Digital Commons Network^™

Myricetin Inhibits Proliferation Of Cisplatin-Resistant Cancer Cells Through A P53-Dependent Apoptotic Pathway, Haizhi Huang, Allen Y. Chen, Xingqian Ye, Bingyun Li, Yon Rojanasakul, Gary O. Rankin, Yi Charlie Chen

Pharmaceutical Science and Research

Cisplatin is a commonly used drug for cancer treatment by crosslinking DNA, leading to apoptosis of cancer cells, resistance to cisplatin treatment often occurs, leading to relapse. Therefore, there is a need for the development of more effective treatment strategies that can overcome chemoresistance. Myricetin is a flavonoid from fruits and vegetables, showing anticancer activity in various cancer cells. In this study, we found myricetin exhibited greater cytotoxicity than cisplatin in two cisplatin-resistant ovarian cancer cell lines, OVCAR-3 and A2780/CP70, and it was less cytotoxic to the normal ovarian cell line IOSE-364. Myricetin selectively induced apoptosis in both cisplatin-resistant cancer …

Reversal Of Aging-Related Neuronal Ca2+ Dysregulation And Cognitive Impairment By Delivery Of A Transgene Encoding Fk506-Binding Protein 12.6/1b To The Hippocampus, John C. Gant, Kuey-Chu Chen, Inga Kadish, Eric M. Blalock, Olivier Thibault, Nada M. Porter, Philip W. Landfield

Pharmacology and Nutritional Sciences Faculty Publications

Brain Ca(2+) regulatory processes are altered during aging, disrupting neuronal, and cognitive functions. In hippocampal pyramidal neurons, the Ca(2+)-dependent slow afterhyperpolarization (sAHP) exhibits an increase with aging, which correlates with memory impairment. The increased sAHP results from elevated L-type Ca(2+) channel activity and ryanodine receptor (RyR)-mediated Ca(2+) release, but underlying molecular mechanisms are poorly understood. Previously, we found that expression of the gene encoding FK506-binding protein 12.6/1b (FKBP1b), a small immunophilin that stabilizes RyR-mediated Ca(2+) release in cardiomyocytes, declines in hippocampus of aged rats and Alzheimer's disease subjects. Additionally, knockdown/disruption of hippocampal FKBP1b in young rats augments neuronal Ca(2+) responses. …

Amikacin Concentrations Predictive Of Ototoxicity In Multidrug-Resistant Tuberculosis Patients, Chawangwa Modongo, Jotam G. Pasipanodya, Nicola M. Zetola, Scott M. Williams

Dartmouth Scholarship

Aminoglycosides, such as amikacin, are used to treat multidrug-resistant tuberculosis. However, ototoxicity is a common problem and is monitored using peak and trough amikacin concentrations based on World Health Organization recommendations. Our objective was to identify clinical factors predictive of ototoxicity using an agnostic machine learning method. We used classification and regression tree (CART) analyses to identify clinical factors, including amikacin concentration t

hresholds that pre- dicted audiometry-confirmed ototoxicity among 28 multidrug-resistant pulmonary tuberculosis patients in Botswana. Amika- cin concentrations were measured for all patients. The quantitative relationship between predictive factors and the probability of ototoxicity were then identified using …

Gallic Acid, A Phenolic Compound, Exerts Anti-Angiogenic Effects Via The Pten/Akt/Hif-1Α/Vegf Signaling Pathway In Ovarian Cancer Cells, Zhiping He, Allen Y. Chen, Yon Rojanasakul, Gary O. Rankin, Yi Charlie Chen

Pharmaceutical Science and Research

Gallic acid (GA), a polyphenol, is widely found in numerous fruits and vegetables, particularly in hickory nuts. In the present study, we found that gallic acid, a natural phenolic compound isolated from fruits and vegetables, had a more potent growth inhibitory effect on two ovarian cancer cell lines, OVCAR-3 and A2780/CP70, than the effect on a normal ovarian cell line, IOSE-364. These results demonstrated that GA selectively inhibits the growth of cancer cells. Gene expression was examined by ELISA and western blot analysis, and gene pathways were examined by luciferase assay. It was found that GA inhibited VEGF secretion and …

Nos Inhibition Modulates Immune Polarization And Improves Radiation-Induced Tumor Growth Delay, Lisa A. Ridnour, Robert Y.S. Cheng, Jonathan M. Weiss, Sukhbir Kaur, David R. Soto-Pantoja, Debashree Basudhar, Julie L. Heinecke, C. Andrew Stewart, William Degraff, Anastasia L. Sowers, Angela Thetford, Aparna H. Kesarwala, David D. Roberts, Howard A. Young, James B. Mitchell, Giorgio Trinchieri, Robert H. Wiltrout, David A. Wink

United States Public Health Resources

Nitric oxide synthases (NOS) are important mediators of progrowth signaling in tumor cells, as they regulate angiogenesis, immune response, and immune-mediated wound healing. Ionizing radiation (IR) is also an immune modulator and inducer of wound response. We hypothesized that radiation therapeutic efficacy could be improved by targeting NOS following tumor irradiation. Herein, we show enhanced radiation-induced (10 Gy) tumor growth delay in a syngeneic model (C3H) but not immunosuppressed (Nu/Nu) squamous cell carcinoma tumor-bearing mice treated post-IR with the constitutive NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME). These results suggest a requirement of T cells for improved radiation tumor response. In …

Zbtb20 Is A Sequence-Specific Transcriptional Repressor Of Alpha-Fetoprotein Gene, Hai Zhang, Dongmei Cao, Luting Zhou, Ye Zhang, Xiaoqin Guo, Hui Li, Yuxia Chen, Brett T. Spear, Jia-Wei Wu, Zhifang Xie, Weiping J Zhang

Microbiology, Immunology, and Molecular Genetics Faculty Publications

Alpha-fetoprotein (AFP) represents a classical model system to study developmental gene regulation in mammalian cells. We previously reported that liver ZBTB20 is developmentally regulated and plays a central role in AFP postnatal repression. Here we show that ZBTB20 is a sequence-specific transcriptional repressor of AFP. By ELISA-based DNA-protein binding assay and conventional gel shift assay, we successfully identified a ZBTB20-binding site at -104/-86 of mouse AFP gene, flanked by two HNF1 sites and two C/EBP sites in the proximal promoter. Importantly, mutation of the core sequence in this site fully abolished its binding to ZBTB20 in vitro, as well …

B Lymphocytes Are Required During The Early Priming Of Cd4+ T Cells For Clearance Of Pneumocystis Infection In Mice, Michael M. Opata, Melissa L. Hollifield, Frances E. Lund, Troy D. Randall, Robert Dunn, Beth A. Garvy, David J. Feola

Microbiology, Immunology, and Molecular Genetics Faculty Publications

B cells play a critical role in the clearance of Pneumocystis. In addition to production of Pneumocystis-specific Abs, B cells are required during the priming phase for CD4⁺ T cells to expand normally and generate memory. Clearance of Pneumocystis was found to be dependent on Ag specific B cells and on the ability of B cells to secrete Pneumocystis-specific Ab, as mice with B cells defective in these functions or with a restricted BCR were unable to control Pneumocystis infection. Because Pneumocystis-specific antiserum was only able to partially protect B cell–deficient mice from infection, we …

Dna-Pkcs-Mediated Transcriptional Regulation Drives Prostate Cancer Progression And Metastasis., Jonathan F Goodwin, Vishal Kothari, Justin M Drake, Shuang Zhao, Emanuela Dylgjeri, Jeffry L. Dean, Matthew J. Schiewer, Christopher Mcnair, Jennifer K. Jones, Alvaro Aytes, Michael S. Magee, Adam E. Snook, Ziqi Zhu, Robert Den, Ruth C. Birbe, Leonard G. Gomella, Nicholas A. Graham, Ajay A. Vashisht, James A. Wohlschlegel, Thomas G. Graeber, R. Jeffrey Karnes, Mandeep Takhar, Elai Davicioni, Scott A. Tomlins, Cory Abate-Shen, Nima Sharifi, Owen N. Witte, Felix Y. Feng, Karen E. Knudsen

Department of Cancer Biology Faculty Papers

Emerging evidence demonstrates that the DNA repair kinase DNA-PKcs exerts divergent roles in transcriptional regulation of unsolved consequence. Here, in vitro and in vivo interrogation demonstrate that DNA-PKcs functions as a selective modulator of transcriptional networks that induce cell migration, invasion, and metastasis. Accordingly, suppression of DNA-PKcs inhibits tumor metastases. Clinical assessment revealed that DNA-PKcs is significantly elevated in advanced disease and independently predicts for metastases, recurrence, and reduced overall survival. Further investigation demonstrated that DNA-PKcs in advanced tumors is highly activated, independent of DNA damage indicators. Combined, these findings reveal unexpected DNA-PKcs functions, identify DNA-PKcs as a potent driver …

Regulated Phosphorylation Of The K-Cl Cotransporter Kcc3 Is A Molecular Switch Of Intracellular Potassium Content And Cell Volume Homeostasis, Norma C. Adragna, Nagendra B. Ravilla, Peter K. Lauf, Gulnaz Begum, Arjun R. Khanna, Dandan Sun, Kristopher K. Kahle

Pharmacology and Toxicology Faculty Publications

The defense of cell volume against excessive shrinkage or swelling is a requirement for cell function and organismal survival. Cell swelling triggers a coordinated homeostatic response termed regulatory volume decrease (RVD), resulting in K+ and Cl− efflux via activation of K+ channels, volume-regulated anion channels (VRACs), and the K+-Cl− cotransporters, including KCC3. Here, we show genetic alanine (Ala) substitution at threonines (Thr) 991 and 1048 in the KCC3a isoform carboxyl-terminus, preventing inhibitory phosphorylation at these sites, not only significantly up-regulates KCC3a activity up to 25-fold in normally inhibitory isotonic conditions, but is also accompanied by reversal of activity of the …

Mir-21 In Extracellular Vesicles Leads To Neurotoxicity Via Tlr7 Signaling In Siv Neurological Disease., Sowmya V. Yelamanchili, Benjamin G. Lamberty, Deborah A. Rennard, Brenda M. Morsey, Colleen G. Hochfelder, Brittney M. Meays, Efrat Levy, Howard S. Fox

Journal Articles: Pharmacology & Experimental Neuroscience

Recent studies have found that extracellular vesicles (EVs) play an important role in normal and disease processes. In the present study, we isolated and characterized EVs from the brains of rhesus macaques, both with and without simian immunodeficiency virus (SIV) induced central nervous system (CNS) disease. Small RNA sequencing revealed increased miR-21 levels in EVs from SIV encephalitic (SIVE) brains. In situ hybridization revealed increased miR-21 expression in neurons and macrophage/microglial cells/nodules during SIV induced CNS disease. In vitro culture of macrophages revealed that miR-21 is released into EVs and is neurotoxic when compared to EVs derived from miR-21-/- knockout …

Selective Involvement Of The Checkpoint Regulator Vista In Suppression Of B-Cell, But Not T-Cell, Responsiveness By Monocytic Myeloid-Derived Suppressor Cells From Mice Infected With An Immunodeficiency-Causing Retrovirus, Kathy A. Green, Li Wang, Randolph J. Noelle, William R. Green

Dartmouth Scholarship

Inhibition of T-cell responses in tumor microenvironments by myeloid-derived suppressor cells (MDSCs) is widely accepted. We demonstrated augmentation of monocytic MDSCs whose suppression of not only T-cell, but also B-cell, responsiveness paralleled the immunodeficiency during LP-BM5 retrovirus infection. MDSCs inhibited T cells by inducible nitric oxide synthase (iNOS)/nitric oxide (NO), but uniquely, inhibition of B cells was ~50% dependent each on iNOS/NO and the MDSC-expressed negative-checkpoint regulator VISTA. Blockade with a combination of iNOS/NO and VISTA caused additive or synergistic abrogation of MDSC-mediated suppression of B-cell responsiveness.

Toll-Like Receptors And Dectin-1, A C-Type Lectin Receptor, Trigger Divergent Functions In Cns Macrophages, John C. Gensel, Yan Wang, Zhen Guan, Kyle A. Beckwith, Kaitlyn J. Braun, Ping Wei, Dana M. Mctigue, Phillip G. Popovich

Spinal Cord and Brain Injury Research Center Faculty Publications

Spinal cord injury (SCI) activates macrophages, endowing them with both reparative and pathological functions. The mechanisms responsible for these divergent functions are unknown but are likely controlled through stochastic activation of different macrophage receptor subtypes. Various danger-associated molecular patterns released from dying cells in the injured spinal cord likely activate distinct subtypes of macrophage pattern recognition receptors, including bacterial toll-like receptors (TLRs) and fungal C-type lectin receptors (e.g., dectin-1). To determine the in vivo consequences of activating these receptors, ligands specific for TLR2 or dectin-1 were microinjected, alone or in combination, into intact spinal cord. Both ligands elicit a florid …

A Self-Lysis Pathway That Enhances The Virulence Of A Pathogenic Bacterium, Kirsty A. Mcfarland, Emily L. Dolben, Michele Leroux, Tracy K. Kambara, Kathryn Ramsey, Robin Kirkpatrick, Joseph Mougous, Deborah Hogan, Simon Dove

Dartmouth Scholarship

In mammalian cells, programmed cell death (PCD) plays important roles in development, in the removal of damaged cells, and in fighting bacterial infections. Although widespread among multicellular organisms, there are relatively few documented instances of PCD in bacteria. Here we describe a potential PCD pathway in Pseudomonas aeruginosa that enhances the ability of the bacterium to cause disease in a lung infection model. Activation of the system can occur in a subset of cells in response to DNA damage through cleavage of an essential transcription regulator we call AlpR. Cleavage of AlpR triggers a cell lysis program through de-repression of …

Genomic Copy Number Variation In Mus Musculus., M Elizabeth O Locke, Maja Milojevic, Susan T Eitutis, Nisha Patel, Andrea E Wishart, Mark Daley, Kathleen A. Hill

Brain and Mind Institute Researchers' Publications

BACKGROUND: Copy number variation is an important dimension of genetic diversity and has implications in development and disease. As an important model organism, the mouse is a prime candidate for copy number variant (CNV) characterization, but this has yet to be completed for a large sample size. Here we report CNV analysis of publicly available, high-density microarray data files for 351 mouse tail samples, including 290 mice that had not been characterized for CNVs previously.

RESULTS: We found 9634 putative autosomal CNVs across the samples affecting 6.87% of the mouse reference genome. We find significant differences in the degree of …

Ceramides Promote Apoptosis For Virus-Infected Lymphoma Cells Through Induction Of Ceramide Synthases And Viral Lytic Gene Expression, Lu Dai, Jimena Trillo-Tinoco, Aiping Bai, Yihan Chen, Jacek Bielawski, Luis Del Valle, Charles D. Smith, Augusto C. Ochoa, Zhiqiang Qin, Chris Parsons

School of Medicine Faculty Publications

Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiologic agent for several human cancers including primary effusion lymphoma (PEL), a rapidly progressive malignancy arising preferentially in immunocompromised patients. With conventional chemotherapy, PEL continues to portend high mortality, dictating the development of novel therapeutic strategies. Sphingosine kinase 2 (SphK2) represents a key gatekeeper for sphingolipid metabolism, responsible for conversion of ceramides to sphingosine-1-phosphate (S1P). We have previously demonstrated that targeting SphK2 using a novel selective inhibitor, ABC294640, leads to intracellular accumulation of ceramides and induces apoptosis for KSHV-infected PEL cells, while suppressing tumor progression in vivo. In the current study, we sought to …

Bacterially-Based Immune Challenges And Trauma Elicit Terminal Investment In Male Aedes Aegypti, Molly K. Schumacher

Theses and Dissertations

Investment in life history traits such as immune function and reproduction is constrained by finite available resources. A cost-of-immunity trade-off may occur in response to infection when resources are diverted away from reproductive effort and into an immune response. Alternatively, an infected individual may enhance reproductive effort to maximize terminal reproductive success in response to the survival threat inherent to infection (terminal investment). We measured male Aedes aegypti reproductive behavior following inoculations with: living bacteria; killed bacteria as an immune elicitor; and a sham control. Mating competitiveness relative to naïve males was also determined through a binary mate choice experiment …

Myasthenia Gravis, Abbe R. Feaver

Nursing Student Class Projects (Formerly MSN)

Myasthenia gravis (MG) is a chronic autoimmune neuromuscular disease characterized by ocular, bulbar, facial, and skeletal muscle weakness due to a defect in the transmission of nerve to muscle impulses at the neuromuscular junction (Mestecky, 2013, p. 110). Approximately 14-20 in 100,000 people are diagnosed with myasthenia gravis in the United States (Leis, Moore, Kofler, Beric, De Visser, 2014, p. 112). Typically, diagnosis occurs in middle-aged adults with women generally acquiring the disease at a younger age than men (Mestecky, 2013, p. 110). MG has the potential to greatly affect the quality of life of a patient. Although the disease …

Neurocysticercosis, Abigail Hill

Nursing Student Class Projects (Formerly MSN)

Neurocysticercosis (NCC) is one of the most common parasitic infections of the central nervous system in humans and is the most serious clinical manifestation of cysticercosis. NCC is caused by the ingestion of the larval form of the pork tapeworm Taenia solium. NCC is endemic in low income developing countries where pigs are commonly raised, including the countries of Central America, South America, and parts of Africa and Asia. (Naddaf, Seeger, & Stafstrom, 2014). The parasite Taenia solium encysts in the brain and can express a broad range of symptoms including seizures, headache, hydrocephalus, encephalitis, stroke and mental health and …

Chagas Disease: Immigrating Into The United States, Angela Metzger

Nursing Student Class Projects (Formerly MSN)

Chagas Disease is starting to make a profound entrance into our communities within the United States. The influx of the immigrant population is the principal cause of the accumulation in the number of reported cases. (Center for Disease Control and Prevention, 2014). The Trypanosoma cruzi is a parasite that causes Chagas disease. The triatomine blood sucking insect enjoys the mucosal membranes of their pray, both humans and animals. The most common regions of the penetrating bite are the conjunctiva of the eye or around the mouth. It is through the feces of the vector entering the inoculation site that initiates …

Exploring The Pathophysiological Concepts Of Ebola Virus, Andrew T. Wasson

Nursing Student Class Projects (Formerly MSN)

The Ebola virus is a member of the filoviridae family. Five distinctive species of ebolavirus have been identified, four of which are known to cause disease in humans (Martines, Ng, Greer, Rollin, and Zaki, 2014). The specific species known to cause disease in humans are Zaire, Sudan, Ivory Coast, and Bundibugyo (Bray & Chertow, 2014). Bah et al. (2015) report that the Zaire ebolavirus (EBOV) was the cause of the most recent West African outbreak and carries the highest human mortality rate among the five known species, with up to 90% of cases being fatal. Ebola is a filamentous, enveloped, …

Differences In Health-Related Behaviors And Attitudes Between Urban, Rural, And Isolated Households In Western West Virginia, Michael Newsome Phd, Tim Hazelett, Monika Sawhney Phd, Msw

Economics Faculty Research

This study uses data from a 2013 survey of 275 randomly sampled households across nine counties in western West Virginia to examine the significant differences between the health behaviors and attitudes of rural and isolated populations. The results show that age, education, and income are significant factors in explaining differences in health-related behaviors and attitudes for all urban, rural and isolated respondents. However, after controlling for socio-demographic differences, isolation is found to have only a few significant effects, and some of the effects run counter to stereotypes of isolated populations. Rural respondents are significantly more likely than isolated respondents to …

Levels Of 8-Oxodg Predict Hepatobiliary Pathology In Opisthorchis Viverrini Endemic Settings In Thailand., Prasert Saichua, Anna Yakovleva, Christine Kamamia, Amar R. Jariwala, Paul J. Brindley, Jeffrey M. Bethony, + 8 More

Microbiology, Immunology, and Tropical Medicine Faculty Publications

Opisthorchis viverrini is distinct among helminth infections as it drives a chronic inflammatory response in the intrahepatic bile duct that progresses from advanced periductal fibrosis (APF) to cholangiocarcinoma (CCA). Extensive research shows that oxidative stress (OS) plays a critical role in the transition from chronic O. viverrini infection to CCA. OS also results in the excision of a modified DNA lesion (8-oxodG) into urine, the levels of which can be detected by immunoassay. Herein, we measured concentrations of urine 8-oxodG by immunoassay from the following four groups in the Khon Kaen Cancer Cohort study: (1) O. viverrini negative individuals, (2) …

Dualism And Doctrine, Dov Fox, Alex Stein

Indiana Law Journal

What kinds of harm among those that tortfeasors inflict are worthy of compensation? Which forms of self-incriminating evidence are privileged against government compulsion? What sorts of facts constitute a criminal defendant’s intent? Existing doctrine pins the answer to all of these questions on whether the injury, facts, or evidence at stake are “mental” or “physical.” The assumption that operations of the mind are meaningfully distinct from those of the body animates fundamental rules in our law.

A tort victim cannot recover for mental harm on its own because the law presumes that he is able to unfeel any suffering arising …

A Genetic Porcine Model Of Cancer, Lawrence B. Schook, Tiago V. Collares, Wenping Hu, Ying Liang, Fernanda M. Rodrigues, Laurie A. Rund, Kyle M. Schachtschneider, Fabiana K. Seixas, Kuldeep Singh, Kevin D. Wells, Eric M. Walters, Randall S. Prather, Christopher M. Counter

Toxicology and Cancer Biology Faculty Publications

The large size of the pig and its similarity in anatomy, physiology, metabolism, and genetics to humans make it an ideal platform to develop a genetically defined, large animal model of cancer. To this end, we created a transgenic "oncopig" line encoding Cre recombinase inducible porcine transgenes encoding KRAS^G12D and TP^53R167H, which represent a commonly mutated oncogene and tumor suppressor in human cancers, respectively. Treatment of cells derived from these oncopigs with the adenovirus encoding Cre (AdCre) led to KRAS^G12D and TP^53R167H expression, which rendered the cells transformed in culture and tumorigenic when engrafted into …

Effect Of Sirna Pre-Exposure On Subsequent Response To Sirna Therapy, Hamidreza Montazeri Aliabadi, Parvin Mahdipoor, Cezary Kucharski, Nicole Chan, Hasan Uludag

Pharmacy Faculty Articles and Research

PURPOSE. An alternative cancer therapy based on RNA interference (RNAi) has shown considerable promise but the possibility of resistance development is not known. This study explored the possibility of therapeutic resistance against siRNA nanoparticles in human cancer cells. METHODS. Two approaches to siRNA treatment were undertaken using lipid-modified polyethylenimines, a single high concentration (shock) and repeated increasing concentrations (gradual). The targets were Mcl-1, RPS6KA5 and KSP in MDA-MB-435 cells. RESULTS. There was no evidence of resistance development in shock-treated cells, while the decrease in mRNA levels of targeted proteins was not as robust in naïve cells in gradual treatment. However, …

Effects Of Cocaine Sensitization On Drug Self-Administration, Mesocorticolimbic Sapap Levels, And Prefrontal Ionotropic Glutamate Receptors, Kyle Christopher Summers

Theses and Dissertations (ETD)

Towards the goal of improving the knowledge base of how drugs of abuse function to create addicts and using currently uninvestigated areas of this knowledge base, we focused our research studies the male albino rat, and strived to explain how cocaine sensitization alters particular molecular mechanisms in the mesocorticolimbic system related to glutamate receptors, SAPAPs, and affects drug self-administration. Taking all the previously discussed research studies into consideration, we hypothesized that low-dose cocaine self-administration would yield a significant elevation in drug seeking behavior for psychostimulant sensitized animals. For specific changes at the PSD, we hypothesized that acute cocaine exposure and/or …

Embracing Multiple Definitions Of Learning, Andrew B. Barron, Eileen A. Hebets, Thomas A. Cleland, Courtney L. Fitzpatrick, Mark E. Hauber, Jeffrey R. Stevens

Eileen Hebets Publications

Definitions of learning vary widely across disciplines, driven largely by different approaches used to assess its occurrence. These definitions can be better reconciled with each other if each is recognized as coherent with a common conceptualization of learning, while appreciating the practical utility of different learning definitions in different contexts.

Learning is a major focus of research in psychology, neuro- science, behavioral ecology, evolutionary theory, and computer science, as well as in many other disciplines. Despite its conceptual prevalence, definitions of learning differ enormously both within and between these disciplines, and new definitions continue to be proposed [1]. Ongoing disputes …

A Structural And Functional Comparison Between Infectious And Non-Infectious Autocatalytic Recombinant Prp Conformers, Geoffrey P. Noble, Daphne W. Wang, Daniel J. Walsh, Justin R. Barone, Michael B. Miller, Koren A. Nishina, Sheng Li, Surachai Supattapone

Dartmouth Scholarship

Infectious prions contain a self-propagating, misfolded conformer of the prion protein termed PrPSc. A critical prediction of the protein-only hypothesis is that autocatalytic PrPSc molecules should be infectious. However, some autocatalytic recombinant PrPSc molecules have low or undetectable levels of specific infectivity in bioassays, and the essential determinants of recombinant prion infectivity remain obscure. To identify structural and functional features specifically associated with infectivity, we compared the properties of two autocatalytic recombinant PrP conformers derived from the same original template, which differ by >105-fold in specific infectivity for wild-type mice. Structurally, hydrogen/deuterium exchange mass spectrometry (DXMS) studies revealed that solvent …

Taranis Functions With Cyclin A And Cdk1 In A Novel Arousal Center To Control Sleep In Drosophila., Dinis J.S. Afonso, Die Liu, Daniel R. Machado, Huihui Pan, James E.C. Jepson, Dragana Rogulja, Kyunghee Koh

Department of Neuroscience Faculty Papers

Sleep is an essential and conserved behavior whose regulation at the molecular and anatomical level remains to be elucidated. Here, we identify TARANIS (TARA), a Drosophila homolog of the Trip-Br (SERTAD) family of transcriptional coregulators, as a molecule that is required for normal sleep patterns. Through a forward-genetic screen, we isolated tara as a novel sleep gene associated with a marked reduction in sleep amount. Targeted knockdown of tara suggests that it functions in cholinergic neurons to promote sleep. tara encodes a conserved cell-cycle protein that contains a Cyclin A (CycA)-binding homology domain. TARA regulates CycA protein levels and genetically …

Concordance Of The Montreal Cognitive Assessment With Standard Neuropsychological Measures, Sally J. Vogel, Sarah J. Banks, Jeffrey Cummings, Justin B. Miller

School of Medicine Faculty Research

Introduction: The concordance of the Montreal cognitive assessment (MoCA) with more comprehensive neuropsychological measures remains unclear. This study examined the individual MoCA domains with more comprehensive and commonly used neuropsychological measures to determine the degree of overlap. Methods: Data included individuals seen in an outpatient neurology clinic specializing in neurodegenerative disease who were administered the MoCA and also underwent neuropsychological assessment (n = 471). A principal component analysis with varimax rotation was completed using the MoCA domain scores and comprehensive neuropsychological evaluation measures. Results: Four factors emerged accounting for 55.6% of the variance: (1) visuospatial/executive functioning; (2) memory; (3) attention; …