Medicine and Health Sciences Commons^™

Mitogen Activated Protein Kinase Phosphatase-1 Prevents The Development Of Tactile Sensitivity In A Rodent Model Of Neuropathic Pain, Christian Ndong, Russell P. Landry, Joyce A. Deleo, Edgar A. Romero-Sandoval

Dartmouth Scholarship

Neuropathic pain due to nerve injury is one of the most difficult types of pain to treat. Following peripheral nerve injury, neuronal and glial plastic changes contribute to central sensitization and perpetuation of mechanical hypersensitivity in rodents. The mitogen activated protein kinase (MAPK) family is pivotal in this spinal cord plasticity. MAPK phosphatases (MKPs) limit inflammatory processes by dephosphorylating MAPKs. For example, MKP-1 preferentially dephosphorylates p-p38. Since spinal p-p38 is pivotal for the development of chronic hypersensitivity in rodent models of pain, and p-p38 inhibitors have shown clinical potential in acute and chronic pain patients, we hypothesize that induction of …

Uterine Epithelial Cells Specifically Induce Interferon-Stimulated Genes In Response To Polyinosinic-Polycytidylic Acid Independently Of Estradiol, Mickey V. Patel, Mimi Ghosh, John V. Fahey, Charles R. Wira

Dartmouth Scholarship

Interferon β (IFNβ) is an antiviral cytokine secreted in response to pathogenic exposure that creates a restrictive intracellular environment through the action of downstream interferon-stimulated genes (ISG). The objective of this study was to examine the expression of IFNβ and ISG in both human uterine epithelial cells (UEC) and the ECC-1 uterine epithelial cell line and determine if expression changes with TLR stimulation and hormone exposure. Stimulation of primary uterine epithelial cells and ECC-1 cells with the TLR3 agonist poly (I∶C) induced the mRNA expression of IFNβ, MxA, OAS2 and PKR. Other TLR agonists including imiquimod and CpG had no …

Data Sharing In Neuroimaging Research, Jean-Baptiste Poline, Janis L. Breeze, Satrajit Ghosh, Krzysztof Gorgolewski, Yaroslav O. Halchenko

Dartmouth Scholarship

Significant resources around the world have been invested in neuroimaging studies of brain function and disease. Easier access to this large body of work should have profound impact on research in cognitive neuroscience and psychiatry, leading to advances in the diagnosis and treatment of psychiatric and neurological disease. A trend toward increased sharing of neuroimaging data has emerged in recent years. Nevertheless, a number of barriers continue to impede momentum. Many researchers and institutions remain uncertain about how to share data or lack the tools and expertise to participate in data sharing. The use of electronic data capture (EDC) methods …

Chromosomal Instability And Cancer: A Complex Relationship With Therapeutic Potential, Samuel F. Bakhoum, Duane A. Compton

Dartmouth Scholarship

Chromosomal instability (CIN) is a hallmark of human neoplasms. Despite its widespread prevalence, knowledge of the mechanisms and contributions of CIN in cancer has been elusive. It is now evident that the role of CIN in tumor initiation and growth is more complex than previously thought. Furthermore, distinguishing CIN, which consists of elevated rates of chromosome missegregation, from aneuploidy, which is a state of abnormal chromosome number, is crucial to understanding their respective contributions in cancer. Collectively, experimental evidence suggests that CIN enables tumor adaptation by allowing tumors to constantly sample the aneuploid fitness landscape. This complex relationship, together with …

Developing Unique Engineering Solutions To Improve Patient Safety, Bradley Watts, Douglas Van Citters, Brian Shiner, Peter Mills

Dartmouth Scholarship

Many efforts to improve healthcare safety have focused on redesigning processes of care or retraining clinicians. Far less attention has been focused on the use of new technologies to improve safety. We present the results of a unique collaboration between the VA National Center for Patient Safety (NCPS) and the Thayer School of Engineering at Dartmouth College. Each year, the NCPS identifies safety problems across the VA that could be addressed with newly-engineered devices. Teams of Thayer students and faculty participating in a senior design course evaluate and engineer a solution for one of the problems. Exemplar projects have targeted …

Caveolae, Fenestrae And Transendothelial Channels Retain Pv1 On The Surface Of Endothelial Cells, Eugene Tkachenko, Dan Tse, Olga Sideleva, Sophie J. Deharvengt, Marcus R. Luciano, Yan Xu, Caitlin L. Mcgarry, John Chidlow, Paul F. Pilch, William C. Sessa, Derek K. Toomre, Radu V. Stan

Dartmouth Scholarship

PV1 protein is an essential component of stomatal and fenestral diaphragms, which are formed at the plasma membrane of endothelial cells (ECs), on structures such as caveolae, fenestrae and transendothelial channels. Knockout of PV1 in mice results in in utero and perinatal mortality. To be able to interpret the complex PV1 knockout phenotype, it is critical to determine whether the formation of diaphragms is the only cellular role of PV1. We addressed this question by measuring the effect of complete and partial removal of structures capable of forming diaphragms on PV1 protein level. Removal of caveolae in mice by knocking …

Ovarian Cancer Progression Is Controlled By Phenotypic Changes In Dendritic Cells, Uciane K. Scarlett, Melanie R. Rutkowski, Adam M. Rauwerdink, Jennifer Fields, Ximena Escovar-Fadul, Jason Baird, Juan R. Cubillos-Ruiz, Ana C. Jacobs, Jorge L. Gonzalez, John Weaver, Steven Fiering, Jose R. Conejo-Garcia

Dartmouth Scholarship

We characterized the initiation and evolution of the immune response against a new inducible p53-dependent model of aggressive ovarian carcinoma that recapitulates the leukocyte infiltrates and cytokine milieu of advanced human tumors. Unlike other models that initiate tumors before the development of a mature immune system, we detect measurable antitumor immunity from very early stages, which is driven by infiltrating dendritic cells (DCs) and prevents steady tumor growth for prolonged periods. Coinciding with a phenotypic switch in expanding DC infiltrates, tumors aggressively progress to terminal disease in a comparatively short time. Notably, tumor cells remain immunogenic at advanced stages, but …

Quantitative Cherenkov Emission Spectroscopy For Tissue Oxygenation Assessment, Johan Axelsson, Adam K. Glaser, David J. Gladstone, Brian W. Pogue

Dartmouth Scholarship

Measurements of Cherenkov emission in tissue during radiation therapy are shown to enable estimation of hemoglobin oxygen saturation non-invasively, through spectral fitting of the spontaneous emissions from the treated tissue. Tissue oxygenation plays a critical role in the efficacy of radiation therapy to kill tumor tissue. Yet in-vivo measurement of this has remained elusive in routine use because of the complexity of oxygen measurement techniques. There is a spectrally broad emission of Cherenkov light that is induced during the time of irradiation, and as this travels through tissue from the point of the radiation deposition, the tissue absorption and scatter …

An Amulet For Trustworthy Wearable Mhealth, Jacob Sorber, Minho Shin, Ronald Peterson, Cory Cornelius, Shrirang Mare, Aarathi Prasad, Zachary Marois, Emma N. Smithayer, David Kotz

Dartmouth Scholarship

Mobile technology has significant potential to help revolutionize personal wellness and the delivery of healthcare. Mobile phones, wearable sensors, and home-based tele-medicine devices can help caregivers and individuals themselves better monitor and manage their health. While the potential benefits of this “mHealth” technology include better health, more effective healthcare, and reduced cost, this technology also poses significant security and privacy challenges. In this paper we propose \emphAmulet, an mHealth architecture that provides strong security and privacy guarantees while remaining easy to use, and outline the research and engineering challenges required to realize the Amulet vision.

An Inside Job: Hacking Into Janus Kinase/Signal Transducer And Activator Of Transcription Signaling Cascades By The Intracellular Protozoan Toxoplasma Gondii, Eric Y. Denkers, David J. Bzik, Barbara A. Fox, Barbara A. Butcher

Dartmouth Scholarship

The intracellular protozoan Toxoplasma gondii is well known for its skill at invading and living within host cells. New discoveries are now also revealing the astounding ability of the parasite to inject effector proteins into the cytoplasm to seize control of the host cell. This review summarizes recent advances in our understanding of one such secretory protein called ROP16. This molecule is released from rhoptries into the host cell during invasion. The ROP16 molecule acts as a kinase, directly activating both signal transducer and activator of transcription 3 (STAT3) and STAT6 signaling pathways. In macrophages, an important and preferential target …

Passive Biometrics For Pervasive Wearable Devices (Poster Paper), Cory Cornelius, Zachary Marois, Jacob Sorber, Ron Peterson, Shrirang Mare, David Kotz

Dartmouth Scholarship

Wearable devices – like the FitBit, MOTOACTV, and Jawbone UP – are increasingly becoming more pervasive whether for monitoring health and fitness, personal assistance, or home automation. While pervasive wearable devices have long been researched, we are now beginning to see the fruits of this research in the form of commercial offerings. Today, many of these commercial wearable devices are closed systems that do not interoperate with other devices a person might carry. We believe, however, these commercial offerings signal the coming of wireless body-area networks that will connect these pervasive wearable devices and leverage existing devices a user already …

Influence Of Medical Journal Press Releases On The Quality Of Associated Newspaper Coverage: Retrospective Cohort Study, Lisa M. Schwartz, Steven Woloshin, Alice Andrews, Therese A. Stukel

Dartmouth Scholarship

Objective: To determine whether the quality of press releases issued by medical journals can influence the quality of associated newspaper stories.

The Social Production Of Substance Abuse And Hiv/Hcv Risk: An Exploratory Study Of Opioid-Using Immigrants From The Former Soviet Union Living In New York City, Honoria Guarino, Sarah K. Moore, Lisa A. Marsch, Sal Florio

Dartmouth Scholarship

Several former Soviet countries have witnessed the rapid emergence of major epidemics of injection drug use (IDU) and associated HIV/HCV, suggesting that immigrants from the former Soviet Union (FSU) may be at heightened risk for similar problems. This exploratory study examines substance use patterns among the understudied population of opioid-using FSU immigrants in the U.S., as well as social contextual factors that may increase these immigrants' susceptibility to opioid abuse and HIV/HCV infection. In-depth interviews were conducted with 10 FSU immigrants living in New York City who initiated opioid use in adolescence or young adulthood, and with 6 drug treatment …

Seg1 Controls Eisosome Assembly And Shape, Karen E. Moreira, Sebastian Schuck, Bianca Schrul, Florian Fröhlich, James B. Moseley

Dartmouth Scholarship

Eisosomes are stable domains at the plasma membrane of the budding yeast Saccharomyces cerevisiae and have been proposed to function in endocytosis. Eisosomes are composed of two main cytoplasmic proteins, Pil1 and Lsp1, that form a scaffold around furrow-like plasma membrane invaginations. We show here that the poorly characterized eisosome protein Seg1/Ymr086w is important for eisosome biogenesis and architecture. Seg1 was required for efficient incorporation of Pil1 into eisosomes and the generation of normal plasma membrane furrows. Seg1 preceded Pil1 during eisosome formation and established a platform for the assembly of other eisosome components. This platform was further shaped and …

Structural Characterization Of A Conserved, Calcium-Dependent Periplasmic Protease From Legionella Pneumophila, Debashree Chatterjee, Chelsea D. Boyd, George A. O'Toole, Holger Sondermann

Dartmouth Scholarship

The bacterial dinucleotide second messenger c-di-GMP has emerged as a central molecule in regulating bacterial behavior, including motility and biofilm formation. Proteins for the synthesis and degradation of c-di-GMP and effectors for its signal transmission are widely used in the bacterial domain. Previous work established the GGDEF-EAL domain-containing receptor LapD as a central switch in Pseudomonas fluorescens cell adhesion. LapD senses c-di-GMP inside the cytosol and relays this signal to the outside by the differential recruitment of the periplasmic protease LapG. Here we identify the core components of an orthologous system in Legionella pneumophila. Despite only moderate sequence conservation at …

Encounters With Witchcraft, Norman Miller

Dartmouth Scholarship

My first experience with witchcraft in Africa occurred in March 1960 in Mombasa, Kenya, just as I stepped off the gangway of the MS Inchanga following a voyage from India. Next to the ship in a dockside kiosk I saw a newspaper with the headline, “European Geologist Attacked in Gogoland: Witchcraft Suspected.” It was the story of a 22-year-old British geologist, William Hanning, who had been prospecting for minerals in a remote part of nearby Tanzania when by mistake he dug into a burial ground. He was believed to be a witch, disguised as a European, out to steal body …

The Formin Fmnl3 Is A Cytoskeletal Regulator Of Angiogenesis, Clare Hetheridge, Alice N. Scott, Rajeeb K. Swain, John W. Copeland, Henry N. Higgs

Dartmouth Scholarship

The process of angiogenesis requires endothelial cells (ECs) to undergo profound changes in shape and polarity. Although this must involve remodelling of the EC cytoskeleton, little is known about this process or the proteins that control it. We used a co-culture assay of angiogenesis to examine the cytoskeleton of ECs actively undergoing angiogenic morphogenesis. We found that elongation of ECs during angiogenesis is accompanied by stabilisation of microtubules and their alignment into parallel arrays directed at the growing tip. In other systems, similar microtubule alignments are mediated by the formin family of cytoskeletal regulators. We screened a library of human …

Prevalence And Risk Factors Of Major Depressive Disorder In Hiv/Aids As Seen In Semi-Urban Entebbe District, Uganda, Eugene Kinyanda, Susan Hoskins, Juliet Nakku, Saira Nawaz, Vikram Patel

Dartmouth Scholarship

Background:

Not much is known about the risk factors of major depressive disorder (MDD) in HIV/AIDS in the African socio-cultural context. Therefore a study was undertaken to examine the prevalence and risk factors of MDD in HIV/AIDS in semi-urban Uganda.

Methods:

A cross-sectional study was undertaken among 618 respondents attending two HIV clinics in Uganda.

Results:

Prevalence of MDD was 8.1%. Factors associated with MDD at univariate analysis only were female gender, family history of mental illness, negative coping style, alcohol dependency disorder, food insecurity and stress; not associated with MDD were social support, neurocognitive impairment, CD4 counts and BMI. …

Partition Decoupling For Multi-Gene Analysis Of Gene Expression Profiling Data, Rosemary Braun, Gregory Leibon, Scott Pauls, Daniel Rockmore

Dartmouth Scholarship

Background:

Multi-gene interactions likely play an important role in the development of complex phenotypes, and relationships between interacting genes pose a challenging statistical problem in microarray analysis, since the genes involved in these interactions may not exhibit marginal differential expression. As a result, it is necessary to develop tools that can identify sets of interacting genes that discriminate phenotypes without requiring that the classification boundary between phenotypes be convex.

Results:

We describe an extension and application of a new unsupervised statistical learning technique, known as the Partition Decoupling Method (PDM), to gene expression microarray data. This method may be used …

Cd2ap Regulates Sumoylation Of Cin85 In Podocytes, Irini Tossidou, Rainer Niedenthal, Malte Klaus, Beina Teng, Kirstin Worthmann, Benjamin King, Kevin Peterson

Dartmouth Scholarship

Podocytes are highly differentiated and polarized epithelial cells located on the visceral side of the glomerulus. They form an indispensable component of the glomerular filter, the slit diaphragm, formed by several transmembrane proteins and adaptor molecules. Disruption of the slit diaphragm can lead to massive proteinuria and nephrotic syndrome in mice and humans. CD2AP is an adaptor protein that is important for the maintenance of the slit diaphragm. Together with its paralogue, CIN85, CD2AP belongs to a family of adaptor proteins that are primarily described as being involved in endocytosis and downregulation of receptor tyrosine kinase activity. We have shown …

Rice Consumption Contributes To Arsenic Exposure In Us Women, Diane Gilbert-Diamond, Kathryn L. Cottingham, Joann F. Gruber, Tracy Punshon, Vicki Sayarath, A. Jay Gandolfi, Emily R. Baker, Brian P. Jackson, Carol L. Folt, Margaret R. Karagas

Dartmouth Scholarship

Emerging data indicate that rice consumption may lead to potentially harmful arsenic exposure. However, few human data are available, and virtually none exist for vulnerable periods such as pregnancy. Here we document a positive association between rice consumption and urinary arsenic excretion, a biomarker of recent arsenic exposure, in 229 pregnant women. At a 6-mo prenatal visit, we collected a urine sample and 3-d dietary record for water, fish/seafood, and rice. We also tested women's home tap water for arsenic, which we combined with tap water consumption to estimate arsenic exposure through water. Women who reported rice intake (n …

Triterpenoid Modulation Of Il-17 And Nrf-2 Expression Ameliorates Neuroinflammation And Promotes Remyelination In Autoimmune Encephalomyelitis, Tej K. Pareek, Abdelmadjid Belkadi, Sashi Kesavapany, Anita Zaremba, Sook L. Loh, Lianhua Bai, Mark L. Cohen, Colin Meyer, Karen T. Liby, Robert H. Miller, Michael B. Sporn, John J. Letterio

Dartmouth Scholarship

Inflammatory cytokines and endogenous anti-oxidants are variables affecting disease progression in multiple sclerosis (MS). Here we demonstrate the dual capacity of triterpenoids to simultaneously repress production of IL-17 and other pro-inflammatory mediators while exerting neuroprotective effects directly through Nrf2-dependent induction of anti-oxidant genes. Derivatives of the natural triterpene oleanolic acid, namely CDDO-trifluoroethyl-amide (CDDO-TFEA), completely suppressed disease in a murine model of MS, experimental autoimmune encephalomyelitis (EAE), by inhibiting Th1 and Th17 mRNA and cytokine production. Encephalitogenic T cells recovered from treated mice were hypo-responsive to myelin antigen and failed to adoptively transfer the disease. Microarray analyses showed significant suppression of …

Functional Genomics Reveals An Essential And Specific Role For Stat1 In Protection Of The Central Nervous System Following Herpes Simplex Virus Corneal Infection, Tracy J. Pasieka, Cristian Cilloniz, Victoria S. Carter, Pamela Rosato, Michael G. Katze, David A. Leib

Dartmouth Scholarship

Innate immune deficiencies result in a spectrum of severe clinical outcomes following infection. In particular, there is a strong association between loss of the signal transducer and activator of transcription (Stat) pathway, breach of the blood-brain barrier (BBB), and virus-induced neuropathology. The gene signatures that characterize resistance, disease, and mortality in the virus-infected nervous system have not been defined. Herpes simplex virus type 1 (HSV-1) is commonly associated with encephalitis in humans, and humans and mice lacking Stat1 display increased susceptibility to HSV central nervous system (CNS) infections. In this study, two HSV-1 strains were used, KOS (wild type [WT]), …

Combined Fluorescence And Reflectance Spectroscopy For In Vivo Quantification Of Cancer Biomarkers In Low- And High-Grade Glioma Surgery, Pablo A. ValdéS, Anthony Kim, Keith D. Paulsen, Frederic Leblond, Olga M. Conde, Brent T. Harris, David W. Roberts

Dartmouth Scholarship

Biomarkers are indicators of biological processes and hold promise for the diagnosis and treatment of disease. Gliomas represent a heterogeneous group of brain tumors with marked intra- and inter-tumor variability. The extent of surgical resection is a significant factor influencing post-surgical recurrence and prognosis. Here, we used fluorescence and reflectance spectral signatures for in vivo quantification of multiple biomarkers during glioma surgery, with fluorescence contrast provided by exogenously-induced protoporphyrin IX (PpIX) following administration of 5-aminolevulinic acid. We performed light-transport modeling to quantify multiple biomarkers indicative of tumor biological processes, including the local concentration of PpIX and associated photoproducts, total hemoglobin …

Chromosome Missegregation In Human Cells Arises Through Specific Types Of Kinetochore–Microtubule Attachment Errors, Sarah L. Thompson, Duane A. Compton

Dartmouth Scholarship

Most solid tumors are aneuploid, and many missegregate chromosomes at high rates in a phenomenon called chromosomal instability (CIN). CIN reflects the erosion of mitotic fidelity, and it correlates with poor patient prognosis and drug resistance. The most common mechanism causing CIN is the persistence of improper kinetochore–microtubule attachments called merotely. Chromosomes with merotelic kinetochores often manifest as lagging chromosomes in anaphase, suggesting that lagging chromosomes fail to segregate properly. However, it remains unknown whether the lagging chromosomes observed in anaphase segregate to the correct or incorrect daughter cell. To address this question, we tracked the segregation of a single …

Lymphotoxin-Beta Receptor Blockade Reduces Cxcl13 In Lacrimal Glands And Improves Corneal Integrity In The Nod Model Of Sjögren's Syndrome, Roy A. Fava, Susan M. Kennedy, Sheryl G. Wood, Anne I. Bolstad, Jadwiga Bienkowska, Adrian Papandile, John A. Kelly

Dartmouth Scholarship

In Sjögren's syndrome, keratoconjunctivitis sicca (dry eye) is associated with infiltration of lacrimal glands by leukocytes and consequent losses of tear-fluid production and the integrity of the ocular surface. We investigated the effect of blockade of the lymphotoxin-beta receptor (LTBR) pathway on lacrimal-gland pathology in the NOD mouse model of Sjögren's syndrome.

Characterization Of Street Food Consumption In Palermo: Possible Effects On Health, Silvio Buscemi, Annamaria Barile, Vincenza Maniaci, John A. Batsis

Dartmouth Scholarship

Background: Street Food (SF) consists of out-of-home food consumption and has old, historical roots with complex social-economic and cultural implications. Despite the emergence of modern fast food, traditional SF persists worldwide, but the relationship of SF consumption with overall health, well-being, and obesity is unknown.

Methods: This is an observational, cross-sectional study. The study was performed in Palermo, the largest town of Sicily, Italy. Two groups were identified: consumers of SF (n = 687) and conventional restaurant food (RES) consumers (n = 315). Study subjects answered a questionnaire concerning their health conditions, nutritional preferences, frequency of consumption of SF and …

Protective Cd8 Memory T Cell Responses To Mouse Melanoma Are Generated In The Absence Of Cd4 T Cell Help, Anik L. Côté, Katelyn T. Byrne, Shannon M. Steinberg, Peisheng Zhang, Mary Jo Turk

Dartmouth Scholarship

Background: We have previously demonstrated that temporary depletion of CD4 T cells in mice with progressive B16 melanoma, followed by surgical tumor excision, induces protective memory CD8 T cell responses to melanoma/melanocyte antigens. We also showed that persistence of these CD8 T cells is supported, in an antigen-dependent fashion, by concurrent autoimmune melanocyte destruction. Herein we explore the requirement of CD4 T cell help in priming and maintaining this protective CD8 T cell response to melanoma.

Adapt-Lite: Privacy-Aware, Secure, And Efficient Mhealth Sensing, Shrirang Mare, Jacob Sorber, Minho Shin, Cory Cornelius, David Kotz

Dartmouth Scholarship

As healthcare in many countries faces an aging population and rising costs, mobile sensing technologies promise a new opportunity. Using mobile health (mHealth) sensing, which uses medical sensors to collect data about the patients, and mobile phones to act as a gateway between sensors and electronic health record systems, caregivers can continuously monitor the patients and deliver better care. Although some work on mHealth sensing has addressed security, achieving strong security and privacy for low-power sensors remains a challenge. \par We make three contributions. First, we propose Adapt-lite, a set of two techniques that can be applied to existing wireless …

2-Heptyl-4-Quinolone, A Precursor Of The Pseudomonas Quinolone Signal Molecule, Modulates Swarming Motility In Pseudomonas Aeruginosa, Dae-Gon Ha, Judith H. Merritt, Thomas H. Hampton, James T. Hodgkinson, Matej Janecek, David R. Spring, Martin Welch, George A. O'Toole

Dartmouth Scholarship

Pseudomonas aeruginosa is an opportunistic pathogen capable of group behaviors, including biofilm formation and swarming motility. These group behaviors are regulated by both the intracellular signaling molecule c-di-GMP and acylhomoserine lactone quorum-sensing systems. Here, we show that the Pseudomonas quinolone signal (PQS) system also contributes to the regulation of swarming motility. Specifically, our data indicate that 2-heptyl-4-quinolone (HHQ), a precursor of PQS, likely induces the production of the phenazine-1-carboxylic acid (PCA), which in turn acts via an as-yet-unknown downstream mechanism to repress swarming motility. We show that this HHQ- and PCA-dependent swarming repression is apparently independent of changes in global …