Life Sciences Commons^™

A Shared Gene Expression Signature In Mouse Models Of Ebv-Associated And Non-Ebv-Associated Burkitt Lymphoma, Kathryn T. Bieging, Kamonwan Fish, Subbarao Bondada, Richard Longnecker

Microbiology, Immunology, and Molecular Genetics Faculty Publications

The link between EBV infection and Burkitt lymphoma (BL) is strong, but the mechanism underlying that link has been elusive. We have developed a mouse model for EBV-associated BL in which LMP2A, an EBV latency protein, and MYC are expressed in B cells. Our model has demonstrated the ability of LMP2A to accelerate tumor onset, increase spleen size, and bypass p53 inactivation. Here we describe the results of total gene expression analysis of tumor and pretumor B cells from our transgenic mouse model. Although we see many phenotypic differences and changes in gene expression in pretumor B cells, the transcriptional …

Planning Combinatorial Disulfide Cross-Links For Protein Fold Determination, Fei Xiong, Alan M Friedman, Chris Bailey-Kellogg

Dartmouth Scholarship

Fold recognition techniques take advantage of the limited number of overall structural organizations, and have become increasingly effective at identifying the fold of a given target sequence. However, in the absence of sufficient sequence identity, it remains difficult for fold recognition methods to always select the correct model. While a native-like model is often among a pool of highly ranked models, it is not necessarily the highest-ranked one, and the model rankings depend sensitively on the scoring function used. Structure elucidation methods can then be employed to decide among the models based on relatively rapid biochemical/biophysical experiments.

Differential Il-21 Signaling In Apcs Leads To Disparate Th17 Differentiation In Diabetes-Susceptible Nod And Diabetes-Resistant Nod.Idd3 Mice., Sue M. Liu, David H. Lee, Jenna M. Sullivan, Denise Chung, Anneli Jäger, Bennett O V. Shum, Nora E. Sarvetnick, Ana C. Anderson, Vijay K. Kuchroo

Journal Articles: Regenerative Medicine

Type 1 diabetes (T1D) is an autoimmune disease that shows familial aggregation in humans and likely has genetic determinants. Disease linkage studies have revealed many susceptibility loci for T1D in mice and humans. The mouse T1D susceptibility locus insulin-dependent diabetes susceptibility 3 (Idd3), which has a homologous genetic interval in humans, encodes cytokine genes Il2 and Il21 and regulates diabetes and other autoimmune diseases; however, the cellular and molecular mechanisms of this regulation are still being elucidated. Here we show that T cells from NOD mice produce more Il21 and less Il2 and exhibit enhanced Th17 cell generation compared with …

Erect Wing Facilitates Context-Dependent Wnt/Wingless Signaling By Recruiting The Cell-Specific Armadillo-Tcf Adaptor Earthbound To Chromatin, Nan Xin, Hassina Benchabane, Ai Tian, Kerrie Nguyen, Lindsay Klofas, Yashi Ahmed

Dartmouth Scholarship

During metazoan development, the Wnt/Wingless signal transduction pathway is activated repetitively to direct cell proliferation, fate specification, differentiation and apoptosis. Distinct outcomes are elicited by Wnt stimulation in different cellular contexts; however, mechanisms that confer context specificity to Wnt signaling responses remain largely unknown. Starting with an unbiased forward genetic screen in Drosophila, we recently uncovered a novel mechanism by which the cell-specific co-factor Earthbound 1 (Ebd1), and its human homolog jerky, promote interaction between the Wnt pathway transcriptional co-activators B-catenin/Armadillo and TCF to facilitate context-dependent Wnt signaling responses. Here, through the same genetic screen, we find an unanticipated requirement …

Splice Variant–Specific Cellular Function Of The Formin Inf2 In Maintenance Of Golgi Architecture, Vinay Ramabhadran, Farida Korobova, Gilbert J. Rahme, Henry N. Higgs

Dartmouth Scholarship

INF2 is a unique formin that can both polymerize and depolymerize actin filaments. Mutations in INF2 cause the kidney disease focal and segmental glomerulosclerosis. INF2 can be expressed as two C-terminal splice variants: CAAX and non-CAAX. The CAAX isoform contains a C-terminal prenyl group and is tightly bound to endoplasmic reticulum (ER). The localization pattern and cellular function of the non-CAAX isoform have not been studied. Here we find that the two isoforms are expressed in a cell type-dependent manner, with CAAX predominant in 3T3 fibroblasts and non-CAAX predominant in U2OS, HeLa, and Jurkat cells. Although INF2-CAAX is ER localized …

Demasculinization And Feminization Of Male Gonads By Atrazine: Consistent Effects Across Vertebrate Classes, Krista A. Mccoy

Integrative Biology Faculty and Staff Publications

Atrazine is the most commonly detected pesticide contaminant of ground water, surface water, and precipitation. Atrazine is also an endocrine disruptor that, among other effects, alters male reproductive tissues when animals are exposed during development. Here, we apply the nine so-called “Hill criteria” (Strength, Consistency, Specificity, Temporality, Biological Gradient, Plausibility, Coherence, Experiment, and Analogy) for establishing cause–effect relationships to examine the evidence for atrazine as an endocrine disruptor that demasculinizes and feminizes the gonads of male vertebrates. We present experimental evidence that the effects of atrazine on male development are consistent across all vertebrate classes examined and we present a …

Differential Interactions Of The Formins Inf2, Mdia1, And Mdia2 With Microtubules, Jeremie Gaillard, Bvinay Ramabhadran, Emmanuelle Neumanne, Pinar Gurel, Laurent Blanchoin, Marylin Vantard, Henry N. Higgs

Dartmouth Scholarship

A number of cellular processes use both microtubules and actin filaments, but the molecular machinery linking these two cytoskeletal elements remains to be elucidated in detail. Formins are actin-binding proteins that have multiple effects on actin dynamics, and one formin, mDia2, has been shown to bind and stabilize microtubules through its formin homology 2 (FH2) domain. Here we show that three formins, INF2, mDia1, and mDia2, display important differences in their interactions with microtubules and actin. Constructs containing FH1, FH2, and C-terminal domains of all three formins bind microtubules with high affinity (K(d) < 100 nM). However, only mDia2 binds microtubules at 1:1 stoichiometry, with INF2 and mDia1 showing saturating binding at approximately 1:3 (formin dimer:tubulin dimer). INF2-FH1FH2C is a potent microtubule-bundling protein, an effect that results in a large reduction in catastrophe rate. In contrast, neither mDia1 nor mDia2 is a potent microtubule bundler. The C-termini of mDia2 and INF2 have different functions in microtubule interaction, with mDia2's C-terminus required for high-affinity binding and INF2's C-terminus required for bundling. mDia2's C-terminus directly binds microtubules with submicromolar affinity. These formins also differ in their abilities to bind actin and microtubules simultaneously. Microtubules strongly inhibit actin polymerization by mDia2, whereas they moderately inhibit mDia1 and have no effect on INF2. Conversely, actin monomers inhibit microtubule binding/bundling by INF2 but do not affect mDia1 or mDia2. These differences in interactions with microtubules and actin suggest differential function in cellular processes requiring both cytoskeletal elements.

Rna Oxidation Adducts 8-Ohg And 8-Oha Change With Aβ42 Levels In Late-Stage Alzheimer's Disease, Adam M. Weidner, Melissa A. Bradley, Tina L. Beckett, Dana M. Niedowicz, Amy L.S. Dowling, Sergey V. Matveev, Harry Levine, Mark A. Lovell, M. Paul Murphy

Sanders-Brown Center on Aging Faculty Publications

While research supports amyloid-β (Aβ) as the etiologic agent of Alzheimer's disease (AD), the mechanism of action remains unclear. Evidence indicates that adducts of RNA caused by oxidation also represent an early phenomenon in AD. It is currently unknown what type of influence these two observations have on each other, if any. We quantified five RNA adducts by gas chromatography/mass spectroscopy across five brain regions from AD cases and age-matched controls. We then used a reductive directed analysis to compare the RNA adducts to common indices of AD neuropathology and various pools of Aβ. Using data from four disease-affected brain …

Stomatin-Like Protein 2 Binds Cardiolipin And Regulates Mitochondrial Biogenesis And Function., Darah Christie, Caitlin D Lemke, Isaac M Elias, Luan A Chau, Mark G Kirchhof, Bo Li, Eric H Ball, Stanley D Dunn, Grant M Hatch, Joaquín Madrenas

Biochemistry Publications

Stomatin-like protein 2 (SLP-2) is a widely expressed mitochondrial inner membrane protein of unknown function. Here we show that human SLP-2 interacts with prohibitin-1 and -2 and binds to the mitochondrial membrane phospholipid cardiolipin. Upregulation of SLP-2 expression increases cardiolipin content and the formation of metabolically active mitochondrial membranes and induces mitochondrial biogenesis. In human T lymphocytes, these events correlate with increased complex I and II activities, increased intracellular ATP stores, and increased resistance to apoptosis through the intrinsic pathway, ultimately enhancing cellular responses. We propose that the function of SLP-2 is to recruit prohibitins to cardiolipin to form cardiolipin-enriched …

Laforin, A Dual Specificity Phosphatase Involved In Lafora Disease, Is Present Mainly As Monomeric Form With Full Phosphatase Activity, Vikas V. Dukhande, Devin M. Rogers, Carlos Romá-Mateo, Jordi Donderis, Alberto Marina, Adam O. Taylor, Pascual Sanz, Matthew S. Gentry

Molecular and Cellular Biochemistry Faculty Publications

Lafora Disease (LD) is a fatal neurodegenerative epileptic disorder that presents as a neurological deterioration with the accumulation of insoluble, intracellular, hyperphosphorylated carbohydrates called Lafora bodies (LBs). LD is caused by mutations in either the gene encoding laforin or malin. Laforin contains a dual specificity phosphatase domain and a carbohydrate-binding module, and is a member of the recently described family of glucan phosphatases. In the current study, we investigated the functional and physiological relevance of laforin dimerization. We purified recombinant human laforin and subjected the monomer and dimer fractions to denaturing gel electrophoresis, mass spectrometry, phosphatase assays, protein-protein interaction assays, …

No Evidence Of Association Between Hiv-1 And Malaria In Populations With Low Hiv-1 Prevalence, Diego F. Cuadros, Adam J. Branscum, Gisela García-Ramos

Biology Faculty Publications

BACKGROUND: The geographic overlap between HIV-1 and malaria has generated much interest in their potential interactions. A variety of studies have evidenced a complex HIV-malaria interaction within individuals and populations that may have dramatic effects, but the causes and implications of this co-infection at the population level are still unclear. In a previous publication, we showed that the prevalence of malaria caused by the parasite Plasmodium falciparum is associated with HIV infection in eastern sub-Saharan Africa. To complement our knowledge of the HIV-malaria co-infection, the objective of this work was to assess the relationship between malaria and HIV prevalence in …

Serum- And Glucocorticoid-Induced Kinase 3 In Recycling Endosomes Mediates Acute Activation Of Na+/H+ Exchanger Nhe3 By Glucocorticoids, Peijian He, Sei-Jung Lee, Songbai Lin, Ursula Seidler, Florian Lang, Geza Fejes-Toth, Aniko Naray-Fejes-Toth, C. Chris Yun

Dartmouth Scholarship

Na(+)/H(+) exchanger 3 (NHE3) is the major Na(+) transporter in the intestine. Serum- and glucocorticoid-induced kinase (SGK) 1 interacts with NHE regulatory factor 2 (NHERF2) and mediates activation of NHE3 by dexamethasone (Dex) in cultured epithelial cells. In this study, we compared short-term regulation of NHE3 by Dex in SGK1-null and NHERF2-null mice. In comparison to wild-type mice, loss of SGK1 or NHERF2 significantly attenuated regulation of NHE3 by Dex but did not completely obliterate the effect. We show that transfection of SGK2 or SGK3 in PS120 cells resulted in robust activation of NHE3 by Dex. However, unlike SGK1 or …

Effect Of Variable Transmission Rate On The Dynamics Of Hiv In Sub-Saharan Africa, Diego F. Cuadros, Phillip H. Crowley, Ben Augustine, Sarah L. Stewart, Gisela García-Ramos

Biology Faculty Publications

BACKGROUND: The cause of the high HIV prevalence in sub-Saharan Africa is incompletely understood, with heterosexual penile-vaginal transmission proposed as the main mechanism. Heterosexual HIV transmission has been estimated to have a very low probability; but effects of cofactors that vary in space and time may substantially alter this pattern.

METHODS: To test the effect of individual variation in the HIV infectiousness generated by co-infection, we developed and analyzed a mathematical sexual network model that simulates the behavioral components of a population from Malawi, as well as the dynamics of HIV and the co-infection effect caused by other infectious diseases, …

Targeted Over-Expression Of Glutamate Transporter 1 (Glt-1) Reduces Ischemic Brain Injury In A Rat Model Of Stroke, Brandon K. Harvey, Mikko Airavaara, Jason Michael Hinzman, Emily M. Wires, Matthew J. Chiocco, Douglas B. Howard, Hui Shen, Greg A. Gerhardt, Barry J. Hoffer, Yun Wang

Neuroscience Faculty Publications

Following the onset of an ischemic brain injury, the excitatory neurotransmitter glutamate is released. The excitotoxic effects of glutamate are a major contributor to the pathogenesis of a stroke. The aim of this study was to examine if overexpression of a glutamate transporter (GLT-1) reduces ischemic brain injury in a rat model of stroke. We generated an adeno-associated viral (AAV) vector expressing the rat GLT-1 cDNA (AAV-GLT1). Functional expression of AAV-GLT1 was confirmed by increased glutamate clearance rate in non-stroke rat brain as measured by in vivo amperometry. AAV-GLT1 was injected into future cortical region of infarction 3 weeks prior …

Origin Of Amphibian And Avian Chromosomes By Fission, Fusion, And Retention Of Ancestral Chromosomes, Stephen R. Voss, D. Kevin Kump, Srikrishna Putta, Nathan Pauly, Anna Reynolds, Rema J. Henry, Saritha Basa, John A. Walker, Jeramiah J. Smith

Biology Faculty Publications

Amphibian genomes differ greatly in DNA content and chromosome size, morphology, and number. Investigations of this diversity are needed to identify mechanisms that have shaped the evolution of vertebrate genomes. We used comparative mapping to investigate the organization of genes in the Mexican axolotl (Ambystoma mexicanum), a species that presents relatively few chromosomes (n = 14) and a gigantic genome (>20 pg/N). We show extensive conservation of synteny between Ambystoma, chicken, and human, and a positive correlation between the length of conserved segments and genome size. Ambystoma segments are estimated to be four to 51 times longer than homologous …

Lafora Disease E3-Ubiquitin Ligase Malin Is Related To Trim32 At Both The Phylogenetic And Functional Level, Carlos Romá-Mateo, Daniel Moreno, Santiago Vernia, Teresa Rubio, Travis M. Bridges, Matthew S. Gentry, Pascual Sanz

Molecular and Cellular Biochemistry Faculty Publications

BACKGROUND: Malin is an E3-ubiquitin ligase that is mutated in Lafora disease, a fatal form of progressive myoclonus epilepsy. In order to perform its function, malin forms a functional complex with laforin, a glucan phosphatase that facilitates targeting of malin to its corresponding substrates. While laforin phylogeny has been studied, there are no data on the evolutionary lineage of malin.

RESULTS: After an extensive search for malin orthologs, we found that malin is present in all vertebrate species and a cephalochordate, in contrast with the broader species distribution previously reported for laforin. These data suggest that in addition to forming …

Uncover Disease Genes By Maximizing Information Flow In The Phenome-Interactome Network., Yong Chen, Tao Jiang, Rui Jiang

Faculty Scholarship for the College of Science & Mathematics

MOTIVATION: Pinpointing genes that underlie human inherited diseases among candidate genes in susceptibility genetic regions is the primary step towards the understanding of pathogenesis of diseases. Although several probabilistic models have been proposed to prioritize candidate genes using phenotype similarities and protein-protein interactions, no combinatorial approaches have been proposed in the literature.

RESULTS: We propose the first combinatorial approach for prioritizing candidate genes. We first construct a phenome-interactome network by integrating the given phenotype similarity profile, protein-protein interaction network and associations between diseases and genes. Then, we introduce a computational method called MAXIF to maximize the information flow in this …

Emotional Climate, Feeding Practices, And Feeding Styles: An Observational Analysis Of The Dinner Meal In Head Start Families, Sheryl O Hughes, Thomas G Power, Maria A Papaioannou, Matthew B Cross, Theresa A Nicklas, Sharon K Hall, Richard M Shewchuk

Faculty Publications

BACKGROUND: A number of studies conducted with ethnically diverse, low-income samples have found that parents with indulgent feeding styles had children with a higher weight status. Indulgent parents are those who are responsive to their child's emotional states but have problems setting appropriate boundaries with their child. Because the processes through which styles impact child weight are poorly understood, the aim of this study was to observe differences in the emotional climate created by parents (including affect, tone of voice, and gestures) and behavioral feeding practices among those reporting different feeding styles on the Caregiver's Feeding Styles Questionnaire. A secondary …

Store-Operated Ca(2+) Entry (Soce) Contributes To Normal Skeletal Muscle Contractility In Young But Not In Aged Skeletal Muscle, Angela M. Thornton, Xiaoli Zhao, Noah Weisleder, Leticia S. Brotto, Sylvain Bougoin, Thomas M. Nosek, Michael B. Reid, Brian Hardin, Zui Pan, Jianjie Ma, Jerome Parness, Marco Brotto

Physiology Faculty Publications

Muscle atrophy alone is insufficient to explain the significant decline in contractile force of skeletal muscle during normal aging. One contributing factor to decreased contractile force in aging skeletal muscle could be compromised excitation-contraction (E-C) coupling, without sufficient available Ca(2+) to allow for repetitive muscle contractility, skeletal muscles naturally become weaker. Using biophysical approaches, we previously showed that store-operated Ca(2+) entry (SOCE) is compromised in aged skeletal muscle but not in young ones. While important, a missing component from previous studies is whether or not SOCE function correlates with contractile function during aging. Here we test the contribution of extracellular …

Variations In Mre11/Rad50/Nbs1 Status And Dna Damage-Induced S-Phase Arrest In The Cell Lines Of The Nci60 Panel, Kristen M. K. Garner, Alan Eastman

Dartmouth Scholarship

The Mre11/Rad50/Nbs1 (MRN) complex is a regulator of cell cycle checkpoints and DNA repair. Defects in MRN can lead to defective S-phase arrest when cells are damaged. Such defects may elicit sensitivity to selected drugs providing a chemical synthetic lethal interaction that could be used to target therapy to tumors with these defects. The goal of this study was to identify these defects in the NCI60 panel of cell lines and identify compounds that might elicit selective cytotoxicity.

Recombination Phenotypes Of The Nci-60 Collection Of Human Cancer Cells, Dawn M. Stults, Michael W. Killen, Brent J. Shelton, Andrew J. Pierce

Microbiology, Immunology, and Molecular Genetics Faculty Publications

BACKGROUND: The NCI-60 is a collection of tumor cell lines derived from a variety of human adult cancer tissue types and is commonly used for genetic analysis and screening of potential chemotherapeutic agents. We wanted to understand the contributions of specific mechanisms of genomic instability to the etiology of cancers represented by the NCI-60.

RESULTS: We screened the NCI-60 for dysregulated homologous recombination by using the gene cluster instability (GCI) assay we pioneered, and for defects in base excision repair by sensitivity to 5-hydroxymethyl-2'-deoxyuridine (hmdUrd). We identified subsets of the NCI-60 lines that either displayed the characteristic molecular signature of …

Digeorge Critical Region 8 (Dgcr8) Is A Double-Cysteine-Ligated Heme Protein., Ian Barr, Aaron T. Smith, Rachel Senturia, Yanqiu Chen, Brooke D. Scheidemantle, Judith N. Burstyn, Feng Guo

Natural Sciences and Mathematics | Faculty Scholarship

All known heme-thiolate proteins ligate the heme iron using one cysteine side chain. We previously found that DiGeorge Critical Region 8 (DGCR8), an essential microRNA processing factor, associates with heme of unknown redox state when overexpressed in Escherichia coli. On the basis of the similarity of the 450-nm Soret absorption peak of the DGCR8-heme complex to that of cytochrome P450 containing ferrous heme with CO bound, we identified cysteine 352 as a probable axial ligand in DGCR8. Here we further characterize the DGCR8-heme interaction using biochemical and spectroscopic methods. The DGCR8-heme complex is highly stable, with a half-life exceeding 4 …

Septin Filaments Exhibit A Dynamic, Paired Organization That Is Conserved From Yeast To Mammals, Bradley S. Demay, Xiaobo Bai, Louisa Howard, Patricia Occhipinti, Rebecca A. Meseroll, Elias T. Spiliotis, Rudolf Oldenbourg, Amy S. Gladfelter

Dartmouth Scholarship

The septins are conserved, GTP-binding proteins important for cytokinesis, membrane compartmentalization, and exocytosis. However, it is unknown how septins are arranged within higher-order structures in cells. To determine the organization of septins in live cells, we developed a polarized fluorescence microscopy system to monitor the orientation of GFP dipole moments with high spatial and temporal resolution. When GFP was fused to septins, the arrangement of GFP dipoles reflected the underlying septin organization. We demonstrated in a filamentous fungus, a budding yeast, and a mammalian epithelial cell line that septin proteins were organized in an identical highly ordered fashion. Fluorescence anisotropy …

Domainrbf: A Bayesian Regression Approach To The Prioritization Of Candidate Domains For Complex Diseases., Wangshu Zhang, Yong Chen, Fengzhu Sun, Rui Jiang

Faculty Scholarship for the College of Science & Mathematics

BACKGROUND: Domains are basic units of proteins, and thus exploring associations between protein domains and human inherited diseases will greatly improve our understanding of the pathogenesis of human complex diseases and further benefit the medical prevention, diagnosis and treatment of these diseases. Within a given domain-domain interaction network, we make the assumption that similarities of disease phenotypes can be explained using proximities of domains associated with such diseases. Based on this assumption, we propose a Bayesian regression approach named "domainRBF" (domain Rank with Bayes Factor) to prioritize candidate domains for human complex diseases.

RESULTS: Using a compiled dataset containing 1,614 …

Aging Is Associated With Positive Responding To Neutral Information But Reduced Recovery From Negative Information, Carien M. Van Reekum, Stacey M. Schaefer, Regina C. Lapate, Catherine J. Norris, Lawrence L. Greischar, Richard J. Davidson

Dartmouth Scholarship

Studies on aging and emotion suggest an increase in reported positive affect, a processing bias of positive over negative information, as well as increasingly adaptive regulation in response to negative events with advancing age. These findings imply that older individuals evaluate information differently, resulting in lowered reactivity to, and/or faster recovery from, negative information, while maintaining more positive responding to positive information. We examined this hypothesis in an ongoing study on Midlife in the US (MIDUS II) where emotional reactivity and recovery were assessed in a large number of respondents (N = 159) from a wide age range (36–84 …

Protein-Protein Fusion Catalyzed By Sortase A, David A. Levary, Ranganath Parthasarathy, Eric T. Boder, Margaret E. Ackerman

Dartmouth Scholarship

Chimeric proteins boast widespread use in areas ranging from cell biology to drug delivery. Post-translational protein fusion using the bacterial transpeptidase sortase A provides an attractive alternative when traditional gene fusion fails. We describe use of this enzyme for in vitro protein ligation and report the successful fusion of 10 pairs of protein domains with preserved functionality — demonstrating the robust and facile nature of this reaction.

Mind Perception: Real But Not Artificial Faces Sustain Neural Activity Beyond The N170/Vpp, Thalia Wheatley, Anna Weinberg, Christine Looser, Tim Moran, Greg Hajcak

Dartmouth Scholarship

Faces are visual objects that hold special significance as the icons of other minds. Previous researchers using event-related potentials (ERPs) have found that faces are uniquely associated with an increased N170/vertex positive potential (VPP) and a more sustained frontal positivity. Here, we examined the processing of faces as objects vs. faces as cues to minds by contrasting images of faces possessing minds (human faces), faces lacking minds (doll faces), and non-face objects (i.e., clocks). Although both doll and human faces were associated with an increased N170/VPP from 175–200 ms following stimulus onset, only human faces were associated with a sustained …

Common And Distinct Mechanisms Of Cognitive Flexibility In Prefrontal Cortex, Chobok Kim, Nathan F. Johnson, Sara E. Cilles, Brian T. Gold

Neuroscience Faculty Publications

The human ability to flexibly alternate between tasks represents a central component of cognitive control. Neuroimaging studies have linked task switching with a diverse set of prefrontal cortex (PFC) regions, but the contributions of these regions to various forms of cognitive flexibility remain largely unknown. Here, subjects underwent functional brain imaging while they completed a paradigm that selectively induced stimulus, response, or cognitive set switches in the context of a single task decision performed on a common set of stimuli. Behavioral results indicated comparable reaction time costs associated with each switch type. Domain-general task-switching activation was observed in the inferior …

Crystal Structure Of A Charge Engineered Human Lysozyme Having Enhanced Bactericidal Activity, Avinash Gill, Thomas C. Scanlon, Daniel C. Osipovitch, Dean R. Madden, Karl E. Griswold

Dartmouth Scholarship

Human lysozyme is a key component of the innate immune system, and recombinant forms of the enzyme represent promising leads in the search for therapeutic agents able to treat drug-resistant infections. The wild type protein, however, fails to participate effectively in clearance of certain infections due to inherent functional limitations. For example, wild type lysozymes are subject to electrostatic sequestration and inactivation by anionic biopolymers in the infected airway. A charge engineered variant of human lysozyme has recently been shown to possess improved antibacterial activity in the presence of disease associated inhibitory molecules. Here, the 2.04 A ̊ crystal structure …

Targeted Drug-Resistance Testing Strategy For Multidrug-Resistant Tuberculosis Detection, Lima, Peru, 2005–2008, Gustavo E. Velásquez, Martin Yagui, J Peter Cegielski, Luis Asencios, Jaime Bayona, Cesar Bonilla, Hector O. Jave, Gloria Yale, Carmen Suárez, Sidney Atwood, Carmen C. Contreras, Sonya S. Shin

Dartmouth Scholarship

The Peruvian National Tuberculosis Control Program issued guidelines in 2006 specifying criteria for culture and drug-susceptibility testing (DST), including district-level rapid DST. All patients referred for culture and DST in 2 districts of Lima, Peru, during January 2005–November 2008 were monitored prospectively. Of 1,846 patients, 1,241 (67.2%) had complete DST results for isoniazid and rifampin; 419 (33.8%) patients had multidrug-resistant (MDR) TB at the time of referral. Among patients with new smear-positive TB, household contact and suspected category I failure were associated with MDR TB, compared with concurrent regional surveillance data. Among previously treated patients with smear-positive TB, adult household …