Chemicals and Drugs Commons^™

Towards The Synthesis Of Dragonamide E And Analogs Thereof, Dante Glover

Chemistry Theses

Leishmaniasis is a disease caused by a parasite spread through the female sand fly. It is categorized as a Neglected Tropical Disease and can cause very severe symptoms, even death, if left untreated. Symptoms include skin lesions that can cause permanent scarring, and mucosal membrane infections that can cause facial deformities. More aggressive forms of leishmaniasis can lead to infections of internal organs like the liver and/or spleen and can lead to death. Drug resistance of these parasites has rendered treatment limited and the side effects of which can be harmful as well.

Scientists looking towards new treatments for tropical …

Decoding The Allosteric Grammar Of Protein Kinases: A Dual-Stream Framework Integrating Protein Language Models And Energy Landscape Frustration Analysis, Will Gatlin, Max Ludwick, Lucas Turano, Brandon Foley, Kamila Riedlova, Vít Škrhák, Marian Novotný, David Hoksza, Gennady M. Verkhivker

Mathematics, Physics, and Computer Science Faculty Articles and Research

The spatial and energetic encoding of allosteric regulatory sites remains a major challenge in structural biology, frequently representing a “blind spot” for sequence-based artificial intelligence (AI) models. We present a protein language model (PLM)-guided approach complemented by the energy landscape frustration analysis as a dual-stream framework to investigate the relationship between AI prediction of binding sites and biophysical organization of regulatory pockets across the human kinome. By probing a fine-tuned residue-level PLM classifier across 453 kinase structures, a clear performance gap is discovered between highly predictable orthosteric pockets (Types I, I.5, and II) and poorly resolved distal allosteric sites (Type …

Computational Insights Into Nucleosome Dynamics In Epigenetics Using Molecular Dynamics Simulations, Rutika Patel

Dissertations, Theses, and Capstone Projects

Nucleosome core particles (NCP) are the building blocks that form a highly organized and compact chromatin structure. Nucleosomes package DNA in the nucleus of eukaryotic cells. The NCP consists of about 147 base pairs of DNA wrapped around the histone octamer, with 1.65 superhelical turns in a left-handed manner. The histone octamer is composed of two copies of H3, H4, H2A, and H2B. Together with histone H1 and linker DNA, they further assemble into a higher-order chromatin structure. The nucleosome complex is stabilized by electrostatic interactions between positively charged histone residues and the negatively charged DNA backbone. To effectively access …

Predicting And Decoding Allosteric Binding Sites Using Protein Language Models And Structure-Based Machine Learning: An Energy Landscape-Guided Explainable Ai Framework, Kamila Riedlová, Vít Skrhák, William G. Gatlin, Max Ludwick, Lucas Turano, Marian Novotný, David Hoksza, Gennady M. Verkhivker

Mathematics, Physics, and Computer Science Faculty Articles and Research

Computational prediction of allosteric binding sites in protein structures remains a persistent challenge, as these regulatory pockets evade detection by both sequence-based and structure-based algorithms. Both computational and physical origins of this predictive asymmetry remain insufficiently understood. In this study, we systematically examine the determinants of binding site predictability using a dual framework that integrates a fine-tuned protein language model and the structure-based method P2Rank as complementary tools probing a diverse data set of 453 human kinases, together with a physics-based interpretability layer derived from energy landscape frustration analysis. Both predictors exhibit a sharp and reproducible dichotomy on protein kinases, …

Herbularyo (Folk Healer): An Herbal Medicine Card Game, Maryjane T. Magsino, Inah Marie Q. Rivera, Armando M. Guidote, Genejane M. Adarlo

Chemistry Faculty Publications

Herbularyo, a card game teaching about herbal plants (HPs), was created and evaluated as a viable educational card game based on Tuomisto and Aksela’s criteria. A quasi-experiment was performed on 81 Grade 8 students from a private high school and 50 Grade 11 from a public high school. Independent t-test revealed that the control group (CG) and experimental group (EG) (p=0.386), and EG1 (played ≤5) and EG2 (played >5) (p=0.681) are not comparable with each other. Paired t-test showed EG performed better (p=0.001) than CG (p=0.901) whereas ANCOVA showed that playing Herbularyo improved students’ information retention (p=0.006). EG1 and EG2 …

Abnormal Trafficking And Processing Of Multiple Matrix Metalloproteinases Drive Cartilage Defects In Congenital Disorders Of Glycosylation, Chia-Lun Wu

All Dissertations

Congenital Disorders of Glycosylation (CDG) are rare metabolic diseases caused by defects in glycosylation. Despite identification of over 200 CDG types, the mechanisms linking glycosylation defects to diverse clinical phenotypes remain unclear. This dissertation uses zebrafish models of PMM2-CDG and STT3-CDG to redefine CDG pathogenesis, shifting from a simple glycan deficiency model to one involving disrupted cellular spatial organization.

We identify a protease-dependent pathway underlying craniofacial cartilage defects. Specifically, defective proteolytic processing of N-cadherin, a key adhesion molecule in chondrogenesis, is a central driver of pathology. We further uncover an unconventional trafficking mechanism in which ER stress and altered secretory …

Understanding The Role Of Toxs As A Bile Sensing Component Of The Toxrs Virulence Regulatory System In Vibrio Spp., Minje Kim

Dartmouth College Ph.D Dissertations

Pathogenic Vibrio bacteria, such as V. cholerae and V. parahaemolyticus, colonize in the human small intestine to cause severe gastrointestinal disease. During the infection, these bacteria encounter bile salts, antimicrobial cholesterol metabolites secreted into the intestine. Pathogenic Vibrio species have evolved to utilize bile salts as signals to regulate virulence. The signaling depends in part on ToxRS, a conserved co-component transmembrane transcription regulator. ToxRS consists of the transcription factor ToxR and its membrane-tethered binding partner ToxS. ToxS is required for ToxR stability and full transcriptional activity. Although bile salts are known to influence ToxRS-dependent virulence gene expression, the molecular …

Mechanisms Of Binding And Immune Escape Resistance For Broadly Neutralizing Antibodies Targeting Distinct Conserved Sars-Cov-2 Spike Epitopes: A Hierarchical Approach Integrating Mutational Profiling And Energy Landscape Analysis, Mohammed Alshahrani, Will Gatlin, Max Ludwick, Lucas Turano, Brandon Foley, Gennady M. Verkhivker

Mathematics, Physics, and Computer Science Faculty Articles and Research

The continued evolution of SARS-CoV-2 has enabled an escape from most monoclonal antibodies, yet a subset of broadly neutralizing antibodies targeting three newly identified super-conserved RBD epitopes—SCORE-A, SCORE-B, and SCORE-C—retains remarkable activity against even the most recent JN.1-derived sublineages. Here, we employed an integrated computational framework combining conformational dynamics, mutational scanning, MM-GBSA binding energetics, and frustration profiling to dissect the molecular mechanisms by which XGI antibodies achieve broad neutralization and resistance to immune escape. Structural analysis revealed that all three SCORE epitopes share a common architecture: a highly conserved, minimally frustrated core that provides stable anchoring, flanked by peripheral regions …

Improving Glp-1 Ra Initiation In Primary Care Through A Paper-Based Clinical Decision Support Tool, Carissa R. Bowery, Karen Carver

Epsilon Sigma at-Large Research Conference

Title: Improving GLP-1 RA Initiation in Primary Care Through a Paper-Based Clinical Decision Support Tool

Authors: Carissa R. Bowery, MSN, FNP-C; East Tennessee State University College of Nursing. Karen M. Carver, PhD, APRN, FNP-C; East Tennessee State University College of Nursing

This quality improvement project focuses on improving evidence-based pharmacologic management of adults with type 2 diabetes mellitus (T2DM) and obesity through implementation of a paper-based clinical decision support (CDS) tool in primary care. The aim is to increase initiation of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) among eligible patients and improve provider adherence to current clinical guidelines.

Processes: This …

Optimizing Itpa R178c Assays Via Hplc, Jared J. Reisnouer, Wally D. Pines

2026 Symposium

Two of the major nucleotide bases in DNA and RNA (Adenine and Guanine) are derived from the purine Inosine Monophosphate (IMP). IMP may occasionally form the noncanonical nucleotide Inosine Triphosphate (ITP) within the cell and become incorporated into DNA during replication, leading to potentially lethal errors. To combat this, human cells produce the “housekeeping” enzyme Inosine Triphosphatase (ITPA) to revert ITP to IMP. A mutation of this protein that replaces the 178th amino acid Arginine with Cysteine (R178C) is associated with a fatal infantile encephalopathy. Previous assessments of enzyme-substrate binding and catalysis for ITPA variants have been run at a …

Addition Of Prg4 To Optimize The Anti‑Adhesive Properties Of Tissue Barrier Sepraflm®, Ava J. Marks, Khaled A. Elsaid, Ling X. Zhang, Timmy Lin, Janette Baird, Tannin A. Schmidt, Gregory D. Jay

Pharmacy Faculty Articles and Research

Purpose

Postsurgical adhesion remains a significant clinical challenge. Seprafilm^® is widely used as a barrier to reduce adhesion formation, however its efficacy may be inconsistent. Recombinant human proteoglycan-4 (rhPRG4), a surface-active, anti-inflammatory glycoprotein found in synovial fluid inhibits cell and protein adhesion. This study investigated whether coating Seprafilm with rhPRG4 could enhance its anti-adhesive potential.

Methods

Macrophages (J774), human fibroblast-like synoviocytes (HFLS), and melanoma (A375) cells were cultured on tissue culture wells treated with rhPRG4 or bovine submaxillary mucin (BSM) to determine optimal seeding density. Seprafilm sheets were coated with rhPRG4 or BSM (0.78–200 µg/mL). Cell adhesion was quantified …

Albumin Use In Cardiopulmonary Bypass Pump Prime And Its Association With Postoperative Renal Function And Acute Kidney Injury: A Scoping Review, Hannah Talbot

Student Works

ABSTRACT

1.Structured summary:

Background: Cardiopulmonary bypass (CPB) is associated with significant hemodilution, inflammatory activation, and alterations in renal perfusion, all of which may contribute to postoperative acute kidney injury (AKI). Albumin is frequently used as a component of CPB pump prime due to its oncotic properties and potential to mitigate fluid shifts and support intravascular volume. However, the extent to which albumin-containing priming solutions influence postoperative renal outcomes remains unclear.

Objective: This scoping review aimed to map the available literature examining the use of albumin in CPB pump prime and its reported effects on renal function and the incidence …

Brain Delivery Of Antibody-Derived Biologicals For Alzheimer’S Disease: An Updated Narrative Review, Rachita K. Sumbria, Ruben J. Boado

Pharmacy Faculty Articles and Research

Antibodies directed against β-amyloid (Aβ) have been developed for the treatment of Alzheimer’s disease (AD). However, the in vivo central efficacy is reduced by the poor penetration of antibodies across the blood–brain barrier (BBB). In addition, these antibodies have been associated with adverse effects like amyloid-related imaging abnormalities. Thus, the development of new antibody-based therapies for AD with improved transport across the BBB may improve efficacy and reduce adverse effects. Antibodies targeting the BBB transferrin receptor (TfR) are able to cross the BBB through receptor-mediated transcytosis, producing a global distribution throughout the brain. Along the same line, bispecific antibodies directed …

Structural Transformation Of A Hydrogel-Forming Cell Division Protein Zapb Of Multidrug Resistant Klebsiella Pneumoniae With Small Molecules, Ayesha Khan, M. Iqbal Choudhary, Sumaira Javaid, Humaira Zafar, Innokentiy Maslennikov, Atia-Tul Wahab

Pharmacy Faculty Articles and Research

Septal ring assembly protein ZapB (EMR18431.1) is involved in Z-ring formation, and nucleoid segregation during the bacterial cell division . It promotes cell division in the initial stages of the cell cycle through direct interaction with FtsZ, thus stimulating Z-ring assembly. The ZapB inhibition can make bacterial cell susceptible to primary antibiotics, and therefore considered as an important approach for adjuvent therapy against MDR bacterial infections. Hence in the current study, ZapB protein of multidrug resistant Klebsiella pneumoniae was cloned, and expressed in E. coli system. To understand its role, and to assess the mechanism of ZapB activation, the characteristic …

Re-Purposing Pre-Existing Tilapia Aquaculture Open-Design System For Zebrafish Biomedical Research Purposes, Luke Cantu, David Sierra, Skyleigh Curtis, Maya Avila

ATU Scholars Symposium

Title: Re-purposing pre-existing tilapia open-design aquaculture systems for zebrafish biomedical research purposes.

Background: Zebrafish (Danio rerio) models are gaining popularity in biomedical research; however, the high infrastructure cost, at approximately $20,000 per unit, is a significant hurdle for primary undergraduate institutions (PUIs) establishing zebrafish facilities. This study assesses if repurposing existing tilapia open-design aquaculture systems could be a cost-effective method for zebrafish facility establishment.

Methods: Between November-2025 to February-2026, the study used a pre-existing tilapia aquaculture open-design system with personnel modified outlet filters. The water quality of this system was monitored and recorded. The study compared the stabilization phase or …

A Ubiquitin Code Written In Circadian Time: Evaluating Protein Linkages In A Drosophila Model, Alejandro Damian, Elinor Harrison, Cj Dalton

Medical Student Research Symposium

Background: Ubiquitin is a small polypeptide that serves many functions within a cell, including modifying proteins, marking them for degradation through the ubiquitin-proteasome system (UPS). Circadian rhythms regulate many cellular processes, but its role on the individual linkages of ubiquitin is poorly understood. This project aims to determine whether there is a circadian pattern for the conjugation of ubiquitin. Methods: Wild-type (Oregon R) Drosophila were entrained to a circadian cycle with standard light and dark environments. The whole heads were then frozen and removed at different times and used to quantify protein linkages using western blotting and antibodies to each …

Increased Backbone Rigidity Of Artificial Transcription Factors, Jasmine Glover, Emma Otey, Joanna K. Kwao, Nicholas Truex

Senior Theses

Programming DNA-binding proteins is an effective strategy for developing therapeutics that regulate gene expression. These proteins can directly bind to DNA to activate or repress transcription of specific genes. Zinc finger proteins are a class of DNA-binding proteins commonly found in eukaryotic organisms. Their DNA-binding function is derived from unique amino acid sequences within each domain that recognizes specific nucleotides, allowing each finger to selectively recognize three DNA base pairs. Adjoining of multiple domains in tandem allows recognition of a specific DNA sequence. Artificial transcription factors can be made of multiple zinc finger domains arranged in tandem and engineered to …

Recombinant Gelonin: Purification And Functional Validation For Electroporation-Assisted Delivery, Eleni Zivla, Giedrė Šilkūnienė, Andrei G. Pakhomov, Mantas Šilkūnas, Olga N. Pakhomova

Knowledge and Creativity Expo

Type I ribosome-inactivating proteins, such as gelonin, are enzymatically potent toxins but are effectively non-toxic under physiological conditions because they are unable to cross the plasma membrane[1]. Pulsed electric fields (PEF) overcome this delivery barrier by transiently permeabilizing the plasma membrane, allowing direct cytosolic entry. This enhances gelonin cytotoxicity by several thousand-fold, highlighting gelonin’s potential as an electrochemotherapy candidate[2]. Here, we present a recombinant gelonin (rGel) expression platform in E. coli with HPLC-based purification that enables reproducible protein production and structure-guided engineering.

The mature gelonin sequence (residues 47–297) was cloned into pET-32a(+) with an N-terminally fused Trx-6×His tag and TEV …

Rapid Resolution Of Psoriatic Arthritis Symptoms Following Initiation Of A Glp-1 Receptor Agonist, Joseph E. Capito, Kate Gelman

Faculty & Staff Scholarship

Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) are widely used for the management of type 2 diabetes mellitus (T2DM) and obesity, with growing evidence of their anti-inflammatory effects. We report the case of a 54-year-old woman with obesity, T2DM, and biopsy-confirmed plaque psoriasis who developed joint pain and stiffness consistent with psoriatic arthritis (PsA). Her symptoms persisted despite appropriate trials of topical corticosteroids, calcipotriene, and oral apremilast. She also declined methotrexate due to concerns about side effects. Imaging of her hands revealed distal interphalangeal joint space narrowing, marginal erosions, and periosteal reaction, supporting the diagnosis of PsA. The patient was …

Selectivity Modulation Of Small Cationic Membrane-Active Cyclic Peptides With Broad-Spectrum Activity Against Bacteria And Fungi, Sandeep Lohan, Rakesh Kumar Tiwari, Innokentiy Maslennikov, Kaustav Das Gupta, Shakti Singh, Keykavous Parang

Pharmacy Faculty Articles and Research

To investigate how ring size and backbone flexibility influence antimicrobial potency and cytotoxicity, we synthesized a series of macrocyclic peptides of lead peptide p1 (c[Arg-Arg-arg-arg-dip-Trp-dip]) by incorporating Gly, 2-aminoethoxyacetic acid (EAA), or 2,4-diaminobutyric acid (Dab). Two optimized peptides, 6b and 10b, retained broad-spectrum activity against drug-resistant Gram-positive (MIC, 1.5–6.2 μg/mL) and Gram-negative bacteria (MIC, 4–25 μg/mL), as well as pathogenic fungi, while exhibiting enhanced selectivity for microbial cells. Their therapeutic indices (TI ∼407 and ∼394, respectively) were ∼2-fold higher than p1, indicating improved safety. Both peptides remained effective against Gram-negative pathogens beyond the reach of daptomycin, were rapidly bactericidal, and …

Plasma Ca125 Levels As A Predictor Of Major Adverse Cardiac Events In Patients With Acute Coronary Syndrome: A Six-Month Follow-Up Study, Nazlı Dilek Çolak, Turgut Karabağ, Onuralp Çalışkan, Songül Tezcan

Journal of the Saudi Heart Association

Objectives: Carbohydrate antigen 125 (CA125) is associated with different cardiovascular conditions. This study aimed to determine CA125 levels in patients with acute coronary syndrome (ACS) and the potential relationship between major adverse cardiac events (MACE) in the short-term following.

Methods: This prospective cohort study was conducted in a coronary care unit between May and November 2022. Plasma CA125 levels were measured only once upon hospital admission. Patients were followed for six months. All-cause mortality, recurrent acute coronary syndrome, requirement for revascularization, decompensated heart failure, cardiogenic pulmonary edema, atrial fibrillation, and stroke were recorded as MACE.

Results: A total of 127 …

Disruption Of Proteoglycan 4 (Prg4)-Cd44 Signaling Modulates Chronic Synovitis In Conditionally Inactivated Mice, Khaled A. Elsaid, Ling Zhang, Thomas Zhao, Ava Marks, Derek Jenkins, Gregory D. Jay

Pharmacy Faculty Articles and Research

Background

Proteoglycan-4 (PRG4) is a mucinous glycoprotein secreted by synovial fibroblasts and superficial zone chondrocytes. PRG4 inhibits synovial macrophage (SM) activation via xanthine oxidase (XO) and hypoxia inducible factor alpha (HIF-1α) suppression. We aimed to evaluate the contribution of PRG4-CD44 interaction to synovial homeostasis and investigate PRG4’s signaling dysfunction in synovial tissues from patients with osteoarthritis (OA). We hypothesized that CD44 mediates synovitis due to PRG4 loss and that PRG4 signaling dysfunction is associated with high-grade synovitis in OA.

Methods

Prg4^{FrtloxP/FrtloxP} are transgenic mice wherein tamoxifen (TAM) inactivates the Frt allele and creates a knockout state (Prg4^{FrtKO/FrtKO …}

Tumor Targeting With Peptide-Drug Conjugates: Showcasing Key Progress And Hurdles, Keykavous Parang, Thuy Do, Clare Dinh, Dorna Davanidavari, Max Foroughi, Troy Khong, Mahsa Moazen, Amir Nasrolahi Shirazi

Pharmacy Faculty Articles and Research

Peptide-drug conjugates (PDCs) are modular, targeted therapeutics composed of a homing peptide linked to a cytotoxic or modulating drug payload via a cleavable/non-cleavable linker. PDCs utilize peptide targeting to enhance the delivery of potent drugs to tumors, providing advantages such as superior tissue penetration, reduced immunogenicity, and simpler manufacture compared to antibody-drug conjugates (ADCs). A comparison of PDCs versus ADCs highlights that PDCs’ small size (~1-3 kDa) enables deeper tumor penetration and faster clearance, whereas ADCs (~150 kDa) benefit from prolonged circulation but suffer from limited tissue diffusion. This review surveys recent advances in PDC design and application. We discuss …

Albumin-Binding Domains In Therapeutic Protein Engineering: A Structural And Computational Perspective On Rational Design, Matthew Argyle, Dallin M. Chipman, Anna Claire Woolley, Bradley C. Bundy, Dennis Della Corte

Faculty Publications

Therapeutic proteins face a critical pharmacokinetic challenge: rapid clearance from circulation limits their clinical efficacy. Albumin-binding domains (ABDs) offer an elegant solution by enabling therapeutic proteins to “hitchhike” on serum albumin’s favorable 19-day half-life through FcRn-mediated recycling. Clinical validation through approved therapeutics like ozoralizumab demonstrates the success of this approach, with preclinical studies showing fusion to an ABD extended half-life to 18 days. This review provides an analysis of ABD-fusion protein design, integrating structural biology, computational prediction, and rational engineering principles. We catalog the major classes of albumin-binding modalities, including bacterial three-helix bundle domains, engineered peptides, antibody-derived binders, and alternative …

Mutations Altering The Dna Binding Domains Of The Human Rad52 Protein Exert Distinct Effects On Homologous Recombination Repair In Saccharomyces Cerevisiae, Glenn M. Manthey, Elise W. Wolf, Jason Xu, M. Cristina Negritto, Renee A. Bouley, Ruben C. Petreaca, Adam M. Bailis

College of Health Professions Faculty Papers

RAD52 is a conserved member of the homologous recombination repair (HRR) apparatus from yeast to humans. Mutating conserved amino acids in the internal and external DNA binding domains of the human RAD52 protein (HsRAD52) has discrete effects in vitro. Previous studies have shown that HsRAD52 supports multiple mechanisms of HRR in budding yeast, suggesting the utility of this model system for exploring the correspondence between losses of HsRAD52 function in vitro and their impact in vivo. We report that disrupting the internal and external DNA binding domains of HsRAD52 produced distinct effects on the repair of genomic DNA double-strand breaks …

Engineering Enac Constructs To Examine Pip2 And Ubiquitin Competition On Enac Regulation And Stability, Lacie Johnson

Chemistry & Biochemistry Undergraduate Honors Theses

The epithelial sodium channel (ENaC) plays a critical role in sodium homeostasis, fluid balance, and blood pressure regulation. ENaC activity is tightly controlled by post-translational mechanisms, including ubiquitination-mediated degradation and phosphatidylinositol 4,5-bisphosphate (PIP2) dependent channel activation. PIP2 is a phospholipid necessary to facilitate the maximal channel opening. Previous studies suggest that intracellular PIP2 binding sites are located in proximity to ubiquitination sites on ENaC subunits, raising the possibility of PIP2 binding to influence channel stability and function. This thesis aimed to engineer and validate molecular tools capable of examining the interplay between PIP2 binding and ubiquitination in ENaC regulation. A …

From Latent Manifolds To Targeted Molecular Probes: An Interpretable, Kinome-Scale Generative Machine Learning Framework For Family-Based Kinase Ligand Design, Gennady M. Verkhivker, Ryan Kassab, Keerthi Krishnan

Mathematics, Physics, and Computer Science Faculty Articles and Research

Scaffold-aware artificial intelligence (AI) models enable systematic exploration of chemical space conditioned on protein-interacting ligands, yet the representational principles governing their behavior remain poorly understood. The computational representation of structurally complex kinase small molecules remains a formidable challenge due to the high conservation of ATP active site architecture across the kinome and the topological complexity of structural scaffolds in current generative AI frameworks. In this study, we present a diagnostic, modular and chemistry-first generative framework for design of targeted SRC kinase ligands by integrating ChemVAE-based latent space modeling, a chemically interpretable structural similarity metric (Kinase Likelihood Score), Bayesian optimization, and …

Apolipoprotein E4 And Its Later-Life Health Effects On The Multiple Sclerosis Population, Dean Zeldich, Chia Hsin Cheng, Yi Guan, Sriman Narain, Bang-Bon Koo

Department of Neurology Faculty Papers

BACKGROUND AND OBJECTIVES: Multiple sclerosis (MS) is a chronic autoimmune disease causing neuroinflammation and neurodegeneration. The apolipoprotein E4 (APOE4) allele, a major genetic risk factor for late-onset Alzheimer's Disease, accelerates cognitive decline and neuroinflammatory processes, including blood-brain-barrier disruption. This study explores the impact of APOE4 on later-life health in MS patients using biomarkers from the UK Biobank.

METHODS: MS patients were grouped by APOE4 carrier status: MS-E4 and MS-nonE4. Age- and sex-matched non-MS controls (control-E4, control-nonE4) were included for comparison. Analyses assessed retinal nerve fiber layer thickness (RNFL) from optical coherence tomography (OCT), blood biomarkers, cognitive performance, and brain magnetic …

Stat-Independent Functions Of Janus Kinases 1 And 2 Are Obligatory For The Postnatal Development Of Mammary Epithelial Ducts, Rayane Dennaoui, Madison N. Wicker, Carson Moen, Michaela Schlederer, Kerry Vistisen, Aleata A. Triplett, Thomas Rülicke, Hallgeir Rui, Lukas Kenner, Emilio Casanova, Kay-Uwe Wagner

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

Janus kinases 1 and 2 and STAT transcription factors are critical signaling nodes for numerous growth factors. In the mammary gland, JAK2 and STAT5a/b are essential for alveolar cell differentiation and lactation, but little is known about the cooperative roles of JAKs and STATs before pregnancy. We examined female mice conditionally deficient in JAK1/2 and discovered that both kinases jointly regulate epithelial cell proliferation and ductal morphogenesis. To assess the role of downstream STATs, we generated genetic models co-deficient in STAT3/5a/5b with or without STAT1 or JAK1. Although loss of STAT3/5a/5b leads to a JAK1-dependent upregulation of STAT1, the formation …

Spatially Distinct Cellular And Molecular Landscapes Define Prognosis In Triple-Negative Breast Cancer, Kavitha Mukund, Darya Veraksa, David Frankhouser, Lixin Yang, Jerneja Tomsic, Raju Pillai, Srijan Atti, Zahra Mesrizadeh, Daniel Schmolze, Jovanny Zabaleta, Xiao-Cheng Wu, Mary-Anne Leblanc, Lucio Miele, Augusto Ochoa, Victoria Seewaldt, Shankar Subramaniam

School of Medicine Faculty Publications

Triple-negative breast cancer (TNBC) is a prevalent breast cancer subtype with the lowest 5-year survival. Several factors influence outcomes, but their inherent molecular and cellular heterogeneity are increasingly acknowledged as crucial determinants. Here, we report on the spatio-molecular heterogeneity underlying TNBC tumors in a retrospective, treatment-naive cohort with differential prognoses (17 good prognoses [GPx] >15-year survival and 15 poor prognoses [PPx] < 3-year survival]) profiled using GeoMx Digital Spatial Profiler. Analyses reveal that epithelial and microenvironment (TME) states are transcriptionally distinct between groups. Invasive GPx epithelia show an increase in immune transcripts, with a more immune-rich TME (via IF). PPx epithelia, in contrast, are more metabolically and translationally active, with a mesenchymal/fibrotic TME. Pre-cancerous epithelia in PPx exhibit a presence of aggressiveness, marked by increased EMT signaling and complement activity. We identify distinct epithelial gene signatures for PPx and GPx that can accurately classify diagnostic samples and likely inform therapy.