Life Sciences Commons^™

Anomalous Constitutive Src Kinase Activity Promotes B Lymphoma Survival And Growth, Jiyuan Ke, R. Lakshman Chelvarajan, Vishal Sindhava, Darrell A. Robertson, Lazaros Lekakis, C. Darrell Jennings, Subbarao Bondada

Microbiology, Immunology, and Molecular Genetics Faculty Publications

Background: Previously we have shown that B cell receptor (BCR) expression and B cell receptor signaling pathways are important for the basal growth of B lymphoma cells. In particular we have shown that the activation of Syk, a non-src family protein tyrosine kinase and the mitogen activated protein kinases (MAPK), ERK and JNK that mediate BCR signals are required for the constitutive growth of B lymphoma cells. Since src family protein tyrosine kinases (SFKs) like Lyn are known to be needed for the phosphorylation of BCR co-receptors, Ig-alpha and Ig-beta, we hypothesized that one or more SFKs will be constitutively …

The Principled Control Of False Positives In Neuroimaging, Craig M. Bennett, George L. Wolford, Michael B. Miller

Dartmouth Scholarship

An incredible amount of data is generated in the course of a functional neuroimaging experiment. The quantity of data gives us improved temporal and spatial resolution with which to evaluate our results. It also creates a staggering multiple testing problem. A number of methods have been created that address the multiple testing problem in neuroimaging in a principled fashion. These methods place limits on either the familywise error rate (FWER) or the false discovery rate (FDR) of the results. These principled approaches are well established in the literature and are known to properly limit the amount of false positives across …

Emerging Role Of Micrornas In Liver Diseases, Shashi Bala, Miguel Marcos, Gyongyi Szabo

Gyongyi Szabo

MicroRNAs are a class of small non-coding RNAs that are found in plants, animals, and some viruses. They modulate the gene function at the post-transcriptional level and act as a fine tuner of various processes, such as development, proliferation, cell signaling, and apoptosis. They are associated with different types and stages of cancer. Recent studies have shown the involvement of microRNAs in liver diseases caused by various factors, such as Hepatitis C, Hepatitis B, metabolic disorders, and by drug abuse. This review highlights the role of microRNAs in liver diseases and their potential use as therapeutic molecules.

Apolipoprotein E But Not B Is Required For The Formation Of Infectious Hepatitis C Virus Particles, Jieyun Jiang, Guangxiang Luo

Microbiology, Immunology, and Molecular Genetics Faculty Publications

Our previous studies have found that hepatitis C virus (HCV) particles are enriched in apolipoprotein E (apoE) and that apoE is required for HCV infectivity and production. Studies by others, however, suggested that both microsomal transfer protein (MTP) and apoB are important for HCV production. To define the roles of apoB and apoE in the HCV life cycle, we developed a single-cycle HCV growth assay to determine the correlation of HCV assembly with apoB and apoE expression, as well as the influence of MTP inhibitors on the formation of HCV particles. The small interfering RNA (siRNA)-mediated knockdown of apoE expression …

Face Gender And Emotion Expression: Are Angry Women More Like Men?, Ursula Hess, Reginald B. Adams, Karl Grammer, Robert E. Kleck

Dartmouth Scholarship

Certain features of facial appearance perceptually resemble expressive cues related to facial displays of emotion. We hypothesized that because expressive markers of anger (such as lowered eyebrows) overlap with perceptual markers of male sex, perceivers would identify androgynous angry faces as more likely to be a man than a woman (Study 1) and would be slower to classify an angry woman as a woman than an angry man as a man (Study 2). Conversely, we hypothesized that because perceptual features of fear (raised eyebrows) and happiness (a rounded smiling face) overlap with female sex markers, perceivers would be more likely …

A Functional Role For The Ventrolateral Prefrontal Cortex In Non-Spatial Auditory Cognition, Y. E. Cohen, B. E. Russ, S. J. Davis, A. E. Baker, A. L. Ackelson, R. Niteck

Dartmouth Scholarship

Spatial and non-spatial sensory information is hypothesized to be evaluated in parallel pathways. In this study, we tested the spatial and non-spatial sensitivity of auditory neurons in the ventrolateral prefrontal cortex (vPFC), a cortical area in the non-spatial pathway. Activity was tested while non-human primates reported changes in an auditory stimulus' spatial or non-spatial features. We found that vPFC neurons were reliably modulated during a non-spatial auditory task but were not modulated during a spatial auditory task. The degree of modulation during the non-spatial task correlated positively with the monkeys' behavioral performance. These results are consistent with the hypotheses that …

Decreased Replication Origin Activity In Temporal Transition Regions, Zeqiang Guan, Christina M. Hughes, Settapong Kosiyatrakul, Paolo Norio, Ranjan Sen, Steven Fiering

Dartmouth Scholarship

In the mammalian genome, early- and late-replicating domains are often separated by temporal transition regions (TTRs) with novel properties and unknown functions. We identified a TTR in the mouse immunoglobulin heavy chain (Igh) locus, which contains replication origins that are silent in embryonic stem cells but activated during B cell development. To investigate which factors contribute to origin activation during B cell development, we systematically modified the genetic and epigenetic status of the endogenous Igh TTR and used a single-molecule approach to analyze DNA replication. Introduction of a transcription unit into the Igh TTR, activation of gene transcription, …

Aging Influences The Neural Correlates Of Lexical Decision But Not Automatic Semantic Priming, Brian T. Gold, Anders H. Andersen, Greg A. Jicha, Charles D. Smith

Neuroscience Faculty Publications

Human behavioral data indicate that older adults are slower to perform lexical decisions (LDs) than young adults but show similar reaction time gains when these decisions are primed semantically. The present study explored the functional neuroanatomic bases of these frequently observed behavioral findings. Young and older groups completed unprimed and primed LD tasks while functional magnetic resonance imaging (fMRI) was recorded, using a fully randomized trial design paralleling those used in behavioral research. Results from the unprimed task found that age-related slowing of LD was associated with decreased activation in perceptual extrastriate regions and increased activation in regions associated with …

Wnt Pathway Reprogramming During Human Embryonal Carcinoma Differentiation And Potential For Therapeutic Targeting, Grace E. Snow, Allison C. Kasper, Alexander M. Busch, Elisabeth Schwarz, Katherine E. Ewings, Thomas Bee, Michael J. Spinella, Ethan Dmitrovsky, Sarah J. Freemantle

Dartmouth Scholarship

Testicular germ cell tumors (TGCTs) are classified as seminonas or non-seminomas of which a major subset is embryonal carcinoma (EC) that can differentiate into diverse tissues. The pluripotent nature of human ECs resembles that of embryonic stem (ES) cells. Many Wnt signalling species are regulated during differentiation of TGCT-derived EC cells. This study comprehensively investigated expression profiles of Wnt signalling components regulated during induced differentiation of EC cells and explored the role of key components in maintaining pluripotency.

Venn, A Tool For Titrating Sequence Conservation Onto Protein Structures, Jay Vyas, Michael R. Gryk, Martin R. Schiller

Life Sciences Faculty Research

Residue conservation is an important, established method for inferring protein function, modularity and specificity. It is important to recognize that it is the 3D spatial orientation of residues that drives sequence conservation. Considering this, we have built a new computational tool, VENN that allows researchers to interactively and graphically titrate sequence homology onto surface representations of protein structures. Our proposed titration strategies reveal critical details that are not readily identified using other existing tools. Analyses of a bZIP transcription factor and receptor recognition of Fibroblast Growth Factor using VENN revealed key specificity determinants. Weblink: http://sbtools.uchc.edu/venn/.

Genetic Population Structure Analysis In New Hampshire Reveals Eastern European Ancestry, Chantel D. Sloan, Angeline D. Andrew, Eric J. Duell, Scott M. Williams, Margaret R. Karagas, Jason H. Moore

Dartmouth Scholarship

Genetic structure due to ancestry has been well documented among many divergent human populations. However, the ability to associate ancestry with genetic substructure without using supervised clustering has not been explored in more presumably homogeneous and admixed US populations. The goal of this study was to determine if genetic structure could be detected in a United States population from a single state where the individuals have mixed European ancestry. Using Bayesian clustering with a set of 960 single nucleotide polymorphisms (SNPs) we found evidence of population stratification in 864 individuals from New Hampshire that can be used to differentiate the …

Neuropeptide Y And Neurovascular Control In Skeletal Muscle And Skin., Gary J Hodges, Dwayne N Jackson, Louis Mattar, John M Johnson, J Kevin Shoemaker

Kinesiology Publications

Neuropeptide Y (NPY) is a ubiquitous peptide with multiple effects on energy metabolism, reproduction, neurogenesis, and emotion. In addition, NPY is an important sympathetic neurotransmitter involved in neurovascular regulation. Although early studies suggested that the vasoactive effects of NPY were limited to periods of high stress, there is growing evidence for the involvement of NPY on baseline vasomotor tone and sympathetically evoked vasoconstriction in vivo in both skeletal muscle and the cutaneous circulation. In Sprague-Dawley rat skeletal muscle, Y(1)-receptor activation appears to play an important role in the regulation of basal vascular conductance, and this effect is similar in magnitude …

Characterization Of Two Outer Membrane Proteins, Flgo And Flgp, That Influence Vibrio Cholerae Motility, Raquel M. Martinez, Madushini N. Dharmasena, Thomas J. Kirn, Ronald K. Taylor

Dartmouth Scholarship

Vibrio cholerae is highly motile by the action of a single polar flagellum. The loss of motility reduces the infectivity of V. cholerae, demonstrating that motility is an important virulence factor. FlrC is the sigma-54-dependent positive regulator of flagellar genes. Recently, the genes VC2206 (flgP) and VC2207 (flgO) were identified as being regulated by FlrC via a microarray analysis of an flrC mutant (D. C. Morris, F. Peng, J. R. Barker, and K. E. Klose, J. Bacteriol. 190:231-239, 2008). FlgP is reported to be an outer membrane lipoprotein required for motility that functions as a colonization factor. The study reported …

Hdl-Cholesterol-Raising Effect Of Orange Juice In Subjects With Hypercholesterolemia, Elzbieta Kurowska, J. Spence, John Jordan, Stephen Wetmore, David Freeman, Leonard Piché, Paula Serratore

Leonard Piché

Background: Orange juice-a rich source of vitamin C, folate, and flavonoids such as hesperidin-induces hypocholesterolemic responses in animals. Objective: We determined whether orange juice beneficially altered blood lipids in subjects with moderate hypercholesterolemia. Design: The sample consisted of 16 healthy men and 9 healthy women with elevated plasma total and LDL-cholesterol and normal plasma triacylglycerol concentrations. Participants incorporated 1, 2, or 3 cups (250 mL each) of orange juice sequentially into their diets, each dose over a period of 4 wk. This was followed by a 5-wk washout period. Plasma lipid, folate, homocyst(e)ine, and vitamin C (a compliance marker) concentrations …

Tumor Necrosis Factor-Alpha (Tnf-Α) Enhances Functional Thermal And Chemical Responses Of Trp Cation Channels In Human Synoviocytes, Mikhail Y. Kochukov, Terry A. Mcnearney, Huaizhi Yin, Liping Zhang, Fei Ma, Larissa Ponomareva, Sarah Abshire, Karin N. Westlund

Physiology Faculty Publications

Background: We have shown functional expression of several TRP channels on human synovial cells, proposing significance in known calcium dependent proliferative and secretory responses in joint inflammation. The present study further characterizes synoviocyte TRP expression and activation responses to thermal and osmotic stimuli after pre-treatment with proinflammatory mediator tumor necrosis factor alpha (TNF-α, EC50 1.3221 x 10^-10 g/L).

Results: Fluorescent imaging of Fura-2 loaded human SW982 synoviocytes reveals immediate and delayed cytosolic calcium oscillations elicited by (1) TRPV1 agonists capsaicin and resiniferatoxin (20-40% of cells), (2) moderate and noxious temperature change, and (3) osmotic stress TRPV4 activation (11.5% of …

Conservation Of The Glucan Phosphatase Laforin Is Linked To Rates Of Molecular Evolution And The Glucan Metabolism Of The Organism, Matthew S. Gentry, Rachel M. Pace

Molecular and Cellular Biochemistry Faculty Publications

BACKGROUND: Lafora disease (LD) is a fatal autosomal recessive neurodegenerative disease. A hallmark of LD is cytoplasmic accumulation of insoluble glucans, called Lafora bodies (LBs). Mutations in the gene encoding the phosphatase laforin account for approximately 50% of LD cases, and this gene is conserved in all vertebrates. We recently demonstrated that laforin is the founding member of a unique class of phosphatases that dephosphorylate glucans.

RESULTS: Herein, we identify laforin orthologs in a protist and two invertebrate genomes, and report that laforin is absent in the vast majority of protozoan genomes and it is lacking in all other invertebrate …

Low-Cost Hiv-1 Diagnosis And Quantification In Dried Blood Spots By Real Time Pcr, Nishaki Mehta, Sonia Trzmielina, Bareng Nonyane, Melissa Eliot, Rongheng Lin, Andrea Foulkes, Kristina Mcneal, Arthur Ammann, Vindu Eulalievyolo, John Sullivan, Katherine Luzuriaga, Mohan Somasundaran

Rongheng Lin

BACKGROUND: Rapid and cost-effective methods for HIV-1 diagnosis and viral load monitoring would greatly enhance the clinical management of HIV-1 infected adults and children in limited-resource settings. Recent recommendations to treat perinatally infected infants within the first year of life are feasible only if early diagnosis is routinely available. Dried blood spots (DBS) on filter paper are an easy and convenient way to collect and transport blood samples. A rapid and cost effective method to diagnose and quantify HIV-1 from DBS is urgently needed to facilitate early diagnosis of HIV-1 infection and monitoring of antiretroviral therapy.

METHODS AND FINDINGS: We …

Failure To Replicate A Genetic Association May Provide Important Clues About Genetic Architecture, Casey S. Greene, Nadia M. Penrod, Scott M. Williams, Jason H. Moore

Dartmouth Scholarship

Replication has become the gold standard for assessing statistical results from genome-wide association studies. Unfortunately this replication requirement may cause real genetic effects to be missed. A real result can fail to replicate for numerous reasons including inadequate sample size or variability in phenotype definitions across independent samples. In genome-wide association studies the allele frequencies of polymorphisms may differ due to sampling error or population differences. We hypothesize that some statistically significant independent genetic effects may fail to replicate in an independent dataset when allele frequencies differ and the functional polymorphism interacts with one or more other functional polymorphisms. To …

Identifying Sleep Regulatory Genes Using A Drosophila Model Of Insomnia, Laurent Seugnet, Yasuko Suzuki, Matthew S. Thimgan, Jeffrey Donlea, Sarah I. Gimbel, Laura Gottschalk, Stephen P. Duntley, Paul J. Shaw

Biological Sciences Faculty Research & Creative Works

Although it is widely accepted that sleep must serve an essential biological function, little is known about molecules that underlie sleep regulation. Given that insomnia is a common sleep disorder that disrupts the ability to initiate and maintain restorative sleep, a better understanding of its molecular underpinning may provide crucial insights into sleep regulatory processes. Thus, we created a line of flies using laboratory selection that share traits with human insomnia. After 60 generations, insomnia-like (ins-l) flies sleep 60 min a day, exhibit difficulty initiating sleep, difficulty maintaining sleep, and show evidence of daytime cognitive impairment. ins-l flies …

Human Cerebral Neuropathology Of Type 2 Diabetes Mellitus, Peter T. Nelson, Charles D. Smith, Erin L. Abner, Frederick A. Schmitt, Stephen W. Scheff, Gregory J. Davis, Jeffrey N. Keller, Gregory A. Jicha, Daron Davis, Wang-Xia Wang, Adria Hartman, Douglas G. Katz, William R. Markesbery

Pathology and Laboratory Medicine Faculty Publications

The cerebral neuropathology of Type 2 diabetes (CNDM2) has not been positively defined. This review includes a description of CNDM2 research from before the ‘Pubmed Era’. Recent neuroimaging studies have focused on cerebrovascular and white matter pathology. These and prior studies about cerebrovascular histopathology in diabetes are reviewed. Evidence is also described for and against the link between CNDM2 and Alzheimer's disease pathogenesis. To study this matter directly, we evaluated data from University of Kentucky Alzheimer's Disease Center (UK ADC) patients recruited while non-demented and followed longitudinally. Of patients who had come to autopsy (N = 234), 139 met …

Plant Vaccines: An Immunological Perspective., Douglas C. Hooper

Department of Cancer Biology Faculty Papers

The advent of technologies to express heterologous proteins in planta has led to the proposition that plants may be engineered to be safe, inexpensive vehicles for the production of vaccines and possibly even vectors for their delivery. The immunogenicity of a variety of antigens of relevance to vaccination expressed in different plants has been assessed. The purpose of this article is to examine the utility of plant-expression systems in vaccine development from an immunological perspective.

Microsaccade Rate Varies With Subjective Visibility During Motion-Induced Blindness, Po-Jang Hsieh, Peter U. Tse

Dartmouth Scholarship

Motion-induced blindness (MIB) occurs when a dot embedded in a motion field subjectively vanishes. Here we report the first psychophysical data concerning effects of microsaccade/eyeblink rate upon perceptual switches during MIB. We find that the rate of microsaccades/eyeblink rises before and after perceptual transitions from not seeing to seeing the dot, and decreases before perceptual transitions from seeing it to not seeing it. In addition, event-related fMRI data reveal that, when a dot subjectively reappears during MIB, the blood oxygen-level dependent (BOLD) signal increases in V1v and V2v and decreases in contralateral hMT+. These BOLD signal changes observed upon perceptual …

Characterization Of Conserved Properties Of Hemagglutinin Of H5n1 And Human Influenza Viruses: Possible Consequences For Therapy And Infection Control, Veljko Veljkovic, Nevena Veljkovic, Claude P. Muller, Sybille Müller, Sanja Glisic, Vladimir Perovic, Heinz Köhler

Microbiology, Immunology, and Molecular Genetics Faculty Publications

BACKGROUND: Epidemics caused by highly pathogenic avian influenza virus (HPAIV) are a continuing threat to human health and to the world's economy. The development of approaches, which help to understand the significance of structural changes resulting from the alarming mutational propensity for human-to-human transmission of HPAIV, is of particularly interest. Here we compare informational and structural properties of the hemagglutinin (HA) of H5N1 virus and human influenza virus subtypes, which are important for the receptor/virus interaction.

RESULTS: Presented results revealed that HA proteins encode highly conserved information that differ between influenza virus subtypes H5N1, H1N1, H3N2, H7N7 and defined an …

Polyglutamine Disruption Of The Huntingtin Exon 1 N Terminus Triggers A Complex Aggregation Mechanism, Ashwani K. Thakur, Murali Jayaraman, Rakesh Mishra, Monika Thakur, Veronique M. Chellgren, In-Ja L Byeon, Dalaver H. Anjum, Ravindra Kodali, Trevor P. Creamer, James F. Conway, Angela M. Gronenborn, Ronald Wetzel

Molecular and Cellular Biochemistry Faculty Publications

Simple polyglutamine (polyQ) peptides aggregate in vitro via a nucleated growth pathway directly yielding amyloid-like aggregates. We show here that the 17-amino-acid flanking sequence (HTT^NT) N-terminal to the polyQ in the toxic huntingtin exon 1 fragment imparts onto this peptide a complex alternative aggregation mechanism. In isolation, the HTT^NT peptide is a compact coil that resists aggregation. When polyQ is fused to this sequence, it induces in HTT^NT, in a repeat-length dependent fashion, a more extended conformation that greatly enhances its aggregation into globular oligomers with HTT^NT cores and exposed polyQ. In a second …

Long-Distance Delivery Of Bacterial Virulence Factors By Pseudomonas Aeruginosa Outer Membrane Vesicles, Jennifer M. Bomberger, Daniel P. Maceachran, Bonita A. Coutermarsh, Siying Ye, George A. O'Toole, Bruce A. Stanton, Frederick M. Ausubel

Dartmouth Scholarship

Bacteria use a variety of secreted virulence factors to manipulate host cells, thereby causing significant morbidity and mortality. We report a mechanism for the long-distance delivery of multiple bacterial virulence factors, simultaneously and directly into the host cell cytoplasm, thus obviating the need for direct interaction of the pathogen with the host cell to cause cytotoxicity. We show that outer membrane–derived vesicles (OMV) secreted by the opportunistic human pathogen Pseudomonas aeruginosa deliver multiple virulence factors, including β-lactamase, alkaline phosphatase, hemolytic phospholipase C, and Cif, directly into the host cytoplasm via fusion of OMV with lipid rafts in the host plasma …

In Vitro And In Vivo Models Of Acute Alcohol Exposure, Angela Dolganiuc, Gyongyi Szabo

Gyongyi Szabo

Alcohol abuse is a global problem due to the financial burden on society and the healthcare system. While the harmful health effects of chronic alcohol abuse are well established, more recent data suggest that acute alcohol consumption also affects human wellbeing. Thus, there is a need for research models in order to fully understand the effect of acute alcohol abuse on different body systems and organs. The present manuscript summarizes the interdisciplinary advantages and disadvantages of currently available human and non-human models of acute alcohol abuse, and identifies their suitability for biomedical research.

Accumulation Of Rhodopsin In Late Endosomes Triggers Photoreceptor Cell Degeneration, Yashodhan Chinchore, Amitavo Mitra, Patrick J. Dolph, Norbert Perrimon

Dartmouth Scholarship

Progressive retinal degeneration is the underlying feature of many human retinal dystrophies. Previous work using Drosophila as a model system and analysis of specific mutations in human rhodopsin have uncovered a connection between rhodopsin endocytosis and retinal degeneration. In these mutants, rhodopsin and its regulatory protein arrestin form stable complexes, and endocytosis of these complexes causes photoreceptor cell death. In this study we show that the internalized rhodopsin is not degraded in the lysosome but instead accumulates in the late endosomes. Using mutants that are defective in late endosome to lysosome trafficking, we were able to show that rhodopsin accumulates …

The Future (Or Lack Of Future) Of Personalized Prescription In Psychiatry, Jose De Leon

Psychiatry Faculty Publications

Rapid technological advances in genetics have created conceptual chaos regarding the genetics of drug response. Terms for differing concepts are used interchangeably: pharmacogenetics with pharmacogenomics, personalized medicine with personalized prescription. Biomarker has many definitions. The author prefers the concept of personalized prescription and uses it with implications beyond pharmacogenetics by considering all scientific information valid for prescribing medication. Genetics may not be crucial for all drugs. In this comprehensive view, clinicians must consider genetic, environmental and personal variables when prescribing medication and incorporate some basic pharmacological principles: (1) safety and efficacy, (2) pharmacokinetics and pharmacodynamics, (3) therapeutic window and prescriber's …

The Specificity Of The Search Template, Mary J. Bravo, Hany Farid

Dartmouth Scholarship

When searching for a target object, observers use an internal representation of the target's appearance as a search template. This study used naturalistic stimuli to examine the specificity of this template. Observers first learned several name-image pairs; they then participated in a search experiment in which the names served as cues and the images served as targets. To test whether the observers searched for the targets using an exact image template, we included targets that were transformations of the studied image and targets that belonged to the same subordinate-level category as the studied image. The same stimuli were also used …

Genic Regions Of A Large Salamander Genome Contain Long Introns And Novel Genes, Jeramiah J. Smith, Srikrishna Putta, Wei Zhu, Gerald M. Pao, Inder M. Verma, Tony Hunter, Susan V. Bryant, David M. Gardiner, Timothy T. Harkins, S. Randal Voss

Biology Faculty Publications

BACKGROUND: The basis of genome size variation remains an outstanding question because DNA sequence data are lacking for organisms with large genomes. Sixteen BAC clones from the Mexican axolotl (Ambystoma mexicanum: c-value = 32 x 10(9) bp) were isolated and sequenced to characterize the structure of genic regions.

RESULTS: Annotation of genes within BACs showed that axolotl introns are on average 10x longer than orthologous vertebrate introns and they are predicted to contain more functional elements, including miRNAs and snoRNAs. Loci were discovered within BACs for two novel EST transcripts that are differentially expressed during spinal cord regeneration and skin …