Digital Commons Network^™

Clinician-Investigator Training And The Need To Pilot New Approaches To Recruiting And Retaining This Workforce., Alison K Hall, Sherry L Mills, P Kay Lund

Neurology Faculty Publications

Clinician–investigators, also called physician–scientists, offer critical knowledge and perspectives that benefit research on basic science mechanisms, improved diagnostic and therapeutic approaches, population and outcomes medicine, health policy, and health services, yet few clinically trained health professionals pursue a research career. Sustaining this workforce requires attention to the unique challenges faced by investigators who must achieve clinical and research competence during training and their careers. These challenges include the duration of required clinical training, limited or discontinuous research opportunities, high levels of educational debt, balancing the dual obligations and rewards of clinical care and research, competition for research funding, and the …

Circulating Early- And Mid-Pregnancy Micrornas And Risk Of Gestational Diabetes., Pandora L Wander, Edward J Boyko, Karin Hevner, Viraj J Parikh, Mahlet G Tadesse, Tanya K Sorensen, Michelle A Williams, Daniel A Enquobahrie

Articles, Abstracts, and Reports

AIMS: Epigenetic regulators, including microRNAs (miRNAs), are implicated in type 2 diabetes, but evidence linking circulating miRNAs in pregnancy and risk of gestational diabetes (GDM) is sparse. Potential modifiers, including pre-pregnancy overweight/obesity and offspring sex, are unexamined. We hypothesized that circulating levels of early-mid-pregnancy (range 7-23weeks of gestation) candidate miRNAs are related to subsequent development of GDM. We also hypothesized that miRNA-GDM associations might vary by pre-pregnancy body-mass index (ppBMI) or offspring sex.

METHODS: In a case-control analysis (36GDM cases/80 controls) from the Omega study, a prospective cohort study of pregnancy complications, we measured early-mid-pregnancy plasma levels of 10miRNAs chosen …

1H, 15N, And 13C Chemical Shift Assignments Of The Regulatory Domain Of Human Calcineurin, Dinesh K. Yadav, Sri Ramya Tata, John Hunt, Erik C. Cook, Trevor P. Creamer, Nicholas C. Fitzkee

Center for Structural Biology Faculty Publications

Calcineurin (CaN) plays an important role in T-cell activation, cardiac system development and nervous system function. Previous studies have demonstrated that the regulatory domain (RD) of CaN binds calmodulin (CaM) towards the N-terminal end. Calcium-loaded CaM activates the serine/threonine phosphatase activity of CaN by binding to the RD, although the mechanistic details of this interaction remain unclear. It is thought that CaM binding at the RD displaces the auto-inhibitory domain (AID) from the active site of CaN, activating phosphatase activity. In the absence of calcium-loaded CaM, the RD is disordered, and binding of CaM induces folding in the RD. In …

Exosomal Microrna For Detection Of Cardiac Sarcoidosis., Elliott D Crouser, Nabeel Y Hamzeh, Lisa A Maier, Mark W Julian, May Gillespie, Mohammad Rahman, David Baxter, Xiaogang Wu, S Patrick Nana-Sinkam, Kai Wang

Articles, Abstracts, and Reports

No abstract provided.

Hne-Modified Proteins In Down Syndrome: Involvement In Development Of Alzheimer Disease Neuropathology, Eugenio Barone, Elizabeth Head, D. Allan Butterfield, Marzia Perluigi

Sanders-Brown Center on Aging Faculty Publications

Down syndrome (DS), trisomy of chromosome 21, is the most common genetic form of intellectual disability. The neuropathology of DS involves multiple molecular mechanisms, similar to AD, including the deposition of beta-amyloid (Aβ) into senile plaques and tau hyperphosphorylating in neurofibrillary tangles. Interestingly, many genes encoded by chromosome 21, in addition to being primarily linked to amyloid-beta peptide (Aβ) pathology, are responsible for increased oxidative stress (OS) conditions that also result as a consequence of reduced antioxidant system efficiency. However, redox homeostasis is disturbed by overproduction of Aβ, which accumulates into plaques across the lifespan in DS as well as …

Secondhand Smoke Exposure And Preclinical Markers Of Cardiovascular Risk In Toddlers, Judith A Groner, Hong Huang, Mandar S. Joshi, Nicholas Eastman, Lisa Nicholson, John Anthony Bauer

Pediatrics Faculty Publications

Objective: Links between secondhand smoke (SHS) exposure and cardiovascular disease in adults are well established but seldom reported during childhood. Although rates of smoking have decreased, young children from low-income backgrounds remain likely to be exposed to SHS. The purpose of this study was to investigate relationships between SHS exposure in young children and several preclinical markers of cardiovascular risk that have been established as relevant to adult populations.

Methods: 139 children, 2–5 years of age, were enrolled in a cross-sectional study. SHS exposure was objectively determined by hair nicotine level; a comprehensive panel of clinical markers (AM blood pressure, …

Psychosocial Functioning And The Cortisol Awakening Response: Meta-Analysis, P-Curve Analysis, And Evaluation Of The Evidential Value In Existing Studies, Ian Andres Boggero, Camelia E. Hostinar, Eric A. Haak, Michael L. M. Murphy, Suzanne C. Segerstrom

Psychology Faculty Publications

Cortisol levels rise immediately after awakening and peak approximately 30-45 minutes thereafter. Psychosocial functioning influences this cortisol awakening response (CAR), but there is considerable heterogeneity in the literature. The current study used p-curve and metaanalysis on 709 findings from 212 studies to test the evidential value and estimate effect sizes of four sets of findings: those associating worse psychosocial functioning with higher or lower cortisol increase relative to the waking period (CARi) and to the output of the waking period (AUCw). All four sets of findings demonstrated evidential value. Psychosocial predictors explained 1%-3.6% of variance in CARi and AUCw …

Targeting Mitochondrial Dysfunction In Cns Injury Using Methylene Blue; Still A Magic Bullet?, Hemendra J. Vekaria, Lora Talley Watts, Ai-Ling Lin, Patrick G. Sullivan

Spinal Cord and Brain Injury Research Center Faculty Publications

Complex, multi-factorial secondary injury cascades are initiated following traumatic brain injury, which makes this a difficult disease to treat. The secondary injury cascades following the primary mechanical tissue damage, are likely where effective therapeutic interventions may be targeted. One promising therapeutic target following brain injury are mitochondria. Mitochondria are complex organelles found within the cell, which act as powerhouses within all cells by supplying ATP. These organelles are also necessary for calcium cycling, redox signaling and play a major role in the initiation of cell death pathways. When mitochondria become dysfunctional, there is a tendency for the cell to loose …

High Trait Shame Undermines The Protective Effects Of Prevalence Knowledge On State Shame Following Hpv/Cin Diagnosis In Women, Sarah Mcqueary Flynn, Tory A. Eisenlohr-Moul, Suzanne C. Segerstrom, Christen T. Logue, Jamie L. Studts

Psychology Faculty Publications

Human papillomavirus (HPV), and the related, cervical intraepithelial neoplasia (CIN), are common yet poorly understood physical conditions. The diagnosis of HPV often elicits shame and guilt, which in turn may undermine psychological and physical health. The current study compared shame and guilt responses to diagnosis among two groups: women diagnosed with HPV/CIN and women diagnosed with Epstein–Barr Virus (EBV/IM). Eighty women recently diagnosed with HPV/CIN or EBV/IM completed measures of shame- and guilt-proneness, shame and guilt following diagnosis, and disease knowledge including prevalence estimates (HPV and EBV, respectively). HPV/CIN (vs. EBV/IM) predicted more diagnosis-related shame and guilt. Estimates of high …

Increased Birth Weight Is Associated With Altered Gene Expression In Neonatal Foreskin, Leryn J. Reynolds, Rebecca I. Pollack, Richard J. Charnigo, Cetewayo S. Rashid, Arnold J. Stromberg, Shu Shen, John O'Brien, Kevin J. Pearson

Pharmacology and Nutritional Sciences Faculty Publications

Elevated birth weight is linked to glucose intolerance and obesity health-related complications later in life. No studies have examined if infant birth weight is associated with gene expression markers of obesity and inflammation in a tissue that comes directly from the infant following birth. We evaluated the association between birth weight and gene expression on fetal programming of obesity. Foreskin samples were collected following circumcision, and gene expression analyzed comparing the 15% greatest birth weight infants (n = 7) v. the remainder of the cohort (n = 40). Multivariate linear regression models were fit to relate expression levels on differentially …

Systems Biology Approach To Late-Onset Alzheimer's Disease Genome-Wide Association Study Identifies Novel Candidate Genes Validated Using Brain Expression Data And Caenorhabditis Elegans Experiments, Shubhabrata Mukherjee, Joshua C. Russell, Daniel T. Carr, Jeremy D. Burgess, Mariet Allen, Daniel J. Serie, Kevin L. Boehme, John S. K. Kauwe, Adam C. Naj, David W. Fardo, Dennis W. Dickson, Thomas J. Montine, Nilufer Ertekin-Taner, Matt R. Kaeberlein, Paul K. Crane

Biostatistics Faculty Publications

Introduction—We sought to determine whether a systems biology approach may identify novel late-onset Alzheimer's disease (LOAD) loci.

Methods—We performed gene-wide association analyses and integrated results with human protein-protein interaction data using network analyses. We performed functional validation on novel genes using a transgenic Caenorhabditis elegans Aβ proteotoxicity model and evaluated novel genes using brain expression data from people with LOAD and other neurodegenerative conditions.

Results—We identified 13 novel candidate LOAD genes outside chromosome 19. Of those, RNA interference knockdowns of the C. elegans orthologs of UBC, NDUFS3, EGR1, and ATP5H were associated with Aβ …

Correcting For Tissue Nitrogen Excretion In Multiple Breath Washout Measurements., Mica Kane, Jonathan H. Rayment, Renee Jensen, Reginald Mcdonald, Sanja Stanojevic, Felix Ratjen

Student Papers, Posters & Projects

Nitrogen excreted from body tissues impacts the calculation of multiple breath nitrogen washout (MBWN2) outcomes. The aim of this study was to determine the effect of tissue N2 on MBWN2 outcomes in both healthy subjects and patients with CF and to assess whether it is possible to correct for tissue N2. The contribution of tissue N2 to MBWN2 outcomes was estimated by comparing MBWN2-derived functional residual capacity (FRCN2) to FRC measured by body plethysmography (FRCpleth) and by comparing MBW outcome measures derived from MBWN2 and sulfur hexafluoride MBW (MBWSF6). Compared to plethysmography and MBWSF6, MBWN2 overestimated FRC and lung clearance …

Association Of Disease Location And Treatment With Survival In Diffuse Large B-Cell Lymphoma Of The Eye And Ocular Adnexal Region., Aseef H H. Ahmed, C. Stephen Foster, Carol L. Shields

Wills Eye Hospital Papers

Importance: Primary diffuse large B-cell lymphoma (DLBCL) of the ocular region is rare, and the utility of surgery and radiation therapy remains unresolved.

Objective: To explore the clinical characteristics and determine factors associated with overall survival in primary vitreoretinal lymphoma (PVRL) and ocular adnexal (OA)-uveal DLBCL.

Design, Setting, and Participants: This retrospective analysis included 396 patients with ophthalmic DLBCL from January 1, 1973, through December 31, 2014, using the Surveillance, Epidemiology, and End Results database. The median follow-up was 39.0 months (interquartile range, 5.1-72.9 months). All patients diagnosed with primary DLBCL of the eye or retina (PVRL) or the eyelid, …

Modeling The Influence Of Early Skin-To-Skin Contact On Exclusive Breastfeeding In A Sample Of Hispanic Immigrant Women, Ana Maria Linares, Karen Wambach, Mary Kay Rayens, Amanda Wiggins, Elizabeth Coleman, Mark B. Dignan

Nursing Faculty Publications

Using data from a longitudinal study of breastfeeding in Hispanics, this study evaluated the influence of early skin-to-skin contact (SSC) on initiation and sustained exclusive breastfeeding (EBF) at 1 month postpartum. Two-thirds of the women in the sample participated in early SSC. At discharge, over half of the women were EBF; this proportion decreased to one-third at 1 month postpartum. Controlling for demographic and clinical variables in the model, participation in early SSC was associated with a greater than sevenfold increase in the odds of EBF at discharge (p = .005) but was not predictive of EBF at 1 …

Genetic Moderation Of Cocaine Subjective Effects By Variation In The Tph1, Tph2, And Slc6a4 Serotonin Genes, Michelle A Patriquin, Sara C Hamon, Mark J Harding, Ellen M Nielsen, Thomas F Newton, Richard De La Garza, David A Nielsen

Staff and Researcher Publications

Objective: This study investigated variants of tryptophan hydroxylase (TPH)1, TPH2, and SLC6A4 in the moderation of the subjective effects of cocaine.

Methods: Non-treatment-seeking cocaine-dependent individuals (N=66) were intravenously administered saline and cocaine (40 mg) in a randomized order. Participants self-reported subjective effects of cocaine using a visual analog scale starting before administration of saline or cocaine (-15 min) to up to 20 min after infusion. Self-report ratings on the visual analog scale ranged from 0 (no effect) to 100 (greatest effect). Participants were genotyped for the TPH1 rs1799913, TPH2 rs4290270, and SLC6A4 5-HTTLPR variants. Repeated-measures analysis of covariance was used …

Increased Habenular Connectivity In Opioid Users Is Associated With An Α5 Subunit Nicotinic Receptor Genetic Variant, Kaylah Curtis, Humsini Viswanath, Kenia M Velasquez, David L Molfese, Mark J Harding, Eduardo Aramayo, Philip R Baldwin, Elisa Ambrosi, Alok Madan, Michelle Patriquin, B Christopher Frueh, J Christopher Fowler, Thomas R Kosten, David A Nielsen, Ramiro Salas

Staff and Researcher Publications

Background and objectives: Opioid use disorder (OUD) is a chronic disorder with relapse based on both desire for reinforcement (craving) and avoidance of withdrawal. The aversive aspect of dependence and relapse has been associated with a small brain structure called the habenula, which expresses large numbers of both opioid and nicotinic receptors. Additionally, opioid withdrawal symptoms can be induced in opioid-treated rodents by blocking not only opioid, but also nicotinic receptors. This receptor co-localization and cross-induction of withdrawal therefore might lead to genetic variation in the nicotinic receptor influencing development of human opioid dependence through its impact on the aversive …

Sleeper Cells: The Stringent Response And Persistence In The Borreliella (Borrelia) Burgdorferi Enzootic Cycle, Felipe C. Cabello, Henry Godfrey, J Bugrysheva, Stuart A. Newman

NYMC Faculty Publications

Infections with tick-transmitted Borreliella (Borrelia) burgdorferi, the cause of Lyme disease, represent an increasingly large public health problem in North America and Europe. The ability of these spirochetes to maintain themselves for extended periods of time in their tick vectors and vertebrate reservoirs is crucial for continuance of the enzootic cycle as well as for the increasing exposure of humans to them. The stringent response mediated by the alarmone (p)ppGpp has been determined to be a master regulator in B. burgdorferi. It modulates the expression of identified and unidentified open reading frames needed to deal with and overcome the many …

Mutsβ Abundance And Msh3 Atp Hydrolysis Activity Are Important Drivers Of Ctg•Cag Repeat Expansions, Norma Keogh, Kara Y. Chan, Guo-Min Li, Robert S. Lahue

Toxicology and Cancer Biology Faculty Publications

CTG•CAG repeat expansions cause at least twelve inherited neurological diseases. Expansions require the presence, not the absence, of the mismatch repair protein MutSβ (Msh2-Msh3 heterodimer). To evaluate properties of MutSβ that drive expansions, previous studies have tested under-expression, ATPase function or polymorphic variants of Msh2 and Msh3, but in disparate experimental systems. Additionally, some variants destabilize MutSβ, potentially masking the effects of biochemical alterations of the variations. Here, human Msh3 was mutated to selectively inactivate MutSβ. Msh3^−/− cells are severely defective for CTG•CAG repeat expansions but show full activity on contractions. Msh3^−/− cells provide a single, isogenic system …

Decorin-Evoked Paternally Expressed Gene 3 (Peg3) Is An Upstream Regulator Of The Transcription Factor Eb (Tfeb) In Endothelial Cell Autophagy., Thomas Neill, Catherine Sharpe, Rick T. Owens, Renato V. Iozzo

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Macroautophagy is a fundamental and evolutionarily conserved catabolic process that eradicates damaged and aging macromolecules and organelles in eukaryotic cells. Decorin, an archetypical small leucine-rich proteoglycan, initiates a protracted autophagic program downstream of VEGF receptor 2 (VEGFR2) signaling that requires paternally expressed gene 3 (PEG3). We have discovered that PEG3 is an upstream transcriptional regulator of transcription factor EB (TFEB), a master transcription factor of lysosomal biogenesis, for decorin-evoked endothelial cell autophagy. We found a functional requirement of PEG3 for TFEB transcriptional induction and nuclear translocation in human umbilical vein endothelial and PAER2 cells. Mechanistically, inhibiting VEGFR2 or AMP-activated protein …

Structural Basis For Selective Inhibition Of Cyclooxygenase-1 (Cox-1) By Diarylisoxazoles Mofezolac And 3-(5-Chlorofuran-2-Yl)-5-Methyl-4-Phenylisoxazole (P6)., Gino Cingolani, Andrea Panella, Maria Grazia Perrone, Paola Vitale, Giuseppe Di Mauro, Cosimo G G. Fortuna, Roger S. Armen, Savina Ferorelli, William L. Smith, Antonio Scilimati

Department of Biochemistry and Molecular Biology Faculty Papers

The diarylisoxazole molecular scaffold is found in several NSAIDs, especially those with high selectivity for COX-1. Here, we have determined the structural basis for COX-1 binding to two diarylisoxazoles: mofezolac, which is polar and ionizable, and 3-(5-chlorofuran-2-yl)-5-methyl-4-phenylisoxazole (P6) that has very low polarity. X-ray analysis of the crystal structures of COX-1 bound to mofezolac and 3-(5-chlorofuran-2-yl)-5-methyl-4-phenylisoxazole allowed the identification of specific binding determinants within the enzyme active site, relevant to generate structure/activity relationships for diarylisoxazole NSAIDs.

Pleiotropy Of Genetic Variants On Obesity And Smoking Phenotypes: Results From The Oncoarray Project Of The International Lung Cancer Consortium, Tao Wang, Jee-Young Moon, Yiqun Wu, Christopher I. Amos, Rayjean J. Hung, Adonina Tardon, Angeline Andrew, Chu Chen, David C. Christiani, Demetrios Albanes, Erik H. F. M. Van Der Heijden, Eric Duell, Gadi Rennert, Gary Goodman, Geoffrey Liu, James D. Mckay, Jian-Min Yuan, John K. Field, Jonas Manjer, Kjell Grankvist, Lambertus A. Kiemeney, Loic Le Marchand, M. Dawn Teare, Matthew B. Schabath, Mattias Johansson, Melinda C. Aldrich, Michael Davies, Mikael Johansson, Ming-Sound Tsao, Neil Caporaso, Susanne Arnold

Internal Medicine Faculty Publications

Obesity and cigarette smoking are correlated through complex relationships. Common genetic causes may contribute to these correlations. In this study, we selected 241 loci potentially associated with body mass index (BMI) based on the Genetic Investigation of ANthropometric Traits (GIANT) consortium data and calculated a BMI genetic risk score (BMI-GRS) for 17,037 individuals of European descent from the Oncoarray Project of the International Lung Cancer Consortium (ILCCO). Smokers had a significantly higher BMI-GRS than never-smokers (p = 0.016 and 0.010 before and after adjustment for BMI, respectively). The BMI-GRS was also positively correlated with pack-years of smoking (p < 0.001) in smokers. Based on causal network inference analyses, seven and five of 241 SNPs were classified to pleiotropic models for BMI/smoking status and BMI/pack-years, respectively. Among them, three and four SNPs associated with smoking status and pack-years (p < 0.05), respectively, were followed up in the ever-smoking data of the Tobacco, Alcohol and Genetics (TAG) consortium. Among these seven candidate SNPs, one SNP (rs11030104, BDNF) …

A Type Of Human Skin Dendritic Cell Marked By Cd5 Is Associated With The Development Of Inflammatory Skin Disease, Daniel Korenfeld, Laurent Gorvel, Adiel Munk, Joshua Man, Andras Schaffer, Thomas Tung, Caroline Mann, Eynav Klechevsky

Open Access Publications

Dendritic cells (DCs) are important in regulating immunity and tolerance and consist of functionally distinct subsets that differentially regulate T lymphocyte function. The underlying basis for this subset specificity is lacking, particularly in humans, where the classification of tissue DCs is currently incomplete. Examination of healthy human epidermal Langerhans cells and dermal skin cells revealed a tissue CD5-expressing DC subtype. The CD5+ DCs were potent inducers of cytotoxic T cells and Th22 cells. The products of these T cells, IL-22 and IFN-γ, play a key role in the pathogenesis of psoriasis. Remarkably, CD5+ DCs were significantly enriched in lesional psoriatic …

Insights Into Onchocerca Volvulus Population Biology Through Multilocus Immunophenotyping, Carmelle T Norice-Tra, José Ribeiro, Sasisekhar Bennuru, Michael P Fay, Rahul Tyagi, Makedonka Mitreva, Thomas B Nutman

2010-2019 OA Pubs

We have developed a serologically based immunophenotyping approach to study Onchocerca volvulus (Ov) population diversity. Using genomic sequence data and polymerase chain reaction-based genotyping, we identified nonsynonymous single-nucleotide polymorphisms (SNPs) in the genes of 16 major immunogenic Ov proteins: Ov-CHI-1/Ov-CHI-2, Ov16, Ov-FAR-1, Ov-CPI-1, Ov-B20, Ov-ASP-1, Ov-TMY-1, OvSOD1, OvGST1, Ov-CAL-1, M3/M4, Ov-RAL-1, Ov-RAL-2, Ov-ALT-1, Ov-FBA-1, and Ov-B8. We assessed the immunoreactivity of onchocerciasis patient sera (n = 152) from the Americas, West Africa, Central Africa, and East Africa against peptides derived from 10 of these proteins containing SNPs. Statistically significant variation in immunoreactivity among the regions was seen in SNP-containing peptides …

Mutations Of Conserved Non-Coding Elements Of Pitx2 In Patients With Ocular Dysgenesis And Developmental Glaucoma., Meredith E. Protas, Eric Weh, Tim Footz, Jay Kasberger, Scott C. Baraban, Alex V. Levin, L. Jay Katz, Robert Ritch, Michael A. Walter, Elena V. Semina, Douglas B. Gould

Natural Sciences and Mathematics | Faculty Scholarship

Mutations in FOXC1 and PITX2 constitute the most common causes of ocular anterior segment dysgenesis (ASD), and confer a high risk for secondary glaucoma. The genetic causes underlying ASD in approximately half of patients remain unknown, despite many of them being screened by whole exome sequencing. Here, we performed whole genome sequencing on DNA from two affected individuals from a family with dominantly inherited ASD and glaucoma to identify a 748-kb deletion in a gene desert that contains conserved putative PITX2 regulatory elements. We used CRISPR/Cas9 to delete the orthologous region in zebrafish in order to test the pathogenicity of …

Transient And Permanent Changes In Dna Methylation Patterns In Inorganic Arsenic-Mediated Epithelial-To-Mesenchymal Transition, Meredith Eckstein, Matthew Rea, Yvonne N. Fondufe-Mittendorf

Molecular and Cellular Biochemistry Faculty Publications

Chronic low dose inorganic arsenic exposure causes cells to take on an epithelial-to-mesenchymal phenotype, which is a crucial process in carcinogenesis. Inorganic arsenic is not a mutagen and thus epigenetic alterations have been implicated in this process. Indeed, during the epithelial-to-mesenchymal transition, morphologic changes to cells correlate with changes in chromatin structure and gene expression, ultimately driving this process. However, studies on the effects of inorganic arsenic exposure/withdrawal on the epithelial-to-mesenchymal transition and the impact of epigenetic alterations in this process are limited. In this study we used high-resolution microarray analysis to measure the changes in DNA methylation in cells …

Neurosyphilis Increases Human Immunodeficiency Virus (Hiv)-Associated Central Nervous System Inflammation But Does Not Explain Cognitive Impairment In Hiv-Infected Individuals With Syphilis., Emily L Ho, Clare L Maxwell, Shelia B Dunaway, Sharon K Sahi, Lauren C Tantalo, Sheila A Lukehart, Christina M Marra

Articles, Abstracts, and Reports

Background: Individuals infected with human immunodeficiency virus (HIV) who have previously had syphilis may have cognitive impairment. We tested the hypothesis that neurosyphilis causes cognitive impairment in HIV by amplifying HIV-related central nervous system (CNS) inflammation.

Methods: HIV-infected participants enrolled in a study of cerebrospinal fluid (CSF) abnormalities in syphilis underwent the mental alternation test (MAT), venipuncture, and lumbar puncture. CSF concentrations of chemokine (C-X-C motif) ligand 10 (CXCL10), chemokine (C-C motif) ligand 2 (CCL2), and neurofilament light (NFL) were determined by commercial assays. The proportion of peripheral blood mononuclear cells (PBMCs) and of CSF white blood cells (WBCs) that …

Design, Synthesis, And Biological Activity Of 5'-Phenyl-1,2,5,6-Tetrahydro-3,3'-Bipyridine Analogues As Potential Antagonists Of Nicotinic Acetylcholine Receptors, Yafei Jin, Xiaoqin Huang, Roger L. Papke, Emily M. Jutkiewicz, Hollis D Showalter, Chang-Guo Zhan

Pharmaceutical Sciences Faculty Publications

Starting from a known non-specific agonist (1) of nicotinic acetylcholine receptors (nAChRs), rationally guided structural-based design resulted in the discovery of a small series of 5′-phenyl-1,2,5,6-tetrahydro-3,3′-bipyridines (3a – 3e) incorporating a phenyl ring off the pyridine core of 1. The compounds were synthesized via successive Suzuki couplings on a suitably functionalized pyridine starting monomer 4 to append phenyl and pyridyl substituents off the 3- and 5-positions, respectively, and then make subsequent modifications on the flanking pyridyl ring to provide target compounds. Compound 3a is a novel antagonist which is highly selective for α3β4 nAChR (K_i = 123 nM) …

Loss Of Fructose-1,6-Bisphosphatase Induces Glycolysis And Promotes Apoptosis Resistance Of Cancer Stem-Like Cells: An Important Role In Hexavalent Chromium-Induced Carcinogenesis, Jin Dai, Yanli Ji, Wei Wang, Donghern Kim, Leonard Yenwong Fai, Lei Wang, Jia Luo, Zhuo Zhang

Toxicology and Cancer Biology Faculty Publications

Hexavalent chromium (Cr(VI)) compounds are confirmed human carcinogens for lung cancer. Our previous studies has demonstrated that chronic exposure of human bronchial epithelial BEAS-2B cells to low dose of Cr(VI) causes malignant cell transformation. The acquisition of cancer stem cell-like properties is involved in the initiation of cancers. The present study has observed that a small population of cancer stem-like cells (BEAS-2B-Cr-CSC) exists in the Cr(VI)-transformed cells (BEAS-2B-Cr). Those BEAS-2B-Cr-CSC exhibit extremely reduced capability of generating reactive oxygen species (ROS) and apoptosis resistance. BEAS-2B-Cr-CSC are metabolic inactive as evidenced by reductions in oxygen consumption, glucose uptake, ATP production, and lactate …

The 9th Conference On Metal Toxicity And Carcinogenesis: The Conference Overview, James T. F. Wise, Lei Wang, Zhuo Zhang, Xianglin Shi

Pharmacology and Nutritional Sciences Faculty Publications

Heavy metals, such as arsenic, chromium, cadmium, nickel, mercury, and uranium are known to cause many human diseases and health complications after occupational or environmental exposure. Consequently, metals are environmental health concerns. This manuscript is an overview of the 9th Conference on Metal Toxicity and Carcinogenesis held in October 2016 in Lexington, Kentucky. Since 2000, this biennial meeting brings together experts in the field to discuss current and prospective research in an effort to advance research pertaining to metal toxicity and carcinogenesis. In this review we summarize the major topics discussed and provide insight regarding current research in the field …

Gucy2c Signaling Opposes The Acute Radiation-Induced Gi Syndrome., Peng Li, Evan Wuthrick, Jeff A. Rappaport, Crystal Kraft, Jieru E. Lin, Glen Marszalowicz, Adam E. Snook, Tingting Zhan, Terry M. Hyslop, Scott A. Waldman

Department of Pharmacology and Experimental Therapeutics Faculty Papers

High doses of ionizing radiation induce acute damage to epithelial cells of the gastrointestinal (GI) tract, mediating toxicities restricting the therapeutic efficacy of radiation in cancer and morbidity and mortality in nuclear disasters. No approved prophylaxis or therapy exists for these toxicities, in part reflecting an incomplete understanding of mechanisms contributing to the acute radiation-induced GI syndrome (RIGS). Guanylate cyclase C (GUCY2C) and its hormones guanylin and uroguanylin have recently emerged as one paracrine axis defending intestinal mucosal integrity against mutational, chemical, and inflammatory injury. Here, we reveal a role for the GUCY2C paracrine axis in compensatory mechanisms opposing RIGS. …