Digital Commons Network^™

Intrinsic And Innate Defenses Of Neurons: Détente With The Herpesviruses, Lynn Enquist, David A. Leib

Dartmouth Scholarship

Neuroinvasive herpesviruses have evolved to efficiently infect and establish latency in neurons. The nervous system has limited capability to regenerate, so immune responses therein are carefully regulated to be nondestructive, with dependence on atypical intrinsic and innate defenses. In this article we review studies of some of these noncanonical defense pathways and how herpesvirus gene products counter them, highlighting the contributions that primary neuronal in vitro models have made to our understanding of this field.

A Longitudinal Cline Characterizes The Genetic Structure Of Human Populations In The Tibetan Plateau, Choongwon Jeong, Benjamin M. Peter, Buddha Basnyat, Maniraj Neupane, Geoff Childs, Sienna Craig, John Novembre, Anna Di Rienzo

Dartmouth Scholarship

Indigenous populations of the Tibetan plateau have attracted much attention for their good performance at extreme high altitude. Most genetic studies of Tibetan adaptations have used genetic variation data at the genome scale, while genetic inferences about their de- mography and population structure are largely based on uniparental markers. To provide genome-wide information on population structure, we analyzed new and published data of 338 individuals from indigenous populations across the plateau in conjunction with world- wide genetic variation data. We found a clear signal of genetic stratification across the east- west axis within Tibetan samples. Samples from more eastern locations …

Inferring Condition-Specific Targets Of Human Tf-Tf Complexes Using Chip-Seq Data, Chia-Chun Yang, Min-Hsuan Chen, Sheng-Yi Lin, Erik H. Andrews, Chao Cheng, Jeremy J.W Chen

Dartmouth Scholarship

Background:

Transcription factors (TFs) often interact with one another to form TF complexes that bind DNA and regulate gene expression. Many databases are created to describe known TF complexes identified by either mammalian two-hybrid experiments or data mining. Lately, a wealth of ChIP-seq data on human TFs under different experiment conditions are available, making it possible to investigate condition-specific (cell type and/or physiologic state) TF complexes and their target genes.

Results:

Here, we developed a systematic pipeline to infer Condition-Specific Targets of human TF-TF complexes (called the CST pipeline) by integrating ChIP-seq data and TF motifs. In total, we predicted …

Calcium-Mediated Actin Reset (Caar) Mediates Acute Cell Adaptations, Pauline Wales, Christian Schuberth, Roland Aufschnaiter, Johannes Fels, Ireth Garcia-Aguilar, Annette Janning, Christopher D. Dlugos, Marco Schaefer-Herte, Christoph Klingner, Mike Waelte, Julian Kuhlmann, Ekaterina Menis, Hockaday Kang Hockaday Kang, Kerstin C. Maier, Wenya Hou, Antonella Russo, Henry N. Higgs

Dartmouth Scholarship

Actin has well established functions in cellular morphogenesis. However, it is not well understood how the various actin assemblies in a cell are kept in a dynamic equilibrium, in particular when cells have to respond to acute signals. Here, we characterize a rapid and transient actin reset in response to increased intracellular calcium levels. Within seconds of calcium influx, the formin INF2 stimulates filament polymerization at the endoplasmic reticulum (ER), while cortical actin is disassembled. The reaction is then reversed within a few minutes. This Calcium-mediated actin reset (CaAR) occurs in a wide range of mammalian cell types and in …

Circnet: A Database Of Circular Rnas Derived From Transcriptome Sequencing Data, Yu-Chen Liu, Jian-Rong Li, Chuan-Hu Sun, Erik Andrews, Rou-Fang Chao, Feng-Mao Lin, Shun-Long Weng, Sheng-Da Hsu, Chieh-Chen Huang, Chao Cheng, Chun-Chi Liu, Hsien-Da Huang

Dartmouth Scholarship

Circular RNAs (circRNAs) represent a new type of regulatory noncoding RNA that only recently has been identified and cataloged. Emerging evidence indicates that circRNAs exert a new layer of post-transcriptional regulation of gene expression. In this study, we utilized transcriptome sequencing datasets to systematically identify the expression of circRNAs (including known and newly identified ones by our pipeline) in 464 RNA-seq samples, and then constructed the CircNet database (http://circnet.mbc.nctu.edu.tw/) that provides the following resources: (i) novel circRNAs, (ii) integrated miRNA-target networks, (iii) expression profiles of circRNA isoforms, (iv) genomic annotations of circRNA isoforms (e.g. 282 948 exon positions), …

Micron-Scale Plasma Membrane Curvature Is Recognized By The Septin Cytoskeleton, Andrew A. Bridges, Maximilian S. Jentzsch, Patrick W. Oakes, Patricia Occhipinti, Amy S. Gladfelter

Dartmouth Scholarship

Cells change shape in response to diverse environmental and developmental conditions, creating topologies with micron-scale features. Although individual proteins can sense nanometer-scale membrane curvature, it is unclear if a cell could also use nanometer-scale components to sense micron-scale contours, such as the cytokinetic furrow and base of neuronal branches. Septins are filament-forming proteins that serve as signaling platforms and are frequently associated with areas of the plasma membrane where there is micron-scale curvature, including the cytokinetic furrow and the base of cell protrusions. We report here that fungal and human septins are able to distinguish between different degrees of micron-scale …

Where Are You Looking? Pseudogaze In Afterimages, Daw-An Wu, Patrick Cavanagh

Dartmouth Scholarship

How do we know where we are looking? A frequent assumption is that the subjective experience of our direction of gaze is assigned to the location in the world that falls on our fovea. However, we find that observers can shift their subjective direction of gaze among different nonfoveal points in an afterimage. Observers were asked to look directly at different corners of a diamond-shaped afterimage. When the requested corner was 3.5° in the periphery, the observer often reported that the image moved away in the direction of the attempted gaze shift. However, when the corner was at 1.75° eccentricity, …

Comprehensive Genetic Testing Identifies Targetable Genomic Alterations In Most Patients With Non-Small Cell Lung Cancer, Specifically Adenocarcinoma, Single Institute Investigation, Janani Vigneswaran, Yi-Hung Carol Tan, Septimiu D. Murgu, Brian M. Won, Kathryn Alexa Patton, Victoria M. Villaflor, Philip C. Hoffman, Thomas Hensing, D. Kyle Hogarth, Renuka Malik

Dartmouth Scholarship

This study reviews extensive genetic analysis in advanced non-small cell lung cancer (NSCLC) patients in order to: describe how targetable mutation genes interrelate with the genes identified as variants of unknown significance; assess the percentage of patients with a potentially targetable genetic alterations; evaluate the percentage of patients who had concurrent alterations, previously considered to be mutually exclusive; and characterize the molecular subset of KRAS. Thoracic Oncology Research Program Databases at the University of Chicago provided patient demographics, pathology, and results of genetic testing. 364 patients including 289 adenocarcinoma underwent genotype testing by various platforms such as FoundationOne, Caris Molecular …

Genomic Characterization Of Patient-Derived Xenograft Models Established From Fine Needle Aspirate Biopsies Of A Primary Pancreatic Ductal Adenocarcinoma And From Patient-Matched Metastatic Sites, Robert J. Allaway, Dawn A. Fischer, Francine B. De Abreu, Timothy B. Gardner, Stuart R. Gordon, Richard J. Barth, Thomas A. Colacchio, Matthew Wood, Balint Z. Kacsoh, Stephanie J. Bouley

Dartmouth Scholarship

N-of-1 trials target actionable mutations, yet such approaches do not test genomically-informed therapies in patient tumor models prior to patient treatment. To address this, we developed patient-derived xenograft (PDX) models from fine needle aspiration (FNA) biopsies (FNA-PDX) obtained from primary pancreatic ductal adenocarcinoma (PDAC) at the time of diagnosis. Here, we characterize PDX models established from one primary and two metastatic sites of one patient. We identified an activating KRAS G12R mutation among other mutations in these models. In explant cells derived from these PDX tumor models with a KRAS G12R mutation, treatment with inhibitors of CDKs (including CDK9) reduced …

Modulating Foveal Representation Can Influence Visual Discrimination In The Periphery, Qing Yu, Won Mok Shim

Dartmouth Scholarship

A previous study by Williams et al. (2008) provided evidence for a novel form of feedback in the visual system, whereby peripheral information is contained in foveal retinotopic cortex. Beyond its possible implication for peripheral object recognition, few studies have examined the effect of a direct behavioral manipulation of the foveal feedback representation. To address this question, we measured participants' peripheral visual discrimination performance while modulating their foveal representation in a series of psychophysical experiments. On each trial, participants discriminated the identities of briefly presented novel, three-dimensional objects or the orientations of gratings in a peripheral location while fixating at …

A Targeted Genetic Association Study Of Epithelial Ovarian Cancer Susceptibility, Madalene Earp, Stacey J. Winham, Nicholas Larson, Jennifer B. Permuth, Hugues Sicotte, Jeremy Chien, Hoda Anton-Culver, Elisa V. Bandera, Andrew Berchuck, Linda S. Cook, Daniel Cramer, Jennifer A. Doherty

Dartmouth Scholarship

BACKGROUND:

Genome-wide association studies have identified several common susceptibility alleles for epithelial ovarian cancer (EOC). To further understand EOC susceptibility, we examined previously ungenotyped candidate variants, including uncommon variants and those residing within known susceptibility loci.

RESULTS:

At nine of eleven previously published EOC susceptibility regions (2q31, 3q25, 5p15, 8q21, 8q24, 10p12, 17q12, 17q21.31, and 19p13), novel variants were identified that were more strongly associated with risk than previously reported variants. Beyond known susceptibility regions, no variants were found to be associated with EOC risk at genome-wide statistical significance (p <5x10(-8)), nor were any significant after Bonferroni correction for 17,000 variants (p< 3x10-6).

METHODS:

A customized genotyping array was used to assess over …

Gender Representation In The Vision Sciences: A Longitudinal Study, Emily A. Cooper, Ana Radonjic

Dartmouth Scholarship

Understanding the current status and historical trends of gender representation within a research field is an important component of fostering a diverse and inclusive scientific community. Here, we report on the gender representation of a large sample of the vision science research community—the attendees of the Annual Meeting of the Vision Sciences Society (VSS). Our analysis shows that the majority of scientists at all career levels in our sample are male. This imbalance is most pronounced for the senior scientists, whereas predoctoral students are nearly balanced between the genders. Historically, the gender imbalance was larger than it is at present, …

Leveraging Global Gene Expression Patterns To Predict Expression Of Unmeasured Genes, James Rudd, René A. Zelaya, Eugene Demidenko, Ellen L. Goode, Casey S. Greene S. Greene, Jennifer A. Doherty

Dartmouth Scholarship

BackgroundLarge collections of paraffin-embedded tissue represent a rich resource to test hypotheses based on gene expression patterns; however, measurement of genome-wide expression is cost-prohibitive on a large scale. Using the known expression correlation structure within a given disease type (in this case, high grade serous ovarian cancer; HGSC), we sought to identify reduced sets of directly measured (DM) genes which could accurately predict the expression of a maximized number of unmeasured genes.

Actin Filaments Target The Oligomeric Maturation Of The Dynamin Gtpase Drp1 To Mitochondrial Fission Sites, Wei-Ke Ji, Anna L. Hatch, Ronald A. Merrill, Stefan Strack, Henry N. Higgs

Dartmouth Scholarship

While the dynamin GTPase Drp1 plays a critical role during mitochondrial fission, mechanisms controlling its recruitment to fission sites are unclear. A current assumption is that cytosolic Drp1 is recruited directly to fission sites immediately prior to fission. Using live-cell microscopy, we find evidence for a different model, progressive maturation of Drp1 oligomers on mitochondria through incorporation of smaller mitochondrially-bound Drp1 units. Maturation of a stable Drp1 oligomer does not forcibly lead to fission. Drp1 oligomers also translocate directionally along mitochondria. Ionomycin, a calcium ionophore, causes rapid mitochondrial accumulation of actin filaments followed by Drp1 accumulation at the fission site, …

A Forward Genetic Screen Reveals Novel Independent Regulators Of Ulbp1, An Activating Ligand For Natural Killer Cells, Benjamin G Gowen, Bryan Chim, Caleb D. Marceau, Trever T Greene, Patrick Burr, Jeanmarie R. Gonzalez, Charles Hesser, Peter A. Dietzen, Teal Russell, Alexandre Iannello, Laurent Coscoy, Charles L. Sentman

Dartmouth Scholarship

Recognition and elimination of tumor cells by the immune system is crucial for limiting tumor growth. Natural killer (NK) cells become activated when the receptor NKG2D is engaged by ligands that are frequently upregulated in primary tumors and on cancer cell lines. However, the molecular mechanisms driving NKG2D ligand expression on tumor cells are not well defined. Using a forward genetic screen in a tumor-derived human cell line, we identified several novel factors supporting expression of the NKG2D ligand ULBP1. Our results show stepwise contributions of independent pathways working at multiple stages of ULBP1 biogenesis. Deeper investigation of selected hits …

Cell Type–Dependent Mechanisms For Formin-Mediated Assembly Of Filopodia, Lorna E. Young, Ernest G. Heimsath, Henry N. Higgs

Dartmouth Scholarship

Filopodia are finger-like protrusions from the plasma membrane and are of fundamental importance to cellular physiology, but the mechanisms governing their assembly are still in question. One model, called convergent elongation, proposes that filopodia arise from Arp2/3 complex-nucleated dendritic actin networks, with factors such as formins elongating these filaments into filopodia. We test this model using constitutively active constructs of two formins, FMNL3 and mDia2. Surprisingly, filopodial assembly requirements differ between suspension and adherent cells. In suspension cells, Arp2/3 complex is required for filopodial assembly through either formin. In contrast, a subset of filopodia remains after Arp2/3 complex inhibition in …

Genetics Of Plasminogen Activator Inhibitor-1 (Pai-1) In A Ghanaian Population, Marquitta J. White, Nuri M. Kodaman, Reed H. Harder, Folkert W. Asselbergs, Douglas E. Vaughan, Nancy J. Brown, Jason H. Moore, Scott M. Williams

Dartmouth Scholarship

Plasminogen activator inhibitor 1 (PAI-1), a major modulator of the fibrinolytic system, is an important factor in cardiovascular disease (CVD) susceptibility and severity. PAI-1 is highly heritable, but the few genes associated with it explain only a small portion of its variation. Studies of PAI-1 typically employ linear regression to estimate the effects of genetic variants on PAI-1 levels, but PAI-1 is not normally distributed, even after transformation. Therefore, alternative statistical methods may provide greater power to identify important genetic variants. Additionally, most genetic studies of PAI-1 have been performed on populations of European descent, limiting the generalizability of their …

A Mitochondria-Anchored Isoform Of The Actin-Nucleating Spire Protein Regulates Mitochondrial Division, Uri Manor, Sadie Bartholomew, Gonen Golani, Eric Christenson, Michael Kozlov, Henry Higgs, James Spudich, Jennifer Lippincott-Schwartz

Dartmouth Scholarship

Mitochondrial division, essential for survival in mammals, is enhanced by an inter-organellar process involving ER tubules encircling and constricting mitochondria. The force for constriction is thought to involve actin polymerization by the ER-anchored isoform of the formin protein inverted formin 2 (INF2). Unknown is the mechanism triggering INF2-mediated actin polymerization at ER-mitochondria intersections. We show that a novel isoform of the formin-binding, actin-nucleating protein Spire, Spire1C, localizes to mitochondria and directly links mitochondria to the actin cytoskeleton and the ER. Spire1C binds INF2 and promotes actin assembly on mitochondrial surfaces. Disrupting either Spire1C actin- or formin-binding activities reduces mitochondrial constriction …

Genome-Wide Meta-Analysis In Alopecia Areata Resolves Hla Associations And Reveals Two New Susceptibility Loci, Regina C. Betz, Lynn Petukhova, Stephan Ripke, Hailiang Huang, Androniki Menelaou, Silke Redeler, Tim Becker, Stefanie Heilmann, Tarek Yamany, Madeleine Duvic, Maria Hordinsky, David Norris, Vera H. Price, Julian Mackay-Wiggan, Annemieke De Jong, Gina M. Destefano, Susanne Moebus, Markus Böhm, Ulrike Blume-Peytavi, Hans Wolff, Gerhard Lutz, Roland Kruse, Li Bian, Christopher I. Amos

Dartmouth Scholarship

Alopecia areata (AA) is a prevalent autoimmune disease with ten known susceptibility loci. Here we perform the first meta-analysis in AA by combining data from two genome-wide association studies (GWAS), and replication with supplemented ImmunoChip data for a total of 3,253 cases and 7,543 controls. The strongest region of association is the MHC, where we fine-map 4 independent effects, all implicating HLA-DR as a key etiologic driver. Outside the MHC, we identify two novel loci that exceed statistical significance, containing ACOXL/BCL2L11(BIM) (2q13); GARP (LRRC32) (11q13.5), as well as a third nominally significant region SH2B3(LNK)/ ATXN2 (12q24.12). Candidate susceptibility gene expression …

Placental Dna Methylation Related To Both Infant Toenail Mercury And Adverse Neurobehavioral Outcomes, Jennifer Zeynab Joukhadar Maccani, Devin C. Koestler, Barry Lester, E Andres Houseman, David A. Armstrong, Karl T. Kelsey, Carmen J. Marsit

Dartmouth Scholarship

Background:

Prenatal mercury (Hg) exposure is associated with adverse child neurobehavioral outcomes. Because Hg can interfere with placental functioning and cross the placenta to target the fetal brain, prenatal Hg exposure can inhibit fetal growth and development directly and indirectly.

Objectives:

We examined potential associations between prenatal Hg exposure assessed through infant toenail Hg, placental DNA methylation changes, and newborn neurobehavioral outcomes.

Methods:

The methylation status of > 485,000 CpG loci was interrogated in 192 placental samples using Illumina’s Infinium HumanMethylation450 BeadArray. Hg concentrations were analyzed in toenail clippings from a subset of 41 infants; neurobehavior was assessed using the NICU …

Iarc Monographs: 40 Years Of Evaluating Carcinogenic Hazards To Humans, Neil E. Pearce, Aaron Blair, Paolo Vineis, Wolfgang Ahrens, Aage Andersom, Josep M. Anto, Bruce K. Armstrong, Andrea A. Baccarelli, Frederick A. Beland, Amy Berrington, Pier Alberto Bertazzi, Linda S. Birnbaum, Ross C. Brownson, John R. Bucher, Kenneth P. Cantor, Elisabeth Cardis, John W. Cherrie, David C. Christiani, Pierluigi Cocco, David Coggon, Pietro Comba, Paul A. Demers, John M. Dement, Jeroen Douwes, Ellen A. Eisen, Lawrence S. Engel, Richard A. Fenske, Lora E. Fleming, Tony Fletcher, Elizabeth Fontham, Francesco Forastiere, Rainer Frentzel-Beyme, Lin Fritschi, Michel Gerin, Marcel Goldberg, Philippe Grandjean, Tom K. Grimsrud, Per Gustavsson, Andy Haines, Patricia Hartge, Johnni Hansen, Michael Hauptmann, Dick Heederik, Kari Hemminki, Denis Hemon, Irva Hertz-Picciotto, Jane A. Hoppin, James Huff, Bengt Jarvholm, Daehee Kang, Margaret R. Karagas

Dartmouth Scholarship

Background: Recently, the International Agency for Research on Cancer (IARC) Programme for the Evaluation of Carcinogenic Risks to Humans has been criticized for several of its evaluations, and also for the approach used to perform these evaluations. Some critics have claimed that failures of IARC Working Groups to recognize study weaknesses and biases of Working Group members have led to inappropriate classification of a number of agents as carcinogenic to humans.

Objectives: The authors of this Commentary are scientists from various disciplines relevant to the identification and hazard evaluation of human carcinogens. We examined criticisms of the IARC classification process …

Spatial Heterogeneity, Host Movement And Mosquito-Borne Disease Transmission, Miguel A. Acevedo, Olivia Prosper, Kenneth Lopiano, Nick Ruktanonchai, T. Trevor Caughlin, Maia Martcheva, Craig W. Osenberg, David L. Smith

Dartmouth Scholarship

Mosquito-borne diseases are a global health priority disproportionately affecting low-income populations in tropical and sub-tropical countries. These pathogens live in mosquitoes and hosts that interact in spatially heterogeneous environments where hosts move between regions of varying transmission intensity. Although there is increasing interest in the implications of spatial processes for mosquito-borne disease dynamics, most of our understanding derives from models that assume spatially homogeneous transmission. Spatial variation in contact rates can influence transmission and the risk of epidemics, yet the interaction between spatial heterogeneity and movement of hosts remains relatively unexplored. Here we explore, analytically and through numerical simulations, how …

Cytoskeletal Dynamics: A View From The Membrane, Magdalena Bezanilla, Amy S. Gladfelter, David R. Kovar, Wei-Lih Lee

Dartmouth Scholarship

Many aspects of cytoskeletal assembly and dynamics can be recapitulated in vitro; yet, how the cytoskeleton integrates signals in vivo across cellular membranes is far less understood. Recent work has demonstrated that the membrane alone, or through membrane-associated proteins, can effect dynamic changes to the cytoskeleton, thereby impacting cell physiology. Having identified mechanistic links between membranes and the actin, microtubule, and septin cytoskeletons, these studies highlight the membrane’s central role in coordinating these cytoskeletal systems to carry out essential processes, such as endocytosis, spindle positioning, and cellular compartmentalization.

Loregic: A Method To Characterize The Cooperative Logic Of Regulatory Factors, Daifeng Wang, Koon-Kiu Yan, Cristina Sisu, Chao Cheng, Joel Rozowsky, William Meyerson, Mark B. Gerstein

Dartmouth Scholarship

The topology of the gene-regulatory network has been extensively analyzed. Now, given the large amount of available functional genomic data, it is possible to go beyond this and systematically study regulatory circuits in terms of logic elements. To this end, we present Loregic, a computational method integrating gene expression and regulatory network data, to characterize the cooperativity of regulatory factors. Loregic uses all 16 possible two-input-one-output logic gates (e.g. AND or XOR) to describe triplets of two factors regulating a common target. We attempt to find the gate that best matches each triplet’s observed gene expression pattern across many conditions. …

Machine Learning Methods Enable Predictive Modeling Of Antibody Feature:Function Relationships In Rv144 Vaccinees, Ickwon Choi, Amy W. Chung, Todd J. Suscovich, Supachai Rerks-Ngarm, Punnee Pitisuttithum, Sorachai Nitayapha, Jaranit Kaewkungwal, Robert J. O'Connell, Donald Francis, Merlin L. Robb, Nelson L. Michael, Jerome H. Kim, Galit Alter, Margaret E. Ackerman, Chris Bailey-Kellogg

Dartmouth Scholarship

The adaptive immune response to vaccination or infection can lead to the production of specific antibodies to neutralize the pathogen or recruit innate immune effector cells for help. The non-neutralizing role of antibodies in stimulating effector cell responses may have been a key mechanism of the protection observed in the RV144 HIV vaccine trial. In an extensive investigation of a rich set of data collected from RV144 vaccine recipients, we here employ machine learning methods to identify and model associations between antibody features (IgG subclass and antigen specificity) and effector function activities (antibody dependent cellular phagocytosis, cellular cytotoxicity, and cytokine …

An Approach For Determining And Measuring Network Hierarchy Applied To Comparing The Phosphorylome And The Regulome, Chao Cheng, Erik Andrews, Koon-Kiu Yan, Matthew Ung, Daifeng Wang, Mark Gerstein

Dartmouth Scholarship

Many biological networks naturally form a hierarchy with a preponderance of downward information flow. In this study, we define a score to quantify the degree of hierarchy in a network and develop a simulated-annealing algorithm to maximize the hierarchical score globally over a network. We apply our algorithm to determine the hierarchical structure of the phosphorylome in detail and investigate the correlation between its hierarchy and kinase properties. We also compare it to the regulatory network, finding that the phosphorylome is more hierarchical than the regulome.

Spectral Gene Set Enrichment (Sgse), H Robert Frost, Zhigang Li, Jason H. Moore

Dartmouth Scholarship

Gene set testing is typically performed in a supervised context to quantify the association between groups of genes and a clinical phenotype. In many cases, however, a gene set-based interpretation of genomic data is desired in the absence of a phenotype variable. Although methods exist for unsupervised gene set testing, they predominantly compute enrichment relative to clusters of the genomic variables with performance strongly dependent on the clustering algorithm and number of clusters. We propose a novel method, spectral gene set enrichment (SGSE), for unsupervised competitive testing of the association between gene sets and empirical data sources. SGSE first computes …

Identification Of A Family Of Fatty Acid-Speciated Sonic Hedgehog Proteins, Whose Members Display Differential Biological Properties, Jun Long, Robert Tokhunts, William M. Old, Stephane Houel, Jezabel Rodgriguez-Blanco, Samer Singh, Neal Schilling, Anthony J. Capobianco, Natalie G. Ahn, David J. Robbins

Dartmouth Scholarship

Hedgehog (HH) proteins are proteolytically processed into a biologically active form that is covalently modified by cholesterol and palmitate. However, most studies of HH biogenesis have characterized protein from cells in which HH is overexpressed. We purified Sonic Hedgehog (SHH) from cells expressing physiologically relevant levels and showed that it was more potent than SHH isolated from overexpressing cells. Furthermore, the SHH in our preparations was modified with a diverse spectrum of fatty acids on its amino termini, and this spectrum of fatty acids varied dramatically depending on the growth conditions of the cells. The fatty acid composition of SHH …

Belief About Nicotine Selectively Modulates Value And Reward Prediction Error Signals In Smokers, Xiaosi Gu, Terry Lohrenz, Ramiro Salas, Philip R. Baldwin, Alireza Soltani

Dartmouth Scholarship

Little is known about how prior beliefs impact biophysically described processes in the presence of neuroactive drugs, which presents a profound challenge to the understanding of the mechanisms and treatments of addiction. We engineered smokers' prior beliefs about the presence of nicotine in a cigarette smoked before a functional magnetic resonance imaging session where subjects carried out a sequential choice task. Using a model-based approach, we show that smokers' beliefs about nicotine specifically modulated learning signals (value and reward prediction error) defined by a computational model of mesolimbic dopamine systems. Belief of "no nicotine in cigarette" (compared with "nicotine in …

Modeling Neurovascular Coupling From Clustered Parameter Sets For Multimodal Eeg-Nirs, M. Tanveer Talukdar, H. Robert Frost, Solomon G. G. Diamond

Dartmouth Scholarship

Despite significant improvements in neuroimaging technologies and analysis methods, the fundamental relationship between local changes in cerebral hemodynamics and the underlying neural activity remains largely unknown. In this study, a data driven approach is proposed for modeling this neurovascular coupling relationship from simultaneously acquired electroencephalographic (EEG) and near-infrared spectroscopic (NIRS) data. The approach uses gamma transfer functions to map EEG spectral envelopes that reflect time-varying power variations in neural rhythms to hemodynamics measured with NIRS during median nerve stimulation. The approach is evaluated first with simulated EEG-NIRS data and then by applying the method to experimental EEG-NIRS data measured from …