Digital Commons Network^™

Plural Molecular And Cellular Mechanisms Of Pore Domain, Timothy J Abreo, Emma C Thompson, Anuraag Madabushi, Kristen L Park, Heun Soh, Nissi Varghese, Carlos G Vanoye, Kristen Springer, Jim Johnson, Scotty Sims, Zhigang Ji, Ana G Chavez, Miranda J Jankovic, Bereket Habte, Aamir R Zuberi, Cathleen M Lutz, Zhao Wang, Vaishnav Krishnan, Lisa Dudler, Stephanie Einsele-Scholz, Jeffrey L Noebels, Alfred L George, Atul Maheshwari, Anastasios Tzingounis, Edward C Cooper

Faculty, Staff and Students Publications

KCNQ2 variants in children with neurodevelopmental impairment are difficult to assess due to their heterogeneity and unclear pathogenic mechanisms. We describe a child with neonatal-onset epilepsy, developmental impairment of intermediate severity, and KCNQ2 G256W heterozygosity. Analyzing prior KCNQ2 channel cryoelectron microscopy models revealed G256 as a node of an arch-shaped non-covalent bond network linking S5, the pore turret, and the ion path. Co-expression with G256W dominantly suppressed conduction by wild-type subunits in heterologous cells. Ezogabine partly reversed this suppression. Kcnq2G256W/+ mice have epilepsy leading to premature deaths. Hippocampal CA1 pyramidal cells from G256W/+ brain slices showed hyperexcitability. G256W/+ pyramidal …

Intrinsic Adaptive Plasticity In Mouse And Human Sensory Neurons, Lisa A Mcilvried, John Smith Del Rosario, Melanie Y Pullen, Andi Wangzhou, Tayler D Sheahan, Andrew J Shepherd, Richard A Slivicki, John A Lemen, Theodore J Price, Bryan A Copits, Robert W Gereau

Faculty, Staff and Student Publications

In response to changes in activity induced by environmental cues, neurons in the central nervous system undergo homeostatic plasticity to sustain overall network function during abrupt changes in synaptic strengths. Homeostatic plasticity involves changes in synaptic scaling and regulation of intrinsic excitability. Increases in spontaneous firing and excitability of sensory neurons are evident in some forms of chronic pain in animal models and human patients. However, whether mechanisms of homeostatic plasticity are engaged in sensory neurons of the peripheral nervous system (PNS) is unknown. Here, we show that sustained depolarization (induced by 24-h incubation in 30 mM KCl) induces compensatory …

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 …

Null Method To Estimate The Maximal Pa At Subsaturating Concentrations Of Agonist, Allison L Germann, Spencer R Pierce, Joe Henry Steinbach, Gustav Akk

2020-Current year OA Pubs

The maximal probability of being in an active state (PA,max) is a measure of gating efficacy for a given agonist acting on a given receptor channel. In macroscopic electrophysiological recordings, PA,max is typically estimated by comparing the amplitude of the current response to a saturating concentration of a test agonist to that of a reference agonist with known PA. Here, we describe an approach to estimate the PA,max for low-efficacy agonists at subsaturating concentrations. In this approach, the amplitude of the response to a high-efficacy control agonist applied alone is compared with the amplitude of the response to a control …

Distinct Properties And Activation Of Hexameric And Heptameric Pannexin 1 Channel Concatemers, Smriti Gupta, Yu-Hsin Chiu, Mohan C Manjegowda, Bimal N Desai, Kodi S Ravichandran, Douglas A Bayliss

2020-Current year OA Pubs

Pannexin 1 (PANX1) is a member of a topologically related and stoichiometrically diverse family of large pore membrane ion channels that support the flux of signaling metabolites (e.g., ATP) and fluorescent dyes. High-resolution structural analyses have identified PANX1 as a heptamer despite early evidence suggesting that it might be a hexamer. To determine if PANX1 channel activity is supported in both hexameric and heptameric conformations, we examined properties of concatenated PANX1 constructs comprising either six or seven subunits with intact or truncated C-termini (the latter to mimic caspase-cleavage activation). In whole-cell recordings from PANX1-deleted cells, the C-tail-truncated hexameric and heptameric …

Intrinsic Adaptive Plasticity In Mouse And Human Sensory Neurons, Lisa A Mcilvried, John Smith Del Rosario, Melanie Y Pullen, Andi Wangzhou, Tayler D Sheahan, Andrew J Shepherd, Richard A Slivicki, John A Lemen, Theodore J Price, Bryan A Copits, Robert W Gereau

2020-Current year OA Pubs

In response to changes in activity induced by environmental cues, neurons in the central nervous system undergo homeostatic plasticity to sustain overall network function during abrupt changes in synaptic strengths. Homeostatic plasticity involves changes in synaptic scaling and regulation of intrinsic excitability. Increases in spontaneous firing and excitability of sensory neurons are evident in some forms of chronic pain in animal models and human patients. However, whether mechanisms of homeostatic plasticity are engaged in sensory neurons of the peripheral nervous system (PNS) is unknown. Here, we show that sustained depolarization (induced by 24-h incubation in 30 mM KCl) induces compensatory …

Rethinking The Rise Of Early-Onset Gastrointestinal Cancers: A Call To Action, Benjamin A Weinberg, Caitlin C Murphy, David R Freyer, K Leigh Greathouse, Jan K Blancato, Elena M Stoffel, Julia L Drewes, Anne Blaes, John M Salsman, Y Nancy You, Hannah Arem, Reetu Mukherji, Priyanka Kanth, Xin Hu, Anne Fabrizio, Marion L Hartley, Marios Giannakis, John L Marshall

Faculty, Staff and Student Publications

Since the early 1990s, there has been a dramatic rise in gastrointestinal cancers diagnosed in patients under age 50 for reasons that remain poorly understood. The most significant change has been the increase in incidence rates of early-onset colorectal cancer, especially rates of left-sided colon and rectal cancers. Increases in gastric, pancreatic, and other gastrointestinal cancer diagnoses have further contributed to this trend. We formed a multidisciplinary Think Tank to develop a strategic, coordinated approach to studying early-onset gastrointestinal cancers. This area of research is challenging given multifactorial etiologies. We focused on epidemiology and the environment, the microbiome, and survivorship …

A Propofol Binding Site In The Voltage Sensor Domain Mediates Inhibition Of Hcn1 Channel Activity, Verena Burtscher, Lei Wang, John Cowgill, Zi-Wei Chen, Christopher Edge, Edward Smith, Yongchang Chang, Lucie Delemotte, Alex S Evers, Baron Chanda

2020-Current year OA Pubs

Hyperpolarization-activated and cyclic nucleotide-gated (HCN) ion channels are members of the cyclic nucleotide-binding family and are crucial for regulating cellular automaticity in many excitable cells. HCN channel activation contributes to pain perception, and propofol, a widely used anesthetic, acts as an analgesic by inhibiting the voltage-dependent activity of HCN channels. However, the molecular determinants of propofol action on HCN channels remain unknown. Here, we use a propofol-analog photoaffinity labeling reagent to identify propofol binding sites in the human HCN1 isoform. Mass spectrometry analyses combined with molecular dynamics simulations show that a binding pocket is formed by extracellularly facing residues in …

Fyn Regulates Aqueous Humor Outflow And Iop Through The Phosphorylation Of Ve-Cadherin., Krishnakumar Kizhatil, Graham Clark, Daniel K Sunderland, Aakriti Bhandari, Logan J Horbal, Revathi Balasubramanian, Simon W M John

Faculty Research 2025

Schlemm's canal endothelial cells (SECs) serve as the final barrier to aqueous humor (AQH) drainage from the eye. SECs adjust permeability to AQH outflow to modulate intraocular pressure (IOP). The broad identification of IOP-related genes implicates SECs in glaucoma. However, the molecular mechanisms by which SECs sense and respond to pressure changes to regulate fluid permeability and IOP remain largely undefined. We hypothesize that mechano-responsive phosphorylation of the cell adhesion molecule VE-CADHERIN (CDH5) in SECs, by FYN and possibly other SRC family kinases, regulates adherens junction (AJ) permeability to AQH in response to IOP. On experimentally raising IOP in mouse …

Enhanced Motivated Behavior Mediated By Pharmacological Targeting Of The Fgf14/Nav16 Complex In Nucleus Accumbens Neurons, Nolan M Dvorak, Paul A Wadsworth, Guillermo Aquino-Miranda, Pingyuan Wang, Douglas S Engelke, Jingheng Zhou, Nghi Nguyen, Aditya K Singh, Giuseppe Aceto, Zahra Haghighijoo, Isabella I Smith, Nana Goode, Mingxiang Zhou, Yosef Avchalumov, Evan P Troendle, Cynthia M Tapia, Haiying Chen, Reid T Powell, Timothy J Baumgartner, Jully Singh, Leandra Koff, Jessica Di Re, Ann E Wadsworth, Mate Marosi, Marc R Azar, Kristina Elias, Paul Lehmann, Yorkiris M Mármol Contreras, Poonam Shah, Hector Gutierrez, Thomas A Green, Martin B Ulmschneider, Marcello D'Ascenzo, Clifford Stephan, Guohong Cui, Fabricio H Do Monte, Jia Zhou, Fernanda Laezza

Faculty, Staff and Student Publications

Protein/protein interactions (PPI) play crucial roles in neuronal functions. Yet, their potential as drug targets for brain disorders remains underexplored. The fibroblast growth factor 14 (FGF14)/voltage-gated Na+ channel 1.6 (Nav1.6) complex regulates excitability of medium spiny neurons (MSN) of the nucleus accumbens (NAc), a central hub of reward circuitry that controls motivated behaviors. Here, we identified compound 1028 (IUPAC: ethyl 3-(2-(3-(hydroxymethyl)-1H-indol-1-yl)acetamido)benzoate), a brain-permeable small molecule that targets FGF14R117, a critical residue located within a druggable pocket at the FGF14/Nav1.6 PPI interface. We found that 1028 modulates FGF14/Nav1.6 complex assembly and depolarizes the voltage-dependence of Nav1.6 channel inactivation with …

Nucleus-Translocated Gclm Promotes Chemoresistance In Colorectal Cancer Through A Moonlighting Function, Jin-Fei Lin, Ze-Xian Liu, Dong-Liang Chen, Ren-Ze Huang, Fen Cao, Kai Yu, Ting Li, Hai-Yu Mo, Hui Sheng, Zhi-Bing Liang, Kun Liao, Yi Han, Shan-Shan Li, Zhao-Lei Zeng, Song Gao, Huai-Qiang Ju, Rui-Hua Xu

Faculty, Staff and Student Publications

Metabolic enzymes perform moonlighting functions during tumor progression, including the modulation of chemoresistance. However, the underlying mechanisms of these functions remain elusive. Here, utilizing a metabolic clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 knockout library screen, we observe that the loss of glutamate-cysteine ligase modifier subunit (GCLM), a rate-limiting enzyme in glutathione biosynthesis, noticeably increases the sensitivity of colorectal cancer (CRC) cells to platinum-based chemotherapy. Mechanistically, we unveil a noncanonical mechanism through which nuclear GCLM competitively interacts with NF-kappa-B (NF-κB)-repressing factor (NKRF), to promote NF-κB activity and facilitate chemoresistance. In response to platinum drug treatment, GCLM is phosphorylated by P38 …

N-Linked Fucosylated Glycans Are Biomarkers For Prostate Cancer With A Neuroendocrine And Metastatic Phenotype, Joseph E Ippolito, Hani Nakhoul, Cody Weimholt, Elena Nunez, Nikolaos A Trikalinos, Et Al.

2020-Current year OA Pubs

Prostate cancer is a heterogeneous disease with a spectrum of pathology and outcomes ranging from indolent to lethal. Although there have been recent advancements in prognostic tissue biomarkers, limitations still exist. We leveraged matrix-assisted laser desorption/ionization imaging of formalin-fixed, paraffin embedded prostate cancer specimens to determine if N-linked glycans expressed in the extracellular matrix of lethal neuroendocrine prostate cancer were also expressed in conventional prostate adenocarcinomas that were associated with poor outcomes. We found that N-glycan fucosylation was abundant in neuroendocrine prostate cancer as well as adenocarcinomas at the time of prostatectomy that eventually developed recurrent metastatic disease. Analysis of …

T Helper 2 Cell-Directed Immunotherapy Eliminates Precancerous Skin Lesions, Tomonori Oka, Neel S. Raval, Mary Tabacchi, Lynn A. Cornelius, Et Al.

2020-Current year OA Pubs

The continuous rise in skin cancer incidence highlights an imperative for improved skin cancer prevention. Topical calcipotriol-plus-5-fluorouracil (calcipotriol-plus-5-FU) immunotherapy effectively eliminates precancerous skin lesions and prevents squamous cell carcinoma (SCC) in patients. However, its mechanism of action remains unclear. Herein, we demonstrate that calcipotriol-plus-5-FU immunotherapy induces T helper type 2 (Th2) immunity, eliminating premalignant keratinocytes in humans. CD4+ Th2 cells were required and were sufficient downstream of thymic stromal lymphopoietin cytokine induction by calcipotriol to suppress skin cancer development. Th2-associated cytokines induced IL-24 expression in cancer cells, resulting in toxic autophagy and anoikis followed by apoptosis. Calcipotriol-plus-5-FU immunotherapy was dependent …

The Cdk8 Kinase Module: A Novel Player In The Transcription Of Translation Initiation And Ribosomal Genes, Brittany Friedson, Stephen D Willis, Natalia Shcherbik, Alicia N Campbell, Katrina F Cooper

Rowan-Virtua School of Osteopathic Medicine Departmental Research

Survival following stress is dependent upon reprogramming transcription and translation. Communication between these programs following stress is critical for adaptation but is not clearly understood. The Cdk8 kinase module (CKM) of the Mediator complex modulates the transcriptional response to various stresses. Its involvement in regulating translational machinery has yet to be elucidated, highlighting an existing gap in knowledge. Here, we report that the CKM positively regulates a subset of ribosomal protein (RP) and translation initiation factor (TIF)-encoding genes under physiological conditions in Saccharomyces cerevisiae. In mouse embryonic fibroblasts and HCT116 cells, the CKM regulates unique sets of RP and TIF …

Cd4+ T Cell-Innate Immune Crosstalk Is Critical During Staphylococcus Aureus Craniotomy Infection, Gunjan Kak, Zachary A. Van Roy, Rachel W. Fallet, Lee E. Korshoj, Tammy Kielian

Journal Articles: Pathology and Microbiology

Access to the brain for treating neurological sequalae requires a craniotomy, which can be complicated by infection. Staphylococcus aureus accounts for half of craniotomy infections, increasing morbidity in a medically fragile patient population. T cells preferentially traffic to the brain during craniotomy infection; however, their functional importance is unknown. Using a mouse model of S. aureus craniotomy infection, CD4+ T cells were critical for bacterial containment, as treatment of WT animals with anti-CD4 exacerbated infection that was similar to phenotypes in Rag1-/- mice. Single-cell RNA-Seq (scRNA-Seq) revealed transcriptional heterogeneity in brain CD3+ infiltrates, with CD4+ cells most prominent that displayed …

Pgc-1Α Activation To Enhance Macrophage Immune Function In Mycobacterial Infections, Joel R. Frandsen, Zhihong Yuan, Brahmchetna Bedi, Zohra Prasla, Seoung-Ryoung Choi, Prabagaran Narayanasamy, Ruxana Sadikot

Journal Articles: Pathology and Microbiology

Nontuberculous Mycobacteria (NTM) are a heterogeneous group of environmental microorganisms with distinct human pathogenesis. Their incidence and prevalence are rising worldwide, due in part to elevated antimicrobial resistance which complicates treatment and potential successful outcomes. Although information exists on the clinical significance of NTMs, little is known about host immune response to infection. NTM infections alter macrophage mitochondrial capacity and decrease ATP production, efficient immune response, and bacterial clearance. Transcription factor peroxisome proliferator activated receptor (PPAR) γ coactivator-1α (PGC-1α) is a master regulator of mitochondrial biogenesis, influencing metabolism, mitochondrial pathways, and antioxidant response. Mitochondrial transcription factor A (TFAM) is a …

Effect Of Praziquantel Treatment On The Nutritional Status Of Children Infected With Schistosoma Haematobium, Louis Fok, Hongying Dai, David Brett-Major, Abebe Animut, Berhanu Erko, John Linville, Yohannes Negash, Abraham Degarege

Journal Articles: Epidemiology

This quasi-experimental trial examined the relationship between Schistosoma haematobium infection and nutritional status, and the impact of single dose praziquantel (PZQ) therapy on undernutrition. A total of 353 children were examined, 112 of which were infected with S. haematobium and treated with PZQ. Children's heights, weights, and mid-upper arm circumferences (MUAC) were measured at baseline and one month post-treatment. Infected children had significantly smaller mean BMI-for-age z-scores (BAZ) (-1.16 vs. 0.11, p < 0.01) and weight-for-age z-scores (WAZ) (-0.61 vs. -0.31, p = 0.03) than the uninfected ones at baseline. S. haematobium infection was associated with underweight (adjusted OR: 1.76, 95% CI: 1.63-1.90). One month after treatment, BAZ, WAZ, …

Zinc Promotes Mitochondrial Health Through Pgc-1alpha Enhancing Bacterial Clearance In Macrophages Infected With Mycobacterium Avium Complex, Ruxana Sadikot, Prabagaran Narayanasamy, Zhihong Yuan, Deandra R. Smith, Daren L. Knoell

Journal Articles: Pulmonary & Critical Care Med

Mitochondria are increasingly recognized as important contributors to immune function, in addition to energy production. They exert this influence through modulation of various signaling pathways that regulate cellular metabolism and immune function in response to pathogens. Peroxisome proliferator-activated receptor (PPAR) coactivator 1 alpha (PGC-1α) is the primary transcription factor and regulator involved in mitochondrial biogenesis. Long known to be involved in immune function, zinc (Zn) is also required for proper mitochondrial function. It is increasingly recognized that many cellular immunometabolic activities are also Zn-dependent. Taken together, we investigated the role of Zn deficiency, both dietary and genetically induced, and Zn …

Catalytic Effect Of Amyloid-Β On Native Tau Aggregation At Physiologically Relevant Concentrations, Rakhi Chowdhury, Apu Chandra Das, Ruan Van Deventer, Luda S. Shlyakhtenko, Yuri L. Lyubchenko

Journal Articles: Pharmaceutical Sciences

Alzheimer's disease (AD) is characterized by the accumulation and aggregation of tau and amyloid-β (Aβ). The pathophysiology and progression of AD are facilitated by the neurotoxic effects of these aggregated proteins, resulting in neurodegeneration and memory loss. In this context, the interaction between tau and Aβ42 is considered, but the mechanism underlying their pathogenic interplay remains unclear. Here, we addressed this question by studying the aggregation of full-length, unmodified tau and Aβ42 at physiologically low concentrations using atomic force microscopy (AFM). AFM imaging and data analyses demonstrate an increase in tau aggregation in the presence of Aβ42, characterized by increased …

Elephant Presence Detection For Early-Warning In Kenya: A Cnn Transfer-Learning Approach, Pascaline Jerotich

All Graduate Theses, Dissertations, and Other Capstone Projects

In Kenya, conflicts between humans and elephants often lead to destruction of crops, lower family income, and put people and elephants at risk at the border of developing farms. Fences, patrols, and manual camera inspection are all expensive and take too long to be useful. This research creates an affordable early warning system that uses transfer learning with convolutional neural networks to find elephants in images. There are two label of elephant and non-elephant wildlife which are a public wildlife corpus of approximately 40,000 photographs of binary task. Cleaning of the dataset was done to ensure high quality and consistency. …

Targeted Deletion Of Cxcl1 In Mscs Regulates Osteogenesis And Suppresses Bone-Metastatic Prostate Cancer, Catherine S. Johnson, Diane L. Costanzo-Garvey, Julio C. Valencia, Sanjana Rajgopal, Theodore Reed, Emma R. Brannon, Jeremy S. Frieling, Deanna Mosley, Todd A. Wyatt, Elijah F. Edmondson, Kabhilan Mohan, Grinu Mathew, Leah M. Cook

Journal Articles: Environmental, Agricultural & Occupational Health

Bone metastasis continues to be the greatest challenge in treating patients with prostate cancer despite ongoing research. In bone, prostate cancer tumors hijack normal bone remodeling processes to drive cancer progression. However, it is unclear how these interactions drive bone-metastatic prostate cancer growth in the bone environment. To understand the mechanisms associated with bone-metastatic prostate cancer regulation of mesenchymal stem cells (MSC), we previously identified that bone-metastatic prostate cancer induces MSC expression of the pro-inflammatory chemokine CXCL8 and its mouse functional homologue Cxcl1. To date, there has been little to no information about the role of CXCL1/8 in MSC biology …

Response Of Cultured Primary Gingival And Periodontal Ligament Cells To Angiotensin Ii And Il1Β Challenges., Thais Francini Garbieri, Thiago José Dionísio, Bella Luna Colombini-Ishikiriama, Rafaela Alves Da Silva, Vanessa Soares Lara, Sandra Helena Penha Oliveira, Maria Helena Fernandes, Andrew S Greene, Carlos Ferreira Santos

Faculty Research 2025

Angiotensin II (Ang II) releases inflammatory mediators from several cell types. The objective of this study was to investigate the potential of Ang II to induce mRNA expression of inflammatory mediators in primary cultured fibroblast-like cells isolated from gingival and periodontal ligament tissues. A synergistic effect of co-treatment with Ang II and Interleukin-1β (IL1β) on the mRNA expression of inflammatory mediators was explored. Immunophenotyping of STRO-1, Ang II type 1 receptor (AT1R), and Ang II type 2 receptor (AT2R) was performed using flow cytometry. Cell cultures were challenged with Ang II (1 µM) for 3, 6, and 24 h with …

Harnessing The Human Gut Microbiota: An Emerging Frontier In Combatting Multidrug-Resistant Bacteria., Wenwen Ding, Yiwen Cheng, Xia Liu, Zhangcheng Zhu, Lingbin Wu, Jie Gao, Wenhui Lei, Yating Li, Xin Zhou, Jian Wu, Yongtao Gao, Zongxin Ling, Ruilai Jiang

Faculty Research 2025

Antimicrobial resistance (AMR) has become a major and escalating global health threat, undermining the effectiveness of current antibiotic and antimicrobial therapies. The rise of multidrug-resistant bacteria has led to increasingly difficult-to-treat infections, resulting in higher morbidity, mortality, and healthcare costs. Tackling this crisis requires the development of novel antimicrobial agents, optimization of current therapeutic strategies, and global initiatives in infection surveillance and control. Recent studies highlight the crucial role of the human gut microbiota in defending against AMR pathogens. A balanced microbiota protects the body through mechanisms such as colonization resistance, positioning it as a key ally in the fight …

Marmosets As Model Systems For The Study Of Alzheimer's Disease And Related Dementias: Substantiation Of Physiological Tau 3r And 4r Isoform Expression And Phosphorylation., Hasi Huhe, Sarah M Shapley, Duc M Duong, Fang Wu, Seung-Kwon Ha, Sang-Ho Choi, Julia Kofler, Yongshan Mou, Thais Rafael Guimaraes, Amantha Thathiah, Caroline M Watson, Lauren K H Schaeffer, Gregory W. Carter, Nicholas T Seyfried, Afonso C Silva, Stacey J Sukoff Rizzo

Faculty Research 2025

INTRODUCTION: Marmosets spontaneously develop pathological hallmarks of Alzheimer's disease (AD) including amyloid beta plaques. However, tau expression in the marmoset brain has been understudied.

METHODS: Isoforms of tau were examined by western blot, mass spectrometry, immunofluorescence, and immunohistochemical staining.

RESULTS: 3R and 4R tau isoforms are expressed in marmoset brains at both the transcript and protein levels across ages. Mass spectrometry analysis revealed that tau peptides in marmoset corresponded to the 3R and 4R peptides in human brain, with 3R predominating at birth and an ≈40%:60% 3R:4R ratios in adolescents and adults; tau was distributed widely in neurons, with localization …

Comprehensive Single-Cell Aging Atlas Of Healthy Mammary Tissues Reveals Shared Epigenomic And Transcriptomic Signatures Of Aging And Cancer., Brittany Lynn Angarola, Siddhartha Sharma, Neerja Katiyar, Hyeon Gu Kang, Djamel Nehar-Belaid, Sunghee Park, Rachel Gott, Giray N Eryilmaz, Mark A Labarge, Karolina Palucka, Jeffrey Chuang, Ron Korstanje, Duygu Ucar, Olga Anczuków

Faculty Research 2025

Aging is the greatest risk factor for breast cancer; however, how age-related cellular and molecular events impact cancer initiation is unknown. In this study, we investigated how aging rewires transcriptomic and epigenomic programs of mouse mammary glands at single-cell resolution, yielding a comprehensive resource for aging and cancer biology. Aged epithelial cells exhibit epigenetic and transcriptional changes in metabolic, pro-inflammatory and cancer-associated genes. Aged stromal cells downregulate fibroblast marker genes and upregulate markers of senescence and cancer-associated fibroblasts. Among immune cells, distinct T cell subsets (Gzmk⁺, memory CD4⁺, γδ) and M2-like macrophages expand with age. …

The Ptp4a3 Inhibitor Kvx-053 Reduces Severe Acute Respiratory Syndrome Coronavirus 2 (Sars-Cov-2) Virulence, Inflammation, And Development Of Acute Lung Injury In K18-Hace2 Mice, Ruben M. L. Colunga-Biancatelli, Pavel A. Solopov, Caitlin M. Woodson, Irving Coy Allen, Ivan Akhrymuk, Maryna Akhrymuk, Brittany N. Heath, Hannah M. Ivester, Tierney Day, Dan E. Austin, Kylene Kehn-Hall, John S. Lazo, Elizabeth R. Sharlow, John D. Catravas

Bioelectrics Publications

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has caused a global health crisis, marked by high transmissibility and virulence. Despite widespread vaccination efforts, effective treatments for COVID-19, particularly for severe cases leading to Acute Respiratory Distress Syndrome (ARDS), remain limited. This study investigates the efficacy of KVX-053, a protein tyrosine phosphatase type IVA (PTP4A3) small molecule inhibitor, in modulating SARS-CoV-2-induced inflammation and lung injury using in vitro cell models and in vivo K18-hACE2 transgenic mice. KVX-053 reduced in vitro pro-inflammatory cytokine expression, including TNFα, CXCL10, and CXCL11, without impacting viral replication or cell viability. K18-hACE2 mice treated with KVX-053 demonstrated …

Perspective On Alcohol-Induced Organ Damage Via Autophagy-Dependent Cellular Changes, Ahmed Bakheet, Murugadas Anbazhagan, Shirish Barve, Srinivasan Dasarathy, John Dickinson, Wen-Xing Ding, Terrence Donohue, Thiyagarajan Gopal, Anna Gukovskaya, Kusum K. Kharbanda, John J. Lemasters, Natalia A. Osna, Pal Pacher, Lucy Sloan, Luis F. Vilches, Viswanathan Saraswathi, Xiao-Ming Yin, Zhi Zhong, Paul G. Thomes

Journal Articles: Internal Medicine

Alcohol-induced organ damage is a major global health concern and a leading cause of disability and mortality. In addition to the liver, chronic alcohol consumption adversely affects multiple organ systems, including the cardiovascular and neuromuscular systems, the gastrointestinal tract, adipose tissue, kidneys, pancreas, and the brain. Organ damage begins with necrosis (cell death) followed by tissue injury, which triggers immune responses aimed at tissue repair. However, with continued heavy drinking, these reparative responses transition into inflammatory responses which exacerbate tissue injury and accelerate disease progression. Macroautophagy, commonly referred to as autophagy, is a vital and evolutionarily-conserved digestive process in eukaryotic …

Tryptophan Kynurenine Pathway-Based Imaging Agents For Brain Disorders And Oncology-From Bench To Bedside, Erik Stauff, Wenqi Xu, Heidi H. Kecskemethy, Sigrid A. Langhans, Vinay V. R. Kandula, Lauren W. Averill, Xuyi Yue

Jefferson Hospital Staff Papers and Presentations

Tryptophan (Trp)-based radiotracers have excellent potential for imaging many different types of brain pathology because of their involvement with both the serotonergic and kynurenine (KYN) pathways. However, radiotracers specific to the kynurenine metabolism pathway are limited. In addition, historically Trp-based radiopharmaceuticals were synthesized with the short-lived isotope carbon-11. A newer generation of Trp-based imaging agents using the longer half-lived and commercially available isotopes, such as fluorine-18 and iodine-124, are being developed. The newly developed amino acid-based tracers have been demonstrated to have favorable radiochemical and imaging characteristics in pre-clinical studies. However, many barriers still exist in the clinical translation of …

Emcreg-International Multidisciplinary Consensus Panel On Management Of Hyperkalemia In Chronic Kidney Disease And Heart Failure, Natalie Kreitzer, Nancy M. Albert, Alpesh N. Amin, Craig J. Beavers, Richard C. Becker, Gregg Fonarow, W. Brian Gibler, Katherine W. Kwon, Robert J. Mentz, Biff F. Palmer, Charles V. Pollack, Iliana L. Piña

Division of Cardiology Faculty Papers

BACKGROUND: Hyperkalemia, generally defined as serum potassium levels greater than 5.0 mEq/L, poses significant clinical risks, including cardiac toxicity and muscle weakness. Its prevalence and severity increase in patients with chronic kidney disease (CKD), diabetes mellitus, and heart failure (HF), particularly when compounded by medications like angiotensin converting inhibitors, angiotensin receptor blockers, and potassium sparing diuretics. Hyperkalemia arises from disruptions in potassium regulation involving intake, excretion, and intracellular-extracellular distribution. In CKD and acute kidney injury, these regulatory mechanisms are impaired, leading to heightened risk. The management of chronic hyperkalemia presents a challenge due to the necessity of balancing effective cardiovascular …

The Relationship Between Socioeconomic Factors And Low Birth Rates In Ohio, Ryan Gora, Hannah Amin

Scholarship in Medicine - All Papers

Background: The incidence of low birth weight (LBW) has not substantially fallen over time despite advances in medical interventions. LBW has been linked to several chronic diseases in adulthood including type 2 diabetes (T2DM) and cardiovascular disease (CVD), making it a particularly salient public health issue.
Objective: To examine socioeconomic factors and diseases associated with LBW in Ohio between 2016-2022.
Methods: Using data from County Health Rankings, we identified socioeconomic factors predictive of LBW in Ohio between 2016-2022. We also examined the relationship between LBW and incidence of T2DM as well as food insecurity (FI). In addition, we investigated how …