Digital Commons Network^™

Use Of Synthetic Isoprenoids To Target Protein Prenylation And Rho Gtpases In Breast Cancer Invasion, Min Chen, Teresa Knifley, Thangaiah Subramanian, H. Peter Spielmann, Kathleen L. O'Connor

Molecular and Cellular Biochemistry Faculty Publications

Dysregulation of Ras and Rho family small GTPases drives the invasion and metastasis of multiple cancers. For their biological functions, these GTPases require proper subcellular localization to cellular membranes, which is regulated by a series of post-translational modifications that result in either farnesylation or geranylgeranylation of the C-terminal CAAX motif. This concept provided the rationale for targeting farnesyltransferase (FTase) and geranylgeranyltransferases (GGTase) for cancer treatment. However, the resulting prenyl transferase inhibitors have not performed well in the clinic due to issues with alternative prenylation and toxicity. As an alternative, we have developed a unique class of potential anti-cancer therapeutics called …

Nuclear Interaction Between Adr-Induced P65 And P53 Mediates Cardiac Injury In Inos (−/−) Mice, Marsha P. Cole, Jitbanjong Tangpong, Terry D. Oberley, Luksana Chaiswing, Kinsley K. Kiningham, Daret K. St. Clair

Toxicology and Cancer Biology Faculty Publications

Adriamycin (ADR) treatment causes an imbalance in the levels of nitric oxide (^•NO) and superoxide (O₂^•−) production leading to cardiac injury. Previously we demonstrated that mice lacking inducible nitric oxide synthase (iNOS) have increased oxidative stress and mitochondrial injury. The molecular events leading to increased mitochondrial injury in iNOS deficient mice is unknown. ADR in the absence of iNOS preferentially activates a proapoptotic pathway without a concurrent increase in prosurvival pathways. Treatment with ADR leads to an increase in DNA binding activity of nuclear factor kappa B (NFκB) and p53 in wildtype mice. Following ADR …

Nuclear Receptor 4a3 (Nr4a3) Regulates Murine Mast Cell Responses And Granule Content, Gianni Garcia-Faroldi, Fabio R. Melo, Dennis Bruemmer, Orla M Conneely, Gunnar Pejler, Anders Lundequist

Internal Medicine Faculty Publications

Nuclear receptor 4a3 (Nr4a3) is a transcription factor implicated in various settings such as vascular biology and inflammation. We have recently shown that mast cells dramatically upregulate Nuclear receptor 4a3 upon activation, and here we investigated the functional impact of Nuclear receptor 4a3 on mast cell responses. We show that Nuclear receptor 4a3 is involved in the regulation of cytokine/chemokine secretion in mast cells following activation via the high affinity IgE receptor. Moreover, Nuclear receptor 4a3 negatively affects the transcript and protein levels of mast cell tryptase as well as the mast cell’s responsiveness to allergen. Together, these findings identify …

B Cell Tolerance In Health And Disease, Murali Gururajan, Vishal J. Sindhava, Subbarao Bondada

Microbiology, Immunology, and Molecular Genetics Faculty Publications

B lymphocyte receptors are generated randomly during the bone marrow developmental phase of B cells. Hence, the B cell repertoire consists of both self and foreign antigen specificities necessitating specific tolerance mechanisms to eliminate self-reactive B cells. This review summarizes the major mechanisms of B cell tolerance, which include clonal deletion, anergy and receptor editing. In the bone marrow presentation of antigen in membrane bound form is more effective than soluble form and the role of dendritic cells in this process is discussed. Toll like receptor derived signals affect activation of B cells by certain ligands such as nucleic acids …

Gene Expression Profiling In Winged And Wingless Cotton Aphids, Aphis Gossypii (Hemiptera: Aphididae), Xiaowei Yang, Xiaoxia Liu, Xiangli Xu, Zhen Li, Yisong Li, Dongyan Song, Tian Yu, Fang Zhu, Qingwen Zhang, Xuguo Zhou

Entomology Faculty Publications

While trade-offs between flight capability and reproduction is a common phenomenon in wing dimorphic insects, the molecular basis is largely unknown. In this study, we examined the transcriptomic differences between winged and wingless morphs of cotton aphids, Aphis gossypii, using a tag-based digital gene expression (DGE) approach. Ultra high-throughput Illumina sequencing generated 5.30 and 5.39 million raw tags, respectively, from winged and wingless A. gossypii DGE libraries. We identified 1,663 differentially expressed transcripts, among which 58 were highly expressed in the winged A. gossypii, whereas 1,605 expressed significantly higher in the wingless morphs. Bioinformatics tools, including Gene Ontology, …

Bis-Quaternary Ammonium Cyclophane Compounds That Interact With Neuronal Nicotinic Acetylcholine Receptors, Peter A. Crooks, Linda P. Dwoskin, Guangrong Zheng, Sangeetha Sumithran, Davis D. Allen, Zhenfa Zheng, Paul Lockman

Pharmaceutical Sciences Faculty Patents

Provided are bis-quaternary ammonium cyclophane compounds which are modulators of nicotinic acetylcholine receptors. Also provided are methods of using the compounds for modulating the function of a nicotinic acetylcholine receptor, and for the prevention and/or treatment of central nervous system disorders, substance use and/or abuse, and or gastrointestinal tract disorders.

Enhancing Transdermal Delivery Of Opioid Antagonists And Agonists Using Codrugs Linked To Bupropion Or Hydroxybupropion, Audra L. Stinchcomb, Peter A. Crooks, Mohamad O. Hamad, Paul K. Kiptoo

Pharmaceutical Sciences Faculty Patents

The present invention is directed to novel codrugs comprising bupropion or hydroxybupropion and an opioid antagonist or an opioid agonist joined together by chemical bonding. The codrugs provide a significant increase in the transdermal flux across human skin, as compared to the basic opioid antagonist or opioid agonist.

River Of Hope, Elizabeth Gritter

Civil Rights

One of the largest southern cities and a hub for the cotton industry, Memphis, Tennessee, was at the forefront of black political empowerment during the Jim Crow era. Compared to other cities in the South, Memphis had an unusually large number of African American voters. Black Memphians sought reform at the ballot box, formed clubs, ran for office, and engaged in voter registration and education activities from the end of the Civil War through the Brown v. Board of Education decision of 1954.

In this groundbreaking book, Elizabeth Gritter examines how and why black Memphians mobilized politically in the period …

Neuronal Growth Cones And Regeneration: Gridlock Within The Extracellular Matrix, Diane M. Snow

Spinal Cord and Brain Injury Research Center Faculty Publications

The extracellular matrix is a diverse composition of glycoproteins and proteoglycans found in all cellular systems. The extracellular matrix, abundant in the mammalian central nervous system, is temporally and spatially regulated and is a dynamic "living" entity that is reshaped and redesigned on a continuous basis in response to changing needs. Some modifications are adaptive and some are maladaptive. It is the maladaptive responses that pose a significant threat to successful axonal regeneration and/or sprouting following traumatic and spinal cord injuries, and has been the focus of a myriad of research laboratories for many years. This review focuses largely on …

Proteoglycans: Road Signs For Neurite Outgrowth, Justin A. Beller, Diane M. Snow

Spinal Cord and Brain Injury Research Center Faculty Publications

Proteoglycans in the central nervous system play integral roles as "traffic signals" for the direction of neurite outgrowth. This attribute of proteoglycans is a major factor in regeneration of the injured central nervous system. In this review, the structures of proteoglycans and the evidence suggesting their involvement in the response following spinal cord injury are presented. The review further describes the methods routinely used to determine the effect proteoglycans have on neurite outgrowth. The effects of proteoglycans on neurite outgrowth are not completely understood as there is disagreement on what component of the molecule is interacting with growing neurites and …

Functional Relevance Of Acrb Trimerization In Pump Assembly And Substrate Binding, Wei Lu, Meng Zhong, Qian Chai, Zhaoshuai Wang, Linliang Yu, Yinan Wei

Chemistry Faculty Publications

AcrB is a multidrug transporter in the inner membrane of Escherichia coli. It is an obligate homotrimer and forms a tripartite efflux complex with AcrA and TolC. AcrB is the engine of the efflux machinery and determines substrate specificity. Active efflux depends on several functional features including proton translocation across the inner membrane through a proton relay pathway in the transmembrane domain of AcrB; substrate binding and migration through the substrate translocation pathway; the interaction of AcrB with AcrA and TolC; and the formation of AcrB homotrimer. Here we investigated two aspects of the inter-correlation between these functional features, …

Computational Design Of The Affinity And Specificity Of A Therapeutic T Cell Receptor, Brian G. Pierce, Lance M. Hellman, Moushumi Hossain, Nishant K. Singh, Craig W. Vander Kooi, Zhiping Weng, Brian M. Baker

Molecular and Cellular Biochemistry Faculty Publications

T cell receptors (TCRs) are key to antigen-specific immunity and are increasingly being explored as therapeutics, most visibly in cancer immunotherapy. As TCRs typically possess only low-to-moderate affinity for their peptide/MHC (pMHC) ligands, there is a recognized need to develop affinity-enhanced TCR variants. Previous in vitro engineering efforts have yielded remarkable improvements in TCR affinity, yet concerns exist about the maintenance of peptide specificity and the biological impacts of ultra-high affinity. As opposed to in vitro engineering, computational design can directly address these issues, in theory permitting the rational control of peptide specificity together with relatively controlled increments in affinity. …

A Review Of Air–Ice Chemical And Physical Interactions (Aici): Liquids, Quasi-Liquids, And Solids In Snow, T. Bartels-Rausch, H. -W. Jacobi, T. F. Kahan, J. L. Thomas, E. S. Thomson, J. P. D. Abbatt, M. Ammann, J. R. Blackford, H. Bluhm, C. Boxe, F. Domine, M. M. Frey, I. Gladich, M. I. Guzmán, D. Heger, Th. Huthwelker, P. Klán, W. F. Kuhs, M. H. Kuo, S. Maus, S. G. Moussa, V. F. Mcneill, J. T. Newberg, J. B. C. Pettersson, M. Roeselová, J. R. Sodeau

Chemistry Faculty Publications

Snow in the environment acts as a host to rich chemistry and provides a matrix for physical exchange of contaminants within the ecosystem. The goal of this review is to summarise the current state of knowledge of physical processes and chemical reactivity in surface snow with relevance to polar regions. It focuses on a description of impurities in distinct compartments present in surface snow, such as snow crystals, grain boundaries, crystal surfaces, and liquid parts. It emphasises the microscopic description of the ice surface and its link with the environment. Distinct differences between the disordered air–ice interface, often termed quasi-liquid …

Compounds And Methods For Reducing Oxidative Stress, Thomas Dziubla, J. Zach Hilt, Dipti Biswal, David B. Cochran, Paritosh Wattamwar

Chemical and Materials Engineering Faculty Patents

Antioxidant polymeric compounds are provided that comprise a plurality of monomeric portions, where each monomeric portion includes an antioxidant molecule interposed between at least two acrylate molecules, and where at least one acrylate molecule of each monomeric portion is linked by a diamine molecule to an acrylate molecule of an adjacent monomeric portion to thereby form the polymer. Methods of synthesizing polymeric compounds and methods of using the antioxidant polymeric compounds to reduce oxidative stress are also provided.

Autoantibody Profiling For Lung Cancer Screening Longitudinal Retrospective Analysis Of Ct Screening Cohorts, Kourtney Trudgen, Nada H. Khattar, Eric Bensadoun, Susanne Arnold, Arnold J. Stromberg, Edward A. Hirschowitz

Internal Medicine Faculty Publications

Recommendations for lung cancer screening present a tangible opportunity to integrate predictive blood-based assays with radiographic imaging. This study compares performance of autoantibody markers from prior discovery in sample cohorts from two CT screening trials. One-hundred eighty non-cancer and 6 prevalence and 44 incidence cancer cases detected in the Mayo Lung Screening Trial were tested using a panel of six autoantibody markers to define a normal range and assign cutoff values for class prediction. A cutoff for minimal specificity and best achievable sensitivity were applied to 256 samples drawn annually for three years from 95 participants in the Kentucky Lung …

Metrics Of The Gynecologic Oncology Literature Focused On Cited Utilization And Costs, Edward J. Pavlik, John Hoff, Dylan Woolum, Yuqing Liang, Christiaan Wijers, Melissa Schwartz, Jason Lefringhouse, Lauren Baldwin

Obstetrics and Gynecology Faculty Publications

OBJECTIVE: The newest findings on literature utilization relevant to gynecologic oncology were published by Thomson Reuters during June 2013 as determinants of journal standing. Our objective was to assess the different metrics reported for relative impact and cost for journals relevant to gynecologic oncology.

METHODS: 55 journals were evaluated for Impact Factor (IF), 5Year IF, Immediacy Index, Cited Half Life, Eigenfactor (EF) Score, Article Influence (AI) scores and subscription costs obtained from publisher information.

RESULTS: CA-A Cancer Journal for Clinicians had the highest IF (101.78) & AI (24.502). The top EF cancer-specific journals were the Journal of Clinical Oncology, Cancer …

Understanding Irrigation Water Test Results And Their Implications On Nursery And Greenhouse Crop Management, Dewayne L. Ingram

Agriculture and Natural Resources Publications

Water quality can have a huge impact on plant growth, especially in soilless plant production systems. Water is certainly one of the most critical inputs in nursery and greenhouse crop production. Such production systems are extremely diverse but are most commonly characterized as container production, raised-bed production or hydroponics. Soilless systems require intensive management of water and nutrients for optimal plant growth and production. Irrigation water quality impacts nutrient levels and availability as well as other chemical characteristics of the soilless growth substrate; therefore it is critical to characterize the irrigation water source before starting a crop and possibly even …

One Hundred Years Of Limited Impact Of Jaspers’ General Psychopathology On Us Psychiatry, Jose De Leon

Psychiatry Faculty Publications

Jaspers, a German psychiatrist, published General Psychopathology in 1913. Jaspers, Schneider, and Mayer-Gross were members of the Heidelberg school. General Psychopathology, indirectly through Schneider’s and Mayer-Gross’ textbooks and directly by its English translation in 1963, led to a narrow set of schizophrenia criteria in the United Kingdom. General Psychopathology had very limited direct impact on US psychiatry, which adopted a broader schizophrenia definition. The difference between UK and US schizophrenia was a key element in the Diagnostic and Statistical Manual of Mental Disorders, Third Edition, and the neo-Kraepelinian revolution. General Psychopathology contains two essential interrelated ideas: a) psychiatry is …

Academic Libraries And Open Access Strategies, C. Sean Burns

Information Science Faculty Publications

With the rise of alternate discovery services, such as Google Scholar, in conjunction with the increase in open access content, researchers have the option to bypass academic libraries when they search for and retrieve scholarly information. This state of affairs implies that academic libraries exist in competition with these alternate services and with the patrons who use them, and as a result, may be disintermediated from the scholarly information seeking and retrieval process. Drawing from decision and game theory, bounded rationality, information seeking theory, citation theory, and social computing theory, this study investigates how academic librarians are responding as competitors …

The Chromatin Architectural Proteins Hmgd1 And H1 Bind Reciprocally And Have Opposite Effects On Chromatin Structure And Gene Regulation, Narasimharao Nalabothula, Graham Mcvicker, John Maiorano, Rebecca Martin, Jonathan K. Pritchard, Yvonne N. Fondufe-Mittendorf

Molecular and Cellular Biochemistry Faculty Publications

BACKGROUND: Chromatin architectural proteins interact with nucleosomes to modulate chromatin accessibility and higher-order chromatin structure. While these proteins are almost certainly important for gene regulation they have been studied far less than the core histone proteins.

RESULTS: Here we describe the genomic distributions and functional roles of two chromatin architectural proteins: histone H1 and the high mobility group protein HMGD1 in Drosophila S2 cells. Using ChIP-seq, biochemical and gene specific approaches, we find that HMGD1 binds to highly accessible regulatory chromatin and active promoters. In contrast, H1 is primarily associated with heterochromatic regions marked with repressive histone marks. We find …

Repair Of Oxidative Dna Damage And Cancer: Recent Progress In Dna Base Excision Repair, Timothy L. Scott, Suganya Rangaswamy, Christina A. Wicker, Tadahide Izumi

Toxicology and Cancer Biology Faculty Publications

SIGNIFICANCE: Reactive oxygen species (ROS) are generated by exogenous and environmental genotoxins, but also arise from mitochondria as byproducts of respiration in the body. ROS generate DNA damage of which pathological consequence, including cancer is well established. Research efforts are intense to understand the mechanism of DNA base excision repair, the primary mechanism to protect cells from genotoxicity caused by ROS.

RECENT ADVANCES: In addition to the notion that oxidative DNA damage causes transformation of cells, recent studies have revealed how the mitochondrial deficiencies and ROS generation alter cell growth during the cancer transformation.

CRITICAL ISSUES: The emphasis of this …

Ether Bridge Formation In Loline Alkaloid Biosynthesis, Juan Pan, Minakshi Bhardwaj, Jerome Ralph Faulkner, Padmaja Nagabhyru, Nikki D. Charlton, Richard M. Higashi, Anne-Frances Miller, Carolyn A Young, Robert B. Grossman, Christopher L. Schardl

Toxicology and Cancer Biology Faculty Publications

Lolines are potent insecticidal agents produced by endophytic fungi of cool-season grasses. These alkaloids are composed of a pyrrolizidine ring system and an uncommon ether bridge linking carbons 2 and 7. Previous results indicated that 1-aminopyrrolizidine was a pathway intermediate. We used RNA interference to knock down expression of lolO, resulting in the accumulation of an alkaloid identified as exo-1-acetamidopyrrolizidine based on high-resolution MS and NMR. Genomes of endophytes differing in alkaloid profiles were sequenced, revealing that those with mutated lolO accumulated exo-1-acetamidopyrrolizidine but no lolines. Heterologous expression of wild-type lolO complemented a lolO mutant, resulting in …

Strengthening Interactions Between Statisticians And Collaborators: Objectives And Sample Sizes, Emily Van Meter, Richard Charnigo

Biostatistics Faculty Publications

No abstract provided.

Expression Profiling In Bemisia Tabaci Under Insecticide Treatment: Indicating The Necessity For Custom Reference Gene Selection, Pei Liang, Yajie Guo, Xuguo Zhou, Xiwu Gao

Entomology Faculty Publications

Finding a suitable reference gene is the key for qRT-PCR analysis. However, none of the reference gene discovered thus far can be utilized universally under various biotic and abiotic experimental conditions. In this study, we further examine the stability of candidate reference genes under a single abiotic factor, insecticide treatment. After being exposed to eight commercially available insecticides, which belong to five different classes, the expression profiles of eight housekeeping genes in the sweetpotato whitefly, Bemisia tabaci, one of the most invasive and destructive pests in the world, were investigated using qRT-PCR analysis. In summary, elongation factor 1α …

Consanguineous Marriage And Intellectual And Developmental Disabilities Among Arab Bedouins Children Of The Negev Region In Southern Israel: A Pilot Study, Hassan Abu Saad, Salman Elbedour, Eyad Hallaq, Joav Merrick, Ariel Tenenbaum

Pediatrics Faculty Publications

No abstract provided.

Ivivc From Long Acting Olanzapine Microspheres, Susan D'Souza, Jabar A. Faraj, Stefano Giovagnoli, Patrick P. Deluca

Pharmaceutical Sciences Faculty Publications

In this study, four PLGA microsphere formulations of Olanzapine were characterized on the basis of their in vitro behavior at 37°C, using a dialysis based method, with the goal of obtaining an IVIVC. In vivo profiles were determined by deconvolution (Nelson-Wagner method) and using fractional AUC. The in vitro and in vivo release profiles exhibited the same rank order of drug release. Further, in vivo profiles obtained with both approaches were nearly superimposable, suggesting that fractional AUC could be used as an alternative to the Nelson-Wagner method. A comparison of drug release profiles for the four formulations revealed that the …

Superoxide Signaling In Perivascular Adipose Tissue Promotes Age-Related Artery Stiffness, Bradley S. Fleenor, Jason S. Eng, Amy L. Sindler, Bryant T. Pham, Jackson D. Kloor, Douglas R. Seals

Graduate Center for Nutritional Sciences Faculty Publications

We tested the hypothesis that superoxide signaling within aortic perivascular adipose tissue (PVAT) contributes to large elastic artery stiffening in old mice. Young (4-6 months), old (26-28 months), and old treated with 4-Hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPOL), a superoxide scavenger (1 mm in drinking water for 3 weeks), male C57BL6/N mice were studied. Compared with young, old had greater large artery stiffness assessed by aortic pulse wave velocity (aPWV, 436 ± 9 vs. 344 ± 5 cm s(-1)) and intrinsic mechanical testing (3821 ± 427 vs. 1925 ± 271 kPa) (both P < 0.05). TEMPOL treatment in old reversed both measures of arterial stiffness. Aortic PVAT superoxide production was greater in old (P < 0.05 vs. Y), which was normalized with TEMPOL. Compared with young, old controls had greater pro-inflammatory proteins in PVAT-conditioned media (P < 0.05). Young recipient mice transplanted with PVAT from old compared with young donors for 8 weeks had greater aPWV (409 ± 7 vs. 342 ± 8 cm s(-1)) and intrinsic mechanical properties (3197 ± 647 vs. 1889 ± 520 kPa) (both P < 0.05), which was abolished with TEMPOL supplementation in old donors. Tissue-cultured aortic segments from old in the presence of PVAT had greater mechanical stiffening compared with old cultured in the absence of PVAT and old with PVAT and TEMPOL (both, P < 0.05). In addition, PVAT-derived superoxide was associated with arterial wall hypertrophy and greater adventitial collagen I expression with aging that was attenuated by TEMPOL. Aging or TEMPOL treatment did not affect blood pressure. Our findings provide evidence for greater age-related superoxide production and pro-inflammatory proteins in PVAT, and directly link superoxide signaling in PVAT to large elastic artery stiffness.

Red Meat And Our Health: Separating Scientific Fact From Politics, Emotion And Misinformation, Peter Ballerstedt

Forage Symposium at the Kentucky Cattlemen’s Convention

The 2010 Dietary Guidelines for Americans recommends restricting our intake of saturated fat to less than 7 percent of calories, and our cholesterol intake to less than 300 mg per day (less than two eggs). They promote the use of low-fat milk and lean meat, and the use of “meat substitutes” in school lunches. These recommendations are consistent with the official dietary policy that began in 1977 with the release of the first Dietary Goals for the United States by the United States Senate Select Committee on Nutrition and Human Needs. These guidelines were not justified by the then-available science. …

Animal Welfare--Animal Rights: "Protecting Animals Or A Threat To U.S. Food Production And Our Way Of Life?", W. Roy Burris

Forage Symposium at the Kentucky Cattlemen’s Convention

Cattle producers are accustomed to dealing with many forms of adversity. Adversity generally comes in the form of blizzards, droughts, floods and economic conditions but now we must deal with animal activists who have their own opinions of what we can and cannot do as it relates to animal welfare and animal rights.

The Rak/Frk Tyrosine Kinase Associates With And Internalizes The Epidermal Growth Factor Receptor, Ling Jin, Rolf J. Craven

Pharmacology and Nutritional Sciences Faculty Publications

Src is the founding member of a diverse family of intracellular tyrosine kinases, and Src has a key role in promoting cancer growth, in part, through its association with receptor tyrosine kinases. However, some Src-related proteins have widely divergent physiological roles, and these proteins include the Rak/Frk tyrosine kinase (Frk stands for Fyn-related kinase), which inhibits cancer cell growth and suppresses tumorigenesis. Rak/Frk phosphorylates and stabilizes the Pten tumor suppressor, protecting it from degradation, and Rak/Frk associates with the retinoblastoma (Rb) tumor suppressor. However, the role of Rak/Frk in receptor-mediated signaling is largely unknown. Here, we demonstrate that Rak/Frk associates …