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The Nestin Progenitor Lineage Is The Compartment Of Origin For Pancreatic Intraepithelial Neoplasia, Catherine Carriere, Elliot S. Seeley, Tobias Goetze, Daniel S. Longnecker, Murray Korc

Dartmouth Scholarship

To determine the cell compartment in which initial oncogenic mutations occur in pancreatic ductal adenocarcinoma (PDAC), we generated a mouse model in which endogenous expression of mutated Kras (Kras(G12D)) was initially directed to a population of pancreatic exocrine progenitors characterized by the expression of Nestin. Targeting of oncogenic Kras to such a restricted cell compartment was sufficient for the formation of pancreatic intraepithelial neoplasias (PanINs), putative precursors to PDAC. PanINs appeared with the same grade and frequency as observed when Kras(G12D) was targeted to the whole pancreas by a Pdx1-driven Cre recombinase strategy. Thus, the Nestin cell lineage is highly …

Perceptual Functions Of Perirhinal Cortex In Rats: Zero-Delay Object Recognition And Simultaneous Oddity Discriminations., Susan J Bartko, Boyer D Winters, Rosemary A Cowell, Lisa M Saksida, Timothy J Bussey

Brain and Mind Institute Researchers' Publications

The perirhinal cortex (PRh) is widely accepted as having an important role in object recognition memory in humans and animals. Contrary to claims that PRh mediates declarative memory exclusively, previous evidence suggests that PRh has a role in the perceptual processing of complex objects. In the present study, we conducted an examination of the possible role of PRh in perceptual function in rats. We examined whether bilateral excitotoxic lesions of PRh or PPRh (perirhinal plus postrhinal cortices) in the rat would cause deficits in a zero-delay object-recognition task and a simultaneous oddity discrimination task. Both of these tasks measured spontaneous …

Transgenic Cyclin E Triggers Dysplasia And Multiple Pulmonary Adenocarcinomas, Yan Ma, Steven Fiering, Candice Black, Xi Liu, Ziqiang Yuan, Vincent A. Memoli, David J. Robbins, Heather A. Bentley, Gregory J. Tsongalis, Eugene Demidenko, Sarah J. Freemantle, Ethan Dmitrovsky

Dartmouth Scholarship

Cyclin E is a critical G(1)-S cell cycle regulator aberrantly expressed in bronchial premalignancy and lung cancer. Cyclin E expression negatively affects lung cancer prognosis. Its role in lung carcinogenesis was explored. Retroviral cyclin E transduction promoted pulmonary epithelial cell growth, and small interfering RNA targeting of cyclin E repressed this growth. Murine transgenic lines were engineered to mimic aberrant cyclin E expression in the lung. Wild-type and proteasome degradation-resistant human cyclin E transgenic lines were independently driven by the human surfactant C (SP-C) promoter. Chromosome instability (CIN), pulmonary dysplasia, sonic hedgehog (Shh) pathway activation, adenocarcinomas, and metastases occurred. Notably, …

Inverse Regulation Of Biofilm Formation And Swarming Motility By Pseudomonas Aeruginosa Pa14, Nicky C. Caiazza, Judith H. Merritt, Kimberly M. Brothers, George A. O'Toole

Dartmouth Scholarship

We previously reported that SadB, a protein of unknown function, is required for an early step in biofilm formation by the opportunistic pathogen Pseudomonas aeruginosa. Here we report that a mutation in sadB also results in increased swarming compared to the wild-type strain. Our data are consistent with a model in which SadB inversely regulates biofilm formation and swarming motility via its ability both to modulate flagellar reversals in a viscosity-dependent fashion and to influence the production of the Pel exopolysaccharide. We also show that SadB is required to properly modulate flagellar reversal rates via chemotaxis cluster IV (CheIV cluster). …

Genetic Factors In Preschool Executive Control: Relations Between Serotonin Genotype, Working Memory, And Set Shifting, S. A. Wiebe, M. Y. Chang, A. R. Johnson, J. Huggenvik, T. Jameson, K. A. Espy

Developmental Cognitive Neuroscience Laboratory: Faculty Publications

No abstract provided.

Transgenic Avian-Derived Recombinant Human Interferon-Alpha2b (Avi-005) In Healthy Subjects: An Open-Label, Single-Dose, Controlled Study., T B Patel, E Pequignot, S H Parker, M C Leavitt, H E Greenberg, Walter K. Kraft

Department of Pharmacology and Experimental Therapeutics Faculty Papers

BACKGROUND/AIMS: This study characterized the safety and pharmacological properties of AVI-005, a novel glycosylated recombinant human interferon-alpha2b produced from the egg whites of chickens transfected with human cDNA.

METHODS: 18 healthy volunteers received single subcutaneous rising doses (0.5, 1.66 or 5 million international units, MIU) of AVI-005. A randomized parallel comparator group of 10 subjects received 5 MIU of unglycosylated IFN-alpha2b (Intron A). The pharmacokinetic parameters t1/2, tmax, Cmax, AUC0-24h, Vd, and clearance were compared between AVI-005 and unglycosylated IFN-alpa2b.

RESULTS: At equipotent doses, AVI-005 had a larger AUC0-24h than the control interferon. Pharmacodynamic markers ofneopterin and beta2-microglobulin for the …

Effect Of Genetic Variations In Platelet Glycoproteins Ibα And Vi On The Risk For Coronary Heart Disease Events In Postmenopausal Women Taking Hormone Therapy, Paul F. Bray, Timothy D. Howard, Eric Vittinghoff, David C. Sane, David M. Harrington

Department of Medicine Faculty Papers

Millions of women still use postmenopausal hormone therapy (HT). We genotyped 2090 women in Heart and Estrogen/progestin Replacement Study for functional polymorphisms in GP1BA and GP6 and assessed the coronary heart disease (CHD) event rate over 5.8 years of follow-up. In patients receiving placebo, there was an increased CHD death/myocardial infarction (MI)/unstable angina (UA) event rate in carriers of the GP1BA -5C allele (adjusted [adj] P = .006). HT increased the hazard ratio (HR) of CHD events in patients with the GP1BA -5TT genotype by 16% and reduced the HR in patients with the TC+CC genotypes by 46% (adj interaction …

Cystic Lymphangioma Of The Pancreas, Madhusudhan R. Sanaka, Thomas E. Kowalski

Department of Medicine Faculty Papers

A case report.

Untangling The Signalling Wires, Boris N. Kholodenko Phd, Dsci

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Mitogen-activated protein kinase (MAPK) cascades process myriads of stimuli, generating receptor-specific cellular outcomes. New work exploits emergent mathematics of network inference to reveal distinct feedback designs of the RAF/MEK/ERK cascade induced by two different growth factors. It shows that response specificity can arise from differential signal-induced wiring of overlapping protein networks.

Functional Taxonomy Of Bacterial Hyperstructures, Vic Norris, Tanneke Den Blaauwen, Armelle Cabin-Flaman, Roy H Doi, Rasika Harshey, Laurent Janniere, Alfonso Jimenez-Sanchez, Ding Jun Jin, Petra Anne Levin, Eugenia Mileykovskaya, Abraham Minsky, Milton Saier, Kirsten Skarstad

Faculty, Staff and Student Publications

The levels of organization that exist in bacteria extend from macromolecules to populations. Evidence that there is also a level of organization intermediate between the macromolecule and the bacterial cell is accumulating. This is the level of hyperstructures. Here, we review a variety of spatially extended structures, complexes, and assemblies that might be termed hyperstructures. These include ribosomal or "nucleolar" hyperstructures; transertion hyperstructures; putative phosphotransferase system and glycolytic hyperstructures; chemosignaling and flagellar hyperstructures; DNA repair hyperstructures; cytoskeletal hyperstructures based on EF-Tu, FtsZ, and MreB; and cell cycle hyperstructures responsible for DNA replication, sequestration of newly replicated origins, segregation, compaction, and …

Expression Of The Neural Stem Cell Markers Ng2 And L1 In Human Angiomyolipoma: Are Angiomyolipomas Neoplasms Of Stem Cells?, So Dug Lim, William Stallcup, Benjamin Lefkove, Baskaran Govindarajan, Kit Sing Au, Hope Northrup, Deborah Lang, David E Fisher, Avani Patel, Mahul B Amin, Jack L Arbiser

Faculty, Staff and Student Publications

Angiomyolipomas are benign tumors of the kidney which express phenotypes of smooth muscle, fat, and melanocytes. These tumors appear with increased frequency in the autosomal dominant disorder tuberous sclerosis and are the leading cause of morbidity in adults with tuberous sclerosis. While benign, these tumors are capable of provoking life threatening hemorrhage and replacement of the kidney parenchyma, resulting in renal failure. The histogenesis of these tumors is currently unclear, although currently, we believe these tumors arise from "perivascular epithelioid cells" of which no normal counterpart has been convincingly demonstrated. Recently, stem cell precursors have been recognized that can give …

Aldosterone-Induced Sgk1 Relieves Dot1a-Af9-Mediated Transcriptional Repression Of Epithelial Na+ Channel Alpha, Wenzheng Zhang, Xuefeng Xia, Mary Rose Reisenauer, Timo Rieg, Florian Lang, Dietmar Kuhl, Volker Vallon, Bruce C Kone

Faculty, Staff and Student Publications

Aldosterone plays a major role in the regulation of salt balance and the pathophysiology of cardiovascular and renal diseases. Many aldosterone-regulated genes--including that encoding the epithelial Na+ channel (ENaC), a key arbiter of Na+ transport in the kidney and other epithelia--have been identified, but the mechanisms by which the hormone modifies chromatin structure and thus transcription remain unknown. We previously described the basal repression of ENaCalpha by a complex containing the histone H3 Lys79 methyltransferase disruptor of telomeric silencing alternative splice variant a (Dot1a) and the putative transcription factor ALL1-fused gene from chromosome 9 (Af9) as well as the release …

Commentary: The Daubert Decision, Robert L. Brent

The Selected Works of Robert Brent

No abstract provided.

Retroviral Vector And Cell-Based Assay For Measuring The Mutation Rate Of Retroviruses Employing Same, Dawn P. Wooley, Kelly Jo Huang

Neuroscience, Cell Biology & Physiology Faculty Publications

Lentiviral-based retrovirus vectors and an in vivo mutation rate assay employing them. More particularly, an assay for directly determining the in vivo mutation rate of HIV-1.

Run-Specific Limits Of Quantitation And Detection (An Alternative To Minimum Peak Height Thresholds), Dan E. Krane

Biological Sciences Faculty Publications

No abstract provided.

Empirical Analysis Of The Str Profiles Resulting From Conceptual Mixtures, Dan E. Krane

Biological Sciences Faculty Publications

No abstract provided.

Assessing The Implications For Close Relatives In The Event Of Similar But Non-Matching Dna Profiles, Dan E. Krane

Biological Sciences Faculty Publications

No abstract provided.

A Cohort Study Of Reproductive And Hormonal Factors And Renal Cell Cancer Risk In Women, Gc Kabat, Stephanie A. Navarro Silvera, Ab Miller, Te Rohan

Department of Public Health Scholarship and Creative Works

We examined the association of reproductive and hormonal factors with renal cell cancer risk in a cohort study of 89 835 Canadian women. Compared with nulliparous women, parous women were at increased risk (hazard ratio (HR) 1.78, 95% confidence interval (CI) 1.02–3.09), and there was a significant gradient of risk with increasing levels of parity: relative to nulliparous women, women who had X5 pregnancies lasting 4 months or more had a 2.4-fold risk (HR 1⁄4 2.41, 95% CI 1⁄4 1.27–4.59, P for trend 0.01). Ever use of oral contraceptives was associated with a modest reduction in risk. No associations were …

Is Gene Therapy A Good Therapeutic Approach For Hiv-Positive Patients?, Jai G. Marathe, Dawn P. Wooley

Neuroscience, Cell Biology & Physiology Faculty Publications

Despite advances and options available in gene therapy for HIV-1 infection, its application in the clinical setting has been challenging. Although published data from HIV-1 clinical trials show safety and proof of principle for gene therapy, positive clinical outcomes for infected patients have yet to be demonstrated. The cause for this slow progress may arise from the fact that HIV is a complex multi-organ system infection. There is uncertainty regarding the types of cells to target by gene therapy and there are issues regarding insufficient transduction of cells and long-term expression. This paper discusses state-of-the-art molecular approaches against HIV-1 and …

Atp Activates A Reactive Oxygen Species-Dependent Oxidative Stress Response And Secretion Of Pro-Inflammatory Cytokines In Macrophages, Christiane M. Cruz, Alessandra Rinna, Henry Jay Forman, Ana L. M. Ventura, Pedro M. Persechini, David M. Ojcius

All Dugoni School of Dentistry Faculty Articles

Secretion of the proinflammatory cytokines, interleukin (IL)-1β and IL-18, usually requires two signals. The first, due to microbial products such as lipopolysaccharide, initiates transcription of the cytokine genes and accumulation of the precursor proteins. Cleavage and secretion of the cytokines is mediated by caspase-1, in association with an inflammasome containing Nalp3, which can be activated by binding of extracellular ATP to purinergic receptors. We show that treatment of macrophages with ATP results in production of reactive oxygen species (ROS), which stimulate the phosphatidylinositol 3-kinase (PI3K) pathway and subsequent Akt and ERK1/2 activation. ROS exerts its effect through glutathionylation of PTEN …

Genes And Behavior In Preschool Children: The Relation Between Dopamine Genotype And Latent Executive Control, S. A. Wiebe, M. J. Moehr, A. R. Johnson, M. Y. Chang, J. Huggenvik, T. Jameson, K. A. Espy

Developmental Cognitive Neuroscience Laboratory: Faculty Publications

Objective: Dopaminergic neurotransmission is implicated in the executive control of cognition and behavior (Braver & Cohen, 2000). Presence or absence of particular dopamine gene alleles relates to executive control performance (Casey, 2002; Roesch-Ely, 2005) and to attention problems and ADHD (Durston, 2005; Schmidt, 2001). The present study examined the relation between dopamine genotype and executive control in normally-developing preschool children. Participants and Methods: The sample included 133 children (66 girls; mean age 4 years, range 2;2-6 years). Children completed a battery of executive control tasks, and were genotyped for 4 dopamine genes: the dopamine receptors DRD2 and DRD4, the dopamine …

Β-N-Methylamino-L-Alanine Enhances Neurotoxicity Through Multiple Mechanisms, Doug Lobner, Peachy Mae T. Piana, Abed K. Salous, Robert W. Peoples

Biomedical Sciences Faculty Research and Publications

The idea that the environmental toxin β-N-methylamino-l-alanine (BMAA) is involved in neurodegenerative diseases on Guam has risen and fallen over the years. The theory has gained greater interest with recent reports that BMAA is biomagnified, is widely distributed around the planet, and is present in the brains of Alzheimer's patients in Canada. We provide two important new findings. First, we show that BMAA at concentrations as low as 10 μM can potentiate neuronal injury induced by other insults. This is the first evidence that BMAA at concentrations below the mM range can enhance death of cortical neurons and …

The Enigma Of Struma Ovarii, Lawrence M. Roth, Aleksander Talerman

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Since its first description in the early part of the twentieth century, struma ovarii has elicited considerable interest because of its many unique features; however, at present a number of aspects remain enigmatic. Although the typical presentation is that of a pelvic mass, unusual clinical manifestations such as hyperthyroidism, ascites, and Meigs' syndrome have been recognised. Uncommon macroscopic and especially histological patterns in struma can cause difficulties in diagnosis. Cystic strumas are challenging to diagnose both macroscopically and histologically. Proliferative changes within struma can be misdiagnosed as cancer. In regard to the occurrence of thyroid-type carcinoma in struma ovarii, precise …

Rad51c Deficiency In Mice Results In Early Prophase I Arrest In Males And Sister Chromatid Separation At Metaphase Ii In Females, Sergey Kuznetsov, Manuela Pellegrini, Kristy Shuda, Oscar Fernandez-Capetillo, Yilun Liu, Betty K. Martin, Sandra Burkett, Eileen Southon, Debananda Pati, Lino Tessarollo, Stephen D. West, Peter J. Donovan, Andre Nussenzweig, Shyam K. Sharan

Department of Biochemistry and Molecular Biology Faculty Papers

RAD51C is a member of the RecA/RAD51 protein family, which is known to play an important role in DNA repair by homologous recombination. In mice, it is essential for viability. Therefore, we have generated a hypomorphic allele of Rad51c in addition to a null allele. A subset of mice expressing the hypomorphic allele is infertile. This infertility is caused by sexually dimorphic defects in meiotic recombination, revealing its two distinct functions. Spermatocytes undergo a developmental arrest during the early stages of meiotic prophase I, providing evidence for the role of RAD51C in early stages of RAD51-mediated recombination. In contrast, oocytes …

Vancomycin-Resistant Enterococcus Faecalis Endocarditis: Linezolid Failure And Strain Characterization Of Virulence Factors, Constantine Tsigrelis, Kavindra V Singh, Thais D Coutinho, Barbara E Murray, Larry M Baddour

Faculty, Staff and Student Publications

Infective endocarditis due to vancomycin-resistant (VR) Enterococcus faecalis has only rarely been reported. We report a case of VR E. faecalis endocarditis that failed to respond to linezolid therapy, outline the virulence traits of the isolate, and review previously published cases of VR E. faecalis endocarditis.

The Myc Transactivation Domain Promotes Global Phosphorylation Of The Rna Polymerase Ii Carboxy-Terminal Domain Independently Of Direct Dna Binding, Victoria H. Cowling, Michael D. Cole

Dartmouth Scholarship

Myc is a transcription factor which is dependent on its DNA binding domain for transcriptional regulation of target genes. Here, we report the surprising finding that Myc mutants devoid of direct DNA binding activity and Myc target gene regulation can rescue a substantial fraction of the growth defect in myc^−/− fibroblasts. Expression of the Myc transactivation domain alone induces a transcription-independent elevation of the RNA polymerase II (Pol II) C-terminal domain (CTD) kinases cyclin-dependent kinase 7 (CDK7) and CDK9 and a global increase in CTD phosphorylation. The Myc transactivation domain binds to the transcription initiation sites of these promoters …

Beta Blocker Specificity: A Building Block Toward Personalized Medicine., Brent R Degeorge, Walter J Koch

Center for Translational Medicine Faculty Papers

Drugs known as beta blockers, which antagonize the beta-adrenergic receptor (beta-AR), are an important component of the treatment regimen for chronic heart failure (HF). However, a significant body of evidence indicates that genetic heterogeneity at the level of the beta(1)-AR may be a factor in explaining the variable responses of HF patients to beta blockade. In this issue of the JCI, Rochais et al. describe how a single amino acid change in beta(1)-AR alters its structural conformation and improves its functional response to carvedilol, a beta blocker currently used in the treatment of HF (see the related article beginning on …

Interaction Of Glycolysis And Mitochondrial Respiration In Metabolic Oscillations Of Pancreatic Islets, Richard Bertram, Leslie S. Satin, Morten Gram Pedersen, Dan S. Luciani, Arthur Sherman

Pharmacology and Toxicology Publications

Abstract

Insulin secretion from pancreatic β-cells is oscillatory, with a typical period of 2–7 min, reflecting oscillations in membrane potential and the cytosolic Ca²⁺ concentration. Our central hypothesis is that the slow 2–7 min oscillations are due to glycolytic oscillations, whereas faster oscillations that are superimposed are due to Ca²⁺ feedback onto metabolism or ion channels. We extend a previous mathematical model based on this hypothesis to include a more detailed description of mitochondrial metabolism. We demonstrate that this model can account for typical oscillatory patterns of membrane potential and Ca²⁺ concentration in islets. It also …

Mlck/Actin Interaction In The Contracting A7r5 Cell And Vascular Smooth Muscle, Sean Eric Thatcher

Theses, Dissertations and Capstones

Myosin light chain kinase (MLCK) is an enzyme that phosphorylates the serine-19 residue on myosin regulatory light chains (MLCs) which serves to activate the Mg2+-ATPase of myosin. This catalytic activity is thought to be the primary role of MLCK; however, it has recently been suggested that MLCK’s actin binding and bundling properties may also be of importance in smooth muscle contraction. In the absence of calcium and calmodulin (CaM), MLCK will bundle actin filaments with its N-terminus. During calcium influx and subsequent CaM activation, MLCK binding to actin decreases resulting in unbundling of actin filaments and allows myosin and actin …

Shear Stress Induced Mtor Signaling In Cultured A7r5 Aortic Smooth Muscle Cell Line, Sriram Prasad Mupparaju

Theses, Dissertations and Capstones

Vascular intervention procedures such as balloon angioplasty and stent implantation lead to denudation of endothelium exposing the underlying smooth muscle layer to effects of blood shear stress. The effect of shear stress on smooth muscle cell signaling has not been studied in depth. In this study, we examined time dependent changes in activation of Akt, mTOR and p70S6k related signaling in response to orbital shear stress on cultured A7r5 cells. A7r5 cells cultured to subconfluence on 150mm culture dishes were subjected to orbital shear of 9.8dynes/cm 2 for zero, 5 min, 15 min, 30 min, 1h, 4h and 24h. The …