Medicine and Health Sciences Commons^™

Parasite Manipulation Of The Invariant Chain And The Peptide Editor H2-Dm Affects Major Histocompatibility Complex Class Ii Antigen Presentation During Toxoplasma Gondii Infection, Louis-Philippe Leroux, Manami Nishi, Sandy El-Hage, Barbara A. Fox, David I Bzik, Florence Dzierszinsk

Dartmouth Scholarship

Toxoplasma gondii is an obligate intracellular protozoan parasite. This apicomplexan is the causative agent of toxoplasmosis, a leading cause of central nervous system disease in AIDS. It has long been known that T. gondii interferes with major histocompatibility complex class II (MHC-II) antigen presentation to attenuate CD4(+) T cell responses and establish persisting infections. Transcriptional downregulation of MHC-II genes by T. gondii was previously established, but the precise mechanisms inhibiting MHC-II function are currently unknown. Here, we show that, in addition to transcriptional regulation of MHC-II, the parasite modulates the expression of key components of the MHC-II antigen presentation pathway, …

Three-Dimensional Matrix Fiber Alignment Modulates Cell Migration And Mt1-Mmp Utility By Spatially And Temporally Directing Protrusions, Stephanie I. Fraley, Pei-Hsun Wu, Lijuan He, Yunfeng Feng, Ranjini Krisnamurthy, Gregory D. Longmore, Denis Wirtz

Dartmouth Scholarship

Multiple attributes of the three-dimensional (3D) extracellular matrix (ECM) have been independently implicated as regulators of cell motility, including pore size, crosslink density, structural organization, and stiffness. However, these parameters cannot be independently varied within a complex 3D ECM protein network. We present an integrated, quantitative study of these parameters across a broad range of complex matrix configurations using self-assembling 3D collagen and show how each parameter relates to the others and to cell motility. Increasing collagen density resulted in a decrease and then an increase in both pore size and fiber alignment, which both correlated significantly with cell motility …

Blood Pressure Changes In Relation To Arsenic Exposure In A U.S. Pregnancy Cohort, Shohreh F. Farzan, Yu Chen, Fen Wu, Jieying Jiang, Mengling Liu, Emily Baker, Susan A. Korrick, Margaret R. Karagas

Dartmouth Scholarship

Background:

Inorganic arsenic exposure has been related to the risk of increased blood pressure based largely on cross-sectional studies conducted in highly exposed populations. Pregnancy is a period of particular vulnerability to environmental insults. However, little is known about the cardiovascular impacts of arsenic exposure during pregnancy.

Objectives:

We evaluated the association between prenatal arsenic exposure and maternal blood pressure over the course of pregnancy in a U.S. population.

Methods:

The New Hampshire Birth Cohort Study is an ongoing prospective cohort study in which > 10% of participant household wells exceed the arsenic maximum contaminant level of 10 μg/L established by …

Validation Of A New Predictive Risk Model: Measuring The Impact Of The Major Modifiable Risks Of Death For Patients And Populations, Stephen S. Lim, Emily Carnahan, Eugene C. Nelson, Catherine W. Gillespie, Ali H. Mokdad, Christopher J. L. Murray, Elliott S. Fisher

Dartmouth Scholarship

Background: Modifiable risks account for a large fraction of disease and death, but clinicians and patients lack tools to identify high risk populations or compare the possible benefit of different interventions.

Methods: We used data on the distribution of exposure to 12 major behavioral and biometric risk factors inthe US population, mortality rates by cause, and estimates of the proportional hazards of risk factor exposure from published systematic reviews to develop a risk prediction model that estimates an adult's 10 year mortality risk compared to a population with optimum risk factors. We compared predicted risk to observed mortality in 8,241 …

Dual Use Of Va And Non-Va Hospitals By Veterans With Multiple Hospitalizations, Alan N. West, Mary E. Charlton, Mary Vaughan-Sarrazin

Dartmouth Scholarship

Background: Veterans who are hospitalized in both VA and non-VA hospitals within a short timespan may be at risk for fragmented or conflicting care. To determine the characteristics of these “dual users,” we analyzed administrative hospital discharge data for VA-enrolled veterans of any age in seven states, including any VA or non-VA hospitalizations they had in 2004 – 2007. Method: For VA enrollees in Arizona, Iowa, Louisiana, Florida, South Carolina, Pennsylvania, or New York in 2007, we merged 2004 – 2007 discharge data for all VA hospitalizations and all non-VA hospitalizations listed in state health department or hospital association databases. …

Risk Factors For Hemorrhoids On Screening Colonoscopy, Anne F. Peery, Robert S. Sandler, Joseph A. Galanko, Robert S. Bresalier, Jane C. Figueiredo, Dennis J. Ahnen, Elizabeth L. L. Barry, John A. Baron

Dartmouth Scholarship

Background: Constipation, a low fiber diet, sedentary lifestyle and gravidity are commonly assumed to increase the risk of hemorrhoids. However, evidence regarding these factors is limited. We examined the association between commonly cited risk factors and the prevalence of hemorrhoids. Methods: We performed a cross sectional study of participants who underwent a colonoscopy in a colorectal adenoma prevention trial and who had a detailed assessment of bowel habits, diet and activity. The presence of hemorrhoids was extracted from the subjects’ colonoscopy reports. We used logistic regression to estimate odds ratios and 95% confidence intervals while adjusting for age and sex. …

International Genome-Wide Meta-Analysis Identifies New Primary Biliary Cirrhosis Risk Loci And Targetable Pathogenic Pathways, Heather J. Cordell, Younghun Han, George F. Mells, Yafang Li, Gideon M. Hirschfield, Casey S. Greene, Gang Xie, Brian D. Juran, Dakai Zhu, David C. Qian, James A.B Floyd, Katherine I. Morley, Daniele Prati, Ana Lleo, Daniele Cusi, Canadian–Us Pbc Consortium, Italian Pbc Genetics Study Group, Uk-Pbc Consortium, M. Eric Gershwin, Carl A. Anderson, Konstantinos N. Lazaridis, Pietro Invernizzi, Michael F. Seldin, Richard N. Sandford, Christopher I. Amos, Katherine A. Siminovitch

Dartmouth Scholarship

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (P_combined<5 × 10⁻⁸) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine–cytokine pathways, for which relevant therapies exist.

Isoflurane Inhibits Synaptic Vesicle Exocytosis Through Reduced Ca2+ Influx, Not Ca2+-Exocytosis Coupling, Joel Baumgart, Zhen-Yu Zhou, Masato Hara, Daniel Cook, Michael Hoppa

Dartmouth Scholarship

Identifying presynaptic mechanisms of general anesthetics is critical to understanding their effects on synaptic transmission. We show that the volatile anesthetic isoflurane inhibits synaptic vesicle (SV) exocytosis at nerve terminals in dissociated rat hippocampal neurons through inhibition of presynaptic Ca2+ influx without significantly altering the Ca2+ sensitivity of SV exocytosis. A clinically relevant concentration of isoflurane (0.7 mM) inhibited changes in [Ca2+]i driven by single action potentials (APs) by 25 ± 3%, which in turn led to 62 ± 3% inhibition of single AP-triggered exocytosis at 4 mM extracellular Ca2+ ([Ca2+]e). Lowering external Ca2+ to match the isoflurane-induced reduction in …

Eisosomes Provide Membrane Reservoirs For Rapid Expansion Of The Yeast Plasma Membrane, Ruth Kabeche, Louisa Howard, James B. Moseley

Dartmouth Scholarship

Cell surface area rapidly increases during mechanical and hypoosmotic stresses. Such expansion of the plasma membrane requires 'membrane reservoirs' that provide surface area and buffer membrane tension, but the sources of this membrane remain poorly understood. In principle, the flattening of invaginations and buds within the plasma membrane could provide this additional surface area, as recently shown for caveolae in animal cells. Here, we used microfluidics to study the rapid expansion of the yeast plasma membrane in protoplasts, which lack the rigid cell wall. To survive hypoosmotic stress, yeast cell protoplasts required eisosomes, protein-based structures that generate long invaginations at …

Development And Validation Of An Epitope Prediction Tool For Swine (Pigmatrix) Based On The Pocket Profile Method, Andres H. Gutiérrez, William D. Martin, Chris Bailey-Kellogg, Frances Terry, Leonard Moise, Anee S. De Groot

Dartmouth Scholarship

Background: T cell epitope prediction tools and associated vaccine design algorithms have accelerated the development of vaccines for humans. Predictive tools for swine and other food animals are not as well developed, primarily because the data required to develop the tools are lacking. Here, we overcome a lack of T cell epitope data to construct swine epitope predictors by systematically leveraging available human information. Applying the “pocket profile method ”, we use sequence and structural similarities in the binding pockets of human and swine major histocompatibility complex proteins to infer Swine Leukocyte Antigen (SLA) peptide binding preferences. We developed epitope-prediction …

A Multiscale Mapping Assessment Of Lake Champlain Cyanobacterial Harmful Algal Blooms, Nathan Torbick, Megan Corbiere, Yu-Pin Lin

Dartmouth Scholarship

Lake Champlain has bays undergoing chronic cyanobacterial harmful algal blooms that pose a public health threat. Monitoring and assessment tools need to be developed to support risk decision making and to gain a thorough understanding of bloom scales and intensities. In this research application, Landsat 8 Operational Land Imager (OLI), Rapid Eye, and Proba Compact High Resolution Imaging Spectrometer (CHRIS) images were obtained while a corresponding field campaign collected in situ measurements of water quality. Models including empirical band ratio regressions were applied to map chlorophylla and phycocyanin concentrations; all sensors performed well with R² and root-mean-square error (RMSE) ranging …

Surgical Clipping Versus Endovascular Intervention For The Treatment Of Subarachnoid Hemorrhage Patients In New York State, Kimon Bekelis, Symeon Missios, Shannon Coy, Redi Rahmani, Robert J. Singer, Todd A. Mackenzie

Dartmouth Scholarship

Object:

Randomized trials have demonstrated a survival benefit for endovascular treatment of ruptured cerebral aneurysms. We investigated the association of surgical clipping and endovascular coiling with outcomes in subarachnoid hemorrhage (SAH) patients in a real-world regional cohort. Methods: We performed a cohort study involving patients with ruptured cerebral aneurysms, who underwent surgical clipping, or endovascular coiling from 2009–2013 and were registered in the Statewide Planning and Research Cooperative System (SPARCS) database. An instrumental variable analysis was used to investigate the association of treatment technique with outcomes. Results: Of the 4,098 patients undergoing treatment, 2,585 (63.1%) underwent coiling, and 1,513 (36.9%) …

Prediction Of Relevant Biomedical Documents: A Human Microbiome Case Study, Paul Thompson, Juliette C. Madan, Jason H. Moore

Dartmouth Scholarship

Background:

Retrieving relevant biomedical literature has become increasingly difficult due to the large volume and rapid growth of biomedical publication. A query to a biomedical retrieval system often retrieves hundreds of results. Since the searcher will not likely consider all of these documents, ranking the documents is important. Ranking by recency, as PubMed does, takes into account only one factor indicating potential relevance. This study explores the use of the searcher’s relevance feedback judgments to support relevance ranking based on features more general than recency.

Results:

It was found that the researcher’s relevance judgments could be used to accurately predict …

Targeting Ezh2 Regulates Tumor Growth And Apoptosis Through Modulating Mitochondria Dependent Cell-Death Pathway In Hnscc, Xuan Zhou, Yu Ren, Lingping Kong, Guoshuai Cai, Shanshan Sun, Wangzhao Song, Yu Wang, Rui Jin, Lisha Qi, Mei Mei

Dartmouth Scholarship

EZH2 is a negative prognostic factor and is overexpressed or activated in most human cancers including head and neck squamous cell carcinoma (HNSCC). Analysis of The Cancer Genome Atlas (TCGA) HNSCC data indicated that EZH2 over-expression was associated with high tumor grade and conferred poor prognosis. EZH2 inhibition triggered cell apoptosis, cell cycle arrest and decreased cell growth in vitro. MICU1 (mitochondrial calcium uptake1) was shown to be down regulated when EZH2 expression was inhibited in HNSCC. When the EZH2 and MICU1 were inhibited, HNSCC cells became susceptible to cell cycle arrest and apoptosis. Mitochondrial membrane potential and cytosolic Ca2+ …

Improving Health Outcomes Through Concurrent Hiv Program Scale-Up And Health System Development In Rwanda: 20 Years Of Experience, Sabin Nsanzimana, Krishna Prabhu, Haley Mcdermott, Etienne Karita, Jamie I. Forrest, Peter Drobac, Paul Farmer, Edward J. Mills, Agnes Binagwaho

Dartmouth Scholarship

The 1994 genocide against the Tutsi destroyed the health system in Rwanda. It is impressive that a small country like Rwanda has advanced its health system to the point of now offering near universal health insurance coverage. Through a series of strategic structural changes to its health system, catalyzed through international assistance, Rwanda has demonstrated a commitment towards improving patient and population health indicators. In particular, the rapid scale up of antiretroviral therapy (ART) has become a great success story for Rwanda. The country achieved universal coverage of ART at a CD4 cell count of 200 cells/mm³ in 2007 …

A Highly Stable Prefusion Rsv F Vaccine Derived From Structural Analysis Of The Fusion Mechanism, Anders Krarup, Daphné Truan, Polina Furmanova-Hollenstein, Lies Bogaert, Pascale Bouchier, Ilona Bisschop, Myra Widjojoatmodjo, Roland Zahn, Hanneke Schuitemaker, Jason Mclellan, Johannes Langedijk

Dartmouth Scholarship

Respiratory syncytial virus (RSV) causes acute lower respiratory tract infections and is the leading cause of infant hospitalizations. Recently, a promising vaccine antigen based on the RSV fusion protein (RSV F) stabilized in the native prefusion conformation has been described. Here we report alternative strategies to arrest RSV F in the prefusion conformation based on the prevention of hinge movements in the first refolding region and the elimination of proteolytic exposure of the fusion peptide. A limited number of unique mutations are identified that stabilize the prefusion conformation of RSV F and dramatically increase expression levels. This highly stable prefusion …

Review Of Fluorescence Guided Surgery Visualization And Overlay Techniques, Jonathan T. Elliott, Alisha V. Dsouza, Scott C. Davis, Jonathan D. Olson, Keith Paulsen, David Roberts, Brian Pogue

Dartmouth Scholarship

In fluorescence guided surgery, data visualization represents a critical step between signal capture and display needed for clinical decisions informed by that signal. The diversity of methods for displaying surgical images are reviewed, and a particular focus is placed on electronically detected and visualized signals, as required for near-infrared or low concentration tracers. Factors driving the choices such as human perception, the need for rapid decision making in a surgical environment, and biases induced by display choices are outlined. Five practical suggestions are outlined for optimal display orientation, color map, transparency/alpha function, dynamic range compression, and color perception check.

Rna-Seq Analysis Of Differential Splice Junction Usage And Intron Retentions By Dexseq, Yafang Li, Xiayu Rao, William W. Mattox, Christopher I. Amos, Bin Liu

Dartmouth Scholarship

Alternative splicing is an important biological process in the generation of multiple functional transcripts from the same genomic sequences. Differential analysis of splice junctions (SJs) and intron retentions (IRs) is helpful in the detection of alternative splicing events. In this study, we conducted differential analysis of SJs and IRs by use of DEXSeq, a Bioconductor package originally designed for differential exon usage analysis in RNA-seq data analysis. We set up an analysis pipeline including mapping of RNA-seq reads, the preparation of count tables of SJs and IRs as the input files, and the differential analysis in DEXSeq. We analyzed the …

Risk Of Death From Cardiovascular Disease Associated With Low-Level Arsenic Exposure Among Long-Term Smokers In A Us Population-Based Study, Shohreh F. Farzan, Yu Chen, Judy R. Rees, M. Scot Zens, Margaret Karagas

Dartmouth Scholarship

High levels of arsenic exposure have been associated with increases in cardiovascular disease risk. However, studies of arsenic’s effects at lower exposure levels are limited and few prospective studies exist in the United States using long-term arsenic exposure biomarkers. We conducted a prospective analysis of the association between toenail arsenic and cardiovascular disease mortality using longitudinal data collected on 3939 participants in the New Hampshire Skin Cancer Study. Using Cox proportional hazard models adjusted for potential confounders, we estimated hazard ratios and 95% confidence intervals associated with the risk of death from any cardiovascular disease, ischemic heart disease, and stroke, …

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 …

Mitochondrial Activity And Cyr1 Are Key Regulators Of Ras1 Activation Of C. Albicans Virulence Pathways, Nora Grahl, Elora G. Demers, Allia K. Lindsay, Colleen E. Harty, Sven D. Wilger, Amy E. Piispanen, Deborah A. Hogan

Dartmouth Scholarship

Candida albicans is both a major fungal pathogen and a member of the commensal human microflora. The morphological switch from yeast to hyphal growth is associated with disease and many environmental factors are known to influence the yeast-to-hyphae switch. The Ras1-Cyr1-PKA pathway is a major regulator of C. albicans morphogenesis as well as biofilm formation and white-opaque switching. Previous studies have shown that hyphal growth is strongly repressed by mitochondrial inhibitors. Here, we show that mitochondrial inhibitors strongly decreased Ras1 GTP-binding and activity in C. albicans and similar effects were observed in other Candida species. Consistent with there …

Role Of The Dna Sensor Sting In Protection From Lethal Infection Following Corneal And Intracerebral Challenge With Herpes Simplex Virus 1, Zachary M. Parker, Aisling A. Murphy, David. A. Leib

Dartmouth Scholarship

STING is a protein in the cytosolic DNA and cyclic dinucleotide sensor pathway that is critical for the initiation of innate responses to infection by various pathogens. Consistent with this, herpes simplex virus 1 (HSV-1) causes invariable and rapid lethality in STING-deficient (STING(-/-)) mice following intravenous (i.v.) infection. In this study, using real-time bioluminescence imaging and virological assays, as expected, we demonstrated that STING(-/-) mice support greater replication and spread in ocular tissues and the nervous system. In contrast, they did not succumb to challenge via the corneal route even with high titers of a virus that was routinely lethal …

Logarithmic Intensity Compression In Fluorescence Guided Surgery Applications, Alisha V. Dsouza, Huiyun Lin, Jason Gunn, Brian W. Pogue

Dartmouth Scholarship

The use of fluorescence video imaging to guide surgery is rapidly expanding, and improvements in camera readout dynamic range have not matched display capabilities. Logarithmic intensity compression is a fast, single-step mapping technique that can map the useable dynamic range of high-bit fluorescence images onto the typical 8-bit display and potentially be a variable dynamic contrast enhancement tool. We demonstrate a ∼4.6  times improvement in image quality quantified by image entropy and a dynamic range reduction by a factor of ∼380 by the use of log-compression tools in processing in vivo fluorescence images.

Maternal Psychiatric Disease And Epigenetic Evidence Suggest A Common Biology For Poor Fetal Growth, Timothy H. Ciesielski, Carmen J. Marsit, Scott M. Williams

Dartmouth Scholarship

We sought to identify and characterize predictors of poor fetal growth among variables extracted from perinatal medical records to gain insight into potential etiologic mechanisms. In this process we reevaluated a previously observed association between poor fetal growth and maternal psychiatric disease. We evaluated 449 deliveries of >36 weeks gestation that occurred between 9/2008 and 9/2010 at the Women and Infants Hospital in Providence Rhode Island. This study group was oversampled for Small-for-Gestational-Age (SGA) infants and excluded Large-for-Gestational-Age (LGA) infants. We assessed the associations between recorded clinical variables and impaired fetal growth: SGA or Intrauterine Growth Restriction (IUGR) diagnosis. After …

Selection Of Depression Measures For Use Among Vietnamese Populations In Primary Care Settings: A Scoping Review, Jill Murphy, Elliot M. Goldner, Charles H. Goldsmith, Pham Thi Oanh, William Zhu, Kitty Corbett, Vu Cong Nguyen

Dartmouth Scholarship

Depression is an important and growing contributor to the burden of disease around the world and evidence suggests the experience of depression varies cross-culturally. Efforts to improve the integration of services for depression in primary care are increasing globally, meaning that culturally valid measures that are acceptable for use in primary care settings are needed. We conducted a scoping review of 27 studies that validated or used 10 measures of depression in Vietnamese populations. We reviewed the validity of the instruments as reported in the studies and qualitatively assessed cultural validity and acceptability for use in primary care. We found …

Principal Component Gene Set Enrichment (Pcgse), H. Robert Frost, Zhigang Li, Jason H. Moore

Dartmouth Scholarship

Background:

Although principal component analysis (PCA) is widely used for the dimensional reduction of biomedical data, interpretation of PCA results remains daunting. Most existing interpretation methods attempt to explain each principal component (PC) in terms of a small number of variables by generating approximate PCs with mainly zero loadings. Although useful when just a few variables dominate the population PCs, these methods can perform poorly on genomic data, where interesting biological features are frequently represented by the combined signal of functionally related sets of genes. While gene set testing methods have been widely used in supervised settings to quantify the …

Prediction Of The Gene Expression In Normal Lung Tissue By The Gene Expression In Blood, Justin W. Halloran, Dakai Zhu, David C. Qian, Jinyoung Byun, Olga Y. Gorlova, Christopher I. I. Amos, Ivan P. Gorlov

Dartmouth Scholarship

Background:

Comparative analysis of gene expression in human tissues is important for understanding the molecular mechanisms underlying tissue-specific control of gene expression. It can also open an avenue for using gene expression in blood (which is the most easily accessible human tissue) to predict gene expression in other (less accessible) tissues, which would facilitate the development of novel gene expression based models for assessing disease risk and progression. Until recently, direct comparative analysis across different tissues was not possible due to the scarcity of paired tissue samples from the same individuals.

Methods:

In this study we used paired whole blood/lung …

Two Novel Genetic Variants In The Mineralocorticoid Receptor Gene Associated With Spontaneous Preterm Birth, Inge Christiaens, Q. Wei Ang, Lindsay N. Gordon, Xin Fang, Scott Williams

Dartmouth Scholarship

Background: Preterm birth is the leading cause of mortality and morbidity in newborn infants. Its etiology is multifactorial with genes and environmental factors, including chronic maternal stress, contributing to its risk. Our objective was to investigate whether single nucleotide polymorphisms (SNPs) in genes involved in the stress response are associated with spontaneous preterm birth using a candidate gene approach.

Methods: A total of 210 cases (singleton spontaneous preterm birth at <37 >weeks) and 412 controls (singleton term birth at 38–42 weeks without a history of preterm birth) were studied. High quality maternal DNA was available from saliva samples of 190 cases …

Implementing Shared Decision-Making: Consider All The Consequences, Glyn Elwyn, Dominick L. Frosch, Sarah Kobrin

Dartmouth Scholarship

The ethical argument that shared decision-making is “the right” thing to do, however laudable, is unlikely to change how healthcare is organized, just as evidence alone will be an insufficient factor: practice change is governed by factors such as cost, profit margin, quality, and efficiency. It is helpful, therefore, when evaluating new approaches such as shared decision-making to conceptualize potential consequences in a way that is broad, long-term, and as relevant as possible to multiple stakeholders. Yet, so far, evaluation metrics for shared decision-making have been mostly focused on short-term outcomes, such as cognitive or affective consequences in patients. The …

Epigenome-Wide And Transcriptome-Wide Analyses Reveal Gestational Diabetes Is Associated With Alterations In The Human Leukocyte Antigen Complex, Alexandra M. Binder, Jessica Larocca, Corina Lesseur, Carmen J. Marsit, Karin B. Michels

Dartmouth Scholarship

Background: Gestational diabetes mellitus (GDM) affects approximately 10% of pregnancies in the United States and increases the risk of adverse health outcomes in the offspring. These adult disease propensities may be set by anatomical and molecular alterations in the placenta associated with GDM. Results: To assess the mechanistic aspects of fetal programming, we measured genome-wide methylation (Infinium HumanMethylation450 BeadChips) and expression (Affymetrix transcriptome microarrays) in placental tissue of 41 GDM cases and 41 matched pregnancies without maternal complications from the Harvard Epigenetic Birth Cohort. Specific transcriptional and epigenetic perturbations associated with GDM status included alterations in the major histocompatibility complex …