Digital Commons Network^™

Extended-Spectrum Antiprotozoal Bumped Kinase Inhibitors: A Review, Wesley C. Van Voorhis, J. Stone Doggett, Marilyn Parsons, Matthew A. Hulverson, Ryan Choi, Samuel L. M. Arnold, Michael W. Riggs, Andrew Hemphill, Daniel K. Howe, Robert H. Mealey, Audrey O. T. Lau, Ethan A. Merritt, Dustin J. Maly, Erkang Fan, Kayode K. Ojo

Veterinary Science Faculty Publications

Many life-cycle processes in parasites are regulated by protein phosphorylation. Hence, disruption of essential protein kinase function has been explored for therapy of parasitic diseases. However, the difficulty of inhibiting parasite protein kinases to the exclusion of host orthologues poses a practical challenge. A possible path around this difficulty is the use of bumped kinase inhibitors for targeting calcium dependent protein kinases that contain atypically small gatekeeper residues and are crucial for pathogenic apicomplexan parasites’ survival and proliferation. In this review, we review efficacy against the kinase target, the parasite growth in vitro, and in animal infection models, as well …

The Rna-Binding Protein Hur Contributes To Neuroinflammation By Promoting C-C Chemokine Receptor 6 (Ccr6) Expression On Th17 Cells., Jing Chen, Jennifer L. Martindale, Carole Cramer, Myriam Gorospe, Ulus Atasoy, Paul D. Drew, Shiguang Yu

Department of Neurology Faculty Papers

In both multiple sclerosis and experimental autoimmune encephalomyelitis (EAE), the C-C chemokine receptor 6 (CCR6) is critical for pathogenic T helper 17 (Th17) cell migration to the central nervous system (CNS). Whereas many cytokines and their receptors are potently regulated via post-transcriptional mechanisms in response to various stimuli, how CCR6 expression is post-transcriptionally regulated in Th17 cells is unknown. Here, using RNA-binding protein HuR conditional knock-out (KO) and wild-type (WT) mice, we present evidence that HuR post-transcriptionally regulates CCR6 expression by binding to and stabilizing Ccr6 mRNA and by promoting CCR6 translation. We also found that HuR down-regulates several microRNA …

Thiamine Deficiency And Neurodegeneration: The Interplay Among Oxidative Stress, Endoplasmic Reticulum Stress, And Autophagy, Dexiang Liu, Zunji Ke, Jia Luo

Pharmacology and Nutritional Sciences Faculty Publications

Thiamine (vitamin B1) is an essential nutrient and indispensable for normal growth and development of the organism due to its multilateral participation in key biochemical and physiological processes. Humans must obtain thiamine from their diet since it is synthesized only in bacteria, fungi, and plants. Thiamine deficiency (TD) can result from inadequate intake, increased requirement, excessive deletion, and chronic alcohol consumption. TD affects multiple organ systems, including the cardiovascular, muscular, gastrointestinal, and central and peripheral nervous systems. In the brain, TD causes a cascade of events including mild impairment of oxidative metabolism, neuroinflammation, and neurodegeneration, which are commonly observed in …

Hyperfiltration-Associated Biomechanical Forces In Glomerular Injury And Response: Potential Role For Eicosanoids., Mukut Sharma, Ram Sharma, Ellen T. Mccarthy, Virginia J. Savin, Tarak Srivastava

Manuscripts, Articles, Book Chapters and Other Papers

Hyperfiltration is a well-known risk factor in progressive loss of renal function in chronic kidney disease (CKD) secondary to various diseases. A reduced number of functional nephrons due to congenital or acquired cause(s) results in hyperfiltration in the remnant kidney. Hyperfiltration-associated increase in biomechanical forces, namely pressure-induced tensile stress and fluid flow-induced shear stress (FFSS) determine cellular injury and response. We believe the current treatment of CKD yields limited success because it largely attenuates pressure-induced tensile stress changes but not the effect of FFSS on podocytes. Studies on glomerular podocytes, tubular epithelial cells and bone osteocytes provide evidence for a …

Strain Specific Effects Of Low Level Lead Exposure On Associative Learning And Memory In Rats., Megha Verma, J. S. Schneider

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Exposure to lead (Pb) remains a significant public health concern. Lead exposure in early life impairs the normal development of numerous cognitive and neurobehavioral processes. Previous work has shown that the effects of developmental Pb exposure on gene expression patterns in the brain are modulated by various factors including the developmental timing of the exposure, level of exposure, sex, and genetic background. Using gene microarray profiling, we previously reported a significant strain-specific effect of Pb exposure on the hippocampal transcriptome, with the greatest number of differentially expressed transcripts in Long Evans (LE) rats and the fewest in Sprague Dawley (SD) …

In Situ Capture Of Chromatin Interactions By Biotinylated Dcas9., Xin Liu, Yuannyu Zhang, Yong Chen, Mushan Li, Feng Zhou, Kailong Li, Hui Cao, Min Ni, Yuxuan Liu, Zhimin Gu, Kathryn E Dickerson, Shiqi Xie, Gary C Hon, Zhenyu Xuan, Michael Q Zhang, Zhen Shao, Jian Xu

College of Science & Mathematics Departmental Research

Cis-regulatory elements (CREs) are commonly recognized by correlative chromatin features, yet the molecular composition of the vast majority of CREs in chromatin remains unknown. Here, we describe a CRISPR affinity purification in situ of regulatory elements (CAPTURE) approach to unbiasedly identify locus-specific chromatin-regulating protein complexes and long-range DNA interactions. Using an in vivo biotinylated nuclease-deficient Cas9 protein and sequence-specific guide RNAs, we show high-resolution and selective isolation of chromatin interactions at a single-copy genomic locus. Purification of human telomeres using CAPTURE identifies known and new telomeric factors. In situ capture of individual constituents of the enhancer cluster controlling human β-globin …

Smartscope2: Simultaneous Imaging And Reconstruction Of Neuronal Morphology., Brian Long, Zhi Zhou, Ali Cetin, Jonathan Ting, Ryder Gwinn, Bosiljka Tasic, Tanya Daigle, Ed Lein, Hongkui Zeng, Peter Saggau, Michael Hawrylycz, Hanchuan Peng

Articles, Abstracts, and Reports

Quantitative analysis of neuronal morphology is critical in cell type classification and for deciphering how structure gives rise to function in the brain. Most current approaches to imaging and tracing neuronal 3D morphology are data intensive. We introduce SmartScope2, the first open source, automated neuron reconstruction machine integrating online image analysis with automated multiphoton imaging. SmartScope2 takes advantage of a neuron's sparse morphology to improve imaging speed and reduce image data stored, transferred and analyzed. We show that SmartScope2 is able to produce the complex 3D morphology of human and mouse cortical neurons with six-fold reduction in image data requirements …

Inhibition Of Post-Transcriptional Steps In Ribosome Biogenesis Confers Cytoprotection Against Chemotherapeutic Agents In A P53-Dependent Manner, Russell T Sapio, Anastasiya N Nezdyur, Matthew Krevetski, Leonid Anikin, Vincent J Manna, Natalie Minkovsky, Dimitri G Pestov

Rowan-Virtua School of Osteopathic Medicine Departmental Research

The p53-mediated nucleolar stress response associated with inhibition of ribosomal RNA transcription was previously shown to potentiate killing of tumor cells. Here, we asked whether targeting of ribosome biogenesis can be used as the basis for selective p53-dependent cytoprotection of nonmalignant cells. Temporary functional inactivation of the 60S ribosome assembly factor Bop1 in a 3T3 cell model markedly increased cell recovery after exposure to camptothecin or methotrexate. This was due, at least in part, to reversible pausing of the cell cycle preventing S phase associated DNA damage. Similar cytoprotective effects were observed after transient shRNA-mediated silencing of Rps19, but not …

Phytoplasma Infection Of A Tropical Root Crop Triggers Bottom-Up Cascades By Favoring Generalist Over Specialist Herbivores, Kris A. G. Wyckhuys, Ignazio Graziosi, Dharani Dhar Burra, Abigail Jan Walter

Entomology Faculty Publications

Global interest on plant-microbe-insect interactions is rapidly growing, revealing the multiple ways in which microorganisms mediate plant-herbivore interactions. Phytopathogens regularly alter whole repertoires of plant phenotypic traits, and bring about shifts in key chemical or morphological characteristics of plant hosts. Pathogens can also cause cascading effects on higher trophic levels, and eventually shape entire plant-associated arthropod communities. We tested the hypothesis that a Candidatus Phytoplasma causing cassava witches’ broom (CWB) on cassava (Manihot esculenta Grantz) is altering species composition of invasive herbivores and their associated parasitic hymenopterans. We conducted observational studies in cassava fields in eastern Cambodia to assess …

Posttranscriptional Upregulation Of Idh1 By Hur Establishes A Powerful Survival Phenotype In Pancreatic Cancer Cells., Mahsa Zarei, Shruti Lal, Seth J. Parker, Avinoam Nevler, Ali Vaziri-Gohar, Katerina Dukleska, Nicole C. Mambelli-Lisboa, Cynthia Moffat, Fernando F Blanco, Saswati N. Chand, Masaya Jimbo, Joseph A. Cozzitorto, Wei Jiang, Charles J. Yeo, Eric R. Londin, Erin L. Seifert, Christian M. Metallo, Jonathan R. Brody, Jordan M. Winter

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Cancer aggressiveness may result from the selective pressure of a harsh nutrient-deprived microenvironment. Here we illustrate how such conditions promote chemotherapy resistance in pancreatic ductal adenocarcinoma (PDAC). Glucose or glutamine withdrawal resulted in a 5- to 10-fold protective effect with chemotherapy treatment. PDAC xenografts were less sensitive to gemcitabine in hypoglycemic mice compared with hyperglycemic mice. Consistent with this observation, patients receiving adjuvant gemcitabine (n = 107) with elevated serum glucose levels (HgbA1C > 6.5%) exhibited improved survival. We identified enhanced antioxidant defense as a driver of chemoresistance in this setting. ROS levels were doubled in vitro by either nutrient withdrawal …

Abl Kinase Regulation By Braf/Erk And Cooperation With Akt In Melanoma, Aditi Jain, Rakshamani Tripathi, Courtney P. Turpin, Chi Wang, Rina Plattner

Pharmacology and Nutritional Sciences Faculty Publications

The melanoma incidence continues to increase, and the disease remains incurable for many due to its metastatic nature and high rate of therapeutic resistance. In particular, melanomas harboring BRAF^V600E and PTEN mutations often are resistant to current therapies, including BRAF inhibitors (BRAFi) and immune checkpoint inhibitors. Abl kinases (Abl/Arg) are activated in melanomas and drive progression; however, their mechanism of activation has not been established. Here we elucidate a novel link between BRAF^V600E/ERK signaling and Abl kinases. We demonstrate that BRAF^V600E/ERK play a critical role in binding, phosphorylating and regulating Abl localization and Abl/Arg activation …

Targeting Hepatic Heparin-Binding Egf-Like Growth Factor (Hb-Egf) Induces Anti-Hyperlipidemia Leading To Reduction Of Angiotensin Ii-Induced Aneurysm Development, Seonwook Kim, Lihua Yang, Seongu Kim, Richard G. Lee, Mark J. Graham, Judith A. Berliner, Aldons J. Lusis, Lei Cai, Ryan E. Temel, Debra L. Rateri, Sangderk Lee

Saha Cardiovascular Research Center Faculty Publications

Objective

The upregulated expression of heparin binding EGF-like growth factor (HB-EGF) in the vessel and circulation is associated with risk of cardiovascular disease. In this study, we tested the effects of HB-EGF targeting using HB-EGF-specific antisense oligonucleotide (ASO) on the development of aortic aneurysm in a mouse aneurysm model.

Approach and results

Low-density lipoprotein receptor (LDLR) deficient mice (male, 16 weeks of age) were injected with control and HB-EGF ASOs for 10 weeks. To induce aneurysm, the mice were fed a high fat diet (22% fat, 0.2% cholesterol; w/w) at 5 week point of ASO administration and infused with angiotensin …

Brain Microvascular Injury And White Matter Disease Provoked By Diabetes-Associated Hyperamylinemia, Han Ly, Nirmal Verma, Fengen Wu, Miao Liu, Kathryn E. Saatman, Peter T. Nelson, John T. Slevin, Larry B. Goldstein, Geert Jan Biessels, Florin Despa

Pharmacology and Nutritional Sciences Faculty Publications

OBJECTIVE: The brain blood vessels of patients with type 2 diabetes and dementia have deposition of amylin, an amyloidogenic hormone cosecreted with insulin. It is not known whether vascular amylin deposition is a consequence or a trigger of vascular injury. We tested the hypothesis that the vascular amylin deposits cause endothelial dysfunction and microvascular injury and are modulated by amylin transport in the brain via plasma apolipoproteins.

METHODS: Rats overexpressing amyloidogenic (human) amylin in the pancreas (HIP rats) and amylin knockout (AKO) rats intravenously infused with aggregated amylin were used for in vivo phenotyping. We also carried out biochemical analyses …

Identification Of Changes In Neuronal Function As A Consequence Of Aging And Tauopathic Neurodegeneration Using A Novel And Sensitive Magnetic Resonance Imaging Approach, Sarah N. Fontaine, Alexandria Ingram, Ryan A. Cloyd, Shelby E. Meier, Emily Miller, Danielle N. Lyons, Grant K. Nation, Elizabeth Mechas, Blaine Weiss, Chiara Lanzillotta, Fabio Di Domenico, Frederick A. Schmitt, David K. Powell, Moriel H. Vandsburger, Jose Francisco Abisambra

Sanders-Brown Center on Aging Faculty Publications

Tauopathies, the most common of which is Alzheimer’s disease (AD), constitute the most crippling neurodegenerative threat to our aging population. Tauopathic patients have significant cognitive decline accompanied by irreversible and severe brain atrophy, and it is thought that neuronal dysfunction begins years before diagnosis. Our current understanding of tauopathies has yielded promising therapeutic interventions but have all failed in clinical trials. This is partly due to the inability to identify and intervene in an effective therapeutic window early in the disease process. A major challenge that contributes to the definition of an early therapeutic window is limited technologies. To address …

A Naturally Generated Decoy Of The Prostate Apoptosis Response-4 Protein Overcomes Therapy Resistance In Tumors, Nikhil Hebbar, Ravshan Burikhanov, Nidhi Shukla, Shirley Qiu, Yanming Zhao, Kojo S. J. Elenitoba-Johnson, Vivek M. Rangnekar

Radiation Medicine Faculty Publications

Primary tumors are often heterogeneous, composed of therapy-sensitive and emerging therapy-resistant cancer cells. Interestingly, treatment of therapy-sensitive tumors in heterogeneous tumor microenvironments results in apoptosis of therapy-resistant tumors. In this study, we identify a prostate apoptosis response-4 (Par-4) amino-terminal fragment (PAF) that is released by diverse therapy-sensitive cancer cells following therapy-induced caspase cleavage of the tumor suppressor Par-4 protein. PAF caused apoptosis in cancer cells resistant to therapy and inhibited tumor growth. A VASA segment of Par-4 mediated its binding and degradation by the ubiquitin ligase Fbxo45, resulting in loss of Par-4 proapoptotic function. Conversely, PAF, which contains this VASA …

Increased Expression Of M1 And M2 Phenotypic Markers In Isolated Microglia After Four-Day Binge Alcohol Exposure In Male Rats, Hui Peng, Chelsea Rhea Geil Nickell, Kevin Y. Chen, Justin A. Mcclain, Kimberly Nixon

Pharmaceutical Sciences Faculty Publications

Microglia activation and neuroinflammation are common features of neurodegenerative conditions, including alcohol use disorders (AUDs). When activated, microglia span a continuum of diverse phenotypes ranging from classically activated, pro-inflammatory (M1) microglia/macrophages to alternatively activated, growth-promoting (M2) microglia/macrophages. Identifying microglia phenotypes is critical for understanding the role of microglia in the pathogenesis of AUDs. Therefore, male rats were gavaged with 25% (w/v) ethanol or isocaloric control diet every 8 h for 4 days and sacrificed at 0, 2, 4, and 7 days after alcohol exposure (e.g., T0, T2, etc.). Microglia were isolated from hippocampus and entorhinal cortices by Percoll density gradient …

Ion Channel Signaling Influences Cellular Proliferation And Phagocyte Activity During Axolotl Tail Regeneration, Brandon M. Franklin, S. Randal Voss, Jeffrey L. Osborn

Biology Faculty Publications

Little is known about the potential for ion channels to regulate cellular behaviors during tissue regeneration. Here, we utilized an amphibian tail regeneration assay coupled with a chemical genetic screen to identify ion channel antagonists that altered critical cellular processes during regeneration. Inhibition of multiple ion channels either partially (anoctamin1/Tmem16a, anoctamin2/Tmem16b, K_V2.1, K_V2.2, L-type CaV channels and H/K ATPases) or completely (GlyR, GABA_AR, K_V1.5 and SERCA pumps) inhibited tail regeneration. Partial inhibition of tail regeneration by blocking the calcium activated chloride channels, anoctamin1&2, was associated with a reduction of cellular proliferation in …

April:Taci Axis Is Dispensable For The Immune Response To Rabies Vaccination., Shannon L. Haley, Evgeni P. Tzvetkov, Andrew G. Lytle, Kishore R. Alugupalli, Joseph R. Plummer, James P. Mcgettigan

Department of Microbiology and Immunology Faculty Papers

There is significant need to develop a single-dose rabies vaccine to replace the current multi-dose rabies vaccine regimen and eliminate the requirement for rabies immune globulin in post-exposure settings. To accomplish this goal, rabies virus (RABV)-based vaccines must rapidly activate B cells to secrete antibodies which neutralize pathogenic RABV before it enters the CNS. Increased understanding of how B cells effectively respond to RABV-based vaccines may improve efforts to simplify post-exposure prophylaxis (PEP) regimens. Several studies have successfully employed the TNF family cytokine a proliferation-inducing ligand (APRIL) as a vaccine adjuvant. APRIL binds to the receptors TACI and B cell …

Life-Shortening Wolbachia Infection Reduces Population Growth Of Aedes Aegypti, Eunho Suh, David R. Mercer, Stephen L. Dobson

Entomology Faculty Publications

Wolbachia bacteria are being introduced into natural populations of vector mosquitoes, with the goal of reducing the transmission of human diseases such as Zika and dengue fever. The successful establishment of Wolbachia infection is largely dependent on the effects of Wolbachia infection to host fitness, but the effects of Wolbachia infection on the individual life-history traits of immature mosquitoes can vary. Here, the effects of life-shortening Wolbachia (wMelPop) on population growth of infected individuals were evaluated by measuring larval survival, developmental time and adult size of Aedes aegypti in intra- (infected or uninfected only) and inter-group (mixed with …

In Vivo Evaluation Of Stem Cell Aggregates On Osteochondral Regeneration., Banupriya Sridharan, Amy D. Laflin, Michael A. Holtz, Donna M. Pacicca, Nicholas K. Wischmeier, Michael S. Detamore

Manuscripts, Articles, Book Chapters and Other Papers

To date, many osteochondral regenerative approaches have utilized varied combinations of biocompatible materials and cells to engineer cartilage. Even in cell-based approaches, to date, no study has utilized stem cell aggregates alone for regenerating articular cartilage. Thus, the purpose of this study was to evaluate the performance of a novel stem cell-based aggregate approach in a fibrin carrier to regenerate osteochondral defects in the Sprague-Dawley rat trochlear groove model. Two different densities of rat bone marrow mesenchymal stem cell (rBMSC) aggregates were fabricated by the hanging drop technique. At 8 weeks, the cell aggregates supported the defects and served as …

Metabolic Differentiation Of Early Lyme Disease From Southern Tick-Associated Rash Illness (Stari), C Molins, L Ashton, Gary Wormser, B Andre, A Hess, J Belisle

NYMC Faculty Publications

Lyme disease, the most commonly reported vector-borne disease in the United States, results from infection with Borrelia burgdorferi. Early clinical diagnosis of this disease is largely based on the presence of an erythematous skin lesion for individuals in high-risk regions. This, however, can be confused with other illnesses including southern tick-associated rash illness (STARI), an illness that lacks a defined etiological agent or laboratory diagnostic test, and is coprevalent with Lyme disease in portions of the eastern United States. By applying an unbiased metabolomics approach with sera retrospectively obtained from well-characterized patients, we defined biochemical and diagnostic differences between early …

Consequences Of Severe Habitat Fragmentation On Density, Genetics, And Spatial Capture-Recapture Analysis Of A Small Bear Population, Sean Mccarthy Murphy, Ben C. Augustine, Wade Allen Ulrey, Joseph Maddox Guthrie, Brian K Scheick, J. Walter Mccown, John J. Cox

Forestry and Natural Resources Faculty Publications

Loss and fragmentation of natural habitats caused by human land uses have subdivided several formerly contiguous large carnivore populations into multiple small and often isolated subpopulations, which can reduce genetic variation and lead to precipitous population declines. Substantial habitat loss and fragmentation from urban development and agriculture expansion relegated the Highlands-Glades subpopulation (HGS) of Florida, USA, black bears (Ursus americanus floridanus) to prolonged isolation; increasing human land development is projected to cause ≥ 50% loss of remaining natural habitats occupied by the HGS in coming decades. We conducted a noninvasive genetic spatial capture-recapture study to quantitatively describe the …

Progressive Age-Dependence And Frequency Difference In The Effect Of Gap Junctions On Active Cochlear Amplification And Hearing, Liang Zong, Jin Chen, Yan Zhu, Hong-Bo Zhao

Otolaryngology--Head & Neck Surgery Faculty Publications

Mutations of Connexin 26 (Cx26, GJB2), which is a predominant gap junction isoform in the cochlea, can induce high incidence of nonsyndromic hearing loss. We previously found that targeted-deletion of Cx26 in supporting Deiters cells and outer pillar cells in the cochlea can influence outer hair cell (OHC) electromotility and reduce active cochlear amplification leading to hearing loss, even though there are no gap junction connexin expressions in the auditory sensory hair cells. Here, we further report that hearing loss and the reduction of active amplification in the Cx26 targeted-deletion mice are progressive and different at high and low …

Seroepidemiology Of Sarcocystis Neurona And Neospora Hughesi Infections In Domestic Donkeys (Equus Asinus) In Durango, Mexico, Cosme Alvarado-Esquivel, Daniel K. Howe, Michelle R. Yeargan, Domingo Alvarado-Esquivel, José Alfredo Zamarripa-Barboza, Jitender P. Dubey

Maxwell H. Gluck Equine Research Center Faculty Publications

There is currently no information regarding Sarcocystis neurona and Neospora hughesi infections in donkeys in Mexico. Here, we determined the presence of antibodies against S. neurona and N. hughesi in donkeys in the northern Mexican state of Durango. Serum samples of 239 domestic donkeys (Equus asinus) were assayed for S. neurona and N. hughesi antibodies using home-made enzyme-linked immunoassays; six (2.5%) of the 239 donkeys tested seropositive for S. neurona. The seroprevalence of S. neurona infection was comparable among donkeys regardless of their origin, health status, or sex. Multivariate analysis showed that seropositivity to S. neurona was …

Mdm2 Is Required For Survival And Growth Of P53-Deficient Cancer Cells., Kyle P Feeley, Clare M. Adams, Ramkrishna Mitra, Christine M. Eischen

Department of Cancer Biology Faculty Papers

p53 deletion prevents the embryonic lethality of normal tissues lacking Mdm2, suggesting that cells can survive without Mdm2 if p53 is also absent. Here we report evidence challenging this view, with implications for therapeutically targeting Mdm2. Deletion of Mdm2 in T-cell lymphomas or sarcomas lacking p53 induced apoptosis and G₂ cell-cycle arrest, prolonging survival of mice with these tumors. p53^-/- fibroblasts showed similar results, indicating that the effects of Mdm2 loss extend to pre-malignant cells. Mdm2 deletion in p53^-/- cells upregulated p53 transcriptional target genes that induce apoptosis and cell-cycle arrest. Mdm2 deletion also increased levels of …

Peripheral Inflammation, Apolipoprotein E4, And Amyloid-Β Interact To Induce Cognitive And Cerebrovascular Dysfunction, Felecia M. Marottoli, Yuriko Katsumata, Kevin P. Koster, Riya Thomas, David W. Fardo, Leon M. Tai

Biostatistics Faculty Publications

Cerebrovascular dysfunction is rapidly reemerging as a major process of Alzheimer’s disease (AD). It is, therefore, crucial to delineate the roles of AD risk factors in cerebrovascular dysfunction. While apolipoprotein E4 (APOE4), Amyloid-β (Aβ), and peripheral inflammation independently induce cerebrovascular damage, their collective effects remain to be elucidated. The goal of this study was to determine the interactive effect of APOE4, Aβ, and chronic repeated peripheral inflammation on cerebrovascular and cognitive dysfunction in vivo. EFAD mice are a well-characterized mouse model that express human APOE3 (E3FAD) or APOE4 (E4FAD) and overproduce human Aβ42 via expression of …

Chloroformate Derivatization For Tracing The Fate Of Amino Acids In Cells And Tissues By Multiple Stable Isotope Resolved Metabolomics (Msirm), Ye Yang, Teresa W. -M. Fan, Andrew N. Lane, Richard M. Higashi

Center for Environmental and Systems Biochemistry Faculty Publications

Amino acids have crucial roles in central metabolism, both anabolic and catabolic. To elucidate these roles, steady-state concentrations of amino acids alone are insufficient, as each amino acid participates in multiple pathways and functions in a complex network, which can also be compartmentalized. Stable Isotope-Resolved Metabolomics (SIRM) is an approach that uses atom-resolved tracking of metabolites through biochemical transformations in cells, tissues, or whole organisms. Using different elemental stable isotopes to label multiple metabolite precursors makes it possible to resolve simultaneously the utilization of these precursors in a single experiment. Conversely, a single precursor labeled with two (or more) different …

Cyclin D1 Restrains Oncogene-Induced Autophagy By Regulating The Ampk-Lkb1 Signaling Axis., Mathew C. Casimiro, Gabriele Disante, Agnese Di Rocco, Emanuele Loro, Claudia Pupo, Timothy G. Pestell, Sara Bisetto, Marco A. Velasco-Velázquez, Xuanmao Jiao, Zhiping Li, Christine M. Kusminski, Erin L. Seifert, Chenguang Wang, Daniel Ly, Bin Zheng, Che-Hung Shen, Philipp E. Scherer, Richard Pestell

Department of Cancer Biology Faculty Papers

Autophagy activated after DNA damage or other stresses mitigates cellular damage by removing damaged proteins, lipids, and organelles. Activation of the master metabolic kinase AMPK enhances autophagy. Here we report that cyclin D1 restrains autophagy by modulating the activation of AMPK. In cell models of human breast cancer or in a cyclin D1-deficient model, we observed a cyclin D1-mediated reduction in AMPK activation. Mechanistic investigations showed that cyclin D1 inhibited mitochondrial function, promoted glycolysis, and reduced activation of AMPK (pT172), possibly through a mechanism that involves cyclin D1-Cdk4/Cdk6 phosphorylation of LKB1. Our findings suggest how AMPK activation by cyclin D1 …

Proteogenomic Analysis Of The Total And Surface-Exposed Proteomes Of Plasmodium Vivax Salivary Gland Sporozoites., Kristian E Swearingen, Scott E Lindner, Erika L Flannery, Ashley M Vaughan, Robert D Morrison, Rapatbhorn Patrapuvich, Cristian Koepfli, Ivo Muller, Aaron Jex, Robert L Moritz, Stefan H I Kappe, Jetsumon Sattabongkot, Sebastian A Mikolajczak

Articles, Abstracts, and Reports

Plasmodium falciparum and Plasmodium vivax cause the majority of human malaria cases. Research efforts predominantly focus on P. falciparum because of the clinical severity of infection and associated mortality rates. However, P. vivax malaria affects more people in a wider global range. Furthermore, unlike P. falciparum, P. vivax can persist in the liver as dormant hypnozoites that can be activated weeks to years after primary infection, causing relapse of symptomatic blood stages. This feature makes P. vivax unique and difficult to eliminate with the standard tools of vector control and treatment of symptomatic blood stage infection with antimalarial drugs. Infection …

Targeting Antioxidant Enzyme Expression As A Therapeutic Strategy For Ischemic Stroke, Stephanie M. Davis, Keith R. Pennypacker

Center for Advanced Translational Stroke Science Faculty Publications

During ischemic stroke, neurons and glia are subjected to damage during the acute and neuroinflammatory phases of injury. Production of reactive oxygen species (ROS) from calcium dysregulation in neural cells and the invasion of activated immune cells are responsible for stroke-induced neurodegeneration. Scientists have failed thus far to identify antioxidant-based drugs that can enhance neural cell survival and improve recovery after stroke. However, several groups have demonstrated success in protecting against stroke by increasing expression of antioxidant enzymes in neural cells. These enzymes, which include but are not limited to enzymes in the glutathione peroxidase, catalase, and superoxide dismutase families, …