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Articles 1261 - 1290 of 8643

Full-Text Articles in Medicine and Health Sciences

Dense Granule Protein 3 Of Toxoplasma Gondii Plays A Crucial Role In The Capability Of The Tissue Cysts Of The Parasite To Persist In The Presence Of Anti-Cyst Cd8+ T Cells During The Chronic Stage Of Infection, Rajesh Mani, Mohamed H. Abdelaziz, Eri Ochiai, Qila Sa, Barbara A. Fox, David J. Bzik, Yasuhiro Suzuki Oct 2023

Dense Granule Protein 3 Of Toxoplasma Gondii Plays A Crucial Role In The Capability Of The Tissue Cysts Of The Parasite To Persist In The Presence Of Anti-Cyst Cd8+ T Cells During The Chronic Stage Of Infection, Rajesh Mani, Mohamed H. Abdelaziz, Eri Ochiai, Qila Sa, Barbara A. Fox, David J. Bzik, Yasuhiro Suzuki

Markey Cancer Center Faculty Publications

Toxoplasma gondii establishes chronic infection by forming tissue cysts, and this chronic infection is one of the most common parasitic infections in humans. Our recent studies revealed that whereas CD8 + T cells of genetically resistant BALB/c mice have the capability to remove the tissue cysts of the parasite through their perforin-mediated activities, small portions of the cysts are capable of persisting in the presence of the anti-cyst CD8+ T cells. It is currently unknown how those small portions of the cysts resist or escape the T-cell immunity and persist in the hosts. In the present study, we discovered that …


Distinct Camp Signaling Microdomains Differentially Regulate Melanosomal Ph And Pigmentation, Maftuna Yusupova, Dalee Zhou, Jaewon You, Jeydi Gonzalez-Guzman, Megha B. Ghanta, Hong Pu, Zalfa Abdel-Malek, Qiuying Chen, Steven S. Gross, John August D'Orazio, Shosuke Ito, Kazumasa Wakamatsu, Melissa L. Harris, Jonathan H. Zippin Oct 2023

Distinct Camp Signaling Microdomains Differentially Regulate Melanosomal Ph And Pigmentation, Maftuna Yusupova, Dalee Zhou, Jaewon You, Jeydi Gonzalez-Guzman, Megha B. Ghanta, Hong Pu, Zalfa Abdel-Malek, Qiuying Chen, Steven S. Gross, John August D'Orazio, Shosuke Ito, Kazumasa Wakamatsu, Melissa L. Harris, Jonathan H. Zippin

Markey Cancer Center Faculty Publications

cAMP signaling is a well-established regulator of melanin synthesis. Two distinct cAMP signaling pathways—the transmembrane adenylyl cyclase pathway, activated primarily by the MC1R, and the soluble adenylyl cyclase (sAC) pathway—affect melanin synthesis. The sAC pathway affects melanin synthesis by regulating melanosomal pH, and the MC1R pathway affects melanin synthesis by regulating gene expression and post-translational modifications. However, whether MC1R genotype affects melanosomal pH is poorly understood. We now report that loss of function MC1R does not affect melanosomal pH. Thus, sAC signaling appears to be the only cAMP signaling pathway that regulates melanosomal pH. We also addressed whether MC1R genotype …


Effects Of Interfraction Dose Variations Of Target And Organs At Risk On Clinical Outcomes In High Dose Rate Brachytherapy For Cervical Cancer, Brien Washington, Dennis C. Cheek, Denise Fabian, Mahesh R. Kudrimoti, Damodar Pokhrel, Chi Wang, Cameron Thayer-Freeman, Wei Luo Oct 2023

Effects Of Interfraction Dose Variations Of Target And Organs At Risk On Clinical Outcomes In High Dose Rate Brachytherapy For Cervical Cancer, Brien Washington, Dennis C. Cheek, Denise Fabian, Mahesh R. Kudrimoti, Damodar Pokhrel, Chi Wang, Cameron Thayer-Freeman, Wei Luo

Markey Cancer Center Faculty Publications

Meeting dose prescription is critical to control tumors in radiation therapy. Interfraction dose variations (IDVs) from the prescribed dose in high dose rate brachytherapy (HDR) would cause the target dose to deviate from the prescription but their clinical effect has not been widely discussed in the literature. Our previous study found that IDVs followed a left-skewed distribution. The clinical effect of the IDVs in 100 cervical cancer HDR patients will be addressed in this paper. An in-house Monte Carlo (MC) program was used to simulate clinical outcomes by convolving published tumor dose response curves with IDV distributions. The optimal dose …


Elongation Of Very Long Chain Fatty Acids-3 (Elovl3) Is Activated By Zhx2 And Is A Regulator Of Cell Cycle Progression, Kate Townsend Creasy, Hui Ren, Jieyun Jiang, Martha L. Peterson, Brett T. Spear Oct 2023

Elongation Of Very Long Chain Fatty Acids-3 (Elovl3) Is Activated By Zhx2 And Is A Regulator Of Cell Cycle Progression, Kate Townsend Creasy, Hui Ren, Jieyun Jiang, Martha L. Peterson, Brett T. Spear

Markey Cancer Center Faculty Publications

Zinc fingers and homeoboxes 2 (Zhx2) are transcriptional regulators of liver gene expression with key functions in embryonic development as well as tissue regeneration in response to damage and disease, presumably through its control of target genes. Previous microarray data suggested that elongation of very long chain fatty acids-3 (Elovl3), a member of the ELOVL family of enzymes that synthesize very long chain fatty acids (VLCFAs), is a putative Zhx2 target gene. VLCFAs are core component of ceramides and other bioactive sphingolipids that are often dysregulated in diseases and regulate key cellular processes including proliferation. Since several previously identified Zhx2 …


Inhibition Of Mitochondrial Fission Activates Glycogen Synthesis To Support Cell Survival In Colon Cancer, Sumati Raj Hasani, Lyndsay E. A. Young, Warren Van Nort, Moumita Banerjee, Dylan R. Rivas, Jinhwan Kim, Xiaopeng Xiong, Ramon C. Sun, Matthew S. Gentry, Hiromi Sesaki, Tianyan Gao Oct 2023

Inhibition Of Mitochondrial Fission Activates Glycogen Synthesis To Support Cell Survival In Colon Cancer, Sumati Raj Hasani, Lyndsay E. A. Young, Warren Van Nort, Moumita Banerjee, Dylan R. Rivas, Jinhwan Kim, Xiaopeng Xiong, Ramon C. Sun, Matthew S. Gentry, Hiromi Sesaki, Tianyan Gao

Markey Cancer Center Faculty Publications

Metabolic reprogramming has been recognized as one of the major mechanisms that fuel tumor initiation and progression. Our previous studies demonstrate that activation of Drp1 promotes fatty acid oxidation and downstream Wnt signaling. Here we investigate the role of Drp1 in regulating glycogen metabolism in colon cancer. Knockdown of Drp1 decreases mitochondrial respiration without increasing glycolysis. Analysis of cellular metabolites reveals that the levels of glucose-6-phosphate, a precursor for glycogenesis, are significantly elevated whereas pyruvate and other TCA cycle metabolites remain unchanged in Drp1 knockdown cells. Additionally, silencing Drp1 activates AMPK to stimulate the expression glycogen synthase 1 (GYS1) mRNA …


Phosphatidic Acid Binding To Patched Contributes To The Inhibition Of Smoothened And Hedgehog Signaling In Drosophila Wing Development, Jie Zhang, Yajuan Liu, Chi Wang, Craig W. Vander Kooi, Jianhang Jia Oct 2023

Phosphatidic Acid Binding To Patched Contributes To The Inhibition Of Smoothened And Hedgehog Signaling In Drosophila Wing Development, Jie Zhang, Yajuan Liu, Chi Wang, Craig W. Vander Kooi, Jianhang Jia

Markey Cancer Center Faculty Publications

Hedgehog (Hh) signaling controls growth and patterning during embryonic development and homeostasis in adult tissues. Hh binding to the receptor Patched (Ptc) elicits intracellular signaling by relieving Ptc-mediated inhibition of the transmembrane protein Smoothened (Smo). We uncovered a role for the lipid phosphatidic acid (PA) in the regulation of the Hh pathway in Drosophila melanogaster. Deleting the Ptc C-terminal tail or mutating the predicted PA-binding sites within it prevented Ptc from inhibiting Smo in wing discs and in cultured cells. The C-terminal tail of Ptc directly interacted with PA in vitro, an association that was reduced by Hh, and increased …


Proteasome Inhibition Protects Blood–Brain Barrier P-Glycoprotein And Lowers Aβ Brain Levels In An Alzheimer’S Disease Model, Milica Vulin, Yu Zhong, Bryan J. Maloney, Björn Bauer, Anika M. S. Hartz Oct 2023

Proteasome Inhibition Protects Blood–Brain Barrier P-Glycoprotein And Lowers Aβ Brain Levels In An Alzheimer’S Disease Model, Milica Vulin, Yu Zhong, Bryan J. Maloney, Björn Bauer, Anika M. S. Hartz

Markey Cancer Center Faculty Publications

Background Loss of P-glycoprotein (P-gp) at the blood–brain barrier contributes to amyloid-β (Aβ) brain accumulation in Alzheimer’s disease (AD). Using transgenic human amyloid precursor protein (hAPP)-overexpressing mice (Tg2576), we previously showed that Aβ triggers P-gp loss by activating the ubiquitin–proteasome pathway, which leads to P-gp degradation. Furthermore, we showed that inhibiting the ubiquitin-activating enzyme (E1) prevents P-gp loss and lowers Aβ accumulation in the brain of hAPP mice. Based on these data, we hypothesized that repurposing the FDA-approved proteasome inhibitor, bortezomib (Velcade®; BTZ), protects blood–brain barrier P-gp from degradation in hAPP mice in vivo.

Methods We treated hAPP mice with …


Regulated Translocation Of Neutral Sphingomyelinase-2 To The Plasma Membrane Drives Insulin Resistance In Steatotic Hepatocytes, Salim S. El-Amouri, Alexander A. Karakashian, Erhard Bieberich, Mariana N. Nikolova‑Karakashian Oct 2023

Regulated Translocation Of Neutral Sphingomyelinase-2 To The Plasma Membrane Drives Insulin Resistance In Steatotic Hepatocytes, Salim S. El-Amouri, Alexander A. Karakashian, Erhard Bieberich, Mariana N. Nikolova‑Karakashian

Markey Cancer Center Faculty Publications

Abstract Obesity-associated diabetes is linked to the accumulation of ceramide in various organs, including the liver. The exact mechanisms by which ceramide contributes to diabetic pathology are unclear, but one proposed scenario is that ceramide accumulation may inhibit insulin signaling pathways. It is unknown however whether the excess ceramide is generated proximal to the insulin receptor, that is, at the plasma membrane (PM), where it could affect the insulin signaling pathway directly, or the onset of insulin resistance is due to ceramide- induced mitochondrial dysfunction and/or lipotoxicity. Using hepatic cell lines and primary cultures, gain- and loss- of function approach, …


Rit1 Regulation Of Cns Lipids Rit1 Deficiency Alters Cerebral Lipid Metabolism And Reduces White Matter Tract Oligodendrocytes And Conduction Velocities, Lei Wu, Fang Wang, Carole L. Moncman, Mritunjay Pandey, Harrison A. Clarke, Hilaree N. Frazier, Lyndsay E. A. Young, Matthew S. Gentry, Weikang Cai, Olivier Thibault, Ramon C. Sun, Douglas A. Andres Oct 2023

Rit1 Regulation Of Cns Lipids Rit1 Deficiency Alters Cerebral Lipid Metabolism And Reduces White Matter Tract Oligodendrocytes And Conduction Velocities, Lei Wu, Fang Wang, Carole L. Moncman, Mritunjay Pandey, Harrison A. Clarke, Hilaree N. Frazier, Lyndsay E. A. Young, Matthew S. Gentry, Weikang Cai, Olivier Thibault, Ramon C. Sun, Douglas A. Andres

Markey Cancer Center Faculty Publications

Oligodendrocytes (OLs) generate lipid-rich myelin membranes that wrap axons to enable efficient transmission of electrical impulses. Using a RIT1 knockout mouse model and in situ high- resolution matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) coupled with MS-based lipidomic analysis to determine the contribution of RIT1 to lipid homeostasis. Here, we report that RIT1 loss is associated with altered lipid levels in the central nervous system (CNS), including myelin-associated lipids within the corpus callosum (CC). Perturbed lipid metabolism was correlated with reduced numbers of OLs, but increased numbers of GFAP+ glia, in the CC, but not in grey matter. This was …


Stat3 Modulates Cd4+ T Mitochondrial Dynamics And Function In Aging, Emelia Zukowski, Marco Sannella, Jack Donato Rockhold, Gabriella Kalantar, Jingting Yu, Sara Santacruz-Calvo, Madison K. Kuhn, Nasun Hah, Ling Ouyang, Tzu-Wen Wang, Lyanne Murphy, Heather Marszalkowski, Kaleigh Gibney, Micah J. Drummond, Elizabeth A. Proctor, Hatice Hasturk, Barbara S. Nikolajczyk, Leena P. Bharath Oct 2023

Stat3 Modulates Cd4+ T Mitochondrial Dynamics And Function In Aging, Emelia Zukowski, Marco Sannella, Jack Donato Rockhold, Gabriella Kalantar, Jingting Yu, Sara Santacruz-Calvo, Madison K. Kuhn, Nasun Hah, Ling Ouyang, Tzu-Wen Wang, Lyanne Murphy, Heather Marszalkowski, Kaleigh Gibney, Micah J. Drummond, Elizabeth A. Proctor, Hatice Hasturk, Barbara S. Nikolajczyk, Leena P. Bharath

Markey Cancer Center Faculty Publications

Aging promotes numerous intracellular changes in T cells that impact their effector function. Our data show that aging promotes an increase in the localization of STAT3 to the mitochondria (mitoSTAT3), which promotes changes in mitochondrial dynamics and function and T-cell cytokine production. Mechanistically, mitoSTAT3 increased the activity of aging T-cell mitochondria by increasing complex II. Limiting mitoSTAT3 using a mitochondria-targeted STAT3 inhibitor, Mtcur-1 lowered complex II activity, prevented age-induced changes in mitochondrial dynamics and function, and reduced Th17 inflammation. Exogenous expression of a constitutively phosphorylated form of STAT3 in T cells from young adults mimicked changes in mitochondrial dynamics and …


Adipocyte-Derived Pxr Signaling Is Dispensable For Diet-Induced Obesity And Metabolic Disorders In Mices, Fang Wang, Jinwei Liu, Rebecca Hernandez, Se-Hyung Park, Ying-Jing Lai, Shuxia Wang, Bruce Blumberg, Changcheng Zhou Sep 2023

Adipocyte-Derived Pxr Signaling Is Dispensable For Diet-Induced Obesity And Metabolic Disorders In Mices, Fang Wang, Jinwei Liu, Rebecca Hernandez, Se-Hyung Park, Ying-Jing Lai, Shuxia Wang, Bruce Blumberg, Changcheng Zhou

UK CARES Faculty Publications

Pregnane X receptor (PXR) is a xenobiotic receptor that can be activated by numerous chemicals including endogenous hormones, dietary steroids, pharmaceutical agents, and environmental chemicals. PXR has been established to function as a xenobiotic sensor to coordinately regulate xenobiotic metabolism by regulating the expression of many enzymes and transporters required for xenobiotic metabolism. Recent studies have implicated a potentially important role for PXR in obesity and metabolic disease beyond xenobiotic metabolism, but how PXR action in different tissues or cell types contributes to obesity and metabolic disorders remains elusive. To investigate the role of adipocyte PXR in obesity, we generated …


Equine In Vivo Metabolite Profiling Of The Selective Androgen Receptor Modulator Lgd-3303 For Doping Control, Malin Nilsson Broberg, Heather Knych, Ulf Bondesson, Curt Pettersson, Börje Tidstedt, Scott Stanley, Mario Thevis, Mikael Hedeland Sep 2023

Equine In Vivo Metabolite Profiling Of The Selective Androgen Receptor Modulator Lgd-3303 For Doping Control, Malin Nilsson Broberg, Heather Knych, Ulf Bondesson, Curt Pettersson, Börje Tidstedt, Scott Stanley, Mario Thevis, Mikael Hedeland

UK CARES Faculty Publications

LGD-3303 is a Selective Androgen Receptor Modulator (SARM) that is prohibited in both equine and human sports due to its anabolic properties. The aim of this study was to investigate the equine in vivo metabolite profile of LGD-3303 and identify drug metabolites that can be suitable as new and improved analytical targets for equine doping control. This was performed by an oral administration of 0.05 mg⋅kg 1 LGD-3303 to horses, where blood and urine samples were collected up to 96 h after administration. The in vivo samples consisting of plasma, urine and hydrolyzed urine were analyzed utilizing ultra-high performance liquid …


Membrane Functionalization Approaches Toward Per- And Polyfluoroalkyl Substances And Selected Metal Ion Separations, Francisco Cecil Léniz-Pizarro, Holly E. Rudel, Nicolas J. Briot, Julie B. Zimmerman, Dibakar Bhattacharyya Sep 2023

Membrane Functionalization Approaches Toward Per- And Polyfluoroalkyl Substances And Selected Metal Ion Separations, Francisco Cecil Léniz-Pizarro, Holly E. Rudel, Nicolas J. Briot, Julie B. Zimmerman, Dibakar Bhattacharyya

UK CARES Faculty Publications

Adsorption and ion exchange technologies are two of the most widely used approaches to separate pollutants from water; however, their intrinsic diffusion limitations continue to be a challenge. Pore functionalized membranes are a promising technology that can help overcome these challenges, but the extents of their competitive benefits and broad applicability have not been systematically evaluated. Herein, three types of adsorptive/ion exchange (IX) polymers containing strong/weak acid, strong base, and iron-chitosan complex groups were synthesized in the pores and partially on the surface of microfiltration (MF) membranes and tested for the removal of organic and inorganic cations and anions from …


Non-Contact Optical Spectroscopy For Tumor-Sensitive Diffuse Reflectance And Fluorescence Measurements On Murine Subcutaneous Tissue Models: Monte Carlo Modeling And Experimental Validations, Zahid Hasan, Pranto Soumik Saha, Madison O. Korfhage, Caigang Zhu Sep 2023

Non-Contact Optical Spectroscopy For Tumor-Sensitive Diffuse Reflectance And Fluorescence Measurements On Murine Subcutaneous Tissue Models: Monte Carlo Modeling And Experimental Validations, Zahid Hasan, Pranto Soumik Saha, Madison O. Korfhage, Caigang Zhu

Markey Cancer Center Faculty Publications

Fiber-optic probes are commonly used in biomedical optical spectroscopy platforms for light delivery and collection. At the same time, it was reported that the inconsistent probe- sample contact could induce significant distortions in measured optical signals, which consequently cause large analysis errors. To address this challenge, non-contact optical spectroscopy has been explored for tissue characterizations. However, existing non-contact optical spectroscopy platforms primarily focused on diffuse reflectance measurements and may still use a fiber probe in which the probe was imaged onto the tissue surface using a lens, which serves as a non-contact probe for the measurements. Here, we report a …


Protocol For Optimizing Production And Quality Control Of Infective Ecohiv Virions, Hammodah Rawhi Hammodah Alfar, Daphne N. Pariser, Harry Chanzu, Smita Joshi, Daniёlle M. Coenen, Joshua Lykins, Kanakanagavalli Shravani Prakhya, Mary Jane Potash, Wei Chao, Jennifer Kelschenbach, David J. Volsky, Kelly Metcalf-Pate Sep 2023

Protocol For Optimizing Production And Quality Control Of Infective Ecohiv Virions, Hammodah Rawhi Hammodah Alfar, Daphne N. Pariser, Harry Chanzu, Smita Joshi, Daniёlle M. Coenen, Joshua Lykins, Kanakanagavalli Shravani Prakhya, Mary Jane Potash, Wei Chao, Jennifer Kelschenbach, David J. Volsky, Kelly Metcalf-Pate

Saha Cardiovascular Research Center Faculty Publications

EcoHIV is a model of HIV infection that recapitulates aspects of HIV-1 pathology in mice. However, there are limited published protocols to guide EcoHIV virion production. Here, we present a protocol for producing infective EcoHIV virions and essential quality controls. We describe steps for viral purification, titering, and multiple techniques to analyze infection efficacy. This protocol produces high infectivity in C57BL/6 mice which will aid investigators in generating preclinical data.


Cell-Free, High-Density Lipoprotein-Specific Phospholipid Efflux Assay Predicts Incident Cardiovascular Disease, Masaki Sato, Edward B. Neufeld, Martin P. Playford, Yu Lei, Alexander V. Sorokin, Angel M. Aponte, Lita A. Freeman, Scott M. Gordon, Amit K. Dey, Kianoush Jeiran, Masato Hamasaki, Maureen L. Sampson, Robert D. Shamburek, Jingrong Tang, Marcus Y. Chen, Kazuhiko Kotani, Josephine L. C. Anderson, Robin P. F. Dullaart, Nehal N. Mehta, Uwe T. F. Tietge, Alan Thomas Remaley Sep 2023

Cell-Free, High-Density Lipoprotein-Specific Phospholipid Efflux Assay Predicts Incident Cardiovascular Disease, Masaki Sato, Edward B. Neufeld, Martin P. Playford, Yu Lei, Alexander V. Sorokin, Angel M. Aponte, Lita A. Freeman, Scott M. Gordon, Amit K. Dey, Kianoush Jeiran, Masato Hamasaki, Maureen L. Sampson, Robert D. Shamburek, Jingrong Tang, Marcus Y. Chen, Kazuhiko Kotani, Josephine L. C. Anderson, Robin P. F. Dullaart, Nehal N. Mehta, Uwe T. F. Tietge, Alan Thomas Remaley

Saha Cardiovascular Research Center Faculty Publications

BACKGROUND. Cellular cholesterol efflux capacity (CEC) is a better predictor of cardiovascular disease (CVD) events than HDL- cholesterol (HDL-C) but is not suitable as a routine clinical METHODS. We developed an HDL-specific phospholipid efflux (HDL-SPE) assay to assess HDL functionality based on whole plasma HDL apolipoprotein–mediated solubilization of fluorescent phosphatidylethanolamine from artificial lipid donor particles. We first assessed the association of HDL-SPE with prevalent coronary artery disease (CAD): study I included NIH severe-CAD (n = 50) and non-CAD (n = 50) participants, who were frequency matched for sex, BMI, type 2 diabetes mellitus, and smoking; study II included Japanese CAD …


A Lamprey Neural Cell Type Atlas Illuminates The Origins Of The Vertebrate Brain, Francesco Lamanna, Francisca Hervas-Sotomayor, A. Phillip Oel, David Jandzik, Daniel Sobrido-Cameán, Gabriel N. Santos-Durán, Megan L. Martik, Jan Stundl, Stephen A. Green, Thoomke Brüning, Katharina Mößinger, Julia Schmidt, Celine Schneider, Mari Sepp, Florent Murat, Jeramiah J. Smith, Marianne E. Bronner, María Celina Rodicio, Antón Barreiro-Iglesias, Daniel M. Medeiros, Detlev Arendt, Henrik Kaessmann Sep 2023

A Lamprey Neural Cell Type Atlas Illuminates The Origins Of The Vertebrate Brain, Francesco Lamanna, Francisca Hervas-Sotomayor, A. Phillip Oel, David Jandzik, Daniel Sobrido-Cameán, Gabriel N. Santos-Durán, Megan L. Martik, Jan Stundl, Stephen A. Green, Thoomke Brüning, Katharina Mößinger, Julia Schmidt, Celine Schneider, Mari Sepp, Florent Murat, Jeramiah J. Smith, Marianne E. Bronner, María Celina Rodicio, Antón Barreiro-Iglesias, Daniel M. Medeiros, Detlev Arendt, Henrik Kaessmann

Markey Cancer Center Faculty Publications

The vertebrate brain emerged more than ~500 million years ago in common evolutionary ancestors. To systematically trace its cellular and molecular origins, we established a spatially resolved cell type atlas of the entire brain of the sea lamprey—a jawless species whose phylogenetic position affords the reconstruction of ancestral vertebrate traits—based on extensive single-cell RNA-seq and in situ sequencing data. Comparisons of this atlas to neural data from the mouse and other jawed vertebrates unveiled various shared features that enabled the reconstruction of cell types, tissue structures and gene expression programs of the ancestral vertebrate brain. However, our analyses also revealed …


Bacteroides Fragilis In The Gut Microbiomes Of Alzheimer’S Disease Activates Microglia And Triggers Pathogenesis In Neuronal C/Ebpβ Transgenic Mice, Yiyuan Xia, Yifan Xiao, Zi-Hao Wang, Ashfaqul M. Alam, John P. Haran, Beth A. Mccormick, Xiji Shu, Xiaochuan Wang, Keqiang Ye Sep 2023

Bacteroides Fragilis In The Gut Microbiomes Of Alzheimer’S Disease Activates Microglia And Triggers Pathogenesis In Neuronal C/Ebpβ Transgenic Mice, Yiyuan Xia, Yifan Xiao, Zi-Hao Wang, Ashfaqul M. Alam, John P. Haran, Beth A. Mccormick, Xiji Shu, Xiaochuan Wang, Keqiang Ye

Markey Cancer Center Faculty Publications

Gut dysbiosis contributes to Alzheimer’s disease (AD) pathogenesis, and Bacteroides strains are selectively elevated in AD gut microbiota. However, it remains unknown which Bacteroides species and how their metabolites trigger AD pathologies. Here we show that Bacteroides fragilis and their metabolites 12-hydroxy-heptadecatrienoic acid (12-HHTrE) and Prostaglandin E2 (PGE2) activate microglia and induce AD pathogenesis in neuronal C/EBPβ transgenic mice. Recolonization of antibiotics cocktail-pretreated Thy1-C/EBPβ transgenic mice with AD patient fecal samples elicits AD pathologies, associated with C/EBPβ/Asparaginyl endopeptidase (AEP) pathway upregulation, microglia activation, and cognitive disorders compared to mice receiving healthy donors’ fecal microbiota transplantation (FMT). Microbial 16S rRNA sequencing …


New Insights On The Differential Interaction Of Sulfiredoxin With Members Of The Peroxiredoxin Family Revealed By Protein-Protein Docking And Experimental Studies, Murli Mishra, Hong Jiang, Qiou Wei Sep 2023

New Insights On The Differential Interaction Of Sulfiredoxin With Members Of The Peroxiredoxin Family Revealed By Protein-Protein Docking And Experimental Studies, Murli Mishra, Hong Jiang, Qiou Wei

Markey Cancer Center Faculty Publications

Sulfiredoxin (Srx) is the enzyme that restores the peroxidase activity of peroxiredoxins (Prxs) through catalyzing the reduction of hyperoxidized Prxs back to their active forms. This process involves protein-protein interaction in an enzyme-substrate binding manner. The integrity of the Srx-Prx axis contributes to the pathogenesis of various oxidative stress related human disorders including cancer, inflammation, cardiovascular and neurological diseases. The purpose of this study is to understand the structural and molecular biology of the Srx-Prx interaction, which may be of significance for prediction of target site for the novel drug-discovery. Homology modeling and protein-protein docking approaches were applied to examine …


Syne1 Mutation Is Associated With Increased Tumor Mutation Burden And Immune Cell Infiltration In Ovarian Cancer, Laura M. Harbin, Nan Lin, Frederick R. Ueland, Jill M. Kolesar Sep 2023

Syne1 Mutation Is Associated With Increased Tumor Mutation Burden And Immune Cell Infiltration In Ovarian Cancer, Laura M. Harbin, Nan Lin, Frederick R. Ueland, Jill M. Kolesar

Markey Cancer Center Faculty Publications

SYNE1, a nuclear envelope protein critical for cellular structure and signaling, is downregulated in numerous malignancies. SYNE1 alterations are found in 10% of gynecologic malignancies and 5% of epithelial ovarian cancers. Previous studies demonstrated an association between SYNE1 mutation, increased tumor mutation burden (TMB), and immunotherapy response. This study evaluates the SYNE1 mutation frequency, association with TMB, and downstream effects of SYNE1 mutation in ovarian cancer. Genetic information, including whole-exome sequencing, RNA analysis, and somatic tumor testing, was obtained for consenting ovarian cancer patients at an academic medical center. Mutation frequencies were compared between the institutional cohort and The Cancer …


Interferon-Stimulated Gene Tdrd7 Interacts With Ampk And Inhibits Its Activation To Suppress Viral Replication And Pathogenesis, Sukanya Chakravarty, Gayatri Subramanian, Sonam Popli, Manoj Veleeparambil, Shumin Fan, Ritu Chakravarti, Saurabh Chattopadhyay Sep 2023

Interferon-Stimulated Gene Tdrd7 Interacts With Ampk And Inhibits Its Activation To Suppress Viral Replication And Pathogenesis, Sukanya Chakravarty, Gayatri Subramanian, Sonam Popli, Manoj Veleeparambil, Shumin Fan, Ritu Chakravarti, Saurabh Chattopadhyay

Markey Cancer Center Faculty Publications

Many viruses activate cellular autophagy in infected cells to facilitate their replication. Recently, we identified an interferon (IFN)-stimulated gene (ISG) Tudor domain containing 7 (TDRD7), which inhibits viral replication by blocking autophagy pathway. Here, we present a molecular mechanism for TDRD7 action and its relative contribution to protection against viral pathogenesis. TDRD7 inhibited the activation of adenosine monophosphate (AMP)-activated protein kinase (AMPK), a kinase required for initiating autophagy. Mechanistically, TDRD7 interacted directly with AMPK in the cytosolic compartment. Domain-mapping analyses revealed C-terminal Tudor domain of TDRD7 interacted with auto-inhibitory domain of AMPK. Deletion of Tudor domains abolished anti-AMPK and antiviral …


Unleashing The Potential Of 1,3-Diketone Analogues As Selective Lh2 Inhibitors, Juhoon Lee, Hou-Fu Guo, Shike Wang, Yazdan Maghsoud, Erik Antonio Vázquez-Montelongo, Zhifeng Jing, Rae M. Sammons, Eun Jeong Cho, Pengyu Ren, G. Andrés Cisneros, Jonathan M. Kurie, Kevin N. Dalby Sep 2023

Unleashing The Potential Of 1,3-Diketone Analogues As Selective Lh2 Inhibitors, Juhoon Lee, Hou-Fu Guo, Shike Wang, Yazdan Maghsoud, Erik Antonio Vázquez-Montelongo, Zhifeng Jing, Rae M. Sammons, Eun Jeong Cho, Pengyu Ren, G. Andrés Cisneros, Jonathan M. Kurie, Kevin N. Dalby

Markey Cancer Center Faculty Publications

Lysyl hydroxylase 2 (LH2) catalyzes the formation of highly stable hydroxylysine aldehyde-derived collagen cross-links (HLCCs), thus promoting lung cancer metastasis through its capacity to modulate specific types of collagen cross-links within the tumor stroma. Using 1 and 2 from our previous high-throughput screening (HTS) as lead probes, we prepared a series of 1,3-diketone analogues, 1−18, and identified 12 and 13 that inhibit LH2 with IC50’s of approximately 300 and 500 nM, respectively. Compounds 12 and 13 demonstrate selectivity for LH2 over LH1 and LH3. Quantum mechanics/molecular mechanics (QM/MM) modeling indicates that the selectivity of 12 and 13 may stem from …


Evaluation Of A Faculty Fellows Program In Science Communication, Stacy Stanifer, Beverly Delidow, Kathy Rademacher, Luz Huntington-Moskos, Kelly Kennoy, Amanda Thaxton-Wiggins, Craig Wilmhoff, Ellen J. Hahn Aug 2023

Evaluation Of A Faculty Fellows Program In Science Communication, Stacy Stanifer, Beverly Delidow, Kathy Rademacher, Luz Huntington-Moskos, Kelly Kennoy, Amanda Thaxton-Wiggins, Craig Wilmhoff, Ellen J. Hahn

Journal of Appalachian Health

Introduction: Science communication plays a crucial role in tackling pressing regional, national, and global health issues. Effective communication with various audiences is integral to dissemination of science findings.

Purpose: This study evaluates changes in self-efficacy and attitudes toward science communication skills over time and also assesses program outcomes and satisfaction with a Faculty Fellows in Science Communication (FFSC) program among faculty (N = 30) with interest in environmental health science and/or education in Appalachia Kentucky.

Methods: A mixed methods program evaluation was employed using longitudinal data on behaviors, attitudes, and program outcomes from three cohorts of Faculty Fellows who participated …


The Appalachian Gap In Preventable Hospitalizations: Are We Seeing Any Progress?, Rachel Hogg-Graham, Juan Lang, Teresa M. Waters Aug 2023

The Appalachian Gap In Preventable Hospitalizations: Are We Seeing Any Progress?, Rachel Hogg-Graham, Juan Lang, Teresa M. Waters

Journal of Appalachian Health

Introduction: Previous studies have documented geographic variation in preventable hospitalizations between rural and urban areas, but much less is known about preventable hospitalization patterns between heterogeneous rural areas. Unique challenges related to access of care and poverty may put the rural Appalachian Region at risk for higher rates of preventable hospitalizations.

Purpose: This study examines whether within-rural differences in Kentucky’s preventable hospitalization rates exist and how these differences may be changing over time.

Methods: Longitudinal and geographic trends in county-level preventable hospitalization rates were examined using Kentucky hospital discharge data from 2016 to 2019. Regression models were run to determine …


Impact Of Interprofessional Student Teams At A Remote Area Medical Event In Rural Appalachia, Emily K. Flores, Karilynn Dowling, Caroline Abercrombie Md, Rick L. Wallace Aug 2023

Impact Of Interprofessional Student Teams At A Remote Area Medical Event In Rural Appalachia, Emily K. Flores, Karilynn Dowling, Caroline Abercrombie Md, Rick L. Wallace

Journal of Appalachian Health

Introduction: Education in interprofessional collaboration is vital to expand healthcare access, especially in areas of higher disparity. To address this need, interprofessional faculty collaborators incorporated undergraduate and graduate health profession students into teams at an annual Remote Area Medical event in rural Appalachia between 2017 and 2020.

Purpose: This article evaluates the impact of an interprofessional student teams model on both patient care experience and students’ interprofessional collaboration attitudes and behaviors.

Methods: Student volunteers completed pre- and post-event surveys containing questions about demographics, open-ended questions, and questions from two instruments: the Student Perceptions of Interprofessional Clinical Education-Revised Instrument, Version 2 …


Association Between Insurer Connectivity In Appalachian Population Health Networks And Preventable Hospitalizations: Evidence From Kentucky, Rachel Hogg-Graham, Kelsey R. Gatton, Rick Ingram, Glen P. Mays Aug 2023

Association Between Insurer Connectivity In Appalachian Population Health Networks And Preventable Hospitalizations: Evidence From Kentucky, Rachel Hogg-Graham, Kelsey R. Gatton, Rick Ingram, Glen P. Mays

Journal of Appalachian Health

Introduction: Addressing complex health and social needs requires cross-sector collaboration to deliver medical, social, and population health services at the community level. Capacity in community health and social services networks may be constrained in regions like Appalachia due to the combined effects of rurality and persistently poor health and social outcomes. One way that cross-sector networks serving low-resource communities can expand their capacity is by engaging partners, like health insurers, who can leverage resources from outside the local area.

Purpose: This study examines insurer connectivity in cross-sector networks across Kentucky’s geographic regions and the association between connectivity and the probability …


The Ninth Myth Of Appalachia, Randolph Wykoff Aug 2023

The Ninth Myth Of Appalachia, Randolph Wykoff

Journal of Appalachian Health

Many stereotypes afflict our much-maligned region, and the Jonesborough­­–Washington County History Museum displays eight of these "myths of Appalachia." Here, our Editor-in-Chief suggests a ninth—that the people of Appalachia "do not care" about their health—and argues that regional health disparities result not from apathy but from a confluence of socioeconomic factors.


Patient Engagement In Patient Portals In Appalachia V. Surrounding U.S. Census Regions: An Analysis Of Hints (Health Information National Trends Survey) Data, 2017–2020, Heather Lea Tudor, Rick Ingram, Sarah Wackerbarth Aug 2023

Patient Engagement In Patient Portals In Appalachia V. Surrounding U.S. Census Regions: An Analysis Of Hints (Health Information National Trends Survey) Data, 2017–2020, Heather Lea Tudor, Rick Ingram, Sarah Wackerbarth

Journal of Appalachian Health

Introduction: Those living in the Appalachian Region face a greater number of significant health disparities than residents of other areas of the U.S. Patient portals can decrease disparities, increase health literacy, and improve health outcomes.

Purpose: This study explores if those living in the Appalachian Region are offered access to and use their patient portals differently than those in the surrounding U.S. Census regions. Additionally, the study aims to determine if there was a difference in reported reasons for the non-use of patient portals.

Methods: A secondary analysis was completed using data from the National Cancer Institute's Health Information National …


Self-Reported Consumption Of Bottled Water V. Tap Water In Appalachian And Non-Appalachian Kentucky, Jason W. Marion Aug 2023

Self-Reported Consumption Of Bottled Water V. Tap Water In Appalachian And Non-Appalachian Kentucky, Jason W. Marion

Journal of Appalachian Health

Introduction: Quantitative studies on drinking water perceptions in Appalachia are limited. High-profile water infrastructure failures in the U.S. and Eastern Kentucky, coupled with human-made and natural disasters in the Appalachian Region, have likely impacted opinions regarding tap water.

Purpose: To use existing unexplored data to describe baseline tap water v. bottled water consumption in Kentucky.

Methods: Telephone-based cross-sectional data were obtained from the 2013 Kentucky Health Issues Poll (KHIP) directed by the Foundation for a Healthy Kentucky. Among many items in KHIP, self-reported consumption of bottled water over tap water, reasons for bottled water use, and demographic data were obtained. …


Scale Model Experiments Of Toxic Gas Production From The Combustion Of Polymers When Applied With Different Droplet Sizes Of Water Mist, Nicharee Thinnakornsutubutr, Masayuki Mizuno, Kazunori Kuwana Aug 2023

Scale Model Experiments Of Toxic Gas Production From The Combustion Of Polymers When Applied With Different Droplet Sizes Of Water Mist, Nicharee Thinnakornsutubutr, Masayuki Mizuno, Kazunori Kuwana

Progress in Scale Modeling, an International Journal

This research experimentally investigated the combustion of polymeric materials with water mist application in an enclosure, with an emphasis on the production of toxic gases. Two different diameters, ~100 and ~260 μm, were tested. The experimental conditions were determined based on Froude similarity laws for low drop Reynolds number conditions. Droplets and polymers’ physical and chemical properties influence the burning/extinguishing behavior and toxic-gas evolution. In general, larger droplets can extinguish a fire in a shorter time, and toxic gas concentrations in a test chamber decreased more rapidly. However, the large droplets tended to cause the flame expansion phenomenon for thermoplastics …