Digital Commons Network^™

Hif-2-Dependent Regulation Of Pthrp And Paraneoplastic Hypercalcemia In Aggressive Clear-Cell Renal Cell Carcinoma, Arijit Mal, Bingqing Xie, Zane Gray, Charlotte Small, Susmita G Ramanand, Yunpeng Gao, Vanina Toffessi Tcheuyap, Sashi Debnath, Alana Christie, Jeffrey Miyata, Brooklyn Jackson, Hua Zhong, Boning Gao, Jay Lohrey, Naim M Maalouf, Sangeetha M Reddy, John D Minna, Ivan Pedrosa, Xiankai Sun, Ram S Mani, Payal Kapur, James Brugarolas

Faculty, Staff and Student Publications

Renal cell carcinoma (RCC) patients with hypercalcemia (HC) have worse outcomes. HC often involves PTHrP, and the role of HIF-2 is incompletely understood. Leveraging RCC tumorgraft (TG) models of HC, which were characterized by tumor cell autonomous inflamatory/immune signatures, we show that HIF-2 inhibition with PT2399 frequently normalized calcium, downregulated circulating PTHrP and reduced HIF-2 binding to the PTHLH (PTHrP) promoter. Likely contributing to the selective induction of PTHrP in a subset of HIF-2-dependent tumors, the PTHLH locus was generally more accessible in TG(HC). However, PTHLH chromatin accessibility was grossly unaffected by PT2399, unlike elsewhere (including EPO locus in a …

Improved Accuracy For Myocardial Blood Flow Mapping With Deep Learning-Enabled Cmr Arterial Spin Labeling (Deepmasl): Validation By Microsphere In Vivo, Ran Li, Caleb Berberet, Qi Huang, Pamela K Woodard, Jie Zheng

2020-Current year OA Pubs

BACKGROUND: Current myocardial arterial spin labeling (ASL) methods are sensitive to noise (background and physiology), which limits the accuracy of myocardial blood flow (MBF) measurement. In this study, we demonstrated a new deep learning-enabled myocardial ASL approach (DeepMASL) and evaluated its accuracy to quantify MBF in a canine model of coronary arterial disease in vivo. The reference method was invasive microsphere measurements.

METHODS: Eighteen mongrel dogs were divided into two groups: healthy (n = 9) and coronary stenosis (n = 9). The latter was induced in an open-chest model with 3 types of stenosis: 50% (n= 3), 70% (n = …

Adverse Experiences, Protective Factors, And Obesity In Latinx And Hispanic Youths, Victoria Goldman, Sevan Esaian, Miguel Ángel Rivas Fernández, Jonatan Ottino Gonzalez, Nicole Karcher, Jeffrey I Gold, Alaina P Vidmar, Shana Adise

2020-Current year OA Pubs

IMPORTANCE: Pediatric obesity rates are rising, and adverse childhood experiences (ACEs) may contribute by promoting stress-induced weight gain. Few studies have examined the association of ACEs with body mass index (BMI) and youth-reported protective factors, particularly among Latinx and Hispanic youths, who face higher rates of ACEs and obesity.

OBJECTIVE: To evaluate the association of ACEs with BMI in a population-based cohort and determine whether youth-reported protective factors (eg, self-coping skills, caregiver or friend support, or overall support) moderate this association, with a focus on Latinx and Hispanic youths.

DESIGN, SETTING, AND PARTICIPANTS: This large, cross-sectional study of youths aged …

Obesity Promotes Conserved Inflammatory And Metabolic Transcriptional Programs In Colon Tumors: Evidence From Mouse Models And The Colocare Study Patient Cohort, Elaine M Glenny, Adetunji T Toriola, Et Al.

2020-Current year OA Pubs

BACKGROUND: The global prevalence of obesity, an established risk and progression factor for colon cancer, is high and rising. Unfortunately, the mechanisms underlying the obesity-colon cancer association are incompletely understood, and new molecular targets enabling more effective intervention strategies to break the obesity-colon cancer link are urgently needed.

OBJECTIVES: This study integrated RNA sequencing data from mouse and human colon tumor samples, as well as human adipose samples, to rigorously establish obesity-associated transcriptomic signatures conserved between the 2 species.

METHODS: We employed a mouse colon cancer model with colonoscopy-guided orthotopic transplantation of syngeneic Apc

RESULTS: Diet-induced obesity reduced survival in …

Lymphoid Gene Expression Supports Neuroprotective Microglia Function, Pinar Ayata, Maud Gratuze, Jason D Ulrich, David M Holtzman, Et Al.

2020-Current year OA Pubs

Microglia, the innate immune cells of the brain, play a defining role in the progression of Alzheimer's disease (AD)

Semi-Annual And Annual Mass Drug Administration Of Diethylcarbamazine And Albendazole Are Equally Effective Regimens For Eliminating Lymphatic Filariasis In Papua New Guinea, Michael C. Payne, Nelly Sanuku, Brooke E. Mancuso, Yao-Chieh Cheng, Gary J. Weil, Peter U. Fischer, Moses Laman, Leanne J. Robinson, Daniel J. Tisch, Christopher L King

2020-Current year OA Pubs

Annual mass drug administration (MDA) is currently recommended for the local elimination of lymphatic filariasis (LF). Modeling studies of LF transmission suggest that conducting MDA twice a year could accelerate LF elimination. To test this idea, we compared the effects of 3 rounds of yearly MDA and 5 rounds of semiannual MDA using diethylcarbamazine with albendazole on LF infection measures in Papua New Guinea (PNG) across 2 treatment areas with high LF prevalence. From 2013 to 2018, we conducted 4 annual community surveys at 4 sentinel sites in each treatment area. We sampled 2,854 people at the start and 2,746, …

Ddt Exposure Induces Microglial Activation And Disease-Associated Microglial Signatures: Relevance To Mechanisms Of Alzheimer’S Disease, Isha Mhatre-Winters, Aseel Eid, Nicole Blum, Yoonhee Han, Ferass M Sammoura, Long-Jun Wu, Jason R Richardson

The Brown Foundation: Institute of Molecular Medicine

Background: Alzheimer's disease (AD) is characterized by the presence of amyloid-β plaques, neurofibrillary tangles, and neuroinflammation. Previously, we reported that serum levels of dichlorodiphenyldichloroethylene (DDE), the primary metabolite of the pesticide dichlorodiphenyltrichloroethane (DDT), were significantly higher in AD patients compared to age-matched controls and that DDT exposure worsened AD pathology in animal models.

Objective: Here, we investigated the effect of DDT on neuroinflammation in primary mouse microglia (PMG) and C57BL/6J mice.

Methods: DDT-induced inflammatory and disease-associated microglial (DAM) gene expression were determined in PMG by qPCR and immunocytochemistry, with and without pretreatment with the sodium channel antagonist tetrodotoxin (TTX). Furthermore, …

Revisiting Soluble Guanylate Cyclase Pharmacology: Additive Potential Of Stimulators And Activators, Alexandra Petraina, Mahmoud H Elbatreek, Christopher T Neullens, Theodora Saridaki, Vu Thao-Vi Dao, Rebecca D Szepanowski, Emil Martin, Wolfgang Sippl, Ana I Casas, Harald H H W Schmidt

Faculty, Staff and Student Publications

Nitric oxide (NO) is a key gasotransmitter that binds to soluble guanylate cyclase (sGC), thereby stimulating cGMP production. Under disease conditions, reactive oxygen species disrupt this signaling by either: (1) scavenging NO, or (2) promoting heme-free, NO-insensitive apo-sGC due to impaired heme incorporation or oxidative damage. To counteract these conditions, two pharmacological approaches have emerged: sGC stimulators, which allosterically enhance sGC sensitivity to low NO levels; and sGC activators, which directly activate apo-sGC (heme-free sGC) by binding to its empty heme pocket, inducing a conformation that mimics NO-bound sGC. Thus, sGC stimulators are thought to target only sGC. Instead, we …

Allogeneic Bone Marrow-Derived Mesenchymal Stem Cells For Parkinson's Disease: A Randomized Trial., Mya C Schiess, Jessika Suescun, Juan D Martinez-Lemus, Charles Green, Tia S Thomas, Mohammad Shahnawaz, Emily Tharp, Nikunj B Satani, Jerome G Saltarrelli, Christopher Adams, Marie-Francoise Doursout, Vanessa Thyne, Rula Abuamouneh, Elsa M Rodarte, Sean I Savitz, Timothy M Ellmore

Faculty, Staff and Student Publications

Background: Neuroinflammation contributes to Parkinson's disease (PD) progression and motor dysfunction. Allogeneic human mesenchymal stem cells (allo-hMSCs) may reduce neuroinflammation and improve motor symptoms.

Objectives: To evaluate the efficacy of repeated intravenous doses of 10 × 106/kg allo-hMSCs in improving motor symptoms in patients with PD (PwP).

Methods: In this phase 2, randomized, placebo-controlled trial (November 2020-July 2023), mild-to-moderate PwP received either three allo-hMSC infusions, one placebo followed by two allo-hMSC infusions, or three placebo infusions at 18-week intervals. Follow-up lasted 88 weeks. The primary outcome was a >70% posterior probability (PP) of a difference in the proportion of participants …

Perceived Utility Of Genetic Carrier Screening In A Diverse Patient Population, Jack A Colleran, Meagan Choates, Syed Hashmi, Brittanie Shelton, Aranza Gonzalez Cendejas, Angela Haynes Burgess, Blair K Stevens

Faculty, Staff and Student Publications

Current reproductive guidelines call for offering expanded carrier screening (ECS) for genetic conditions. Currently available panels can include screening for carrier status of tens to hundreds of autosomal recessive and/or X-linked conditions. Clinical utility is based on alterations to reproductive decision-making, but study cohorts supporting the utility of ECS largely consist of individuals of European ancestry who are highly educated, of high income, and who often receive preconception counseling. There is a lack of research on the views of patients from diverse backgrounds. Therefore, we aimed to assess and compare perceptions of the utility of ECS and targeted carrier screening …

Evidence For Improved Dna Repair In The Long-Lived Bowhead Whale, Denis Firsanov, Max Zacher, Xiao Tian, Todd L Sformo, Yang Zhao, Gregory Tombline, J Yuyang Lu, Zhizhong Zheng, Luigi Perelli, Enrico Gurreri, Li Zhang, Jing Guo, Anatoly Korotkov, Valentin Volobaev, Seyed Ali Biashad, Zhihui Zhang, Johanna Heid, Alexander Y Maslov, Shixiang Sun, Zhuoer Wu, Jonathan Gigas, Eric C Hillpot, John C Martinez, Minseon Lee, Alyssa Williams, Abbey Gilman, Nicholas Hamilton, Ekaterina Strelkova, Ena Haseljic, Avnee Patel, Maggie E Straight, Nalani Miller, Julia Ablaeva, Lok Ming Tam, Chloé Couderc, Michael R Hoopmann, Robert L Moritz, Shingo Fujii, Amandine Pelletier, Dan J Hayman, Hongrui Liu, Yuxuan Cai, Anthony K L Leung, Zhengdong Zhang, C Bradley Nelson, Lisa M Abegglen, Joshua D Schiffman, Vadim N Gladyshev, Carlo C Maley, Mauro Modesti, Giannicola Genovese, Mirre J P Simons, Jan Vijg, Andrei Seluanov, Vera Gorbunova

Faculty, Staff and Student Publications

At more than 200 years, the maximum lifespan of the bowhead whale exceeds that of all other mammals. The bowhead is also the second-largest animal on Earth1, reaching over 80,000 kg. Despite its very large number of cells and long lifespan, the bowhead is not highly cancer-prone, an incongruity termed Peto’s paradox2. Here, to understand the mechanisms that underlie the cancer resistance of the bowhead whale, we examined the number of oncogenic hits required for malignant transformation of whale primary fibroblasts. Unexpectedly, bowhead whale fibroblasts required fewer oncogenic hits to undergo malignant transformation than human fibroblasts. …

Whipple Disease Initial Presentation As Supraclavicular Lymphadenopathy In A Patient With Rheumatoid Arthritis: A Diagnostic Challenge, Sara E Amin, Swati Gite, Audrey Wanger, Violeta Chavez, Jacob Armstrong, Beenu Thakral, Patricia Navarro, Jennifer Makhoul, Amer Wahed, Navneet Narula, Karan Saluja

Faculty, Staff and Student Publications

Whipple disease is a rare systemic disease caused by Tropheryma whipplei. It can present with a wide range of nonspecific symptoms that might overlap with underlying medical conditions, posing a diagnostic challenge. We present a 61-year-old man with a past medical history of rheumatoid arthritis and chronic inflammatory demyelinating polyneuropathy, who presented with persistent leukocytosis and supraclavicular lymphadenopathy. A positron emission tomography scan revealed hypermetabolic activity in the supraclavicular, abdominal, and pelvic lymph nodes along with a myocardial hypermetabolic lesion, concerning a lymphoproliferative disorder versus sarcoidosis. A supraclavicular lymph node excisional biopsy revealed complete architectural effacement by a diffuse foamy …

Evaluation Of Renal Masses With Cest Mri: Protocol Optimization And Preliminary Results, Xiaojing Wang, Jochen Keupp, Ivan E Dimitrov, Ananth Madhuranthakam, Durga Udayakumar, Mahsa Taherzadeh, Emin Albayrak, Orson W Moe, Payal Kapur, Robert E Lenkinski, Ivan Pedrosa, Elena Vinogradov

Faculty, Staff and Student Publications

Purpose: This study investigates the application of CEST MRI in human kidneys, with the overarching goal of developing CEST MRI for renal mass characterization. Here, the focus is on the development of a protocol and the proof-of-principle evaluation of CEST for the characterization of clear cell renal cell carcinoma (ccRCC).

Methods: Ten healthy volunteers and five patients diagnosed with ccRCC underwent CEST MRI scans at 3 T. The sequence performance was characterized in healthy volunteers and tested using three saturation power levels, B1rms = 0.7, 1.2, and 1.6 μT. We compared the magnetization transfer ratio asymmetry (MTRasym) values at 1.0, …

Extracellular Domain Shedding Of Trop2 Activates Egfr Signaling To Drive Prostate Cancer Metastasis, Shiqin Liu, En-Chi Hsu, Merve Aslan, Fernando Garcia-Marques, Michelle Shen, Alifiani B Hartono, Francisco Solano, Kewei Le, Hyeonji Hwang, Chung S Lee, Abel Bermudez, Rosalie Nolley, Donna M Peehl, James D Brooks, Michael A Liss, Sharon J Pitteri, Tanya Stoyanova

Faculty, Staff and Student Publications

UNLABELLED: Metastasis is the main cause of prostate cancer-associated deaths, highlighting the urgent need to determine the mechanisms underlying prostate cancer progression. TROP2 (also known as tumor-associated calcium signal transducer 2) is an oncogenic transmembrane surface protein that is highly expressed in metastatic prostate cancer. Naturally occurring cleavage of TROP2 leads to a release of the TROP2 extracellular domain (TECD) into the extracellular environment. In this study, we identified an important functional role of TECD in prostate cancer metastasis. TECD was detectable in media from prostate cancer cells and serum from patients with clinically significant prostate cancer. Although shed TECD …

Differential Effects Of Murine Stroke Models On Dopaminergic Neurons, Glial Responses, And Neurobehavioral Outcomes, Sidra Tabassum, Heng Hu, Silin Wu, Shuning Huang, Bosco Seong Kyu Yang, Chang-Hun Lee, Aaron W Gusdon, Xuefang S Ren

Faculty, Staff and Student Publications

Stroke is a leading cause of disability worldwide, often resulting in persistent motor, cognitive, and emotional impairments. While the hippocampus and amygdala play critical roles in post-stroke behavioral changes, specific neuronal alterations and prolonged glial responses within these regions across different stroke types remain unclear. This study investigates the behavioral, neuronal, and glial effects of subarachnoid hemorrhage (SAH), transient middle cerebral artery occlusion (tMCAO), and photothrombotic stimulation (PTS) in mice. SAH and tMCAO models exhibited significant motor deficits, spatial and recognition memory impairments, and increased anxiety- and depressive-like behaviors, whereas the PTS model showed similar motor and cognitive impairments but …

Inhibiting Monocyte Migration Reduces Arterial Thrombosis And Facilitates Thrombolysis, Hee Jeong Jang, Jiwon Kim, Ha Kim, Taesu Kim, Jinyong Chung, Sebastian Cremer, Marvin Krohn-Grimberghe, Eo Jin Kim, Dawid Schellingerhout, Matthias Nahrendorf, Dong-Eog Kim

Faculty, Staff and Student Publications

Background: Monocytes contribute to the initiation and propagation of venous thrombosis. Little is known about the roles monocytes play in arterial thrombosis, the cause of stroke and myocardial infarction.

Methods: We investigated how CCR2 (CC chemokine receptor 2) knockout (-/-)-mediated monocyte deficiency affects platelet function, blood coagulation, thrombus volume, and thrombolytic susceptibility in 666 male mice with FeCl3-mediated carotid arterial thrombosis, including 365 C57BL/6 wild type (WT) mice, 295 CCR2-/- mice, and 6 CX3CR1-GFP (CX3C chemokine receptor 1-green fluorescent protein) mice.

Results: Intravital microscopy and flow cytometry showed that both neutrophils and monocytes were recruited to the acute arterial thrombus, …

Profiling The Preclinical Pharmacokinetics And Biodistribution Of A Platinum(Iv)-Based Oxaliplatin Prodrug Oxalitex And Their Significance To Antitumor Response, Guangan He, Gregory D Thiabaud, Kathryn A Shelton, Luke J Segura, Jonathan F Arambula, Jonathan L Sessler, Rick A Finch, Zahid H Siddik

Faculty, Staff and Student Publications

OxaliTEX (NOVO-111) is a novel gadolinium(III) texaphyrin-platinum(IV) complex that is under development for clinical trials. It was designed as a prodrug of oxaliplatin (1,2-diaminocyclohexane-platinum(II) oxalate) tethered to a tumor-affinic texaphyrin moiety to improve drug delivery to the tumor. However, oxaliTEX was not only more effective as an antitumor agent but also better tolerated in mice. To appreciate this higher therapeutic index and advance its preclinical development, studies were undertaken to profile its plasma pharmacokinetics, distribution to tumor and normal tissues, and pharmacodynamics of the p53/p21 molecular pathway. Nude mice, with or without a subcutaneous colorectal HCT-116 xenograft harboring a phenotypically …

Decoding Fibrosis In Nonresolvable Covid-19: A Role For Myeloid-Specific Hif1a Deletion, Kemly Philip, Hannah P Thompson, Scott D Collum, Isabella Lefebvre, Bindu Akkanti, Bihong Zhao, Rahat Hussain, Manish Patel, Michael R Blackburn, Tingting W Mills, Harry Karmouty-Quintana

Faculty, Staff and Student Publications

A complication of viral lung infections is the development of pulmonary fibrosis. This phenomenon is most evident in patients with COVID-19, where in its most aggressive form patients developed nonresolvable (NR) COVID-19 requiring lung transplantation. NR-COVID-19 was characterized by the presentation of a fulminant fibrotic lung injury that progressed rapidly, even in patients with limited comorbidities. However, the mechanisms that led to this rapidly progressing form of fibrosis are not fully understood. A common clinical manifestation in the most severe cases of COVID-19 was the presence of "silent" hypoxemia. Thus, we hypothesized that a dysfunctional hypoxic response may result in …

Secretory Iga Dysfunction Underlies Poor Prognosis In Fusobacterium-Infected Colorectal Cancer, Ilseok Choi, Kyung-A Kim, Sang Cheol Kim, Donghwan Park, Ki Taek Nam, Jun Hyung Cha, Seungbyn Baek, Junha Cha, Hye-Yeong Jo, Minsun Jung, Melody Y Zeng, Irina Matei, Susan Bullman, Joong Bae Ahn, Yoon Dae Han, Han Sang Kim, Insuk Lee

Faculty, Staff and Student Publications

Fusobacterium nucleatum (Fn) is commonly enriched in colorectal cancer (CRC) and associated with poor outcomes, though its mechanisms remain unclear. Our study investigated how Fn affects the tumor microenvironment through single-cell transcriptomic analyses of 42 CRC patient tissues, comparing Fn-positive and Fn-negative tumors. We discovered that Fn impairs IgA plasma cell development and secretory IgA (sIgA) production by disrupting communication with tumor-associated macrophages. Additional experiments in germ-free mice, together with our re-analysis of a publicly available single-cell RNA-seq data set from a CRC mouse model with an intact gut microbiome–both models having been orally gavaged with Fn–jointly validated the causal …

Impact Of Peripheral Circadian Misalignment And Alcohol On The Resiliency Of Intestinal Barrier And Microbiota, Laura Tran, Maliha Shaikh, Phillip A Engen, Ankur Naqib, Dulce M Frausto, Vivian Ramirez, Malia Gasteier, Zlata Bogin, Kristi Lawrence, Lijuan Zhang, Shiwen Song, Stefan J Green, Faraz Bishehsari, Christopher B Forsyth, Ali Keshavarzian, Garth R Swanson

Faculty, Staff and Student Publications

Circadian organization is involved in many gastrointestinal tract (GIT) functions such as the maintenance of intestinal barrier integrity. There is compelling evidence that perturbation of the circadian clock decreases intestinal epithelial cells' resiliency to alcohol-induced injury. One of the most common causes of circadian misalignment is wrong-time eating (largest meal at dinner) in modern societies. Yet, few studies have examined the importance of peripheral circadian rhythms of the GIT to alcohol consumption. Eating patterns during physiologic rest time, defined as wrong-time eating (WTE), misalign the peripheral circadian clock of the GIT and the body's central clock. This study aims to …

Decorin Deficiency Promotes D-Galactose-Induced Skeletal Muscle Atrophy And Fibrosis By Regulating Itgb1/Akt/Mtor Signalling Pathway, Xiaoqin Luo, Mengxue Zhang, Lili Chen, Ruichang Wang, Jiabing Lian, Zhe Yang, Renato V. Iozzo, Jin Wang, Yan Zhang, Xiuli Bi

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

BACKGROUND: Primary sarcopenia is an age-associated disorder with progressive and generalised loss of skeletal muscle strength and mass. Skeletal muscle fibrosis is one of the significant pathological manifestations of age-associated sarcopenia. Decorin, a small dermatan-sulfate proteoglycan, participates in extracellular matrix assembly. In numerous studies, the involvement of decorin is not restricted to matrix structural proteins, and it also affects a diverse variety of biological functions like cell growth, adhesion, migration, proliferation and differentiation. Additionally, it modulates the process of inflammation and fibrillogenesis. Based on these preclinical evidences, we hypothesised that decorin may potentially play an important role in skeletal muscles …

Abca4-Mutant Human Retinal Organoids Sequencing Reveals Organoids Application In Inherited Retinal Diseases, Yourong Bao, Sujung Soh, Jean Li, Zhen Zuo, Salma Ferdous, Xinye Qian, Jin Li, Jiaxiong Lu, Xuesen Cheng, Anna Matynia, Yumei Li, Rui Chen

Faculty, Staff and Students Publications

In the studies of Inherited Retinal Diseases (IRDs), the knockout of traditional animal models like mice often fails to accurately replicate human phenotypes due to genetic and anatomical differences. Human retinal organoids (ROs) derived from stem cells have emerged as promising developmental models in retinal studies to delineate cell growth, but their ability to represent the characteristics of late-onset IRDs remains unclear. This study aims to validate ROs as a disease model for Stargardt's Disease (STGD) caused by ABCA4 mutations. Using single-cell RNA sequencing, ROs from 2 STGD patients were compared with healthy control-derived ROs at two developmental stages on …

Exploration Of Zileuton Protective Mechanisms Against Vancomycin-Associated Nephrotoxicity, Cole S Hudson, James E Smith, Rongjin Sun, Linh T Vuong, Luan D Truong, David Sheikh-Hamad, Masayuki Nigo, Ming Hu, Vincent H Tam

Faculty, Staff and Students Publications

Vancomycin is one of the most commonly used parenteral antibiotics for treating drug-resistant bacterial infections, however, it is hindered by nephrotoxicity. We previously demonstrated that zileuton could delay the onset of vancomycin-associated nephrotoxicity in rats. Here, we sought to understand the mechanism(s) of zileuton renal protection. Sprague-Dawley rats were administered vancomycin (200 mg/kg) and zileuton (1 and 4 mg/kg) daily for 10 days. After 3 days, kidneys were collected from select animals for histopathological analysis of renal injury. Single-dose vancomycin serum pharmacokinetics and renal tissue spatial distribution with adjuvant zileuton were evaluated. In vitro, proximal tubular cells were exposed …

Ataxia-Telangiectasia Mutated Activation Mediates Transforming Growth Factor Beta Signaling In Acetaminophen-Induced Liver Injury In Mice, Matthew Mcmillin, Christopher S Chu, Elaina Williams, Juliet Venter, Kiersten Bell, Anca D Petrescu, Patrick Mireles, Sharon Demorrow

Faculty and Staff Publications

Acetaminophen (APAP) overdose is associated with increased transforming growth factor beta 1 (TGFβ1) signaling and elevated oxidative stress, which exacerbate DNA damage. TGFβ1 has been shown to regulate ataxia-telangiectasia mutated (ATM) signaling and DNA repair in other cell types. This study investigates the DNA damage response (DDR) during APAP-induced liver injury, focusing on ATM-mediated regulation of TGFβ1 signaling. APAP administration in vitro and in vivo resulted in DNA damage, increased ATM signaling, accumulation of γH2AX, and activation of phosphorylated ataxia telangiectasia mutated (pATM) and phosphorylated checkpoint kinase 2 (pChk2). Pretreatment with an ATM inhibitor, KU55933, attenuated APAP-induced hepatocyte damage and …

The Microstructure Of Metastatic Bone Lesions Suggests Tumor Mediated Alterations In Bone Mineralization, Hanwen Fan, Zhan Xu, Carla Berrospe Rodriguez, Noah Dover, Andrei Demkov, Morgan Lilly, Guillermo Aguilar, Larry J Suva, Xiang H-F Zhang, Yuxiao Zhou

Faculty, Staff and Students Publications

Breast, prostate and lung cancer cells frequently metastasize to bone, leading to disruption of the bone microstructure. This study utilized mechanical testing coupled with micro-CT imaging, digital volume correlation (DVC), and atomic force microscopy (AFM) nanomechanical testing to examine the mechanical property variations in mouse long bones (tibia) with metastatic lung cancer cell involvement, spanning from the whole-bone scale to the microstructural level. In addition, we also investigated how metastatic invasion alters the morphology of hydroxyapatite nanocrystals in bone at the nanometer scale. The biochemical composition within metastatic lesions was assessed using Raman spectroscopy and correlated with AFM mechanical testing …

Gene Therapy Cm-Yapon Protects The Mouse Heart From Myocardial Infarction, Fansen Meng, Jeffrey D Steimle, Elizabeth Straight, Rich G Li, Yuka Morikawa, Zohaib Iqbal, Bing Xie, Jun Wang, Wyatt G Paltzer, Yi Zhao, Chang-Ru Tsai, Lin Liu, Maggie Lim, Rita A Schack, Daniel Ramirez, Katherine Carlson, Vaibhav Deshmukh, Jason M Karch, Robia G Pautler, Xiao Li, James F Martin

Faculty, Staff and Students Publications

Myocardial infarction (MI) affects millions of people worldwide, causing irreversible injury to the heart and impairing cardiac function1. In both mouse and pig MI models, activating YAP in cardiomyocytes (CMs) stimulates regenerative repair2,3. Here we developed an adeno-associated virus 9 (AAV9)-based therapy, termed CM-YAPon, which enables transient expression of an active YAP variant (YAP5SA) in CMs following exposure to the small molecule LMI070. A single LMI070 dose in mice triggers YAP5SA expression, CM cell cycle re-entry, and reprogramming of the cardiac microenvironment. YAP5SA induction after MI rapidly improves cardiac function while pre-MI induction confers …

Cross-Species Standardised Cortico-Subcortical Tractography, Stephania Assimopoulos, Shaun Warrington, Davide Folloni, Katherine Bryant, Ali-Reza Mohammadi-Nejad, Wei Tang, Saad Jbabdi, Sarah R Heilbronner, Rogier B Mars, Stamatios N Sotiropoulos

Faculty, Staff and Students Publications

Despite their importance for brain function, cortico-subcortical white matter tracts are under-represented in diffusion magnetic resonance imaging tractography studies. Their non-invasive mapping is more challenging and less explored compared to other major cortico-cortical bundles. We introduce a set of standardised tractography protocols for delineating tracts between the cortex and various deep subcortical structures, including the caudate, putamen, amygdala, thalamus, and hippocampus. To enable comparative studies, our protocols are designed for both human and macaque brains. We demonstrate how tractography reconstructions follow topographical principles obtained from tracers in the macaque and how these translate to humans. We show that the proposed …

Cerebellar Purkinje Cell Stripe Patterns Reveal A Differential Vulnerability And Resistance To Cell Loss During Normal Aging In Mice, Sarah G Donofrio, Cheryl Brandenburg, Amanda M Brown, Tao Lin, Hsiang-Chih Lu, Roy V Sillitoe

Faculty, Staff and Students Publications

Age-related neurodegenerative diseases involve reduced cell numbers and impaired behavioral capacity. Neurodegeneration and behavioral deficits also occur during aging, and notably in the absence of disease. The cerebellum, which modulates movement and cognition, is susceptible to cell loss in both aging and disease. Here, we demonstrate that cerebellar Purkinje cell loss in aged mice is not spatially random but rather occurs in a pattern of parasagittal stripes. We also find that aged mice exhibit impaired motor coordination and more severe tremor compared to younger mice. However, the relationship between patterned Purkinje cell loss and motor dysfunction is not straightforward. Examination …

Plasma Metabolomic And Proteomic Signatures Of Blood Pressure Management After Bariatric Surgery Among Adolescents, Shudi Pan, Zhenjiang Li, Juan Pablo Lewinger, Jesse A Goodrich, Hongxu Wang, Sarah Rock, Carmen Chen, Todd M Jenkins, Stephanie Sisley, Stephen R Daniels, Douglas I Walker, Max T Aung, Erika Garcia, Rob Mcconnell, Sandrah P Eckel, Michele A La Merrill, Tanya L Alderete, Zhuanghua Chen, Frank D Gilliland, Thomas H Inge, David V Conti, Justin R Ryder, Lida Chatzi

Faculty, Staff and Students Publications

Background: Emerging omics approaches, including metabolomics and proteomics, can be integrated into obesity treatment for better blood pressure management. We tested whether preoperative metabolomic and proteomic profiles predict long-term elevated blood pressure (EBP) changes better than known risk factors in adolescents undergoing bariatric surgery.

Methods: We included 108 participants from the Teen-LABS (Teen-Longitudinal Assessment of Bariatric Surgery). Plasma untargeted metabolomics (via liquid chromatography with high-resolution mass spectrometry) and Olink proteomics were assessed pre surgery. An elastic net model with stability selection was used to identify features predictive of EBP reductions 5 years post surgery. Models including identified metabolites, proteins, and …

Characterization Of Water Intake And Water Conversion Ratio For Male And Female Broilers From Four Commercial Broiler Lines Reared To Eight Weeks Of Age, J.Z. Hiltz, C.W. Maynard, T.W. Tabler, M.A. Maquesda, K.M. Shafer, K.B. Nelson, M.T. Kidd, N.B. Anthony, S.K. Orlowski-Workman

Poultry Science Faculty Publications and Presentations

Increased interest and investigation into the sustainability of broiler production has led to a need for reliable and repeatable means to measure water intake and its conversion rate into salable meat. Therefore, a study was conducted to characterize the water intake and water conversion ratio (WCR) of male and female broilers from four modern broiler strains. Two of these lines represented fast growing broiler strains (FGB A and FGB B) targeting a small bird market and two represented high yielding broiler strains (HYB A and HYB B). Three replicates of 25 sexed broilers from each line were placed into 24 …