Digital Commons Network^™

Expression Of The Intestinal Biomarkers Guanylyl Cyclase C And Cdx2 In Poorly Differentiated Colorectal Carcinomas., Brody Winn, Rosemarie Tavares, Andres Matoso, Lelia Noble, Jacqueline Fanion, Scott A Waldman, Murray B Resnick

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Guanylyl cyclase C, a receptor for bacterial diarrheagenic enterotoxins, is expressed selectively by intestinal epithelium and is an endogenous downstream target of CDX2. The expression of Guanylyl cyclase C is preserved throughout the adenoma/carcinoma sequence in the colorectum. Detection of Guanylyl cyclase C expression by reverse transcriptase-polymerase chain reaction is currently being validated as a technique to identify occult lymph node metastases in patients with colorectal cancer and for circulating cells in the blood for postoperative surveillance. Although Guanylyl cyclase C is widely expressed by well-differentiated colorectal cancer, its expression in poorly differentiated colorectal cancer has not been evaluated. A …

Dopamine D1 Receptor-Mediated Nmda Receptor Insertion Depends On Fyn But Not Src Kinase Pathway In Prefrontal Cortical Neurons, Jian-Li Hu, Gang Liu, Yan-Chun Li, Wen-Jun Gao, Yueqiao Huang

PCOM Scholarly Works

Background. Interactions between dopamine and glutamate in the prefrontal cortex are essential for cognitive functions such as working memory. Modulation of N-methyl-D-aspartic acid (NMDA) receptor functions by dopamine D1 receptor is believed to play a critical role in these functions. The aim of the work reported here is to explore the signaling pathway underlying D1 receptor-mediated trafficking of NMDA receptors in cultured rat prefrontal cortical neurons. Results. Activation of D1 receptor by selective agonist SKF-81297 significantly increased the expression of NR2B subunits. This effect was completely blocked by small interfering RNA knockdown of Fyn, but not Src. Under control conditions, …

The Relationship Between Mosquito Abundance And Rice Field Density In The Republic Of Korea, Erin E. Richards, Penny Masuoka, David Brett-Major, Matthew Smith, Terry A. Klein, Heung Chul Kim, Assaf Anyamba, John Grieco

Journal Articles: Epidemiology

BACKGROUND: Japanese encephalitis virus (JEV), the causative agent of Japanese encephalitis (JE), is endemic to the Republic of Korea (ROK) where unvaccinated United States (U.S.) military Service members, civilians and family members are stationed. The primary vector of the JEV in the ROK is Culex tritaeniorhynchus. The ecological relationship between Culex spp. and rice fields has been studied extensively; rice fields have been shown to increase the prevalence of Cx. tritaeniorhynchus. This research was conducted to determine if the quantification of rice field land cover surrounding U.S. military installations in the ROK should be used as a parameter in a …

Differential Gene Expression Profile Of Retinoblastoma Compared To Normal Retina., Arupa Ganguly, Carol L Shields

Wills Eye Hospital Papers

PURPOSE: The retinoblastoma gene (RB1) is a tumor suppressor gene that was first discovered in a rare ocular pediatric tumor called retinoblastoma (RB). The RB1 gene is essential for normal progression through the cell cycle and exerts part of its function through the family of transcription factors (E2F) and many other intermediaries. In the absence of normal RB1, genomic instability and chromosomal aberrations accumulate, leading to tumor initiation, progression, and ultimately metastasis. The purpose of this report was to identify the molecular pathways that are deregulated in retinoblastoma.

METHODS: We compared gene expression signatures of matched normal retinal tissue and …

Female Humpback Whale (Megaptera Novaeangliae) Reproductive Class And Male-Female Interactions During The Breeding Season, Meagan E. Jones

Antioch University Dissertations & Theses

This study examined whether female reproductive class (i.e., presence or absence of a calf) in humpback whales (Megaptera novaeangliae) affects female behavior and male-female interactions on the Hawaiian breeding grounds. From 2003-2008, 295 female-calf groups (with or without a male escort) and 256 female no-calf groups (with a male) were observed. Forty-one female no-calf groups were confirmed male-female pairs by genetic sexing or photo-identification. Focal follows of 36 male-female pairs and 50 female-calf groups (29 escorted and 21 unescorted female-calf groups) were analyzed for time budget and movement estimates. Relative fluke size (fluke photogrammetry, n=30) and sighting histories …

Does Diabetes Mellitus Influence Pathologic Complete Response And Tumor Downstaging After Neoadjuvant Chemoradiation For Esophageal And Gastroesophageal Cancer? A Two-Institution Report., Shayna L. Showalter, Ernest L. Rosato, P Rani Anne, Walter Scott, Edith Mitchell, Adam C. Berger

Department of Surgery Faculty Papers

BACKGROUND: Esophageal carcinoma is an aggressive disease that is often treated with neoadjuvant therapy followed by surgical resection. Diabetes mellitus (DM) has been associated with reduced efficacy of chemoradiation (CRT) in other gastrointestinal cancers. The goal of this study was to determine if DM affects response to neoadjuvant CRT in the management of gastroesophageal carcinoma.

METHODS: We retrospectively reviewed the esophageal cancer patient databases and subsequently analyzed those patients who received neoadjuvant CRT followed by surgical resection at two institutions, Thomas Jefferson University (TJUH) and Fox Chase Cancer Center (FCCC). Comparative analyses of rates of pathologic complete response rate (pCR) …

Imaging Spontaneous Mmtvneu Transgenic Murine Mammary Tumors: Targeting Metabolic Activity Versus Genetic Products., Mathew L Thakur, Devakumar Devadhas, Kaijun Zhang, Richard G Pestell, Chenguang Wang, Peter Mccue, Eric Wickstrom

Department of Radiology Faculty Papers

INTRODUCTION: Despite the great strides made in imaging breast cancer (BC) in humans, the current imaging modalities miss up to 30% of BC, do not distinguish malignant lesions from benign ones, and require histologic examinations for which invasive biopsy must be performed. Annually in the United States, approximately 5.6 million biopsies find benign lesions. More than 50% of human BCs overexpress cyclin D1, and all BCs exhibit VPAC1 oncogene products. Together, these gene products may provide an excellent biomarker for the early and accurate detection of BC. We have evaluated 4 biologically active peptide analogs that have high affinity for …

Manganese Flux Across The Blood-Brain Barrier, Robert A. Yokel

Pharmaceutical Sciences Faculty Publications

Manganese (Mn) is essential for brain growth and metabolism, but in excess can be a neurotoxicant. The chemical form (species) of Mn influences its kinetics and toxicity. Significant Mn species entering the brain are the Mn²⁺ ion and Mn citrate which, along with Mn transferrin, enter the brain by carrier-mediated processes. Although the divalent metal transporter (DMT-1) was suggested to be a candidate for brain Mn uptake, brain Mn influx was not different in Belgrade rats, which do not express functional DMT-1, compared to controls. Brain Mn influx was not sodium dependent or dependent on ATP hydrolysis, but was …

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 …

Brazilian Adolescents Infected By Hiv: Epidemiologic Characteristics And Adherence To Treatment, Julia K. C. Machado, Maria J. C. Sant'anna, Veronica Coates, Flavia J. Almeida, Eitan N. Berezin, Hatim A. Omar

Pediatrics Faculty Publications

Over the last 3 decades since the first AIDS cases appeared, we have witnessed great progress in therapeutic methodologies that have transformed the evolution of the disease from debilitating and fatal, into chronic and controllable. HIV-infected children are arriving at adolescence and bringing specific challenges, not only to themselves, but also to their families and caregivers. This retrospective study sets forth epidemiological and treatment characteristics of 46 HIV-infected adolescents followed in a specialized university service relating said characteristics to therapy adherence assessed through a combination of three indirect methods. Therapy adherence did not reveal any association with either epidemiologic characteristics …

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 …

An Exploratory Analysis Of The Impact Of Family Functioning On Treatment For Depression In Adolescents., Norah C. Feeny, Susan G. Silva, Mark A. Reinecke, Steven Mcnulty, Robert L. Findling, Paul Rohde, John F. Curry, Golda S. Ginsburg, Christopher J. Kratochvil, Sanjeev M. Pathak, Diane E. May, Betsy D. Kennard, Anne D. Simons, Karen C. Wells, Michele Robins, David Rosenberg, John S. March

Journal Articles: Psychiatry

This article explores aspects of family environment and parent-child conflict that may predict or moderate response to acute treatments among depressed adolescents (N = 439) randomly assigned to fluoxetine, cognitive behavioral therapy, their combination, or placebo. Outcomes were Week 12 scores on measures of depression and global impairment. Of 20 candidate variables, one predictor emerged: Across treatments, adolescents with mothers who reported less parent-child conflict were more likely to benefit than their counterparts. When family functioning moderated outcome, adolescents who endorsed more negative environments were more likely to benefit from fluoxetine. Similarly, when moderating effects were seen on cognitive behavioral …

Accurate Molecular Classification Of Cancer Using Simple Rules., Xiaosheng Wang, Osamu Gotoh

Journal Articles: Genetics, Cell Biology & Anatomy

BACKGROUND: One intractable problem with using microarray data analysis for cancer classification is how to reduce the extremely high-dimensionality gene feature data to remove the effects of noise. Feature selection is often used to address this problem by selecting informative genes from among thousands or tens of thousands of genes. However, most of the existing methods of microarray-based cancer classification utilize too many genes to achieve accurate classification, which often hampers the interpretability of the models. For a better understanding of the classification results, it is desirable to develop simpler rule-based models with as few marker genes as possible.

METHODS: …

The Leishmania Donovani Lipophosphoglycan Excludes The Vesicular Proton-Atpase From Phagosomes By Impairing The Recruitment Of Synaptotagmin V, Adrien F. Vinet, Mitsunori Fukuda, Salvatore J. Turco, Albert Descoteaux

Molecular and Cellular Biochemistry Faculty Publications

We recently showed that the exocytosis regulator Synaptotagmin (Syt) V is recruited to the nascent phagosome and remains associated throughout the maturation process. In this study, we investigated the possibility that Syt V plays a role in regulating interactions between the phagosome and the endocytic organelles. Silencing of Syt V by RNA interference revealed that Syt V contributes to phagolysosome biogenesis by regulating the acquisition of cathepsin D and the vesicular proton-ATPase. In contrast, recruitment of cathepsin B, the early endosomal marker EEA1 and the lysosomal marker LAMP1 to phagosomes was normal in the absence of Syt V. As Leishmania …

Keap1 E3 Ligase-Mediated Downregulation Of Nf-Kappab Signaling By Targeting Ikkbeta, Dung-Fang Lee, Hsu-Ping Kuo, Mo Liu, Chao-Kai Chou, Weiya Xia, Yi Du, Jia Shen, Chun-Te Chen, Longfei Huo, Ming-Chuan Hsu, Chia-Wei Li, Qingqing Ding, Tsai-Lien Liao, Chien-Chen Lai, Ann-Chi Lin, Ya-Hui Chang, Shih-Feng Tsai, Long-Yuan Li, Mien-Chie Hung

Faculty, Staff and Student Publications

IkappaB kinase beta (IKKbeta) is involved in tumor development and progression through activation of the nuclear factor (NF)-kappaB pathway. However, the molecular mechanism that regulates IKKbeta degradation remains largely unknown. Here, we show that a Cullin 3 (CUL3)-based ubiquitin ligase, Kelch-like ECH-associated protein 1 (KEAP1), is responsible for IKKbeta ubiquitination. Depletion of KEAP1 led to the accumulation and stabilization of IKKbeta and to upregulation of NF-kappaB-derived tumor angiogenic factors. A systematic analysis of the CUL3, KEAP1, and RBX1 genomic loci revealed a high percentage of genome loss and missense mutations in human cancers that failed to facilitate IKKbeta degradation. Our …

The Pars Triangularis In Dyslexia And Adhd: A Comprehensive Approach., Michelle Y. Kibby, Judith M Kroese, Hillery Krebbs, Crystal E Hill, George W Hynd

Publications

Limited research has been conducted on the structure of the pars triangularis (PT) in dyslexia despite functional neuroimaging research finding it may play a role in phonological processing. Furthermore, research to date has not examined PT size in ADHD even though the right inferior frontal region has been implicated in the disorder. Hence, one of the purposes of this study was to examine the structure of the PT in dyslexia and ADHD. The other purposes included examining the PT in relation to overall expressive language ability and in relation to several specific linguistic functions given language functioning often is affected …

Ethnic Differences In Do-Not-Resuscitate Orders After Intracerebral Hemorrhage, Darin B Zahuranec, Devin L Brown, Lynda D Lisabeth, Nicole R Gonzales, Paxton J Longwell, Melinda A Smith, Nelda M Garcia, Lewis B Morgenstern

Faculty, Staff and Student Publications

OBJECTIVE: To explore ethnic differences in do-not-resuscitate orders after intracerebral hemorrhage.

DESIGN: Population-based surveillance.

SETTING: Corpus Christi, Texas.

PATIENTS: All cases of intracerebral hemorrhage in the community of Corpus Christi, TX were ascertained as part of the Brain Attack Surveillance in Corpus Christi (BASIC) project.

INTERVENTIONS: None.

MEASUREMENTS AND MAIN RESULTS: Medical records were reviewed for do-not-resuscitate orders. Unadjusted and multivariable logistic regression were used to test for associations between ethnicity and do-not-resuscitate orders, both overall ("any do-not-resuscitate") and within 24 hrs of presentation ("early do-not-resuscitate"), adjusted for age, gender, Glasgow Coma Scale, intracerebral hemorrhage volume, intraventricular hemorrhage, infratentorial hemorrhage, …

Role Of Mammalian Ecdysoneless In Cell Cycle Regulation., Jun Hyun Kim, Channabasavaiah B. Gurumurthy, Mayumi Naramura, Ying Zhang, Andrew T. Dudley, Lynn Doglio, Hamid Band, Vimla Band

Journal Articles: Genetics, Cell Biology & Anatomy

The Ecdysoneless (Ecd) protein is required for cell-autonomous roles in development and oogenesis in Drosophila, but the function of its evolutionarily conserved mammalian orthologs is not clear. To study the cellular function of Ecd in mammalian cells, we generated Ecd(lox/lox) mouse embryonic fibroblast cells from Ecd floxed mouse embryos. Cre-mediated deletion of Ecd in Ecd(lox/lox) mouse embryonic fibroblasts led to a proliferative block due to a delay in G(1)-S cell cycle progression; this defect was reversed by the introduction of human Ecd. Loss of Ecd led to marked down-regulation of E2F target gene expression. Furthermore, Ecd directly bound to Rb …

N-Glycosylation Status Of E-Cadherin Controls Cytoskeletal Dynamics Through The Organization Of Distinct Β-Catenin- And Γ-Catenin-Containing Ajs., Basem T Jamal, Mihai Nita-Lazar, Zhennan Gao, Bakr Amin, Janice Walker, Maria A Kukuruzinska

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

N-glycosylation of E-cadherin has been shown to inhibit cell-cell adhesion. Specifically, our recent studies have provided evidence that the reduction of E-cadherin N-glycosylation promoted the recruitment of stabilizing components, vinculin and serine/threonine protein phosphatase 2A (PP2A), to adherens junctions (AJs) and enhanced the association of AJs with the actin cytoskeleton. Here, we examined the details of how N-glycosylation of E-cadherin affected the molecular organization of AJs and their cytoskeletal interactions. Using the hypoglycosylated E-cadherin variant, V13, we show that V13/β-catenin complexes preferentially interacted with PP2A and with the microtubule motor protein dynein. This correlated with dephosphorylation of the microtubule-associated protein …

Adapting To Dynamic Stimulus-Response Values: Differential Contributions Of Inferior Frontal, Dorsomedial, And Dorsolateral Regions Of Prefrontal Cortex To Decision Making., Derek G V Mitchell, Qian Luo, Shelley B Avny, Tomasz Kasprzycki, Karanvir Gupta, Gang Chen, Elizabeth C Finger, R James R Blair

Brain and Mind Institute Researchers' Publications

Dorsomedial prefrontal cortex (dmPFC), dorsolateral prefrontal cortex (dlPFC), and inferior frontal gyrus (IFG) have all been implicated in resolving decision conflict whether this conflict is generated by having to select between responses of similar value or by making selections following a reversal in reinforcement contingencies. However, work distinguishing their individual functional contributions remains preliminary. We used functional magnetic resonance imaging to delineate the functional role of these systems with regard to both forms of decision conflict. Within dmPFC and dlPFC, blood oxygen level-dependent responses increased in response to decision conflict regardless of whether the conflict occurred in the context of …

Human Amniotic Fluid Stem Cells Do Not Differentiate Into Dopamine Neurons In Vitro Or After Transplantation In Vivo., Angela E Donaldson, Jingli Cai, Ming Yang, Lorraine Iacovitti

Farber Institute for Neuroscience Faculty Papers

Although embryonic stem (ES) cells can generate dopamine (DA) neurons that are potentially useful as a cell replacement therapy in Parkinson's disease (PD), associated ethical and practical concerns remain major stumbling blocks to their eventual use in humans. In this study, we examined human amniotic fluid stem (hAFS) cells derived from routine amniocenteses for their potential to give rise to DA neurons in vitro and following transplantation into the 6-hydroxydopamine-lesioned rat brain. We show that undifferentiated hAFS cells constitutively expressed mRNAs and proteins typical of stem cells but also cell derivatives of all three germ layers, including neural progenitors/neurons (nestin, …

Aging And Environmental Exposures Alter Tissue-Specific Dna Methylation Dependent Upon Cpg Island Context, Brock C. Christensen, E Andres Houseman, Carmen J. Marsit, Shichun Zheng, Margaret R. Wrensch, Joseph L. Wiemels, Heather H. Nelson, Margaret R. Karagas

Dartmouth Scholarship

Epigenetic control of gene transcription is critical for normal human development and cellular differentiation. While alterations of epigenetic marks such as DNA methylation have been linked to cancers and many other human diseases, interindividual epigenetic variations in normal tissues due to aging, environmental factors, or innate susceptibility are poorly characterized. The plasticity, tissue-specific nature, and variability of gene expression are related to epigenomic states that vary across individuals. Thus, population-based investigations are needed to further our understanding of the fundamental dynamics of normal individual epigenomes. We analyzed 217 non-pathologic human tissues from 10 anatomic sites at 1,413 autosomal CpG loci …

Intra-Tumor Heterogeneity Of Mlh1 Promoter Methylation Revealed By Deep Single Molecule Bisulfite Sequencing., Katherine E Varley, David G Mutch, Tina B Edmonston, Paul J Goodfellow, Robi D Mitra

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

A single tumor may contain cells with different somatic mutations. By characterizing this genetic heterogeneity within tumors, advances have been made in the prognosis, treatment and understanding of tumorigenesis. In contrast, the extent of epigenetic intra-tumor heterogeneity and how it influences tumor biology is under-explored. We have characterized epigenetic heterogeneity within individual tumors using next-generation sequencing. We used deep single molecule bisulfite sequencing and sample-specific DNA barcodes to determine the spectrum of MLH1 promoter methylation across an average of 1000 molecules in each of 33 individual samples in parallel, including endometrial cancer, matched blood and normal endometrium. This first glimpse, …

Functional State Following The Fontan Procedure., Ismee A. Williams, Lynn A. Sleeper, Steven D. Colan, Minmin Lu, Elizabeth A. Stephenson, Jane W. Newburger, Welton M. Gersony, Meryl S. Cohen, James F. Cnota, Andrew M. Atz, Richard V. Williams, Renee Margossian, Andrew J. Powell, Mario P. Stylianou, Daphne T. Hsu, Pediatric Heart Network Investigators, Girish S. Shirali

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Despite improvements in outcomes after completion of the Fontan circulation, long-term functional state varies. We sought to identify pre- and postoperative characteristics associated with overall function.

METHODS AND RESULTS: We analyzed data from 476 survivors with the Fontan circulation enrolled in the Pediatric Heart Network Fontan Cross-sectional Study. Mean age at creation of the Fontan circulation was 3.4 plus or minus 2.1 years, with a range from 0.7 to 17.5 years, and time since completion was 8.7 plus or minus 3.4 years, the range being from 1.1 to 17.3 years. We calculated a functional score for the survivors by …

An Investigation Of Middle School Student Interest, Perception, And Attitude Toward Technology And Engineering, Kari Marie Cook

Theses and Dissertations

The purpose of this study was to investigate middle school student perception and attitude toward technology and engineering and to better understand how the gender of the teacher, gender of the student, and information provided in technology classes affected their perception and attitude. To accomplish this, the Technology Attitude Scale, and the Pupil's Attitudes Toward Technology—United States assessment instruments were used to form the basis of a new survey instrument focused on technology and engineering perception, use, and interest. The new survey instrument is called the Technology and Engineering Attitude Scale (TEAS) survey. Multiple 7th grade technology engineering classes from …

Evaluation Of A Social Support Measure That May Indicate Risk Of Depression During Pregnancy, Lori Spoozak

Yale Medicine Thesis Digital Library

The objective of this study was to evaluate the psychometric properties of the Kendler Social Support Interview modified for administration to pregnant women and to assess the relationship between social support and depression in the first trimester of pregnancy. Subjects were administered the Modified Kendler Social Support Interview (MKSSI) and the Composite International Diagnostic Index to diagnose depression. Principal components analysis was employed to construct the MKSSI score. Cronbachs coefficient alpha and principal factor analysis were run for items included in the MKSSI score. The relationship between a depressive diagnosis and the MKSSI score and subscales was assessed by logistic …

Intussusception Of The Appendix: New Trends And Comprehensive Analysis Of 140 Case Reports, Barbara Wexelman

Yale Medicine Thesis Digital Library

INTUSSUSCEPTION OF THE APPENDIX: NEW TRENDS AND COMPREHENSIVE ANALYSIS OF 140 PUBLISHED CASE REPORTS. Barbara A. Wexelman, Cassius Ochoa Chaar, and Walter Longo. Section of Colorectal Surgery, Department of Surgery, Yale University, School of Medicine, New Haven, CT. Statement of Purpose: This paper uses 139 published case reports to understand the demographic, diagnostic, and treatment trends of intussusception of the appendix. Methods: Using the PubMed literature search engine to find all English references of intussusception and appendix, and reviewing those that contained actual case reports of intussusception of the appendix, we analyzed the demographics, presentation, diagnostic methods, surgical treatment, and …

Dicer Is Required For Female Reproductive Tract Development And Fertility In The Mouse, Gabriel Gonzalez, Richard R Behringer

Faculty, Staff and Student Publications

Dicer encodes a riboendonuclease required for microRNA biosynthesis. Dicer was inactivated in Müllerian duct mesenchyme-derived tissues of the reproductive tract of the mouse, using an Amhr2-Cre allele. Although Amhr2-Cre; Dicer conditional mutant males appeared normal and were fertile, mutant females were infertile. In adult mutant females, there was a reduction in the size of the oviducts and uterine horns. The oviducts were less coiled compared to controls and cysts formed at the isthmus near the uterotubal junction. Unfertilized, degenerate oocytes were commonly found within these cysts, indicating a defect in embryo transit. Beads transferred into the mutant oviduct failed to …

A Truncation Mutation In Tbc1d4 In A Family With Acanthosis Nigricans And Postprandial Hyperinsulinemia, Satya Dash, Hiroyuki Sano, Justin J. Rochford, Robert K. Semple

Dartmouth Scholarship

Tre-2, BUB2, CDC16, 1 domain family member 4 (TBC1D4) (AS160) is a Rab-GTPase activating protein implicated in insulin-stimulated glucose transporter 4 (GLUT4) translocation in adipocytes and myotubes. To determine whether loss-of-function mutations in TBC1D4 might impair GLUT4 translocation and cause insulin resistance in humans, we screened the coding regions of this gene in 156 severely insulin-resistant patients. A female presenting at age 11 years with acanthosis nigricans and extreme postprandial hyperinsulinemia was heterozygous for a premature stop mutation (R363X) in TBC1D4. After demonstrating reduced expression of wild-type TBC1D4 protein and expression of the truncated protein in lymphocytes from the proband, …

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 …