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Macrophage-Derived Mlkl In Alcohol-Associated Liver Disease: Regulation Of Phagocytosis, Xiaoqin Wu, Xiude Fan, Megan R Mcmullen, Tatsunori Miyata, Adam Kim, Vai Pathak, Jianguo Wu, Le Z Day, Josiah E Hardesty, Nicole Welch, Jaividhya Dasarathy, Daniela S Allende, Arthur J Mccullough, Jon M Jacobs, Daniel M Rotroff, Srinivasan Dasarathy, Laura E Nagy Mar 2023

Macrophage-Derived Mlkl In Alcohol-Associated Liver Disease: Regulation Of Phagocytosis, Xiaoqin Wu, Xiude Fan, Megan R Mcmullen, Tatsunori Miyata, Adam Kim, Vai Pathak, Jianguo Wu, Le Z Day, Josiah E Hardesty, Nicole Welch, Jaividhya Dasarathy, Daniela S Allende, Arthur J Mccullough, Jon M Jacobs, Daniel M Rotroff, Srinivasan Dasarathy, Laura E Nagy

Faculty, Staff and Student Publications

BACKGROUND AND AIMS: Mixed lineage kinase domain-like pseudokinase (MLKL), a key terminal effector of necroptosis, also plays a role in intracellular vesicle trafficking that is critical for regulating liver inflammation and injury in alcohol-associated liver disease (ALD). Although receptor interacting protein kinase 3 (Rip3)-/- mice are completely protected from ethanol-induced liver injury, Mlkl-/- mice are only partially protected. Therefore, we hypothesized that cell-specific functions of MLKL may contribute to ethanol-induced injury.

APPROACH AND RESULTS: Bone marrow transplants between Mlkl-/- mice and littermates were conducted to distinguish the role of myeloid versus nonmyeloid Mlkl in the Gao-binge model of ALD. Ethanol-induced …


Electrophysiological Normative Responses To Emotional, Neutral, And Cigarette-Related Images, Francesco Versace, Nicola Sambuco, Menton M Deweese, Paul M Cinciripini Mar 2023

Electrophysiological Normative Responses To Emotional, Neutral, And Cigarette-Related Images, Francesco Versace, Nicola Sambuco, Menton M Deweese, Paul M Cinciripini

Faculty, Staff and Student Publications

To create reproducible emotional probes, affective scientists rely on sets of standardized pictures that are normed using subjective ratings of valence and emotional arousal. However, when emotional responses are investigated using neurophysiological measures, it might be more appropriate to select pictures integrating information from normative subjective reports and normative neurophysiological responses. Here, we provide electrophysiological normative responses for 323 emotional pictures (215 from the IAPS) covering a wide range of categories (erotica, romantic, appetizing foods, landscapes, people engaged in mundane activities, household objects, disgusting objects, accidents, sad people, violence, mutilations, and cigarette-related contents). Event-related potentials (ERPs) and subjective ratings of …


Persistent Nociceptor Hyperactivity As A Painful Evolutionary Adaptation, Edgar T Walters, Robyn J Crook, G Gregory Neely, Theodore J Price, Ewan St John Smith Mar 2023

Persistent Nociceptor Hyperactivity As A Painful Evolutionary Adaptation, Edgar T Walters, Robyn J Crook, G Gregory Neely, Theodore J Price, Ewan St John Smith

Faculty, Staff and Student Publications

Chronic pain caused by injury or disease of the nervous system (neuropathic pain) has been linked to persistent electrical hyperactivity of the sensory neurons (nociceptors) specialized to detect damaging stimuli and/or inflammation. This pain and hyperactivity are considered maladaptive because both can persist long after injured tissues have healed and inflammation has resolved. While the assumption of maladaptiveness is appropriate in many diseases, accumulating evidence from diverse species, including humans, challenges the assumption that neuropathic pain and persistent nociceptor hyperactivity are always maladaptive. We review studies indicating that persistent nociceptor hyperactivity has undergone evolutionary selection in widespread, albeit selected, animal …


Endotrophin Neutralization Through Targeted Antibody Treatment Protects From Renal Fibrosis In A Podocyte Ablation Model, Yu A An, Wei Xiong, Shiuhwei Chen, Dawei Bu, Joseph M Rutkowski, Joel P Berger, Christine M Kusminski, Ningyan Zhang, Zhiqiang An, Philipp E Scherer Mar 2023

Endotrophin Neutralization Through Targeted Antibody Treatment Protects From Renal Fibrosis In A Podocyte Ablation Model, Yu A An, Wei Xiong, Shiuhwei Chen, Dawei Bu, Joseph M Rutkowski, Joel P Berger, Christine M Kusminski, Ningyan Zhang, Zhiqiang An, Philipp E Scherer

Faculty, Staff and Student Publications

OBJECTIVE: Renal fibrosis is a hallmark for chronic kidney disease (CKD), and often leads to end stage renal disease (ESRD). However, limited interventions are available clinically to ameliorate or reverse renal fibrosis.

METHODS: Herein, we evaluated whether blockade of endotrophin through neutralizing antibodies protects from renal fibrosis in the podocyte insult model (the "POD-ATTAC" mouse). We determined the therapeutic effects of endotrophin targeted antibody through assessing renal function, renal inflammation and fibrosis at histological and transcriptional levels, and podocyte regeneration.

RESULTS: We demonstrated that neutralizing endotrophin antibody treatment significantly ameliorates renal fibrosis at the transcriptional, morphological, and functional levels. In …


A Potent And Broad Neutralization Of Sars-Cov-2 Variants Of Concern By Darpins, Vikas Chonira, Young D Kwon, Jason Gorman, James Brett Case, Zhiqiang Ku, Rudo Simeon, Ryan G Casner, Darcy R Harris, Adam S Olia, Tyler Stephens, Lawrence Shapiro, Michael F Bender, Hannah Boyd, I-Ting Teng, Yaroslav Tsybovsky, Florian Krammer, Ningyan Zhang, Michael S Diamond, Peter D Kwong, Zhiqiang An, Zhilei Chen Mar 2023

A Potent And Broad Neutralization Of Sars-Cov-2 Variants Of Concern By Darpins, Vikas Chonira, Young D Kwon, Jason Gorman, James Brett Case, Zhiqiang Ku, Rudo Simeon, Ryan G Casner, Darcy R Harris, Adam S Olia, Tyler Stephens, Lawrence Shapiro, Michael F Bender, Hannah Boyd, I-Ting Teng, Yaroslav Tsybovsky, Florian Krammer, Ningyan Zhang, Michael S Diamond, Peter D Kwong, Zhiqiang An, Zhilei Chen

Faculty, Staff and Student Publications

We report the engineering and selection of two synthetic proteins-FSR16m and FSR22-for the possible treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. FSR16m and FSR22 are trimeric proteins composed of DARPin SR16m or SR22 fused with a T4 foldon. Despite selection by a spike protein from a now historical SARS-CoV-2 strain, FSR16m and FSR22 exhibit broad-spectrum neutralization of SARS-CoV-2 strains, inhibiting authentic B.1.351, B.1.617.2 and BA.1.1 viruses, with respective IC


Association Of IsvSa3 With Multidrug Resistance In Salmonella Enterica Isolates From Cattle (Bos Taurus), Gentry L. Lewis, Robert J. Fenton, Etsuko Moriyama, John Dustin Loy, Rodney A. Moxley Feb 2023

Association Of IsvSa3 With Multidrug Resistance In Salmonella Enterica Isolates From Cattle (Bos Taurus), Gentry L. Lewis, Robert J. Fenton, Etsuko Moriyama, John Dustin Loy, Rodney A. Moxley

School of Veterinary and Biomedical Sciences: Faculty Publications

Salmonella enterica is, globally, an important cause of human illness with beef being a significant attributable source. In the human patient, systemic Salmonella infection requires antibiotic therapy, and when strains are multidrug resistant (MDR), no effective treatment may be available. MDR in bacteria is often associated with the presence of mobile genetic elements (MGE) that mediate horizontal spread of antimicrobial resistance (AMR) genes. In this study, we sought to determine the potential relationship of MDR in bovine Salmonella isolates with MGE. The present study involved 111 bovine Salmonella isolates obtained collectively from specimens derived from healthy cattle or their environments …


Narrative Review Of Single Ventricle: Where Are We After 40 Years?, Antonio F Corno, Tina O Findley, Jorge D Salazar Feb 2023

Narrative Review Of Single Ventricle: Where Are We After 40 Years?, Antonio F Corno, Tina O Findley, Jorge D Salazar

Faculty, Staff and Student Publications

Background and objective: Key medical and surgical advances have been made in the longitudinal management of patients with "functionally" single ventricle physiology, with the principles of Fontan circulation applied to other complex congenital heart defects. The purpose of this article is to review all of the innovations, starting from fetal life, that led to a change of strategy for single ventricle.

Methods: Our literature review included all full articles published in English language on the Cochrane, MedLine, and Embase with references to "single ventricle" and "univentricular hearts", including the initial history of the treatments for this congenital heart defects as …


Does The Potocki-Lupski Syndrome Convey The Autism Spectrum Disorder Phenotype? Case Report And Scoping Review, Oksana I Talantseva, Galina V Portnova, Raisa S Romanova, Daria A Martynova, Olga V Sysoeva, Elena L Grigorenko Feb 2023

Does The Potocki-Lupski Syndrome Convey The Autism Spectrum Disorder Phenotype? Case Report And Scoping Review, Oksana I Talantseva, Galina V Portnova, Raisa S Romanova, Daria A Martynova, Olga V Sysoeva, Elena L Grigorenko

Faculty, Staff and Students Publications

Potocki-Lupski Syndrome (PTLS) is a rare condition associated with a duplication of 17p11.2 that may underlie a wide range of congenital abnormalities and heterogeneous behavioral phenotypes. Along with developmental delay and intellectual disability, autism-specific traits are often reported to be the most common among patients with PTLS. To contribute to the discussion of the role of autism spectrum disorder (ASD) in the PTLS phenotype, we present a case of a female adolescent with a de novo dup(17) (p11.2p11.2) without ASD features, focusing on in-depth clinical, behavioral, and electrophysiological (EEG) evaluations. Among EEG features, we found the atypical peak-slow wave patterns …


Excess Folic Acid Intake Increases Dna De Novo Point Mutations, Xuanye Cao, Jianfeng Xu, Ying L Lin, Robert M Cabrera, Qiuying Chen, Chaofan Zhang, John W Steele, Xiao Han, Steven S Gross, Bogdan J Wlodarczyk, James R Lupski, Wei Li, Hongyan Wang, Richard H Finnell, Yunping Lei Feb 2023

Excess Folic Acid Intake Increases Dna De Novo Point Mutations, Xuanye Cao, Jianfeng Xu, Ying L Lin, Robert M Cabrera, Qiuying Chen, Chaofan Zhang, John W Steele, Xiao Han, Steven S Gross, Bogdan J Wlodarczyk, James R Lupski, Wei Li, Hongyan Wang, Richard H Finnell, Yunping Lei

Faculty, Staff and Students Publications

No abstract provided.


Jaml Immunotherapy Targets Recently Activated Tumor-Infiltrating Cd8+ T Cells, Simon Eschweiler, Alice Wang, Ciro Ramírez-Suástegui, Adrian Von Witzleben, Yingcong Li, Serena J Chee, Hayley Simon, Monalisa Mondal, Matthew Ellis, Gareth J Thomas, Vivek Chandra, Christian H Ottensmeier, Pandurangan Vijayanand Feb 2023

Jaml Immunotherapy Targets Recently Activated Tumor-Infiltrating Cd8+ T Cells, Simon Eschweiler, Alice Wang, Ciro Ramírez-Suástegui, Adrian Von Witzleben, Yingcong Li, Serena J Chee, Hayley Simon, Monalisa Mondal, Matthew Ellis, Gareth J Thomas, Vivek Chandra, Christian H Ottensmeier, Pandurangan Vijayanand

Faculty, Staff and Student Publications

Junctional adhesion molecule-like protein (JAML) serves as a co-stimulatory molecule in γδ T cells. While it has recently been described as a cancer immunotherapy target in mice, its potential to cause toxicity, specific mode of action with regard to its cellular targets, and whether it can be targeted in humans remain unknown. Here, we show that JAML is induced by T cell receptor engagement, reveal that this induction is linked to cis-regulatory interactions between the CD3D and JAML gene loci. When compared with other immunotherapy targets plagued by low target specificity and end-organ toxicity, we find JAML to be mostly …


Allosteric Autoregulation Of Dna Binding Via A Dna-Mimicking Protein Domain: A Biophysical Study Of Znf410-Dna Interaction Using Small Angle X-Ray Scattering, Gundeep Kaur, Ren Ren, Michal Hammel, John R Horton, Jie Yang, Yu Cao, Chenxi He, Fei Lan, Xianjiang Lan, Gerd A Blobel, Robert M Blumenthal, Xing Zhang, Xiaodong Cheng Feb 2023

Allosteric Autoregulation Of Dna Binding Via A Dna-Mimicking Protein Domain: A Biophysical Study Of Znf410-Dna Interaction Using Small Angle X-Ray Scattering, Gundeep Kaur, Ren Ren, Michal Hammel, John R Horton, Jie Yang, Yu Cao, Chenxi He, Fei Lan, Xianjiang Lan, Gerd A Blobel, Robert M Blumenthal, Xing Zhang, Xiaodong Cheng

Faculty, Staff and Student Publications

ZNF410 is a highly-conserved transcription factor, remarkable in that it recognizes a 15-base pair DNA element but has just a single responsive target gene in mammalian erythroid cells. ZNF410 includes a tandem array of five zinc-fingers (ZFs), surrounded by uncharacterized N- and C-terminal regions. Unexpectedly, full-length ZNF410 has reduced DNA binding affinity, compared to that of the isolated DNA binding ZF array, both in vitro and in cells. AlphaFold predicts a partially-folded N-terminal subdomain that includes a 30-residue long helix, preceded by a hairpin loop rich in acidic (aspartate/glutamate) and serine/threonine residues. This hairpin loop is predicted by AlphaFold to …


Determinants And Mechanisms Of The Low Fusogenicity And High Dependence On Endosomal Entry Of Omicron Subvariants, Panke Qu, John P Evans, Chaitanya Kurhade, Cong Zeng, Yi-Min Zheng, Kai Xu, Pei-Yong Shi, Xuping Xie, Shan-Lu Liu Feb 2023

Determinants And Mechanisms Of The Low Fusogenicity And High Dependence On Endosomal Entry Of Omicron Subvariants, Panke Qu, John P Evans, Chaitanya Kurhade, Cong Zeng, Yi-Min Zheng, Kai Xu, Pei-Yong Shi, Xuping Xie, Shan-Lu Liu

Faculty, Staff and Student Publications

The rapid spread and strong immune evasion of the SARS-CoV-2 Omicron subvariants has raised serious concerns for the global COVID-19 pandemic. These new variants exhibit generally reduced fusogenicity and increased endosomal entry pathway utilization compared to the ancestral D614G variant, the underlying mechanisms of which remain elusive. Here, we show that the C-terminal S1 mutations of the BA.1.1 subvariant, H655Y and T547K, critically govern the low fusogenicity of Omicron. Notably, H655Y also dictates the enhanced endosome entry pathway utilization. Mechanistically, T547K and H655Y likely stabilize the spike trimer conformation as suggested by increased molecular interactions in structural modeling and enhanced …


Mecp2 Regulates Gdf11, A Dosage-Sensitive Gene Critical For Neurological Function, Sameer S Bajikar, Ashley G Anderson, Jian Zhou, Mark A Durham, Alexander J Trostle, Ying-Wooi Wan, Zhandong Liu, Huda Y Zoghbi Feb 2023

Mecp2 Regulates Gdf11, A Dosage-Sensitive Gene Critical For Neurological Function, Sameer S Bajikar, Ashley G Anderson, Jian Zhou, Mark A Durham, Alexander J Trostle, Ying-Wooi Wan, Zhandong Liu, Huda Y Zoghbi

Faculty, Staff and Students Publications

Loss- and gain-of-function of MeCP2 causes Rett syndrome (RTT) and MECP2 duplication syndrome (MDS), respectively. MeCP2 binds methyl-cytosines to finely tune gene expression in the brain, but identifying genes robustly regulated by MeCP2 has been difficult. By integrating multiple transcriptomics datasets, we revealed that MeCP2 finely regulates growth differentiation factor 11 (Gdf11). Gdf11 is down-regulated in RTT mouse models and, conversely, up-regulated in MDS mouse models. Strikingly, genetically normalizing Gdf11 dosage levels improved several behavioral deficits in a mouse model of MDS. Next, we discovered that losing one copy of Gdf11 alone was sufficient to cause multiple neurobehavioral …


Uncovering Novel Regulators Of Memory Using C Elegans Genetic And Genomic Analysis, Katie L Brandel-Ankrapp, Rachel N Arey Feb 2023

Uncovering Novel Regulators Of Memory Using C Elegans Genetic And Genomic Analysis, Katie L Brandel-Ankrapp, Rachel N Arey

Faculty, Staff and Students Publications

How organisms learn and encode memory is an outstanding question in neuroscience research. Specifically, how memories are acquired and consolidated at the level of molecular and gene pathways remains unclear. In addition, memory is disrupted in a wide variety of neurological disorders; therefore, discovering molecular regulators of memory may reveal therapeutic targets for these disorders. C. elegans are an excellent model to uncover molecular and genetic regulators of memory. Indeed, the nematode's invariant neuronal lineage, fully mapped genome, and conserved associative behaviors have allowed the development of a breadth of genetic and genomic tools to examine learning and memory. In …


Recent Advances In Psychopharmacology: From Bench To Bedside Novel Trends In Schizophrenia, Asim A Shah, Syed Z Iqbal Feb 2023

Recent Advances In Psychopharmacology: From Bench To Bedside Novel Trends In Schizophrenia, Asim A Shah, Syed Z Iqbal

Faculty, Staff and Students Publications

Research in the field of psychopharmacology is ongoing to develop novel compounds which can revolutionize the treatment of psychiatric disorders. The concept of bench-to-bedside is a tedious process, transforming the initial research performed in the laboratories into novel treatment options. Schizophrenia (SCZ) is a chronic psychiatric illness with significant morbidity and mortality. SCZ not only presents with psychotic symptoms including hallucinations and delusions but also with negative and cognitive symptoms. The negative symptoms include the diminished ability to express emotions, loss of pleasure, and motivation with minimal social interactions. Conventional antipsychotics primarily target positive symptoms with minimal therapeutic benefits for …


New Synthetic Opioids: Clinical Considerations And Dangers, Amber Edinoff, David Martinez Garza, Stephen Vining, Megan Vasterling, Eric Jackson, Kevin Murnane, Adam Kaye, Richard Fair, Yair Jose Lopez Torres, Ahmed Badr, Elyse Cornett, Alan Kaye Feb 2023

New Synthetic Opioids: Clinical Considerations And Dangers, Amber Edinoff, David Martinez Garza, Stephen Vining, Megan Vasterling, Eric Jackson, Kevin Murnane, Adam Kaye, Richard Fair, Yair Jose Lopez Torres, Ahmed Badr, Elyse Cornett, Alan Kaye

School of Medicine Faculty Publications

Since the early 2010s, synthetic opioids have significantly contributed to overall opioid-related overdose mortalities. For point of reference, of the 68,630 opioid-related deaths recorded in 2020, 56,516 involved synthetic opioids. During much of this period, fentanyl has been the most commonly used synthetic opioid. This time when fentanyl was the most popular opioid has been called the “third wave” of the opioid crisis, partly because it led to a sharp rise in deaths from overdoses. Other synthetic opioids, such as carfentanil, protonitazene, and isotonitazene, have also become more widely diverted for nonmedical used. Carfentanil is an even more potent fentanyl …


Feasibility Of [18f]Fspg Pet For Early Response Assessment To Combined Blockade Of Egfr And Glutamine Metabolism In Wild-Type Kras Colorectal Cancer, Seong-Woo Bae, Jianbo Wang, Dimitra K Georgiou, Xiaoxia Wen, Allison S Cohen, Ling Geng, Mohammed Noor Tantawy, H Charles Manning Feb 2023

Feasibility Of [18f]Fspg Pet For Early Response Assessment To Combined Blockade Of Egfr And Glutamine Metabolism In Wild-Type Kras Colorectal Cancer, Seong-Woo Bae, Jianbo Wang, Dimitra K Georgiou, Xiaoxia Wen, Allison S Cohen, Ling Geng, Mohammed Noor Tantawy, H Charles Manning

Faculty, Staff and Student Publications

Early response assessment is critical for personalizing cancer therapy. Emerging therapeutic regimens with encouraging results in the wild-type (WT) KRAS colorectal cancer (CRC) setting include inhibitors of epidermal growth factor receptor (EGFR) and glutaminolysis. Towards predicting clinical outcome, this preclinical study evaluated non-invasive positron emission tomography (PET) with (4S)-4-(3-[18F]fluoropropyl)-L-glutamic acid ([18F]FSPG) in treatment-sensitive and treatment-resistant WT KRAS CRC patient-derived xenografts (PDXs). Tumor-bearing mice were imaged with [18F]FSPG PET before and one week following the initiation of treatment with either EGFR-targeted monoclonal antibody (mAb) therapy, glutaminase inhibitor therapy, or the combination. Imaging was correlated with tumor volume and histology. In PDX …


Macroh2a Histone Variants Modulate Enhancer Activity To Repress Oncogenic Programs And Cellular Reprogramming, Wazim Mohammed Ismail, Amelia Mazzone, Flavia G Ghiraldini, Jagneet Kaur, Manvir Bains, Amik Munankarmy, Monique S Bagwell, Stephanie L Safgren, John Moore-Weiss, Marina Buciuc, Lynzie Shimp, Kelsey A Leach, Luis F Duarte, Chandandeep S Nagi, Saul Carcamo, Chi-Yeh Chung, Dan Hasson, Neda Dadgar, Jian Zhong, Jeong-Heon Lee, Fergus J Couch, Alexander Revzin, Tamas Ordog, Emily Bernstein, Alexandre Gaspar-Maia Feb 2023

Macroh2a Histone Variants Modulate Enhancer Activity To Repress Oncogenic Programs And Cellular Reprogramming, Wazim Mohammed Ismail, Amelia Mazzone, Flavia G Ghiraldini, Jagneet Kaur, Manvir Bains, Amik Munankarmy, Monique S Bagwell, Stephanie L Safgren, John Moore-Weiss, Marina Buciuc, Lynzie Shimp, Kelsey A Leach, Luis F Duarte, Chandandeep S Nagi, Saul Carcamo, Chi-Yeh Chung, Dan Hasson, Neda Dadgar, Jian Zhong, Jeong-Heon Lee, Fergus J Couch, Alexander Revzin, Tamas Ordog, Emily Bernstein, Alexandre Gaspar-Maia

Faculty, Staff and Students Publications

Considerable efforts have been made to characterize active enhancer elements, which can be annotated by accessible chromatin and H3 lysine 27 acetylation (H3K27ac). However, apart from poised enhancers that are observed in early stages of development and putative silencers, the functional significance of cis-regulatory elements lacking H3K27ac is poorly understood. Here we show that macroH2A histone variants mark a subset of enhancers in normal and cancer cells, which we coined 'macro-Bound Enhancers', that modulate enhancer activity. We find macroH2A variants localized at enhancer elements that are devoid of H3K27ac in a cell type-specific manner, indicating a role for macroH2A at …


Effects Of Hepatocyte Growth Factor On Porcine Mammary Cell Growth And Senescence, Chi-Ping Huang, Liang-Chih Liu, Hsin-Ling Lu, Chih-Rong Shyr Feb 2023

Effects Of Hepatocyte Growth Factor On Porcine Mammary Cell Growth And Senescence, Chi-Ping Huang, Liang-Chih Liu, Hsin-Ling Lu, Chih-Rong Shyr

BioMedicine

Background: The porcine mammary glands share morphological and physiological similarities with human ones, making primary porcine mammary cells (PMC) suitable for biomedical research and a potential cellular therapeutic for breast cancer xenogeneic cell immunotherapy. Primary cells isolated from tissues remain the physiological functions of origin tissues but their self-renewal ability is restricted and cells acquire senescence during in vitro expansion. To overcome these drawbacks, here we sought to establish an approach to efficiently increase PMC’s in vitro growth. We studied the effects of the hepatocyte growth factor (HGF) to maintain the expansion capacity of porcine mammary cells and identify the …


New-Onset Diabetes In Covid-19: The Molecular Pathogenesis, Desak Made Wihandani, Made Lady Adelaida Purwanta, W. Riski Widya Mulyani, I Wayan Ardyan Sudharta Putra, I Gede Putu Supadmanaba Feb 2023

New-Onset Diabetes In Covid-19: The Molecular Pathogenesis, Desak Made Wihandani, Made Lady Adelaida Purwanta, W. Riski Widya Mulyani, I Wayan Ardyan Sudharta Putra, I Gede Putu Supadmanaba

BioMedicine

Diabetes mellitus (DM) is still a challenging metabolic disease worldwide. In the current situation, the world is facing a COVID-19 pandemic due to SARS-CoV-2 infection. DM is one of comorbid that can worsen the severity of the COVID-19 condition. Surprisingly, SARS-CoV-2 infection can induce new-onset diabetes, a condition in which acute hyperglycemia occurs and may potentially develop into a complication in non-diabetic patients. Angiotensin-converting enzyme 2 (ACE2) is a crucial entry factor of SARS-CoV-2 infection. ACE2 will bind to the spike protein of SARS-CoV-2, making its entrance to the potentially damaging process of many tissues in the human body, including …


Tfeb-Mediated Lysosomal Exocytosis Alleviates High-Fat Diet-Induced Lipotoxicity In The Kidney, Jun Nakamura, Takeshi Yamamoto, Yoshitsugu Takabatake, Tomoko Namba-Hamano, Satoshi Minami, Atsushi Takahashi, Jun Matsuda, Shinsuke Sakai, Hiroaki Yonishi, Shihomi Maeda, Sho Matsui, Isao Matsui, Takayuki Hamano, Masatomo Takahashi, Maiko Goto, Yoshihiro Izumi, Takeshi Bamba, Miwa Sasai, Masahiro Yamamoto, Taiji Matsusaka, Fumio Niimura, Motoko Yanagita, Shuhei Nakamura, Tamotsu Yoshimori, Andrea Ballabio, Yoshitaka Isaka Feb 2023

Tfeb-Mediated Lysosomal Exocytosis Alleviates High-Fat Diet-Induced Lipotoxicity In The Kidney, Jun Nakamura, Takeshi Yamamoto, Yoshitsugu Takabatake, Tomoko Namba-Hamano, Satoshi Minami, Atsushi Takahashi, Jun Matsuda, Shinsuke Sakai, Hiroaki Yonishi, Shihomi Maeda, Sho Matsui, Isao Matsui, Takayuki Hamano, Masatomo Takahashi, Maiko Goto, Yoshihiro Izumi, Takeshi Bamba, Miwa Sasai, Masahiro Yamamoto, Taiji Matsusaka, Fumio Niimura, Motoko Yanagita, Shuhei Nakamura, Tamotsu Yoshimori, Andrea Ballabio, Yoshitaka Isaka

Duncan NRI Faculty and Staff Publications

Obesity is a major risk factor for end-stage kidney disease. We previously found that lysosomal dysfunction and impaired autophagic flux contribute to lipotoxicity in obesity-related kidney disease, in both humans and experimental animal models. However, the regulatory factors involved in countering renal lipotoxicity are largely unknown. Here, we found that palmitic acid strongly promoted dephosphorylation and nuclear translocation of transcription factor EB (TFEB) by inhibiting the mechanistic target of rapamycin kinase complex 1 pathway in a Rag GTPase-dependent manner, though these effects gradually diminished after extended treatment. We then investigated the role of TFEB in the pathogenesis of obesity-related kidney …


Asprosin Promotes Feeding Through Sk Channel-Dependent Activation Of Agrp Neurons, Bing Feng, Hesong Liu, Ila Mishra, Clemens Duerrschmid, Peiyu Gao, Pingwen Xu, Chunmei Wang, Yanlin He Feb 2023

Asprosin Promotes Feeding Through Sk Channel-Dependent Activation Of Agrp Neurons, Bing Feng, Hesong Liu, Ila Mishra, Clemens Duerrschmid, Peiyu Gao, Pingwen Xu, Chunmei Wang, Yanlin He

Faculty, Staff and Students Publications

Asprosin, a recently identified adipokine, activates agouti-related peptide (AgRP) neurons in the arcuate nucleus of the hypothalamus (ARH) via binding to protein tyrosine phosphatase receptor δ (Ptprd) to increase food intake. However, the intracellular mechanisms responsible for asprosin/Ptprd-mediated activation of AgRPARH neurons remain unknown. Here, we demonstrate that the small-conductance calcium-activated potassium (SK) channel is required for the stimulatory effects of asprosin/Ptprd on AgRPARH neurons. Specifically, we found that deficiency or elevation of circulating asprosin increased or decreased the SK current in AgRPARH neurons, respectively. AgRPARH-specific deletion of SK3 (an SK channel subtype highly expressed in AgRPARH neurons) blocked asprosin-induced …


Alternative Splicing Mediates The Compensatory Upregulation Of Mbnl2 Upon Mbnl1 Loss-Of-Function, Larissa Nitschke, Rong-Chi Hu, Andrew N Miller, Lathan Lucas, Thomas A Cooper Feb 2023

Alternative Splicing Mediates The Compensatory Upregulation Of Mbnl2 Upon Mbnl1 Loss-Of-Function, Larissa Nitschke, Rong-Chi Hu, Andrew N Miller, Lathan Lucas, Thomas A Cooper

Faculty, Staff and Students Publications

Loss of gene function can be compensated by paralogs with redundant functions. An example of such compensation are the paralogs of the Muscleblind-Like (MBNL) family of RNA-binding proteins that are sequestered and lose their function in Myotonic Dystrophy Type 1 (DM1). Loss of MBNL1 increases the levels of its paralog MBNL2 in tissues where Mbnl2 expression is low, allowing MBNL2 to functionally compensate for MBNL1 loss. Here, we show that loss of MBNL1 increases the inclusion of Mbnl2 exon 6 and exon 9. We find that inclusion of Mbnl2 exon 6 increases the translocation of MBNL2 to the nucleus, while …


Evofosfamide For The Treatment Of Human Papillomavirus-Negative Head And Neck Squamous Cell Carcinoma, Stephen Mf Jamieson, Peter Tsai, Maria K Kondratyev, Pratha Budhani, Arthur Liu, Neil N Senzer, E Gabriela Chiorean, Shadia I Jalal, John J Nemunaitis, Dennis Kee, Avik Shome, Way W Wong, Dan Li, Nooriyah Poonawala-Lohani, Purvi M Kakadia, Nicholas S Knowlton, Courtney Rh Lynch, Cho R Hong, Tet Woo Lee, Reidar A Grénman, Laura Caporiccio, Trevor D Mckee, Mark Zaidi, Sehrish Butt, Andrew Mj Macann, Nicholas P Mcivor, John M Chaplin, Kevin O Hicks, Stefan K Bohlander, Bradly G Wouters, Charles P Hart, Cristin G Print, William R Wilson, Michael A Curran, Francis W Hunter Feb 2023

Evofosfamide For The Treatment Of Human Papillomavirus-Negative Head And Neck Squamous Cell Carcinoma, Stephen Mf Jamieson, Peter Tsai, Maria K Kondratyev, Pratha Budhani, Arthur Liu, Neil N Senzer, E Gabriela Chiorean, Shadia I Jalal, John J Nemunaitis, Dennis Kee, Avik Shome, Way W Wong, Dan Li, Nooriyah Poonawala-Lohani, Purvi M Kakadia, Nicholas S Knowlton, Courtney Rh Lynch, Cho R Hong, Tet Woo Lee, Reidar A Grénman, Laura Caporiccio, Trevor D Mckee, Mark Zaidi, Sehrish Butt, Andrew Mj Macann, Nicholas P Mcivor, John M Chaplin, Kevin O Hicks, Stefan K Bohlander, Bradly G Wouters, Charles P Hart, Cristin G Print, William R Wilson, Michael A Curran, Francis W Hunter

Faculty, Staff and Student Publications

Evofosfamide (TH-302) is a clinical-stage hypoxia-activated prodrug of a DNA-crosslinking nitrogen mustard that has potential utility for human papillomavirus (HPV) negative head and neck squamous cell carcinoma (HNSCC), in which tumor hypoxia limits treatment outcome. We report the preclinical efficacy, target engagement, preliminary predictive biomarkers and initial clinical activity of evofosfamide for HPV-negative HNSCC. Evofosfamide was assessed in 22 genomically characterized cell lines and 7 cell line–derived xenograft (CDX), patient-derived xenograft (PDX), orthotopic, and syngeneic tumor models. Biomarker analysis used RNA sequencing, whole-exome sequencing, and whole-genome CRISPR knockout screens. Five advanced/metastatic HNSCC patients received evofosfamide monotherapy (480 mg/m2 qw × …


Inflammatory Cytokine Elaboration Following Secondhand Smoke Exposure Is Mediated In Part By Rage Signaling, Paul Reynolds Feb 2023

Inflammatory Cytokine Elaboration Following Secondhand Smoke Exposure Is Mediated In Part By Rage Signaling, Paul Reynolds

Annual Research Symposium

No abstract provided.


Rage Availability Lessens The Degree Of Dysfunctional Mitochondrial Bioenergetics Following Chronic Secondhand Smoke Exposure, Paul Reynolds Feb 2023

Rage Availability Lessens The Degree Of Dysfunctional Mitochondrial Bioenergetics Following Chronic Secondhand Smoke Exposure, Paul Reynolds

Annual Research Symposium

No abstract provided.


Gestational Dependent Responses To Second Hand Smoke (Shs) In Mouse Pregnancies, Paul Reynolds Feb 2023

Gestational Dependent Responses To Second Hand Smoke (Shs) In Mouse Pregnancies, Paul Reynolds

Annual Research Symposium

No abstract provided.


Promoting Health Equity: Identifying Parent And Child Reactions To A Culturally-Grounded Obesity Prevention Program Specifically Designed For Black Girls Using Community-Engaged Research, Haley Allen, Chishinga Callender, Debbe Thompson Feb 2023

Promoting Health Equity: Identifying Parent And Child Reactions To A Culturally-Grounded Obesity Prevention Program Specifically Designed For Black Girls Using Community-Engaged Research, Haley Allen, Chishinga Callender, Debbe Thompson

Children’s Nutrition Research Center Staff Publications

The Butterfly Girls (BFG) Study is a culturally and developmentally appropriate online obesity prevention program for 8-10-year-old Black girls designed with key stakeholders in the Black community. This multi-methods investigation, conducted with parent-child dyads who participated in an outcome evaluation of the intervention, aimed to understand parent and child reactions to the program. We were particularly interested in understanding perceptions regarding its cultural and developmental appropriateness, relevance and acceptability. Program participation and survey data (demographics, parent and child write-in comments on process evaluation surveys) were analyzed. Participation data demonstrated high adherence in treatment and comparison groups. Descriptive statistics were calculated …


Identification Of Small-Molecule Inhibitors Of The Salmonella Frab Deglycase Using A Live-Cell Assay, Anice Sabag-Daigle, Erin F Boulanger, Pankajavalli Thirugnanasambantham, Jamison D Law, Alex J Bogard, Edward J Behrman, Venkat Gopalan, Brian M M Ahmer Feb 2023

Identification Of Small-Molecule Inhibitors Of The Salmonella Frab Deglycase Using A Live-Cell Assay, Anice Sabag-Daigle, Erin F Boulanger, Pankajavalli Thirugnanasambantham, Jamison D Law, Alex J Bogard, Edward J Behrman, Venkat Gopalan, Brian M M Ahmer

Faculty, Staff and Student Publications

Nontyphoidal salmonellosis is one of the most significant foodborne diseases in the United States and globally. There are no vaccines available for human use to prevent this disease, and only broad-spectrum antibiotics are available to treat complicated cases of the disease. However, antibiotic resistance is on the rise and new therapeutics are needed. We previously identified the Salmonella fraB gene, that mutation of causes attenuation of fitness in the murine gastrointestinal tract. The FraB gene product is encoded in an operon responsible for the uptake and utilization of fructose-asparagine (F-Asn), an Amadori product found in several human foods. Mutations in …


Slo3 In The Fast Lane: The Latest Male Contraceptive Target With A Promising Small-Molecule Inhibitor, Zhi Tan, Thomas X Garcia Feb 2023

Slo3 In The Fast Lane: The Latest Male Contraceptive Target With A Promising Small-Molecule Inhibitor, Zhi Tan, Thomas X Garcia

Faculty, Staff and Students Publications

No abstract provided.