Digital Commons Network^™

Joint Effect Of Multiple Common Snps Predicts Melanoma Susceptibility, Shenying Fang, Jiali Han, Mingfeng Zhang, Li-E Wang, Qingyi Wei, Christopher I. Amos, Jeffrey E. Lee

Dartmouth Scholarship

Single genetic variants discovered so far have been only weakly associated with melanoma. This study aims to use multiple single nucleotide polymorphisms (SNPs) jointly to obtain a larger genetic effect and to improve the predictive value of a conventional phenotypic model. We analyzed 11 SNPs that were associated with melanoma risk in previous studies and were genotyped in MD Anderson Cancer Center (MDACC) and Harvard Medical School investigations. Participants with ≥15 risk alleles were 5-fold more likely to have melanoma compared to those carrying ≤6. Compared to a model using the most significant single variant rs12913832, the increase in predictive …

Contrast Enhanced-Magnetic Resonance Imaging As A Surrogate To Map Verteporfin Delivery In Photodynamic Therapy, Kimberley S. Samkoe, Amber Bryant, Jason R. Gunn, Stephen P. Pereira, Tayyaba Hasan, Brian W. Pogue

Dartmouth Scholarship

The use of in vivo contrast-enhanced magnetic resonance (MR) imaging as a surrogate for photosensitizer (verteporfin) dosimetry in photodynamic therapy of pancreas cancer is demonstrated by correlating MR contrast uptake to ex vivo fluorescence images on excised tissue. An orthotopic pancreatic xenograft mouse model was used for the study. A strong correlation ([i]r=0.57 ) was found for bulk intensity measurements of T1-weighted gadolinium enhancement and verteporfin fluorescence in the tumor region of interest. The use of contrast-enhanced MR imaging shows promise as a method for treatment planning and photosensitizer dosimetry in human photodynamic therapy (PDT) of pancreas …

Divergent Antibody Subclass And Specificity Profiles But Not Protective Hla-B Alleles Are Associated With Variable Antibody Effector Function Among Hiv-1 Controllers, Jennifer I. Lai, Anna F. Licht, Anne-Sophie Dugast, Todd Suscovich, Ickwon Choi, Chris Bailey-Kellogg, Galit Alter, Margaret E. Ackerman

Dartmouth Scholarship

Understanding the coordination between humoral and cellular immune responses may be the key to developing protective vaccines, and because genetic studies of long-term HIV-1 nonprogressors have associated specific HLA-B alleles with spontaneous control of viral replication, this subject group presents an opportunity to investigate relationships between arms of the adaptive immune system. Given evidence suggesting that cellular immunity may play a role in viral suppression, we sought to determine whether and how the humoral immune response might vary among controllers. Significantly, Fc-mediated antibody effector functions have likewise been associated with durable viral control. In this study, we compared the effector …

Enrichment And Training Improve Cognition In Rats With Cortical Malformations, Kyle R. Jenks, Marcella M. Lucas, Ben A. Duffy, Ashlee A. Robbins, Barjor Gimi, Jeremy M. Barry, Rod C. Scott

Dartmouth Scholarship

Children with malformations of cortical development (MCD) frequently have associated cognitive impairments which reduce quality of life. We hypothesized that cognitive deficits associated with MCD can be improved with environmental manipulation or additional training. The E17 methylazoxymethanol acetate (MAM) exposure model bears many anatomical hallmarks seen in human MCDs as well as similar behavioral and cognitive deficits. We divided control and MAM exposed Sprague-Dawley rats into enriched and non-enriched groups and tested performance in the Morris water maze. Another group similarly divided underwent sociability testing and also underwent Magnetic Resonance Imaging (MRI) scans pre and post enrichment. A third group …

A Pil1–Sle1–Syj1–Tax4 Functional Pathway Links Eisosomes With Pi(4,5)P2 Regulation, Ruth Kabeche, Assen Roguev, Nevan J. Krogan, James B. Moseley

Dartmouth Scholarship

Stable compartments of the plasma membrane promote a wide range of cellular functions. In yeast cells, cytosolic structures called eisosomes generate prominent cortical invaginations of unknown function. Through a series of genetic screens in fission yeast, we found that the eisosome proteins Pil1 and Sle1 function with the synaptojanin-like lipid phosphatase Syj1 and its ligand Tax4. This genetic pathway connects eisosome function with the hydrolysis of phosphatidylinositol (4,5)-bisphosphate [PI(4,5)P2] in cells. Defects in PI(4,5)P2 regulation led to eisosome defects, and we found that the core eisosome protein Pil1 can bind to and tubulate liposomes containing PI(4,5)P2. Mutations in components of …

Contrast Negation Differentiates Visual Pathways Underlying Dynamic And Invariant Facial Processing, Pamela M. Pallett, Ming Meng

Dartmouth Scholarship

Abstract Bruce and Young (1986) proposed a model for face processing that begins with structural encoding, followed by a split into two processing streams: one for the dynamic aspects of the face (e.g., facial expressions of emotion) and the other for the invariant aspects of the face (e.g., gender, identity). Yet how this is accomplished remains unclear. Here, we took a psychophysical approach using contrast negation to test the Bruce and Young model. Previous research suggests that contrast negation impairs processing of invariant features (e.g., gender) but not dynamic features (e.g., expression). In our first experiment, participants discriminated differences in …

Use Of Irf-3 And/Or Irf-7 Knockout Mice To Study Viral Pathogenesis: Lessons From A Murine Retrovirus-Induced Aids Model, Megan A. O'Connor, William R. Green

Dartmouth Scholarship

Interferon regulatory factor (IRF) regulation of the type I interferon response has not been extensively explored in murine retroviral infections. IRF-3(-/-) and select IRF-3/7(-/-) mice were resistant to LP-BM5-induced pathogenesis. However, further analyses strongly suggested that resistance could be attributed to strain 129-specific contamination of the known retrovirus resistance gene Fv1. Therefore, caution should be taken when interpreting phenotypes observed in these knockout mice, as strain 129-derived genetic polymorphisms may explain observed differences.

The Halo Occupation Distribution Of X-Ray-Bright Active Galactic Nuclei: A Comparison With Luminous Quasars, Jonathan Richardson, Suchetana Chatterjee, Zheng Zheng, Adam D. Myers, Ryan Hickox

Dartmouth Scholarship

We perform halo occupation distribution (HOD) modeling of the projected two-point correlation function (2PCF) of high-redshift (z~1.2) X-ray-bright active galactic nuclei (AGN) in the XMM-COSMOS field measured by Allevato et al. The HOD parameterization is based on low-luminosity AGN in cosmological simulations. At the median redshift of z~1.2, we derive a median mass of (1.02+0.21/-0.23)x10^{13} Msun/h for halos hosting central AGN and an upper limit of ~10% on the AGN satellite fraction. Our modeling results indicate (at the 2.5-sigma level) that X-ray AGN reside in more massive halos compared to more bolometrically luminous, optically-selected quasars at similar redshift. The modeling …

Magnetic Inhibition Of Convection And The Fundamental Properties Of Low-Mass Stars. I. Stars With A Radiative Core, Gregory A. Feiden, Brian Chaboyer

Dartmouth Scholarship

Magnetic fields are hypothesized to inflate the radii of low-mass stars—defined as less massive than 0.8 M _☉—in detached eclipsing binaries (DEBs). We investigate this hypothesis using the recently introduced magnetic Dartmouth stellar evolution code. In particular, we focus on stars thought to have a radiative core and convective outer envelope by studying in detail three individual DEBs: UV Psc, YY Gem, and CU Cnc. Our results suggest that the stabilization of thermal convection by a magnetic field is a plausible explanation for the observed model-radius discrepancies. However, surface magnetic field strengths required by the models are significantly stronger …

Association Between In Utero Arsenic Exposure, Placental Gene Expression, And Infant Birth Weight: A Us Birth Cohort Study, Dennis Liang Fei, Devin C. Koestler, Zhigang Li, Camilla Giambelli, Avencia Sanchez-Mejias, Julie Gosse, Carmen J. Marsit, Margaret R. Karagas, David J. Robbins

Dartmouth Scholarship

Epidemiologic studies and animal models suggest that in utero arsenic exposure affects fetal health, with a negative association between maternal arsenic ingestion and infant birth weight often observed. However, the molecular mechanisms for this association remain elusive. In the present study, we aimed to increase our understanding of the impact of low-dose arsenic exposure on fetal health by identifying possible arsenic-associated fetal tissue biomarkers in a cohort of pregnant women exposed to arsenic at low levels.

Methods: Arsenic concentrations were determined from the urine samples of a cohort of 133 pregnant women from New Hampshire. Placental tissue samples collected from …

Neurovascular Unit Dysfunction With Blood-Brain Barrier Hyperpermeability Contributes To Major Depressive Disorder: A Review Of Clinical And Experimental Evidence, Souhel Najjar, Daniel M. Pearlman, Orrin Devinsky, Amanda Najjar, David Zagzag

Dartmouth Scholarship

About one-third of people with major depressive disorder (MDD) fail at least two antidepressant drug trials at 1 year. Together with clinical and experimental evidence indicating that the pathophysiology of MDD is multifactorial, this observation underscores the importance of elucidating mechanisms beyond monoaminergic dysregulation that can contribute to the genesis and persistence of MDD. Oxidative stress and neuroinflammation are mechanistically linked to the presence of neurovascular dysfunction with blood-brain barrier (BBB) hyperpermeability in selected neurological disorders, such as stroke, epilepsy, multiple sclerosis, traumatic brain injury, and Alzheimer’s disease. In contrast to other major psychiatric disorders, MDD is frequently comorbid with …

Role Of The Cipa Scaffoldin Protein In Cellulose Solubilization, As Determined By Targeted Gene Deletion And Complementation In Clostridium Thermocellum, Daniel G. Olson, Richard J. Giannone, Robert L. Hettich, Lee R. Lynd

Dartmouth Scholarship

The CipA scaffoldin protein plays a key role in the Clostridium thermocellum cellulosome. Previous studies have revealed that mutants deficient in binding or solubilizing cellulose also exhibit reduced expression of CipA. To confirm that CipA is, in fact, necessary for rapid solubilization of crystalline cellulose, the gene was deleted from the chromosome using targeted gene deletion technologies. The CipA deletion mutant exhibited a 100-fold reduction in cellulose solubilization rate, although it was eventually able to solubilize 80% of the 5 g/liter cellulose initially present. The deletion mutant was complemented by a copy of cipA expressed from a replicating plasmid. In …

“Many Miles To Go …”: A Systematic Review Of The Implementation Of Patient Decision Support Interventions Into Routine Clinical Practice, Glyn Elwyn, Isabelle Scholl, Caroline Tietbohl, Mala Mann, Adrian G. K. Edwards, Catharine Clay

Dartmouth Scholarship

Two decades of research has established the positive effect of using patient-targeted decision support interventions: patients gain knowledge, greater understanding of probabilities and increased confidence in decisions. Yet, despite their efficacy, the effectiveness of these decision support interventions in routine practice has yet to be established; widespread adoption has not occurred. The aim of this review was to search for and analyze the findings of published peer-reviewed studies that investigated the success levels of strategies or methods where attempts were made to implement patient-targeted decision support interventions into routine clinical settings.

Recent Accumulation Variability In Northwest Greenland From Ground-Penetrating Radar And Shallow Cores Along The Greenland Inland Traverse, Robert L. Hawley, Zoe R. Courville, Laura M. Kehrl, Eric R. Lutz, Erich C. Osterberg, Thomas B. Overly, Gifford J. Wong

Dartmouth Scholarship

Accumulation is a key parameter governing the mass balance of the Greenland ice sheet. Several studies have documented the spatial variability of accumulation over wide spatial scales, primarily using point data, remote sensing or modeling. Direct measurements of spatially extensive, detailed profiles of accumulation in Greenland, however, are rare. We used 400 MHz ground-penetrating radar along the 1009 km route of the Greenland Inland Traverse from Thule to Summit during April and May of 2011, to image continuous internal reflecting horizons. We dated these horizons using ice-core chemistry at each end of the traverse. Using density profiles measured along the …

On The Evolution Of The Serotonin Transporter Linked Polymorphic Region (5-Httlpr) In Primates, Seth D. Dobson, Lauren J.N Brent

Dartmouth Scholarship

Some allelic variants of the serotonin transporter linked polymorphic region (5-HTTLPR) result in lower levels of expression of the serotonin transporter gene (SLC6A4). These low-expressing (LE) alleles are associated with mental-health disorders in a minority of humans that carry them. Humans are not the only primates that exhibit this polymorphism; other species, including some monkeys, also have LE and high-expressing (HE) variants of 5-HTTLPR. We propose a behavioral genetic framework to explain the adaptive evolution of this polymorphism in primates, including humans. We hypothesize that both LE and HE alleles are maintained by balancing selection in species characterized …

Real-Time In Vivo Cherenkoscopy Imaging During External Beam Radiation Therapy, Rongxiao Zhang, David J. Gladstone, Lesley A. Jarvis, Rendall R. Strawbridge, P Jack Hoopes, Oscar D. Friedman, Adam K. Glaser, Brian W. Pogue

Dartmouth Scholarship

Cherenkov radiation is induced when charged particles travel through dielectric media (such as biological tissue) faster than the speed of light through that medium. Detection of this radiation or excited luminescence during megavoltage external beam radiotherapy (EBRT) can allow emergence of a new approach to superficial dose estimation, functional imaging, and quality assurance for radiation therapy dosimetry. In this letter, the first in vivo Cherenkov images of a real-time Cherenkoscopy during EBRT are presented. The imaging system consisted of a time-gated intensified charge coupled device (ICCD) coupled with a commercial lens. The ICCD was synchronized to the linear accelerator to …

Short Duration Waveforms Recorded Extracellularly From Freely Moving Rats Are Representative Of Axonal Activity, Ashlee A. Robbins, Steven E. Fox, Gregory L. Holmes, Rod C. Scott, Jeremy M. Barry

Dartmouth Scholarship

While extracellular somatic action potentials from freely moving rats have been well characterized, axonal activity has not. We report direct extracellular tetrode recordings of putative axons whose principal feature is a short duration waveform (SDW) with an average peak-trough length less than 179 μs. While SDW recordings using tetrodes have previously been treated as questionable or classified as cells, we hypothesize that they are representative of axonal activity. These waveforms have significantly shorter duration than somatic action potentials, are triphasic and are therefore similar to classic descriptions of microelectrode recordings in white matter and of in vitro action potential propagation …

Diet And Toenail Arsenic Concentrations In A New Hampshire Population With Arsenic-Containing Water, Kathryn L. Cottingham, Roxanne Karimi, Joann F. Gruber, M Scot Zens, Vicki Sayarath, Carol L. Folt, Tracy Punshon, J. Steven Morris, Margaret R. Karagas

Dartmouth Scholarship

Background: Limited data exist on the contribution of dietary sources of arsenic to an individual's total exposure, particularly in populations with exposure via drinking water. Here, the association between diet and toenail arsenic concentrations (a long-term biomarker of exposure) was evaluated for individuals with measured household tap water arsenic. Foods known to be high in arsenic, including rice and seafood, were of particular interest.

Methods: Associations between toenail arsenic and consumption of 120 individual diet items were quantified using general linear models that also accounted for household tap water arsenic and potentially confounding factors (e.g., age, caloric intake, sex, smoking) …

Socially Excluded Individuals Fail To Recruit Medial Prefrontal Cortex For Negative Social Scenes, Katherine E. Powers, Dylan D. Wagner, Catherine J. Norris, Todd F. Heatherton

Dartmouth Scholarship

Converging behavioral evidence suggests that people respond to experiences of social exclusion with both defensive and affiliative strategies, allowing them to avoid further distress while also encouraging re-establishment of positive social connections. However, there are unresolved questions regarding the cognitive mechanisms underlying people's responses to social exclusion. Here, we sought to gain insight into these behavioral tendencies by using functional magnetic resonance imaging (fMRI) to examine the impact of social exclusion on neural responses to visual scenes that varied on dimensions of sociality and emotional valence. Compared to socially included participants, socially excluded participants failed to recruit dorsomedial prefrontal cortex …

Interictal Neurocognitive Processing Of Visual Stimuli In Migraine: Evidence From Event-Related Potentials, Marla J. S Mickleborough, Christine M. Chapman, Andreea Simina Toma, Jeremy H. M Chan, Grace Truong, Todd C. Handy

Dartmouth Scholarship

Research has established decreased sensory habituation as a defining feature in migraine, while decreased cognitive habituation has only been found with regard to cognitive assessment of the relative probability of the occurrence of a stimulus event. Our study extended the investigation of interictal habituation in migraine to include cognitive processing when viewing of a series of visually-complex images, similar to those we encounter on the internet everyday. We examined interictal neurocognitive function in migraine from a habituation perspective, using a novel paradigm designed to assess how the response to a series of images changes over time. Two groups of participants--migraineurs …

The Composite Effect For Inverted Faces Is Reliable At Large Sample Sizes And Requires The Basic Face Configuration, Tirta Susilo, Constantin Rezlescu, Bradley Duchaine

Dartmouth Scholarship

Abstract The absence of the face composite effect (FCE) for inverted faces is often considered evidence that holistic processing operates only on upright faces. However, such absence might be explained by power issues: Most studies that have failed to find the inverted FCE tested 24 participants or less. Here we find that the inverted FCE exists reliably when we tested at least 60 participants. The inverted FCE was ∼ 18% the size of the upright FCE, and it was unaffected by testing order: It did not matter whether participants did the upright condition first (Experiment 1, n = 64) or …

Stable Isotope And Modelling Evidence For Co2 As A Driver Of Glacial-Interglacial Vegetation Shifts In Southern Africa, F. J. Bragg, I. C. Prentice, S. P. Harrison, G. Eglinton, P. N. Foster

Dartmouth Scholarship

Atmospheric CO2 concentration is hypothesized to influence vegetation distribution via tree-grass competition, with higher CO2 concentrations favouring trees. The stable carbon isotope (delta C-13) signature of vegetation is influenced by the relative importance of C-4 plants (including most tropical grasses) and C-3 plants (including nearly all trees), and the degree of stomatal closure - a response to aridity in C-3 plants. Compound-specific delta C-13 analyses of leaf-wax biomarkers in sediment cores of an offshore South Atlantic transect are used here as a record of vegetation changes in subequatorial Africa. These data suggest a large increase in C3 relative to C4 …

Recurrent Tissue-Specific Mtdna Mutations Are Common In Humans, David C. Samuels, Chun Li, Bingshan Li, Zhuo Song, Eric Torstenson, Hayley Boyd Clay, Antonis Rokas, Tricia A. Thornton-Wells, Jason H. Moore, Tia M. Hughes, Robert D. Hoffman, Jonathan L. Haines, Deborah G. Murdock, Douglas P. Mortlock, Scott M. Williams

Dartmouth Scholarship

Mitochondrial DNA (mtDNA) variation can affect phenotypic variation; therefore, knowing its distribution within and among individuals is of importance to understanding many human diseases. Intra-individual mtDNA variation (heteroplasmy) has been generally assumed to be random. We used massively parallel sequencing to assess heteroplasmy across ten tissues and demonstrate that in unrelated individuals there are tissue-specific, recurrent mutations. Certain tissues, notably kidney, liver and skeletal muscle, displayed the identical recurrent mutations that were undetectable in other tissues in the same individuals. Using RFLP analyses we validated one of the tissue-specific mutations in the two sequenced individuals and replicated the patterns in …

The Xmm-Newton Spectrum Of A Candidate Recoiling Supermassive Black Hole: An Elusive Inverted P-Cygni Profile, G. Lanzuisi, F. Civano, S. Marchesi, A. Comastri

Dartmouth Scholarship

We present a detailed spectral analysis of new XMM-Newton data of the source CXOC J100043.1+020637, also known as CID-42, detected in the COSMOS survey at z = 0.359. Previous works suggested that CID-42 is a candidate recoiling supermassive black hole (SMBH) showing also an inverted P-Cygni profile in the X-ray spectra at ~6 keV (rest) with an iron emission line plus a redshifted absorption line (detected at 3σ in previous XMM-Newton and Chandra observations). Detailed analysis of the absorption line suggested the presence of ionized material flowing into the black hole at high velocity. In the …

Corruption Dynamics: The Golden Goose Effect, Paul Niehaus, Sandip Sukhtankar

Dartmouth Scholarship

Theoretical work on disciplining corrupt agents has emphasized the role of expected future rents -- for example, efficiency wages. Yet taken seriously this approach implies that illicit future rents should also deter corruption. We study this "golden goose" effect in the context of a statutory wage increase in India's employment guarantee scheme, comparing official microrecords to original household survey data to measure corruption. We estimate large golden goose effects that reduced the total impact of the wage increase on theft by roughly 64 percent. In short, rent expectations matter. (JEL D73, D82, H83, J41, K42, O17, O21)

Profiting From Regulation: Evidence From The European Carbon Market, James B. Bushnell, Howard Chong, Erin T. Mansur

Dartmouth Scholarship

We investigate how cap-and-trade regulation affects profits. In late April 2006, the EU CO2 allowance price dropped 50 percent, equating to a €28 billion reduction in the value of aggregate annual allowances. We examine daily returns for 552 stocks from the EUROSTOXX index. Despite reductions in environmental costs, we find that stock prices fell for firms in both carbon- and electricity-intensive industries, particularly for firms selling primarily within the EU. Our results imply that investors focus on product price impacts, rather than just compliance costs and the nominal value of pollution permits.

Killerflip: A Novel Lytic Peptide Specifically Inducing Cancer Cell Death, B Pennarun, G. Gaidos, O Bucur, A Tinari

Dartmouth Scholarship

One of the objectives in the development of effective cancer therapy is induction of tumor-selective cell death. Toward this end, we have identified a small peptide that, when introduced into cells via a TAT cell-delivery system, shows a remarkably potent cytoxicity in a variety of cancer cell lines and inhibits tumor growth in vivo, whereas sparing normal cells and tissues. This fusion peptide was named killer FLIP as its sequence was derived from the C-terminal domain of c-FLIP, an anti-apoptotic protein. Using structure activity analysis, we determined the minimal bioactive core of killerFLIP, namely killerFLIP-E. Structural analysis of cells using …

Residual Fmri Sensitivity For Identity Changes In Acquired Prosopagnosia, Christopher J. Fox, Giuseppe Iaria, Bradley C. Duchaine, Jason J. S. Barton

Dartmouth Scholarship

While a network of cortical regions contribute to face processing, the lesions in acquired prosopagnosia are highly variable, and likely result in different combinations of spared and affected regions of this network. To assess the residual functional sensitivities of spared regions in prosopagnosia, we designed a rapid event-related functional magnetic resonance imaging (fMRI) experiment that included pairs of faces with same or different identities and same or different expressions. By measuring the release from adaptation to these facial changes we determined the residual sensitivity of face-selective regions-of-interest. We tested three patients with acquired prosopagnosia, and all three of these patients …

Flexiterm: A Flexible Term Recognition Method, Irena Spasić, Mark Greenwood, Alun Preece, Nick Francis, Glyn Elwyn

Dartmouth Scholarship

Background: The increasing amount of textual information in biomedicine requires effective term recognition methods to identify textual representations of domain-specific concepts as the first step toward automating its semantic interpretation. The dictionary look-up approaches may not always be suitable for dynamic domains such as biomedicine or the newly emerging types of media such as patient blogs, the main obstacles being the use of non-standardised terminology and high degree of term variation.

Too Good To Be True: Rhesus Monkeys React Negatively To Better-Than-Expected Offers, Emily J. Knight, Kristen M. Klepac, Jerald D. Kralik

Dartmouth Scholarship

To succeed in a dynamically changing world, animals need to predict their environments. Humans, in fact, exhibit such a strong desire for consistency that one of the most well-established findings in social psychology is the effort people make to maintain consistency among their beliefs, attitudes, and behavior. However, displeasure with unpredictability leads to a potential paradox, because a positive outcome that exceeds one’s expectations often leads to increased subjective value and positive affect, not the opposite. We tested the hypothesis that two evolutionarily-conserved evaluation processes underlie goal-directed behavior: (1) consistency, concerned with prediction errors, and (2) valuation, concerned with outcome …