Digital Commons Network^™

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

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

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

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

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

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

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

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

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 …

Bridging The Gap Between Academic Research And Reduction To Practice: Manufacturing Scale-Up Of Polymeric Membranes For Water Treatment, David Lu, Isabel C. Escobar

Kentucky Water Resources Annual Symposium

No abstract provided.

Modeling, Managing, And Mitigating Stormwater Flooding Using A Real-Time Monitoring Network And Environmental Equity Approach, Ben Hauschild, Jason S. Polk, Trayson Lawler, Adam Desloge

Kentucky Water Resources Annual Symposium

No abstract provided.

Stormwater Management Advances Using Smart Sensing Network Architecture For Precipitation Monitoring, Brittany Pekara, Jason S. Polk, James Adam Shelley

Kentucky Water Resources Annual Symposium

No abstract provided.

Development Of A Spatial And Statistical Diagnostic Tool To Prioritize Pfas Sample Locations In Kentucky Surface Waters, Ariel Robinson, Angela Gutierrez, Kelly G. Pennell

Kentucky Water Resources Annual Symposium

No abstract provided.

A Flood Of Consequences In Louisville, Kentucky: Using Hgis To Track Refugees Impacted By The 1937 Ohio River Flood, Trevor Harry, Margaret M. Gripshover

Kentucky Water Resources Annual Symposium

No abstract provided.

Sewer Gas, Siphons And Long-Term Stewardship For Community Interventions, Hong Cheng Tay, Kelly G. Pennell

Kentucky Water Resources Annual Symposium

No abstract provided.

Perceptions And Visual Awareness Of Urban Karst Flooding To Inform Preparedness Planning And Management Actions, Grace Herrmann, Jason Polk

Kentucky Water Resources Annual Symposium

No abstract provided.

Contaminant Transport Mechanisms And Source Tracking In Karst Groundwater Systems Under Agriculture Land Use, Shreya Pandley, Jason S. Polk

Kentucky Water Resources Annual Symposium

No abstract provided.

Identifying Controls On Sediment Hysteresis Patterns Using Interpretable Machine Learning, Arlex Marin-Ramirez, David Tyler Mahoney, Brendan Riddle, Leonie Bettel, James Fox

Kentucky Water Resources Annual Symposium

No abstract provided.

Modifying The Cop Karst Groundwater Vulnerability Model Using Spring Storm Response, Benjamin Tobin, Sara Arpin, Solomon Nketsia, Chelsea Parada, Maaz Fareedi, Will Hemenover, Charlies Taylor

Kentucky Water Resources Annual Symposium

No abstract provided.

Exploring Water Quality On The Reclaimed Surface Mines Lands In Eastern Kentucky, Whitney Tara Maynard, Buddhi Gyawali, George Antonious

Kentucky Water Resources Annual Symposium

No abstract provided.

Modeling Moisture Content Variations In The Shallow Subsurface Soil Under Rainfall Infiltration And Different Atmospheric Conditions, Omid Ghasemi-Fare, Mohammadreza Mir Tamizdoust, Fereydoun Najafian Jazi, Amin Mohammadzadeh, Tom Rockaway

Kentucky Water Resources Annual Symposium

No abstract provided.

Karst Watershed Planning For The Jennings Creek/Lost River Watershed In South-Central Kentucky To Improve Water Quality And Community Awareness, Jason S. Polk, Adam Desloge, Brittany Pekara, Trayson Lawler, Shreya Pandey, Kara Brunot, Mara Neace, Meghan Forbes, Matt Powell

Kentucky Water Resources Annual Symposium

No abstract provided.

River And Conduit Stage Tomography For Characterizing Karst Aquifers, Junfeng Zhu, Steven Webb, James Fox

Kentucky Water Resources Annual Symposium

No abstract provided.

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.

Investigating The Impact Of Stream Restoration On Sediment Transport At A Karst Spring Using Hydrograph Unmixing, Sediment Transport Modeling And Multi-Source Hysteresis, Leonie Bettel, Jimmy Fox, Admin Husic, Tyler Mahoney, Arlex Marin, Zunfeng Zhu, Benjamin Tobin, Nabil Al Aamer, Chloe Osborne

Kentucky Water Resources Annual Symposium

No abstract provided.

Methane Dynamics Of Kentucky Bottomland Hardwood Forested Systems, Marissa Miles, Jessica B. Moon, Skylar Ross, Jarred Asselta, Niklas Klauss, Rosie Carey, Kabi Raj Khatiwada, Bassil El Masri, Gary Stinchcomb, Benjamin R. K. Runkle

Kentucky Water Resources Annual Symposium

No abstract provided.

A Critical Review Of Vegetation Issues In So-Called “Stream Restoration” On Daniel Boone National Forest, Julian J. N. Campbell

Kentucky Water Resources Annual Symposium

No abstract provided.

Floating Vegetation As A Driver Of Ch4 Emissions In Small Ponds Across Louisville, Ky, Mark Tierney, C. Jalink, J. H. Loughrin, S. W. Antle, Andrew S. Mehring

Kentucky Water Resources Annual Symposium

No abstract provided.

Measuring The Contribution Of Bald Cypress “Knees” To Greenhouse Gas Emissions During Climate Extremes, Skylar Ross, Jessica B. Moon, Niklas Klauss, Marissa Miles, Kabi Raj Khatiwada4, Bassil El Masri, Gary Stinchcomb, Benjamin R. K. Runkle

Kentucky Water Resources Annual Symposium

No abstract provided.

Impacts Of Land Use And Groundwater Inputs On Biological Stream Health And Habitat Of Jennings Creek, Bowling Green, Kentucky, Allison Francis, Jason S. Polk

Kentucky Water Resources Annual Symposium

No abstract provided.