Diseases Commons^™

Nrf2/Cyclooxygenase 2 Signaling In Cr(Vi)-Induced Carcinogenesis, Lei Zhao, Yi-Fang Wang, Andrea Adamcakova-Dodd, Peter Thorne, Ranakul Islam, Ke Jian Liu, Fei Chen, Jia Luo, Ling-Zhi Liu

Kimmel Cancer Center Faculty Papers

Long-term exposure to hexavalent chromium [Cr(VI)] has been linked to lung cancer, and cyclooxygenase-2 (COX-2) is a well-known inflammatory factor. However, the role and mechanism of COX-2 in Cr(VI)-induced carcinogenesis are not clear yet. To address this question, we employed a mouse model exposed to Cr(VI) through intranasal instillation of particulate zinc chromate (ZnCrO4) for 12 weeks. Metabolomics and RNA-seq assays revealed enhanced activity of the arachidonic acid (AA)/eicosanoid metabolism pathway in lung tissues from mice exposed to Cr(VI). COX-2, the key enzyme of the AA/eicosanoid pathway, was significantly upre- gulated in Cr(VI)-exposed lung tissues, as well as in the …

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, …

Genetics And Biology Of Pancreatic Ductal Adenocarcinoma, Haoqiang Ying, Alec C Kimmelman, Nabeel Bardeesy, Raghu Kalluri, Anirban Maitra, Ronald A Depinho

Faculty, Staff and Student Publications

Pancreatic ductal adenocarcinoma (PDAC) poses a grim prognosis for patients. Recent multidisciplinary research efforts have provided critical insights into its genetics and tumor biology, creating the foundation for rational development of targeted and immune therapies. Here, we review the PDAC genomic landscape and the role of specific oncogenic events in tumor initiation and progression, as well as their contributions to shaping its tumor biology. We further summarize and synthesize breakthroughs in single-cell and metabolic profiling technologies that have illuminated the complex cellular composition and heterotypic interactions of the PDAC tumor microenvironment, with an emphasis on metabolic cross-talk across cancer and …

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 …

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 …

Schistosoma Mansoni Infection Causes Consistent Changes To The Fecal Bacterial Microbiota Of Mice Across And Within Sites, Mariam A. Mhanna, David T. Gauthier, Lisa M. Shollenberger

Biological Sciences Faculty Publications

Eggs of Schistosoma mansoni are produced by adult female worms in mesenteries of infected hosts. Eggs can cross the intestinal barrier and form granulomas in the tissue or breach and exit the host through fecal excretion. These interactions may affect the host microbiome assemblages. Given the potential for schistosomal alteration of host gut microbiome and subsequent effects on the fecal bacterial composition, it is important to conduct controlled microbiome studies on model animals. While pursuing these studies, it is important to take into account the different conditions in which microbiome studies are conducted and their consequent impacts on variability and …

Combination Of Hsp90 Inhibitors And Hsp70 Inducers Prevent Hydrochloric Acid-Induced Pulmonary Fibrosis In Rabbits, Ruben M. L. Colunga Biancatelli, Pavel A. Solopov, Tierney Day, Dan E. Austin Jr., Len E. Murray, John D. Catravas

Bioelectrics Publications

Combined therapies with Heat Shock Protein 90 (HSP90) inhibitors and Heat Shock Protein 70 (HSP70) inducers are gaining significant interest in cancer and cardiovascular research. Here, we tested the hypothesis that HSP90 inhibitors and HSP70 inducers, together, can block the development of pulmonary fibrosis. We exposed New Zealand White Rabbits to hydrochloric acid (HCl, 0.1 N, 1.5 mL/kg), one of the top five chemicals most commonly involved in accidental exposures and inhalation injuries worldwide, and treated animals with either the orally available HSP90 inhibitor TAS-116 (1.7 mg/kg 5x/week) or TAS-116 combined with the HSP70 inducer, geranylgeranyl acetone (GGA, 50 mg/kg, …

The Ptp4a3 Inhibitor Kvx-053 Reduces Severe Acute Respiratory Syndrome Coronavirus 2 (Sars-Cov-2) Virulence, Inflammation, And Development Of Acute Lung Injury In K18-Hace2 Mice, Ruben M. L. Colunga-Biancatelli, Pavel A. Solopov, Caitlin M. Woodson, Irving Coy Allen, Ivan Akhrymuk, Maryna Akhrymuk, Brittany N. Heath, Hannah M. Ivester, Tierney Day, Dan E. Austin, Kylene Kehn-Hall, John S. Lazo, Elizabeth R. Sharlow, John D. Catravas

Bioelectrics Publications

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has caused a global health crisis, marked by high transmissibility and virulence. Despite widespread vaccination efforts, effective treatments for COVID-19, particularly for severe cases leading to Acute Respiratory Distress Syndrome (ARDS), remain limited. This study investigates the efficacy of KVX-053, a protein tyrosine phosphatase type IVA (PTP4A3) small molecule inhibitor, in modulating SARS-CoV-2-induced inflammation and lung injury using in vitro cell models and in vivo K18-hACE2 transgenic mice. KVX-053 reduced in vitro pro-inflammatory cytokine expression, including TNFα, CXCL10, and CXCL11, without impacting viral replication or cell viability. K18-hACE2 mice treated with KVX-053 demonstrated …

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). …

Altering The Intracellular Trafficking Of Necator Americanus Gst-1 Antigen Yields Novel Hookworm Mrna Vaccine Candidates, Athos Silva De Oliveira, Leroy Versteeg, Neima Briggs, Rakesh Adhikari, Maria Jose Villar, Jeanna R Redd, Peter Hotez, Maria Elena Bottazzi, Jeroen Pollet

Faculty, Staff and Students Publications

BACKGROUND: The antigen Na-GST-1, expressed by the hookworm Necator americanus, plays crucial biochemical roles in parasite survival. This study explores the development of mRNA vaccine candidates based on Na-GST-1, building on the success of recombinant Na-GST-1 (rNa-GST-1) protein, currently assessed as a subunit vaccine candidate, which has shown promise in preclinical and clinical studies.

METHODOLOGY/FINDINGS: By leveraging the flexible design of RNA vaccines and protein intracellular trafficking signal sequences, we developed three variants of Na-GST-1 as native (cytosolic), secretory, and plasma membrane-anchored (PM) antigens. After one immunization in mice, mRNA vaccines induced an earlier onset of antigen-specific antibodies compared to …

Use Of A Mouse Model For The Isolation Of Borrelia Puertoricensis From Soft Ticks, Edwin Vázquez-Guerrero, Alexander R Kneubehl, Guadalupe C Reyes-Solís, Carlos Machain-Williams, Aparna Krishnavajhala, Paulina Estrada-De Los Santos, Job E Lopez, José Antonio Ibarra

Faculty, Staff and Students Publications

The isolation of tick-borne relapsing fever (TBRF) spirochetes has proven to be a useful tool to understand their distribution in geographic areas where the tick vectors inhabit. However, their isolation and culture are not easy and in general an animal model is needed to achieve this task. Here, argasid ticks were collected from a neighborhood in Ciudad Caucel, and they were identified as Ornithodoros (Alectorobius) puertoricensis. To determine whether these were infected with TBRF bacteria they were fed with healthy mice but only a low burden of spirochetes was observed. An immunosuppressed mouse model was used to feed the ticks …

Contributions Of Pathobiological And Translational Science To Understanding And Managing Ischemic Heart Disease: Progress, Impediments, And Future Directions, L Maximilian Buja

The Texas Heart Institute Journal

Key pathobiological components of ischemic heart disease have been identified as follows: (1) In 1970 to 1973, myocardial infarct size was found to be the primary determinant of prognosis after acute myocardial infarction (AMI); (2) in 1973 to 1989, vulnerable coronary artery plaques were found to predispose individuals to coronary plaque disruption and thrombosis, causing major AMI; (3) in 1972, timely coronary reperfusion was demonstrated to limit the size of evolving AMI but with risk of reperfusion injury; and (4) in 1986, myocardial conditioning was found to be a clinically significant modulator capable of delaying AMI progression. Promising cardioprotective strategies …

Proteomic Characterization And Comparison Of The Infective And Adult Life Stage Secretomes From Necator Americanus And Ancylostoma Ceylanicum, Yide Wong, Bruce A Rosa, Luke Becker, Mali Camberis, Graham Legros, Bin Zhan, Maria Elena Bottazzi, Ricardo T Fujiwara, Edita Ritmejeryte, Thewarach Laha, Sujittra Chaiyadet, Piyanan Taweethavonsawat, Paul J Brindley, Bethany K Bracken, Paul R Giacomin, Makedonka Mitreva, Alex Loukas

Faculty, Staff and Students Publications

More than 470 million people globally are infected with the hookworms Ancylostoma ceylanicum and Necator americanus, resulting in an annual loss of 2.1 to 4 million disability-adjusted-life-years. Current infection management approaches are limited by modest drug efficacy, the costs associated with frequent mass drug administration campaigns, and the risk of reinfection and burgeoning drug resistance. Subunit vaccines based on proteins excreted and secreted (ES) by hookworms that reduce worm numbers and associated disease burden are a promising management strategy to overcome these limitations. However, studies on the ES proteomes of hookworms have mainly described proteins from the adult life stage …

Predicting Sinonasal Inverted Papilloma Attachment Using Machine Learning: Current Lessons And Future Directions, Sean P Mckee, Xiaomin Liang, William C Yao, Brady Anderson, Jumah G Ahmad, David Z Allen, Salman Hasan, Andy J Chua, Chinmay Mokashi, Samia Islam, Amber U Luong, Martin J Citardi, Luca Giancardo

Faculty, Staff and Student Publications

Background: Hyperostosis is a common radiographic feature of inverted papilloma (IP) tumor origin on computed tomography (CT). Herein, we developed a machine learning (ML) model capable of analyzing CT images and identifying IP attachment sites.

Methods: A retrospective review of patients treated for IP at our institution was performed. The tumor attachment site was manually segmented on CT scans by the operating surgeon. We used a nnU-Net model, a state-of-the-art deep learning-based segmentation algorithm that automatically configures image preprocessing, network architecture, training, and post-processing to identify the IP attachment site. The model was trained and evaluated using a 5-fold cross …

Lp-118 Is A Novel B-Cell Lymphoma 2 / Extra-Large Inhibitor That Demonstrates Efficacy In Models Of Venetoclaxresistant Chronic Lymphocytic Leukemia, Janani Ravikrishnan, Daisy Y Diaz-Rohena, Elizabeth Muhowski, Xiaokui Mo, Tzung-Huei Lai, Shrilekha Misra, Charmelle D Williams, John Sanchez, Andrew Mitchell, Suresh Satpati, Elizabeth Perry, Tierney Kaufman, Chaomei Liu, Arletta Lozanski, Gerard Lozanski, Kerrya Rogers, Adam S Kittai, Seema A Bhat, Mary C Collins, Matthew S Davids, Nitin Jain, William G Wierda, Rosa Lapalombella, John C Byrd, Fenlai Tan, Yi Chen, Yu Chen, Yue Shen, Stephen P Anthony, Jennifer A Woyach, Deepa Sampath

Faculty, Staff and Student Publications

Patients with chronic lymphocytic leukemia (CLL) respond well to initial treatment with the B-cell lymphoma 2 (BCL2) inhibitor venetoclax. Upon relapse, they often retain sensitivity to BCL2 targeting, but durability of response remains a concern. We hypothesize that targeting both BCL2 and B-cell lymphoma-extra large (BCLXL) will be a successful strategy to treat CLL, including for patients who relapse on venetoclax. To test this hypothesis, we conducted a pre-clinical investigation of LP-118, a highly potent inhibitor of BCL2 with moderate BCLXL inhibition to minimize platelet toxicity. This study demonstrated that LP-118 induces efficient BAK activation, cytochrome C release, and apoptosis …

Zika Virus Modulates Arthropod Histone Methylation For Its Survival In Mosquito Cells, Telvin Harrell

Biological Sciences Faculty Publications

Zika virus (ZIKV) is a mosquito-borne human pathogen that causes mild febrile illness in adults and severe neurological complications and microcephaly in newborns. Studies have reported that ZIKV modulates methylation of human and viral RNA critical for its replication in vertebrate cells. In this study, we show that ZIKV modulates mosquito S-adenosyl methionine (SAMe)-synthase, an enzyme involved in the production of SAMe (methyl donor), and histone methylation for its survival in mosquito cells. Reverse transcription quantitative PCR followed by immunoblotting analysis showed increased amounts of SAMe synthase at both RNA and protein levels, respectively, in C6/36 mosquito cells infected with …

Mitochondrial-Targeted Therapies In Traumatic Brain Injury: From Bench To Bedside, Sidra Tabassum, Silin Wu, Chang-Hun Lee, Bosco Seong Kyu Yang, Aaron M Gusdon, Huimahn A Choi, Xuefang S Ren

Faculty, Staff and Student Publications

Traumatic brain injury (TBI) is a leading cause of morbidity and mortality worldwide, with limited effective therapeutic options currently available. Recent research has highlighted the pivotal role of mitochondrial dysfunction in the pathophysiology of TBI, making mitochondria an attractive target for therapeutic intervention. This review comprehensively examines advancements in mitochondrial-targeted therapies for TBI, bridging the gap from basic research to clinical applications. We discuss the underlying mechanisms of mitochondrial damage in TBI, including oxidative stress, impaired bioenergetics, mitochondrial dynamics, and apoptotic pathways. Furthermore, we highlight the complex interplay between mitochondrial dysfunction, inflammation, and blood-brain barrier (BBB) integrity, elucidating how these …

Spatial Dynamics Of Culex Quinquefasciatus Abundance: Geostatistical Insights From Harris County, Texas, Morgan Jibowu, Melissa S Nolan, Ryan Ramphul, Heather T Essigmann, Abiodun O Oluyomi, Eric L Brown, Maximea Vigilant, Sarah M Gunter

Faculty, Staff and Students Publications

Mosquito-borne diseases pose a significant public health threat, prompting the need to pinpoint high-risk areas for targeted interventions and environmental control measures. Culex quinquefasciatus is the primary vector for several mosquito-borne pathogens, including West Nile virus. Using spatial analysis and modeling techniques, we investigated the geospatial distribution of Culex quinquefasciatus abundance in the large metropolis of Harris County, Texas, from 2020 to 2022. Our geospatial analysis revealed clusters of high mosquito abundance, predominantly located in central Houston and the north-northwestern regions of Harris County, with lower mosquito abundance observed in the western and southeastern areas. We identified persistent high mosquito …

Targeting The Glutamine-Arginine-Proline Metabolism Axis In Cancer, Di Wang, Jiang-Jie Duan, Yu-Feng Guo, Jun-Jie Chen, Tian-Qing Chen, Jun Wang, Shi-Cang Yu

Faculty, Staff and Student Publications

Metabolic abnormalities are an important feature of tumours. The glutamine-arginine-proline axis is an important node of cancer metabolism and plays a major role in amino acid metabolism. This axis also acts as a scaffold for the synthesis of other nonessential amino acids and essential metabolites. In this paper, we briefly review (1) the glutamine addiction exhibited by tumour cells with accelerated glutamine transport and metabolism; (2) the methods regulating extracellular glutamine entry, intracellular glutamine synthesis and the fate of intracellular glutamine; (3) the glutamine, proline and arginine metabolic pathways and their interaction; and (4) the research progress in tumour therapy …

Immunopeptidomic Mhc-I Profiling And Immunogenicity Testing Identifies Tcj2 As A New Chagas Disease Mrna Vaccine Candidate, Leroy Versteeg, Rakesh Adhikari, Gonteria Robinson, Jungsoon Lee, Junfei Wei, Nelufa Islam, Brian Keegan, William K Russell, Cristina Poveda, Maria Jose Villar, Kathryn Jones, Maria Elena Bottazzi, Peter Hotez, Edwin Tijhaar, Jeroen Pollet

Faculty, Staff and Students Publications

Trypanosoma cruzi is a protozoan parasite that causes Chagas disease. Globally 6 to 7 million people are infected by this parasite of which 20-30% will progress to develop Chronic Chagasic Cardiomyopathy (CCC). Despite its high disease burden, no clinically approved vaccine exists for the prevention or treatment of CCC. Developing vaccines that can stimulate T. cruzi-specific CD8+ cytotoxic T cells and eliminate infected cells requires targeting parasitic antigens presented on major histocompatibility complex-I (MHC-I) molecules. We utilized mass spectrometry-based immunopeptidomics to investigate which parasitic peptides are displayed on MHC-I of T. cruzi infected cells. Through duplicate experiments, we identified an …

Randomized, Observer-Blind, Controlled Phase 1 Study Of The Safety And Immunogenicity Of The Na-Gst-1/Alhydrogel Hookworm Vaccine With Or Without A Cpg Odn Adjuvant In Hookworm-Naïve Adults, David J Diemert, Maria Zumer, Mark Bova, Christina Gibbs-Tewary, Elissa M Malkin, Doreen Campbell, Lara Hoeweler, Guangzhao Li, Maria Elena Bottazzi, Peter J Hotez, Jeffrey M Bethony

Faculty, Staff and Students Publications

BACKGROUND: Recombinant Necator americanus Glutathione-S-Transferase-1 (Na-GST-1) formulated on Alhydrogel (Na-GST-1/Alhydrogel) is being developed to prevent anemia and other complications of N. americanus infection. Antibodies induced by vaccination with recombinant Na-GST-1 are hypothesized to interfere with the blood digestion pathway of adult hookworms in the host. Phase 1 trials have demonstrated the safety of Na-GST-1 formulated on Alhydrogel, but further optimization of the vaccine adjuvant formulation may improve humoral immune responses, thereby increasing the likelihood of vaccine efficacy.

METHODS: A randomized, observer-blind, dose escalation Phase 1 trial was conducted in 24 healthy, hookworm-naïve adults. In each cohort of 12 participants, 4 …

Antithrombotic Efficacy And Bleeding Risks Of Vaccine-Induced Immune Thrombotic Thrombocytopenia Treatments, Halina H.L. Leung, Zohra Ahmadi, Brendan Lee, John Casey, Sumita Ratnasingam, Steven E. Mckenzie, Jose Perdomo, Beng H. Chong

Cardeza Foundation for Hematologic Research

Current guidelines for treating vaccine-induced immune thrombotic thrombocytopenia (VITT) recommend nonheparin anticoagulants and IV immunoglobulin (IVIg). However, the efficacy of these treatments remains uncertain due to case studies involving small patient numbers, confounding factors (eg, concurrent treatments), and a lack of animal studies. A recent study proposed danaparoid and heparin as potential VITT therapies because of their ability to disrupt VITT IgG-platelet factor 4 (PF4) binding. Here, we examined the effects of various anticoagulants (including unfractionated [UF] heparin, danaparoid, bivalirudin, fondaparinux, and argatroban), IVIg, and the FcγRIIa receptor-blocking antibody, IV.3. Our investigation focused on VITT IgG-PF4 binding, platelet activation, thrombocytopenia, …

Cd4+ T Cells Drive Corneal Nerve Damage But Not Epitheliopathy In An Acute Aqueous-Deficient Dry Eye Model, Alexia Vereertbrugghen, Manuela Pizzano, Agostina Cernutto, Florencia Sabbione, Irene A Keitelman, Douglas Vera Aguilar, Ariel Podhorzer, Federico Fuentes, Celia Corral-Vázquez, Mauricio Guzmán, Mirta N Giordano, Analía Trevani, Cintia S De Paiva, Jeremías G Galletti

Faculty, Staff and Students Publications

Dry eye disease (DED) is characterized by a dysfunctional tear film in which the corneal epithelium and its abundant nerves are affected by ocular desiccation and inflammation. Although adaptive immunity and specifically CD4+ T cells play a role in DED pathogenesis, the exact contribution of these cells to corneal epithelial and neural damage remains undetermined. To address this, we explored the progression of a surgical DED model in wild-type (WT) and T cell-deficient mice. We observed that adaptive immune-deficient mice developed all aspects of DED comparably to WT mice except for the absence of functional and morphological corneal nerve changes, …

Insights Into Human Norovirus Cultivation In Human Intestinal Enteroids, Khalil Ettayebi, Gurpreet Kaur, Ketki Patil, Janam Dave, B Vijayalakshmi Ayyar, Victoria R Tenge, Frederick H Neill, Xi-Lei Zeng, Allison L Speer, Sara C Di Rienzi, Robert A Britton, Sarah E Blutt, Sue E Crawford, Sasirekha Ramani, Robert L Atmar, Mary K Estes

Faculty, Staff and Students Publications

Human noroviruses (HuNoVs) are a significant cause of epidemic and sporadic acute gastroenteritis worldwide. The lack of a reproducible culture system hindered the study of HuNoV replication and pathogenesis for almost a half-century. This barrier was overcome with our successful cultivation of multiple HuNoV strains in human intestinal enteroids (HIEs), which has significantly advanced HuNoV research. We optimized culture media conditions and generated genetically modified HIE cultures to enhance HuNoV replication in HIEs. Building upon these achievements, we now present new insights into this culture system, which involve testing different media, unique HIE lines, and additional virus strains. HuNoV infectivity …

Il-37 Suppresses Cns Autoimmunity By Increasing The Frequency Of Treg Cells And Reducing Cd4 + T Cell-Derived Il-10 Production, Reza Yazdani, Hamed Naziri, Gholamreza Azizi, Bogoljub Ciric, Mozhde Askari, Amir Moghadam-Ahmadi, Jaya Aseervatham, Guang-Xian Zhang, Mohamad Rostami

Department of Neurology Faculty Papers

BACKGROUND: Interleukin-37 (IL-37) has anti-inflammatory properties in innate and adaptive immunity. Patients with multiple sclerosis (MS), an autoimmune inflammatory demyelinating disease of the central nervous system (CNS), have increased serum levels of IL-37. However, it is unknown whether IL-37 has an inhibitory effect on ongoing autoimmune neuroinflammation, thus offering a potential MS therapy.

AIM: Here, we examined the effect of IL-37 in an experimental autoimmune encephalomyelitis (EAE) model after disease onset to determine if it was protective.

FINDINGS: IL-37-treated mice developed a less severe disease than control mice, with reduced demyelination as determined by increased expression of myelin basic protein. …

Modeling Antisense Oligonucleotide Therapy In Mecp2 Duplication Syndrome Human Ipsc-Derived Neurons Reveals Gene Expression Programs Responsive To Mecp2 Levels, Sameer S Bajikar, Yehezkel Sztainberg, Alexander J Trostle, Harini P Tirumala, Ying-Wooi Wan, Caroline L Harrop, Jesse D Bengtsson, Claudia M B Carvalho, Davut Pehlivan, Bernhard Suter, Jeffrey L Neul, Zhandong Liu, Paymaan Jafar-Nejad, Frank Rigo, Huda Y Zoghbi

Faculty, Staff and Students Publications

Genomic copy-number variations (CNVs) that can cause neurodevelopmental disorders often encompass many genes, which complicates our understanding of how individual genes within a CNV contribute to pathology. MECP2 duplication syndrome (MDS or MRXSL in OMIM; OMIM#300260) is one such CNV disorder caused by duplications spanning methyl CpG-binding protein 2 (MECP2) and other genes on Xq28. Using an antisense oligonucleotide (ASO) to normalize MECP2 dosage is sufficient to rescue abnormal neurological phenotypes in mouse models overexpressing MECP2 alone, implicating the importance of increased MECP2 dosage within CNVs of Xq28. However, because MDS CNVs span MECP2 and additional genes, we generated human …

A Comparison Of The Diagnostic Capability Of Kato-Katz And Real-Time Pcr For The Assessment Of Treatment Efficacy Of Ivermectin And Albendazole Combination Against T Trichiura Infections, Gabriela Matamoros, Ana Sanchez, Ruben Cimino, Alejandro Krolewiecki, Rojelio Mejia

Faculty, Staff and Students Publications

BACKGROUND: Trichuris trichiura is humans' second most prevalent soil-transmitted helminth (STH) infection after Ascaris lumbricoides, affecting approximately 460 million people worldwide. Despite its sub-optimal sensitivity, especially in low prevalence and infection intensity settings, the modified Kato-Katz (K-K) is still recommended as a diagnostic method by the World Health organization (WHO) guidelines.

METHODOLOGY/PRINCIPAL FINDINGS: Within a randomized clinical trial (RCT) comprising four treatment arms with two different anthelmintics, the present study reports an important secondary research objective to determine the diagnostic agreement between K-K and real-time PCR evaluating treatment efficacy against T. trichiura. The parasitological results were analyzed, including cure rates …

Macrophage Iron Dyshomeostasis Promotes Aging-Related Renal Fibrosis, Lingzhi Wu, Hongchun Lin, Shaomin Li, Yuebo Huang, Yuxiang Sun, Shuangshuang Shu, Ting Luo, Tiantian Liang, Weiyan Lai, Jialing Rao, Zhaoyong Hu, Hui Peng

Faculty, Staff and Students Publications

Renal aging, marked by the accumulation of senescent cells and chronic low-grade inflammation, leads to renal interstitial fibrosis and impaired function. In this study, we investigate the role of macrophages, a key regulator of inflammation, in renal aging by analyzing kidney single-cell RNA sequencing data of C57BL/6J mice from 8 weeks to 24 months. Our findings elucidate the dynamic changes in the proportion of kidney cell types during renal aging and reveal that increased macrophage infiltration contributes to chronic low-grade inflammation, with these macrophages exhibiting senescence and activation of ferroptosis signaling. CellChat analysis indicates enhanced communications between macrophages and tubular …

Suppression Of Matrigel-Induced Choroidal Neovascularization By Aav Delivery Of A Novel Anti-Scg3 Antibody, Chengchi Huang, Avinash Kaur, Liyang Ji, Hong Tian, Keith A Webster, Wei Li

Faculty, Staff and Students Publications

Efforts to develop gene therapy for long-term treatment of neovascular disease are hampered by ongoing concerns that biologics against vascular endothelial growth factor (VEGF) inhibit both physiological and pathological angiogenesis and are therefore at elevated risk of adverse side effects. A potential solution is to develop disease-targeted gene therapy. Secretogranin III (Scg3), a unique disease-restricted angiogenic factor described by our group, contributes significantly to ocular neovascular disease. We have shown that Scg3 blockade with a monoclonal antibody Fab fragment (Fab) stringently inhibits pathological angiogenesis without affecting healthy vessels. Here we tested the therapeutic efficacy of adeno-associated virus (AAV)-anti-Scg3Fab to block …

An Ancient Ecospecies Of Helicobacter Pylori, Elise Tourrette, Roberto C Torres, Sarah L Svensson, Takashi Matsumoto, Muhammad Miftahussurur, Kartika Afrida Fauzia, Ricky Indra Alfaray, Ratha-Korn Vilaichone, Vo Phuoc Tuan, Helicobacter Genomics Consortium, Difei Wang, Abbas Yadegar, Lisa M Olsson, Zhemin Zhou, Yoshio Yamaoka, Kaisa Thorell, Daniel Falush

Faculty, Staff and Students Publications

Helicobacter pylori disturbs the stomach lining during long-term colonization of its human host, with sequelae including ulcers and gastric cancer1,2. Numerous H. pylori virulence factors have been identified, showing extensive geographic variation1. Here we identify a ‘Hardy’ ecospecies of H. pylori that shares the ancestry of ‘Ubiquitous’ H. pylori from the same region in most of the genome but has nearly fixed single-nucleotide polymorphism differences in 100 genes, many of which encode outer membrane proteins and host interaction factors. Most Hardy strains have a second urease, which uses iron as a cofactor rather than …