitochondrial superoxide dismutase (MnSOD) protein compared to cells from young counterparts. We investigated putative anti-inflammatory effects of a MnSOD enhancer in stimulated human CD4+ T (CD4s) and, for a broader perspective, peripheral blood mononuclear cells (PBMCs) from older (60+yrs) and younger (18-35yrs) subjects in the overweight/obesity category (BMI 27-40 Kg/m2). Treatment with a MnSOD enhancer promoted a quiescent state in all cell types, as indicated by reduced cell size and metabolic rate. The MnSOD-enhancer also reduced signatures of Th1/Th17- (but not Th2-) mediated inflammation in CD4s from both cohorts. Moreover, the MnSOD-enhancer decreased mitochondrial superoxide production and glutaminolysis only in CD4s from older individuals. Preliminary data in PBMCs from older individuals indicated that removal of the MnSOD enhancer forced cells to exit this transient quiescent state by resetting metabolism to levels approximating those of vehicle-treated cells from younger subjects. Collectively, these results indicate that ability of MnSOD enhancement on inflammation and metabolism is not cell-type nor cohort-specific. A more in-depth investigation will determine whether resetting immune cell metabolism changes inflammatory signatures.

Operation Tooth Fairy: Using primary shed teeth as a way to assess prenatal exposures to trace elements

Courtney Walker | University of Kentucky | College of Medicine | Behavioral Sciences

Poster board #022

To overcome the limitations of assessing prenatal exposures to trace elements, we are assessing the feasibility of examining primary teeth, specifically incisors, shed in childhood between the ages of 5 – 9 as a non-invasive method to estimate trace element exposure. The formation of the individual primary teeth, which begins around 12-13 weeks gestation, is similar to the growth rings of a tree. During the mineralization of the protein matrix, trace elements bond with phosphorus and calcium and are deposited within the tooth matrix. Although some tooth development continues post-partum, development after birth is delineated with the neonatal line, so the prenatal tooth region is identifiable. Primary tooth analysis has not been widely undertaken, despite its promise as a non-invasive method to assess prenatal exposures that can be employed during periods where children are more likely to be diagnosed with health conditions (pediatric cancers, learning disorders, etc.) Developing and refining this study protocol can lead to improved assessments of prenatal exposures for local and global research as teeth do not require special accommodations for collection or transportation.

An efficient numerical approximation to a two-dimensional fourth-order partial differential equation in a polygonal domain

Charuka Wickramasinghe | University of Kentucky | College of Arts and Sciences | Mathematics

Poster board #023

Introduction: In this research, we study a two-dimensional fourth-order partial differential equation called biharmonic equation in a polygonal domain. There are many applications where the biharmonic equation occurs in mathematics, engineering, physics, chemistry, medicine, and many other fields. Some prominent examples are radar imaging, thin beams and plates, human face recognition, the flow of molten metal, and bio-fluid dynamics. The exact solution to many of those problems is not known. Therefore, finding an efficient numerical solution to the biharmonic problem is essential.

Methods: To this end, we use the finite element method, a popular method for numerically solving differential equations arising in engineering and mathematical modeling. Solving the biharmonic problem in the presence of corner singularities in the domain is more challenging than solving it in a smooth domain. This work aims to find a method that works for smooth domains and domains with corner singularities. We propose two algorithms that effectively decouple the fourth-order problem into systems of second-order problems.

Results, and Discussion: It is shown that the solution of each system is equivalent to that of the original fourth-order problem on both convex and non-convex polygonal domains. We further derive the optimal error estimates for the numerical solutions on both quasi-uniform and graded meshes. We adopt the ifem MATLAB software package to generate numerical solutions. Our numerical test results justify the theoretical findings and demonstrate the performance of our approach.