Cells Commons^™

Successful Use Of Chimeric Antigen Receptor T-Cell (Car-T) Therapy With Lisocabtagene Maraleucel In A Renal Transplant Recipient With Refractory/Relapsed Diffuse Large B-Cell Lymphoma (Dlbcl), Waqqas Tai, Fatima Chaudhry, Nesreen Shahrour, Jessica Thomas, Afoma Anyadibe, Anuoluwa Oyetoran, Swathi Gopishetty, Precious Idogun, Dilip Samarapungavan, Jassim H. Sarmad, Ishmael Jaiyesimi

Department of Medicine Faculty Publications

This case describes a 53-year-old male with end-stage renal disease who developed monomorphic post-transplant lymphoproliferative disorder (PTLD) in the form of diffuse large B-cell lymphoma (DLBCL) after kidney transplantation. Despite initial treatment with rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP), the patient's disease progressed, and he was referred for chimeric antigen receptor (CAR) T-cell therapy with lisocabtagene maraleucel (liso-cel). Given his post-transplant status, his immunosuppressive agents (tacrolimus and mycophenolate) were held, and prednisone was tapered to 5 mg daily to maintain minimal baseline immunosuppression. After lymphodepleting chemotherapy and liso-cel infusion, the patient experienced no significant toxicities, including cytokine release syndrome (CRS) …

Integrating Genetic Modifier Genotype With Serum Proteomics In Duchenne Muscular Dystrophy Clinical Trials Links Ltbp4 Genetic Modifier To Il-23/Cd93 Pathways In Muscle, Utkarsh J. Dang, Yuan Fang, Daniele Sabbatini, Elena Pegoraro, Luca Bello, Paula R. Clemens, Michela Guglieri, John Van Den Anker, Jesse Damsker, Laura Hagerty, Yetrib Hathout, Michael Ziemba, Lauren Morgenroth, Surajit Bhattacharya, Kanneboyina Nagaraju, Jyoti K. Jaiswal, Eric P. Hoffman

Mathematics & Statistics Faculty Publications

Genetic modifiers of Duchenne muscular dystrophy (DMD) that alter disease severity or response to therapy have been reported using natural history or registry data sets of older corticosteroid-treated patients. We tested associations of genetic modifiers on motor function outcomes in young (4 to <  7 years) steroid naïve clinical trial participants. Participants in clinical trials (VBP15-002/003 [n = 48]; VBP15-004 [n = 121]; DNA available for n = 110) were genotyped for eight published genetic modifier loci, and associations of genotypes with baseline motor function defined via an age-adjusted linear model. Corticosteroid drug response was modeled by genotype-stratified placebo vs. steroid treatment at 12- and 24-weeks posttreatment (mixed model for repeated measures). …

Metabolic Reprogramming Following Mitochondrial Transfer Between Idh2-Mutant Chondrosarcoma Cells And A Normal B-Cell Line, Caleb Wyckoff, Christopher Osgood, Ellen Jing, Michael Stacey

Bioelectrics Publications

Background/Objectives: Chondrosarcoma, glioblastoma, acute myeloid leukemia, chronic lymphocytic leukemia, and cholangiocarcinoma cancers all contain mutations in the gene isocitrate dehydrogenase 2 (IDH2). The mutant IDH2 enzyme metabolizes alpha-ketoglutarate (αKG) into the potent oncometabolite D-2-hydroxyglutarate (D2HG) in the mitochondria of these cancers, leading to altered cellular metabolism. Emerging evidence suggests that mitochondrial transfer between cancer and recipient cells represents an important form of intercellular communication that may influence cellular metabolism. The presence of intercellular TNTs between IDH2-mutant chondrosarcoma cells motivated an investigation into mitochondria-associated physiological changes occurring during an intercellular exchange with immune cells. A mitochondrial transfer is a two-way …

Establishment And Histopathological Characterization Of A Kyse-30 Subcutaneous Xenograft Model Of Esophageal Squamous Cell Carcinoma, Pavel A. Solopov, Alayna Enos, Mantas Silkunas, Giedre Silkuniene, Eleni Zivla, Andrei G. Pakhomov, Olga N. Pakhomova

Bioelectrics Publications

Background/Objectives: Esophageal squamous cell carcinoma (ESCC) is an aggressive malignancy with poor prognosis and limited treatment options, highlighting the need for reliable preclinical models for translational research. Although xenograft models are widely used in cancer biology, systematic characterization of subcutaneous ESCC models under defined implantation conditions remains limited. The objective of this study was to systematically compare implantation conditions and define histopathological and growth-related parameters that enable reproducible tumor establishment while maintaining a practical experimental window for therapeutic studies. Methods: We established and characterized a subcutaneous ESCC xenograft model using human ESCC cell line KYSE-30 implanted into immunodeficient J:NU mice. …

Synergistic Sensitization Of Pancreatic Cancer Cells By Nanosecond Pulsed Electric Fields And Cold Atmospheric Plasma Via Amplifying Ros And Apoptotic Signaling, Zobia Minhas, Edwin A. Oshin, Lifang Yang, Chunqi Jiang, Siqi Guo

Bioelectrics Publications

Pancreatic cancer remains a highly lethal malignancy, with standard therapies offering limited benefits in advanced stages; thus, novel strategies that exploit specific cancer cell vulnerabilities are urgently needed. Building on our previous findings that nanosecond pulsed electric fields (nsPEF) combined with cold atmospheric plasma (CAP) produce enhanced cytotoxicity, this study investigates the molecular mechanisms underlying this synergy. Pan02 pancreatic cancer cells were subjected to nsPEF, CAP, or a combination of both. We assessed cell viability, reactive oxygen species (ROS) production, and mitochondrial integrity using metabolic assays, flow cytometry, and fluorescence microscopy. Apoptotic markers were evaluated via Western blotting and caspase …

Nanosecond Electric Pulses As A Novel In Situ Vaccination Strategy For Cancer Treatment: Mechanisms, Challenges And Prospects, Siqi Guo

Bioelectrics Publications

Nanosecond electric pulses (nsEPs) are an emerging pulsed-power technology with unique bioelectric characteristics distinct from conventional long-pulse electroporation. As a tunable physical modality, nsEPs can modulate intracellular structures, membrane dynamics, and signaling pathways. Increasing evidence supports nsEPs as a promising non-thermal tumor ablation approach due to their high spatial precision, preservation of critical tissue structures, and minimal adverse effects. One of the most significant discoveries associated with nsEP tumor ablation is the induction of potent systemic antitumor immunity, particularly in situ vaccination (ISV) effects and, in some cases, abscopal effects against distant untreated tumors. Substantial evidence demonstrates that nsEPs can …

Peculiarities Of Phosphatidylserine Externalization By Nano- And Microsecond Electric Pulses, Mantas Silkunas, Alayna Enos, Iurii Semenov, Giedre Silkuniene, Eleni Zivla, Olga N. Pakhomova, Andrei G. Pakhomov

Bioelectrics Publications

Phosphatidylserine (PS) externalization is a hallmark of apoptosis but can also be triggered within seconds by pulsed electric fields (PEFs). Whether PS reaches the outer leaflet by lateral migration through electropores or indirectly through Ca²⁺-dependent signaling and scramblase activation remains debated. We used total internal reflection fluorescence (TIRF) microscopy with Annexin V-Alexa Fluor 568 and/or bovine lactadherin-FITC to resolve PS externalization in HEK293 cells placed on an indium tin oxide (ITO) transparent electrode. PEF exposures produced discrete PS-positive puncta ("freckles") within ~ 10 s after a 20-µs pulse (1.2-2.5 kV/cm) or with a ~ 1-min delay after a …

Stim1-Dependent Treg Dysfunction Promotes Cardiometabolic Hfpef: Insights From Patients And Animal Studies, Balaji Srinivas, Alluri Kiran, Hongmei Peng, Jiang Xu, Paula Fortuno, Jennifer May, Ismail El Moudden, Nour-Eddine Rhaleb, John M. Herre, Raymond L. Benza, Khalid Matrougui

Department of Biomedical and Translational Sciences Faculty Publications

Background

Heart failure with preserved ejection fraction (HFpEF) arises from chronic cardiometabolic and vascular stress and is increasingly recognized as an inflammatory syndrome with immune dysregulation. Regulatory T cells (Tregs) are critical modulators of cardiovascular inflammation, yet the mechanisms driving Treg dysfunction in HFpEF remain poorly defined. stromal interaction molecule 1 (STIM1)-dependent calcium signaling is a key stress-responsive pathway in immune cells; however, its role in Treg maladaptation during HFpEF remains unknown.

Methods

Circulating Tregs from patients with and without HFpEF were analyzed for abundance, STIM1 expression, and stress-associated signaling pathways. To establish causality, mice with Treg-specific deletion of STIM1 …

Depemokimab: A Twice Yearly Anti-Il 5 Biologic For Chronic Rhinosinusitis With Nasal Polyps (Crswnp) - A Narrative Review, Marn Joon Park, Joseph K. Han, Kent K. Lam

Department of Otolaryngology (ENT) Faculty Publications

Depemokimab is a monoclonal antibody that targets interleukin-5 with enhanced binding affinity and an extended terminal elimination half‑life of 6-8 weeks. The unique pharmacodynamic features of depemokimab enable sustained suppression of type 2 inflammation with twice‑yearly subcutaneous dosing. This narrative review provides details of depemokimab's molecular profile, pharmacokinetics, and pharmacodynamics and results regarding the clinical efficacy and safety of depemokimab from recently published Phase 3 clinical trials for the treatment of chronic rhinosinusitis with nasal polyposis (CRSwNP). In 528 severe adult CRSwNP patients (ANCHOR‑1/‑2 trials), depemokimab achieved Δ total endoscopic nasal polyp score by -0.70 (p <  .001) and Δ nasal obstruction verbal response scale by -0.24 (p = .003) at week 52, compared to placebo. Twice‑yearly 100 mg depemokimab provides durable eosinophil suppression and with a safety profile comparable to placebo in Phase 3 trials for CRSwNP. Future work should refine biomarkers and assess comparative cost‑effectiveness and long‑term adherence, safety, and effectiveness.

Neurotensin Drives Theca Cell Migration During Ovulation In Primates, Jessica S. Miller, Megan A. G. Sage, Thomas E. Curry Jr., Diane M. Duffy

Department of Biomedical and Translational Sciences Faculty Publications

Theca cells are a critical steroidogenic cell type of the ovarian follicle and corpus luteum. The ovulatory luteinizing hormone (LH) surge (or human chorionic gonadotropin (hCG)) stimulates theca cell relocation from the stroma surrounding the dominant follicle to full integration into the developing corpus luteum. Luteinizing hormone/human chorionic gonadotropin also stimulates granulosa cells to produce local mediators of ovulation, including the peptide neurotensin (NTS). To determine if hCG-stimulated NTS regulates theca cell relocation within the ovulatory follicle, vehicle or an NTS receptor antagonist was injected into a macaque dominant follicle, and ovaries were removed 48 h after hCG administration. Additional …

Brief Pulses Of High-Level Fluid Shear Stress Enhance Metastatic Potential And Rapidly Alter The Metabolism Of Cancer Cells, Amanda N. Pope, Devon L. Moose, Guy O. Hudson, Hank R. Weresh, Marion R. Dykstra, Aabha Y. Joshi, Patrick Breheny, Eric B. Taylor, Michael D. Henry

Department of Biomedical and Translational Sciences Faculty Publications

Circulating tumor cells (CTCs) face challenges to their survival, including mechanical and oxidative stresses that are different from cancer cells in solid primary and metastatic tumors. The impact of adaptations to the fluid microenvironment of the circulation on the outcome of the metastatic cascade is not well understood. Here, we find that cancer cells exposed to brief pulses of high-level fluid shear stress (FSS) exhibit enhanced invasiveness and anchorage-independent proliferation in vitro and enhanced metastatic colonization/tumor formation in vivo. Cancer cells exposed to FSS rapidly alter their metabolism in a manner that promotes survival by providing energy for cytoskeletal remodeling …

Deletion Of Stim1 In Treg Cells Protects Against Lung Fibrosis And Associated Cardiovascular Complications In A Pre-Clinical Mouse Model, Nagaraja Nagre, Balaji Srinivas, Nicholas Richards, Ryan Washington, Gregory Nicholson, Yan Sanders, Beata Kosmider, Khalid Matrougui

Department of Biomedical and Translational Sciences Faculty Publications

Idiopathic pulmonary fibrosis (IPF) is a progressive and incurable lung disease characterized by excessive tissue remodeling and impaired gas exchange. Evidence highlights the critical interplay between immune regulation, calcium signaling, and redox biology implications in the pathogenesis of fibrotic lung disease. Regulatory T-cells (Tregs), known to modulate cardiovascular and immune function, are diminished in IPF, contributing to inflammation and tissue damage. Here, we demonstrate that the stromal interaction molecule 1 (STIM1), a key regulator of intracellular calcium homeostasis, is significantly upregulated in Treg cells isolated from IPF patients and mice subjected to bleomycin-induced lung injury. This upregulation is associated with …

Lipid And Foam Cell Accumulation As Novel Pathological Features Of Benign Prostatic Hyperplasia, Dita Julianingsih, Samara V. Silver, Thaissa Horne, Kasun Gunawardena, Savannah Ward, Alicia Malewska, Douglas Strand, Julius Nyalwidhe, Ilya Sobol, Petra Popovics

Department of Biomedical and Translational Sciences Faculty Publications

Background

Benign prostatic hyperplasia (BPH) encompasses a heterogeneous set of pathological processes that instigate lower urinary tract symptoms (LUTS). Using a mouse model of steroid hormone imbalance-induced lower urinary tract dysfunction, we identified luminal lipid-laden foamy macrophages, although their presence and contribution to human pathology have not yet been established. The objective of this study was to determine whether luminal macrophages are associated with human BPH and to assess how lipid accumulation relates to underlying pathological features and clinical parameters.

Methods

Whole-mount tissue sections from simple prostatectomy specimens and prostates from healthy donors were used to evaluate the association of …

Nanosecond Pulsed Electric Fields For Extracellular Vesicle Engineering: From Electro-Exocytosis To Cargo Modulation, Art Neal, Teresa Graham, Mohamadmahdi Samandari, Arash Ghorbannia, Anca Dobrian, Stephen J. Beebe, Ruben M. L. Colunga-Biancatelli

Bioelectrics Publications

Extracellular vesicles (EVs), including small extracellular vesicles (sEVs) and medium/large extracellular vesicles (MVs), have emerged as promising therapeutic vectors and diagnostic biomarkers across various branches of biomedicine. However, the clinical translation of EV-based technologies remains constrained by persistent challenges in manufacturing: insufficient yield from primary cell sources, limited control over cargo composition, and the absence of scalable, standardized production platforms. Nanosecond pulsed electric fields (nsPEF) represent an emerging biophysical approach that can address several of these limitations. Unlike conventional electroporation, which targets the plasma membrane using microsecond-to-millisecond pulses, nsPEF delivers ultrashort (1–300 ns), high-amplitude (10–300 kV/cm) pulses that penetrate intracellularly …

The Effects Of Abused Drugs On Ferroptosis Pathways: Potential Therapeutic Targets For Substance Use Disorders, Tamara Bouchard, Brooke Russell, Liam Liyang Guo, Tina Nguyen, Yan Cheng, Yan Y. Sanders, Ming-Lei Guo

Department of Biomedical and Translational Sciences Faculty Publications

Substance use disorders (SUDs) remain major public health concerns worldwide, particularly in developed countries. SUDs are characterized by persistent neuroinflammation and synaptic dysfunction in the brain. Despite decades of extensive investigation, the detailed mechanisms underlying SUDs remain elusive. Ferroptosis is a highly regulated cell death process deeply affected by iron metabolism, lipid peroxidation, reactive oxygen species (ROS) production, and antioxidant systems. It has been implicated in multiple neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, multiple sclerosis, and ischemic stroke. Recently, emerging evidence has highlighted the role of ferroptosis in drug-induced pathological changes. Various types of abused substances including alcohol, cocaine, …

Senescent Fibroblasts In Aging And Pulmonary Fibrosis, Sara B. Palega, Aiwei Y. Borengasser, Yan Y. Sanders

Microbiology & Molecular Cell Biology Faculty Publications

Aging is a major risk factor for many chronic lung diseases, including Idiopathic Pulmonary Fibrosis (IPF), a fatal and incurable disease characterized by progressive fibrotic remodeling. Age-associated structural alterations, impaired regenerative capacity, and dysregulated cellular signaling collectively create a pro-fibrotic microenvironment. A central driver of this pathological shift is the accumulation of senescent cells, which undergo irreversible growth arrest and develop a robust pro-inflammatory senescence-associated secretory phenotype (SASP). Emerging evidence identifies senescent lung fibroblasts as critical mediators of IPF pathogenesis. These cells promote excessive extracellular matrix deposition, myofibroblast differentiation, and tissue stiffening, while simultaneously impairing epithelial regeneration. Together, these effects …

Single-Cell Transciptomic Analysis Reveals Age-Related Remodeling Of Brain Endothelial Cells, Hai Duc Nguyen, Summer Siddiqui, Diana G. Bohannon, Robert V. Blair, Hong-Wen Deng, Alexandre Prat, Woong-Ki Kim

Microbiology & Molecular Cell Biology Faculty Publications

Blood–brain barrier (BBB) integrity naturally declines with age. Brain endothelial cells (ECs) and pericytes (PCs) form the BBB, and aging impairs tight junctions, likely via altered PC-to-EC signaling. However, the molecular mechanisms underlying this impairment remain unclear. Using single-cell RNA sequencing, we profiled 68,316 brain ECs expressing 15,564 genes from young and old mice. Unsupervised clustering and annotation revealed five distinct EC subtypes—Capillary EC1, Capillary EC2, Arterial EC, Venous EC1, and Venous EC2—defined by marker genes Mfsd2a, Plvap, Bmx, Nr2f2, and Vcam1, respectively. Aging shifted EC subtype distribution, with reduced Capillary EC1 (45% vs. 57%) and increased Arterial …

Chromnet: A Multi-Task Learning Framework For Cross-Cell Type Prediction Of 3d Chromatin Interactions Using Epigenetic Signals, Bin Wang, Shaokai Wang, Liqing Ding, Hongdong Li, Yaohang Li, Jianxin Wang

Computer Science Faculty Publications

The 3D organization of chromatin plays a fundamental role in gene regulation, cellular function, and disease mechanisms. However, current experimental techniques, such as Hi-C, remain costly and labor-intensive, limiting their application in large-scale and disease-related studies. To address this challenge, ChromNet is presented, a multi-task learning framework that integrates epigenetic signals across diverse cell types to enable high-precision prediction of chromatin architecture. By incorporating noise perturbation and auxiliary classification tasks, ChromNet improves the identification of topologically associating domains (TADs) and cell-type-specific chromatin structures, demonstrating superior generalization performance. Notably, ChromNet accurately predicts chromatin interactions in acute myeloid leukemia (AML) samples by …

Excitation And Polarization Of Isolated Neurons By High-Frequency Sine Waves For Temporal Interference Stimulation, Iurii Semenov, Vitalii Kim, Giedre Silkuniene, Andrei G. Pakhomov

Bioelectrics Publications

The capacity of temporal interference (TI) stimulation to target deep brain regions without affecting nearby surface electrodes remains uncertain. Using artifact-free optical recording, we compare excitation patterns and thresholds in hippocampal neurons stimulated by “pure” and amplitude-modulated sine waves, representing TI waveforms near electrodes and at the target, respectively. We show that pure 2- and 20-kHz sine waves induce repetitive firing at rates that increase up to 60–90 Hz with stronger electric fields. Beyond this limit, action potentials merge into sustained depolarization, resulting in an excitation block. Modulating the sine waves at 20 Hz aligns firing with amplitude “beats” and …

Neuroinflammatory Signaling And Immune Cell Infiltration Differ In Brains Of Rats Exposed To Space Radiation And Social Isolation, Austin M. Adkins, Zachary N. M. Luyo, Alea F. Boden, Riley S. Heerbrandt, Richard A. Britten, Laurie L. Wellman, Larry D. Sanford

Center for Integrative Neuroscience and Inflammatory Diseases (CINID) Faculty Publications

Astronauts on the proposed Mars missions will be exposed to extended periods of social isolation (SI) and space radiation (SR). SI and SR-induced immune dysregulation can result in persistent neuroinflammation and neuronal damage which could negatively impact an astronaut’s health and ability to maintain adequate levels of performance. The synergistic effects of combined SI and SR on immune system functionality and the brain remain unknown. Determining how single and combined inflight stressors modulate the immune system is crucial for fully understanding pathways impacting astronaut health and performance. We used ground-based analogs of SI and SR in rodent models to investigate …

Wrongful Migration: A Hidden Culprit Behind Flank Pain, Ryan Miller, Anjeza Cipi, Emma Pierce

Department of Emergency Medicine Faculty Publications

[Introduction] A 32-year-old woman with no significant past medical history presented to the emergency department with 11 days of fever, fatigue, chills, and new-onset fullness in her left flank. She denied dysuria, abdominal pain, or vaginal bleeding. Vital signs showed fever and mild hypotension, and the physical examination revealed left-sided abdominal distension. Laboratory results demonstrated leukocytosis and a lactate of 3.2 mmol/L. She appeared nontoxic but was persistently febrile despite initial fluids and antibiotics. Computed tomography—shown in Figure 1, and ultrasound—shown in Figure 2, were obtained and revealed the diagnosis.

Potentiation Of Gelonin Cytotoxicity By Pulsed Electric Fields, Olga N. Pakhomova, Eleni Zivla, Giedre Silkuniene, Mantas Silkunas, Andrei G. Pakhomov

Bioelectrics Publications

Gelonin is a ribosome-inactivating protein with extreme intracellular toxicity but poor permeation into cells. Targeted disruption of cell membranes to facilitate gelonin entry is explored for cancer and tissue ablation. We demonstrate a hundreds- to thousands-fold enhancement of gelonin cytotoxicity by pulsed electric fields in the T24, U-87, and CT26 cell lines. The effective gelonin concentration to kill 50% of cells (EC₅₀) after electroporation ranged from <1 nM to about 100 nM. For intact cells, the EC₅₀ was unattainable even at the highest gelonin concentration of 1000 nM, which reduced cell survival by only 5–15%. For isoeffective electroporation treatments using 300 ns, 9 µs, and 100 µs pulses, longer pulses were more efficient at lowering gelonin EC₅₀. Increasing the electric field strength of 8, 100 µs pulses from 0.65 to 1.25 kV/cm reduced gelonin EC₅₀ from 128 nM to 0.72 nM. Conversely, the presence of 100 nM gelonin enabled a more than 20-fold reduction in the number of pulses required for equivalent cell killing. Pulsed electric field-mediated delivery of gelonin shows promise for hyperplasia ablation at concentrations sufficiently low to minimize or avoid systemic toxicity.

Traction Force Microscopy Using An Epifluorescence Microscope: Experimental Considerations And Caveats, Zaria Booth, Mazen Mezher, Rudra Patel, Venkat Maruthamuthu

Mechanical & Aerospace Engineering Faculty Publications

Forces exerted by cells due to their internal contractility play fundamental roles in a host of processes, including adhesion, migration, survival and differentiation. Traction force microscopy (TFM) enables the determination of forces exerted by cells or cell collectives on their environment, which is typically taken to be an extra-cellular matrix (ECM)-coated substrate. Sample preparation for TFM involves the plating of cells onto an environment embedded with fiducial markers. The imaging of these fiducial markers in the presence and absence of the cells then enables calculation of the displacement of localized regions of the environment, and, consequently, the spatial distribution of …

Microbial Remodeling Of Gut Tryptophan Metabolism And Indole-3-Lactate Production Regulate Epithelial Barrier Repair And Viral Suppression In Human And Simian Immunodeficiency Virus Infections, Clarissa Santos Rocha, Katie L. Alexander, Carolina Herrera, Mariana G. Weber, Irina Grishina, Lauren A. Hirao, Dylan J. Kramer, Juan Arredondo, Abigail Mende, Katti R. Crakes, Anne N. Fenton, Maria L. Marco, David A. Mills, John C. Kappes, Lesley E. Smythies, Paul Ziprin, Sumathi Sankaran-Walters, Phillip D. Smith, Satya Dandekar

Department of Obstetrics & Gynecology Faculty Publications

Gut inflammatory diseases cause microbial dysbiosis. Human immunodeficiency virus-1 (HIV) infection disrupts intestinal integrity, subverts repair/renewal pathways, impairs mucosal immunity and propels microbial dysbiosis. However, microbial metabolic mechanisms driving repair mechanisms in virally inflamed gut are not well understood. We investigated the capability and mechanisms of gut microbes to restore epithelial barriers and mucosal immunity in virally inflamed gut by using a multipronged approach: an in vivo simian immunodeficiency virus (SIV)-infected nonhuman primate model of HIV/AIDS, ex vivo HIV-exposed human colorectal explants and primary human intestinal epithelial cells. SIV infection reprogrammed tryptophan (TRP) metabolism, increasing kynurenine catabolite levels that are …

Nucleotide-Derived Bacterial Alarmones Attenuate The Induction Of Type-I Interferon Responses In A Murine Macrophage Reporter Cell Line, Ryan P. Kilduff, Erin B. Purcell, Lisa M. Shollenberger

Chemistry & Biochemistry Faculty Publications

The stringent response is a well-studied phenomenon in many bacterial systems and regulates resource-consuming activities such as transcription, translation, and replication. The stringent response is a well-conserved signaling framework, as are the nucleotide-derived signaling mediators, collectively referred to as (p)ppGpp or as alarmones. There is a wealth of research evaluating nucleotide-derived alarmone signaling in bacterial models, however, their potential to modulate innate immune signaling has not yet been evaluated. Several common pathogen-synthesized molecules, such as lipopolysaccharide (LPS) and cyclic-di-AMP (c-di-AMP), act as pathogen-associated molecular patterns (PAMPs), which are common patterns that alert the innate immune system of bacterial infection. The …

Caveolin-Mediated Endocytosis: Bacterial Pathogen Exploitation And Host-Pathogen Interaction, Dibyasri Barman, Rishi Drolia

Biological Sciences Faculty Publications

Within mammalian cells, diverse endocytic mechanisms, including phagocytosis, pinocytosis, and receptor-mediated endocytosis, serve as gateways exploited by many bacterial pathogens and toxins. Among these, caveolae-mediated endocytosis is characterized by lipid-rich caveolae and dimeric caveolin proteins. Caveolae are specialized microdomains on cell surfaces that impact cell signaling. Caveolin proteins facilitate the creation of caveolae and have three members in vertebrates: caveolin-1, caveolin-2, and caveolin-3. Many bacterial pathogens hijack caveolin machinery to invade host cells. For example, the Gram-positive facultative model intracellular bacterial pathogen Listeria monocytogenes exploits caveolin-mediated endocytosis for efficient cellular entry, translocation across the intestinal barrier, and cell–cell spread. Caveolin …

Protonic Capacitor Cell Energetics: Transmembrane-Electrostatically Localized Protons/Cations, James Weifu Lee

Chemistry & Biochemistry Faculty Publications

The transmembrane-electrostatically localized protons/cations charges (TELPs/TELCs) theory can serve as a theoretical framework to better explain cell electrophysiology and elucidate bioenergetic systems including both delocalized and localized protonic coupling. According to the TELCs model, the excess positive charges of TELCs at one side of the membrane are balanced by the excess negative charges of transmembrane-electrostatically localized hydroxides anions (TELAs) at the other side of the membrane. Through the TELCs-membrane-TELAs capacitor model, the energetics of oxidative phosphorylation have recently been better elucidated in mitochondria and alkalophilic bacteria, leading to the identification of a novel Type-B energetic process. Both the TELCs model …

Neurotensin Regulates Primate Ovulation Via Multiple Neurotensin Receptors, Andrew C. Pearson, Jessica S. Miller, Hannah J. Jensen, Ketan Shrestha, Thomas E. Curry Jr., Diane M. Duffy

Department of Biomedical and Translational Sciences Faculty Publications

Neurotensin (NTS), a small neuropeptide, was recently established as a key paracrine mediator of ovulation. NTS mRNA is highly expressed by granulosa cells in response to the luteinizing hormone (LH) surge, and multiple NTS receptors are expressed by cells of the ovulatory follicle. To identify the role of NTS receptors NTSR1 and SORT1 in ovulation in vivo, the dominant follicle of cynomolgus macaques (Macaca fascicularis) was injected with either vehicle control, the general NTS receptor antagonist SR142948, the NTSR1-selective antagonist SR48692, or the SORT1-selective antagonist AF38469. Human chorionic gonadotropin (hCG) was then administered to initiate ovulatory events. …

Cannabinoid-2 Receptor Activation Attenuates Sulfur Mustard Analog 2-Chloroethyl-Ethyl-Sulfide-Induced Acute Lung Injury In Mice, Gregory Nicholson, Nicholas Richards, Janette Lockett, My Boi Ly, Raj V. Nair, Woong-Ki Kim, K. Yaragudri Vinod, Nagaraja Nagre

Department of Biomedical and Translational Sciences Faculty Publications

Background: Exposure to sulfur mustard (SM; 2,2′-dichlorodiethyl sulfide) causes toxicity in the human body, particularly the lungs. The molecular mechanisms of SM-induced lung damage are elusive, and no effective treatments exist. This study explores the anti-inflammatory potential of cannabinoid receptor 2 (CB2R) activation in mitigating acute lung injury (ALI) and inflammation induced by 2-chloroethyl ethyl sulfide (CEES), a structural analog of SM. Methods: C57BL/6J mice were exposed to CEES via intratracheal administration to model ALI. CB2R activation was achieved through the intraperitoneal administration of HU308, a selective synthetic agonist. ALI and inflammation were evaluated at 48 h post-exposure to CEES. …

Swinging Lever Mechanism Of Myosin Directly Shown By Time-Resolved Cryo-Em, David P. Klebl, Sean N. Mcmillan, Cristina Risi, Eva Forgacs, Betty Virok, Jennifer L. Atherton, Sarah A. Harris, Michele Stofella, Donald A. Winkelmann, Frank Sobott, Vitold E. Galkin, Peter J. Knight, Stephen P. Muench, Charlotte A. Scarfi, Howard D. White

Department of Biomedical and Translational Sciences Faculty Publications

Myosins produce force and movement in cells through interactions with F-actin¹. Generation of movement is thought to arise through actin-catalysed conversion of myosin from an ATP-generated primed (pre-powerstroke) state to a post-powerstroke state, accompanied by myosin lever swing²,³. However, the initial, primed actomyosin state has never been observed, and the mechanism by which actin catalyses myosin ATPase activity is unclear. Here, to address these issues, we performed time-resolved cryogenic electron microscopy (cryo-EM)⁴ of a myosin-5 mutant having slow hydrolysis product release⁵,⁶. Primed actomyosin was predominantly captured 10 ms after …