Life Sciences Commons^™

Alcohol Consumption Exacerbates High-Fat Diet- Mediated Disruptions In Myelopoiesis And Osteoclastogenesis In Mouse Models Of Metabolic Dysfunction-Associated Liver Diseases, Hami Hemati, Madison B. Blanton, Lauren Rutt, Nicholas Keiran, Rebecca Geron, Florence Lima, Rebecca L. Mccullough, Ilhem Messaoudi

Microbiology, Immunology, and Molecular Genetics Faculty Publications

Objective: Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) and Metabolic Dysfunction-Associated Alcohol-related Liver Disease (MetALD) exhibit systemic immune abnormalities. Given that such immune dysregulation is closely linked to the skeletal complications frequently observed in MASLD and MetALD, we sought to comprehensively characterize the bone marrow hematopoietic compartment and its link to osteoclastogenesis.

Methods: We utilized bone marrow from mouse models of MASLD (high-fat diet, HFD) and MetALD (high-fat diet plus ethanol, HFD+EtOH), followed by flow cytometric analysis to phenotype hematopoietic stem and progenitor cells (HSPCs), as well as in vitro and in vivo assays to evaluate osteoclastogenesis.

Results: We found that …

Assessing Radio Transmitter Weight Effect And Evaluation Of Northern Bobwhite Chick Survival In Coastal North Carolina, Autumn S. Randall, Theron M. Terhune Ii, Matthew T. Springer, Darin J. Mcneil

Forestry and Natural Resources Faculty Publications

Studies on the earliest life stages are essential to our ecological understanding of avian demography; however, monitoring technologies that allow tracking of small birds are still limited in a variety of ways. One critical limitation, until recently, has been the development of methods for attaching transmitters to young birds with precocial development (e.g., Galliformes, Charadriiformes, etc.). The modified suture technique offers a means to attach transmitters to precocial chicks while accommodating rapid growth characterized by birds with precocial young. Although the sutured transmitter method was developed for northern bobwhite (Colinus virginianus) chicks, there remain key unknowns regarding best …

Aggregation Bias In Multi-Industry Economic Contribution Analysis: The Case Of Kentucky Forest Sector, Domena A. Agyeman, Thomas Ochuodho, Omkar Joshi

Forestry and Natural Resources Faculty Publications

Closely related industries are often aggregated in US forest sector economic contribution analysis, yet the choice of aggregation scheme can influence results. The Impact Analysis for Planning (IMPLAN) system is the most widely applied input–output model for forest economic contribution analysis in the US. In IMPLAN, the level of industry aggregation determines which inter-industry transactions are restricted, thereby influencing the magnitude of estimated indirect and induced effects. Although IMPLAN practitioners can model individual industries to avoid aggregation bias, they must still decide whether to analyze forest industries as a single group, as traditional subsectors, or individually. This decision can alter …

Effects Of Headwater Wetland Restoration On The Demography, Fecundity And Ecology Of The U.S. Federally Threatened White Fringeless Orchid (Platanthera Integrilabia) In The Cumberland Plateau Of Kentucky, Tara R. Littlefield, Catherine Hoy, Christopher Barton

Forestry and Natural Resources Faculty Publications

Wetland habitats represent a critical component of biodiversity hotspots that support numerous rare species, including terrestrial orchids. In North America, over half of all terrestrial orchids are found in wetlands, more than a quarter of which are now threatened with extinction (G1–G3). This concerning trend is exacerbated by a lack of information on effective restoration strategies aimed at orchids and other species that inhabit these areas. The white fringeless orchid, Platanthera integrilabia (Correll) Luer, the subject of this study, is restricted to mostly shaded wetland habitats along the Cumberland Plateau of the Appalachian Mountains and has suffered widespread declines due …

Fecal Microbiota Transplantation Modulates Gut Microbiota And Lipid Metabolism To Reduce Diarrhea In Low-Birth-Weight Neonatal Calves, Zhanhe Zhang, Duo You, Donglin Wu, Xintong Li, Yang Jia, David L. Harmon, Ming Xu

Animal and Food Sciences Faculty Publications

This study aimed to elucidate the mechanism by which colonic fecal microbiota transplantation (FMT) improves lipid metabolism in low-birth-weight neonatal calves via modulation of the gut microbial ecosystem. In a completely randomized design, seventy newborn Holstein calves (1 day old, 32.63 ± 3.13 kg BW) were assigned to two groups (35 calves/treatment; 30 females and 5 males per group). A healthy calf was used as a fecal donor. A 10% fecal bacterial suspension was prepared and administered colonically (50 mL, twice daily for 5 days). All calves were fed the same milk replacer and weaned using a step-down protocol at …

Wet Aging And Internal Endpoint Cooking Temperature Influence Color Of Lamb Longissimus Lumborum Muscle, Oluwatobi M. Ogunsola

Theses and Dissertations--Animal and Food Sciences

Color is a critical quality attribute that influences consumer purchase decisions for fresh and cooked lamb and is governed by myoglobin's redox chemistry. Wet aging is commonly used to enhance lamb tenderness, while endpoint cooking temperature is the primary determinant of internal cooked color. However, the combined effects of these factors on the color stability of the lamb longissimus lumborum (LL) muscle during refrigerated storage remain unclear. The objective of this thesis was to evaluate the effect of wet aging duration on the color attributes and lipid oxidation of fresh lamb LL chops and endpoint cooking temperature and refrigerated storage …

Balancing Wood And Food: Assessing The Drivers And Spatiotemporal Conflicts Of Eucalyptus Plantation Expansion In Guangxi, China, Wen H. Cai, Qiuxia Huang, Jian Yang, Le Yu, Yuanzheng Yang, Jiaxing Zu, Jiali Wang, Zhenxian Li

Forestry and Natural Resources Faculty Publications

Eucalyptus has become one of the most widely cultivated tree genera in subtropical China, generating significant economic returns but raising land-use conflicts with agriculture. Understanding the driving mechanisms behind this expansion is crucial for sustainable land-use management. To inform strategies for balancing wood production and agricultural stability, we investigated the spatiotemporal expansion dynamics and predicted the potential suitable habitat distribution of Eucalyptus plantations using a Boosted Regression Tree (BRT) model. Our analysis revealed three distinct spatiotemporal expansion phases. Crucially, this expansion has progressively shifted from marginal sloped terrain onto flat valley bottoms, intensifying the agriculture-forestry conflict in the region. Climatic …

Transcriptional Signatures Of Rapid Protection From Sudan Virus Infection By A Single Dose Of A Vesicular Stomatitis Virus-Based Vaccine, Brianna M. Doratt, Sheridan B. Wagner, Delphine C. Malherbe, Gregory T. Smith, Andrea Marzi, Ilhem Messaoudi

Microbiology, Immunology, and Molecular Genetics Faculty Publications

Sudan virus (SUDV) has caused multiple outbreaks of human disease with case fatality rates ranging from 41 to 100%. We have previously shown that a single vaccination with a recombinant vesicular stomatitis virus-based vaccine expressing the SUDV-Gulu glycoprotein (VSV-SUDV) prevented clinical and fatal disease from lethal SUDV challenge in cynomolgus macaques. With the high probability of future outbreaks, it is critical to determine the molecular mechanisms of VSV-SUDV-mediated protection and the ability to impart rapid protection against SUDV infection. In this study, RNA from whole blood samples obtained from nine cynomolgus macaques that were challenged with SUDV-Gulu post-vaccination with either …

Characterizing Immune Perturbations In Peripheral Blood Following The East Palestine, Ohio Train Derailment, Sheridan B. Wagner, Hami Hemati, Siva Gandhapudi, Timothy J. Hilbert, Candace J. Brancato, Erin N. Haynes, Ilhem Messaoudi

Microbiology, Immunology, and Molecular Genetics Faculty Publications

Background: The East Palestine, Ohio, train derailment on February 3rd, 2023, resulted in the exposure of residents and the surrounding area to numerous hazardous chemicals, which included known acute irritants and human carcinogens. Despite evacuation and cleanup, both residents and responders reported high occurrences of symptoms associated with exposure in the months following, such as eye, skin, and respiratory irritation, headaches, and fatigue. The long-term health consequences for residents remain uncertain.

Objective: To assess the potential for immune perturbations resulting from the exposure, we performed a broad investigation of circulating immune cells and mediators from residents of East Palestine, OH, …

Combinatorial Immunotherapy Drives Exhaustion In Tumor Antigen–Specific Cd8+ T Cells Within The Mouse Renal Tumor Microenvironment, Holly R. Stephens, Elizabeth Elkins, Jing Li, Zoey N. Swalley, Henry Nnaemeka Ogbonna, Pia Muri, Zachary Roberts, Francesca R. Dempsey, Md Akkas Ali, Md Hasanul Banna Siam, Richard Kirkman, Jianqing Zhang, Sunil Sudarshan, Daniel J. Tyrrell, Hubert M. Tse, Daniel L. Smith Jr, Lyse A. Norian

Microbiology, Immunology, and Molecular Genetics Faculty Publications

Immunotherapies have greatly improved outcomes for patients with renal cell carcinoma (RCC), yet response rates remain suboptimal and the factors promoting therapy resistance versus sensitivity are incompletely understood. Currently, no preclinical model of orthotopic renal cancer exists that permits evaluation of tumor antigen–specific (TAS) CD8⁺ tumor-infiltrating lymphocytes (TILs). To address this deficiency, we developed a mouse renal cancer model that permits tracking of adoptively transferred TAS CD8⁺ T cells. Renca-LUC tumor cells were transduced to express tumor ERK (tERK), a model antigen expressing a one-amino-acid change from wild-type ERK, resulting in recognition by tERK/H-2K^d-specific DUC Thy1.1 …

Limitations Of Reproductive Manipulation By Bacterial Endosymbionts In A Spider Host, Jordyn D. Proctor

Theses and Dissertations--Entomology

Maternally inherited bacterial endosymbionts are common in arthropods. Many of these bacteria manipulate host reproduction to favor the production of infected females, thereby increasing bacterial prevalence in the host population, even if cost is incurred to the host. However, there are also many factors that may inhibit symbionts’ ability to spread in host populations, including environmental constraints, symbiont-imposed costs on the host, interactions with co-infecting bacteria, or host biology. I explored two aspects of symbiont biology within a spider host, Mermessus fradeorum (Linyphiidae), which has varying combinations of up to five different bacterial endosymbionts in local populations: Rickettsiella, Tisiphia …

Impacts Of Livestock Dewormers On Dung Beetle Foraging Choices Across Spatial Scales, Madison L. Kluge

Theses and Dissertations--Entomology

Dung beetles provide ecosystem services in pasture systems but are vulnerable to chemical residues in livestock dung. Parasiticides containing macrocyclic lactones (MLs) are used to control parasites in livestock and are excreted unmetabolized in dung, exposing non-target organisms to these compounds. We used a multi-scale approach to examine whether ML residues alter dung beetle foraging ecology. At the field scale, we assessed dung beetle abundance and community composition using traps baited with dung from untreated cattle and cattle treated with ivermectin, moxidectin, or eprinomectin across eight farms and natural areas. At a smaller scale, we conducted behavioral assays to quantify …

A Conserved Ethylene-Triggered Cell Death Mechanism May Underlie Hollow Stem Formation Across Plant Species, Mengxiao Yan, Weijuan Fan, Yinghui Meng, Jiamin Zhao, Wei Yang, Ziyin Xu, Yusen Gao, Haiyan Zhuang, Wuyu Zhou, Yuqin Wang, Qingjun Huang, Ling Yuan, Hongxia Wang, Jun Yang

Plant and Soil Sciences Faculty Publications

Hollow stems have independently evolved multiple times across the plant kingdom and play crucial roles in plant development and various environmental adaptations. However, the mechanisms underlying stem hollowness remain poorly understood. Water spinach (Ipomoea aquatica) is one of the few hollow-stemmed plants in the Convolvulaceae family (eudicot: asterid), and its hollow stems are essential for thriving in aquatic environments. Using histochemical staining and transcriptome analysis, we found that programmed cell death (PCD) is involved in cavity formation at water spinach shoot tips. Single-cell and spatial transcriptome analyses further revealed that ethylene and reactive oxygen species (ROS) likely drive …

Excess Nitric Oxide Alters Cellular Ph To Restrict Salicylic Acid Movement And Systemic Immunity, Fan Xia, Huazhen Liu, Keshun Yu, Xinyu Yuan, Aardra Kachroo, Pradeep Kachroo

Plant Pathology Faculty Publications

Plants carrying a mutation in S-nitrosoglutathione reductase 1 (GSNOR1) accumulate high nitric oxide (NO) and exhibit impaired immunity characterized by reduced pathogen-responsive salicylic acid (SA) accumulation and failure to activate normal SA signaling. We show that this reduced SA responsiveness in gsnor1 plants arises from impaired vascular-associated movement of SA, thereby compromising systemic acquired resistance (SAR). Elevated NO perturbs cellular pH homeostasis, acidifying the apoplast and alkalinizing the cytosol, which likely interferes with phloem-associated SA movement and renders gsnor1 plants unresponsive to foliar SA. In contrast, SA supplied via root drench restores SA signaling and SAR in gsnor1, …

Evaluation And Enhancement Of Suspected Opioid Overdose Definitions In Emergency Medical Services Data Using Machine Learning With Natural Language Processing, Peter Rock, Svetla Slavova, Sharon L. Walsh, Julia Martin, Daniel R. Harris

Institute for Biomedical Informatics Faculty Publications

Background: Fatal and non-fatal drug overdoses have evolved into a critical public health crisis, with over a 50% increase in the rate of fatal drug overdose since 2019. Emergency Medical Services (EMS) data has advantages over traditional emergency department data, including timeliness and captured non-transport encounters. However, there is no consensus EMS definition for suspected opioid overdose (SOO), and currently implemented knowledge-based (KB) definition may miss ambiguous cases. Machine learning with natural language processing (ML-NLP) has the potential to enhance SOO identification.

Methods: Secondary data originated from an oversampled dataset of 2,327 weighted encounters from Kentucky State EMS data (2018–2022). …

Temporal Evolution Of Brain Inflammation In The Bilateral Common Carotid Artery Stenosis Model Of Chronic Cerebral Hypoperfusion, Makayla F. Cox, Jill M. Roberts, Ryan K. Shahidehpour, David L. Dornbos Iii, Adam D. Bachstetter

Neuroscience Faculty Publications

Chronic cerebral hypoperfusion is a major contributor to vascular cognitive impairment and dementia, primarily through its disruption of white matter integrity and promotion of neuroinflammatory cascades. The bilateral common carotid artery stenosis (BCAS) model has emerged as the predominant experimental approach for studying the effects of chronic cerebral hypoperfusion, particularly in aging-relevant contexts. This review synthesizes current knowledge of inflammatory responses in the BCAS model, with an emphasis on their temporal progression and functional consequences. We begin by outlining the clinical burden of hypoperfusion, the rationale for BCAS, and the hemodynamic phases it produces. We then examine early neurovascular unit …

Dim Light At Night Impacts Circadian Rhythms And Alzheimer’S Disease-Like Neuroinf Lammation And Neuropathology In Humanized App Saa Knock-In Mice, Marilyn J. Duncan, Margaret R. Hawkins, Leke Bytyqi, Haleigh R. Whitlock, Savannah M. Shepard, Makayla F. Cox, Esther G. Drinkard, Teresa Macheda, Kelly N. Roberts, Katharina Kohler, Mary-Claire Schmidt, Carrie E. Johnson, Sridhar Sunderam, Bruce F. O'Hara, Michael Paul Murphy, Adam D. Bachstetter

Neuroscience Faculty Publications

Artificial light at night (light pollution) is widespread but understudied in the context of Alzheimer’s disease (AD). Sleep and circadian disruption have been linked to amyloid-β (Aβ) accumulation and neuroinflammation, but whether dim light at night (dLAN) modifies these processes remains unclear. We tested whether chronic dLAN exposure (8 lux during the dark phase, 8 weeks) alters circadian rhythms, amyloid pathology, and neuroinflammation in 12–13 month-old humanized APP knock-in (KI) mice. hAPP^SAA KI mice, which develop plaques, were compared with hAPP^WT KI controls carrying only a humanized APP sequence. dLAN reduced circadian rhythm amplitude and stability while increasing …

Brain-Derived Extracellular Vesicles Potentially Mediate Crosstalk With Peripheral Organs In Neurodegenerative Diseases, Ramzi H. Hamdalla, Vibha B. Bhaskar, Changhai Tian

Toxicology and Cancer Biology Faculty Publications

Brain-Derived Extracellular vesicles (BDEVs) are emerging mediators of intra- and interorgan communication in neurodegenerative diseases (NDs) such as Alzheimer’s Disease (AD) and Parkinson’s Disease (PD). A growing body of evidence suggests that BDEVs play an important role in modulating intercellular communication within the central nervous system in the pathogenesis of many NDs. By transporting non-coding RNAs (e.g., miRNAs) and important pathological proteins, BDEVs also influence peripheral organs and contribute to the progression of disease in the central nervous system (CNS). This review extends the understanding of NDs beyond solely brain dysfunction and gives a novel framework for the progression of …

A Ubiquitous Organophosphate Flame Retardant Disrupts Energy And Glucose Homeostasis In Mice, Krystal M. Sewell, Kelly Oriakhi, Sara Y. Ngo Tenlep, Megan L. Weaver, Mansura Shahad Bawa, Se-Hyung Park, Shubh Saraswat, Xiaohua D. Zhang, Robert N. Helsley, Samir Softic, Cetewayo S. Rashid

Pharmacology and Nutritional Sciences Faculty Publications

Organophosphate flame retardants (OPFRs) are used in many consumer products, and their presence in our environment raises concerns about potential health dangers. In humans, exposure to OPFRs, such as tris(1,3-dichloro-2-propyl) phosphate (TDCPP) is associated with metabolic disorders such as obesity, hyperglycemia, and insulin resistance. Our current study seeks to determine how TDCPP exposure affects body composition, glucose homeostasis, and energy balance in a rodent model. C57Bl/6 J mice were divided into two weight-matched groups and fed purified low phytoestrogen diets containing either 0.1 % DMSO (control) or TDCPP 415 mg/kg resulting in an approximate exposure of 50 mg/kg/day. Both male …

Contribution Of Metabolism-Independent Glucose Sensing To Metabolic Homeostasis, Nadia Rashid, Kavaljit H. Chhabra

Pharmacology and Nutritional Sciences Faculty Publications

Glucose sensing and signaling are central to cellular metabolic machinery for the regulation of metabolic homeostasis. Glucose sensing has been almost always assumed to be coupled with glucose metabolism; however, recent findings have unraveled metabolism-independent sensing mechanisms. Here, we discuss whether glucose transporters (GLUTs) and sodium-glucose co-transporters (SGLTs) may also function as glucose sensors independent of their roles in transporting glucose. Moreover, we review the emerging roles of G protein-coupled receptors (GPCRs) in sensing glucose and, consequently, initiating its signaling pathways in a cell-specific manner. Altogether, this review offers insights into the newly identified glucose sensing mechanisms and highlights the …

Anatomical Atlas Of Kinase Responsiveness To Weight Gain: Adipose Depot Reprogramming In Diet-Induced Adiposity, Wang-Hsin Lee, Zachary A. Kipp, Sally N. Pauss, Genesee J. Martinez, Mei Xu, Terry D. Hinds, Jr.

Pharmacology and Nutritional Sciences Faculty Publications

Background/Objectives: Adipose tissue depots located at different anatomical sites exert differential functions in response to adiposity and glucose intolerance. These fat depots exhibit distinct metabolic signaling patterns that may influence pathological fat accumulation, thereby affecting the efficacy of anti-obesity interventions. Nonetheless, the mechanisms underpinning depot-specific signaling and pathway responsiveness remain insufficiently understood.

Methods: Kinase activity was characterized during the progression of adiposity across five adipose tissue depots in obese versus lean mice using the advanced PamGene kinome technology. Furthermore, kinase pathways in human preadipocytes and mouse 3T3-L1 preadipocytes were analyzed and compared with those in their differentiated, mature adipocytes. The …

Granulomatous Cellular Signatures In Nontuberculous And Tuberculous Mycobacterial Infections, Brianna M. Doratt, Ethan G. Napier, Mahdi Eskandarian Boroujeni, Sarah Douglas, Michael H. Davies, Luiz Bermudez, Eliot Spindel, Erin F. Mccaffrey, Ilhem Messaoudi

Microbiology, Immunology, and Molecular Genetics Faculty Publications

Mycobacterium tuberculosis (Mtb) and nontuberculous mycobacteria (NTM) are acid-fast bacilli that trigger granuloma formation, a hallmark immune response aimed at containing infection. While the biology of Mtb granulomas has been widely investigated, far less is known about granulomas caused by NTM infection, despite the increasing prevalence and clinical challenge of NTM cases worldwide. Because granulomas influence infection control, pathology, and treatment response, understanding their cellular organization and signaling is critical to improving therapeutic strategies. Therefore, we characterized granulomas formed following infection of rhesus macaques with Mycobacterium avium subsp. hominissuis (MAH) and compared them to granulomas from cynomolgus macaques infected with …

Glycoprotein-Specific Transcriptional Response Contributes To Differential Vaccine Protection Against Lethal Ebola Virus Infection, Sheridan B. Wagner, Delphine C. Malherbe, Ethan G. Napier, Andrea Marzi, Ilhem Messaoudi

Microbiology, Immunology, and Molecular Genetics Faculty Publications

Since the West African Ebola virus (EBOV) epidemic in 2014-2016, recurrent outbreaks of the EBOV-Makona variant have been driven by recrudescence and human-to-human transmission emphasizing the need for effective vaccination strategies. A live-attenuated recombinant vesicular stomatitis virus (VSV)-based vaccine expressing the EBOV-Kikwit variant glycoprotein (VSV-Kik) received FDA approval in December 2019 and provides complete, rapid protection against EBOV-Makona as early as 7 days post-vaccination (DPV). During the 2018-2020 Ebola outbreak, the VSV-Kik vaccine, known as ERVEBO, was administered to lower-risk individuals at a 5-fold dose reduction of the standard 2 × 10 ⁷ PFU to provide broader population protection. Identification …

Role Of Estrogen Receptor Alpha In Modulating The Circadian System In Female Mice, Victoria Alvord

Theses and Dissertations--Biology

Circadian rhythms are approximately 24-hour cycles of physiology and behavior. Circadian rhythms of eating, or meal timing, are linked to cardiometabolic dysfunction in humans. Mistimed eating, such as breakfast skipping and eating late at night, increases the risk of obesity, diabetes, and cardiovascular disease in humans. Likewise, disrupted eating rhythms cause obesity in mice. This dissertation investigates how estrogens regulate eating behavior rhythms and tissue clock timing in female mice. Chapter 1 reviews three key components critical to this work. The first is an overview of the field of chronobiology and the function of the circadian system. The second is …

The Rhesus Macaque Model Of Mycobacterium Avium Infection Reveals That Age-Related Disease Is Due In Part To Chronic Inflammation And Lung Microbial Dysbiosis, Ethan G. Napier

Theses and Dissertations--Microbiology, Immunology, and Molecular Genetics

Aging is associated with dysregulated immunity and increased susceptibility to infection, a phenomenon dubbed as immunosenescence and characterized by reduced naïve T and B cell pools, altered innate immune function, and chronic low-grade inflammation. Nontuberculous mycobacterial (NTM) pulmonary disease (NTMPD) is an increasingly relevant chronic lung infection that disproportionately affects older adults (65+ years) and immunocompromised individuals. However, the host factors underlying increased disease severity in aged patients remain poorly defined. Literature suggests that effective control of NTM relies on coordinated innate and adaptive immune responses, particularly macrophage activation and Th1 cytokine signaling. Using a rhesus macaque model that closely …

A Framework For Characterizing The Peripheral Immune Isonome Using Long-Read Single-Cell Rna Sequencing And Its Relevance To Neurological Disease, Patricia Hayes Doyle

Theses and Dissertations--Neuroscience

Long-read single-cell RNA sequencing provides an opportunity to understand human health and disease at isoform resolution, revealing cellular diversity and disease mechanisms difficult to resolve with bulk or short-read methodologies.

Using a modified PIPseq workflow and computational pipeline adapted for Oxford Nanopore (ONT) sequencing, we profiled isoform usage across immune cells, integrating marker expression and isoform discovery, generating the largest long-read single-cell dataset of human immune cells from a single individual to date. We identified non-canonical protein-coding variants of GZMB and CD3G enriched in unexpected cell types. We also discovered novel transcripts from CMC1 and LYAR with cell-type-specific signatures that …

Metabolism As A Regulator Of Sleep And Cortical Activity In Health And Alzheimer’S Disease, Nicholas J. Constantino

Theses and Dissertations--Neuroscience

Metabolic flexibility is essential for maintaining normal physiological function, enabling an organism to sense, flux, utilize, and switch fuel sources in response to changing energetic availability, demand, and cellular needs. Energetic demands are state-dependent, with wake and sleep exhibiting distinct metabolic profiles. Sleep is highly sensitive to changes in metabolism and requires metabolic flexibility to both transition into and maintain sleep stability. Alzheimer’s disease (AD) is increasingly recognized as a disease of altered metabolism yet is often framed as a disease of energetic failure. We instead define AD as a disease of metabolic inflexibility, characterized not by insufficient energy availability, …

Design And Advancement Of Analytical Frameworks For In Vivo Single-Photon Calcium Imaging To Characterize Temporal- And Treatment-Dependent Neural Adaptations To Opioid Exposure And Withdrawal In The Medial Prefrontal Cortex, Alexia R. Alsum Dr.

Theses and Dissertations--Pharmacy

Despite the availability of several approved medications for opioid use disorder (OUD), it remains a significant public health concern characterized by persistent neurobiological adaptations that drive relapse and impede successful recovery. The medial prefrontal cortex (mPFC), a region critical for executive control and decision-making, undergoes pronounced functional changes during chronic opioid exposure and withdrawal, yet the cellular mechanisms underlying these adaptations remain poorly understood. This dissertation aims to investigate longitudinal alterations in mPFC neural activity across opioid exposure and withdrawal using in vivo single-photon calcium imaging and newly developed computational frameworks.

Following standard preprocessing to extract and normalize calcium traces, …

Exploring The Limitations Of Substrate Scope In Dimethylallyltryptophan Synthases, Evan T. Miller

Theses and Dissertations--Pharmacy

Natural products (NPs), are the largest source of bioactive compounds in Nature, and are essential to the treatment of human disease. Nearly 50% of drugs approved for use from 1981 to 2019 owe some aspect of their development to NPs, either in terms of their structure, pharmacophore, or mechanism of action. However, NPs are difficult to structurally optimize. Chemoenzymatic methods for NP derivatization have been increasingly seen as practical alternatives to traditional synthetic methods. Prenyltransferases (PTs) are involved in the primary and secondary metabolism of plants, bacteria, and fungi, and they are key enzymes in the biosynthesis of many clinically …

Molecular Mechanisms And Metabolic Consequences Of Glucocorticoid Resistance, Genesee J. Martinez

Theses and Dissertations--Pharmacology and Nutritional Sciences

Glucocorticoids are vital steroid hormones that govern metabolism, stress responses, and immune functions through intricate, tissue-specific mechanisms, both genomic and non-genomic. These hormones bind to the glucocorticoid receptor (GR), which then acts as a transcription factor to modulate gene expression. Chronic elevation of glucocorticoid levels may lead to glucocorticoid resistance, resulting in adiposity, inflammation, and insulin resistance, thereby adversely affecting multiple metabolic tissues. Whether produced endogenously or administered exogenously, excessive, chronic glucocorticoid concentrations impair glucocorticoid signaling. Although there are two primary isoforms of the receptor, GR⍺ and GRβ, only GR⍺ interacts with glucocorticoids.Through the research conducted in this dissertation, we …