Medical Specialties Commons^™

Tamm-Horsfall Protein Augments Neutrophil Netosis During Urinary Tract Infection, Vicki Mercado-Evans, Holly Branthoover, Claude Chew, Camille Serchejian, Alexander B Saltzman, Marlyd E Mejia, Jacob J Zulk, Ingrid Cornax, Victor Nizet, Kathryn A Patras

Faculty, Staff and Students Publications

Urinary neutrophils are a hallmark of urinary tract infection (UTI), yet the mechanisms governing their activation, function, and efficacy in controlling infection remain incompletely understood. Tamm-Horsfall glycoprotein (THP), the most abundant protein in urine, uses terminal sialic acids to bind an inhibitory receptor and dampen neutrophil inflammatory responses. We hypothesized that neutrophil modulation is an integral part of THP-mediated host protection. In a UTI model, THP-deficient mice showed elevated urinary tract bacterial burdens, increased neutrophil recruitment, and more severe tissue histopathological changes compared with WT mice. Furthermore, THP-deficient mice displayed impaired urinary NETosis during UTI. To investigate the effect of …

A Β-Hydroxybutyrate Shunt Pathway Generates Anti-Obesity Ketone Metabolites, Maria Dolores Moya-Garzon, Mengjie Wang, Veronica L Li, Xuchao Lyu, Wei Wei, Alan Sheng-Hwa Tung, Steffen H Raun, Meng Zhao, Laetitia Coassolo, Hashim Islam, Barbara Oliveira, Yuqin Dai, Jan Spaas, Antonio Delgado-Gonzalez, Kenyi Donoso, Aurora Alvarez-Buylla, Francisco Franco-Montalban, Anudari Letian, Catherine P Ward, Lichao Liu, Katrin J Svensson, Emily L Goldberg, Christopher D Gardner, Jonathan P Little, Steven M Banik, Yong Xu, Jonathan Z Long

Children’s Nutrition Research Center Staff Publications

β-Hydroxybutyrate (BHB) is an abundant ketone body. To date, all known pathways of BHB metabolism involve the interconversion of BHB and primary energy intermediates. Here, we identify a previously undescribed BHB secondary metabolic pathway via CNDP2-dependent enzymatic conjugation of BHB and free amino acids. This BHB shunt pathway generates a family of anti-obesity ketone metabolites, the BHB-amino acids. Genetic ablation of CNDP2 in mice eliminates tissue amino acid BHB-ylation activity and reduces BHB-amino acid levels. The most abundant BHB-amino acid, BHB-Phe, is a ketosis-inducible congener of Lac-Phe that activates hypothalamic and brainstem neurons and suppresses feeding. Conversely, CNDP2-KO mice exhibit …

Molecular Logic For Cellular Specializations That Initiate The Auditory Parallel Processing Pathways, Junzhan Jing, Ming Hu, Tenzin Ngodup, Qianqian Ma, Shu-Ning Natalie Lau, M Cecilia Ljungberg, Matthew J Mcginley, Laurence O Trussell, Xiaolong Jiang

Faculty, Staff and Students Publications

The cochlear nuclear complex (CN), the starting point for all central auditory processing, encompasses a suite of neuronal cell types highly specialized for neural coding of acoustic signals. However, the molecular logic governing these specializations remains unknown. By combining single-nucleus RNA sequencing and Patch-seq analysis, we reveal a set of transcriptionally distinct cell populations encompassing all previously observed types and discover multiple hitherto unknown subtypes with anatomical and physiological identity. The resulting comprehensive cell-type taxonomy reconciles anatomical position, morphological, physiological, and molecular criteria, enabling the determination of the molecular basis of the specialized cellular phenotypes in the CN. In particular, …

Functional Characterization Of Qt Interval Associated Scn5a Enhancer Variants Identify Combined Additive Effects, Lavanya Gunamalai, Parul Singh, Brian Berg, Leilei Shi, Ernesto Sanchez, Alexa Smith, Ghislain Breton, Mark T Bedford, Darius Balciunas, Ashish Kapoor

Faculty, Staff and Student Publications

Several empirical and theoretical studies suggest the presence of multiple enhancers per gene that collectively regulate gene expression, and that common sequence variation impacting on the activities of these enhancers is a major source of inter-individual gene expression variability. However, for the vast majority of genes, enhancers and the underlying regulatory variation remains unknown. Even for the genes with well-characterized enhancers, the nature of the combined effects from multiple enhancers and their variants, when known, on gene expression regulation remains unexplored. Here, we have evaluated the combined effects from five SCN5A enhancers and their regulatory variants that are known to …

Alleviation Of Liver Fibrosis By Inhibiting A Non-Canonical Atf4-Regulated Enhancer Program In Hepatic Stellate Cells, Li-Xian Yang, Chuangye Qi, Si Lu, Xiang-Shi Ye, Parnaz Merikhian, Du-Yu Zhang, Tao Yao, Jiang-Sha Zhao, Ying Wu, Yongshi Jia, Bo Shan, Jinghai Chen, Xiaozhou Mou, Jia You, Wenbo Li, Yu-Xiong Feng

Faculty, Staff and Student Publications

Liver fibrosis is a critical liver disease that can progress to more severe manifestations, such as cirrhosis, yet no effective targeted therapies are available. Here, we identify that ATF4, a master transcription factor in ER stress response, promotes liver fibrosis by facilitating a stress response-independent epigenetic program in hepatic stellate cells (HSCs). Unlike its canonical role in regulating UPR genes during ER stress, ATF4 activates epithelial-mesenchymal transition (EMT) gene transcription under fibrogenic conditions. HSC-specific depletion of ATF4 suppresses liver fibrosis in vivo. Mechanistically, TGFβ resets ATF4 to orchestrate a unique enhancer program for the transcriptional activation of pro-fibrotic EMT genes. …

Advancing De Novo Lipogenesis: Genetic And Metabolic Insights, Sean M Hartig, Mark A Herman

Faculty, Staff and Students Publications

De novo lipogenesis (DNL) is the process whereby cells synthesize fatty acids from acetyl-CoA, contributing to steatosis in fatty liver disease. Two new studies, using genetic mouse models, metabolomics, and pharmacology, identified alternative pathways in DNL and unexpected physiological effects when targeting key enzymes in this pathway.

Yap Overcomes Mechanical Barriers To Induce Mitotic Rounding And Adult Cardiomyocyte Division, Yuka Morikawa, Jong H Kim, Rich Gang Li, Lin Liu, Shijie Liu, Vaibhav Deshmukh, Matthew C Hill, James F Martin

Faculty, Staff and Students Publications

Background: Many specialized cells in adult organs acquire a state of cell cycle arrest and quiescence through unknown mechanisms. Our limited understanding of mammalian cell cycle arrest is derived primarily from cell culture models. Adult mammalian cardiomyocytes, a classic example of cell cycle arrested cells, exit the cell cycle postnatally and remain in an arrested state for the life of the organism. Cardiomyocytes can be induced to re-enter the cell cycle by YAP5SA, an active form of the Hippo signaling pathway effector YAP.

Methods: We performed clonal analyses to determine the cell cycle kinetics of YAP5SA cardiomyocytes. We also performed …

Microtubules Sequester Acetylated Yap In The Cytoplasm And Inhibit Heart Regeneration, Shijie Liu, Vaibhav Deshmukh, Fansen Meng, Yidan Wang, Yuka Morikawa, Jeffrey D Steimle, Rich Gang Li, Jun Wang, James F Martin

Faculty, Staff and Students Publications

Background: The Hippo pathway effector YAP (Yes-associated protein) plays an essential role in cardiomyocyte proliferation and heart regeneration. In response to physiological changes, YAP moves in and out of the nucleus. The pathophysiological mechanisms regulating YAP subcellular localization after myocardial infarction remain poorly defined.

Methods: We identified YAP acetylation at site K265 by in vitro acetylation followed by mass spectrometry analysis. We used adeno-associated virus to express YAP-containing mutations that either abolished acetylation (YAP-K265R) or mimicked acetylation (YAP-K265Q) and studied how acetylation regulates YAP subcellular localization in mouse hearts. We generated a cell line with YAP-K265R mutation and investigated the …

Targeted Inhibition Of Aurora Kinase A Promotes Immune Checkpoint Inhibition Efficacy In Human Papillomavirus-Driven Cancers, Soma Ghosh, Madison P O'Hara, Pragya Sinha, Tuhina Mazumdar, Lacin Yapindi, Jagannadha K Sastry, Faye M Johnson

Faculty, Staff and Student Publications

Background: Human papillomavirus (HPV)-driven cancers include head and neck squamous cell carcinoma and cervical cancer and represent approximately 5% of all cancer cases worldwide. Standard-of-care chemotherapy, radiotherapy, and immune checkpoint inhibitors (ICIs) are associated with adverse effects and limited responses in patients with HPV-driven cancers. The integration of targeted therapies with ICIs may improve outcomes. In a previous study, we demonstrated that Aurora kinase A (AURKA, Aurora A) inhibitors lead to apoptosis of human HPV-positive cancer cells in vitro and in vivo. Here, we explored the potential of Aurora A inhibition to enhance response to ICIs in immune-competent …

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 …

Mechanisms Underlying Dilated Cardiomyopathy Associated With Fkbp12 Deficiency, Amy D Hanna, Ting Chang, Kevin S Ho, Rachel Sue Zhen Yee, William Cameron Walker, Nadia Agha, Chih-Wei Hsu, Sung Yun Jung, Mary E Dickinson, Md Abul Hassan Samee, Christopher S Ward, Chang Seok Lee, George G Rodney, Susan L Hamilton

Faculty, Staff and Students Publications

Dilated cardiomyopathy (DCM) is a highly prevalent and genetically heterogeneous condition that results in decreased contractility and impaired cardiac function. The FK506-binding protein FKBP12 has been implicated in regulating the ryanodine receptor in skeletal muscle, but its role in cardiac muscle remains unclear. To define the effect of FKBP12 in cardiac function, we generated conditional mouse models of FKBP12 deficiency. We used Cre recombinase driven by either the α-myosin heavy chain, (αMHC) or muscle creatine kinase (MCK) promoter, which are expressed at embryonic day 9 (E9) and E13, respectively. Both conditional models showed an almost total loss of FKBP12 in …

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 …

Atrx Silences Cartpt Expression In Osteoblastic Cells During Skeletal Development, Yi-Ting Chen, Ming-Ming Jiang, Carolina Leynes, Mary Adeyeye, Camilla F Majano, Barakat Ibrahim, Urszula Polak, George Hung, Zixue Jin, Denise G Lanza, Lan Liao, Brian Dawson, Yuqing Chen-Evenson, Oscar E Ruiz, Richard J Gibbons, Jason D Heaney, Yangjin Bae, Brendan Lee

Faculty, Staff and Students Publications

ATP-dependent chromatin remodeling protein ATRX is an essential regulator involved in maintenance of DNA structure and chromatin state and regulation of gene expression during development. ATRX was originally identified as the monogenic cause of X-linked α-thalassemia mental retardation (ATR-X) syndrome. Affected individuals display a variety of developmental abnormalities and skeletal deformities. Studies from others investigated the role of ATRX in skeletal development by tissue-specific Atrx knockout. However, the impact of ATRX during early skeletal development has not been examined. Using preosteoblast-specific Atrx conditional knockout mice, we observed increased trabecular bone mass and decreased osteoclast number in bone. In vitro coculture …

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 …

Interferon-Gamma Receptor Signaling Regulates Innate Immunity During Staphylococcus Aureus Craniotomy Infection, Zachary Van Roy, Gunjan Kak, Rachel W. Fallet, Tammy Kielian

Journal Articles: Pathology and Microbiology

A craniotomy is a neurosurgical procedure performed to access the intracranial space. In 3-5% of cases, infections can develop, most caused by Staphylococcus aureus biofilm formation on the skull surface. Medical management of this infection is difficult, as biofilm properties confer immune and antimicrobial recalcitrance to the infection and necessitate additional surgical procedures. Furthermore, treatment failure rates can be appreciably high. These factors, compounded with rapidly expanding rates of antimicrobial resistance, highlight the need to develop alternative treatment strategies to target and reverse the immune dysfunction that occurs during biofilm infection. Our recent work has identified CD4+ Th1 and Th17 …

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 …

Extracellular Adherence Proteins Reduce Matrix Porosity And Enhance Staphylococcus Aureus Biofilm Survival During Prosthetic Joint Infection, Mohini Bhattacharya, Tyler D. Scherr, Jessica Lister, Tammy Kielian, Alexander R. Horswill

Journal Articles: Pathology and Microbiology

Biofilms are a cause of chronic, non-healing infections. Staphylococcus aureus is a proficient biofilm-forming pathogen commonly isolated from prosthetic joint infections that develop following primary arthroplasty. Extracellular adherence protein (Eap), previously characterized in planktonic or non-biofilm populations as being an adhesin and immune evasion factor, was recently identified in the exoproteome of S. aureus biofilms. This work demonstrates that Eap and its two functionally orphaned homologs EapH1 and EapH2 contribute to biofilm structure and prevent macrophage invasion and phagocytosis in these communities. Biofilms unable to express Eap proteins demonstrated increased porosity and reduced biomass. We describe the role of Eap …

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 …

Cooperative Role Of Distinctive Tp53 And Pten Combined Loss In The Peripheral T Cell Lymphoma-Gata3 Molecular Subgroup, Waseem G. Lone, Jiayu Yu, Xuxiang Liu, Dylan T. Jochum, Alyssa Bouska, Kunal Shetty, Tyler Herek, Sunandini Sharma, Chengfeng Bi, Rauf Shah, Zaina W. Nasser, Catalina Amador, Aiza Arif, Abdul Rouf Mir, Yuping Li, Tayla B. Heavican-Foral, Jacob Robinson, R. Katherine Hyde, Mamiko Sakata-Yanagimoto, Satyanarayana Rachagani, Timothy W. Mckeithan, David W. Scott, Louis M. Staudt, Giorgio Inghirami, Andrew Feldman, Timothy Greiner, Julie M. Vose, Lisa Rimsza, Joseph Khoury, Wing C. Chan, Javeed Iqbal, Lymphoma/Leukemia Molecular Profiling Project (Llmpp)

Journal Articles: Oncology and Hematology

Peripheral T cell lymphoma (PTCL) is a heterogeneous group of postthymic T cell neoplasms, with ~40% classified as PTCL-not otherwise specified (PTCL-NOS). PTCL-GATA3, a molecularly defined subtype, associated with T helper 2 (T_H2)-like differentiation and poor prognosis, has frequent co-occurrence of TP53 loss/mutation and heterozygous PTEN loss. CD4+ T cell conditional mouse models with Trp53 mutation/deletion and Pten loss demonstrated mature T cell lymphomas (mTCLs) with T_H2-like transcriptomic and immunophenotypic profiles. Molecular studies revealed that codeletion of Trp53/Pten induced T cell receptor and Janus kinase-signal transducer and activator of transcription signaling, promoting T_H2 differentiation …

Identification Of Potential Prophylactic Medical Countermeasures Against Acute Radiation Syndrome (Ars), Kia T. Liermann-Wooldrik, Arpita Chatterjee, Elizabeth A. Kosmacek, Molly Myers, Oluwaseun Adebisi, Louise Monga-Wells, Liu Mei, Michelle P. Takacs, Patrick H. Dussault, Daniel R. Draney, Robert Powers, James W. Checco, Chittibabu Guda, Tomáš Helikar, David B. Berkowitz, Kenneth W. Bayles, Alan H. Epstein, Lynnette Cary, Daryl J. Murry, Rebecca E. Oberley-Deegan

Journal Articles: Pathology and Microbiology

Acute radiation syndrome (ARS) occurs when hematopoietic or gastrointestinal cells are damaged by radiation exposure causing DNA damage to the bone marrow and gastrointestinal epithelial stem cell populations. In these highly proliferative cell types, DNA damage inhibits stem cell repopulation. In humans and animals, this inability to regenerate stem cells is lethal. Within this manuscript, several compounds, Amifostine, Captopril, Ciprofloxacin, PrC-210, 5-AED (5-androstene-3β,17β-diol), and 5-AET (5-androstene-3β,7β,17B-triol), are assessed for their ability to protect against ARS in an in vitro and/or in vivo setting. ARS was accomplished by irradiating mouse bone marrow cells or rat intestinal epithelial (IEC-6) cells in vitro …

Novel Insights Into Beta Cell Er Stress Chop And It's Role In Hfpef Development, Balaji Srinivas, Paula Fortuno, Hongmei Peng, Jiang Xu, Hamid Suhail, Hani N. Sabbah, Nour-Eddine Rhaleb, Khalid Matrougui

Department of Physiological Sciences Faculty Publications

Introduction: Heart failure with preserved ejection fraction (HFpEF) is a multifactorial cardiovascular disorder characterized by diastolic dysfunction and often associated with hypertension and metabolic disturbances. We aimed to determine the inter-relationship between C/EBP homologous protein (CHOP) in b-cells and HFpEF development.

Methods: Eight-week-old male mice b-cell^flox/flox and b-cell^CHOP-/- were randomly divided into four groups: control b-cell^flox/flox and b-cell^CHOP-/- mice subjected to standard diet and water. b -cell^flox/flox and b-cell^CHOP-/- mice fed a high-fat diet (HFD) and L-NAME (0.5 g/L) for five weeks. A comprehensive cardiovascular, metabolic, and histological evaluation was conducted.

Results: Following …

Depletion Of Adipose Stroma-Like Cancer-Associated Fibroblasts Potentiates Pancreatic Cancer Immunotherapy, Joseph Rupert, Alexes Daquinag, Yongmei Yu, Yulin Dai, Zhongming Zhao, Mikhail G Kolonin

Faculty, Staff and Student Publications

This study shows that populations of CAFs have distinct effects on pancreatic cancer progression and shows that depletion of CAFs expressing adipose markers potentiates tumor/metastasis suppression effects of immune checkpoint blockade.

Tagraxofusp Maintenance Post-Hematopoietic Stem Cell Transplantation Provides Long-Term Survival And Manageable Safety For A Patient With Blastic Plasmacytoid Dendritic Cell Neoplasm, Qaiser Bashir, Marina Konopleva, Glorette Abueg, Jeremy Ramdial, Chitra Hosing, Samer A Srour, Amin Alousi, Uday R Popat, Yago Nieto, Gheath Alatrash, Richard E Champlin, Elizabeth J Shpall, Muzaffar Qazilbash, Naveen Pemmaraju

Faculty, Staff and Student Publications

Presented here is the case of a 68-year-old woman with blastic plasmacytoid dendritic cell neoplasm (BPDCN) treated with tagraxofusp (TAG) maintenance therapy post-allogeneic hematopoietic stem cell transplantation (allo-HCT). Prior to allo-HCT, the patient was treated with hydroxyurea and mini-CVD (cyclophosphamide, vincristine, and dexamethasone alternating with methotrexate (Methotrexate) and cytarabine) + venetoclax + TAG for 5 cycles, which induced morphologic complete remission with minimal residual disease. After allo-HCT, the patient had persistent cytogenic abnormalities 45,XX,der(7)add(7)(p13)del(7)(q11.2q22)add(7)(q32),add(12)(p13),-15,del(16)(q23),-17,+22,+2mar[1]/46,XX[19], and was then treated with TAG maintenance therapy at 9 mg/kg on a 28-day cycle for 16 cycles. At mid-treatment (cycle 6 of 16 cycles of …

A Natural Small Molecule Isoginkgetin Alleviates Hypercholesterolemia And Atherosclerosis By Targeting Acly, Zhidan Zhang, Meijie Chen, Yitong Xu, Zhihua Wang, Zhenghong Liu, Chenyang He, Fanshun Zhang, Xiaojun Feng, Xiayun Ni, Yuanli Chen, Jixia Wang, Xinmiao Liang, Zhifu Xie, Jingya Li, Maciej Banach, Jaroslav Pelisek, Yuqing Huo, Yunhui Hu, Paul C Evans, Li Wang, Xiao-Yu Tian, Jianbo Xiao, Yuhua Shang, Yijun Zheng, Xunde Xian, Jianping Weng, Suowen Xu

Faculty, Staff and Students Publications

Rationale: Atherosclerotic cardiovascular disease (ASCVD) represents the predominant cause of mortality and morbidity globally. Given the established role of hypercholesterolemia as a significant risk factor for ASCVD, the discovery of new lipid-lowering medications is of paramount importance. ATP citrate lyase (ACLY) is a crucial enzyme in cellular metabolism, providing acetyl-CoA as the building block for the biosynthesis of fatty acids and cholesterol. Consequently, it has emerged as a promising drug target for innovative treatments of lipid metabolic disorders.

Methods: Virtual screening of a natural product library was performed to identify small-molecule ACLY inhibitors, leading to the discovery of isoginkgetin (ISOGK). …

Efficacy Of Nampt Inhibition In T-Cell Acute Lymphoblastic Leukemia, Chelsea Vrana, Matthew Zhang, Max Rochette, Michelle Alozie, Hailey Oviedo, Alan Gonzalez, Jaden Sherman, Barry Zorman, Pavel Sumazin, Karen R Rabin, Jacob J Junco

Faculty, Staff and Students Publications

Novel agents targeting upregulated signaling pathways are needed to improve outcomes in T-cell acute lymphoblastic leukemia (T-ALL), since conventional cytotoxic chemotherapy regimens have reached the limits of tolerability. We identified upregulated, targetable signaling pathways common to both human T-ALL samples and a KrasLSL-G12D/+.Mb1Cre/+ murine model of T-ALL. We found the NAMPT inhibitor FK866 had the greatest cytotoxicity of a panel of small molecule inhibitors tested in human and mouse T-ALL cell lines, and in patient derived xenograft (PDX)-expanded T-ALL patient samples. We subsequently tested FK866 in vivo in PDX mouse models of T-ALL, and found that it significantly reduced the …

Assessing The Cardioprotective Effects Of Exercise In Apoe Mouse Models Using Deep Learning And Photon-Counting Micro-Ct, Alex J Allphin, Rohan Nadkarni, Zay Y Han, Darin P Clark, Ketan B Ghaghada, Alexandra Badea, Cristian T Badea

Faculty, Staff and Students Publications

Background: The allelic variations of the apolipoprotein E (APOE) gene play a critical role in regulating lipid metabolism and significantly impact cardiovascular disease risk (CVD). This study aimed to evaluate the impact of exercise on cardiac structure and function in mouse models expressing different APOE genotypes using photon-counting computed tomography (PCCT) and deep learning-based segmentation.

Methods: A total of 140 mice were grouped based on APOE genotype (APOE2, APOE3, APOE4), sex, and exercise regimen. All mice were maintained on a controlled diet to isolate the effects of exercise. Low dose cardiac photon counting micro-CT imaging with intrinsic gating was performed …

Exercise Mitigates High-Fat Diet-Induced Cardiac Dysfunction Via Apoe Genotype- And Immune-Dependent Mechanisms: A Photon-Counting Ct Study In Adult Mice, Rohan Nadkarni, Alex J Allphin, Darin P Clark, Yi Qi, Zay Yar Han, Ketan B Ghaghada, Alexandra Badea, Cristian T Badea

Faculty, Staff and Students Publications

Background: Cardiovascular dysfunction frequently accompanies aging and is often worsened by adverse lifestyle factors and genetic susceptibility. The apolipoprotein E (APOE) gene modulates susceptibility to cardiovascular disease, but how exercise and diet interact with APOE genotype remains insufficiently understood. We investigate the cardioprotective potential of exercise in humanized APOE-targeted replacement mice on control and high-fat diet, using photon-counting computed tomography (PCCT) and deep learning-based image segmentation.

Methods: This study included 251 male and female mice in mid-to-late life of APOE2, APOE3, and APOE4 genotypes with variation in humanized NOS2 (HN) mediated innate immune response, exercise status (exercised vs. sedentary) and …

Microbiota Dynamics During Ascaris Suum Larval Migration: Implications For Host Microbial Communities In A Murine Model, Sergio Castañeda, Cristina Poveda, Charlie Suarez-Reyes, Yifan Wu, Noah Haugen, Luz H Patiño, Jill E Weatherhead, Juan David Ramírez

Faculty, Staff and Students Publications

The complex interactions between parasites, their hosts, and associated microbiota hold significant implications for host health and disease outcomes. Helminths like Ascaris lumbricoides and Ascaris suum can significantly alter the host's intestinal microbiota, affecting both parasite biology and host pathology. Despite extensive research on host-microbiota changes due to helminth infections, the study of helminth-associated microbiota remains limited. This study aims to characterize the microbiota associated with Ascaris larvae and surrounding host tissues at distinct developmental stages (day 4, day 8, day 14), during larval migration through the liver, lungs, and intestine, and its impact on the host's microbiota in a …