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Transcriptomic Transformations And Epigenetic Elements: The Heart Of The Matter Across Diverse Cardiac Pathophysiologies, Sayan Bakshi

All ETDs from UAB

Cardiovascular disease (CVD) comprises a complex array of disorders affecting the heart and blood vessels, representing the leading cause of mortality worldwide. This multifaceted nature of CVD has prompted extensive research into its molecular underpinnings and etiological diversity. Despite significant advances, the majority of CVD management strategies are guideline-based symptomatic treatment. This necessitates extensive research studies on therapeutic interventions aimed at disease prevention or cure. In this dissertation, we have employed next-generation sequencing (NGS) techniques to elucidate the cardiac transcriptional and epigenetic landscape across various conditions, including ischemic heart failure (IHF), Cardiogenic shock (CS), and diabetic heart failure (DHF). Our …

Characterization Of Dhdds Rp59 Knock-In Mouse Models Of Retinitis Pigmentosa, Mai Ngoc Nguyen

All ETDs from UAB

Cis-prenyltransferase (CPT), a prenyl chain elongation enzyme made up of two copies of dehydrodolichyl diphosphate synthase (DHDDS) and two copies of Nogo-B Receptor (NgBR), condenses metabolites from the mevalonate pathway to create dolichol, a sugar carrier required for glycosylation in all cells of the body. However, certain missense mutations in DHDDS cause non-syndromic retinitis pigmentosa (RP59). Three missense mutations, K42E, T206A, and R98W have been found in RP59 patients that present the cardinal phenotypes of RP – diminished ERG responses, attenuated retinal vessels, bone spicule-like pigmentation, and retinal thinning due to photoreceptor loss. However, no global changes in glycosylation are …

Causal Models And Prediction In Cell Line Perturbation Experiments, James P Long, Yumeng Yang, Shohei Shimizu, Thong Pham, Kim-Anh Do

Faculty, Staff and Student Publications

In cell line perturbation experiments, a collection of cells is perturbed with external agents and responses such as protein expression measured. Due to cost constraints, only a small fraction of all possible perturbations can be tested in vitro. This has led to the development of computational models that can predict cellular responses to perturbations in silico. A central challenge for these models is to predict the effect of new, previously untested perturbations that were not used in the training data. Here we propose causal structural equations for modeling how perturbations effect cells. From this model, we derive two estimators for …

Development Of Sacb-Based Counterselection For Efficient Allelic Exchange In Fusobacterium Nucleatum, Peng Zhou, Bibek G C, Bo Hu, Chenggang Wu

Faculty, Staff and Student Publications

Fusobacterium nucleatum, prevalent in the oral cavity, is significantly linked to overall human health. Our molecular comprehension of its role in oral biofilm formation and its interactions with the host under various pathological circumstances has seen considerable advancements in recent years, primarily due to the development of various genetic tools for DNA manipulation in this bacterium. Of these, counterselection-based unmarked in-frame mutation methods have proved notably effective. Under suitable growth conditions, cells carrying a counterselectable gene die, enabling efficient selection of rare, defined allelic exchange mutants. The sacB gene from Bacillus subtilis, encoding levansucrase, is a widely used …

A Regularized Bayesian Dirichlet-Multinomial Regression Model For Integrating Single-Cell-Level Omics And Patient-Level Clinical Study Data, Yanghong Guo, Lei Yu, Lei Guo, Lin Xu, Qiwei Li

Faculty, Staff and Student Publications

The abundance of various cell types can vary significantly among patients with varying phenotypes and even those with the same phenotype. Recent scientific advancements provide mounting evidence that other clinical variables, such as age, gender, and lifestyle habits, can also influence the abundance of certain cell types. However, current methods for integrating single-cell-level omics data with clinical variables are inadequate. In this study, we propose a regularized Bayesian Dirichlet-multinomial regression framework to investigate the relationship between single-cell RNA sequencing data and patient-level clinical data. Additionally, the model employs a novel hierarchical tree structure to identify such relationships at different cell-type …

Genetics And Biology Of Pancreatic Ductal Adenocarcinoma, Haoqiang Ying, Alec C Kimmelman, Nabeel Bardeesy, Raghu Kalluri, Anirban Maitra, Ronald A Depinho

Faculty, Staff and Student Publications

Pancreatic ductal adenocarcinoma (PDAC) poses a grim prognosis for patients. Recent multidisciplinary research efforts have provided critical insights into its genetics and tumor biology, creating the foundation for rational development of targeted and immune therapies. Here, we review the PDAC genomic landscape and the role of specific oncogenic events in tumor initiation and progression, as well as their contributions to shaping its tumor biology. We further summarize and synthesize breakthroughs in single-cell and metabolic profiling technologies that have illuminated the complex cellular composition and heterotypic interactions of the PDAC tumor microenvironment, with an emphasis on metabolic cross-talk across cancer and …

Strength Training Can Modulate Urinary Adipokine Levels In Healthy Young Males, Marcelo Henrique Salviano De Faria, Lucélia Scarabeli Silva Barroso, Antonio Felipe Souza-Gomes, João Luís Vieira Monteiro De Barros, Adriana Maria Kakehasi, Erica Leandro Marciano Vieira, Ana Cristina Simões E Silva, Albená Nunes Silva

International Journal of Exercise Science

International Journal of Exercise Science 18(2): 107-118, 2025. Adipose tissue stores energy in fat-rich adipocytes, which can produce and release several adipokines and modulate body metabolism. Exercise may induce adipokine production in adipocytes; however, the relationship between the two remains unclear. Few studies have shown the relationship between adipokines and strength training. Thus, we aimed to evaluate the acute and chronic effects of strength training (ST) on urinary adiponectin, leptin, and resistin levels. Twelve untrained young men (23.42 ± 2.67 years) were included in this study. Body composition was evaluated at baseline and after completing of the training protocol using …

Evaluation Of Green Tea Yoghurt Enriched With Lacticaseibacillus Paracasei E1 Microcapsules On Macrophage M1 Profile In High Fat-Fructose Diet Mice, Esha Ardiansyah, Nur Alfi Maghfirotus Sa’Adah, Rahmi Izati, Belinda Nabiila Al Faizah, Dawama Nur Fadlilah, Septhyanti Aprilia Kavitarna, Mochammad Fitri Atho’Illah, Siti Nur Arifah, Yoga Dwi Jatmiko, Muhaimin Rifa’I

Karbala International Journal of Modern Science

Obesity is caused by an energy imbalance that increases chronic low-grade inflammation, including macrophage cell infiltration. Adipose tissue macrophages are polarized into pro-inflammatory macrophage type 1 (M1), secrete large amounts of pro-inflammatory cytokines, and activate transcription factors. Yoghurt with probiotics is popular at all ages for its health benefits and must be protected by microencapsulation. Green tea (Camellia sinensis L.) fortification provides yoghurt nutrients while improving its functional qualities and bioactivity. This study aimed to evaluate the effect of microencapsulation of Lacticaseibacillus paracasei E1 in green tea yoghurt (GTY) on the profile of M1 macrophages in mice fed a …

Monitoring And Assessment Of Population, Reproductive, And Health Effects In Colonial Waterbirds Breeding At Contaminated Great Lakes Sites In Michigan, Keith A. Grasman, Mandy Annis, Carly Eakin, Jeremy Moore, Lisa L. Williams

University Faculty Publications and Creative Works

Immunological, reproductive, and population endpoints were assessed in fish-eating birds during 2010–2019 in the Saginaw River and Bay and River Raisin Areas of Concern (AOCs) and Grand Traverse Bay, which are ecosystems historically contaminated with polychlorinated biphenyls, dibenzo-p-dioxins, and dibenzofurans. Reference sites were in the lower St. Marys River (herring gulls and Caspian terns), eastern Lake Superior (terns), and eastern Lake Huron (black-crowned night herons). Relative risk ratios for embryonic nonviability (from both infertility and mortality) in gull embryos were 2–3-fold higher than the reference site in both AOCs and Grand Traverse Bay. Twelve of 13 deformed embryos and chicks …

Circakb: A Comprehensive Knowledgebase Of Circadian Genes Across Multiple Species, Xingchen Zhu, Xiao Han, Zhijin Li, Xiaobo Zhou, Seung-Hee Yoo, Zheng Chen, Zhiwei Ji

Faculty, Staff and Student Publications

Circadian rhythms, which are the natural cycles that dictate various physiological processes over a 24-h period, have been increasingly recognized as important in the management and treatment of various human diseases. However, the lack of sufficient data and reliable analysis methods have been a major obstacle to understanding the bidirectional interaction between circadian variation and human health. We have developed CircaKB, a comprehensive knowledgebase of circadian genes across multiple species. CircaKB is the first knowledgebase that provides systematic annotations of the oscillatory patterns of gene expression at a genome-wide level for 15 representative species. Currently, CircaKB contains 226 time-course transcriptome …

Scproatlas: An Atlas Of Multiplexed Single-Cell Spatial Proteomics Imaging In Human Tissues, Tiangang Wang, Xuanmin Chen, Yujuan Han, Jiahao Yi, Xi Liu, Pora Kim, Liyu Huang, Kexin Huang, Xiaobo Zhou

Faculty, Staff and Student Publications

Spatial proteomics can visualize and quantify protein expression profiles within tissues at single-cell resolution. Although spatial proteomics can only detect a limited number of proteins compared to spatial transcriptomics, it provides comprehensive spatial information with single-cell resolution. By studying the spatial distribution of cells, we can clearly obtain the spatial context within tissues at multiple scales. Spatial context includes the spatial composition of cell types, the distribution of functional structures, and the spatial communication between functional regions, all of which are crucial for the patterns of cellular distribution. Here, we constructed a comprehensive spatial proteomics functional annotation knowledgebase, scProAtlas (https://relab.xidian.edu.cn/scProAtlas/#/), …

Metabolic And Physiological Characteristics Of Diet Manipulation And Genetic Modification In Two Rat Models Of Aging, Soe Maung Maung Phone Myint

All ETDs from UAB

As society and human civilization advances, humans have begun to live longer and most people live to be longer than 60, which was not the case several decades ago. According to the World Health Organization(WHO), by the turn of the next decade at 2030, 1 in 6 people will be 60 years or older, accounting for almost 1.4 billion people. Aging affects people differently but in general, it has a propensity to induce widespread and progressive molecular and cellular damage which leads to a myriad of diseases and eventually death. The greatest risk factor for most of the chronic diseases …

Investigating The Thermodynamic Properties Of Fat10 And Fat10ylated Proteins, Aravind R

Theses and Dissertations

Degradation of proteins by the proteasome is crucial in regulating protein levels in the cell. Post-translational modifications, such as ubiquitylation and Fat10ylation, trigger proteasomal degradation of the substrate proteins. While ubiquitylation orchestrates multiple cellular processes, Fat10ylation is primarily involved in the inflammatory response. Unlike ubiquitin, recycled upon substrate degradation, Fat10 is degraded along with its substrate. Although the thermodynamic properties of the substrate are critical for effective proteasomal degradation, they remain poorly understood for the Fat10-proteasome pathway.

Here, we demonstrate that Fat10 exhibits markedly lower thermodynamic stability and faster unfolding kinetics compared to ubiquitin. This is due to the absence …

Selectivity Of Invasive Species Suppression Efforts Influences Control Efficacy, Rae Fadlovich, Kevin Landom, Timothy E. Walsworth

Watershed Sciences Student Research

1. Highly fecund invaders and size-selective suppression efforts often limit the effectiveness of invasive species control programs, as compensatory processes can allow suppressed populations to recover. While population models have long explored how demographic characteristics impact management feasibility, there is a growing need to evaluate how the selectivity of suppression efforts might impact the long-term feasibility of control.
2. We use a simulation framework that integrates age-based selectivity to evaluate the effect of increasing the range of ages selected for during harvest-based invasive species control. We applied this approach to common carp in Utah Lake, the location of one of the world's …

Can Trichoderma Spp. Contribute To The Bioremediation And Biostimulation Of Plants In Soil Contaminated With Herbicides?, Elaine Damiani Conte, Elton José Da Rosa, Gabriel Rieth Silvestrini, Daiane Da Silva Motta, Christiane Fernandes De Oliveira, Carine Cocco, Gabriel Fernandes Pauletti, Taísa Dal Magro, Joséli Schwambach

School of Earth, Environmental, & Marine Sciences Faculty Publications

This work aimed to evaluate the potential of Trichoderma spp. in the bioremediation of herbicides and biostimulation of plants in herbicide-contaminated soils. In the first phase, the experiment followed a completely randomized design in a 4 × 3 × 4 factorial scheme with five replications, four strains of Trichoderma spp., three herbicides, and four herbicide doses. The mycelial growth speed index (MGSI) of Trichoderma spp. was obtained by growing it in a Petri dish with PDA associated with different doses of herbicides and evaluated every 24 h for 10 days. Results indicated the selection ofTrichoderma harzianumT1A to continue …

Unraveling The Kinetic Mechanisms Of Protein Unfolding And Translocation Catalyzed By Hsp100 Unfoldases, Jaskamaljot Kaur Banwait

All ETDs from UAB

Escherichia coli ClpB and Saccharomyces cerevisiae Hsp104 are part of the Hsp100 family of proteins responsible for maintaining protein homeostasis in a cell during heat-stress conditions. Structurally, ClpB and Hsp104, in their active state, assemble into hexameric ring complexes with a hollow axial channel. Functionally, these enzymes are hypothesized to couple energy from ATP binding and hydrolysis to unfold protein substrates and translocate them through their axial channel. However, the molecular mechanisms of protein unfolding and translocation catalyzed by both ClpB and Hsp104 are not well understood. In this dissertation, we report the development of a single-turnover transient state kinetics …

Role Of Ring-Box E3 Ligases In Runx2 And Sp7 Protein Turnover During Osteoblast Differentiation, Abeera Sikandar

All ETDs from UAB

The bone matrix synthesis by osteoblast during skeletogenesis is regulated by several transcription factors and signaling pathways. Runx2 and Sp7 are master regulators of osteoblast differentiation and bone formation. Deletion of both genes in mice results in the complete failure of ossification. In humans, Sp7 and Runx2 genes mutations cause osteogenesis imperfecta and cleidocranial dysplasia, respectively. The progression of osteoblast differentiation requires a coordinated and temporal expression of Runx2 and Sp7 genes. Posttranslational modifications regulate the cellular levels and function of Runx2 and Sp7 proteins. Ubiquitination controls protein turnover through targeted degradation. The multi-subunit SCF-complex is the largest class of …

St6gal1 Is Upregulated In Pancreatic Cancer Cells By Pro-Inflammatory Cytokines, Austin David Silva

All ETDs from UAB

The sialyltransferase ST6GAL1 is overexpressed in several cancers, including pancreatic ductal adenocarcinoma (PDAC). ST6GAL1 adds an α2-6-linked sialic acid to N-glycosylated membrane proteins, modifying their structure and function. Despite extensive research on how ST6GAL1 affects cell phenotype, the mechanisms regulating its expression remain largely unexplored. In this study, we investigated how two pro-inflammatory cytokines, IL-1β and IL-6, prevalent in the PDAC tumor microenvironment, regulate ST6GAL1 expression. We used the Suit-2 PDAC cell line and its metastatic subclones, S2-013 and S2-LM7AA, to monitor cytokine activity. Treatment with IL-1β or IL-6 increased ST6GAL1 protein and mRNA expression across all cell models. Specifically, …

Mechanistic Insights Of Translational Readthrough To Suppress Nonsense Mutations, Kari Thrasher

All ETDs from UAB

A nonsense mutation is a point mutation in DNA that gives rise to a premature termination codon (PTC) in the open reading frame of the transcribed mRNA. Translation of this PTC-containing transcript terminates prematurely, leading to the creation of truncated non-functional protein. Translational readthrough is one therapeutic option being explored to suppress nonsense mutations that cause disease. Here, we further elucidate amino acid incorporation and the functional consequences of readthrough of nonsense mutations that cause cystic fibrosis. Additionally, we reveal the molecular mechanisms activated by a recently described small molecule readthrough agent, SRI- 41315. Finally, we discuss the various therapeutic …

Alternative Splicing In The Brain: Across Disease States, Sexes, Regions, And Cell Types, Emma Finn Jones

All ETDs from UAB

Molecular phenotype heterogeneity is prevalent across multiple contexts and is mediated by mRNA expression differences and the gene and isoform level. Isoform-level mRNA complexity in the brain is essential for healthy neurodevelopment, and perturbations in AS are associated with many neurological and psychiatric disorders. While previous research has examined how AS changes in the brain, there is still a gap in using newer techniques to study these changes with greater specificity. Therefore, we address this gap by using long-read and scRNA-seq technologies to study isoform-level diversity in AS across four contexts (i.e., disease, sex, region, and cell type) in the …

Characterization Of The Roles Of U1-70k In Alternative Splicing And Nuclear Speckle Formation, Trenton Myers Paul

All ETDs from UAB

RNA-binding proteins (RBPs) play critical roles in RNA processing and regulation. Among these RBPs, U1-70K is a key protein involved in RNA processing, nuclear speckle formation, and has implications in neurodegenerative diseases such as Alzheimer's. Despite its significance in transcription, RNA processing, nuclear speckle formation, and nonsense-mediated decay, studies on U1-70K have been limited primarily to its well-structured N-terminal domain due to challenges in solubilizing and expressing the full-length protein. In this dissertation, we address these challenges by optimizing cell strain and co expressing DnaK and DnaJ, enabling the successful expression, solubilization, and purification of full-length U1-70K. Using fluorescence polarization …

Cytotoxic, Genotoxic, And Metabolic Effects Of Dihydroxyacetone In Heart, Liver And Lung Models, Arlet Hernandez

All ETDs from UAB

Dihydroxyacetone (DHA) is a triose sugar found as an active ingredient in sunless tanning products (STPs) and by-product in electronic cigarettes (e-cigarettes). DHA can rapidly be absorbed into cells and tissues and incorporated into several metabolic pathways through its conversion into dihydroxyacetone phosphate (DHAP). Previous studies have shown that DHA promotes cytotoxicity and genotoxicity primarily characterized in skin models. The extent of these effects in systemic models is highly cell-type specific. Here we investigate the cytotoxic, genotoxic, and metabolic effects of DHA across several cell models. First, we investigated the effects of DHA in a metabolically active cell line, hepatocellular …

The Evolutionary Ecology Of Reproductive System Variation In Haploid-Diploid Freshwater Red Macroalgae, Sarah Connelly

All ETDs from UAB

Reproductive systems describe the relative rates of sexual versus asexual reproduction and selfing versus outcrossing, governing the transmission of genetic diversity between generations and shaping evolutionary responses to environmental change. Though sex has inherent costs, it contributes to the reproductive system for most eukaryotes, generating incredible life cycle diversity. Life cycles are expected to be correlated with different reproductive systems. Diploid life cycles should be associated with outcrossing, whereas life cycles with a long-lived haploid phase are hypothesized to be associated with selfing and asexual reproduction. To test this hypothesis, we used ten polymorphic microsatellite loci to genotype 311 gametophytes …

Targeted Exon Skipping Of Nf1 Exon 52 As A Mutation Specific Therapeutic For Neurofibromatosis Type 1, Cameron Lee Church

All ETDs from UAB

Modification of pre-mRNA splicing using antisense oligonucleotides (ASOs) can be used to skip one or more exons carrying pathogenic DNA sequence variants. Our previ-ously published data indicates NF1 exon 52 is a good target for exon skipping as a cDNA screen indicates an NF1 isoform lacking exon 52 maintains both high neurofi-bromin expression and the ability to suppress Ras activity. To develop an exon skipping approach, we designed antisense phosphorodiamidate morpholino oligomers (PMOs) to skip exon 52. Our lead PMO has a low IC50 of 45nM and is able to restore NF1 expres-sion and Ras-suppression in a cell line with …

Single Nucleus Multiomics Reveals The Drought-Driven Gene Regulatory Atlas In Arabidopsis, Jinbao Liu

All ETDs from UAB

The regulation of gene expression in plant responses to drought has been thoroughly in-vestigated in previous studies. Despite this, a detailed understanding of the cell type-specific regulatory mechanisms, encompassing multi-layered biological processes, is lack-ing. In this study, we report the use of single nucleus multiomic analysis in Arabidopsis seedlings in response to drought stress. Our single-nuclei RNA (snRNA) analysis deline-ated 14 distinct clusters representing major root and shoot cell types and discovered new cell type-specific drought markers. Integration of snRNA with single-nuclei ATAC (snATAC) data in leaf epidermis, root endodermis, and guard cells revealed accessible chromatin regions (ACRs)-linked genes predominantly …

Controlled By Disorder: Modifications To An Unstructured C-Terminal Region Alter Srsf1'S Intramolecular Interactions And Tendency To Phase Separate, Talia Fargason

All ETDs from UAB

The protein Serine-Arginine-rich Splicing Factor 1 (SRSF1) is essential in multiple stages of the mRNA lifecycle, including alternative splicing, nonsense-mediated decay, and nuclear export. SRSF1’s dysfunction is linked to cancers, viral evasion, and developmental disorders. Its function depends on interactions between structured and unstructured regions, modulated by phosphorylation. However, the unstructured regions, while critical for regulation, contribute to protein insolubility, hindering full-length studies. Prior to the work presented here, structural studies of SRSF1 were limited to analysis of its isolated domains. This dissertation develops new techniques to characterize SRSF1, focusing on its intermolecular interactions driving phase separation and intramolecular interactions …

Diurnal Function And Expression Of Aquaporins In The Mouse Kidney, Phi Hung Nguyen

All ETDs from UAB

Aquaporins (AQPs) are a family of proteins that play a major role in maintaining water homeostasis. Aquaporin 2 (AQP2) and aquaporin 3 (AQP3) are expressed in the collecting duct and regulated by the antidiuretic hormone arginine vasopressin (AVP) through the AVPR2 receptor. It is well known that biological circadian rhythms are critical for maintaining homeostasis. In both humans and rodents, the kidneys exhibit time-of-day-dependent changes in function. We hypothesized that there is a diurnal pattern in urine and/or plasma osmolality, and that this may reflect changes in kidney aquaporins in mice. Male and female C57BL/6J mice (10-11 weeks old) were …

Mammonc-Db: A Proteo-Genomic Platform For Comprehensive Breast Cancer Data Analysis, Integration And Visualization, Santhosh Kumar Karthikeyan

All ETDs from UAB

ABSTRACT In 2024, breast cancer (BCa) emerged as the most prevalent cancer among women, accounting for 15% of fatalities in the United States. BCa is a multifaceted disease characterized by various molecular alterations associated with tumor initiation, progression, and metastasis. Clinically, different treatments such as endocrine therapy, chemotherapy, and anti-HER2 therapy are employed based on the molecular subtypes of breast cancer. Despite initial treatment responses, some cases experience recurrence due to therapy resistance. The application of next-generation sequencing techniques and data analysis has significantly enhanced our understanding of BCa biology, including its initiation and progression. By exploring BCa multi-omics data, …

Understanding The Insecticidal Toxin Xpta2: A Shift In Toxin Complex Biology, Cole Lorenza Martin

All ETDs from UAB

Pore forming toxins (PFTs) belonging to the ABC toxin complex (Tc) family are responsible for targeting and translocating toxins into target cells. ABC toxins consist of three separate subunits, each subunit providing a vital role in the cytotoxic mechanism of the Tc. The A subunit or TcA is the largest subunit of the complex and contains the binding domains and the translocation channel that perforates the membrane. The B subunit or TcB functions as a gated linker that forms a cocoon with the TcC which houses the toxic peptide and subsequently gets translocated through the TcB and TcA into the …

Dimensionality Reduction For Visualizing Spatially Resolved Profiling Data Using Spasne, Yuansheng Zhou, Chen Tang, Xue Xiao, Xiaowei Zhan, Tao Wang, Guanghua Xiao, Lin Xu

Faculty, Staff and Student Publications

Background: Spatially resolved profiling technologies to quantify transcriptomes, epigenomes, and proteomes have been emerging as groundbreaking methods for comprehensive molecular characterizations. Dimensionality reduction and visualization is an essential step to analyze and interpret spatially resolved profiling data. However, state-of-the-art dimensionality reduction methods for single-cell sequencing data, such as the t-distributed stochastic neighbor embedding (t-SNE) and uniform manifold approximation and projection (UMAP), were not tailored for spatially resolved profiling data.

Results: Here we developed a spatially resolved t-SNE (SpaSNE) method to integrate both spatial and molecular information. We applied it to a variety of public spatially resolved profiling datasets that were …