Digital Commons Network^™

Increased Igfbp2 Levels By Placenta-Derived Mesenchymal Stem Cells Enhance Glucose Metabolism In A Taa-Injured Rat Model Via Ampk Signaling Pathway, Dae-Hyun Lee, Hyeri Park, Jun-Hyeong You, Jin Seok, Dong-Wook Kwon, Young-Ran Kim, Gi-Jin Kim

Faculty, Staff and Student Publications

The insulin resistance caused by impaired glucose metabolism induces ovarian dysfunction due to the central importance of glucose as a source of energy. However, the research on glucose metabolism in the ovaries is still lacking. The objectives of this study were to analyze the effect of PD-MSCs on glucose metabolism through IGFBP2-AMPK signaling and to investigate the correlation between glucose metabolism and ovarian function. Thioacetamide (TAA) was used to construct a rat injury model. PD-MSCs were transplanted into the tail vein (2 × 10

Vaginal Microbial Dynamics And Pathogen Colonization In A Humanized Microbiota Mouse Model, Marlyd E Mejia, Vicki Mercado-Evans, Jacob J Zulk, Samantha Ottinger, Korinna Ruiz, Mallory B Ballard, Stephanie W Fowler, Robert A Britton, Kathryn A Patras

Faculty, Staff and Students Publications

Vaginal microbial composition is associated with differential risk of urogenital infection. Although Lactobacillus spp. are thought to confer protection against infection, the lack of in vivo models resembling the human vaginal microbiota remains a prominent barrier to mechanistic discovery. Using 16S rRNA amplicon sequencing of C57BL/6J female mice, we found that vaginal microbial composition varies within and between colonies across three vivaria. Noting vaginal microbial plasticity in conventional mice, we assessed the vaginal microbiome of humanized microbiota mice (

Molecular Basis Of Retinal Remodeling In A Zebrafish Model Of Retinitis Pigmentosa, Abirami Santhanam, Eyad Shihabeddin, Haichao Wei, Jiaqian Wu, John O'Brien

Faculty, Staff and Student Publications

A hallmark of inherited retinal degenerative diseases such as retinitis pigmentosa (RP) is progressive structural and functional remodeling of the remaining retinal cells as photoreceptors degenerate. Extensive remodeling of the retina stands as a barrier for the successful implementation of strategies to restore vision. To understand the molecular basis of remodeling, we performed analyses of single-cell transcriptome data from adult zebrafish retina of wild type AB strain (WT) and a P23H mutant rhodopsin transgenic model of RP with continuous degeneration and regeneration. Retinas from both female and male fish were pooled to generate each library, combining data from both sexes. …

Architecture Of The Baculovirus Nucleocapsid Revealed By Cryo-Em, Xudong Jia, Yuanzhu Gao, Yuxuan Huang, Linjun Sun, Siduo Li, Hongmei Li, Xueqing Zhang, Yinyin Li, Jian He, Wenbi Wu, Harikanth Venkannagari, Kai Yang, Matthew L Baker, Qinfen Zhang

Faculty, Staff and Student Publications

Baculovirus Autographa californica multiple nucleopolyhedrovirus (AcMNPV) has been widely used as a bioinsecticide and a protein expression vector. Despite their importance, very little is known about the structure of most baculovirus proteins. Here, we show a 3.2 Å resolution structure of helical cylindrical body of the AcMNPV nucleocapsid, composed of VP39, as well as 4.3 Å resolution structures of both the head and the base of the nucleocapsid composed of over 100 protein subunits. AcMNPV VP39 demonstrates some features of the HK97-like fold and utilizes disulfide-bonds and a set of interactions at its C-termini to mediate nucleocapsid assembly and stability. …

Efficacy Of Futibatinib, An Irreversible Fibroblast Growth Factor Receptor Inhibitor, In Fgfr-Altered Breast Cancer, Turcin Saridogan, Argun Akcakanat, Ming Zhao, Kurt W Evans, Erkan Yuca, Stephen Scott, Bryce P Kirby, Xiaofeng Zheng, Min Jin Ha, Huiqin Chen, Patrick K S Ng, Timothy P Diperi, Gordon B Mills, Jordi Rodon Ahnert, Senthil Damodaran, Funda Meric-Bernstam

Faculty, Staff and Student Publications

Several alterations in fibroblast growth factor receptor (FGFR) genes have been found in breast cancer; however, they have not been well characterized as therapeutic targets. Futibatinib (TAS-120; Taiho) is a novel, selective, pan-FGFR inhibitor that inhibits FGFR1-4 at nanomolar concentrations. We sought to determine futibatinib's efficacy in breast cancer models. Nine breast cancer patient-derived xenografts (PDXs) with various FGFR1-4 alterations and expression levels were treated with futibatinib. Antitumor efficacy was evaluated by change in tumor volume and time to tumor doubling. Alterations indicating sensitization to futibatinib in vivo were further characterized in vitro. FGFR gene expression between patient tumors and …

Dynamics Of Cwd Prion Detection In Feces And Blood From Naturally Infected White-Tailed Deer, Francisca Bravo-Risi, Paulina Soto, Rebeca Benavente, Tracy A Nichols, Rodrigo Morales

Faculty, Staff and Student Publications

Chronic wasting disease (CWD) is a prion disease affecting cervids. Confirmatory testing of CWD is currently performed postmortem in obex and lymphoid tissues. Extensive evidence demonstrates the presence of infectious prions in feces of CWD-infected deer using in vitro prion-amplification techniques and bioassays. In experimental conditions, this has been achieved as soon as 6-month post-inoculation, suggesting this sample type is a candidate for antemortem diagnosis. In the present study, we optimized the detection of CWD-prions in fecal samples from naturally infected, pre-clinical white-tailed deer by comparing protocols aiming to concentrate CWD-prions with direct spiking of the sample into the PMCA …

Blood-Based Proteomic Signatures Associated With Men1-Related Duodenopancreatic Neuroendocrine Tumor Progression, Johannes F Fahrmann, Amanda R Wasylishen, Carolina R C Pieterman, Ehsan Irajizad, Jody Vykoukal, Ranran Wu, Jennifer B Dennison, Christine B Peterson, Hua Zhao, Kim-Anh Do, Daniel M Halperin, Sunita K Agarwal, Jenny E Blau, Smita Jha, Jaydira Del Rivero, Naris Nilubol, Mary F Walter, James M Welch, Lee S Weinstein, Menno R Vriens, Rachel S Van Leeuwaarde, Mark J C Van Treijen, Gerlof D Valk, Nancy D Perrier, Samir M Hanash, Hiroyuki Katayama

Faculty, Staff and Student Publications

PURPOSE: Patients with multiple endocrine neoplasia type 1 (MEN1) are predisposed to develop duodenopancreatic neuroendocrine tumors (dpNETs), and metastatic dpNET is the primary cause of disease-related mortality. Presently, there is a paucity of prognostic factors that can reliably identify patients with MEN1-related dpNETS who are at high risk of distant metastasis. In the current study, we aimed to establish novel circulating molecular protein signatures associated with disease progression.

EXPERIMENTAL DESIGN: Mass spectrometry-based proteomic profiling was conducted on plasmas procured through an international collaboration between MD Anderson Cancer Center, the National Institutes of Health, and the University Medical Center Utrecht from …

Pmca Screening Of Retropharyngeal Lymph Nodes In White-Tailed Deer And Comparisons With Elisa And Ihc, Rebeca Benavente, J Hunter Reed, Mitch Lockwood, Rodrigo Morales

Faculty, Staff and Student Publications

Chronic wasting disease (CWD) is a prion disease affecting cervids. CWD diagnosis is conducted through enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry (IHC) in retropharyngeal lymph nodes. Unfortunately, these techniques have limited sensitivity against the biomarker (CWD-prions). Two in vitro prion amplification techniques, real-time quaking-induced conversion (RT-QuIC) and protein misfolding cyclic amplification (PMCA), have shown promise in detecting CWD-prions in tissues and bodily fluids. Recent studies have demonstrated that RT-QuIC yields similar results compared to ELISA and IHC. Here, we analyzed 1003 retropharyngeal lymph nodes (RPLNs) from Texas white-tailed deer. PMCA detected CWD at a higher rate compared to ELISA/IHC, identified …

Simulation Study Of A Novel Small Animal Flash Irradiator (Safi) With Integrated Inverse-Geometry Ct Based On Circularly Distributed Kv X-Ray Sources, Yuewen Tan, Shuang Zhou, Jonathan Haefner, Qinghao Chen, Thomas R Mazur, Arash Darafsheh, Tiezhi Zhang

2020-Current year OA Pubs

Ultra-high dose rate (UHDR) radiotherapy (RT) or FLASH-RT can potentially reduce normal tissue toxicity. A small animal irradiator that can deliver FLASH-RT treatments similar to clinical RT treatments is needed for pre-clinical studies of FLASH-RT. We designed and simulated a novel small animal FLASH irradiator (SAFI) based on distributed x-ray source technology. The SAFI system comprises a distributed x-ray source with 51 focal spots equally distributed on a 20 cm diameter ring, which are used for both FLASH-RT and onboard micro-CT imaging. Monte Carlo simulation was performed to estimate the dosimetric characteristics of the SAFI treatment beams. The maximum dose …

Mutation Of Key Signaling Regulators Of Cerebrovascular Development In Vein Of Galen Malformations, Shujuan Zhao, Po-Ying Fu, Yung-Chun Wang, Sheng Chih Jin, Et Al.

2020-Current year OA Pubs

To elucidate the pathogenesis of vein of Galen malformations (VOGMs), the most common and most severe of congenital brain arteriovenous malformations, we performed an integrated analysis of 310 VOGM proband-family exomes and 336,326 human cerebrovasculature single-cell transcriptomes. We found the Ras suppressor p120 RasGAP (RASA1) harbored a genome-wide significant burden of loss-of-function de novo variants (2042.5-fold, p = 4.79 x 10

Contribution Of Macrophages To Neural Survival And Intracochlear Tissue Remodeling Responses Following Cochlear Implantation, Muhammad Taifur Rahman, Brian J Mostaert, Bryce Hunger, Utsow Saha, Alexander D Claussen, Ibrahim Razu, Farjana Nasrin, Nashwaan Ali Khan, Peter Eckard, Sarah Coleman, Jacob Oleson, Jonathon R Kirk, Keiko Hirose, Marlan R Hansen

2020-Current year OA Pubs

BACKGROUND: Cochlear implants (CIs) restore hearing to deafened patients. The foreign body response (FBR) following cochlear implantation (post-CI) comprises an infiltration of macrophages, other immune and non-immune cells, and fibrosis into the scala tympani, a space that is normally devoid of cells. This FBR is associated with negative effects on CI outcomes including increased electrode impedances and loss of residual acoustic hearing. This study investigates the extent to which macrophage depletion by an orally administered CSF-1R specific kinase (c-FMS) inhibitor, PLX-5622, modulates the tissue response to CI and neural health.

MAIN TEXT: 10- to 12-week-old CX3CR1 + /GFP Thy1 + …

Galectin-3 Cooperates With Cd47 To Suppress Phagocytosis And T-Cell Immunity In Gastric Cancer Peritoneal Metastases, Yibo Fan, Shumei Song, Yuan Li, Shilpa S Dhar, Jiankang Jin, Katsuhiro Yoshimura, Xiaodan Yao, Ruiping Wang, Ailing W Scott, Melissa Pool Pizzi, Jingjing Wu, Lang Ma, George A Calin, Samir Hanash, Linghua Wang, Michael Curran, Jaffer A Ajani

Faculty, Staff and Student Publications

UNLABELLED: The peritoneal cavity is a common site of gastric adenocarcinoma (GAC) metastasis. Peritoneal carcinomatosis (PC) is resistant to current therapies and confers poor prognosis, highlighting the need to identify new therapeutic targets. CD47 conveys a "don't eat me" signal to myeloid cells upon binding its receptor signal regulatory protein alpha (SIRPα), which helps tumor cells circumvent macrophage phagocytosis and evade innate immune responses. Previous studies demonstrated that the blockade of CD47 alone results in limited clinical benefits, suggesting that other target(s) might need to be inhibited simultaneously with CD47 to elicit a strong antitumor response. Here, we found that …

Nad+ Rescues Aging-Induced Blood-Brain Barrier Damage Via The Cx43-Parp1 Axis, Rui Zhan, Xia Meng, Dongping Tian, Jie Xu, Hongtu Cui, Jialei Yang, Yangkai Xu, Mingming Shi, Jing Xue, Weiwei Yu, Gaofei Hu, Ke Li, Xiaoxiao Ge, Qi Zhang, Mingming Zhao, Jianyong Du, Xin Guo, Wenli Xu, Yang Gao, Changyu Yao, Fan Chen, Yue Chen, Wenxin Shan, Yujie Zhu, Liang Ji, Bing Pan, Yan Yu, Wenguang Li, Xuyang Zhao, Qihua He, Xiaohui Liu, Yue Huang, Shengyou Liao, Bin Zhou, Dehua Chui, Y Eugene Chen, Zheng Sun, Erdan Dong, Yongjun Wang, Lemin Zheng

Faculty, Staff and Students Publications

Blood-brain barrier (BBB) function deteriorates during aging, contributing to cognitive impairment and neurodegeneration. It is unclear what drives BBB leakage in aging and how it can be prevented. Using single-nucleus transcriptomics, we identified decreased connexin 43 (CX43) expression in cadherin-5

The Role Of Noncoding Rnas In Pancreatic Birth Defects, Ziyue Zoey Yang, Ronald J Parchem

Faculty, Staff and Students Publications

Congenital defects in the pancreas can cause severe health issues such as pancreatic cancer and diabetes which require lifelong treatment. Regenerating healthy pancreatic cells to replace malfunctioning cells has been considered a promising cure for pancreatic diseases including birth defects. However, such therapies are currently unavailable in the clinic. The developmental gene regulatory network underlying pancreatic development must be reactivated for in vivo regeneration and recapitulated in vitro for cell replacement therapy. Thus, understanding the mechanisms driving pancreatic development will pave the way for regenerative therapies. Pancreatic progenitor cells are the precursors of all pancreatic cells which use epigenetic changes …

A Paracrine Circuit Of Il-1Β/Il-1r1 Between Myeloid And Tumor Cells Drives Genotype-Dependent Glioblastoma Progression, Zhihong Chen, David H. Gutmann, Et Al.

2020-Current year OA Pubs

Monocytes and monocyte-derived macrophages (MDMs) from blood circulation infiltrate glioblastoma (GBM) and promote growth. Here, we show that PDGFB-driven GBM cells induce the expression of the potent proinflammatory cytokine IL-1β in MDM, which engages IL-1R1 in tumor cells, activates the NF-κB pathway, and subsequently leads to induction of monocyte chemoattractant proteins (MCPs). Thus, a feedforward paracrine circuit of IL-1β/IL-1R1 between tumors and MDM creates an interdependence driving PDGFB-driven GBM progression. Genetic loss or locally antagonizing IL-1β/IL-1R1 leads to reduced MDM infiltration, diminished tumor growth, and reduced exhausted CD8+ T cells and thereby extends the survival of tumor-bearing mice. In contrast …

Dietary L-Tryptophan Consumption Determines The Number Of Colonic Regulatory T Cells And Susceptibility To Colitis Via Gpr15, Nguyen Van, Karen Zhang, Rachel Wigmore, Anne Kennedy, Carolina Dasilva, Jialing Huang, Manju Ambelil, Jose Villagomez, Gerald O'Connor, Randy Longman, Miao Cao, Adam Snook, Michael Platten, Gerard Kasenty, Luis Sigal, George C Prendergast, Sangwon Kim

Department of Microbiology and Immunology Faculty Papers

Environmental factors are the major contributor to the onset of immunological disorders such as ulcerative colitis. However, their identities remain unclear. Here, we discover that the amount of consumed L-Tryptophan (L-Trp), a ubiquitous dietary component, determines the transcription level of the colonic T cell homing receptor, GPR15, hence affecting the number of colonic FOXP3⁺ regulatory T (Treg) cells and local immune homeostasis. Ingested L-Trp is converted by host IDO1/2 enzymes, but not by gut microbiota, to compounds that induce GPR15 transcription preferentially in Treg cells via the aryl hydrocarbon receptor. Consequently, two weeks of dietary L-Trp supplementation nearly double …

Dhodh: A Promising Target In The Treatment Of T-Cell Acute Lymphoblastic Leukemia, Amy N Sexauer, Gabriela Alexe, Karin Gustafsson, Elizabeth Zanetakos, Jelena Milosevic, Mary Ayres, Varsha Gandhi, Yana Pikman, Kimberly Stegmaier, David B Sykes

Faculty, Staff and Student Publications

Patients with relapsed or refractory T-cell acute lymphoblastic leukemia (T-ALL) have a poor prognosis with few therapeutic options. With the goal of identifying novel therapeutic targets, we used data from the Dependency Map project to identify dihydroorotate dehydrogenase (DHODH) as one of the top metabolic dependencies in T-ALL. DHODH catalyzes the fourth step of de novo pyrimidine nucleotide synthesis. Small molecule inhibition of DHODH rapidly leads to the depletion of intracellular pyrimidine pools and forces cells to rely on extracellular salvage. In the absence of sufficient salvage, this intracellular nucleotide starvation results in the inhibition of DNA and RNA synthesis, …

Targeted Suppression Of Mtorc2 Reduces Seizures Across Models Of Epilepsy, James Okoh, Jacqunae Mays, Alexandre Bacq, Juan A Oses-Prieto, Stefka Tyanova, Chien-Ju Chen, Khalel Imanbeyev, Marion Doladilhe, Hongyi Zhou, Paymaan Jafar-Nejad, Alma Burlingame, Jeffrey Noebels, Stephanie Baulac, Mauro Costa-Mattioli

Faculty, Staff and Students Publications

Epilepsy is a neurological disorder that poses a major threat to public health. Hyperactivation of mTOR complex 1 (mTORC1) is believed to lead to abnormal network rhythmicity associated with epilepsy, and its inhibition is proposed to provide some therapeutic benefit. However, mTOR complex 2 (mTORC2) is also activated in the epileptic brain, and little is known about its role in seizures. Here we discover that genetic deletion of mTORC2 from forebrain neurons is protective against kainic acid-induced behavioral and EEG seizures. Furthermore, inhibition of mTORC2 with a specific antisense oligonucleotide robustly suppresses seizures in several pharmacological and genetic mouse models …

Tlr7 Promotes Smoke-Induced Experimental Lung Damage Through The Activity Of Mast Cell Tryptase, Gang Liu, Tatt Jhong Haw, Malcolm R Starkey, Ashleigh M Philp, Stelios Pavlidis, Christina Nalkurthi, Prema M Nair, Henry M Gomez, Irwan Hanish, Alan Cy Hsu, Elinor Hortle, Sophie Pickles, Joselyn Rojas-Quintero, Raul San Jose Estepar, Jacqueline E Marshall, Richard Y Kim, Adam M Collison, Joerg Mattes, Sobia Idrees, Alen Faiz, Nicole G Hansbro, Ryutaro Fukui, Yusuke Murakami, Hong Sheng Cheng, Nguan Soon Tan, Sanjay H Chotirmall, Jay C Horvat, Paul S Foster, Brian Gg Oliver, Francesca Polverino, Antonio Ieni, Francesco Monaco, Gaetano Caramori, Sukhwinder S Sohal, Ken R Bracke, Peter A Wark, Ian M Adcock, Kensuke Miyake, Don D Sin, Philip M Hansbro

Faculty, Staff and Students Publications

Toll-like receptor 7 (TLR7) is known for eliciting immunity against single-stranded RNA viruses, and is increased in both human and cigarette smoke (CS)-induced, experimental chronic obstructive pulmonary disease (COPD). Here we show that the severity of CS-induced emphysema and COPD is reduced in TLR7-deficient mice, while inhalation of imiquimod, a TLR7-agonist, induces emphysema without CS exposure. This imiquimod-induced emphysema is reduced in mice deficient in mast cell protease-6, or when wild-type mice are treated with the mast cell stabilizer, cromolyn. Furthermore, therapeutic treatment with anti-TLR7 monoclonal antibody suppresses CS-induced emphysema, experimental COPD and accumulation of pulmonary mast cells in mice. …

Missense Mutations In Crx Homeodomain Cause Dominant Retinopathies Through Two Distinct Mechanisms, Yiqiao Zheng, Chi Sun, Xiaodong Zhang, Philip A Ruzycki, Shiming Chen

2020-Current year OA Pubs

Homeodomain transcription factors (HD TFs) are instrumental to vertebrate development. Mutations in HD TFs have been linked to human diseases, but their pathogenic mechanisms remain elusive. Here, we use

Mechanical Loading And Hyperosmolarity As A Daily Resetting Cue For Skeletal Circadian Clocks, Michal Dudek, Dharshika R J Pathiranage, Beatriz Bano-Otalora, Anna Paszek, Natalie Rogers, Cátia F Gonçalves, Craig Lawless, Dong Wang, Zhuojing Luo, Liu Yang, Farshid Guilak, Judith A Hoyland, Qing-Jun Meng

2020-Current year OA Pubs

Daily rhythms in mammalian behaviour and physiology are generated by a multi-oscillator circadian system entrained through environmental cues (e.g. light and feeding). The presence of tissue niche-dependent physiological time cues has been proposed, allowing tissues the ability of circadian phase adjustment based on local signals. However, to date, such stimuli have remained elusive. Here we show that daily patterns of mechanical loading and associated osmotic challenge within physiological ranges reset circadian clock phase and amplitude in cartilage and intervertebral disc tissues in vivo and in tissue explant cultures. Hyperosmolarity (but not hypo-osmolarity) resets clocks in young and ageing skeletal tissues …

A Cre-Dependent Massively Parallel Reporter Assay Allows For Cell-Type Specific Assessment Of The Functional Effects Of Non-Coding Elements In Vivo, Tomas Lagunas Jr, Stephen P Plassmeyer, Anthony D Fischer, Ryan Z Friedman, Michael A Rieger, Din Selmanovic, Simona Sarafinovska, Yvette K Sol, Michael J Kasper, Stuart B Fass, Alessandra F Aguilar Lucero, Joon-Yong An, Stephan J Sanders, Barak A Cohen, Joseph D Dougherty

2020-Current year OA Pubs

The function of regulatory elements is highly dependent on the cellular context, and thus for understanding the function of elements associated with psychiatric diseases these would ideally be studied in neurons in a living brain. Massively Parallel Reporter Assays (MPRAs) are molecular genetic tools that enable functional screening of hundreds of predefined sequences in a single experiment. These assays have not yet been adapted to query specific cell types in vivo in a complex tissue like the mouse brain. Here, using a test-case 3'UTR MPRA library with genomic elements containing variants from autism patients, we developed a method to achieve …

Usp38 Exacerbates Atrial Inflammation, Fibrosis, And Susceptibility To Atrial Fibrillation After Myocardial Infarction In Mice, Yang Gong, Tingting Yu, Wei Shuai, Tao Chen, Jingjing Zhang, He Huang

Faculty, Staff and Student Publications

BACKGROUND: Inflammation plays an important role in the pathogenesis of atrial fibrillation (AF) after myocardial infarction (MI). The role of USP38, a member of the ubiquitin-specific protease family, on MI-induced atrial inflammation, fibrosis, and associated AF is unclear.

METHODS: In this study, we surgically constructed a mouse MI model using USP38 cardiac conditional knockout (USP38-CKO) and cardiac-specific overexpression (USP38-TG) mice and applied biochemical, histological, electrophysiological characterization and molecular biology to investigate the effects of USP38 on atrial inflammation, fibrosis, and AF and its mechanisms.

RESULTS: Our results revealed that USP38-CKO attenuates atrial inflammation, thereby ameliorating fibrosis, and abnormal electrophysiologic properties, …

Single-Cell Analysis Differentiates The Effects Of P53 Mutation And P53 Loss On Cell Compositions Of Oncogenic Kras-Driven Pancreatic Cancer, Xinlei Sun, Daowei Yang, Yang Chen

Faculty, Staff and Student Publications

Pancreatic ductal adenocarcinoma (PDAC) is a devastating malignant disease with a dismal prognosis. In the past decades, a plethora of genetically engineered mouse models (GEMMs) with autochthonous pancreatic tumor development have greatly facilitated studies of pancreatic cancer. Commonly used GEMMs of PDAC often harbor the oncogenic KRAS driver mutation (KrasG12D), in combination with either p53 mutation by knock-in strategy (Trp53R172H) or p53 loss by conditional knockout (Trp53cKO) strategy, in pancreatic cell lineages. However, the systematic comparison of the tumor microenvironment between KrasG12D; Trp53R172H (KPmut) mouse models and KrasG12D; Trp53cKO (KPloss) mouse models …

Increase In Hnrnpa1 Expression Suffices To Kill Motor Neurons In Transgenic Rats, Xionghao Liu, Tingting Zhang, Qinxue Wu, Cao Huang, Xu-Gang Xia, Hongxia Zhou, Bo Huang

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

A dominant mutation in hnRNPA1 causes amyotrophic lateral sclerosis (ALS), but it is not known whether this mutation leads to motor neuron death through increased or decreased function. To elucidate the relationship between pathogenic hnRNPA1 mutation and its native function, we created novel transgenic rats that overexpressed wildtype rat hnRNPA1 exclusively in motor neurons. This targeted expression of wildtype hnRNPA1 caused severe motor neuron loss and subsequent denervation muscle atrophy in transgenic rats that recapitulated the characteristics of ALS. These findings demonstrate that the augmentation of hnRNPA1 expression suffices to trigger motor neuron degeneration and the manifestation of ALS-like phenotypes. …

Repeated Multi-Domain Cognitive Training Prevents Cognitive Decline, Anxiety And Amyloid Pathology Found In A Mouse Model Of Alzheimer Disease, Jogender Mehla, Scott H Deibel, Hadil Karem, Nancy S Hong, Shakhawat R Hossain, Sean G Lacoursiere, Robert J Sutherland, Majid H Mohajerani, Robert J Mcdonald

2020-Current year OA Pubs

Education, occupation, and an active lifestyle, comprising enhanced social, physical, and mental components are associated with improved cognitive functions in aged people and may delay the progression of various neurodegenerative diseases including Alzheimer's disease. To investigate this protective effect, 3-month-old APP

A Novel Machine-Learning Framework Based On A Hierarchy Of Dispute Models For The Identification Of Fish Species Using Multi-Mode Spectroscopy, Mitchell Sueker, Amirreza Daghighi, Alireza Akhbardeh, Nicholas Mackinnon, Gregory Bearman, Insuck Baek, Chansong Hwang, Jianwei Qin, Amanda M Tabb, Jiahleen B Roungchun, Rosalee S Hellberg, Fartash Vasefi, Moon Kim, Kouhyar Tavakolian, Hossein Kashani Zadeh

Faculty, Staff and Student Publications

Seafood mislabeling rates of approximately 20% have been reported globally. Traditional methods for fish species identification, such as DNA analysis and polymerase chain reaction (PCR), are expensive and time-consuming, and require skilled technicians and specialized equipment. The combination of spectroscopy and machine learning presents a promising approach to overcome these challenges. In our study, we took a comprehensive approach by considering a total of 43 different fish species and employing three modes of spectroscopy: fluorescence (Fluor), and reflectance in the visible near-infrared (VNIR) and short-wave near-infrared (SWIR). To achieve higher accuracies, we developed a novel machine-learning framework, where groups of …

Mucopolysaccharidosis Iva: Current Disease Models And Drawbacks, Andrés Felipe Leal, Carlos Javier Alméciga-Díaz, Shunji Tomatsu

Department of Pediatrics Faculty Papers

Mucopolysaccharidosis IVA (MPS IVA) is a rare disorder caused by mutations in the N-acetylgalactosamine-6-sulfate-sulfatase (GALNS) encoding gene. GALNS leads to the lysosomal degradation of the glycosaminoglyccreasans keratan sulfate and chondroitin 6-sulfate. Impaired GALNS enzymes result in skeletal and non-skeletal complications in patients. For years, the MPS IVA pathogenesis and the assessment of promising drugs have been evaluated using in vitro (primarily fibroblasts) and in vivo (mainly mouse) models. Even though value information has been raised from those studies, these models have several limitations. For instance, chondrocytes have been well recognized as primary cells affected in MPS IVA and responsible for …

Mechanopathology Of Biofilm-Like Mycobacterium Tuberculosis Cords, Richa Mishra, Melanie Hannebelle, Vishal P Patil, Anaëlle Dubois, Cristina Garcia-Mouton, Gabriela M Kirsch, Maxime Jan, Kunal Sharma, Nicolas Guex, Jessica Sordet-Dessimoz, Jesus Perez-Gil, Manu Prakash, Graham W Knott, Neeraj Dhar, John D Mckinney, Vivek V Thacker

Faculty, Staff and Student Publications

Mycobacterium tuberculosis (Mtb) cultured axenically without detergent forms biofilm-like cords, a clinical identifier of virulence. In lung-on-chip (LoC) and mouse models, cords in alveolar cells contribute to suppression of innate immune signaling via nuclear compression. Thereafter, extracellular cords cause contact-dependent phagocyte death but grow intercellularly between epithelial cells. The absence of these mechanopathological mechanisms explains the greater proportion of alveolar lesions with increased immune infiltration and dissemination defects in cording-deficient Mtb infections. Compression of Mtb lipid monolayers induces a phase transition that enables mechanical energy storage. Agent-based simulations demonstrate that the increased energy storage capacity is sufficient for the formation …

Pericentrin Deficiency In Smooth Muscle Cells Augments Atherosclerosis Through Hsf1-Driven Cholesterol Biosynthesis And Perk Activation, Suravi Majumder, Abhijnan Chattopadhyay, Jamie M Wright, Pujun Guan, L Maximilian Buja, Callie S Kwartler, Dianna M Milewicz

Faculty, Staff and Student Publications

Microcephalic osteodysplastic primordial dwarfism type II (MOPDII) is caused by biallelic loss-of-function variants in pericentrin (PCNT), and premature coronary artery disease (CAD) is a complication of the syndrome. Histopathology of coronary arteries from patients with MOPDII who died of CAD in their 20s showed extensive atherosclerosis. Hyperlipidemic mice with smooth muscle cell-specific (SMC-specific) Pcnt deficiency (PcntSMC-/-) exhibited significantly greater atherosclerotic plaque burden compared with similarly treated littermate controls despite similar serum lipid levels. Loss of PCNT in SMCs induced activation of heat shock factor 1 (HSF1) and consequently upregulated the expression and activity of HMG-CoA reductase (HMGCR), the rate-limiting enzyme …