Life Sciences Commons^™

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 …

Mir319a Targeting Of Tcp4 Is Critical For Petal Growth And Development In Arabidopsis, Anwesha Nag, Stacey King, Thomas Jack

Dartmouth Scholarship

In a genetic screen in a drnl-2 background, we isolated a loss-of-function allele in miR319a (miR319a¹²⁹). Previously, miR319a has been postulated to play a role in leaf development based on the dramatic curled-leaf phenotype of plants that ectopically express miR319a (jaw-D). miR319a¹²⁹ mutants exhibit defects in petal and stamen development; petals are narrow and short, and stamens exhibit defects in anther development. The miR319a¹²⁹ loss-of-function allele contains a single-base change in the middle of the encoded miRNA, which reduces the ability of miR319a to recognize targets. Analysis of the expression patterns of the …

Proteolytic Regulation Of Toxin-Antitoxin Systems By Clppc In Staphylococcus Aureus, Niles P. Donegan, Earl T. Thompson, Zhibiao Fu, Ambrose L. Cheung

Dartmouth Scholarship

Bacterial toxin-antitoxin (TA) systems typically consist of a small, labile antitoxin that inactivates a specific longer-lived toxin. In Escherichia coli, such antitoxins are proteolytically regulated by the ATP-dependent proteases Lon and ClpP. Under normal conditions, antitoxin synthesis is sufficient to replace this loss from proteolysis, and the bacterium remains protected from the toxin. However, if TA production is interrupted, antitoxin levels decrease, and the cognate toxin is free to inhibit the specific cellular component, such as mRNA, DnaB, or gyrase. To date, antitoxin degradation has been studied only in E. coli, so it remains unclear whether similar mechanisms of regulation …

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 …

Ceramide Kinase Regulates Phospholipase C And Phosphatidylinositol 4, 5, Bisphosphate In Phototransduction, Ujjaini Dasgupta, Takeshi Bamba, Salvatore Chiantia, Pusha Karim, Ahmad N. Abou Tayoun

Dartmouth Scholarship

Phosphoinositide-specific phospholipase C (PLC) is a central effector for many biological responses regulated by G-protein-coupled receptors including Drosophila phototransduction where light sensitive channels are activated downstream of NORPA, a PLCbeta homolog. Here we show that the sphingolipid biosynthetic enzyme, ceramide kinase, is a novel regulator of PLC signaling and photoreceptor homeostasis. A mutation in ceramide kinase specifically leads to proteolysis of NORPA, consequent loss of PLC activity, and failure in light signal transduction. The mutant photoreceptors also undergo activity-dependent degeneration. Furthermore, we show that a significant increase in ceramide, resulting from lack of ceramide kinase, perturbs the membrane microenvironment of …

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 …

Quantifying And Resolving Multiple Vector Transformants In S. Cerevisiae Plasmid Libraries, Thomas C. Scanlon, Elizabeth C. Gray, Karl E. Griswold

Dartmouth Scholarship

In addition to providing the molecular machinery for transcription and translation, recombinant microbial expression hosts maintain the critical genotype-phenotype link that is essential for high throughput screening and recovery of proteins encoded by plasmid libraries. It is known that Escherichia coli cells can be simultaneously transformed with multiple unique plasmids and thusly complicate recombinant library screening experiments. As a result of their potential to yield misleading results, bacterial multiple vector transformants have been thoroughly characterized in previous model studies. In contrast to bacterial systems, there is little quantitative information available regarding multiple vector transformants in yeast. Saccharomyces cerevisiae is the …

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, …

Microevolution And Macroevolution Are Governed By The Same Processes, Michael Dietrich

Dartmouth Scholarship

This collection of specially commissioned essays puts top scholars head to head to debate the central issues in the lively and fast growing field of philosophy of biology Brings together original essays on ten of the most hotly debated ...

Levels Of The Secreted Vibrio Cholerae Attachment Factor Gbpa Are Modulated By Quorum-Sensing-Induced Proteolysis, Brooke A. Jude, Raquel M. Martinez, Karen Skorupski, Ronald K. Taylor

Dartmouth Scholarship

Vibrio cholerae is the etiologic agent of cholera in humans. Intestinal colonization occurs in a stepwise fashion, initiating with attachment to the small intestinal epithelium. This attachment is followed by expression of the toxin-coregulated pilus, microcolony formation, and cholera toxin (CT) production. We have recently characterized a secreted attachment factor, GlcNAc binding protein A (GbpA), which functions in attachment to environmental chitin sources as well as to intestinal substrates. Studies have been initiated to define the regulatory network involved in GbpA induction. At low cell density, GbpA was detected in the culture supernatant of all wild-type (WT) strains examined. In …

Human Uterine Natural Killer Cells But Not Blood Natural Killer Cells Inhibit Human Immunodeficiency Virus Type 1 Infection By Secretion Of Cxcl12, Teddy F. Mselle, Aexandra L. Howell, Mimi Ghosh, Charles R. Wira, Charles L. Sentman

Dartmouth Scholarship

Natural killer (NK) cells derived from the human female reproductive tract (FRT) are phenotypically and functionally distinct from those obtained from peripheral blood. Because the FRT is a primary site of human immunodeficiency virus type 1 (HIV-1) infection in women, we determined whether soluble factors secreted by uterine-derived NK (uNK) cells inhibit HIV-1 infection. Clonal populations of uNK cells were activated with interleukin-12 (IL-12) and IL-15, and conditioned media (CM) from these cultures evaluated for their ability to inhibit infection of cells by HIV-1_IIIB, HIV-1_NL4.3, and HIV-1_HC4 (X4-tropic) or HIV-1_BaL (R5-tropic) viruses. We found …

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.

Integral Membrane Proteins Brr6 And Apq12 Link Assembly Of The Nuclear Pore Complex To Lipid Homeostasis In The Endoplasmic Reticulum, Christine A. Hodge, Vineet Choudhary, Michael J. Wolyniak, John J. Scarcelli, Roger Schneiter, Charles N. Cole

Dartmouth Scholarship

Cells of Saccharomyces cerevisiae lacking Apq12, a nuclear envelope (NE)-endoplasmic reticulum (ER) integral membrane protein, are defective in assembly of nuclear pore complexes (NPCs), possibly because of defects in regulating membrane fluidity. We identified BRR6, which encodes an essential integral membrane protein of the NE-ER, as a dosage suppressor of apq12 Delta. Cells carrying the temperature-sensitive brr6-1 allele have been shown to have defects in nucleoporin localization, mRNA metabolism and nuclear transport. Electron microscopy revealed that brr6-1 cells have gross NE abnormalities and proliferation of the ER. brr6-1 cells were hypersensitive to compounds that affect membrane biophysical properties and to …

Identification Of The [Fefe]-Hydrogenase Responsible For Hydrogen Generation In Thermoanaerobacterium Saccharolyticum And Demonstration Of Increased Ethanol Yield Via Hydrogenase Knockout, A. Joe Shaw, David A. Hogsett, Lee R. Lynd

Dartmouth Scholarship

Three putative hydrogenase enzyme systems in Thermoanaerobacterium saccharolyticum were investigated at the genetic, mRNA, enzymatic, and phenotypic levels. A four-gene operon containing two [FeFe]-hydrogenase genes, provisionally termed hfs (hydrogenase-Fe-S), was found to be the main enzymatic catalyst of hydrogen production. hfsB, perhaps the most interesting gene of the operon, contains an [FeFe]-hydrogenase and a PAS sensory domain and has several conserved homologues among clostridial saccharolytic, cellulolytic, and pathogenic bacteria. A second hydrogenase gene cluster, hyd, exhibited methyl viologen-linked hydrogenase enzymatic activity, but hyd gene knockouts did not influence the hydrogen yield of …

Spatially Uniform Relieff (Surf) For Computationally-Efficient Filtering Of Gene-Gene Interactions, Casey S. Greene, Nadia M. Penrod, Jeff Kiralis, Jason H. Moore

Dartmouth Scholarship

Genome-wide association studies are becoming the de facto standard in the genetic analysis of common human diseases. Given the complexity and robustness of biological networks such diseases are unlikely to be the result of single points of failure but instead likely arise from the joint failure of two or more interacting components. The hope in genome-wide screens is that these points of failure can be linked to single nucleotide polymorphisms (SNPs) which confer disease susceptibility. Detecting interacting variants that lead to disease in the absence of single-gene effects is difficult however, and methods to exhaustively analyze sets of these variants …

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 …

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 …

Microbial Nad Metabolism: Lessons From Comparative Genomics, Francesca Gazzaniga, Rebecca Stebbins, Sheila Z. Chang, Mark A. Mcpeek, Charles Brenner

Dartmouth Scholarship

NAD is a coenzyme for redox reactions and a substrate of NAD-consuming enzymes, including ADP-ribose transferases, Sir2-related protein lysine deacetylases, and bacterial DNA ligases. Microorganisms that synthesize NAD from as few as one to as many as five of the six identified biosynthetic precursors have been identified. De novo NAD synthesis from aspartate or tryptophan is neither universal nor strictly aerobic. Salvage NAD synthesis from nicotinamide, nicotinic acid, nicotinamide riboside, and nicotinic acid riboside occurs via modules of different genes. Nicotinamide salvage genes nadV and pncA, found in distinct bacteria, appear to have spread throughout the tree of life …

Mtorc1 Hyperactivity Inhibits Serum Deprivation-Induced Apoptosis Via Increased Hexokinase Ii And Glut1 Expression, Sustained Mcl-1 Expression, And Glycogen Synthase Kinase 3Β Inhibition, Prashanth T. Bhaskar, Veronique Nogueira, Krushna C. Patra, Sang-Min Jeon, Youngkyu Park, R. Brooks Robey, Nissim Hay

Dartmouth Scholarship

The current concept is that Tsc-deficient cells are sensitized to apoptosis due to the inhibition of Akt activity by the negative feedback mechanism induced by the hyperactive mTORC1. Unexpectedly, however, we found that Tsc1/2-deficient cells exhibit increased resistance to serum deprivation-induced apoptosis. mTORC1 hyperactivity contributes to the apoptotic resistance of serum-deprived Tsc1/2-deficient cells in part by increasing the growth factor-independent expression of hexokinase II (HKII) and GLUT1. mTORC1-mediated increase in hypoxia-inducible factor 1α (HIF1α) abundance, which occurs in the absence of serum in normoxic Tsc2-deficient cells, contributes to these changes. Increased HIF1α abundance in these cells is attributed to both …

Manipulating Testosterone To Assess Links Between Behavior, Morphology, And Performance In The Brown Anole Anolis Sagrei, Robert M. Cox, Derek S. Stenquist, Justin P. Henningsen, Ryan Calsbeek

Dartmouth Scholarship

Survival and reproductive success are determined by the complex interplay between behavior, physiology, morphology, and performance. When optimal trait combinations along these various phenotypic axes differ between sexes or across seasons, regulatory mechanisms such as sex steroids can often facilitate sex‐specific and/or seasonal trait expression. In this study, we used surgical castration and replacement of exogenous testosterone in adult male brown anoles (Anolis sagrei) to simultaneously examine the effects of testosterone on a suite of morphological (dewlap area, body size), physiological (immune function), behavioral (dewlap, head bob, and push‐up displays), and performance (stamina, sprint speed, bite force) traits. …

Insulin Stimulates The Phosphorylation Of The Exocyst Protein Sec8 In Adipocytes, Patrick D. Lyons, Grantley R. Peck, Arminja N. Kettenbach, Scott A. Gerber, Liya Roudaia, Gustav E. Lienhard

Dartmouth Scholarship

The signal transduction pathway leading from the insulin receptor to stimulate the fusion of vesicles containing the glucose transporter GLUT4 with the plasma membrane in adipocytes and muscle cells is not completely understood. Current evidence suggests that in addition to the Rab GTPase-activating protein AS160, at least one other substrate of Akt (also called protein kinase B), which is as yet unidentified, is required. Sec8 is a component of the exocyst complex that has been previously implicated in GLUT4 trafficking. In the present study, we report that insulin stimulates the phosphorylation of Sec8 on Ser-32 in 3T3-L1 adipocytes. On the …

Chronic Exposure To Arsenic In The Drinking Water Alters The Expression Of Immune Response Genes In Mouse Lung, Courtney D. Kozul, Thomas H. Hampton, Jennifer C. Davey, Julie A. Gosse, Athena P. Nomikos, Phillip L. Eisenhauer, Daniel J. Weiss, Jessica E. Thorpe, Michael A. Ihnat, Joshua W. Hamilton

Dartmouth Scholarship

Background:

Chronic exposure to drinking water arsenic is a significant worldwide environmental health concern. Exposure to As is associated with an increased risk of lung disease, which may make it a unique toxicant, because lung toxicity is usually associated with inhalation rather than ingestion.

Objectives:

The goal of this study was to examine mRNA and protein expression changes in the lungs of mice exposed chronically to environmentally relevant concentrations of As in the food or drinking water, specifically examining the hypothesis that As may preferentially affect gene and protein expression related to immune function as part of its mechanism of …

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 …

Disruption Of Osysl15 Leads To Iron Inefficiency In Rice Plants, Sichul Lee, Jeff C. Chiecko, Sun A. Kim, Elsbeth L. Walker, Youngsook Lee, Mary Lou Guerinot, Gyhheung An

Dartmouth Scholarship

Uptake and translocation of metal nutrients are essential processes for plant growth. Graminaceous species release phytosiderophores that bind to Fe³⁺; these complexes are then transported across the plasma membrane. We have characterized OsYSL15, one of the rice (Oryza sativa) YS1-like (YSL) genes that are strongly induced by iron (Fe) deficiency. The OsYSL15 promoter fusion to β-glucuronidase showed that it was expressed in all root tissues when Fe was limited. In low-Fe leaves, the promoter became active in all tissues except epidermal cells. This activity was also detected in flowers and seeds. The OsYSL15:green …

Minimum Criteria For Dna Damage-Induced Phase Advances In Circadian Rhythms, Christian I. Hong, Judit Zámborszky, Attila Csikász-Nagy

Dartmouth Scholarship

Robust oscillatory behaviors are common features of circadian and cell cycle rhythms. These cyclic processes, however, behave distinctively in terms of their periods and phases in response to external influences such as light, temperature, nutrients, etc. Nevertheless, several links have been found between these two oscillators. Cell division cycles gated by the circadian clock have been observed since the late 1950s. On the other hand, ionizing radiation (IR) treatments cause cells to undergo a DNA damage response, which leads to phase shifts (mostly advances) in circadian rhythms. Circadian gating of the cell cycle can be attributed to the cell cycle …

The Rise Of The Classical Gene: A Review Of In Pursuit Of The Gene: From Darwin To Dna, Michael Dietrich

Dartmouth Scholarship

Review of The rise of the classical gene: a review of In Pursuit of the Gene: From Darwin to DNA by James Schwartz, 2008.

Correcting The Site Frequency Spectrum For Divergence-Based Ascertainment, Andrew D. Kern

Dartmouth Scholarship

Comparative genomics based on sequenced referenced genomes is essential to hypothesis generation and testing within population genetics. However, selection of candidate regions for further study on the basis of elevated or depressed divergence between species leads to a divergence-based ascertainment bias in the site frequency spectrum within selected candidate loci. Here, a method to correct this problem is developed that obtains maximum-likelihood estimates of the unascertained allele frequency distribution using numerical optimization. I show how divergence-based ascertainment may mimic the effects of natural selection and offer correction formulae for performing proper estimation into the strength of selection in candidate regions …

The C. Elegans Snail Homolog Ces-1 Can Activate Gene Expression In Vivo And Share Targets With Bhlh Transcription Factors, John S. Reece-Hoyes, Bart Deplancke, M. Inmaculada Barrasa, Julia Hatzold, Ryan B. Smit, H Efsun Arda, Patricia A. Pope, Jeb Gaudet, Barbara Conradt, Albertga J.M. Walhout

Dartmouth Scholarship

Snail-type transcription factors (TFs) are found in numerous metazoan organisms and function in a plethora of cellular and developmental processes including mesoderm and neuronal development, apoptosis and cancer. So far, Snail-type TFs are exclusively known as transcriptional repressors. They repress gene expression by recruiting transcriptional co-repressors and/or by preventing DNA binding of activators from the basic helix-loop-helix (bHLH) family of TFs to CAGGTG E-box sequences. Here we report that the Caenorhabditis elegans Snail-type TF CES-1 can activate transcription in vivo. Moreover, we provide results that suggest that CES-1 can share its binding site with bHLH TFs, in different tissues, …

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 …

Regulation Of The Mazef Toxin-Antitoxin Module In Staphylococcus Aureus And Its Impact On Sigb Expression, Niles P. Donegan, Ambrose L. Cheung

Dartmouth Scholarship

In Staphylococcus aureus, the sigB operon codes for the alternative sigma factor σ^Band its regulators that enable the bacteria to rapidly respond to environmental stresses via redirection of transcriptional priorities. However, a full model of σ^Bregulation in S. aureus has not yet emerged. Earlier data has suggested that mazEF, a toxin-antitoxin (TA) module immediately upstream of the sigB operon, was transcribed with the sigB operon. Here we demonstrate that the promoter P_mazE upstream of mazEF is essential for full σ^B activity and that instead of utilizing autorepression typical of TA systems, sigB …