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Overview Of Hil Co-Simulation For Very Large Distribution Systems And Power Electronic Converters With A Dc Fast Charging Ev Benchmark Study On An Ieee Test Feeder, Rosemary E. Alden, Donovin D. Lewis, Dan M. Ionel Oct 2023

Overview Of Hil Co-Simulation For Very Large Distribution Systems And Power Electronic Converters With A Dc Fast Charging Ev Benchmark Study On An Ieee Test Feeder, Rosemary E. Alden, Donovin D. Lewis, Dan M. Ionel

Electrical and Computer Engineering Graduate Research

Current development towards implementation of the future smart grid includes advanced controller and power hardware-in-the-loop (CHIL/PHIL) testing of new technology. The impact of new loads, distributed energy resources (DER) equipment, and controls spans two fields, both electric distribution power systems modeling, typically completed in the phasor domain, and electromagnetic transient (EMT) analysis across the frequency domain. The co-simulation of distribution power systems and power electronic converter controls is a growing field of research for improved design using real-time HIL capability. Within this paper, over fifty references are reviewed to summarize the current state of HIL technology, specifically with co-simulation in …


Distribution System Optimal Operation Of Smart Homes With Battery And Equivalent Hvac Energy Storage For Virtual Power Plant Controls, Steven B. Poore, Rosemary E. Alden, Evan S. Jones, Dan M. Ionel Oct 2023

Distribution System Optimal Operation Of Smart Homes With Battery And Equivalent Hvac Energy Storage For Virtual Power Plant Controls, Steven B. Poore, Rosemary E. Alden, Evan S. Jones, Dan M. Ionel

Electrical and Computer Engineering Graduate Research

Battery energy storage systems (BESS) that can be utilized for demand response (DR) and load shifting are limited in adoption by high capital cost. Large residential loads such as electric water heaters (EWH) and heating, ventilation and air-conditioning (HVAC) may be controlled using distributed energy resource management systems (DERMS) to perform functions like batteries, such as reducing cost and decreasing energy storage capacity requirements when implemented at the aggregate level. Increasing levels of renewable generation further incentivizes shifting loads in time through controls and energy storage to reduce curtailment and carbon footprint. This paper proposes techniques for the optimization and …


A Blunted Th17 Cytokine Signature In Women With Mild Cognitive Impairment: Insights From Inflammatory Profiling Of A Community-Based Cohort Of Older Adults, Adam D. Bachstetter, Jenny Lutshumba, Edric D. Winford, Erin L. Abner, Barbra J. Martin, Jordan P. Harp, Linda J. Van Eldik, Frederick A. Schmitt, Donna M. Wilcock, Ann M. Stowe, Gregory A. Jicha, Barbara S. Nikolajczyk Oct 2023

A Blunted Th17 Cytokine Signature In Women With Mild Cognitive Impairment: Insights From Inflammatory Profiling Of A Community-Based Cohort Of Older Adults, Adam D. Bachstetter, Jenny Lutshumba, Edric D. Winford, Erin L. Abner, Barbra J. Martin, Jordan P. Harp, Linda J. Van Eldik, Frederick A. Schmitt, Donna M. Wilcock, Ann M. Stowe, Gregory A. Jicha, Barbara S. Nikolajczyk

Markey Cancer Center Faculty Publications

People with dementia have an increase in brain inflammation, caused in part by innate and adaptive immune cells. However, it remains unknown whether dementia-associated diseases alter neuro-immune reflex arcs to impact the systemic immune system. We examined peripheral immune cells from a community-based cohort of older adults to test if systemic inflammatory cytokine signatures associated with early stages of cognitive impairment. Human peripheral blood mononuclear cells were cultured with monocyte or T-cell-targeted stimuli, and multiplex assays quantitated cytokines in the conditioned media. Following T-cell-targeted stimulation, cells from women with cognitive impairment produced lower amounts of TH17 cytokines compared with cells …


Control Of Cd4+ T Cells To Restrain Inflammatory Diseases Via Eukaryotic Elongation Factor 2 Kinase, Hao-Yun Peng, Liqing Wang, Jugal Kishore Das, Anil Kumar, Darby J. Ballard, Yijie Ren, Xiaofeng Xiong, Paul De Figueiredo, Jin-Ming Yang, Jianxun Song Oct 2023

Control Of Cd4+ T Cells To Restrain Inflammatory Diseases Via Eukaryotic Elongation Factor 2 Kinase, Hao-Yun Peng, Liqing Wang, Jugal Kishore Das, Anil Kumar, Darby J. Ballard, Yijie Ren, Xiaofeng Xiong, Paul De Figueiredo, Jin-Ming Yang, Jianxun Song

Markey Cancer Center Faculty Publications

CD4+ T cells, particularly IL-17-secreting helper CD4+ T cells, play a central role in the inflammatory processes underlying autoimmune disorders. Eukaryotic Elongation Factor 2 Kinase (eEF2K) is pivotal in CD8+ T cells and has important implications in vascular dysfunction and inflammation-related diseases such as hypertension. However, its specific immunological role in CD4+ T cell activities and related inflammatory diseases remains elusive. Our investigation has uncovered that the deficiency of eEF2K disrupts the survival and proliferation of CD4+ T cells, impairs their ability to secrete cytokines. Notably, this dysregulation leads to heightened production of pro-inflammatory cytokine IL-17, fosters a pro-inflammatory microenvironment …


Copy Number Variation That Influences The Ionizing Radiation Sensitivity Of Oral Squamous Cell Carcinoma, Tadahide Izumi, Piotr G. Rychahou, Li Chen, Molly H. Smith, Joseph Valentino Oct 2023

Copy Number Variation That Influences The Ionizing Radiation Sensitivity Of Oral Squamous Cell Carcinoma, Tadahide Izumi, Piotr G. Rychahou, Li Chen, Molly H. Smith, Joseph Valentino

Markey Cancer Center Faculty Publications

Genome instability in cancer cells causes not only point mutations but also structural variations of the genome, including copy number variations (CNVs). It has recently been proposed that CNVs arise in cancer to adapt to a given microenvironment to survive. However, how CNV influences cellular resistance against ionizing radiation remains unknown. PRMT5 (protein arginine methyltransferase 5) and APE1 (apurinic/apyrimidinic endonuclease 1), which enhance repair of DNA double-strand breaks and oxidative DNA damage, are closely localized in the chromosome 14 of the human genome. In this study, the genomics data for the PRMT5 and APE1 genes, including their expression, CNVs, and …


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 …


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 …


Antibiotic-Resistant E.Coli In Kentucky Watersheds Impacted By Various Land Uses, Jayden Hamlet, Jason Marion, Travis Altheide Sep 2023

Antibiotic-Resistant E.Coli In Kentucky Watersheds Impacted By Various Land Uses, Jayden Hamlet, Jason Marion, Travis Altheide

Kentucky Water Resources Annual Symposium

No abstract provided.


Full Program Proceedings For 2023 Kentucky Water Resources Symposium, Kentucky Water Research Institute Sep 2023

Full Program Proceedings For 2023 Kentucky Water Resources Symposium, Kentucky Water Research Institute

Kentucky Water Resources Annual Symposium

No abstract provided.


Inspection Training Course On Bridge Preventive Maintenance Activities, Danny Wells, Sudhir Palle Sep 2023

Inspection Training Course On Bridge Preventive Maintenance Activities, Danny Wells, Sudhir Palle

Kentucky Transportation Center Research Report

Despite over 30 percent of bridges in the United States having exceeded their 50-year design lives, most state departments of transportation (DOTs) lack the funding needed to replace bridges on a large scale. In response, agencies have increasingly turned to bridge preventive maintenance activities to prolong bridge service lives. These activities provide a safe and cost-effective way to slow the rate at which structures deteriorate, mitigate the effects of aging, and improve bridge functional condition. The Kentucky Transportation Cabinet (KYTC) has become increasingly reliant on preventive maintenance to preserve and extend the service lives of its steel and concrete bridges. …


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 …


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. …


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 …


Assessment Of Land And Renewable Energy Resource Potential For Regional Power System Integration With Ml Spatio-Temporal Clustering, Rosemary E. Alden, Claire Halloran, Donovin D. Lewis, Dan M. Ionel Aug 2023

Assessment Of Land And Renewable Energy Resource Potential For Regional Power System Integration With Ml Spatio-Temporal Clustering, Rosemary E. Alden, Claire Halloran, Donovin D. Lewis, Dan M. Ionel

Electrical and Computer Engineering Graduate Research

Toward the planning and development of future electric power systems with extremely large penetration of renewable resources (DERs), detailed assessment of power and energy potential is needed considering both spatial and temporal data per region. Within this paper, a methodology for spatio-temporal DER capacity potential considering land cover types and weather variation are presented using spatio-temporal data. Additionally, an application of empirical orthogonal functions (EOFs) and max-p unsupervised learning techniques is proposed for DER generation to identify zones of similar output power in space and time. A detailed case study for the example region of Kentucky, USA is completed with …


Exposure To A Phthalate Mixture Disrupts Ovulatory Progesterone Receptor Signaling In Human Granulosa Cells In Vitro, Patrick R. Hannon, James W. Akin, Thomas E. Curry Jr Aug 2023

Exposure To A Phthalate Mixture Disrupts Ovulatory Progesterone Receptor Signaling In Human Granulosa Cells In Vitro, Patrick R. Hannon, James W. Akin, Thomas E. Curry Jr

UK CARES Faculty Publications

Exposure to phthalates disrupts ovarian function. However, limited studies have investigated the effects of phthalate mixtures on ovulation, especially in women. Human granulosa cells were used to test the hypothesis that exposure to a phthalate mixture (PHTmix) disrupts progesterone (P4)/progesterone receptor (PGR) signaling, which is a crucial pathway for ovulation. In addition, progestin and cyclic adenosine 3′, 5′-monophosphate (cAMP) supplementation were tested as methods to circumvent phthalate toxicity. Granulosa cells from women undergoing in vitro fertilization were acclimated in culture to regain responsiveness to human chorionic gonadotropin (hCG; clinical luteinizing hormone analogue). Granulosa cells were treated with or without hCG, …


Histamine Excretion In Common Indoor And Hematophagous Arthropods, Simona Principato, Alvaro Romero, Chow-Yang Lee, Kathleen Campbell, Dong-Hwan Choe, Coby Schal, Zachary C. Devries Aug 2023

Histamine Excretion In Common Indoor And Hematophagous Arthropods, Simona Principato, Alvaro Romero, Chow-Yang Lee, Kathleen Campbell, Dong-Hwan Choe, Coby Schal, Zachary C. Devries

UK CARES Faculty Publications

Histamine is a biogenic amine that regulates multiple physiological functions in diverse organisms, specifically playing a central role in the mammalian immune response. The common bed bug, Cimex lectularius L. (Hemiptera: Cimicidae), excretes histamine in large amounts in its feces as a component of its aggregation pheromone, which contaminates homes. The potential health risks associated with the presence of indoor histamine are unclear, but to predict future exposure risks, it is critical that we understand if other arthropods excrete histamine in any discernible phylogenetic pattern. In the present study, we evaluated histamine excretion by various arthropods; specifically those commonly found …


Combined Behavioral And Engineering Approach To Preventing Highway Fatalities, Benjamin Blandford, Reginald Souleyrette, Caitlin N. Pope, Tony Fields, Erin Lammers-Staats Aug 2023

Combined Behavioral And Engineering Approach To Preventing Highway Fatalities, Benjamin Blandford, Reginald Souleyrette, Caitlin N. Pope, Tony Fields, Erin Lammers-Staats

Kentucky Transportation Center Research Report

Traditional, single-discipline highway safety approaches can be augmented through multidisciplinary approaches that consider both engineering and behavioral interventions (e.g., education, enforcement, public outreach campaigns). Leveraging a systems-based conceptual framework of roadway safety, multiple forms of statistical and geospatial analysis, and SPF modeling and network screening, this report proposes and demonstrates methods for unpacking the influence of behavioral-related factors on crash occurrences and outcomes. The primary focus is on behaviors targeted in the Strategic Highway Safety Plan — aggressive driving, distracted driving, impaired driving, and driving without proper restraint (i.e., seatbelts). Based on application of these methods, the report highlights areas …


Innovative Methods To Strengthen Internal Kytc Communications, P. Gayle Marks, Jeff Jasper Aug 2023

Innovative Methods To Strengthen Internal Kytc Communications, P. Gayle Marks, Jeff Jasper

Kentucky Transportation Center Research Report

Communication is the linchpin of every organization. Poor communication leads to inefficiencies, frustration among staff, and employee disaffection and disengagement. Although some state transportation agencies have adopted comprehensive strategic plans for internal communications, many have taken a more piecemeal approach, with some Offices and units (e.g., incident management) developing their own plans that apply only to their operations. The latter approach is less than ideal because establishing a comprehensive communications plan provides an organizing framework for all communications within an organization and is critical for uniting staff around a shared sense of purpose and equipping them with the tools they …


Exploring Food-Based Cultural Practices To Address Food Insecurity In Rural Appalachia, Lauren Cassidy Batey, Emily M. Dewitt, Dawn Brewer, Kathryn M. Cardarelli, Heather Norman-Burgdolf Aug 2023

Exploring Food-Based Cultural Practices To Address Food Insecurity In Rural Appalachia, Lauren Cassidy Batey, Emily M. Dewitt, Dawn Brewer, Kathryn M. Cardarelli, Heather Norman-Burgdolf

UK CARES Faculty Publications

Background. Health behaviors, like diet, are influenced by a person’s culture and the society where they reside, contributing to the presence of health disparities within a unique region. Such disparities are evident in Central Appalachia where a unique cultural identity exists. Culture-based initiatives focused on improving food security and other nutritional challenges have had success in other diverse groups, yet similar interventions considering geographically tied culture, like Appalachia, are limited. Aim. This study aims to identify specific aspects of Appalachian culture that address food insecurity to inform future initiatives that may improve adult dietary habits and food security status. Methods. …


Fault Tolerant Electric Machine Concept For Aircraft Propulsion With Pm Rotor And Dc Current Stator Dual-Stage Excitation, Donovin D. Lewis, Oluwaseun A. Badewa, Ali Mohammadi, Matin Vatani, Dan M. Ionel Aug 2023

Fault Tolerant Electric Machine Concept For Aircraft Propulsion With Pm Rotor And Dc Current Stator Dual-Stage Excitation, Donovin D. Lewis, Oluwaseun A. Badewa, Ali Mohammadi, Matin Vatani, Dan M. Ionel

Electrical and Computer Engineering Graduate Research

The development of electrically propelled aircraft requires electric machines that are fault-tolerant, compact, and efficient at multiple operating points. This paper proposes a novel machine topology combining a coreless Halbach PM array axial flux unit and a PM-less synchronous hybrid excited radial flux unit. Both units are coupled on the same shaft to take advantage of the opportunities available in the unique usage profile for aviation. The machines can be used simultaneously for the take off and altitude climbing stage or used individually during the cruising stage. The coreless axial flux PM (CAFPM) motor unit consists of two Halbach array …


Coreless Axial Flux Halbach Array Permanent Magnet Generator Concept For Direct-Drive Wind Turbine, Matin Vatani, Ali Mohammadi, Donovin Lewis, John F. Eastham, Dan M. Ionel Aug 2023

Coreless Axial Flux Halbach Array Permanent Magnet Generator Concept For Direct-Drive Wind Turbine, Matin Vatani, Ali Mohammadi, Donovin Lewis, John F. Eastham, Dan M. Ionel

Electrical and Computer Engineering Graduate Research

This paper proposes a concept for a coreless axial flux permanent magnet (CAFPM) generator with a double sided Halbach array rotor for direct-drive offshore wind turbine applications. The application of printed circuit board (PCB) technology is explored as applied to a concentrated winding stator due to its high reliability, repeatability, and fast mass production. A double-sided Halbach array rotor is employed to intensify the airgap flux density and to enable the elimination of the rotor back iron, decreasing the generator’s total active mass. The effect of the Halbach array rotor pole number and magnet-to-magnet (M2M) gap on the airgap flux …


Fructose Induced Khk-C Can Increase Er Stress Independent Of Its Effect On Lipogenesis To Drive Liver Disease In Diet-Induced And Genetic Models Of Nafld, Se-Hyung Park, Robert N. Helsley, Taghreed Fadhul, Jennifer L. S. Willoughby, Leila Noetzli, Ho-Chou Tu, Marie H. Solheim, Shiho Fujisaka, Hui Pan, Jonathan M. Dreyfuss, Joanna Bons, Jacob Rose, Christina D. King, Birgit Schilling, Aldons J. Lusis, Calvin Pan, Manoj Gupta, Rohit N. Kulkarni, Kevin Fitzgerald, Philip A. Kern, Senad Divanovic, C. Ronald Kahn, Samir Softic Aug 2023

Fructose Induced Khk-C Can Increase Er Stress Independent Of Its Effect On Lipogenesis To Drive Liver Disease In Diet-Induced And Genetic Models Of Nafld, Se-Hyung Park, Robert N. Helsley, Taghreed Fadhul, Jennifer L. S. Willoughby, Leila Noetzli, Ho-Chou Tu, Marie H. Solheim, Shiho Fujisaka, Hui Pan, Jonathan M. Dreyfuss, Joanna Bons, Jacob Rose, Christina D. King, Birgit Schilling, Aldons J. Lusis, Calvin Pan, Manoj Gupta, Rohit N. Kulkarni, Kevin Fitzgerald, Philip A. Kern, Senad Divanovic, C. Ronald Kahn, Samir Softic

Saha Cardiovascular Research Center Faculty Publications

Non-alcoholic fatty liver disease (NAFLD) is a liver manifestation of metabolic syndrome, and is estimated to affect one billion individuals worldwide. An increased intake of a high-fat diet (HFD) and sugar-sweetened beverages are risk-factors for NAFLD development, but how their combined intake promotes progression to a more severe form of liver injury is unknown. Here we show that fructose metabolism via ketohexokinase (KHK) C isoform leads to unresolved endoplasmic reticulum (ER) stress when coupled with a HFD intake. Conversely, a liver-specific knockdown of KHK in mice consuming fructose on a HFD is adequate to improve the NAFLD activity score and …


Asparagine Restriction Enhances Cd8+ T Cell Metabolic Fitness And Antitumoral Functionality Through An Nrf2-Dependent Stress Response, J. N. Rashida Gnanaprakasam, Bhavana Kushwaha, Lingling Liu, Xuyong Chen, Siwen Kang, Tingting Wang, Teresa A. Cassel, Christopher M. Adams, Richard M. Higashi, David A. Scott, Gang Xin, Zihai Li, Jun Yang, Andrew N. Lane, Teresa Whei-Mei Fan, Ji Zhang, Ruoning Wang Aug 2023

Asparagine Restriction Enhances Cd8+ T Cell Metabolic Fitness And Antitumoral Functionality Through An Nrf2-Dependent Stress Response, J. N. Rashida Gnanaprakasam, Bhavana Kushwaha, Lingling Liu, Xuyong Chen, Siwen Kang, Tingting Wang, Teresa A. Cassel, Christopher M. Adams, Richard M. Higashi, David A. Scott, Gang Xin, Zihai Li, Jun Yang, Andrew N. Lane, Teresa Whei-Mei Fan, Ji Zhang, Ruoning Wang

Markey Cancer Center Faculty Publications

Robust and effective T cell immune surveillance and cancer immunotherapy require proper allocation of metabolic resources to sustain energetically costly processes, including growth and cytokine production. Here, we show that asparagine (Asn) restriction on CD8+ T cells exerted opposing effects during activation (early phase) and differentiation (late phase) following T cell activation. Asn restriction suppressed activation and cell cycle entry in the early phase while rapidly engaging the nuclear factor erythroid 2-related factor 2 (NRF2)-dependent stress response, conferring robust proliferation and effector function on CD8+ T cells during differentiation. Mechanistically, NRF2 activation in CD8+ T cells conferred by Asn restriction …


Chemokine Receptor Cxcr7 Activates Aurora Kinase A And Promotes Neuroendocrine Prostate Cancer Growth, Galina Gritsina, Ka-Wing Fong, Xiaodong Lu, Zhuoyuan Lin, Wanqing Xie, Shivani Agarwal, Dong Lin, Gary E. Schiltz, Himisha Beltran, Eva Corey, Colm Morrissey, Yuzhuo Wang, Jonathan C. Zhao, Maha Hussain, Jindan Yu Aug 2023

Chemokine Receptor Cxcr7 Activates Aurora Kinase A And Promotes Neuroendocrine Prostate Cancer Growth, Galina Gritsina, Ka-Wing Fong, Xiaodong Lu, Zhuoyuan Lin, Wanqing Xie, Shivani Agarwal, Dong Lin, Gary E. Schiltz, Himisha Beltran, Eva Corey, Colm Morrissey, Yuzhuo Wang, Jonathan C. Zhao, Maha Hussain, Jindan Yu

Markey Cancer Center Faculty Publications

CXCR7 is an atypical chemokine receptor that recruits β-arrestin (ARRB2) and internalizes into clathrin-coated intracellular vesicles where the complex acts as a scaffold for cytoplasmic kinase assembly and signal transduction. Here, we report that CXCR7 was elevated in the majority of prostate cancer (PCa) cases with neuroendocrine features (NEPC). CXCR7 markedly induced mitotic spindle and cell cycle gene expression. Mechanistically, we identified Aurora Kinase A (AURKA), a key regulator of mitosis, as a novel target that was bound and activated by the CXCR7-ARRB2 complex. CXCR7 interacted with proteins associated with microtubules and golgi, and, as such, the CXCR7-ARRB2-containing vesicles trafficked …


Identification Of Immunodominant T Cell Epitopes Induced By Natural Zika Virus Infection, Christopher S. Eickhoff, Krystal A. Meza, Frances E. Terry, Chase G. Colbert, Azra Blazevic, Andres H. Gutiérrez, E. Taylor Stone, James D. Brien, Amelia K. Pinto, Hana M. El Sahly, Mark J. Mulligan, Nadine Rouphael, Maria L. Alcaide, Kay M. Tomashek, Chris Focht, William D. Martin, Leonard Moise, Anne S. De Groot, Daniel F. Hoft Aug 2023

Identification Of Immunodominant T Cell Epitopes Induced By Natural Zika Virus Infection, Christopher S. Eickhoff, Krystal A. Meza, Frances E. Terry, Chase G. Colbert, Azra Blazevic, Andres H. Gutiérrez, E. Taylor Stone, James D. Brien, Amelia K. Pinto, Hana M. El Sahly, Mark J. Mulligan, Nadine Rouphael, Maria L. Alcaide, Kay M. Tomashek, Chris Focht, William D. Martin, Leonard Moise, Anne S. De Groot, Daniel F. Hoft

Markey Cancer Center Faculty Publications

Zika virus (ZIKV) is a flavivirus primarily transmitted by Aedes species mosquitoes, first discovered in Africa in 1947, that disseminated through Southeast Asia and the Pacific Islands in the 2000s. The first ZIKV infections in the Americas were identified in 2014, and infections exploded through populations in Brazil and other countries in 2015/16. ZIKV infection during pregnancy can cause severe brain and eye defects in offspring, and infection in adults has been associated with higher risks of Guillain-Barré syndrome. We initiated a study to describe the natural history of Zika (the disease) and the immune response to infection, for which …


Metabolic Disruption Induced By Mtor Signaling Pathway Inhibition In Regulatory T-Cell Expansion For Clinical Application, Roberto Gedaly, Gabriel Orozco, Alexandre P. Ancheta, Mackenzie Donoho, Siddharth Desai, Fanny Chapelin, Aman Khurana, Lillie J. Lewis, Cuiping Zhang, Francesc Marti Aug 2023

Metabolic Disruption Induced By Mtor Signaling Pathway Inhibition In Regulatory T-Cell Expansion For Clinical Application, Roberto Gedaly, Gabriel Orozco, Alexandre P. Ancheta, Mackenzie Donoho, Siddharth Desai, Fanny Chapelin, Aman Khurana, Lillie J. Lewis, Cuiping Zhang, Francesc Marti

Markey Cancer Center Faculty Publications

Background: Regulatory T cell (Treg) therapy is considered an alternative approach to induce tolerance in transplantation. If successful, this therapy may have implications on immunosuppression minimization/withdrawal to reduce drug-induced toxicity in patients. The aim of this study was to assess the efficacy of the mTORC1/C2 inhibitor, AZD8055, in the manufacturing of clinically competent Treg cells and compare the effects with those induced by rapamycin (RAPA), another mTOR inhibitor commonly used in Treg expansion protocols.

Methods: Primary human Treg cells were isolated from leukapheresis product. Cell viability, expansion rates, suppressive function, autophagy, mitochondrial unfolded protein response (mitoUPR), and cell metabolic profile …


Phosphatase And Pseudo-Phosphatase Functions Of Phosphatase Of Regenerating Liver 3 (Prl-3) Are Insensitive To Divalent Metals In Vitro, Jeffery T. Jolly, Ty C. Cheatham, Jessica S. Blackburn Aug 2023

Phosphatase And Pseudo-Phosphatase Functions Of Phosphatase Of Regenerating Liver 3 (Prl-3) Are Insensitive To Divalent Metals In Vitro, Jeffery T. Jolly, Ty C. Cheatham, Jessica S. Blackburn

Markey Cancer Center Faculty Publications

Phosphatase of regenerating liver 3 (PRL-3) is associated with cancer metastasis and has been shown to interact with the cyclin and CBS domain divalent metal cation transport mediator (CNNM) family of proteins to regulate the intracellular concentration of magnesium and other divalent metals. Despite PRL-3’s importance in cancer, factors that regulate PRL-3’s phosphatase activity and its interactions with CNNM proteins remain unknown. Here, we show that divalent metal ions, including magnesium, calcium, and manganese, have no impact on PRL-3’s structure, stability, phosphatase activity, or CNNM binding capacity, indicating that PRL-3 does not act as a metal sensor, despite its interaction …


Portable Optical Spectroscopic Assay For Non-Destructive Measurement Of Key Metabolic Parameters On In Vitro Cancer Cells And Organotypic Fresh Tumor Slices, Jing Yan, Carlos Frederico Lima Goncalves, Madison O. Korfhage, Zahid Hasan, Teresa Whei-Mei Fan, Xiaoqin Wang, Caigang Zhu Aug 2023

Portable Optical Spectroscopic Assay For Non-Destructive Measurement Of Key Metabolic Parameters On In Vitro Cancer Cells And Organotypic Fresh Tumor Slices, Jing Yan, Carlos Frederico Lima Goncalves, Madison O. Korfhage, Zahid Hasan, Teresa Whei-Mei Fan, Xiaoqin Wang, Caigang Zhu

Markey Cancer Center Faculty Publications

To enable non-destructive metabolic characterizations on in vitro cancer cells and organotypic tumor models for therapeutic studies in an easy-to-access way, we report a highly portable optical spectroscopic assay for simultaneous measurement of glucose uptake and mitochondrial function on various cancer models with high sensitivity. Well-established breast cancer cell lines (MCF-7 and MDA-MB-231) were used to validate the optical spectroscopic assay for metabolic characterizations, while fresh tumor samples harvested from both animals and human cancer patients were used to test the feasibility of our optical metabolic assay for non-destructive measurement of key metabolic parameters on organotypic tumor slices. Our optical …


The Role Of Vaccination Route With An Adenovirus-Vectored Vaccine In Protection, Viral Control, And Transmission In The Sars-Cov-2/K18-Hace2 Mouse Infection Model, Alexandria Dickson, Elizabeth Geerling, E. Taylor Stone, Mariah Hassert, Tara L. Steffen, Taneesh Makkena, Madeleine Smither, Katherine E. Schwetye, Jianfeng Zhang, Bertrand Georges, M. Scot Roberts, John J. Suschak, Amelia K. Pinto, James D. Brien Aug 2023

The Role Of Vaccination Route With An Adenovirus-Vectored Vaccine In Protection, Viral Control, And Transmission In The Sars-Cov-2/K18-Hace2 Mouse Infection Model, Alexandria Dickson, Elizabeth Geerling, E. Taylor Stone, Mariah Hassert, Tara L. Steffen, Taneesh Makkena, Madeleine Smither, Katherine E. Schwetye, Jianfeng Zhang, Bertrand Georges, M. Scot Roberts, John J. Suschak, Amelia K. Pinto, James D. Brien

Markey Cancer Center Faculty Publications

Introduction: Vaccination is the most effective mechanism to prevent severe COVID-19. However, breakthrough infections and subsequent transmission of SARS-CoV-2 remain a significant problem. Intranasal vaccination has the potential to be more effective in preventing disease and limiting transmission between individuals as it induces potent responses at mucosal sites.

Methods: Utilizing a replication-deficient adenovirus serotype 5-vectored vaccine expressing the SARS-CoV-2 RBD (AdCOVID) in homozygous and heterozygous transgenic K18-hACE2, we investigated the impact of the route of administration on vaccine immunogenicity, SARS-CoV-2 transmission, and survival.

Results: Mice vaccinated with AdCOVID via the intramuscular or intranasal route and subsequently challenged with SARS-CoV-2 showed …