Cell and Developmental Biology Commons^™

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 …

Investigation Into The A/Ss Of Cervical Cancer And Its Effects On Tumor Control Probability In Radiation Therapy, Cameron Thayer-Freeman

Theses and Dissertations--Radiation Medicine

The standard of care for locally advanced cervical cancer is chemoradiation, consisting of conventional external beam therapy (EBT) followed by a boost of high dose rate (HDR) brachytherapy. These two radiation treatments will illicit different degrees of biological response depending on the tissue in question, and quantifying the overall effect the combined treatments will have require some form of biological modeling. The linear quadratic (LQ) model of cell survival is the most widely used radiobiological model in clinics across the nation.

It is quantified by the parameters a and ß, which model how radiation generates lethal damage in a population …

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 …

Modeling Inherited Retinal Disease In Zebrafish, Meet Patel

Theses and Dissertations--Biology

Inherited retinal diseases (IRDs) affect millions of people worldwide. Majority of IRDs are caused by degeneration of rod and cone photoreceptor cells (PRCs) due to gene mutations. The overarching goal of my dissertation is to model and evaluate the molecular role of various gene candidates involved in IRDs such as cone rod dystrophy (CRD) and retinitis pigmentosa (RP).

Mutations in CDHR1, a photoreceptor specific cadherin have been associated with CRD and recapitulated in mouse CDHR1 knockouts. However, the molecular function of CDHR1 remains unknown. CDHR1 has been shown to localize at the leading edge of murine rod nascent outer segment …

Investigation Of Genx Exposure To Pathways Associated With Colorectal Cancer Risk, Emily J. Ferguson

Theses and Dissertations--Toxicology and Cancer Biology

Per- and polyfluoroalkyl substances (PFAS) are persistent environmental contaminants widely detected in drinking water and food sources, resulting in chronic human exposure. Among these compounds, hexafluoropropylene oxide dimer acid (HFPO-DA), commonly known as GenX, has been introduced as a short-chain replacement for legacy PFAS such as perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA). Although GenX is believed to be a safer alternative, emerging research suggests it can still affect human health.

Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the second leading cause of cancer-related death in the United States, highlighting the need to better understand environmental …

Uncovering The Mechanism Of Reep2-Mediated Emt-Driven Membrane Trafficking In Lung Adenocarcinoma, Kevin Fulp

Theses and Dissertations--Toxicology and Cancer Biology

Membrane trafficking is frequently disrupted during cancer progression, and the underlying mechanisms remain largely unknown. Currently, no effective drugs target dysregulated membrane trafficking for cancer treatment. Recent evidence has demonstrated that epithelial-to-mesenchymal transition (EMT) in lung adenocarcinoma (LUAD) employs a membrane trafficking program to coordinate cancer cell invasion and immunosuppression. To further dissect the pro-tumorigenic membrane trafficking program, we initiated an in vivo CRISPRi screen to assess more than 2,000 membrane trafficking-related genes in a syngeneic mouse LUAD model. We identified REEP2, an endoplasmic reticulum (ER) shaping protein, as a novel regulator of EMT-driven membrane trafficking. High REEP2 expression is …

Reep2-Driven Pro-Metastatic Secretion Promotes Lung Cancer Progression, Oluwafunminiyi E. Obaleye

Theses and Dissertations--Toxicology and Cancer Biology

Membrane trafficking plays a critical role in cellular function and is frequently dysregulated in cancer to promote metastasis. In lung adenocarcinoma (LUAD), the epithelial-to-mesenchymal transition (EMT) activating transcription factor, ZEB1, drives a pro-metastatic membrane trafficking program; however, the underlying molecular mechanisms remain poorly understood. Using a CRISPR interference (CRISPRi) in vivo screen of 2,099 membrane trafficking regulators in a syngeneic mouse model of EMT-driven LUAD, we identified REEP2 — an endoplasmic reticulum (ER) shaping protein — as a critical regulator of tumor progression. REEP2 mRNA expression correlates with poor prognosis, EMT signatures, and an immunosuppressive tumor microenvironment in LUAD patients. …

Steroid Receptors And Coregulators: Dissemination Of Sex Differences And Emerging Technologies, Sally Pauss, Evelyn A. Bates, Genesee J. Martinez, Zane T. Bates, Zachary A. Kipp, Cassandra D. Gipson, Terry D. Hinds Jr.

Markey Cancer Center Faculty Publications

Steroid receptors are ligand-induced transcription factors that have broad functions among all living animal species, ranging from control of sex differences, body weight, stress responses, and many others. Their binding to coregulator proteins is regulated by corepressors and coactivators that interchange upon stimulation with a ligand. Coregulator proteins are an imperative and understudied aspect of steroid receptor signaling. Here, we discuss steroid receptor basics from protein domain structures that allow them to interact with coregulators and other proteins, their essential functions as transcription factors, and other elemental protein–protein interactions. We deliberate about the mechanisms that coregulators control in steroid receptor …

Artesunate Enhances The Efficacy Of Enzalutamide In Advanced Prostate Cancer, Xinyi Wang, Jinghui Liu, Fengyi Mao, Yifan Kong, Qiongsi Zhang, Chaohao Li, Daheng He, Chi Wang, Yanquan Zhang, Ruixin Wang, Sally R. Ellingson, Qiou Wei, Zhiguo Li, Xiaoqi Liu

Markey Cancer Center Faculty Publications

Prostate cancer (PCa) is one of the leading causes of death among men worldwide. Treatments targeting the androgen receptor pathway remain the standard therapy for PCa patients. Enzalutamide (ENZ), a second-generation androgen receptor inhibitor, was developed to treat castration-resistant prostate cancer. However, while patients initially respond to ENZ, drug resistance typically develops within a few months. Artesunate (ART), a semisynthetic derivative of the Artemisinin plant, is approved for antimalaria treatment. In this study, we conducted an FDA-approved drug screening and identified ART as a potential candidate for overcoming ENZ resistance in PCa. Mechanistically, ART induces the degradation of c-Myc, enhancing …

Staying Sane In The Membrane: Neutral Sphingomyelinase 2 As A Master Regulator Of Plasma Membrane Ceramide, Zainuddin Quadri, Erhard Bieberich

Markey Cancer Center Faculty Publications

Ceramide, a key signaling sphingolipid in the plasma membrane, plays a pivotal role in fundamental cellular processes such as adhesion, polarity, and programmed cell death. The generation of plasma membrane ceramide is largely attributed to the activity of two types of sphingomyelinases: neutral sphingomyelinase 2 (nSMase2, Smpd3) and acid sphingomyelinase (aSMase, Smpd1). While many studies have explored ceramide generation following experimental activation of these enzymes, the mechanisms governing basal or steady- state ceramide levels have remained poorly understood. Using an innovative mass spectrometry approach developed in the Canals’ lab, the team has quantified the distinct contributions of nSMase2 and aSMase …

Artesunate Enhances The Efficacy Of Enzalutamide In Advanced Prostate Cancer, Xinyi Wang, Jinghui Liu, Fengyi Mao, Yifan Kong, Qiongsi Zhang, Chaohao Li, Daheng He, Chi Wang, Yanquan Zhang, Ruixin Wang, Sally R. Ellingson, Qiou Wei, Zhiguo Li, Xiaoqi Liu

Toxicology and Cancer Biology Faculty Publications

Prostate cancer (PCa) is one of the leading causes of death among men worldwide. Treatments targeting the androgen receptor pathway remain the standard therapy for PCa patients. Enzalutamide (ENZ), a second-generation androgen receptor inhibitor, was developed to treat castration-resistant prostate cancer. However, while patients initially respond to ENZ, drug resistance typically develops within a few months. Artesunate (ART), a semisynthetic derivative of the Artemisinin plant, is approved for antimalaria treatment. In this study, we conducted an FDA-approved drug screening and identified ART as a potential candidate for overcoming ENZ resistance in PCa. Mechanistically, ART induces the degradation of c-Myc, enhancing …

Characterizing And Targeting The Non-Catalytic Functions Of Phosphatase Of Regenerating Liver 3 (Prl-3) In Oncogenesis And Cancer Progression, Jeffery T. Jolly

Theses and Dissertations--Molecular and Cellular Biochemistry

Phosphatase of Regenerating Liver 3 (PRL-3) is frequently upregulated in various cancers and is associated with poor patient prognosis. Although traditionally studied for its phosphatase activity, PRL-3 also interacts with the CNNM family of magnesium transporters through its catalytic site, and these two functions are mutually exclusive at any given time. Most previous studies relied on a commonly used PRL-3 mutation that disrupts both phosphatase activity and CNNM binding, making it challenging to determine which function drives its oncogenic effects. To address this gap in the field, I utilized a panel of PRL-3 mutants that selectively disrupt either phosphatase activity …

Spermidine And Polyamine Blockade As Key Mediators Of Intestinal Epithelial Cell Functions, Madison Lynn Flory

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

Frequently, alterations in the composition of the gut microbiota and its metabolites are linked with intestinal diseases, including inflammatory bowel disease and colorectal cancer. However, the direct connections between alterations in the microbiome and disease states often remain elusive. Prior research has identified increases in both polyamines, which are a class of microbial metabolite, and in the abundance of bacteria that can produce polyamines, in a murine colorectal cancer model. Understanding the significance of the interaction between these microbial metabolites and intestinal epithelial cells (IECs) will provide new and expanded evidence of the importance of the gut microbiome in colorectal …

The Impact Of Maternal Environmental Exposures On The Immune Landscape Of The Maternal-Fetal Interface, Heather E. True

Theses and Dissertations--Pharmacy

Maternal environmental exposures and inflammation are known to impact fetal development in utero as well as increase the risk for chronic diseases later in life. Therefore, it is essential that we understand how the maternal environment alters placental structure and immune function.

Therefore, we isolated fetal (chorionic villous) tissues from the placentas of healthy pregnant participants (control) and those with inflammatory conditions, including SARS-COV-2 infection, pregravid obesity, and opioid use disorder. Isolated placental leukocytes were subjected to a series of assays to uncover the phenotypic, functional, and transcriptional (single-cell RNA-sequencing) landscape of placental immune cells. Additional placental tissues were subjected …

Cardiac Injury Regulates Neuroinflammation Through Extracellular Vesicle–Mediated Heart-Brain Crosstalk, Qingxuan Li, Ramzi H. Hamdalla, Neha Dhyani, Lijun Sun, Lie Gao, Tara L. Rudebush, Irving H. Zucker, Changhai Tian

Toxicology and Cancer Biology Faculty Publications

Cognitive impairment is common in heart failure patients, contributing to morbidity and mortality. This impairment may be linked to neuroinflammation in heart failure. However, the primacy of the heart-brain axis remains to be completely understood. Here, we elucidate the potential effects of myocardial injury on pathways and inflammatory mediators responsible for cognitive impairment using a rodent myocardial injury model. The results demonstrate direct extracellular vesicle (EV)-mediated heart-brain crosstalk and the glial uptake of cardiac EVs. In addition, brain inflammation was also elicited following myocardial injury. Moreover, cardiac EVs promote brain microglial cell activation in vitro, potentially mediated by EV-enriched micro-RNAs …

Exploring The Links Among Brain Iron Accumulation, Cognitive Performance, And Dietary Intake In Older Adults: A Longitudinal Mri Study, Valentinos Zachariou, Colleen A. Pappas, Christopher E. Bauer, Elayna R. Seago, Brian T. Gold

Neurology Faculty Publications

This study evaluated longitudinal brain iron accumulation in older adults, its association with cognition, and the role of specific nutrients in mitigating iron accumulation. MRI-based, quantitative susceptibility mapping estimates of brain iron concentration were acquired from seventy-two healthy older adults (47 women, ages 60–86) at a baseline timepoint (TP1) and a follow-up timepoint (TP2) 2.5–3.0 years later. Dietary intake was evaluated at baseline using a validated questionnaire. Cognitive performance was assessed at TP2 using the uniform data set (Version 3) neuropsychological tests of episodic memory (MEM) and executive function (EF). Voxel-wise, linear mixed-effects models, adjusted for longitudinal gray matter volume …

Metabolic And Barrier Function In Response To Β-Caryophyllene In Intestinal Epithelial Cells, Hannah Scroggins

Theses and Dissertations--Animal and Food Sciences

Butyrate, a short-chain fatty acid, regulates cellular metabolism and energy status in intestinal epithelial cells. β-caryophyllene (BCP) is a plant-derived compound that may provide advantageous effects on intestinal barrier function and nutrient utilization. The goal of this thesis was to investigate the effects of BCP on butyrate utilization and metabolism in intestinal epithelial cells. Throughout this thesis, Caco-2 cells in hanging inserts in multi-well plates were used as a model for the intestinal barrier. One study was conducted to investigate the effect of BCP on butyrate utilization and barrier function in intestinal epithelial cells. A second study aimed to elucidate …

Temporal Dynamics Of Programmed Genome Rearrangement In Sea Lamprey Embryogenesis: A Deep Learning & Lightsheet Imaging Approach To Studying Early Developmental Transitions, Kasturi Rajandran

Theses and Dissertations--Biology

Programmed genome rearrangement (PGR) in the sea lamprey (Petromyzon marinus) leads to the elimination of ~0.5Gb (20%) of the germline genome during early embryogenesis, yet its timing relative to the maternal-to-zygotic transition (MZT) remains unclear. In this study, we imaged embryos cleared at 3-hour intervals (up to 72 hours post fertilization (hpf)) using high-resolution lightsheet fluorescence microscopy and a custom deep-learning image-analysis pipeline (~80% accuracy) to quantify nuclei and micronuclei counts. Micronuclei, which are the hallmarks of PGR first appear between 24 to 27hpf (vs ~36hpf previously reported) indicating PGR starts earlier than previously reported in the sea …

The Role Of Metabolic Gate Keepers In Cell Fate Decision Making, Brian Kelly

Theses and Dissertations--Biology

Maintaining cellular energy balance and redox stability is crucial to cell survival, with glutamine metabolism playing a central role. While extensively studied in cancer, where it supports biosynthesis and reduces oxidative stress to promote tumor growth, its function in non-cancerous contexts like tissue development and muscle regeneration remains less understood. A key aspect of stem cell biology is quiescence, a metabolically dormant state that preserves the stem cell pool, yet the mechanisms regulating this state are not fully clear. Here, we identify glutamine metabolism as a critical factor governing myoblast proliferation and quiescence through a metabolic program distinct from that …

Pharmacological Or Genetic Inhibition Of Ltcc Promotes Cardiomyocyte Proliferation Through Inhibition Of Calcineurin Activity, Lynn A. C. Devilée, Abou Bakr M. Salama, Jessica M. Miller, Janice D. Reid, Qinghui Ou, Nourhan M. Baraka, Kamal Abou Farraj, Madiha Jamal, Yibing Nong, Todd K. Rosengart, Douglas A. Andres, Jonathan Satin, Tamer M. A. Mohamed, James E. Hudson, Riham R. E. Abouleisa

Markey Cancer Center Faculty Publications

Cardiomyocytes (CMs) lost during ischemic cardiac injury cannot be replaced due to their limited proliferative capacity. Calcium is an important signal transducer that regulates key cellular processes, but its role in regulating CM proliferation is incompletely understood. Here we show a robust pathway for new calcium signaling-based cardiac regenerative strategies. A drug screen targeting proteins involved in CM calcium cycling in human embryonic stem cell-derived cardiac organoids (hCOs) revealed that only the inhibition of L-Type Calcium Channel (LTCC) induced the CM cell cycle. Furthermore, overexpression of Ras-related associated with Diabetes (RRAD), an endogenous inhibitor of LTCC, induced CM cell cycle …

Mir-27a-3p Regulates Intestinal Cell Proliferation And Differentiation Through Wnt/Β-Catenin Signalling, Chang Li, Yuning Zhou, Yinping Jiang, Zhijie Yin, Heidi L. Weiss, Qingding Wang, B. Mark Evers

Markey Cancer Center Faculty Publications

Intestinal stem cells differentiate into absorptive enterocytes, characterised by increased brush border enzymes such as intestinal alkaline phosphatase (IAP), making up the majority (95%) of the terminally differentiated cells in the villus. Loss of integrity of the intestinal epithelium plays a key role in inflammatory diseases and gastrointestinal infection. Here, we show that the intestinal microRNA (miR)-27a-3p is an important regulator of intestinal epithelial cell proliferation and enterocyte differentiation. Repression of endogenous miR-27a-3p leads to increased enterocyte differentiation and decreased intestinal epithelial cell proliferation in mouse and human small intestinal organoids. Mechanistically, miR-27a-3p regulates intestinal cell differentiation and proliferation at …

Developing Novel Therapeutic Strategies For Mcrc With A Brafv600e Mutation, Mariah Geisen

Theses and Dissertations--Toxicology and Cancer Biology

Colorectal cancer (CRC) is the second leading cause of cancer death worldwide. The overall incidence rates of CRC have decreased in those over 50, but there is an increasing incidence rate in those under 50. Risk factors for CRC include diet, family history, and a sedentary lifestyle. Early detection of CRC is key to patient survival and treatment response. Localized CRC has a survival rate of 90% and allows for surgical resection and chemotherapy. The 5-year survival for metastatic CRC (mCRC) is significantly reduced to around 14%. Despite early detection, 50% of patients will develop metastasis after surgical resection and …

Apoa2 Increases Cholesterol Efflux Capacity To Plasma Hdl By Displacing The C-Terminus Of Resident Apoa1, Snigdha Sarkar, Jamie Morris, Youngki You, Hannah Sexmith, Scott E. Street, Stephanie M. Thibert, Isaac K. Attah, Chelsea M. Hutchinson Bunch, Irina V. Novikova, James E. Evans, Amy S. Shah, Scott M. Gordon, Jere P. Segrest, Karin E. Bornfeldt, Tomas Vaisar, Jay W. Heinecke, W. Sean Davidson, John T. Melchior

Saha Cardiovascular Research Center Faculty Publications

Abstract The ability of high-density lipoprotein (HDL) to promote cellular cholesterol efflux is a more robust predictor of cardiovascular disease protection than HDL-cholesterol levels in plasma. Previously, we found that lipidated HDL containing both apolipoprotein A-I (APOA1) and A-II (APOA2) promotes cholesterol efflux via the ATP-binding cassette transporter (ABCA1). In the current study, we directly added purified, lipid-free APOA2 to human plasma and found a dose-dependent increase in whole plasma cholesterol efflux capacity. APOA2 likewise increased the cholesterol efflux capacity of isolated HDL with the maximum effect occurring when equal masses of APOA1 and APOA2 coexisted on the particles. Follow-up …

Untargeted Lipidomics Reveals Novel Hdl Metabotypes And Lipid-Clinical Correlates, Peer W. F. Karmaus, Scott M. Gordon, Marcus Y. Chen, Alison A. Motsinger-Reif, Rodney W. Snyder, Timothy R. Fennell, Suramya Waidyanatha, Reshan A. Fernando, Alan T. Remaley, Michael B. Fessler

Saha Cardiovascular Research Center Faculty Publications

Plasma high-density lipoprotein (HDL), originally studied for its role in lipid transport, is now appreciated to have wide-ranging biological functions that become defective during disease. While >200 lipids have collectively been detected in HDL, published HDL lipidomic analyses in different diseases have commonly been targeted to prespecified subsets of lipids. Here, we report the results of untargeted lipidomic analysis of HDL isolated from 101 subjects referred for computed tomographic coronary imaging for whom multiple additional clinical and lipoprotein metadata were measured. Unsupervised clustering of the total HDL lipidome revealed that the subjects fell into one of two discrete groups, herein …

Conditional Deletion Of Ceacam1 In Hepatic Stellate Cells Causes Their Activation, Harrison T. Muturi, Hilda E. Ghadieh, Suman Asalla, Sumona G. Lester, Getachew D. Belew, Sobia Zaidi, Raziyeh Abdolahipour, Abhishek P. Shrestha, Agnes O. Portuphy, Hannah L. Stankus, Raghd Abu Helal, Stefaan Verhulst, Sergio Duarte, Ali Zarrinpar, Leo A. Van Grunsven, Scott L. Friedman, Robert F. Schwabe, Terry D. Hinds, Jr., Sivarajan Kumarasamy, Sonia M. Najjar

Markey Cancer Center Faculty Publications

Objectives: Hepatic CEACAM1 expression declines with advanced hepatic fibrosis stage in patients with metabolic dysfunction-associated steatohepatitis (MASH). Global and hepatocyte-specific deletions of Ceacam1 impair insulin clearance to cause hepatic insulin resistance and steatosis. They also cause hepatic inflammation and fibrosis, a condition characterized by excessive collagen production from activated hepatic stellate cells (HSCs). Given the positive effect of PPARg on CEACAM1 transcription and on HSCs quiescence, the current studies investigated whether CEACAM1 loss from HSCs causes their activation.

Methods: We examined whether lentiviral shRNA-mediated CEACAM1 donwregulation (KD-LX2) activates cultured human LX2 stellate cells. We also generated LratCre þ Cc1fl/fl mutants …

Novel Psychoplastogen Dm506 Reduces Cue-Induced Heroin-Seeking And Inhibits Tonic Gaba Currents In The Prelimbic Cortex, Kassandra Looschen, Shailesh N. Khatri, Malabika Maulik, Colin Salisbury, Alaina F. Carman, Katilyn Corriveau, Colton Smith, Dina Manetti, Maria Novella Romanelli, Hugo R. Arias, Cassandra D. Gipson, Swarup Mitra

Markey Cancer Center Faculty Publications

Opioid use disorder is a major public health crisis that is manifested by persistent drug-seeking behavior and high relapse frequency. Most of the available treatments rely on targeting opioid receptors using small molecules that do not provide sustained symptom alleviation. Psychoplastogens are a novel class of non-opioid drugs that produce rapid and sustained effects on neuronal plasticity, intended to produce therapeutic benefits. Ibogalogs are synthetic derivatives of iboga alkaloids that lack hallucinogenic or adverse side effects. In the current study, we examine the therapeutic potential of DM506, a novel ibogalog lacking any cardiotoxic or hallucinogenic effects, in cue-induced seeking behavior …

Ceramide-Mediated Orchestration Of Oxidative Stress Response Through Filopodia-Derived Small Extracellular Vesicles, Zainuddin Quadri, Ahmed Elsherbini, Simone M. Crivelli, Salim S. El-Amouri, Priyanka Tripathi, Zhihui Zhu, Xiaojia Ren, Liping Zhang, Stefka D. Spassieva, Mariana N. Nikolova‑Karakashian, Erhard Bieberich

Markey Cancer Center Faculty Publications

Extracellular vesicles (EVs) are shed from the plasma membrane, but the regulation and function of these EVs remain unclear. We found that oxidative stress induced by H 2 O 2 in Hela cells stimulated filopodia formation and the secretion of EVs. EVs were small (150 nm) and labeled for CD44, indicating that they were derived from filopodia. Filopodia-derived small EVs (sEVs) were enriched with the sphingolipid ceramide, consistent with increased ceramide in the plasma membrane of filopo- dia. Ceramide was colocalized with neutral sphingomyelinase 2 (nSMase2) and acid sphingomyelinase (ASM), two sphingomyelinases generating ceramide at the plasma membrane. Inhibition of …

Soxb1 Transcription Factors Are Essential For Initiating And Maintaining Neural Plate Border Gene Expression, Elizabeth Schock, Joshua R. York, Austin P. Li, Ashlyn Y. Tu, Carole Labonne

Markey Cancer Center Faculty Publications

SoxB1 transcription factors (Sox2/3) are well known for their role in early neural fate specification in the embryo, but little is known about functional roles for SoxB1 factors in non-neural ectodermal cell types, such as the neural plate border (NPB). Using Xenopus laevis, we set out to determine whether SoxB1 transcription factors have a regulatory function in NPB formation. Here, we show that SoxB1 factors are necessary for NPB formation, and that prolonged SoxB1 factor activity blocks the transition from a NPB to a neural crest state. Using ChIP-seq, we demonstrate that Sox3 is enriched upstream of NPB genes in …

A Probabilistic Approach To Estimate The Temporal Order Of Pathway Mutations Accounting For Intra-Tumor Heterogeneity, Menghan Wang, Yanqi Xie, Jinpeng Liu, Austin Li, Li Chen, Arnold Stromberg, Susanne Arnold, Chunming Liu, Chi Wang

Markey Cancer Center Faculty Publications

The development of cancer involves the accumulation of somatic mutations in several essential biological pathways. Delineating the temporal order of pathway mutations during tumori- genesis is crucial for comprehending the biological mechanisms underlying cancer development and identifying potential targets for therapeutic intervention. Several computational and statistical methods have been introduced for estimating the order of somatic mutations based on mutation profile data from a cohort of patients. However, one major issue of current methods is that they do not take into account intra-tumor heterogeneity (ITH), which limits their ability to accurately discern the order of pathway mutations. To address this …

Protein Oxidation In Aging And Alzheimer’S Disease Brain, Rukhsana Sultana, D. Allan Butterfield

Markey Cancer Center Faculty Publications

Proteins are essential molecules that play crucial roles in maintaining cellular homeostasis and carrying out biological functions such as catalyzing biochemical reactions, structural proteins, immune response, etc. However, proteins also are highly susceptible to damage by reactive oxygen species (ROS) and reactive nitrogen species (RNS). In this review, we summarize the role of protein oxidation in normal aging and Alzheimer’s disease (AD). The major emphasis of this review article is on the carbonylation and nitration of proteins in AD and mild cognitive impairment (MCI). The oxidatively modified proteins showed a strong correlation with the reported changes in brain structure, carbohydrate …