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Funded Research Abstracts

PI: Abriola, Linda
Title: Metric Identification and Protocol Development for Characterizing DNAPL Sources Zone Architecture and Associated Plume Response
Widespread use of chlorinated ethenes, such as trichloroethene (TCE) and tetrachloroethene (PCE), in dry cleaning and degreasing operations has led to groundwater contamination at thousands of industrial facilities and governmental installations. The majority of contaminant plumes at such sites emanate from aquifer regions containing dense nonaqueous phase liquid (DNAPL). Although significant effort has been directed toward improving methods for recovering DNAPL from the subsurface, it is now generally accepted that no single technology will result in complete mass removal. Recently, focus has shifted from complete mass removal to quantifying the benefits and limitations of partial mass removal. Research has revealed that there is a strong link between source zone architecture (local-scale DNAPL distribution) and down gradient plume response to partial mass removal. Our work on SERDP Project ER-1293, suggests that features of a DNAPL distribution, such as ganglia-to-pool (GTP) ratio, may be (i) of far greater importance for source zone remedy selection and analysis of technical feasibility and (ii) far easier to estimate in practice than the precise spatial distribution of the DNAPL saturations. While the GTP ratio has been demonstrated useful in the assessment and prediction of system behavior in simulated and laboratory experiments, no general guidance exists for its quantification in practice, nor is it clear that the GTP ratio is the most appropriate parameter to characterize long term plume response to mass removal in the field. Thus, there is a clear need for systematic development and assessment of alternative metrics to quantify DNAPL architecture based upon field-observable parameters.

The primary objective of this research is to develop and demonstrate a comprehensive approach for field characterization of DNAPL source zones which quantifies the key features that control plume response. This goal will be accomplished by:

  1. Identification of the most information rich metrics for linking NAPL architecture to plume response
  2. Development and refinement of in situ test methods and modeling tools that can be used to quantify identified metrics in targeted regions of the source zone
  3. Integration of these metrics and tools with current characterization methods for an overall source zone assessment protocol
  4. Development of simplified models for prediction of plume response

Mentor: Ambady, Nalini
Fellow: Freeman, Jon
Title: Impaired Processing of Social Context Cues in Socially Anxious Individuals
Social anxiety is prevalent, estimated to affect 7% to 13% of the population during the lifetime. It is also often very disruptive, affecting well-being and bearing numerous social and economic burdens. Broadly, the proposed research seeks to further an understanding of social anxiety at behavioral and neurobiological levels of analysis for enhancing treatment and helping pave the way for better prevention and recovery. The proposed research will shed light on basic perceptual and affective biases in social anxiety, and the results will be able to be used for better clinical intervention. Prior research suggests that socially anxious individuals show an abnormal attentional bias toward threatening social cues, such as an angry face. It is possible that a heightened attention to threatening social cues could impair socially anxious individuals' ability to process important context cues (e.g., non-angry cues of the body) that need to be used to appropriately perceive other's emotions. If true, an underutilization of context cues might lead socially anxious individuals to have misguided perceptions of and affective reactions to others' emotions.

The specific aims of the proposed research are to (a) examine how context cues influence perceptual judgments of emotional faces in social anxiety; (b) examine how context cues influence affective reactions to emotional faces in social anxiety; and (c) identify the neural basis of these contextual influences. This will be examined in 6 studies. The first 2 studies will examine whether individuals high in social anxiety (relative to low) show impairments in incorporating emotional body contexts (Study 1A) and semantic contexts (Study 1B) into their perceptions of facial emotion, assessed using an emotion-categorization task. If socially anxious individuals show impairments in incorporating context cues into their perceptions of emotional faces, the faces are likely to trigger misguided affective responses.

The following 2 studies will use an affective priming paradigm to test whether individuals high in social anxiety (relative to low) show misguided affective responses to emotional faces accompanied by emotional body contexts (Study 2A) and semantic contexts (Study 2B). Lastly, functional magnetic resonance imaging (fMRI) will be used to identify the neural basis of socially anxious individuals' impairments in context-cue processing when reacting to emotional faces, both in body contexts (Study 3A) and semantic contexts (Study 3B). Across the 6 studies, it is hypothesized that perceptual, affective, and neural responses to emotional faces will reflect utilization of context cues in individuals low in social anxiety, but that this utilization will be disrupted in individuals high in social anxiety. These results will have important implications for understanding and treating social anxiety.

PI: Anwer, Sawkat
Title: Role of Protein Kinase C in Isoforms in Bile Formation and Cholestasis
The long-term goal of this proposal is to understand the mechanism of canalicular bile formation and cholestasis. Our present understanding of the pathogenesis of cholestasis is based on studies to define the physiological regulation of transporters involved in bile formation and their deregulation in cholestasis. During the last granting period we have defined the role of aPKCζ, Rab4 and phosphorylation in Ntcp translocation and started defining the role of nPKCδ, nPKCε and p38 MAPK in Mrp2 translocation. The present proposal extends these studies to further define the role of nPKCδ and nPKCε in Ntcp/NTCP and Mrp2/MRP2 translocation/retrieval. One of the key goals is to define the mechanism involved in opposing effects of these kinases in hepatocytes. The following hypotheses are proposed:

  1. nPKCδ-pThr505 mediates translocation of Ntcp/NTCP by cAMP and translocation of Mrp2/MRP2 by cAMP and TUDC to the plasma membrane.

  2. nPKCε mediates TLC-induced retrieval of Mrp2/MRP2 from the plasma membrane by phosphorylating MARCKS and/or Mrp2/MRP2, and cAMP and TUDC reverse this effect by inhibiting TLC-induced nPKCε activation.

Proposed studies will be conducted in perfused livers and hepatocytes from rat livers, primary human hepatocytes and hepatic cell lines. In addition, studies will be conducted in perfused livers and hepatocytes isolated from nPKCδ-/- and nPKCε-/- mice to further confirm the role of these kinases. Role of these kinases will be evaluated by manipulating their activity and expression using chemical inhibitors, wild type-, constitutively active- and dominant negative-plasmids and Si- and/or ShRNA. Immunofluorescence and co-immunoprecipitation studies will be used to determine colocalization of desired proteins in subcellular organelles and with other proteins. Collectively, proposed studies should further define the role of nPKCδ in Ntcp/NTCP and Mrp2/MRP2 translocation, the role of nPKCε in Mrp2/MRP2 retrieval, and mechanism of reversal of TLC-induced cholestasis by cAMP and TUDC. Since a kinase may produce beneficial or toxic effect in an isoform specific manner, a better understanding of isoform specific effects should allow for better therapeutic agents that could avoid potential liver toxicity.

PI: Baise, Laurie
Title: Identifying and Modeling Complex Site Response Behavior
The near-surface properties of the earth modify seismic waves as they propagate from depth to the surface where they are felt and effect society. This process is often called site response, and is an important factor that contributes to the seismic hazard at a specific location. As observed in past earthquakes, the slower materials near the free surface influence damage patterns over short distances (Hanks and Brady, 1991; Borcherdt, 1970; Graves, 1993; Boatwright et al., 1991). Site response is a function of both the physical properties of near surface materials and the spatial distribution of those properties. Unfortunately, blind prediction experiments both in the linear and nonlinear range for soil behavior have consistently shown that predicted amplifications rarely match the observed amplifications (Boore, 2004; Kwok et al., 2008). We hypothesize that the poor performance of existing site response models is that the standard assumptions do not adequately represent the complexity of site response behavior in many cases. The majority of site response models rely on the assumption of vertically propagating S-waves through laterally homogeneous media (SH1D) (e.g., Boore, 2004; Kwok et al., 2008). In the proposed work, we set out to evaluate site response at multiple sites where both weak and strong motions have been measured and three-dimensional (3D) soil information exists. The selected sites provide a sequence from simple to complex site response behavior. In the proposed work, site response models will include 3D wave propagation through a 3D spatially variable and nonlinear medium.

The proposed work will test whether or not a more complex site response model can explain the behavior that is observed at some of these sites. Further, we will outline a method to identify and model complex site response when needed.

PI: Barber, Lisa
Title: Feasibility of Tissue Collections and Molecular Profiling
A feasibility study to evaluate a clinical SOP of tumor tissue collections for molecular profiling in dogs with cancer. Tumor samples will be collected across histologies and, additionally in breed specific cohorts in bladder transitional cell carcinoma, lymphoma and melanoma. Lymphoma and solid tumor expression studies will be conducted to ensure viable tissue sampling and define potential therapeutic targets for future personalized medicine studies. Defining a clinical turnaround time for these analyses is the study’s main goal. Blood and saliva/buccal swab collections will also be made and stored for post hoc studies. Results will be used as rationale to plan additional studies in the dog to evaluate proof of concept patient prescribed molecular profiling for human cancer patients.

PI: Bedenice, Daniela
Title: Subcutaneous and Intramuscular Pharmacokinetics of Florfenicol in Healthy Adult Alpacas
The purpose of this study is to determine the pharmacokinetics of florfenicol (NuFlor®; Schering-Plough) following subcutaneous (SQ) and intramuscular (IM) administration in healthy adult alpacas. We aim to evaluate the potential for florfenicol to maintain plasma drug levels above the minimum inhibitor concentration (MIC ≤ 2.0 μg/mL) throughout the dosing interval, without inducing adverse effects. We hypothesize that the maximum plasma florfenicol concentration [Cmax] will be lower and the elimination half-life [t½] will be shorter in alpacas, compared to reported data in cattle.

PI: Berger-Sweeney, Joanne
Title: Tufts Collaborative Cluster in Genome Structure and Development Patterning
In this proposal we request funding to create an intellectually- and technologically-advanced research environment focused on understanding the patterns and mechanisms of normal development and disease progression using a multi-scale approach—from genome to organism. Through the creation of laboratory space, we will establish the Collaborative Cluster in Genome Structure and Developmental Patterning in Health and Disease. This cluster of scientists will address the roles of genome instability and developmental deregulation from multiple perspectives and multiple scales of size and complexity.

The objective is to construct a modern sustainably-designed research space contiguous with the Tufts Center for Regenerative and Developmental Biology, thereby creating the Collaborative Cluster. This cluster will bring seven distinguished biology faculty into integrated space, facilitating their ability to work together to address key problems in biology and medicine. In addition, these scientists will be working in the same building as Tufts’ Department of Biomedical Engineering researchers involved in tissue engineering for regenerative medicine and nanobiological structures, expanding collaborative opportunities in a translational environment.

The establishment of the Collaborative Cluster will allow us to accomplish the following Aims:

  1. Unravel the links between gene networks and epigenetic physiological signals using molecular genetics, cell biology, and mathematical modeling, to develop groundbreaking applications in regenerative medicine and aging;
  2. Accelerate interdisciplinary progress on the effects of intrinsic and environmental factors on genome structure and stability, harnessing the understanding of global-scale gene expression in development to address birth defects, human hereditary diseases, and cancer; and
  3. Harness new, integrated knowledge in development, disease and regeneration by partnering with biomedical engineers to translate research results into techniques and devices to alleviate human disease and heal injury.

We will create research space to establish the Collaborative Cluster through renovation of existing offices to 19,627nsf of wet laboratories and associated support spaces, serving 70 researchers. The space includes an electrophysiology suite and specialized rooms for fly, fish, and frog experimental models. We estimate the project will create 195 jobs. The Cluster has been designed to bring established and early-stage faculty within steps of one another in laboratories equipped with the necessary tools to facilitate great strides in relationships among genome structure, developmental patterning, and human health and disease.

PI: Bers, Marina
Title: Collaborative Research: ScratchJr: Computer Programming in Early Childhood Education as a Pathway to Academic Readiness and Success
This collaborative project between Tufts University and the Massachusetts Institute of Technology is researching and developing a new version of the Scratch programming language to be called ScratchJr, designed specifically for early childhood education (K-2). The current version of Scratch, which is widely implemented, is intended for ages 8-16 and is not developmentally appropriate for young children. This work will provide research-based evidence regarding young children's abilities to use an object-oriented programming language and to study the impact this has on the children's learning of scientific concepts and procedures. The team will develop ScratchJr in an iterative cycle, testing it in both the Devtech lab at Tufts and the Eliot Pearson lab school and with a wider network of early childhood partners. At the end of the three-year project, ScratchJr will have been tested with approximately 350 students in K-2, 40 parents, and 58 early childhood educators.

ScratchJr will have three components: 1) a developmentally appropriate interface, with both touch screen and keyboard/mouse options; 2) an embedded library of curricular modules with STEM content to meet federal and state mandates in early childhood education; and 3) an on-line resource and community for early childhood educators and parents. The research questions focus on whether ScratchJr can help these young children learn foundational knowledge structures such as sequencing, causality, classification, composition, symbols, patterns, estimation, and prediction; specific content knowledge; and problem solving skills.

This interdisciplinary proposal makes contributions to the fields of learning technologies, early childhood education and human computer interaction. ScratchJr has the potential for broad implementation in both formal and informal settings.

PI: Bers, Marina
Title: Ready for Robotics: The Missing T and E of STEM in Early Childhood Education
The project investigates the use of robotics in early childhood education. It addresses two objectives: to develop and evaluate a low-cost, developmentally appropriate robotic construction kit specifically designed for early childhood education (PreK-2) and to pilot a robotics-based professional development model for early childhood educators to teach engineering and technology. A number of research questions are included:

  • To what extent did participating teachers gain knowledge about robotics, engineering and programming, and pedagogies?
  • To what extent have they increased their familiarity of, comfort with, and understanding of the use of robotics in early childhood?
  • To what extent participating in the institute can support the passage from knowledge to action?
  • What processes/standards are used by early childhood teachers to integrate engineering and technology into their traditional curriculum?
  • Do teachers adopt the robotics kit and curriculum for their classrooms?
  • How do they adapt it to their own practices?
  • What are the factors that predict successful outcomes in terms of adoption and adaptation?
  • To what extent has the teaching practice of the teachers changed in a way that demonstrates understanding of the role of T and E in early childhood education?

Robotics provides a playful bridge to make early childhood programs more academically challenging while honoring the importance of play in the developmental trajectory. The assumption is that young children can become engineers by playing with gears, levers, motors, sensors; and programmers by exploring sequences, loops and variables. Robotics can be a gateway for children to learn about applied mathematical concepts, the scientific method of inquiry, and problem solving. Moreover, working with robotic manipulatives engages children in social interactions and negotiations while playing to learn and learning to play.

For robotics to be successfully integrated into the early childhood classroom, there are three factors that need to be considered: the robotics technology needs to be developmentally appropriate and low-cost; and teachers should be exposed to professional development. This project addresses these issues. It contributes to the emerging field of robotics in education by addressing the needs of an educational segment, early childhood, where there is a lack of new technologies and approaches to teach technology and engineering in a developmentally appropriate way.

PI: Black, Lauren
Title: Restoring LV Function Post-MI Using Fibrin-Gel Based Engineering Myocardium
Cardiovascular disease can lead to myocardial infarction (MI) and subsequent heart failure. There are currently a number of therapies aimed at preventing or treating heart failure post-MI. Only heart transplantation replaces infarcted myocardium to restore heart function, but there is a paucity of donor hearts and the incidence of cardiovascular disease continues to rise. A new and innovative option is the use of “heart patches” created in vitro for implantation in vivo. The research proposed in the independent phase of this award aims to address 3 critical issues pertaining to the function and eventual use of such heart patches:

  1. The effect of cellular composition on the contraction force and construct mechanical stability,
  2. The effect of a biomimetic culture environment on tissue morphology and function, and
  3. The efficacy of myocardial equivalents biomimetically-engineered in vitro in restoring left ventricular function post-MI.

The overall hypothesis of this work is that myocardium engineered in vitro in biomimetic culture conditions restores post-MI left ventricular function better than cell therapy-based methods of repair. The environment at Tufts University uniquely positions me to address this hypothesis, as the world-renowned Tissue Engineering Research Center and Molecular Cardiology Research Institute are both located nearby. This environment will give me the opportunity to augment my already considerable background in tissue mechanics and tissue engineering methods with cardiac anatomy and physiology in health and disease and cardiac surgical techniques. The continuation of my career plan during the independent phase includes gaining more expertise in cell and tissue culture techniques and bioreactor development, while learning new skills in areas including cardiac surgical techniques and physiological evaluation in a rat model of MI. The ultimate goal of the project is to leverage these skills to directly compare the efficacy of myocardial tissue engineered in vitro with current cell-therapy based methods of cardiac repair in restoring function to the left ventricle post-MI. This research is especially critical considering the continuing rise in incidence of heart disease. The results of this research may help elucidate design parameters that are critical to the creation of functional myocardium engineered in vitro and thus advance the concept of the “heart patch” closer to reality.

Mentor: Black, Lauren
Fellow: Tang, Katherine
Title: The Capacity of the Properties of the Infarct Extracellular Matrix (ECM) to Inhibit Mesenchymal Stem Cells' (MSC) Adhesion, Proliferation, and Differentiation to Cardiomyocytes
The promising new therapy of injecting mesenchymal stem cells (MSCs) into a myocardial infarction (MI) to restore the contractile function of the heart following injury is limited by incomplete differentiation and lack of cell retention. It is postulated that the physical properties and composition of the myocardium's extracellular matrix (ECM) as well as other factors of the environment of an infarcted tissue, such as hypoxia, affect the cell growth and differentiation of injected MSCs. Therefore, examining how changes in ECM composition, stiffness, and oxygen delivery, both individually and in combination, affect MSC adhesion, proliferation, and differentiation to cardiomyocytes could lead to improved methods for MSC therapy. At Tufts University, Dr. Black's laboratory aims at developing novel methods for treating diseased myocardium, including examining the extracellular environment's role in disease progression and how it affects the repair process of cell therapy. Within his laboratory, my project will study the effects of alterations in stiffness, collagen composition, and oxygen content between normal and infarct heart tissue on the adhesion, proliferation, and differentiation of MSCs. I hypothesize that increased stiffness, change in ECM composition, and hypoxia will create an inhospitable environment for MSCs, resulting in a low rate of adhesion, proliferation and differentiation to cardiomyocytes in the conditions mimicking the infarct.

I expect the success of adhesion, proliferation, and differentiation of MSC to decline with each factor that further mimics the infarct environment. Since differentiation is determined by signals from the extracellular environment, such as collagen content, I expect changing the environment will depreciate MSCs ability to differentiate to cardiomyocytes. Further, I expect increasing stiffness will lead to poor cardiac differentiation since stiffness is a factor in how cells differentially sort themselves into tissues during development and studies have demonstrated that stiffness alone can affect MSC differentiation lineage. Finally, I expect growth in a hypoxic environment to be less successful than in normoxia since oxygen is critical to myocyte function. While, I expect each factor alone to have a detrimental effect on the MSCs, I anticipate that combining multiple factors will increase the negative effect. I anticipate that I will be able to determine which factor has the greatest influence in preventing MSC integration and differentiation. Ultimately, the results of this study could be used to improve cell therapy by developing new methods of pre-conditioning MSCs to improve their integration and differentiation to cardiac cells in the infarct — leading to enhanced methods for treating cardiac disease.

PI: Blanco-Pillado, Jose Juan
Title: Aspects of String Theory Cosmology
For the past two decades, string theory has been one of the most intensely investigated areas of theoretical high-energy physics. This is true chiefly because string theory offers what is currently the most successful method of unifying gravity with the other fundamental forces (strong, weak, and electromagnetic). Results from string theory have also spilled over into many other branches of physics, leading to improved understanding of gauge theories, condensed-matter physics, and heavy-ion physics. String theory has also led to powerful new insights in mathematics. In this project, Professor Blanco-Pillado aims to apply string theory to cosmology. Specifically, he proposes to study the cosmological implications of a certain class of string models (so-called "flux compactifications"), paying particular attention to the effects of the complex structure moduli part of the four-dimensional potential.

This project will also have significant broader impacts. Beyond the interdisciplinary reach of the proposed research — connecting high-energy physics and cosmology through the paradigm of string theory — this project will also involve the training of a graduate student to conduct research in this cutting-edge field of study.

PI: Blumberg, Jeffrey
Title: Effects of Almonds on Vascular Reactivity and Biomarkers of Inflammation, Oxidative Stress and Endothelial Function in Patients with Coronary Artery Disease
Observational studies have shown that frequent nut consumption decreases the risk of cardiovascular disease (CVD), with those individuals consuming >4-5 servings of nuts/wk achieving ~50% reduction in their adjusted relative risk of CVD compared to those who do not consume nuts. A diet rich in nuts, fruits, and vegetable has the potential to reduce CVD risk and is recommended by the American Heart Association as part of a strategy for primary and secondary prevention. The specific dietary components that account for this effect have not been fully characterized, but a large body of evidence suggests that a dietary pattern with a plentiful intake of a variety of fruits and vegetables, low in saturated fat and higher in mono- and polyunsaturated fats, rich in fiber and flavonoid-containing foods is associated with a reduced risk of CVD as well as other chronic diseases. Whole almonds are among the foods capable of providing the right fats, vitamin E, and flavonoid when added to the diet. Recently, there has been particular interest in the possibility that, in addition to vitamins C and E, flavonoids also reduce CVD risk by improving the function of the vascular endothelium and there is evidence that flavonoids can affect endothelial function.

We hypothesize that addition of 3oz almonds daily to a NCEP Step 1 diet will improve endothelial function in patients with CAD and that these effects are mediated via an increase in NO synthesis and reductions in dyslipidemia and systemic inflammation.

We propose to conduct in 40 CAD patients a randomized, controlled, cross-over study to compare a National Cholesterol Education Program (NCEP) Step 1 diet absent nuts (STEP 1) to a Step 1 diet with the same total calories and including 3 oz. almonds daily (STEP 1A) for 6 wk. periods with suitable run-in (6 wk.) and washout period (4 wk.). The primary study endpoint is endothelial function as assessed non-invasively by Dr. Joseph A. Vita, MD at the Whitaker Cardiovascular Institute and Vascular Research Unit (VRU), Cardiology Department, Boston Medical Center, Boston University School of Medicine by FMD of the brachial artery, peripheral arterial tonometry, and pulse wave velocity. Secondary study outcomes providing valuable information concerning the mechanisms of action of the almond intervention include serum biomarkers of dyslipidemia (lipid profiles), inflammation (CRP, IL-6, and TNF-•) oxidative stress (antibodies against oxidized LDL, and vitamin E) and markers of endothelial function sVCAM-1 and soluble E-selectin. These biomarkers of endothelial function will be measured by Dr. Paul E. Milbury in the Antioxidants Research Laboratory at the USDA HNRCA at Tufts University.

PI: Bode, Patty
Title: Digital Visual Cultural Project
This project facilitates participatory action research among a university art educator, a university multi-media specialist, a K-8 art teacher and her students in an urban public school art room. The research will highlight multicultural voices of students and their teacher collaboratively reflecting on their engagement in visual digital media in an urban art classroom to draw implications for practices in the field of PK-12 art education and also in art teacher preparation.

PI: Bode, Patty
Title: Senegal-America Project
The primary goal of the SAP is to bring people together in meaningful collaborations that create transformational experiences. Since the Senegal-America Project has been active for more than twenty years, it has infrastructure in place to provide travel arrangements, lodging and resources in country. The SAP also provides connections with a wide range of community members such as artists, teachers, and community leaders, as well as with arrangements for family stays. Just as important, is what the SAP does not do. It is not a specific "program" and there is no required agenda or project goal, even though it provides a menu of activities for travelers who may want to participate in organized events. It encourages participants to form their own vision of what they hope to gain from the travel and what they hope to contribute to the communities of Senegal. The SAP trip for 2011 is planned for June 21-July 6, 2011. I may also be able to extend my visit in Senegal, depending on funding. The Senegal-America Project provides an ideal situation in which to study abroad in new environments, cultures, languages and social structures to stimulate and broaden my mind as a teacher. This is certain to improve and enhance the quality of my instruction.

PI: Bohm, Andrew
Title: Selection of the 3'-End mRNA Processing Site by Cleavage Factor I
Gene expression is the process of synthesizing functional proteins using information stored in the nucleus as DNA and transmitted to cellular sites of protein synthesis in the form of mRNA molecules, produced by copying (transcribing) DNA. An essential step in gene expression is the precise trimming of the 3'-ends of messenger RNA (mRNA) molecules by 3'-end processing enzymes that recognize specific RNA sequences. This process determines the length of each mRNA molecule and affects the efficiency with which it is utilized as a template for protein synthesis. Roughly half of human genes contain more than one potential site of 3'-end processing and are subject to alternative processing. Selection of the appropriate processing site is particularly important in the synthesis of proteins involved in immune responses and in cell differentiation. This project uses yeast as a model system to study the mechanism of 3'-end processing and focuses on an evolutionarily conserved complex of five proteins called Cleavage Factor I (CF I) that recognizes mRNA signal sequences which define the sites of 3'-end processing. The research will utilize single-particle electron microscopy, coupled with RNA foot-printing and molecular modeling techniques to construct models of the overall structure of CF I and elucidate how it recognizes mRNA signal sequences and directs processing of the 3'-ends of mRNAs. Yeast genetics, coupled with biochemical binding experiments, will be used to verify and refine the resulting molecular models. This work is of fundamental importance because mRNA 3'-end processing affects the expression of all proteins in all eukaryotic cells.

PI: Booth, Sarah
Title: Factors Related to Obesity in Latinos Living in the Phoenix Area
Latinos are at high risk for obesity as many suffer from increased prevalence of cardiometabolic disease risk factors. They are also disproportionately affected by social and environmental factors which further contribute to increased risk. While there are existing data on dietary quality, little is known about how sociocultural and environmental conditions contribute to specific diet quality and behavioral risk factors for cardiometabolic disease among Latinos. The rationale is to determine feasibility of using vitamin K concentrations as biomarkers of poor diet quality among Latinos, an ethnic group that has been poorly characterized for vitamin K status.

The working hypothesis is that low circulating concentrations of vitamin K will be associated with obesity, metabolic syndrome and chronic disease risk among Latino adults.

To measure circulating concentrations of different forms of vitamin K among Latino men and women, who have been characterized for risk factors for cardiometabolic disease.

PI: Booth, Sarah
Title: Vitamin K Analysis of Food and Dietary Supplements
To identify and quantify vitamin K and related compounds in representative samples of foods and dietary supplements to improve and expand analyses to the USDA Nutrient Databases.

PI: Bridges, Robert
Title: NCRR Research Training for Tufts Veterinary Students
There is a crucial need for veterinarians with research training to participate in academic as well as corporate based research in the fields of animal and human health. Veterinarians trained in this century need to acquire the scientific skills and technical training together with the conceptual framework to participate both as independent researchers and collaborators to meet the projected national research needs in the biomedical sciences.

The objective of the proposed training described here is to provide bright, and highly-motivated veterinary students with a one year, in-depth research experience in a productive and active research setting. Training will involve the use of animal models to develop skills at hypothesis-based, biomedical research. Over a five year period, our aim is to train ten students (2/year). Applicants will be actively recruited from incoming and existing veterinary classes at Tufts Cummings School of Veterinary Medicine with an effort to insure minority student participation. Participants receive 12 months of consecutive research training following completion of their second year of veterinary school. The training is integrated into a Master of Science degree program (D.V.M./M.S.) specifically designed for trainees in this program. This degree program includes limited course work and complementary seminars. Program faculty consists of 12 NIH supported faculty members from both our basic and clinical departments. Using animal models that include pigs, horses, sheep, goats, cats, dogs, rats, and mice, program faculty will provide intensive laboratory training in the research areas of infectious diseases, reproductive biology, digestive diseases, neuroscience and behavior, nutrition, and respiratory physiology.

Our long-term objective is to make this research training experience an effective launching pad for career involvement in biomedical research for Tufts' graduates. The success of the program will be evaluated by determining the number and quality of trainees that integrate health science research into their professional careers.

PI: Bridges, Robert
Title: Neural and Endocrine Consequence of Parity
Reproductive experience (i.e. pregnancy, parturition and lactation) results in long lasting alterations in the female mammal’s neural and endocrine systems. In the previous grant period, using a rat animal model, we demonstrated that reproductive experience alters circulating prolactin and estradiol levels, estradiol-stimulated prolactin secretion, neural prolactin receptor expression, and prolactin receptor transduction mechanisms. Significant effects of reproductive experience on anxiety-like behavior were also found in reproductively experienced animals during their subsequent reproductive cycles that were dependent upon the stage of the estrous cycle and the age of the female. Based on these findings, we propose to test the following hypothesis: “Reproductive Experience Induces a Fundamental Shift in the Neural Regulation of Hormone Secretion and Action in Female Mammals.”

We propose that this shift in hormone sensitivity is brought about in part by an up-regulation of prolactin receptor function in both neural and peripheral tissues that renders endocrine target tissues less dependent on circulating hormones. In addition, we propose that differential shifts in the sensitivities of estrogen receptor subtypes develop as a function of reproductive experience that alter the female’s responses to estrogen. Specific studies will investigate the effects of reproductive experience on prolactin and estradiol receptor expression, prolactin transduction mechanisms, and shifts in estradiol and prolactin receptor sensitivity. Another experiment examines whether postpartum hyperprolactinemia and the age of reproductive experience contribute to the effects of reproductive experience on subsequent endocrine activity.

Next, a series of studies investigate the impact of reproductive experience on anxiety, examining the hormonal regulation of anxiety within the context of the female’s reproductive experience and how aging may interact with reproductive experience to affect anxiety. Finally, the possible effects of reproductive experience on non-neural endocrine target tissues, i.e. mammary tissue and liver, are examined to determine whether hormone receptor systems are altered in non-neural tissues as they are in the brain.

Techniques used include real time RT-PCR, Western blot analysis, in situ hybridization, radioimmunoassay, and behavioral testing. The results of these studies should provide insight regarding the role of the hypothalamus in neuroendocrine plasticity and significant information regarding the transformative nature of reproductive experience.

PI: Brodsky, Barbara
Title: Structural Studies of Triple-Helical Proteins
Collagen is the most abundant protein in the body, defined by its unique triple-helical conformation and repeating sequence pattern with glycine as every third residue. Biophysical studies are proposed to relate the (Gly-X-Y)n amino acid sequence and breaks in this pattern with molecular features and higher order structure of collagens, which are directly related to their function and pathology. Our studies on the classic triple helix will be extended to characterization of the consequences of natural breaks in the (Gly-X-Y)n pattern found in non-fibrillar collagens, such as type IV collagen in basement membranes and type VII collagen that mediates dermal-epidermal attachment. The effects of the length and sequence of such breaks on triple-helix stability, folding and conformation will be investigated using model peptides. To complement peptide studies, flexibility, folding and enzyme susceptibility will be examined on an expressed bacterial product where a break is introduced between two tandem triple-helix modules. These studies will provide information about the structural consequences of breaks and their biological role. The association of collagen molecules to higher order structures is essential to their mechanical and biological function.

Our goal is to define the relation between sequence, the process of triple-helix association to higher order structures, and the morphology of the final product. Studies will be carried out to further characterize non-specific lateral assembly observed for collagen peptides and to introduce electrostatic and hydrophobic residues in peptide sequences to produce more specific axial interactions and defined higher order structures. The effects of natural breaks in the (Gly-X-Y)n repeat on self-association will be investigated. Gly missense mutations in fibrillar and non-fibrillar collagen lead to hereditary disease. The folding, stability, hydrodynamic and conformational consequences of Gly missense mutations will be characterized in peptides and in an expressed construct where a missense mutation is introduced between tandem triple-helix modules. Peptides will be studied to test the hypothesis that missense mutations disrupt folding of non-fibrillar collagens by interfering with the folding through natural breaks. Definition of the fundamental principles of collagen triple-helix molecular structure and association into higher order structures will further our understanding of normal matrix structure/function relationships and enhance the development of collagen-based biomaterials. In addition, it will provide a basis for defining extracellular matrix alterations in disease and for developing drugs which could inhibit the breakdown of collagens in cancer and osteoarthritis.

PI: Brugge, Douglas
Title: Community Assessment of Freeway Pollution and Health
We propose a CBPR study of the relationship between air pollution gradients and health effects in individuals living next to major highways. There is evidence that:

  1. People living close to highways experience significantly elevated exposures to constituents of motor vehicle exhaust including ultrafine particles (UFP; 0.01-1 microns) and black carbon
  2. That motor vehicle pollution is associated with cardiac mortality and morbidity in adults, and asthma and reduced lung function in children

C-reactive protein (CRP), an inflammatory marker of risk for cardiac illness, has been shown to increase in response to changes in particulate exposure, making it a viable indicator of the potential impact on cardiac health. Our core study involves measuring 5 traffic-related pollutants (i.e., UFP, PM2.5, NOx, CO, black carbon, particulate PAH) in 6 neighborhoods within 400 meters of highways through in the Boston area. A background site >1000m from highways will also be monitored. We will complete a scientific survey of residents living in the neighborhoods to determine pediatric asthma prevalence. We will determine the time residents spent within the near highway zone currently and rigorously measure highway pollution gradients in the neighborhoods. We will document exposures at work, school and while commuting. For a subset of non-smoking households we will obtain pulmonary function tests from children and analyze multiple blood samples per person from adults for CRP and fibrinogen. Our study will be:

  1. The first to test associations between highway pollution gradients and biological markers of health
  2. The first CBPR study of highway pollution
  3. The most comprehensive collection of data on time spent in the exposure zone and many confounders and effect modifiers

We will conduct bivariate and regression analyses and have developed preliminary mathematical models that frame our approach to analyzing the large set of data. Our team consists of faculty at Tufts University and 6 co-investigators from community organizations that are concerned about the impact of highways on the health of residents in their communities. We will train and hire field staff from the communities and have an advisory board. We will link community participation to the science through participation in our steering committee and through our advisory board. Our study is designed to report useful information locally as well as influence pressing national policy needs.

PI: Brugge, Douglas
Title: Health Careers Opportunity Program (HCOP)
In a city with both world-class medical resources and medically underserved communities our HCOP brings together institutions with the capacity to make a difference. Our HCOP is a unique and groundbreaking partnership between the Boston Public Schools and the University of Massachusetts Boston (UMass) – which have large numbers of educationally and economically disadvantaged students – the educational opportunities at Tufts University School of Medicine (TUSM) and dozens of professional volunteers at Tufts and the Center for Community Health Education Research and Service (CCHERS – a community organization). Our program will increase the number of disadvantaged students graduating from:

  1. Medical school in primary care and/or
  2. Public health graduate programs. The partnership includes students, teachers, professors, professionals, administrators, and parents.

We will have two structured programs in the summer, one for 25 middle school students and one for 25 high school students. Each will run for 7 weeks, 5 days/week with classes 6 hours/day. We focus on summer academic programs, and intensive tutoring, mentoring, and test preparation at the college and graduate level. We address all 7 HCOP program purposes. Tutoring, standardized test preparation and training on cultural competence will occur at all levels of the pipeline. We will also conduct recruitment, primary care exposure, financial aid dissemination and facilitation of entry at each stage of the pipeline. Our partnership is designed to develop a more competitive applicant pool. Further, we meet all 4 legislative funding preferences:

  1. We have a signed formal agreement (an MOU);
  2. Coordination within a geographic area (Boston) with health professions shortages (Roxbury, Dorchester and Mattapan);
  3. A focus on formation of a competitive applicant pool; and
  4. A focus on cultural competence. It must be emphasized that we meet all criteria for a comprehensive HCOP.

Our objectives address two of the National Workplace goals:

  1. Increasing disadvantaged graduates and program completers; and
  2. Increasing the number of disadvantaged enrollees.

Further, we leverage existing infrastructure, including the relationship between UMass and the public schools, the close connections between the Tufts undergraduate campus and its medical school, the many resources at Tufts and the energies of dozens of volunteers from Tufts and CCHERS.

PI: Bullock, Peter
Title: Elimination of PML via Development of a Genetic Screen for Inhibitors of T-Antigen
Tysabri, a monoclonal antibody developed by Biogen Idec, can effectively treat Multiple Sclerosis. However, patients treated with Tysabri become immunocompromised. Furthermore, a significant number of these individuals progress to Progessive Multifocal Leukoencephalopathy (PML), a demyelinating disease of the central nervous system. Indeed, doctors frequently do not prescribe Tysabri for their MS patients due to the severity of PML. In view of these considerations, it is clear that the threat of PML must be eliminated before Tysabri can be used as a cure for Multiple Sclerosis.

PML is caused by JC polyomavirus, a small DNA virus that normally infects children and remains asymptomatic until patients become immunocompromised by treatment with Tysabri. Replication of JC virus is initiated when a viral protein termed T-antigen (T-ag) binds to a DNA sequence termed the origin of replication. Much of what is known about JC T-ag and its interactions with the viral origin has been established via studies of the highly related Simian Virus 40 (SV40). The power of the SV40 replication system stems from the fact that much of the structure of SV40 T-ag has been determined, powerful assays developed to examine the initiation of viral replication and an extensive literature is available to interpret novel findings.

Using genetic techniques, we have developed strains of E. coli that can be used for monitoring T-ag’s interactions with the origin of DNA replication. These strains, will be used to screen libraries of small molecules (both cyclic peptides and chemicals) for molecules that will disrupt the T-ag/origin interaction(s). Using standard techniques, we will then verify that the inhibitors are functional in human cells. Collectively, these studies are designed to identify inhibitors of T-ag and thus lead compounds for the elimination of JC virus.

Mentor: Bunnell, Stephen
Fellow: Lewis, Juliana
Title: Investigating the Homing and Engraftment of CML Stem Cells in the Bone Marrow
Chronic Myeloid Leukemia (CML) is a hematopoietic stem cell (HSC) malignancy that is induced upon the balanced translocation of chromosomes 9 and 22 and the resulting formation of a Philadelphia (Ph) chromosome. The product of the Ph chromosome is the BCR-ABL tyrosine kinase. The constitutively active tyrosine kinase activity of BCR-ABL is the crux of the malignancy and causes defective integrin signaling and adhesion in HSCs. Recent studies in our laboratory indicate an abnormal and increased dependency on selectins and their ligands for homing and engraftment of these leukemic stem cells within the bone marrow (BM) niche. The main objectives of this proposal are to 1) investigate and further define the nature of the adhesive molecules that contribute to engraftment of malignant stem cells in CML patients and 2) develop methods that will block engraftment of CML stem cells without affecting the engraftment of normal stem cells.

To induce CML in donor stem cells we will employ our BCR-ABL transduction/transplantation model system. To delineate the critical adhesion molecules that mediate malignant stem cell engraftment compound donor and/or recipient mutant mice will express genetic mutations for adhesion molecules expressed in HSCs or BM endothelium, respectively. These BM transplantation studies will collectively determine the critical adhesion factors for engraftment of leukemic stem cells. Neuraminidase, anti-selectin reagents, monoclonal antibodies and small molecule selectin antagonists will be tested for their efficacy to block CML stem cell engraftment first in a murine model for CML and then using xenografts of human CML stem cells transplanted into NOD/SCID/γc-deficient mice. The observations from these studies will engender novel clinically applicable methods for blocking CML stem cell engraftment in autographed patients.

PI: Byrnes, Elizabeth
Title: Maternally Transmitted Opiate Abuse Vulnerability
Many studies have demonstrated that the hereditary nature of drug abuse is due to both genetic and environmental factors. Recent findings demonstrate that one mechanism regulating interactions between genes and the environment are epigenetic modifications. The term epigenetics refers to DNA and histone protein modifications that regulate gene expression and which are transmitted from a mother cell to a daughter cell or from a parent to a progeny, but which do not change the underlying DNA sequence. While it is clear that epigenetic modifications can be passed from one generation to the next, the mechanisms involved in the transmission of these effects are not fully understood. Several recent findings indicate that the maternal environment, both pre- and postnatal, may play a critical role in epigenetic transfer. To date, the role of epigenetics in familial patterns of drug abuse has not been well studied.

Prescription narcotics use by adolescent females has increased dramatically in the past decade. We have developed an animal model of adolescent morphine exposure in female rats to examine the long-term consequences of opiate use during this unique developmental period. Our findings demonstrate that in addition to significant alterations in gene expression in adult female rats exposed to morphine during adolescence, the offspring of adolescent-exposed females demonstrate enhanced responsiveness to morphine. These offspring effects suggest adolescent morphine exposure increases the risk of drug abuse in the next generation. One of important aspect of this model is that adolescent morphine-exposed females are drug-free for at least 10 days prior to mating. Thus, developing offspring are never directly exposed to morphine. This means that any effect observed in the offspring is maternally-derived.

The purpose of the present proposal is to determine the role of epigenetics in the long-term effects of adolescent morphine exposure on both the female and her offspring. The current proposal will identify transgenerational epigenetic modifications in the adult offspring of females exposed to morphine during adolescent development (Specific Aim 1). It will also examine possible changes in the maternal environment which may play a role in the transmission of these offspring effects (Specific Aim 2). Finally, we will test whether postnatal manipulations can ameliorate or prevent the transgenerational effects of adolescent morphine exposure (Specific Aim 3). Understanding how drug-induced alterations in morphine sensitivity may be passed from one generation to the next will help identify basic mechanisms underlying familial patterns of drug abuse as well as possible interventions.

Mentor: Camilli, Andrew
Fellow: Van Opijnen, Tim
Title: Functional Organization of the Streptococcus pneumoniae Two Component System Regulatory Network
By reconstructing the functional organization of the Streptococcus pneumoniae two component system regulatory networks I hope to fulfill three specific aims:

  1. TCSs serve as decision-making circuits within bacteria that trigger specific transcriptional programs that enable adaptation, growth and survival of the organism. Because such deeply integrated systems generally work according to the same principles across different species this will lead to universal understanding of TCS activation and their strategy of regulation and may therefore lead to new and widely applicable approaches to tackle infectious diseases.

  2. The network will show how TCSs isolate their messages from out-of-control-cross talk. This will add to our understanding of transcriptional regulation and will aid in the engineering of sensitive and controllable gene-circuits.

  3. This is a first but essential step in the long-term goal of creating predictive models for infectious diseases such as S. pneumoniae. Such models are an essential development, as it will enable researchers and clinicians as well, to make predictions on the phenotypic outcome of, for instance, an infection in response to a certain perturbation or intervention.

The exciting thing about our approach is that new data can keep on being added by us and by others in the community, which will speed-up the creation of truly detailed predictive models.

PI: Camilli, Andrew
Title: Medically Oriented Research in Graduate Education
Tufts University Sackler School of Graduate Biomedical Sciences proposes a new training program that will serve as a blueprint for integrating medical knowledge and clinical perspective into PhD education. Building from strength in graduate education and research, the MERGE-Infectious Disease (MERGE-ID) program will combine PhD training in the basic microbiology and immunology of pathogenic organisms and host interactions with in-depth exposure to the pathogenesis, diagnosis, prevention, treatment and epidemiology of infectious disease. The program will retain discipline-specific depth and add new courses that integrate clinical exposure from day one of the program throughout the training. A basic researcher and a clinician-scientist expert in ID will equally co-mentor each trainee in laboratory rotations and in hypothesis driven thesis research that addresses a question of clinical importance. Trainees will complete discipline-specific courses as well as an ID-Problem-Based Learning course, a specialized team-taught pathogenesis module that integrates human physiology and pathology with in-depth study of human pathogens, and an intensive three-month Clinical Practicum based on their dissertation research. Seminars and enrichment activities that focus on interaction with clinical ID fellows and physicians will supplement the training. Four students, specifically selected for MERGE-ID will be admitted to the program each year, bringing the cohort to 16 by the fourth year of the program. When our trainees complete their education, we expect them to conduct highly effective, clinically relevant research that integrates basic approaches to medical problems. Based on the results from ongoing evaluation of the program, we propose to expand the MERGE-ID model to create similar programs focused on other disease-related areas before the end of the funding period.

PI: Camilli, Andrew
Title: Role of c-di-GMP Signaling in Vibrio cholerae Virulence
Knowledge is very limited with respect to how facultative pathogens, i.e., pathogens that spend portions of their life cycles both inside and outside of the human body, adapt to drastically changing conditions when passing from a human host into an environmental reservoir. Advances in understanding of the basic mechanisms of adaptation during this transition are needed to provide new molecular targets and strategies for limiting transmission, dissemination and environmental persistence, and thus reduce the large medical burden imposed by this diverse group of pathogens. In the facultative, water-borne pathogen Vibrio cholerae (the causative agent of cholera), signaling by the intracellular secondary messenger molecule cyclic diguanylate (c-di-GMP) leads to the repression of virulence genes, and at the same time, the induction of environmental survival genes. At a late stage of infection, just prior to excretion of V. cholerae in watery stool, expression of three genes that encode c-di-GMP synthetases is induced, leading to the hypothesize that c-di-GMP mediates the transition from a state of virulence to one of environmental suitability.

In this project the role of c-di-GMP in the biology of V. cholerae late in infection and in the process of dissemination will be determined using genetic and biochemical methods, including some novel methods created for these studies. In addition, the roles of a family of five c-di-GMP-binding proteins in transducing the c-di-GMP signal into biological changes will be determined. It is anticipated that this work will provide a working model of the central regulatory pathway in V. cholerae that represses virulence gene expression and induces expression of genes important for dissemination. It is also anticipated that these studies will have application to a broad range of bacterial pathogens since most contain multiple c-di-GMP synthetic, degradative and sensory proteins.

PI: Canyes, Barbara
Title: MACC AmeriCorps Student Leaders in Service
Massachusetts Campus Compact, Connecticut Campus Compact and the University of Sacred Heart, a consortium of 90 colleges and universities, propose to continue into a new grant cycle with a strategic national service initiative that will simultaneously 1) advance the public service mission of higher education; 2) leverage resources for the benefit of communities throughout our region; 3) develop students as civic leaders. With nine years of experience with Education Award Programs, Massachusetts Campus Compact will act as the lead for the program.

Annually, over 675,000 students are enrolled in higher education institutions in MA, CT, and PR. However, according to the Corporation for National and Community Service Report, Volunteering in America, on average less than a quarter of these college students are volunteering in their communities. AmeriCorps Student Leaders in Service seeks to take advantage of the unharnessed resource of young people creating change in their communities. College students who actively volunteer are more likely to actively participate in civic life as adults. AmeriCorps Student Leaders in Service will be a vehicle for college students to be more active in their local communities by developing their civic skills and beliefs as they recruit their peers to volunteer alongside them. In the current economic climate, community-based organizations rely even more on skilled volunteers to increase their capacity. This program will help fulfill that need.

AmeriCorps Student Leaders in Service will capitalize on the skills, energy and passion of one of the greatest resources in Massachusetts, Connecticut and Puerto Rico, our college students. This program will continue to empower college students to connect campuses and communities from across all three regions through active citizenship and service. As AmeriCorps members, 325 college students will each provide direct service to community and faith-based organizations, through tutoring, mentoring, addressing immediate needs of food, clothing, and shelter, and a variety of other efforts. Through their service, students will additionally build the capacity of campus-community partnerships for long-term sustainability through volunteer recruitment and coordination and service program management and development. This aligns with the Corporation for National and Community Service's goals of mobilizing more volunteers, engaging students in communities and ensuring a brighter future for America's youth.

Furthermore, AmeriCorps Student Leaders in Service will strengthen the civic mission of higher education by creating a pathway to lifelong civic engagement for college students. This assertion has been confirmed by the Massachusetts Campus Compact's previous AmeriCorps Education Award grant. College students enrolled as AmeriCorps members reported an increased belief in their ability to create change along with stronger civic competencies and leadership skills. A significant majority reported that their experience in AmeriCorps service contributed to a deeper understanding of their role as citizens and enhanced their understanding of the needs facing their communities. Students also reported that they will continue to serve within the community throughout college and after graduation.

PI: Castellot, John
Title: Regulation of Uterine Fibroids by CCN5
Leiomyomata (fibroids) are a non-malignant neoplasia of uterine smooth muscle cells (UtSMC) that afflict approximately 20% of all women and 80% of black women in the U.S. The most common tumor in women, fibroids cause severe pain and bleeding as well as infertility. Though temporary respite from the symptoms can be achieved by medical and surgical interventions, the only treatment that prevents recurrence is hysterectomy. More than 200,000 hysterectomies are performed annually in the U.S., with direct health care costs exceeding $2B; the emotional distress caused by loss of the uterus is incalculable. Despite its prevalence and severity, this condition has received sparse attention in the basic research community until quite recently. If we are to advance our understanding of the pathogenesis and improve treatment options for fibroids, it is critical to elucidate the mechanisms that underlie UtSMC proliferation.

Work in our laboratory showed that the growth-arrest protein CCN5 was nearly absent in human fibroids, yet abundant in the normal myometrium of the same patients. We have also demonstrated that the CCN5 protein blocks human UtSMC proliferation in culture and in animal models by >80%. Gene profiling indicates that CCN5 regulates clusters of genes that control mitogenic signal transduction and cell cycle progression. These observations underpin our central hypothesis that CCN5 has a key role in maintaining normal smooth muscle function in the uterus, and that dysregulation of CCN5 expression is a major factor in the pathogenesis of fibroids. A corollary hypothesis is that administration of CCN5 will reduce or prevent fibroid formation. To test these hypotheses, in this revised proposal we will carry out structure-function analyses to determine the mechanisms by which CCN5 regulates UtSMC function using a combination of in vitro and in vivo model systems. Using immunocompromised mice implanted with human fibroid UtSMC engineered to express CCN5, we will determine if CCN5 or related peptides can suppress fibroid formation.

These experiments are designed to provide a comprehensive assessment of the effects of CCN5 in human UtSMC from the molecular to the physiologic and pharmacologic levels. We hope the results of the proposed work will provide new insights into the pathophysiologic role of CCN5 in fibroids, and lead to novel therapeutic targets for treating this important women’s health issue.

PI: Catley, Andrew
Title: Livestock Emergency Guidelines and Standards: Support to Phase III
Throughout the developing world, livestock are a crucial livelihoods asset for vulnerable communities. In the face of continued political instability, conflict, population growth and climate change, natural and man-made disasters affect increasing numbers of people globally. The Livestock Emergency Guidelines and Standards (LEGS) are a set of international standards and guidelines for the assessment, design, implementation and evaluation of livestock interventions to assist people affected by humanitarian crises. The ultimate aim of LEGS is to improve the quality and livelihoods impact of livestock-related projects in humanitarian situations.

In early 2009 and with OFDA support, LEGS was published and made available as a free soft copy from the LEGS website, and as a hard copy version. After publication, a global LEGS training program was developed and tested, and LEGS was translated into French and Arabic. From mid 2009 to mid 2011 LEGS training courses were run in eight regions, and national courses in 14 countries. Combined with various regional and national awareness-raising events, these activities have helped to start to establish LEGS as the key point of reference for the design of livelihoods-based livestock programs in humanitarian crises. LEGS has attracted broad stakeholder acceptance and support, and continues to be overseen by a Steering Group comprising FAO, ICRC, Tufts University, African Union and Vetwork UK. Post publication activities were largely funded by ECHO and DFID, as part of a funding strategy to ensure broad donor support. In May 2011, LEGS was recognized as a Companion Module to Sphere, further reflecting its growing acceptance by the international humanitarian community.

Despite the good progress made by LEGS, there is still a considerable amount of work to be done to institutionalize LEGS in the humanitarian sector. For example, LEGS trainees now need to actually apply LEGS in new projects and evaluate the impact, and far more people need to know about LEGS, be trained, and use the guidelines. The momentum created by LEGS so far provides a strong platform for further work, but critically, the core coordination and management capacity of LEGS needs to be continued.

PI: Catley, Andrew
Title: Policy and Institutional Support to Livestock Development Relief in Pastoral Areas of Ethiopia
It is widely recognized that livestock are the crucial livelihoods asset for pastoralists in Ethiopia, and vulnerability is directly related to access to livestock resources and livestock-derived benefits. In common with other countries in the Horn of Africa region, livestock interventions in Ethiopia can be categorized as ‘relief’ or ‘development’ projects. However, the frequent provision of relief has often disrupted development work and to date, there have been few attempts to view livestock projects from a livelihoods perspective or within a "developmental-relief" framework. In summary, these approaches view relief as a means not only to save human lives but also to protect and enhance livelihoods in the long-term.

The Ministry of Agriculture and Rural Development (MoARD) in Ethiopia increasingly supports pastoralism through policies which aim to link pastoralists to a growing livestock export trade, and provide them with improved veterinary services by supporting privatized and veterinary-supervised community-based systems. The linkages between pastoralism, vulnerability, animal health and trade are becoming more obvious to the MoARD as new markets enable pastoralists to convert livestock into cash.

This proposal uses the USAID Pastoralist Livelihoods Initiative (PLI) Program to begin to address issues of policy coherence in the general area of pastoralism as a viable livelihood, and more specifically in developing policies and best-practice for livestock developmental-relief approaches. The PLI Program includes four separate NGO consortia for PLI component 1 (stocking rates and production of livestock optimized) and 1 US university for sheep and goat management; 1 NGO for component 2 (early warning and response systems); 1 NGO for component 3 (market development) and 1 US university for livestock sanitary standards and marketing. This proposal aims to ensure technically proficient and harmonized implementation of these interventions, and systematic impact assessment and research to draw lessons to inform policy and best-practice within an overall drought contingency plan. To create government leadership of the policy process, the project will support a national multi-stakeholder Pastoralist Livestock Policy Forum (PLPF) to be convened by the MoARD. Within the PLPF, four Working Groups will be established to examine each type of livestock intervention in the PLI, identify key policy issues, support impact assessment and research, and make recommendations accordingly. A fifth Working Group will be used to examine an additional policy issue with a view to achieving progress within the two-year project period. This fifth issue has been provisionally identified as rangeland degradation due to bush encroachment. In addition to these activities, the project will use awareness-raising and training events to expose the other government ministries to the benefits of pastoralism and its potential contribution to economic, market-led growth in Ethiopia.

The final outputs of the project will be a national livestock development-relief policy framework and guidelines, a national policy forum which will continue to function after the PLI to address a broader range of issues around pastoralism and livestock, and a more propastoralist approach within federal government as a whole. The project builds on the USAID funded work of Tufts University in the Horn of Africa since the early 1990s, and the Feinstein International Famine Center since 1996. The latter includes successful coordination of large-scale livestock programs projects and policy reform. The project also complements existing USAID support to pastoralism and livestock interventions in Ethiopia through the FOCUS, PARIMA, STI and other initiatives.

PI: Cebe, Peggy
Title: An Internship Opportunity for Deaf and Hard of Hearing Students in Polymer Blends
This project provides an opportunity for deaf and hard of hearing (DHH) students to participate in classroom and laboratory research work in the field of polymer blends for fuel cell technologies. A small team of college-age students will perform an internship at Tufts University for six weeks during the summer. The classroom and laboratory components address the materials chemistry and physics of polymers and polymer blends, crystallization and melting of polymers, the interaction of X-rays and light with polymers, mechanical properties of polymers, and the connection between thermal processing, structure, and ultimate properties of polymers. To prepare the DHH students for participation in the scientific community, a strong component of pre-professional training is incorporated, including discussion of ethical issues in the performance of research and in scholarship. The objectives of the laboratory research component are:

  • To expose the DHH interns to working with hearing persons in a laboratory environment;
  • To introduce them to the concepts of formulating and testing hypotheses;
  • To assist interns as they conduct systematic studies while controlling variables;
  • To illustrate the use of modern analytical equipment; and
  • To demonstrate the connection between processing variables, structure, and properties.
The specific program objectives are to:
  1. Increase the interns’ knowledge about polymers and polymer blends, and their use in fuel cell technologies;
  2. Increase the interns’ confidence in performing laboratory work;
  3. Demonstrate the importance of teamwork as an approach to real-time problem solving;
  4. Improve group presentation communication skills;
  5. Impart knowledge of the standards of ethics associated with the scientific endeavor.

DHH interns will make and characterize polymer blends, comprising a semicrystalline polymer, poly (vinylidene fluoride), PVDF, with an amorphous polymer, poly (4,5-vinyl imidazole), PVIm, protonated with a liquid ionic salt, for ultimate use as novel proton exchange membranes for fuel cell technologies. They will fabricate films, electro-spun fibers, and/or oriented tapes, and characterize the structure and properties of the resulting materials. This research will contribute to a fundamental understanding of the effects of blend composition and thermal treatment on crystal structure of PVDF, and ultimately on the potential of these blends to serve as proton exchange membranes for fuel cell technologies.

PI: Chen, Jake Jinkun
Title: Therapeutic Strategies for Treating Type 2 Diabetes Mellitus-Associated Periodontitis
Periodontitis is twice as prevalent in diabetics as in non-diabetics. Diabetic periodontal diseases are more severe and refractory because T2DM and obesity trigger the release of excess inflammatory factors, such as TNF-α and IL-6, which in turn stimulate osteoclasts to resorb the alveolar bone that supports the teeth.

Adiponectin, a fat cell derived hormone, is emerging as a potent molecule with multiple biological functions including regulating insulin sensitivity, suppressing inflammation, and improving diabetic symptoms. It also promotes osteoblastic differentiation and bone formation. Our recent studies have shown that adiponectin inhibits osteoclast differentiation and increases osteoclast apoptosis.

Our long-term objective is to identify and characterize an ideal endogenous mediator as a potent therapeutic remedy for the treatment of the widely prevalent T2DM-associated periodontitis. The objective of this application is to investigate the mechanisms of adiponectin in the pathogenesis of T2DM-associated periodontitis and to specifically reconstruct the inflammatorily damaged periodontal tissues by the replenishment of adiponectin in vivo. The central hypothesis to be tested is that the decreased level of adiponectin, together with the consequent removal of its suppressive effects on osteoclasts and proinflammatory factors, contributes to the pathogenesis of T2DM and T2DM-associated periodontitis. Also, a systemic adiponectin infusion promotes the reconstruction of the damaged periodontal tissues.

Aim 1: Using an animal model for the first time to determine the effects of anti-inflammatory factor in periodontal pathogenesis including inhibition of differentiation of osteoclasts that directly resorb alveolar bone.

Aim 2: To determine the therapeutic effect of systemic adiponectin infusion in dampening inflammation and in reconstruction of damaged periodontal tissues in vivo.

PI: Chen, Oliver
Title: The Effect of Whole Almonds on Glucoregulation, Endothelial Function, Inflammation, Lipid Profile, and Oxidative Stress in Chinese Patients with Type 2 Diabetes
The benefit of nuts in lowering serum cholesterol has been largely substantiated, with a consequent FDA-approved qualified health claim for the reduction of risk for coronary heart disease. In addition, nut consumption has been associated with improvement in biomarkers of inflammation, endocrine dysfunction, and oxidative stress that are related to the risk of cardiovascular disease (CVD). Our previous study demonstrated almonds (~60 g/d) improved lipid profile, glucoregulation, inflammation, and oxidative stress in 20 Chinese patients with type 2 diabetes mellitus (T2DM). To follow-up and expand this work with a more robust trial, we propose a larger (n = 40), longer-term (90-d) investigation of the effect of almonds (~60 g/d) on adipokine regulation, endothelial function, glucoregulation, inflammation, lipid profile, and oxidative stress in Chinese patients with T2DM as compared to a placebo control.

The main goal of the randomized, crossover, placebo-controlled, controlled feeding trial is to determine if 3-month supplementation of ~60 g/d almonds that are incorporated into the NCBP step II diet to replace 20% calories will improve measures of glucoregulation, endothelial function, adipokine regulation, inflammation, oxidative stress, and lipid profile.

The clinical trial will be conducted at Taipei Medical University in Taiwan. We will conduct a 7-mo randomized, cross-over, placebo controlled clinical trial in which all meals will be provided to all subjects. During the first 2 wks (run-in period), all subjects will receive a control diet resembling a typical Taiwan diet, prepared based on the NCEP Step 2 guidelines. During the following 3 mo (Phase I), subjects will be randomized to receive either the control diet or the control diet with whole almonds (~60 g/d) incorporated to replace 20% calories. After a 2-wk washout period during which all subjects will once again receive the control diet, subjects will receive the opposite diet to the one assigned during the Phase I for the other 3 months (Phase II). The caloric content of each diet will be adjusted to each subjects’ energy needs to prevent any change in body weight. The following biomarkers will be determined at the baseline and end of each dietary intervention: Glucoregulation: fasted serum HbA1c, glucose and insulin, postprandial serum glucose and insulin, and urinary C-peptide; Endothelial Function; brachial artery FMD and serum nitric oxide, e-selectin, endothelial-1 (ET-1), and intracellular adhesion molecule-1 (ICAM-1); Adipokine Regulation: serum adiponectin, leptin, and resistin; Inflammation: serum high-sensitivity C-reactive protein (CRP), interleukin (IL)-6, IL-10, retinol binding protein-4 (RBP-4), and tumor necrosis factor (TNF)-α; Oxidative Stress: urinary isoprostanes (adjusted for creatinine) and serum protein carbonyls and oxidized LDL; and Lipid Profile: serum cholesterol, triglycerides, and apolipoproteins A1 and B.

PI: Chiesa, Luisa
Title: Superconducting Technology for Magnet Systems in Fusion Machines
Superconducting magnets play a key role for the confinement of plasma in a large fusion energy machine providing magnetic fields high enough to confine the plasma and produce substantial fusion power density. The magnet components alone account for a considerable fraction (~30% for ITER) of the investment in the fusion machine (~50% of the magnet system cost is for superconducting materials). High field fusion magnets of Nb3Sn low temperature superconductors have showed unexpected sizable degradations compared to the expected currents estimated from single strand values. Those degradations are due to the inherent mechanical loads caused by thermal contractions and operational electro-magnetic forces. ITER model coil tests have shown the degradations could be as high as 50% in fusion magnets. My long term career goal is to pursue research and education in superconducting materials and magnet systems for fusion machines. The objective of this proposal is to understand the electromechanical behaviors of superconducting materials both low (LTS) and high temperature superconductors (HTS).

PI: Chisholm, Karen
Title: MACC AmeriCorps*VISTA Program (2011-2012)
Massachusetts Campus Compact (MACC) is a statewide consortium of 73 colleges and universities committed to developing the civic skills of students, building partnerships with the community, and integrating civic engagement with teaching and research. Through technical assistance, grant distribution, training, and resource development, MACC aids students, faculty, staff and presidents in developing and improving community service and service-learning programs to respond to specific local and regional needs throughout Massachusetts. MACC supports the leveraging of college and university resources to address community problem-solving and directly target issues faced by low-income communities.

Non-profit community based organizations (CBOs) face a number of challenges in their respective communities. These can include an increasing demand for their services that does not match their capacity; fewer resources; unmet funding needs; and increasing need for assessment and evaluation. Developing a partnership with a neighboring college and/or university can be an effective way to respond to these challenges.

The MACC VISTA program has been successful in deepening higher education's impact on low-income communities through a focus on the development of sustainable internal systems for civic engagement and the development of partnerships between colleges and community-based organizations. As a result of MACC VISTA efforts, there are more partnerships between community-based organizations and colleges and universities. There are more students civically engaged in their communities through volunteer opportunities, community service federal work-study, and service learning programs, among other things. Overall, there is an increased capacity for institutions of higher education to continue to serve communities in meaningful ways.

PI: Chishti, Athar
Title: Cytoskeletal Regulation of Erythorocyte Glucose Transporter-1
The overall aim is to test the hypothesis that the spectrin-actin junctions play a critical role in the maintenance of red blood cell shape and membrane properties. This hypothesis will be tested by identifying new membrane receptors for dematin and adducing in both erythroid and non-erythroid cells.

PI: Chiu, Chung-Jung
Title: Development of a Prediction Model for Advanced Age-Related Macular Degeneration
Age-related macular degeneration (AMD) is a progressive disease, the advanced forms of which account for over 50% of legal blindness in the US. Vision impairment due to advanced AMD also significantly reduces quality of life and consumes a large portion of Medicare budget. Diminishing the modifiable risk factors for the progression of AMD could lead to significant clinical benefit and save health care cost. However, early identification and close follow-up of patients at high risk of developing advanced AMD are essential to allow for implementing strategies to delay progression of the disease to stages when vision is compromised. Recently, using the Age-Related Eye Disease Study (AREDS) dataset PI (Chiu) developed a prediction model for advanced AMD (c-index=0.877). However, validation analysis of this AREDS model in the Blue Mountains Eye Study (BMES) cohort indicated that it is necessary to use data from multiple cohorts to develop a prediction model with maximal generalizability.

Our objective is to use risk factor information provided in the patient history and clinical eye examinations to develop a widely applicable tool for the early prediction of advanced AMD.

PI: Choi, Sang Woon
Title: Effects of Aging and Folate on Colonic Carcinogenesis
Elder age and inadequate folate intake are each strongly implicated as important risk factors for colon cancer. In a preliminary study we observed that aging and folate depletion alter one-carbon metabolism in the rodent colon, increasing uracil misincorporation into DNA, thereby creating a predisposition to chromosomal and DNA aberrancy and carcinogenesis. By the same token we observed that dietary folate at supplemental levels prevents the appearance of the abnormal biochemical and molecular effects of aging in the colon. We also found altered expression of several critical genes in response to aging and folate depletion. We, therefore, hypothesize that the increased uracil content in DNA produced by aging and inadequate folate availability increases chromosomal and genomic DNA damage, affects expression of critical genes and consequently enhances colonic carcinogenesis. However, reduction of uracil in colonic DNA will reverse the pro-carcinogenic effects of aging and folate depletion.

Our long-term goal is to find an effective strategy for the chemoprevention of colon cancer. The studies outlined in this proposal are aimed at defining molecular and cellular mechanisms that determine how aging and folate status affect colonic carcinogenesis. The specific aim of this proposal is to determine whether such molecular anomalies enhance colonic carcinogenesis and whether folate supplementation or any other modalities to reduce uracil misincorporation attenuates such molecular changes and finally prevents cancer development. We propose animal studies using a normal aging mouse model, a mouse model of colon cancer and a genetically-modified mouse model, the latter mimicking a common genetic condition that diverts folate more to nucleotide synthesis.

By defining molecular pathways towards cancer modulated by aging and folate, we will have a better understanding of the nutritional circumstances which constitute high risk and thereby will be able to define the precise manner in which folate can be used effectively as chemopreventive agents.

PI: Coates, Jennifer
Title: Development of M&E Framework for GAIN Integrated Program Strategy
Large-scale mass fortification is a proven, cost-effective market-based strategy for improving the intake of vitamins and minerals, leading to a reduction in the prevalence of micronutrient deficiencies. The dependence on private channels as the sole means for the distribution of fortified foods, however, can leave some individuals without access to fortified foods because they are outside of the market economy. As a result, in order to increase the reach and impact of its programs, GAIN is developing novel distribution channels to reach these population segments that will complement market-based food fortification.

Specifically, in five pilot countries, GAIN will work with local governments and private and civil society partners to develop multiple delivery models for fortified foods to reach additional populations at-risk of micronutrient deficiencies. Large scale fortification using commercial markets will remain the foundation of GAIN’s investments in each country but will be complemented by approaches that will benefit the lowest economic strata and other groups vulnerable to malnutrition, including individuals affected by infectious diseases. Examples of such complementary approaches include small-scale fortification (appropriate for rural settings) or subsidized food distributed to special target groups through public sector safety net programs.

The use of complementary distribution channels is at a “proof of concept” stage whereby it must be demonstrated that individuals most at-risk of micronutrient deficiencies are in fact reached and that the additional distribution channels are sustainable, cost-effective and imparting a biological impact.

A robust monitoring and evaluation framework has been designed specifically to test these multiple channels in Rajasthan, India, which will evaluate coverage and impact on target populations through to economic and policy analysis, with the aim of identifying the most cost-effective mix of strategies to reduce micronutrient malnutrition in this context.

PI: Cochran, Brent
Title: RNAi Screen of the Glioblastoma Stem Cell Kinome under Hypoxia and Normoxia
Glioblastomas are highly aggressive brain tumors with a mean survival time of only 14 months. There is increasing evidence that brain tumors and glioblastomas in particular are driven by a subpopulation of cancer stem cells. It has recently been possible to isolate and maintain continuously in culture these putative tumor stem cells. These cells grow as neurospheres and retain the ability to differentiate into neurons and astrocytes despite being highly tumorigenic mouse xenografts. We have developed methods for high throughput screening of these GBM stem cells using RNAi. Here we propose to comprehensively identify kinases that are required for the growth and survival of glioblastoma stem cells under normoxic and hypoxic conditions. We will focus on kinases since they are druggable targets for which a great many inhibitors are already available and for which several have already been clinical successes.

Our first aim will be to perform shRNA screens of the human kinome to identify kinases commonly required for the growth and survival of glioblastoma stem cell lines. Our preliminary results indicate that the kinases required for tumor stem cell growth are distinct from the kinases required for growth of traditional serum grown cell lines. Thus, these screens are likely to uncover new kinase targets for glioblastoma therapy. Moreover, glioblastomas are known to be tumors that have hypoxic microenvironments that can limit the efficacy of traditional therapies. Our evidence indicates that glioblastoma stem cells actually thrive under hypoxia. Our preliminary data also indicates that there are kinases that are required for tumor stem cell growth under normoxic conditions, but not hypoxic conditions and vice versa. Identifying the kinases that are required for growth and survival under hypoxic conditions is thus critical for elimination of cancer stem cells in the tumor. Thus, we will screen these GBM stem cells under both hypoxic and normoxic conditions.

In the second aim, we will investigate the cellular functions of kinases identified in the RNAi screens. In addition, we will determine whether key kinases identified in the screen are in fact activated in primary human glioblastomas, and determine whether inhibition of these kinases in mouse xenografts will inhibit tumor growth. Results of these studies should identify and prioritize new kinase targets for treatment of glioblastoma.

PI: Coffin, John
Title: Retrovirus Evolution
Retroviruses exhibit a wealth of evolutionary phenomena, including the ability to undergo rapid genetic change in response to varying selective pressure; the ability to vary in the use of host cell receptors; and the ability to become integrated in the genome of their host species and passed down through the generations as endogenous proviruses. In the prior project period, we have studied all these aspects of retrovirus evolution: We have looked at the mechanism of evolution of env genes by analyzing an unusual mutant that extends the host range of ALV beyond chicken, to quail, dog, and even human cells. We have isolated and studied an unusual mouse endogenous provirus that appears to occupy a special phylogenetic location between mouse and non-mouse species. We have extensively analyzed the coevolution of humans and their endogenous proviruses, particularly the relatively recently inserted HERV-K family. We have developed sophisticated mathematical models for the evolution of replicating virus populations, describing the effects of mutation, selection, drift, linkage, and recombination on the accumulation (or loss) of deleterious mutations. Future work will address the following aims:

  1. How do retroviral envelope genes evolve to use new receptors and to alter other important properties? We will use our extended host range mutants to test specific hypotheses for this process.
  2. What are the functional and pathogenic properties of human endogenous retroviruses, particularly HERV-K? Can we isolate infectious virus? Is their expression or reintegration associated with malignancy?
  3. How do important the forces of mutation, selection, recombination, and drift combine to direct retrovirus evolution? We will combine mathematical and in vitro modeling of virus replication to test specific evolutionary models.

PI: Cowen, Lenore
Title: Clare Boothe Luce Graduate Fellowships
Tufts University is applying for two Clare Boothe Luce Graduate Fellowships in Computer Science. These fellowships will enhance the efforts that Computer Science at Tufts is making to increase the number of women in computer science. While Computer Science is a field where the proportion of women is generally small, Tufts has perhaps the highest proportion of tenure-track women of any Computer Science department in the nation. The high percentage of women faculty in the department together with strong institutional support from the Tufts School of Engineering produces a vibrant and supportive environment where women doctoral students thrive. If Tufts is granted support for two Clare Boothe Luce Graduate Fellowships, we will advertise broadly – we are a place where women graduate students do extremely well. Based on our experience we know that having the Luce fellowships will highlight this.

PI: Cowen, Lenore
Title: Computational Methods for Wrapping and Threading Remote Protein Homologs
The “twilight zone” is a term coined by Burkhard Rost to refer to remote protein homologs whose sequence similarity to proteins of known structure is sufficiently low that computational detection of the homology becomes quite challenging. We propose to construct new threading methods that extend protein structure prediction and sequence/structure alignments further into the “twilight zone”.

We attack the problem on two fronts: first, we intend to extend the “wrapping” methods we designed to successfully attack two hard special cases of this problem to other SCOP superfamilies. This involves casting the pairwise dependencies in the wrapping portion of the energy function into the general framework of Markov Random Fields, while still allowing them to wrap multiple aligned sequences to narrow the search space; then using a more sophisticated energy function based on a backbone-dependent rotamer library for sidechain packing. Second, our programs for the beta-helix and trefoil folds used human intervention to construct the core structural templates on which we are wrapping the sequences to predict whether they could fold into these structures or not. In order to construct a general threading program with reasonable fold library coverage for the PDB, we need to solve the challenge of automating the construction of a structural template from a set of proteins that, for example, all belong to the same SCOP superfamily. Most current threading programs train too closely to a backbone of one particular structure to be able to capture remote homologs. We propose a novel multiple structure alignment that adds geometric flexibility to capture similarities between more distant homologs, from which more general core templates can be abstracted.

The applications of better computational protein structure prediction to speed up medical discovery are well-known. BetaWrap, our first beta-helix prediction program, already uncovered a previously-unknown relationship between the beta-helix fold and the virulence of microbial pathogens. A striking prediction of the BetaWrap program is that the beta-helix fold is predicted for many surface adhesins, toxins, and other recognition/penetration proteins of human pathogens. Our prediction that a major pollen allergen forms the beta-helix shape has just recently been confirmed experimentally.

Mentor: Cowen, Lenore
Fellow: Shah, Michael
Title: GEM Fellowship, Michael Shah

  • Automate redundant processes such as the installation of software through remote tools and using scripting languages that utilize the windows API.
  • Build scripts to automate the setup of machines to a preferred state with software installed, hardware setup, and drivers installed.
  • Build tools to interface with hardware, such as web power switches, through websites.
  • Validate installations and uninstalls of tools to insure installations and installs were completed correctly.
  • Build a website to monitor and schedule the use of cypress river boards to individual team members located across four different intel sites.

PI: Crane, Gregory
Title: DC: Large: Collaborative Research: Mining a Million Scanned Books: Linguistic and Structure Analysis, Fast Expanded Search, and Improved OCR
The Center for Intelligent Information Retrieval at UMass Amherst, the Perseus Digital Library Project at Tufts, and the Internet Archive are investigating large-scale information extraction and retrieval technologies for digitized book collections. To provide effective analysis and search for scholars and the general public, and to handle the diversity and scale of these collections, this project focuses on improvements in seven interlocking technologies:

  1. Improved OCR accuracy through word spotting, creating probabilistic models using joint distributions of features, and building topic-specific language models across documents;
  2. Structural metadata extraction to mine headers, chapters, tables of contents, and indices;
  3. Linguistic analysis and information extraction, to perform syntactic analysis and entity extraction on noisy OCR output;
  4. Inferred document relational structure to mine citations, quotations, translations, and paraphrases;
  5. Latent topic modeling through time to improve language modeling for OCR and retrieval, and to track the spread of ideas across periods and genres;
  6. Query expansion for relevance models to improve relevance in information retrieval by offline pre-processing of document comparisons; and
  7. Interfaces for exploratory data analysis to provide users of the document collection with efficient tools to update complex models of important entities, events, topics, and linguistic features.

When applied across large corpora, these technologies reinforce each other: improved topic modeling enables more targeted language models for OCR; extracting structural metadata improves citation analysis; and entity extraction improves topic modeling and query expansion. The test bed for this project is the growing corpus of over one million open-access books from the Internet Archive.

PI: Crane, Gregory
Title: The Hellespont Project: Integrating Arachne and Perseus
We propose to combine and expand the collections of two of the oldest and most established digital projects in Classical Studies – Arachne at the University of Cologne and Perseus at Tufts University – and thus to create a single comprehensive digital library about the ancient world. The resulting collection will contain CIDOC-CRM metadata for more than 250,000 archaeological sites and objects, MODS/FRBR bibliographic records for editions of every major Greek and Latin author whose work survives either in the manuscript tradition or in substantial fragments, and TEI P5 compliant XML transcriptions for 20 million words of Greek and Latin primary sources, as well as for more than 50 million words of archaeological documentation, major lexica, commentaries, and encyclopedias. The lead partners at Cologne and Tufts University are, in addition, already collaborating closely with computer science projects at Leipzig and the University of Massachusetts at Amherst and dedicated to the analysis of text from the humanities and classics. This collection will therefore include a range of metadata extracted from existing databases and mined from the full text of much larger collections, including content relevant to classical studies in JSTOR and in the 1.5 million books from the Internet Archive (IA) alone. Users of Arachne and Perseus will have access to the full collections available in each. More importantly, everything that we produce will be available for download under a Creative Commons License in formats that conform to optimal standards and best practices. The German Archaeological Institute (DAI) will, for example, be able to integrate a new generation of cataloguing data into its Zenon Union Catalogue, and general repositories such as the Hathi Trust, internet giants such as Google, and small groups of collaborators and individual researchers will be able to present and extend the work that we conduct to serve the study of the Greco-Roman world in ways that we cannot now predict.

Both Arachne and Perseus have devoted substantial resources to collecting digital images of archaeological sites and objects. The CIDOC-CRM metadata will facilitate the distribution of approximately 150,000 images of Greco-Roman antiquity, but in this project we will also focus upon the challenge of documentation. With the rise of inexpensive digital cameras and the increasing acceptance of flashless photography in museums, the challenge has shifted from collecting digital images to contextualizing and analyzing the many images becoming available online. In an August 2009 visit to Berlin, American PI Crane, for example, took more than 300 digital pictures in an intensive visit of the Antikensammlung and Pergamonmuseum, including many details not visible in published images. What is still lacking for users of these images is information necessary to enhance their understanding of them, descriptions of traditional museum catalogues but the full record, textual and material, of the Greco-Roman world.

PI: Crane, Gregory
Title: Working with Text in a Digital Age
The focus of this Institute will be on linguistic sources that shed light upon the human record. While collections in Greek, Latin, Arabic, German, and English will be prominent, participants with many different linguistic interests are encouraged to apply. This Institute introduces students of the Humanities to established Digital Humanities technologies such as TEI XML markup as well as new methods from fields such as Corpus and Computational Linguistics, information retrieval and data visualization. It will provide its participants with three weeks not only to acquire new skills but also to transform the way in which they conceive of their research and teaching. We will particularly encourage graduate students and library professionals as well as faculty to apply either as individuals or as small groups or as representatives of established collaborations.

PI: Crott, Jimmy
Title: Effect of Paternal B Vitamin Intake on Intestinal Tumorigenesis in Offspring
Parental diet and exposures are increasingly recognized as determinants of disease risk in offspring. Our contribution here has been to demonstrate that maternal supplementation with vitamins B2, B6, B12 and folate can suppress, while mild deficiency can promote, intestinal tumorigenesis in mouse offspring. We propose that modulating paternal diet will have similar effect on tumorigenesis in offspring. This issue is of importance because there may exist an opportunity to exploit a previously ignored means to lower the incidence of cancer in our society. Unlike the situation for expectant mothers, there are no dietary recommendations for men prior to conception and the incidence of mild deficiencies of vitamins B2, B6, B12 remains high in the US (10-50%). Furthermore, despite the rarity of folate deficiency in the US, our data in mothers indicates that intakes above and beyond those considered adequate are required to maximally suppress intestinal tumorigenesis in offspring and that intakes considered 'adequate' are associated with elevated tumor incidence in offspring.

Our long term goal is to minimize the risk of cancer in offspring by optimizing diet throughout the life cycle, including that of both parents. The objectives of this application are to determine whether paternal supplementation and depletion with vitamins B2, B6, B12 and folate can alter tumor incidence in offspring and to gain an understanding of the mechanisms involved. We hypothesize that supplemental quantities of vitamins B2, B6, B12 and folate in the paternal diet will suppress, while combined mild deficiency will promote tumorigenesis in offspring. Furthermore, that such effects will be associated with the prevention or promotion of deleterious promoter methylation and gene expression changes of members of the "Wnt" signaling pathway, a pathway that regulates cell division and death and is commonly disrupted in colorectal cancer. The primary specific aim of this proposal is to determine whether paternal supplementation of mild depletion of vitamins B2, B6, B12 and folate alters the incidence of intestinal tumors in offspring. A secondary aim is to determine whether observed changes in tumor incidence are associated with changes in the expression and methylation of Wnt pathway genes in the normal intestinal mucosa. This contribution is significant because understanding how B vitamins modulate the development of cancer in individuals and their offspring is essential for developing intelligently-constructed and effective measures that will utilize these vitamins in the prevention of cancer.

PI: Danahy, Ethan
Title: InterLACE: Interactive Learning and Collaborative Environment
This project, under the Tufts University Center for Engineering Education and Outreach (CEEO) designs, constructs, and field-tests a web-based, online collaborative environment for supporting the teaching and learning of inquiry-based high school physics. Based on prior NSF-funded work on RoboBooks, an interactive digital workbook environment, the team is customizing the platform to include scaffolds and other supports for learning physics, fostering interaction and collaboration within the classroom, and facilitating a design-based approach to scientific experiments. The InterLACE team hypothesizes that technology seamlessly integrating physics content and process skills within a classroom learning activity will provide a wide variety of student benefits, ranging from improved learning outcomes and increased content knowledge to gains in attitudinal and social displays as well.

The hypothesis for this work is based on research that indicates teachers believe proper implementation of design-based, inquiry projects are time consuming and can be difficult to manage and facilitate in classrooms without great scaffolding or other supports. Using design-based research with a small number of teachers and students, the PIs iteratively develop the system and supporting materials and generate a web-based implementation that supports students through the various stages of design inquiry. A quasi-experimental trial in the final years of the project is used to determine the usability of the technology and efficacy of the system in enhancing teaching and learning. Through the tools and activities developed, the researchers anticipate showing increases in effective inquiry learning and enhanced accessibility to meet the needs of diverse learners and teachers, leading to changes in classroom practice.

Through this project the PIs (1) gain insights that will enable them to refine the InterLACE platform so it can be implemented and brought to scale in the near terms as a support for design-based inquiry science projects, and (2) advance theory, design and practice to support the design of technology-based learning environments, and (3) understand how connecting students hypotheses, ideas, and data impacts their learning of physics content and scientific inquiry skills.

PI: Dawson-Hughes, Bess
Title: Musculoskeletal Benefits of Bicarbonate in Older Adults – A Dose-finding Trial
With aging, men and women develop a mild and progressive metabolic acidosis. This occurs as a result of declining renal function and ingestion of acid-producing diets. There is extensive evidence that severe metabolic acidosis causes bone and muscle loss, but the impact of the chronic, mild acidosis on bone and muscle in older individuals has not been established. In our recently completed NIH-funded trial in 171 older men and women, alkalinizing the diet with a bicarbonate supplement daily for 3 months significantly reduced urinary excretion of N-telopeptide (NTX), a marker of bone resorption, and urinary nitrogen, a marker of muscle wasting. Moreover, bicarbonate supplements significantly improved muscle performance in the women. These and other data support a potential role for bicarbonate as a means of reducing the musculoskeletal declines that lead to extensive morbidity and mortality in the elderly. Before proceeding to a long-term bicarbonate intervention study, however, it is important to identify the dose of bicarbonate most likely to be optimal and to characterize the subjects who benefit most from it.

The proposed dose-finding study will extend our previous work in this area by evaluating the effects of placebo and two doses of bicarbonate on urinary NTX and nitrogen excretion and on lower extremity performance. The lowest dose we plan to test is similar to the dose shown in our recent trial to be effective. The proposed study is a double blind, randomized, placebo-controlled, parallel-group trial in which 138 men and 138 women, age 60 and older, will take potassium bicarbonate in doses of 1.0 or 1.5 mmol/kg of body weight or placebo daily for three months. Changes in urinary excretion of NTX and nitrogen and in selected measures of lower extremity performance will be compared across the three groups. The safety and tolerability of the interventions will also be evaluated. This investigation should provide needed information on the appropriate dosing regimen and on the study population that should be enrolled in a future long-term bicarbonate intervention trial to assess the long-term effects of this simple, low cost intervention on important clinical outcomes including rates of loss in bone and muscle mass, falls, and fractures.

PI: Degterev, Alexei
Title: Molecular and Functional Analysis of Necrotosis Activation Complex
Extensive evidence suggests that two “classic” cell death pathways, apoptosis and necrosis, do not encompass the full variety of physiological and pathological cell death mechanisms. Our and other laboratories have established the existence of a common third pathway, termed “programmed necrosis” or “necroptosis.” Necroptosis is a regulated cell death pathway with phenotypic features of necrosis. It is activated in cells that are induced to undergo apoptosis, yet prevented from its completion. We have recently developed a potent and selective small molecule inhibitor of necroptosis, Necrostatin-1, and using this molecule has demonstrated the important role of necroptosis in various paradigms of pathologic cell death in vitro and in vivo. Discovery of necroptosis offers unique opportunity to develop novel therapies specifically targeting necrotic component of pathologic cell death, which was previously not pursued due to the notion that necrosis is an unregulated form of death.

However, little is currently known regarding the specific mechanisms of activation and execution of necroptosis. Ser/Thr kinase RIP has emerged as the key upstream activator of necroptosis. Furthermore, we have recently established that RIP kinase activity is a specific cellular target of Necrostatin-1 and several other structurally unrelated potent necrostatins that were also developed in our laboratory, highlighting the critical role of RIP kinase in necroptosis. In our preliminary studies, we developed new assays to specifically measure RIP kinase activation and necroptosis induction. We performed preliminary mass spectrometry-based characterization of RIP kinase that led to the identification of a number of novel and specific posttranslational modification (phosphorylation) events that are potentially involved in the regulation of necroptotic activity of RIP. We also demonstrated the feasibility of assessing dynamic changes in the composition of the endogenous RIP interactome using mass spectrometry analysis.

Our current proposal focuses on further studies of the mechanism of necroptosis induction by RIP kinase. The specific aims of the project include confirming the role of RIP phosphorylation changes, previously identified by us, in the activation of necroptosis; characterization of RIP kinase activation process in vitro and in vivo using phosphospecific RIP antibodies and RIP kinase assay; dissection of RIP interactome using high resolution mass spectrometry followed by functional characterization of the role of RIP interacting factors in necroptosis initiation; and establishing the feasibility of the necroptosis inhibition by necrostatins as a new direction for cytoprotective therapies against acute pathologic necrosis.
Overall, our studies will provide important new insights into the regulation of necroptosis through elucidating the molecular basis of the induction of the key upstream step in necroptosis, RIP kinase activation, and will validate a potential new direction for therapeutic inhibition of pathologic necrosis through selective targeting of necroptosis-specific initiation factors.

PI: Donini, Antonio
Title: Humanitarian Action and Politics Research Project
Since the summer of 2009, researchers at the Feinstein International Center (FIC) at Tufts University have initiated a major two-year research project on Humanitarian Action and Politics. This project builds upon and expands on the earlier “Humanitarian Agenda: Principles, Power and Perceptions” research (HA2015) which involved 13 country case studies of local perceptions of humanitarian action and a synthesis report. The new research is in two separate but related phases. Phase one is more policy oriented: building on the HA2015 case studies and subsequent field work, it looks at the challenges faced by humanitarian actors in recent crises – Afghanistan, Sudan, Sri Lanka and possibly others – and at the policy and operational implications for UN agencies, NGOs and donors. Phase two will take a historical approach and analyze a number of long-running crises, as well as some cross-cutting themes, with a view to gaining a better understanding of the humanitarian present through in-depth analysis of the past. Phase I will run through the summer of 2010. Phase II will run through the end of 2011.

PI: Dorfmann, Luis
Title: Anisotropic Magneto-Sensitive Composites
Magneto-sensitive composites change their shape and properties in response to magnetic stimulation. Among the various classes of smart materials, in which non-mechanical excitation fields are used to induce mechanical deformations, the class of magneto-sensitive composites is an outstanding one. These composites undergo large deformations, extract large forces, their response time is short, they can be remotely activated, and their manufacturing is relatively simple. Consequently, they can be used in variety of applications such as switches, sensors, actuators and manipulators, vibration isolation, and energy harvesting devices. Moreover, the fact that permanently magnetized inclusions are available may result in a unique response, which is yet to be explored. However, the constitutive description of these materials, where geometrically nonlinear deformations of heterogeneous and anisotropic materials on top of inherently nonlinear magneto-mechanical coupling must be accounted for, is quite complicated.

We wish to exploit possible procedures and advance a framework for tackling the nontrivial aspects associated with magneto-sensitive composites. At the scientific level we will be using and developing modern homogenization techniques in the context of a most demanding application. The unique class of magneto-sensitive composites with permanently magnetized inclusions will be explored together with the role of the inclusions spatial arrangement. Analytical results will be compared with corresponding numerical simulations that incorporate simultaneous solutions of magnetic and elastic problems. The goal is to bring relevant data from the microscopic level up to the macroscopic one in terms of anisotropic energy-density functions that will be made available and implemented numerically for both the scientific and the engineering communities.

PI: Drag, Darren
Title: Comprehensive Oral Health Care Program for Individuals with Mental Retardation and Developmental Disabilities
The program will:

  1. Provide comprehensive routine and emergency oral health care to individuals with mental retardation and other developmental disabilities residing in developmental centers and the community in a timely manner. This includes access to dental clinics as well as operating rooms tor surgical procedures.

  2. Staff and oversee programs at multiple dental facilities located at sites throughout Massachusetts.

  3. Train dental residents, dental and dental hygiene students, and licensed dentists and dental hygienists to provide oral health care with knowledge of the medical and behavioral needs of individuals with mental retardation and developmental disabilities.

  4. Monitor and promote appropriate utilization and maintenance of oral health care among clients.

  5. Maintain relationships with the dental community to provide a referral resource for individuals with mental retardation and developmental disabilities

  6. Maintain an even geographic distribution of service sites including operating room facilities and teaching sites for dentists and dental hygienists interested in training.

  7. Promote good oral hygiene practices and preventive measures through coordinated training opportunities for care givers.

  8. Maintain and disseminate management reports regarding utilization, client populations served, billing, wait times, cancellations and "no-shows."

PI: Dunlap, Kathleen
Title: Synapse Neurobiology Training Program
Multidisciplinary approaches drive progress in the neurosciences perhaps more than in most other areas of biomedical research. The next generation of research neuroscientists, therefore, must be equipped with a multi-faceted skill set if they are to transition to successful independent careers and contribute meaningfully to the field. To meet this challenge, we propose a new predoctoral Synapse Neurobiology Training Program (SNTP) at Tufts University School of Medicine that will provide in-depth, multidisciplinary research education of 4 trainees in the area of synaptic function – a particular strength of the Tufts neuroscience faculty. The synapse forms the foundation of nervous system function, and research on synapses is, arguably, one of the most interdisciplinary areas in modern neurobiology. The SNTP training plan, thus, includes several mechanisms that position trainees to become leading neuroscientists, working at the interface between traditional disciplines:

  • Each trainee will be co-mentored by two SNTP faculty members who provide training in distinct yet complementary areas.

  • Through subsidized, one-on-one training in imaging, bioinformatics, electrophysiology, and animal behavior methods (provided via the core facilities and PhD-level Managers in the NINDS-funded Center for Neuroscience Research at Tufts), SNTP trainees will acquire the state-of-the-art tools and training required for an effective and influential multidisciplinary approach.

  • Innovative quantitative skills and techniques courses and individualized training plans will further aid each SNTP trainee in mastering the necessary skills to accomplish his/her research career goals.

  • Frequent opportunities for individual interactions with visiting speakers will provide SNTP trainees with further exposure to new methodologies and ideas as well as advice and guidance.

Mentor: Durant, John
Fellow: St. Vincent, Allison
Title: Developing Time-Resolved Models for Predicting Atmospheric Concentrations of Highway-Generated Nanoparticles in Urban Neighborhoods
Environmental and Water Resources Engineers study natural and man made environmental systems for the dual purpose of improving human health and protecting the natural environment. This scientific knowledge informs environmental regulations and natural resource management. Through the Tufts University Program in Environmental and Water Resources Engineering (EWRE), I expect to expand on my undergraduate degree in environmental engineering from MIT to better augment the knowledge of environmental systems related to public health that is available to policymakers and private citizens. The EWRE Ph.D. program at Tufts requires fifteen courses, three of which are core classes (Chemical Principles in Environmental and Water Resources, Transport Principles in Environmental and Water Resources Engineering, and Environmental and Water Resources Systems). As a first semester student, I am currently taking the first two core classes. The remaining courses will be directed towards acquiring knowledge required for development of the thesis, with courses on such topics as air pollution science and modeling, numerical methods, and environmental statistics. In addition, all Ph.D. candidates must pass a qualifying exam consisting of both written and oral components to be formally admitted to doctoral candidacy. In addition, students must pass a proposal defense, a final dissertation defense, and submit a written thesis to be awarded a degree.

PI: Easterbrooks, Ann
Title: Massachusetts Healthy Families Evaluation – 2
This six-year evaluation study consists of two main components: an Impact Study, which, through its experimental design, will allow us to make assertions about program effects; and an Integrative Study, which focuses intently on specific issues (e.g., mental health, school experience, etc.) in participants and programs from particular communities, allowing for a more concentrated and comprehensive understanding of the contextual factors that influence participants' trajectories as they transition both to parenthood and adulthood. Increased attention to the community contexts in which these HFM programs operate — in essence, enhanced activities at Tier Three — also are being integrated into this second-cohort study as the Program Community Study. The following sections explain each of these components in greater detail.

Impact Study: This large-scale randomized, controlled trial (total sample of 699, with 429 participants in the program group [Home Visiting Services Group, or HVS] and 270 in the control group [called the Referrals and Information Only Group, or RIO]) will determine the extent to which HFM's main program goals have been achieved, and to attribute these outcomes, with greater certainty, to the HFM program. In other words, Impact Study data will be used to establish program effects on participants' rates of maltreatment; repeat births; educational achievement; economic self-sufficiency; maternal health and well-being' and child development.

Integrative Study: This study uses a mixed methods (qualitative and quantitative data) approach with a smaller sample of participants (277 from the HVS group, and 200 from the RIO group) to examine if and how program/community contexts and participant characteristics mediate the achievement of HFM's short-term (intermediate outcomes) and long-term (distal outcomes) goals. Whereas the experimental Impact Study will answer questions about HFM's overall effects, data from the Integrative Study will deepen our understanding of how participants' personal, family, and community contexts, and HFM program operations and utilization, influence and/or explain participants' attainment of the five HFM stated goals (also called distal outcomes), and shorter-term outcomes (also called intermediate objectives) that might mark progress toward these longer-term goals.

PI: Economos, Christina
Title: Assessing and Preventing Obesity Among New Immigrants
Immigrant populations, by virtue of being medically-underserved, low-income, and of race-/ethnic and linguistic minority status are at particularly high risk to become obese as they adapt to the obesogenic environment in which they reside once in the US. Preventive interventions developed with the active participation of these communities have the potential to prevent or moderate the weight gain.

We will demonstrate, using measures of effectiveness, the feasibility of partnering with the immigrant community in Somerville, MA to refine, implement, evaluate, and disseminate a 2-year preventive intervention to moderate or reduce weight gain in 435 mother/child dyads of new immigrants. The 435 mother/child dyads will be randomized to either receive the intervention or to serve as controls that will receive a delayed intervention, once the main trial is completed. We will enroll immigrants from Brazil, Haiti, and Latin-American countries, groups who are coming in large numbers to eastern MA, and are served by local community agencies. Intervention targets focus on 10 family-based goals in the areas of healthy eating, increased physical activity, and the reduction of sedentary behavior. Specifically, the intervention is designed to bring adults into the healthy weight range by reducing or maintaining BMI by providing education, skill development and support. In children it will be designed to result in an increased energy expenditure of up to 125 kcals per day beyond the increases in energy expenditure and energy intake that accompany growth. Based on our formative research within these groups, intervention elements will be delivered in small groups at the agencies of our community partners. “Lifestyle coaching” sessions and support groups tailored to the specific immigrant groups’ needs will capitalize on traditional healthy behaviors practiced by new immigrants and teach specific strategies that effect family environments. The proposed project reflects the ongoing work of a multidisciplinary research group and builds on two successful research initiatives in Somerville, one completed and one ongoing.

The goals of this community-based participatory research study have been developed from community interest and involvement. The community partners engaged with us to conduct the formative research used to develop this application, and will be involved in the design, recruitment, delivery, and research evaluation throughout the project. Dissemination of results to the affected community was deemed critical and will be done with the intention of strengthening community resources, preventive health care and education for immigrants. Furthermore, if successful, national dissemination of this trial can assist other communities with large immigrant populations to reduce the risk of obesity in this vulnerable population.

PI: Economos, Christina
Title: ChildObesity180
Obesity is the single largest health problem in the United States and in the rest of the developed world. Its epidemic proportions have damaging implications across all segments of society and children are the logical focus. Today, a full one third of children are overweight or obese; many experts project that these children may be the first generation in history to have a shorter life expectancy than their parents. There is an urgent need to address this crisis and seemingly no shortage of ideas or interventions aimed at achieving this objective; however, many of these initiatives work in isolation with little synergy, information sharing, or collaborative problem solving. A long-term, coordinated, and strategic approach, developed through collaboration across multiple sectors, is required to turn the tide on obesity and ultimately reduce the prevalence of overweight and obesity in children.

ChildObesity180 is a national, multi-sector leadership group committed to reversing childhood obesity by strengthening and accelerating ongoing efforts and leading and facilitating other key activities and coordination among influential sectors of society. The central objective of ChildObesity180 is to spearhead collaboration across multiple sectors of society to bring about the systemic changes necessary to reduce the prevalence of childhood obesity.

ChildObesity180 will create an overall strategic action plan, engaging national leaders from multiple sectors who all have a common desire to reduce childhood obesity. The seniority, experience, and collective judgment of the group will allow for the development of recommendations on how we can fast forward and effect change more rapidly and effectively. In brief, the group will attempt to synergize and catalyze the efforts of all sectors of society working towards the collective goal of reversing the trend of childhood obesity.

PI: Economos, Christina
Title: ChildObesity 180: Reverse the Trend
There is growing recognition that obesity is the single largest health problem in the United States and the rest of the developed world. At an annual estimated cost of $270 billion in the U.S. alone, this is an epidemic with catastrophic implications. Preventable diseases related to obesity are major contributors to rising healthcare costs, diminished worldwide economic competitiveness, and decreased military readiness. Unless we address it with careful consideration and a sense of urgency, the obesity epidemic will have a devastating ripple effect across all segments of society. The Robert Wood Johnson Foundation, having recognized the urgent need to address this crisis, has stepped forward with a major commitment to fund those organizations and programs which are most likely to play a role in reversing the epidemic and improving the health of children. ChildObesity180, through its innovative approach of working across sectors, is uniquely positioned to work with the Robert Wood Johnson Foundation to achieve this shared objective.

ChildObesity180 seeks to provide an integrated national strategy and become a major catalyst to prioritize and drive the necessary systemic changes to reverse childhood obesity within one generation’s time. The group promotes interdisciplinary dialogue in the development of a strategic plan to influence the complex systems that have fueled the obesity epidemic. Seventeen leaders have been drawn from government, academia, public health advocacy, community organizations, healthcare, the food industry (manufacturers, retailers, and restaurants), and children’s media to serve as ChildObesity180 Charter Members and Liaisons.

Over the past twelve months, the ChildObesity180 group has drawn up a strategic action plan and has selected its initial priorities; seed grants from the Robert Wood Johnson Foundation have supported this work. Over the proposed grant period, we will continue to cultivate engagement from committed national leaders across multiple sectors while expanding our innovative organizational model to support the implementation of a diverse portfolio of large-scale initiatives. Working with traditional and non-traditional partners, we will utilize best practices from across sectors to initiate long-term, sustainable change. As we conduct this work, we will maintain a focus on generating and broadly disseminating knowledge resulting from ChildObesity180’s impact and application of innovative and collaborative strategies. Success means that our nation will be set on a dynamic new course—a “180” that reverses the trend and lowers the overall prevalence of childhood obesity for current and future generations of children. Our children deserve our best effort.

PI: Edwards, Aurelie
Title: Mathematical Model of Vascular and Tubular Transport in the Rat Outer Medulla
The overall objective of the proposed work is to use mathematical modeling to gain fundamental insights into the mechanisms by which nitric oxide (NO), superoxide (O2-), and heme oxygenase (HO) regulate renal medullary blood flow, oxygenation, and sodium reabsorption. We will develop numerical models, with inputs from experimental data, to investigate:

  1. How NO and O2- regulate medullary thick ascending limb (mTAL) active sodium reabsorption and oxygen consumption. We will develop a new, steady-state model of vascular and tubular transport in the rat outer medulla (OM), that accounts for the three-dimensional architecture of the medulla, the presence of red blood cells, as well as the production and consumption of oxygen, NO and O2-. We will determine how interactions between NO and O2- affect mTAL sodium reabsorption under physiological and pathological conditions. We will examine the hypothesis that NO, as an endogenous inhibitor of active transport, plays an important role in modulating the susceptibility of the medulla to anoxic injury.

  2. How NO and O2- regulate medullary blood flow, blood distribution, and oxygen supply. We will convert the new steady-state model into a dynamic model, and incorporate the effects of vasodilation on medullary blood flow (MBF). We will examine the hypothesis that the diffusion of paracrine substances such as NO from adjacent tubules to vasa recta pericytes provides an efficient mechanism whereby local perfusion is precisely matched to tubular oxygen demand. We will determine whether the enhancement of NO generation that is mediated by constrictors of the medullary circulation (such as Angiotensin II) may serve to protect the outer medulla from ischemic injury.

  3. How renal medullary heme oxygenase (HO) and its products carbon monoxide (CO) and biliverdin modulate tubular sodium reabsorption and medullary blood flow. Recent evidence suggests that the renal medullary HO/CO system constitutes a significant antihypertensive mechanism. We will incorporate the activity of HO, the formation of its products, and their effects on reactive oxygen species and NO, first into a two dimensional, steady-state model of the rat OM, then into the newly developed, three-dimensional, dynamic model. We will examine the hypothesis that significant expression of HO in the renal medulla serves to protect this region from ischemic injury, through CO-induced vasodilation and bilirubin-mediated antioxidant effects. We will simulate the effects of renal perfusion pressure-induced elevations in medullary CO concentrations on mTAL sodium reabsorption, so as to gain some insight into the mechanisms underlying pressure natriuresis.

PI: Ellis, Julie
Title: Establishing SEANET Programs in the Carolinas
To recruit and train “Local SEANET Coordinators” in the south Atlantic region of the Atlantic Flyway to help maintain regular surveillance of beaches by volunteers in the region.

Currently, an immediate reporting of diagnostic results does not exist for mass mortality events in seabirds on the Atlantic Coast. A large die-off of shearwaters in the Southeast in July 2007 brought to light the need for such a reporting system. During this event, shearwaters were observed dead or dying on the water and on beaches in the Bahamas, Florida, Georgia, and the Carolinas. Staff at SEANET, wildlife refuges, and federal agencies (such as the WDIN) received numerous reports from members of the public and biologists. However, there was no system in place for receiving and summarizing reports, no clear mechanism through which the public could relay their observations and counts of dying or dead birds, and no real-time mechanism to track the spatial extent of the die-off. Moreover, there was confusion about what type of samples to take and where to send them, samples were sent to different testing laboratories, and there was no coordination in reporting the results of laboratory analyses. State agency staff in North Carolina and Florida attempted to compile and summarize the mortality event at a regional scale (e.g. # of dead birds and species, specimens deposited in freezers, 11 specimens necropsied or sent out for testing, results of tests, live birds in rehab). However, they were unable to successfully summarize this information due to the lack of coordinated reporting and the limited amount of time that agency staff could devote to this activity. SEANET can serve this role as a coordinated reporting system.

PI: Feig, Larry
Title: Genetic Analysis of Ras and G Protein Function
The execution of complex functions and their breakdown in disease involves the interplay between an animal’s genetics and environment. The overall goals of this proposal are to reveal how Ras-family GTPases influence signaling networks that control synaptic plasticity, and how an “enriched environment” (EE) alters these networks to change the way synaptic plasticity is induced in adolescent mice and remarkably, across generations.

One focus of this proposal is on GRF1 and GRF2, which form a family of multi-catalytic, calcium-stimulated, guanine nucleotide exchange factors that have the potential to activate both Ras and Rac GTPases. Despite these similarities, we found that GRF1 and GRF2 promote opposing forms of synaptic plasticity induced by NMDA-type glutamate receptors (NMDA-Rs) beginning at early adolescence. GRF1 promotes long-term depression (LTD), while GRF2 promotes long-term potentiation (LTP), at least in part, because they regulate different MAP kinases. The experiments outlined below combine genetic, biochemical and electrophysiological studies to reveal how GRF1 and GRF2 respond to different upstream signals, and how signaling downstream from their Ras- and Rac-activating domains is differentially regulated in the hippocampus. These experiments will add new insight into how specificity is achieved in neuronal signal transduction. They will also add significantly to our understanding of the molecular basis of LTP and LTD induction. Defects in these well-established cellular paradigms of learning and memory are thought to contribute to a variety of neurological and mental health disorders.

A second focus of this proposal concerns how environmental stimulation, involving exposure to novel objects, enhanced socialization and voluntary exercise particularly during pre-adolescence, changes the way LTP is induced. We discovered that adolescent enrichment unlocks a previously unidentified latent signaling pathway that promotes LTP in mice and rescues defective LTP and contextual fear memory in GRF knockout mice. Even more dramatic is our finding that these effects of pre-adolescent enrichment are passed on to the next generation through their adolescence. The experiments described will use multiple approaches to reveal how this novel EE-gated signaling pathway promotes LTP, and how EE unlocks this cascade to affect synaptic plasticity and memory across generations. A better understanding of the transgenerational effects of the environment on brain function may reveal new approaches to overcome neurological and mental health disorders.

PI: Feig, Larry
Title: The Function of the Ras-Related Ral Proteins
The overall goal of this proposal is to exploit our understanding of the Ral signaling cascade to reveal how it contributes to cancer in both tumor cells and adjacent stromal fibroblasts. RalA and RalB are members of the Ras superfamily that become activated by a distinct set of guanine nucleotide exchange factors, like RalGDS, in response to a variety of extracellular signals. Once activated, Ral proteins influence a unique set of downstream signaling molecules that regulate multiple cellular processes including vesicle trafficking, apoptosis, cell migration and cell proliferation. A key property of the Ral signaling cascade is that it is stimulated by Ras proteins. In many studies, including those involving RalGDS knockout mice, the Ral signaling cascade supports Ras-induced oncogenic transformation, however the mechanisms involved are poorly understood. Thus, there is intense interest in revealing how the Ral signaling cascade contributes to cancer.

In order to understand how Ral GTPases function in squamous carcinoma of the skin, where activated Ras is often an important component, we used a bioengineered tissue model of human skin that allows us to manipulate the Ral signaling cascade in both epithelial and stromal compartments. We found that RalA plays a cell-type dependent role in Ras-mediated squamous cell carcinoma. In keratinocytes of the epithelium, RalA inhibits, rather than supports tumorigenesis, since suppression of RalA expression enhances tumor progression at least in part by promoting cell invasiveness, through its effector protein the exocyst subunit Exo84 and decreased E-cadherin stability. Moreover, tumor progression in this model system is associated with, and requires, down-regulation of RalA levels. RalB knock-down complements the effects of RalA inhibition by enhancing keratinocyte proliferation. Specific Aim I will elucidate how RalA and RalB play these surprising tumor-suppressing activities, and reveal how tumor progression down-regulates RaIA levels in cells to allow tumor progression.

In fibroblasts of the dermis, RalA has the opposite function. It supports tumorigenesis, since RalA knock-down in these cells blocks the invasive properties of adjacent epithelial cells. Specific Aim 2 will reveal the mechanism behind this striking phenomenon and test the hypothesis that at least part of the tumorresistant phenotype of RalGDS knockout mice is due to the loss of this protein in dermal fibroblasts. Finally, we will test the exciting possibility that the components of a RalA signaling cascade in genetically stable fibroblasts represent new drug targets to block the formation of not only skin squamous carcinoma but also breast adenocarcinoma.

PI: Feng, Hanping
Title: Development of Vaccines against Clostridium difficile Infection
This proposal is to develop vaccines for selected pathogens including Clostridium difficile, the cause of pseudomembranous colitis, which accounts for a quarter of all cases of antibiotic-associated diarrhea. With the recent emergence of hypervirulent strains, the incidence of C. difficile infection (CDI) has increased significantly in both North America and Europe, causing lengthy hospitalization, substantial morbidity and mortality. CDI is thought to be mainly mediated by exotoxins TcdA and TcdB, which glucosylate low molecular mass GTPase of the Rho family, leading to massive fluid secretion, acute inflammation, and necrosis of the colonic mucosa. Protection against CDI was shown to be mediated through systemic and mucosal antibodies against the 2 key toxins, although other virulence attributes are known, to exist which may also contribute to the manifestation of CDI. The goal of this proposal is to design a vaccine that targets both TcdA and TcdB, with a view to elicit strong systemic and mucosal immunity to prevent CDI, reduce the severity, or eliminate an ongoing chronic disease.

We propose to exploit the recently expressed atoxic C. difficile holotoxin proteins in an endotoxin-free Bacillus megaterium system. Two immunogens will be evaluated: a mixture of atoxic full-length C. difficile toxin A and B generated by point mutations (designated as aTxAB), and a chimera protein containing full-length TcdB but with its receptor binding domain replaced with that of TcdA (designated as cTxAB). cTxAB has a small deletion (97 amino acids) in transmembrane domain rendering it non-toxic. Preliminary studies showed that atoxic TcdB vaccination induced antibody responses against a wide-spectrum of epitopes and potent protective immunity superior to toxoid; cTxAB immunization induced antibody and protective responses against both TcdA and TcdB.

In this project, we will first evaluate the ability of these atoxic recombinant proteins to induce protective antibody responses following parenteral immunization followed by challenge with wild type toxins (Aim 1). This will be followed by evaluating several regimens of mucosal immunizations (oral, intranasal and sublingual) designed to induce protection against systemic and mucosal challenges with wild type toxins (Aim 2). We will test the protective efficacy of the various immunization regimens developed in Aims 1 and 2 in the recently described mouse acute infection model (Aim 3a), and the most efficient immunization method resulting from the mouse infection studies will undergo preclinical evaluation in the chronic piglet model of CDI developed in this laboratory (Aim 3b). Because at this early stage the nature of the candidate vaccine is unknown, nor is the adjuvant required, we are not in a position to form a suitable partnership.

PI: Feng, Hanping
Title: Epithelium, Dendritic Cells, and Clostridium difficile Associated Colitis
Clostridium difficile, an etiologic agent for pseudomembranous colitis, accounts for a quarter cases of antibiotic-associated diarrhea. With the recent emergence of hypervirulent strains, the incidence of C. difficile infection (CDI) has increased significantly in both North America and Europe, causing lengthy hospitalization, substantial morbidity and mortality. CDI is thought to be mainly mediated by exotoxins TcdA and TcdB, which glucosylate low molecular mass GTPase of the Rho family, leading to massive fluid secretion, acute inflammation, and necrosis of the colonic mucosa. Our long-term goal is to understand the mechanisms mediating intestinal inflammation in C. difficile infection and to utilize this knowledge for the design of better immune interventions in order to reduce the incidence of CDI and severity of the disease. The interaction of intestinal epithelial cells (IECs) with intestinal antigen presenting cells (APCs), such as dendritic cells (DCs) and macrophages, in the gut orchestrates mucosal immune homeostasis and inflammatory response.

Our objective is to elucidate the immune response of IECs and intestinal DCs after their exposure to C. difficile toxins and to determine the nature of their interaction on initiating intestinal inflammation and tissue destruction. To achieve this objective, we will test several working hypotheses:

  1. C. difficile toxin-intoxicated IECs are capable of mobilizing and activating DCs;
  2. In severe cases of CDI, C. difficile toxins can cross a severely damaged intestinal barrier and further activate DCs and macrophages; and
  3. Proinflammatory cytokine TNF-α synergizes with the toxins to induce apoptosis of IECs, thus exacerbating tissue destruction and enterocolitis.

By testing these hypotheses, we expect to gain a better understanding of not only the underlying mechanisms by which C. difficile toxins induce severe enterocolitis, but also the role of IEC-DC interaction in the onset and development of intestinal inflammatory diseases in general. We believe that such an understanding will help us to design better immune interventions against CDI and other intestinal inflammatory diseases.

PI: Feng, Hanping
Title: The Role of Dendritic Cells in T Cell Immunity to Cryptosporidium
Our goal is to elucidate the mechanisms by which immune cells initiate resistance against cryptosporidiosis with a view that a better understanding of the various components of the immune response will lead to development of effective vaccines and adjuvants to combat the infection in humans. Our central hypothesis is that lamina propria dendritic cells directly sample Cryptosporidium antigen from the intestinal lumen to prime T cells and initiate the immune response. We base this on the observations that:

  1. Lamina propria dendritic cells directly sample pathogens by protruding dendrites into intestinal lumen. We have found in our preliminary studies that mouse dendritic cells can be infected by C. parvum and produce proinflammatory cytokines such as IL-12;
  2. IL-12, which is produced predominantly dendritic cells, is critical in inducing gamma interferon and controlling C. parvum infection;
  3. T cells, which can only be primed by dendritic cells, are indispensable in controlling the infection of Cryptosporidium.

Based on these observations, the specific aims are designed to provide a comprehensive assessment of the nature of dendritic cell interaction with Cryptosporidium and induction of T cell immunity. They include:

  1. Identify the mechanisms of Cryptosporidium antigen acquisition by dendritic cells;
  2. Determine the activation and migration of dendritic cells after infection with Cryptosporidium;
  3. Investigate dendritic cell-mediated T cell activation in response to Cryptosporidium infection.

The proposed studies will provide the basis for understanding the mechanisms for the induction of T cell-mediated anti-Cryptosporidium immunity necessary for future design of vaccines and other methods of interventions against cryptosporidiosis.

PI: Fisher, Kathleen
Title: DARPA Contract
Dr. Fisher will serve as a Program Manager for the conceptualization and implementation of programs in software development. She will assist DARPA in resolving some difficult technical and managerial issues and gain an in-depth understanding of current and long-term defense issues on the role that Tufts University can play in helping to resolve these issues.

Dr. Fisher will lead programs in the area of software development with an emphasis on technology to ensure high levels of assurance for military application. Dr. Fisher's goal is to create static and dynamic techniques to increase confidence in such applications while maintaining low costs and fast delivery time.

PI: Flytzani-Stephanopoulos, Maria
Title: Metal Ion Sites on Oxide Supports as Catalysts for the Water-Gas Shift and Methanol Steam Reforming Reactions
The overall goal of this project is to elucidate how catalysis is manifested by stabilized atomic dispersions of metal ions on oxide supports. This is particularly important for the catalytic reactions of interest to fuel reforming for hydrogen generation where atomically-dispersed metals on various oxide surfaces have been identified as the active sites. Working with trace amounts of precious metals is both intriguing fundamentally as well as of great practical interest in our continual search for low-cost, efficient and stable catalysts for the conversion of fuels to hydrogen under highly demanding operating conditions, such as in practical low-temperature fuel cell systems. The current DOE project investigates trace amounts of sub-nm clusters and ions of gold or platinum in nanostructured oxides (ceria, iron oxide, zinc oxide) as potential new catalysts meeting these requirements. Our findings to date point to the importance of the particle size, shape, and oxygen defect density of the host oxide for proper distribution of the active metal sites to effectively catalyze the low-temperature water-gas shift and methanol steam reforming reactions. In an exciting new development, we have shown how to turn the Pt/SiO2 system, from a totally inactive state for the low-temperature water-gas shift reaction to a catalyst superior to Pt/CeO2 by simply adding alkali to the surface. The alkali-promoted Pt(OH)x site is active and stable up to ~350°C. All indications point to a support-independent active site, therefore allowing tremendous flexibility in catalyst design. Low-cost, abundant supports rather than the rare earths can now be employed. In the proposed work, we are extending our investigation to understand the electronic and ligand effects of metal-metal oxide and alkali atom interactions at the atomic scale, making particular use of atomic-layer deposition for controlled metal site decoration of support surfaces, and of state-of-the-art scanning tunneling microscopy/spectroscopy to follow atom-atom-oxygen interactions. The complementary catalysis and surface science studies, aided also by computational investigations, will provide a comprehensive approach to understand atomic-scale catalysis, using as examples the water-gas shift and methanol reactions which remain of interest to this project.

Novel preparation methods to control the size and shape of oxide nanoparticles, applied successfully in the project to date, will continue in the new phase. Particles with special surface planes preferentially exposed, and decorated with Au, Pd, Pt, or bimetallics provide a viable new way to study crystal surface reactivity and structure sensitivity of reactions at normal pressures. For example, we have shown that the {110} surface of ceria and the {0010} polar surface of ZnO nanocrystals are the best in providing the largest number of stably bound Au-O sites, and thus maximum activity for the WGS and SRM reactions. These studies will continue and extend to other systems to probe metal-support interactions and specific structure — function correlations. Finally, we will continue and extend to other systems the use of in situ techniques for gaining mechanistic insights of the reactions under investigation; in situ XANES/EXAFS has been used in the current project to follow the structural evolution of gold clusters on CeO2 and Fe3O4; and the stability of Pt-Ox-K-(OH) clusters on silica as a function of gas composition and temperature.

The project involves a close collaboration of a team of academic investigators at Tufts, Columbia, and Wisconsin. The advancement in our understanding and considerable progress made in our project over the past three years, has enabled us to sharpen our objectives as outlined above. New scope to the proposed collaborative effort has been added as necessary to obtain key answers and meet our objectives in an effective manner. Our on-going collaborations with scientists at Brookhaven National Lab (EXAFS, HREM, TR-XRD) will continue and be strengthened as they are essential to the success of our program.

PI: Ford, Lawrence
Title: Research on Gravitation and Quantum Fluctuation Phenomena
This award is funded under the American Recovery and Reinvestment Act of 2009 (Public Law 111-5). This project will involve theoretical studies of several topics relating to quantum fluctuations and gravitation. Particular attention will be paid to issues relating to the correlation and anti-correlation of fluctuations of the quantum stress tensor that describes, among other things, the local energy density in a quantum field. The topics to be investigated include the effects of quantum stress tensor fluctuation in cosmology, especially in inflationary models. Previous work by the PI and his collaborators has indicated that these effects may be able to slowly accumulate, and thereby have a potentially significant role in the evolution of the universe. This possibility will be further studied. A closely related topic is the search for the probability distribution for stress tensor fluctuations, which is of interest in inflationary models, including ones which explore the possibility of a "multiverse" much larger than the observable universe. Other aspects of this project will seek to propose new laboratory experiments looking for negative energy density and related "sub-vacuum" phenomena, where some quantity fluctuates below its usual value in empty space. The project will examine selected aspects of the Casimir force, especially its fluctuations, and of fluctuations in condensed matter systems. These topics are of interest both for their own sake, and as analog models to better understand quantum effects in gravity theory.

This project is expected to have a broader impact through possible benefits to other fields of science, to education, and to technology. The insights and techniques of this work may be useful outside of the specific subfields of physics being investigated. The project will further education through the training of graduate students and by the involvement of faculty at primarily teaching institutions. It should also produce examples which can be used to explain some of the concepts of quantum theory and relativity to students on a variety of educational levels. The work on Casimir forces may eventually be useful in nanotechnology. A better knowledge of Casimir forces is likely to become important for the construction of small scale devices. Similarly, the study of quantum correlations in this project may have applications to quantum information and quantum computing.

PI: Frank, Eric
Title: Electrophysiological Studies of Synapse Formation by Regenerating CST Axons
Most functional deficits after spinal cord injury are caused by the disruption of nerve fibers that project longitudinally and interconnect the brain and spinal cord. In principle, there are two possible strategies for re-building functional circuits to repair this loss of communication: nerve fibers that were not damaged can be stimulated to sprout collateral axons and build compensatory connections, and injured axons can be stimulated to grow across the lesion to reconnect with their original targets. Major progress has been made recently in promoting sprouting and regeneration of the corticospinal tract (CST), a major pathway for controlling movement. It is not known; however, if these sprouted and regenerated CST axons can re-establish functional synaptic connections. This proposal addresses that second step, determining if sprouting or regenerating CST axons can make functional synaptic contacts with their normal target neurons in the spinal cord. Recent studies have shown that genetic deletion of PTEN in CST neurons results in robust contralateral sprouting of their axons in the spinal cord following ablation of the contralateral CST and also promotes unprecedented regeneration of CST axons across spinal cord lesions. It remains unknown, however, if sprouted or regenerated axons can make functional synaptic connections. A major target of CST axons in mice is Clarke's column neurons, located in the C11 – L2 segments of the spinal cord, in close proximity to the CST. We propose to utilize in vivo electrophysiological approaches to assess the ability of re-growing CST axons form functional synapses with Clarke's column neurons.

In the first aim, we will induce the axons in one CST to sprout into the contralateral spinal cord by interrupting the other CST via a unilateral pyramidotomy in PTEN-deleted mice. We will test if sprouted CST axons establish functional synaptic connections by selectively stimulating the CST while recording intracellularly from Clarke's column neurons. We can thus test if axonal sprouts can form functional synapses with appropriate synaptic targets in the spinal cord. In the second aim, the CST will be lesioned bilaterally by a complete spinal cord crush at T10. This surgical procedure interrupts all axons that project through the crush region. After allowing CST axons to regenerate through the lesion in PTEN-deleted mice, we will record intracellularly from Clarke's column neurons just caudal to the crush while stimulating the CST at cervical levels above the crush. These experiments will test if CST axons regenerating through the lesion are able to form functional synaptic connections below the lesion.

Taken together, these experiments will allow us to assess an important functional aspect of sprouting and regenerating CST axons, namely their ability to form functional synaptic connections. These results should provide direct insights into designing therapeutic strategies for re-establishing corticospinal connections and promoting functional recovery after spinal cord injuries.

PI: Garven, Grant
Title: Collaborative Research: Modeling Coupled Reactive Flow at the TAG Hydrothermal Mound
Over the past 30+ years much has been learned about hydrothermal venting along mid-ocean ridges (MOR) and back-arc spreading centers. Ship-based seafloor sampling, drilling, instrumentation, and submersible studies have provided a wealth of observations that document important differences in the style and distribution of discharge at individual vent fields. These different styles of discharge affect the sizes and morphologies of deposits, habitats for organisms on and below the surface, and partitioning of heat and mass flux, and underscore the complexities of sub-seafloor physical and chemical processes. But predicting the dynamics of how these systems operate and evolve below the seafloor remains elusive. For example, mineralization can feedback on the flow system, changing permeability within the actively forming deposits and the seafloor below. Until recently there has been little application of theoretical methods to analyze these coupled processes.

The primary goal of this project is to mathematically model in 2-D and 3-D (for the first time) the physical and chemical processes occurring within the subsurface upflow and outflow portions of a well-characterized MOR hydrothermal system. Our objective is to test several hydrogeochemical hypotheses about controls on the distribution of focused and diffuse flow, and extents of precipitation, and thermal/chemical conditions, in the subsurface. This will be done through numerical modeling at scales of about 0.1 to 100m. Our efforts will focus on the TAG active hydrothermal mound, which has been well studied and where reasonable boundary conditions can be confidently assigned based on past field studies and/or past numerical modeling studies carried out at larger spatial scales. The scale is designed to effectively “zoom in” on the local upflow and outflow zones and study the roles of locally-entrained seawater, heating and cooling of fluid mixtures, and mineral precipitation and dissolution on the fluid flow and thermal regime in the region in and surrounding the active vent field.

A well-developed and well-tested reactive flow software package called RST2D (Garven et al., 2008) will be used to conduct this new modeling study. The approach has been tested using preliminary hydrothermal flow simulations. Fully-coupled reactive-flow investigations will be used to examine the sensitivity of the flow systems and geochemistry to different geologic variables and transport parameters (e.g., structure, permeability, thermal conductivity, chemical dispersivity), which are not always well constrained by seafloor observations. The project is a collaborative effort by Meg Tivey (WHOI), an expert on seafloor hydrothermal systems, Grant Garven (Tufts University), a geohydrologist, an expert on the mathematical and numerical modeling of hydrothermal and reactive flow systems, and Ann Mulligan (WHOI), a groundwater hydrologist who has done earlier modeling studies of TAG. Work is also proposed to migrate RST2D to RST3D utilizing high-performance cluster computing, so three-dimensional flow systems can be analyzed too. This type of mathematical modeling will provide an extremely valuable tool for examining feedbacks in these dynamic systems that can be sampled only sparsely (e.g., with drilling) or indirectly (e.g., using geophysical methods).

Mentor: Georgakoudi, Irene
Fellow: Quinn, Kyle
Title: Non-Invasive Optical Biomarkers to Quantify Engineered Bone Tissue Development
Bone tissue regeneration is necessary to restore skeletal function following a variety of clinical procedures, including bone fracture repair, reconstructive surgery, and spinal fusions. Tissue-engineered bone offers a number of advantages over traditional bone grafts used for the repair and regeneration of bone. However, the current methods employed to evaluate and optimize the growth of engineered bone tissue lack the spatial and temporal resolution to characterize the dynamic cell-matrix interactions that occur during tissue development. The objective of this project is to develop quantitative optical biomarkers to identify and monitor changes in the biochemical, microstructural, and overall mechanical properties of engineered bone tissue during its in vitro development. This work focuses on the dynamic changes that occur as three-dimensional silk scaffolds seeded with human mesenchymal stem cells develop into functional bone tissue. The central hypothesis of this proposal is that endogenous optical signals can be measured non-invasively using multi-photon imaging and depth-resolved light scattering spectroscopy to determine the biochemical and microstructural properties of the developing tissue. To test this hypothesis, the intrinsic fluorescence and light scattering signals from different cellular and extracellular matrix components will be identified in Aim 1 and correlated with traditional histological and molecular biology techniques. The optical biomarkers for microstructural organization identified in Aim 1 will be used to predict the overall mechanical function of the bone tissue in tension and compression in Aim 2. Collectively, these aims will provide a unique understanding of how the biochemical status and mechanical function of engineered tissue changes during osteogenesis. By using only non-invasive techniques that identify intrinsic sources of optical contrast, the outcomes of this proposed research can be used to optimize the future approaches to engineering functional bone tissue and will enable a means to monitor engineered constructs as they are incorporated into native tissue following surgical repair.

PI: Georgakoudi, Irene
Title: Optical Biomarkers for the Non-Invasive Detection of Early Cancer
Most cancers develop in the uppermost layer of tissue that covers our body cavities and organs. If cancer changes are detected when they are confined to this superficial layer, they can be treated effectively. Unfortunately, these early lesions are very small and are difficult to detect using standard equipment that is used in a doctor’s office. Their accurate detection usually requires invasive, costly, labor intensive and time-consuming procedures. Our long term goal is to develop optical, noninvasive imaging methods that enable improved cancer detection in its early stages with instrumentation that is portable, provides results immediately and can be operated without highly specialized training. Towards this aim, we have begun to identify optical signals that rely on the natural ways with which cells and tissues interact with and modify light depending on their biochemical composition and organization. We have also found that a set of such signals does change when precancerous cells are present, either in experimental models of tissue or in live human tissues.

In this proposal, we plan to identify how changes in optical signals are related to specific microscopic changes that are commonplace in early cancers. The optical techniques that we will use include a combination of methods, some of which we have invented, that can be implemented together to provide complementary information about the function and structure of the specimen from microscopic to macroscopic scales. The studies we will perform are particularly relevant to cancers caused by a virus (human papillomavirus), such as those in the uterine cervix, head and neck. However, because development of these cancers involves aberrations in cellular pathways that are disturbed in many cancers, we expect that the methods we develop will be even more broadly applicable. Since these methods are noninvasive (i.e. do not require a biopsy) and rely on entirely natural sources of contrast (i.e. no stains are needed), they can be easily transferred to the clinical setting. Therefore, we expect that these methods will improve the rates at which we detect cancers at a stage when effective treatments are available and will, thus, have a positive impact on patients’ lives.

PI: Georgakoudi, Irene
Title: Optical Monitoring of Engineered Tissues
Our long-term goal is to develop non-invasive, optical technologies to monitor the functional development of engineered tissues in vitro and in vivo. The objective of this application is to develop optical biomarkers based on endogenous sources of optical contrast that obviate the use of exogenous stains and can be used to report quantitatively on the biochemical and structural composition of engineered tissues. The proposed studies focus on the characterization of adipose and bone engineered tissues developed from silk scaffolds seeded with human mesenchymal stem cells.

The central hypothesis of the application is that linear and non-linear depth-resolved imaging methods based on the natural light scattering and fluorescence signatures of cell and matrix components of engineered tissues can be developed to report on the dynamic changes that occur prior to and following implantation of engineered tissues. Our hypothesis is based on preliminary evidence acquired from in vitro samples, which indicate that endogenous optical signals can be used to monitor changes in the biochemistry and morphology of differentiating stem cells, silk scaffolds and deposited collagen.

The rationale for the proposed research is that the establishment of non-invasive methods that allow monitoring of the dynamic changes that occur within engineered tissues will play an essential role in the development and optimization of innovative, functional engineered tissue constructs. To achieve our goal we will characterize the endogenous fluorescence and light scattering signals from different cell and matrix components of engineered tissues developed in vitro (Aim 1). We will develop a system that will optimize acquisition of these optical signals from animals (Aim 2) and we will use these biomarkers to characterize non-invasively the integration of these engineered tissues in vivo following implantation either within a mammary fat pad or a cavarial bone defect mouse model (Aim 3). This will be the first time that dynamic monitoring of the biochemical and structural function of implanted engineered tissues is achieved in vivo using non-invasive means based on endogenous optical signals.

This proposal is highly relevant to the improvement of public health as it will enable the efficient development of functional bone and adipose engineered tissues. Thus, millions of patients that undergo surgical procedures for the repair or reconstruction of such tissues will ultimately benefit from this work.

PI: Goldberg, Jeanne
Title: The GREEN (Growing Right: Eating Eco-Friendly and Nutritious) Project
Poor diet quality in children contributes to obesity, chronic disease, and diminished quality of life. Many efforts have focused on foods provided in schools. But elementary school children regularly bring snacks and lunches. Little attention has been directed toward improving the nutrient profiles of foods brought from home. The proposed intervention, The GREEN (Growing Right: Eating Eco-friendly and Nutritious) Project takes advantage of a natural synergy between healthy eating and eco-friendly behaviors to address the quality of foods brought to school from home. Our novel, school-based communications campaign will combine messages about the nutritional and eco-friendly qualities of foods. Our target population is third and fourth graders and their caregivers in Eastern Massachusetts.

Our central hypothesis is that at the end of one school year, children who receive a campaign with combined healthy eating and eco-friendly messages will show greater improvement in diet quality and eco-friendliness of snacks and lunches brought from home than those who receive healthy eating communications alone or those in a control group. The theory-based multi-channel communications campaign will be developed on the basis of qualitative research with the target population. For the campaign, schools will be randomized to three conditions to receive:

  1. Healthy eating and eco-friendly messages;
  2. Healthy eating only messages; or
  3. Delayed healthy eating eco-friendly messages after serving as controls.

The primary outcome is change in the number of servings of fruits and vegetables brought to school. Secondary outcomes will include changes in the quantity of sugar-sweetened beverages and processed, energy-dense foods, as well as the weight of trash associated with foods brought from home. Baseline and outcome assessments of these outcomes will be made using digital photography. After the GREEN Project has been implemented, the RE-AIM framework will be used to make revisions to the intervention which will then be disseminated to the delayed intervention group. This design will provide an opportunity to test the feasibility of replication. If successful, this novel approach, taking advantage of the synergy between healthy eating and eco-friendly messages, could be extended to elementary schools across the US and adapted to other populations. In addition, the strategy might be extended to other behaviors affecting personal health that can be tied to eco-friendly behaviors.

PI: Gorbach, Sherwood
Title: Center for Metabolic Research on HIV and Drug Use
Five years ago, the Tufts Nutrition Collaborative – Center for Drug Abuse and AIDS Research (TNC-CDAAR) was funded by NIDA as just one of two CDAAR's in the nation. The CDAARs were charged with the following mission: to foster a collaborative approach to drug abuse and addiction research; to enable studies that would not occur without the climate, facilities, and resources that a research center can uniquely provide; to serve as a resource to attract established and promising investigators into drug abuse research; and to provide opportunities for research training, career development, and mentoring. The TNC-CDAAR was formed as a partnership between three East Coast Institutions (Tufts, Brown and Johns Hopkins) with a specific focus on studying nutritional and metabolic disorders among HIV-positive and HIV-negative drug users. Over the past five years, we have expanded the TNC-CDAAR to include collaborators from 3 international sites: Argentina, India, and Vietnam.

Our major accomplishments, thus far, have been to:

  1. design and implement several new studies to assess and compare the prevalence and incidence of specific nutritional and metabolic disorders in drug users of different ethnicities, both in the U.S. and abroad;
  2. develop training materials, protocols, and manuals for investigators who want to undertake similar studies in their localities;
  3. help in the development of new grant proposals in Center-related areas of research; and
  4. become a resource center on nutrition and metabolic disorders in drug users.

The TNC-CDAAR will continue to operate five of its original six cores: Administrative (Core A), Developmental (Core B); Drug User Resources (Core C); Nutrition and Metabolism (Core D); and Epidemiology and Biostatistics (Core F). Core E (Endocrine) will be merged with Core D and a new core on Hepatitis and Liver Function (Core G) will be added. This new core was developed in response to the needs of TNC-CDAAR investigators and members who have found that nutritional and metabolic abnormalities are likely linked not only to HIV, but also to chronic liver disease among persons who use drugs.

The center will continue to work to raise awareness of the importance of nutritional and metabolic disorders on outcomes in the drug using population and to encourage investigators to include studies of nutritional and metabolic status in their research in drug using populations. The five center cores will continue to work synergistically to provide a multitude of services for center members.

PI: Greenberg, Andrew
Title: Age Dependent Role of Bisphenol A in Obesity and Insulin Resistance
The objective of this application is to determine the doses and mechanism(s) by which early-life exposure to the ubiquitous industrial chemical, bisphenol A (BPA), promotes insulin resistance (IR) and type 2 diabetes (T2DM) in adults. Prior studies and preliminary data from this investigative team suggest that early-life (perinatal) exposure to BPA promotes IR and T2DM by increasing adiposity, altering pancreatic insulin secretion, and in females, promoting a phenotype similar to human polycystic ovarian syndrome (PCOS), which typically includes obesity and IR. The rationale for the proposed studies is that public health policy regarding the prevention of insulin resistance and T2DM will be significantly enhanced by definitive, mechanistic studies of BPA's role in promoting obesity and/or dysregulating glucose and insulin homeostasis. Accordingly, this project will investigate the effects of early BPA exposure (gestation through postnatal day 21) on the development of IR, T2DM and obesity in male and female rats and potential ovarian dysfunction in female rats. Glucose homeostasis, adiposity and adiposity-related biohumoral and tissue read-outs will be monitored at 4, 8, 12 and 18 months in male and female rats exposed to vehicle and 4 different doses of BPA. Blood and tissues (white and brown adipose depots, pancreas, liver, skeletal muscle and ovaries) will be collected for various biohumoral, histological, biochemical, gene expression and epigenetic analyses.

Specific Aim 1 will determine the dose(s) of perinatal BPA exposure that dysregulate glucose/insulin homeostasis in adult rats and will determine the chronology and progression of this dysregulation. Specific Aim 2 will test the hypothesis that BPA-induced IR reflects the metabolic and inflammatory impacts of obesity and/or hormonal dysregulation in females. Specific Aim 3 will identify BPA-induced transcriptional and epigenetic changes (DNA and histone methylation) in both white and brown adipose tissue that are associated with the development of IR and/or obesity. Completion of Aims 1-3 and integration of their results will provide an in-depth assessment of the effects of early-life BPA exposure on the development of impaired glucose homeostasis, IR and T2DM in the adult and the associated BPA-induced adipose, pancreatic and ovarian changes that may promote this metabolic dysregulation.

The significance of the proposed studies lies in their ability to identify the multiple effects of BPA exposure on gene expression, metabolism, body composition and hormones that may be contributing to societal increases in obesity, IR and T2DM.

PI: Greenberg, Andrew
Title: Estrogen Replacement in Postmenopausal Women
When women undergo menopausal transition, their risk of developing central adiposity, diabetes and cardiovascular disease increases greatly. Estrogen treatment of postmenopausal women results in protection against diabetes and is thought to improve body composition. However, the mechanisms and pathways that underlie the ability of estrogen to protect against body fat accumulation and diabetes in humans are unknown. Previously, we have demonstrated that estrogen administration to ovariectomized mice reduces adipocyte size, reduces adipocyte death and adipose tissue inflammation, increases activation of oxidative metabolic pathways in muscle and appears to improve insulin sensitivity. An important objective of our OSQR is to understand the mechanisms that underlie adipocyte death and adipose tissue inflammation. Estrogen may protect against adipocyte death and additionally estrogen may promote adipocyte hyperplasia which we hypothesize would protect against adipocyte death. We also hypothesize that increasing oxidative metabolism in muscle may protect against the development of adipocyte hypertrophy and adipocyte death.

In this proposal we will determine the whole body and tissue specific effects of estrogen in postmenopausal women and determine whether estrogen attenuates the detrimental metabolic effects of energy surplus in postmenopausal women. We propose to determine the effects of delineating the mechanisms by which estrogen is beneficial by providing estrogen via a skin patch, which is more physiologic than oral administration of estrogen, to early postmenopausal women. With the knowledge gained in this study, we will be able to develop nutrition therapies that will result in healthy aging in women. Women entering the study will participate in a double blind randomized placebo controlled trial and receive estrogen for 3 months. We will characterize glucose-insulin homeostasis using an intravenous glucose tolerance test. We plan to perform adipose and skeletal muscle biopsies to allow us to understand the cellular and molecular mechanisms by which estrogen acts on these tissues. Body composition studies will be performed using DEXA. Additionally, at the end of three months, subjects will participate in a three-day overfeeding study to determine effects of estrogen on the metabolic effects of energy surplus.

Upon completion of this study we will be able to develop a more rational nutritional approach to aiding women as they undergo the menopause transition which places them at increased risk of developing central adiposity, diabetes, and heart disease.

PI: Greenberg, Andrew
Title: Regulation of Adipocyte Lipolysis Through Lysosome-Mediated Degradation of Lipid Droplet-Associated Proteins – Relation to Insulin Resistance
Adipocyte lipolysis is a fundamental process in energy homeostasis. In conditions like obesity and lipodystrophy, the rate of un-stimulated (basal) lipolysis is increased, contributing to insulin resistance and inflammation. Yet, since insulin is the major anti-lipolytic hormone, insulin resistance is also a cause of enhanced lipolysis, suggesting a vicious cycle. During a BSF-supported start-up grant, we unraveled a novel mechanism by which basal lipolysis could be regulated in pathophysiological states: Nelfinavir (HTV protease inhibitor that causes lipodystrophy), increased lipolysis by enhancing proteolysis of a lipid-droplet protein (LDP), perilipin. Inhibitors of lysosome protein degradation, but not of the proteasome, prevented this effect, suggesting that lysosomal degradation of LDP may regulated adipocyte lipolysis.

For the present proposal, we formulated 3 objectives:

  1. To determine whether other activators of basal lipolysis, TNF and chronic insulin, also do so by enhancing lysosome-related degradation of perilipin, and/or of the LDPs ADRP and Fsp27. If so, is autophagy involved and how LDPs reach lysosomal-organelles.

  2. To assess whether insulin resistance (induced by nelfinavir, TNF, chronic insulin) causes lipolysis through impaired signaling through PIP3 and Akt, which could be induced by increased expression of TRB3, and/or by decreased stabilizing phosphorylation of perilipin on Ser216.

  3. To investigate whether inhibiting lysosomal-related degradation of LDPs would attenuate the capacity of adipocytes to induce insulin resistance in hepatocytes and muscle cells, and activate macrophages. The studies will unravel aspects of fundamental biological processes (autophagy, lipolysis, insulin action), and will likely reveal novel strategies to interfere with pathophysiological processes related to elevated lipolytic flux.

PI: Greenberg, Andrew
Title: Research Training Program in Nutrition and Chronic Disease
The objective of this proposal is to obtain funds for the training of PhD scientists committed to academic careers in nutrition research and chronic disease prevention. The importance of training future researchers in these two areas follows from our increasing awareness that nutrition is an underlying pathogenic component of many chronic diseases. These include obesity, diabetes and its complications, non-alcoholic steatohepatitis (NASH), digestive diseases, chronic kidney disease (CKD), hepatic and colon cancer and cardiovascular disease. Although these disorders have traditionally been viewed as pathologies of the middle-aged and/or elderly, it is now clear that appropriate interventions for these conditions need to be initiated decades earlier in the life cycle. Interventions that can delay or prevent chronic disease(s) afford potentially profound public health benefit, both from reduced morbidity and mortality as well as from cost savings. A recent (2000) CDC study reported that obesity alone accounts for 9% ($180 billion) of national health care costs.

The rationale for this proposal is based on the firm belief that nutrition is the most significant and tractable environmental factor that can be modified to prevent or delay chronic disease. This proposal therefore seeks funds to train the next generation of nutrition research investigators to address chronic disease prevention at the molecular, cellular, organismal and/or population levels. Support is requested for six predoctoral training slots for each of five years.

All trainees are first admitted to a graduate degree program at the Friedman School and, after one year of coursework, are eligible to be admitted to the Training Program. Acceptance into the Training Program is predicated upon outstanding academic and research achievement during the first year. Faculty preceptors on the Boston Health Sciences Campus, all members of Tufts University's Friedman School of Nutrition Science and Policy, will provide exemplary research training to predoctoral students interested in the broad research areas of obesity, diabetes, metabolism, digestive diseases, endocrinology, genomics and gene therapy, epidemiology, and diseases of the kidney and pancreas. Program administration and trainee supervision will be the responsibility of the Program Director and a Steering Committee, which will meet every 6 months to review and discuss trainee progress and program enrichment.

Mentor: Greenblatt, David
Fellow: Hanley, Michael
Title: Effects of Anthocyanins on Cytochrome P450 Enzymes and P-Glycoprotein
Anthocyanins are a class of flavonoids found in many berry fruits, including blueberries. Public interest in blueberries and other anthocyanin-containing products has increased in recent years due to their reported health-promoting properties. In turn, the concomitant consumption of anthocyanin-containing products with prescription drugs is likely to occur. Unfortunately, little information is currently available regarding the potential drug interaction risks associated with anthocyanins.

The objective of this proposal is to establish the effects of anthocyanins on the cytochrome P450 (CYP) enzymes and the drug transporter, P-glycoprotein. In Aim 1, we will determine the potential of anthocyanins and anthocyanidins to inhibit GYP activity in vitro. In preliminary work, blueberry juice inhibited the in vitro activity of CYP3A and CYP2C9 at concentrations that could easily be achieved in the gastrointestinal tract after BBJ consumption.

Consequently, in Aim 2, we will ascertain the clinical relevance of these in vitro interactions by conducting pharmacokinetic studies in which blueberry juice will be co-administered with the probe substrates buspirone (CYP3A) and flurbiprofen (CYP2C9). Since alterations in the activity of P-glycoprotein can also influence drug disposition.

In Aim 3, we will examine the effects of anthocyanins and anthocyanidins on P-glycoprotein-mediated fexofenadine transport across Caco-2 cell monolayers. Taken together, the knowledge gained from these studies will help ensure the safe use of anthocyanin-containing products by the public.

PI: Guyer, Samuel
Title: CAREER: Cooperative Virtual Machines: Mechanisms, and Policies for Application-Aware Runtime Services
Modern managed programming languages, from Java and C# to JavaScript and Ruby, provide a compelling set of software engineering advantages over traditional languages like C and C++. Unfortunately, they continue to suffer from a range of well-documented performance problems. Their inefficient use of memory, in particular, imposes a significant penalty, with debilitating consequences for the quality and capacity of critical server software built in these languages. In spite of intensive research and development, these problems have remained stubbornly unsolved. As a result programmers face a difficult dilemma: choose a safe and secure managed language, but take a major performance hit, or continue taking their chances with C and C++.

This project explores a new approach, called cooperative virtual machines, which attacks the problem by improving communication and cooperation between the programmer and the managed language runtime system (the virtual machine). The key idea is that with extra information, virtual machines can provide much more efficient services because they are customized to each application's needs. The project involves building new tools for exploring and quantifying memory performance, designing a configurable garbage collector for large server applications, and developing techniques to give programmers more control over the low-level representation and management of data structures. Significant improvements in memory utilization and performance will allow existing computing infrastructure (hardware and software) to deliver higher quality services to more users. A crucial component of this project is improved pedagogical tools and techniques to help new programmers reason about the performance of these complex systems.

PI: Guyer, Samuel
Title: SHF: Small: Detecting Heap-Based Bugs in Deployed Software
Identifying bugs in software continues to be a challenging, but essential problem to solve. One particularly difficult task is ensuring the integrity of large-scale data structures stored in memory. Existing bug-finding techniques, such as static analysis of the code, have not been effective on this problem, especially for complex and highly dynamic software, such as web applications.

This project explores a new technique for checking data structures dynamically as the program executes. Dynamic checking is effective and precise, but must be efficient in order to avoid significantly slowing program execution. The key idea in this work is to piggyback checking on the garbage collector, which already periodically visits all data structures in the program. An efficient and precise tool for detecting data structure errors could be widely deployed to improve the reliability of critical software infrastructure.

The project consists of three specific avenues of research. The first involves developing a declarative language for expressing dynamic data structure properties, building on existing techniques from static analysis and verification. The second investigates the class of properties that can be checked during a single pass of the garbage collector. The third builds on the machinery of concurrent garbage collection, allowing heap checks to proceed concurrently with the application on available extra CPU cores.

PI: Hannon, Daniel
Title: Team Performance in an Intelligence, Surveillance, and Reconnaissance (ISR) Simulation Game
The purpose of this work is to investigate the parameters involved in team performance in the ISR Red/Blue Exercise. The work will involve empirical research involving human subjects participating in the Red/Blue exercise. This task includes compensation to human participants and technical advice based on gathered data.

PI: Harris, Jonathan
Title: Social Science Library Distribution
The Social Science Library (SSL) is an electronic collection of writings relating to sustainable development and human well-being. The collection includes a rich bibliography, with abstracts of nearly 10,000 entries, including journal articles, book chapters, research reports, and working papers. The full texts of about 3,400 of these titles are provided in PDF format. The disciplines represented are: Anthropology, Economics, History, Philosophy, Political Science, Social Psychology, and Sociology.

The SSL is distributed in the form of both USB drives and CD-ROMs. It does not require Internet access. It is carefully organized to facilitate use by students, teachers, and researchers, including an easy-to-use interface with advanced searching and browsing functions. An online version, with the extensive bibliography and all search/browse functions, but without the full-text articles (due to copyright restrictions), may be seen at: http://asitssgdae.ase.tufts.edu/ssl/cgi-bin/library.exe.

In addition to the SSL materials, the packages that will be sent to recipients also include a CD containing writings on environmental subjects from the World Watch Institute, and a pair of CDs containing articles from the UN Research Institute for Sustainable Development (UNRISD). The collections can be loaded onto all computers in the institutions that receive them, and can be easily copied by individuals for their own use, so that students, teachers and researchers can have their own "pocket library."

Goals and Impact

As noted by Rehman Sobhan, Chairman of the Centre for Policy Dialogue, Bangladesh, " ... it is hardly possible to promote the effective governance needed for a successful implementation of development policies without establishing domestic ownership over our policy agendas." The challenges of the 21st century will require excellent thinking in the social sciences, from people everywhere in the world – not only in the wealthy countries, which have hitherto dominated most publication in these fields. Accordingly, the goals of the Social Science Library Project are:

  • To further the education and publishing capacities of social scientists in the world's less-wealthy nations;
  • To ensure that global debates on the future of humanity will increasingly include these voices;
  • To strengthen the ability of social scientists in these countries to influence their own local policies; and
  • To give global attention and emphasis to those science writings that contribute to understanding and promotion of sustainability and human well-being.

An example of the potential impact of the SSL materials may be seen in Guinea, one of the poorest countries in the world, which has recently had a change of government from one that was corrupt and incompetent to one that appears genuinely concerned for the welfare of the people. The new administration is essentially rebuilding its higher education from the ground up. Recognizing that the SSL is not only useful for research, but also helpful for faculty who are coming newly to course design, the Ministry of Higher Education and Scientific Research has set in motion plans to use the SSL as the centerpiece of their future social science curricula. A ceremony has been held in Guinea to celebrate the arrival of the first batch of SSL materials, and ambitious plans are being mooted to include instructions for computer translation software so that users can translate at least some of the full-text articles in the SSL into French.

PI: Hashley, Jennifer
Title: Massachusetts Beginning Farmer Agricultural Alliance
The objectives are:

  1. Establish the Massachusetts Beginning Farmer Agricultural Alliance (BFAA) – a statewide collaboration of beginning farmers, farm service providers, and farm support agencies – to expand use of new and existing agricultural education and technical assistance resources.

  2. Farmland access: Develop a statewide farmland outreach, training and technical assistance program to connect new producers to farmland resources.

  3. Develop a statewide livestock training and technical assistance program.

PI: Hata, Akiko
Title: Mechanisms of TGFB Signal Transduction
Idiopathic pulmonary arterial hypertension (IPAH) is a rare but terminal disease with a median survival rate of 2-3 years from the time of diagnosis if left untreated. Bone morphogenetic proteins (BMPs), the largest subset in the transforming growth factor β (TGFβ) superfamily of cytokines, play a crucial role in such fundamental processes as dorso-ventral patterning, left-right asymmetry, neurogenesis, somite and skeletal development, limb patterning, and organogenesis. Germline mutations of the type II BMP receptor (BMPRII) genes are associated with IPAH. Mutations causing IPAH are distributed throughout the BMPRII gene, including the carboxyl (C)-terminal tail domain [BMPRII(TD)], which has no catalytic activity. There is a critical need to understand how mutations in BMPRII, and in particular in the poorly characterized BMPRII(TD), contribute to the pathogenesis of IPAH, so that an effective and rational therapy may be devised.

The long-term objective of this proposal is to elucidate the mechanism by which BMPRII(TD) transmits a specific signal, in order to gain further insights into the molecular pathogenesis of IPAH. We discovered that four-and-a-half LIM-domains 2 (FHL2) interacts with the wild type BMPRII(TD) but not with the C-terminal deletion mutant of BMPRII(TD) identified in IPAH.

The central hypothesis of the application is that FHL2, through its interaction with BMPRII(TD), plays a critical role in the maintenance of normal vascular tone. Upon BMP4 stimulation, FHL2 translocates to the nucleus and inhibits BMP-mediated activation of vascular smooth muscle cell (VSMC)-specific contractile genes in pulmonary artery smooth muscle cells (PASMCs). VSMC-specific gene promoters are regulated by a complex of proteins composed of serum response factor (SRF) and coactivators, such as MRTFs (MRTF-A or MRTF-B), and chromatin remodeling factor Brg1, which binds to a DNA element named “CArG box”. Our results indicate that FHL2 disrupts BMP-mediated recruitment of Brg1 to VSMC-specific gene promoters, thereby resulting in inhibition of recruitment of RNA polymerase II (Pol II) and transcription.

Preliminary studies of FHL2 homozygous-null [FHL2(KO)] mice revealed the exciting finding that these mice are hypertensive and exhibit abnormality in the vascular tone of large blood vessels. In SA1, we will elucidate the molecular mechanism by which the BMPRII(TD)-FHL2 pathway modulates VSMC gene transcription. In SA2, we will clarify the role of the BMPRII(TD)-FHL2-mediated signal in VSMC phenotype control. In SA3, we will investigate the role of BMPRII(TD)-FHL2 in vascular remodeling and vascular homeostasis. Successful completion of these aims is expected to provide insight into the etiology of IPAH and new targets for preventive or therapeutic interventions of vascular proliferative diseases, such as IPAH, restenosis, and atherosclerosis.

PI: Hatini, Victor
Title: Cellular Interactions in Patterning and Morphogenesis
Apical constriction is an ancient developmental process that triggers key morphogenetic events such as neurulation in vertebrates and gastrulation in insects. However, the pathways involved are not fully understood. During pupariation, presumptive leg joints undergo apical constriction and epithelial invagination to initiate joint morphogenesis. We hypothesize that the process is mediated by an increase in actomyosin contractility and a decrease in cell-cell adhesion. The goal of this grant is to study the roles of the Rho GTPases Rho1, Rac1 and Cdc42 and their regulators, the RhoGEFs and RhoGAPs, in controlling the stability and turnover of adherence junctions (AJs), and the contribution of these genes to apical constriction and epithelial invagination during joint morphogenesis. We find that the inhibition of Rho1 or the activation of Rac1 or Cdc42 blocks joint morphogenesis. We also find that RhoGAP68F (GAP68F), a putative GAP for Cdc42, and RhoGAP5A (GAP5A), a putative GAP for Rac1, are expressed at presumptive joints and are required to initiate joint morphogenesis. We provide strong preliminary evidence to suggest that these regulators act through distinct pathways to control apical constriction.

To test the role of the Rho GTPases and their regulators in apical constriction we propose the following specific AlMs:

  • AIM 1: We will test the hypothesis that Rho1, Cdc42 and Rac1 respectively regulate the influx, efflux and the stable pool of AJs at the ZA to promote apical constriction.

  • AIM 2: Large-scale interaction screens identified Rab4 and Sec3 as partners of GAP68F suggesting that GAP68F inhibits endocytic recycling from two distinct recycling routes to decrease the surface expression of AJs and thereby adhesive cell-cell contacts. In agreement, we find accumulation of GAP68F in the endocytic compartment. Therefore, we will test the hypothesis that GAP68F inhibits endocytic recycling and thereby adhesive cell-cell contacts to promote apical constriction.

  • AIM 3: We find that GAP5A is enriched at or near the zonula adherence (ZA). We will test the hypothesis that GAP5A acts at the ZA to decrease the stability of AJs and thereby adhesive cell-cell contacts to promote apical constriction.

The successful completion of these studies will highlight the contribution of junctional stability and endocytic trafficking to apical constriction and epithelial invagination with implications to vertebrate systems.

PI: Haydon, Philip
Title: Astrocyte-Neuron Signaling
Researchers are increasingly aware that astrocytes respond to neuronal activity with Ca2+ signals that can induce the release of chemical transmitters. The roles of these gliotransmitters in the control of neural function and behavior are poorly defined. Our studies have revealed that astrocytes are responsible for the control of extracellular adenosine that activates neuronal adenosine 1 receptors (A1R). The expression of a dominant negative dnSNARE domain in astrocytes, to inhibit the release of gliotransmitters, causes a reduction in the magnitude of CA3-CA1 long term potentiation (LTP), as well as a reduction in synaptic N-methyl-D-aspartate receptor (NMDAR) current (prelim studies) and impairments in sleep homeostasis. Since Ca2+ supplied by NMDARs is essential for the induction of LTP, we propose a novel hypothesis linking astrocyte-derived adenosine with NMDARs and LTP: Astrocyte-derived adenosine acting through A1 receptors enhances synaptic NMDAR currents and consequently the magnitude of NMDAR-dependent LTP.

To test this hypothesis we will use conditional astrocyte-specific transgenic mice that allow both activation and inhibition of glial signaling pathways. We have four specific aims: First, we will test the hypothesis that astrocyte-derived adenosine acting on A1 receptors regulates synaptic NMDAR currents. Second, we will test the hypothesis that astrocytic Ca2+ signaling promotes NMDAR-dependent LTP. Third, we will test the hypothesis that astrocytic enhancement of LTP is mediated via A1 receptor-dependent augmentation of NMDA receptors. There are likely to be wide ranging effects of adenosine, NMDAR and LTP on behavior. To maintain focus we will build on our recent studies in the fourth specific aim to identify roles for astrocyte-Ca2+ signals and adenosine in the control of sleep homeostasis.

This project will provide entirely new information on the role of astrocytes in brain function. Using molecular genetic studies in situ and in vivo we will determine under which conditions astrocytes contribute to information processing and behavior. Since we propose that astrocyte-derived signals regulate NMDA receptors, receptors known to be central to numerous disorders, this project has the potential to identify novel glial targets to enhance learning and memory and to treat sleep disorders.

PI: Haydon, Philip
Title: Enhancing Neuroscience Research at Tufts: Expansion of the Animal Behavior Core
A serious global public health problem concerns maintaining the quality and effectiveness of life as people live longer and are thus susceptible to more chronic and acute diseases and disorders. Recognizing this opportunity, the current administration of Tufts University has invested in the interdisciplinary area of Neurosciences research and education with the goal of developing this field into one of its leading programs.

At the heart of this plan is the identification of the behavioral consequences of molecular genetic manipulations with the long term goal of identifying new therapeutic targets for the treatment of disorders such as epilepsy, depression, disorders of learning, memory and cognition, as well as neurodegenerative disorders. Such studies require a detailed analysis of murine behavior, and thus access to behavioral testing facilities is essential for contemporary translational neuroscience research. At Tufts University School of Medicine (TUSM), our behavioral testing facility is an integral component of our Division of Laboratory Animal Medicine (DLAM). However, the behavioral facility of DLAM no longer has the capacity required to support the research of our growing research community. We request funds to expand the murine behavioral facility within DLAM.

Our goal is to provide the Neuroscience research community at Tufts with a shared facility totaling 1,753 square feet (a 1.78-fold increase over the current facility) that provides a necessary range of advanced state-of-the-art behavioral testing services in order to accelerate high-impact research.

Aim 1: Enlarge the Animal Behavior Facility within the existing Division of Laboratory Animal Medicine (DLAM) facilities. We will expand the Behavior Core into adjacent DLAM space, resulting in a doubling of the number of testing rooms for studying murine behavior. We will also expand the cage capacity of a reverse light cycle mouse holding room that is located in the facility while maintaining additional facilities that include a procedure room for surgery. The behavior core expansion will leverage additional funds from TUSM for the renovation of new space for DLAM that will yield a net increase in cage capacity.

Aim 2: Provide adequate capacity and facilities for advanced behavioral testing modules and animal holding rooms. Because of limited space within the existing behavior core, much of behavioral testing equipment sits in storage and needs to be shuttled in and out of the behavior core to accommodate each investigator's needs. The expansion of the core will allow us to develop individual testing rooms targeted to specific behavioral modalities and will allow us to accommodate this equipment on a full time basis within the core.

Support from the NCRR together with other investments provided by Tufts University, will allow a partnership that allows dramatic breakthroughs in our understanding of disorders of the brain, including epilepsy, depression, schizophrenia and Alzheimer's disease.

PI: Haydon, Philip
Title: Roles for Gliotransmission in Substance Abuse
Synaptic plasticity is at least one of the cellular underpinnings of addiction to drugs of abuse. NMDA receptors, which are necessary for some forms of synaptic plasticity, play pivotal roles in mediating behavioral responses to cocaine. Infusion of cocaine can lead to NMDA receptor-dependent long term potentiation of synaptic transmission in the ventral tegmental area (VTA). Infusion of NMDA receptor antagonists into the VTA prevent cocaine-induced conditioned place preference. We will test the novel hypothesis that astrocytes are critical for the control of NMDA receptor function, synaptic plasticity, and as a consequence addictive behaviors.

There is a new appreciation for roles of astrocytes in the control of synaptic transmission. In 1994, we discovered that astrocytic Ca2+ signals stimulate the release chemical transmitters from these glia. Since then we and others have shown that this process of gliotransmission can regulate neuronal excitability and synaptic transmission leading to the idea of the Tripartite Synapse, which accounts for roles of astrocytes in synaptic transmission. Using lines of inducible, astrocyte-specific transgenic mice impaired in gliotransmission we have made two observations essential for this project: First, inhibiting gliotransmission significantly reduces synaptic NMDA receptor density. Second, this inhibition of gliotransmission blunts cocaine-induced conditioned place preference. Given the known importance of NMDA receptors in mediating rewarding properties of drugs of abuse we hypothesize that astrocytes regulate neuronal NMDA receptor density and synaptic plasticity and thereby behavioral responses to drugs of abuse.

Specific Aim I: Test the hypothesis that gliotransmission regulates functional NMDA receptor density on dopaminergic neurons in the VTA.

Specific Aim II: Test the hypothesis that gliotransmission promotes synaptic plasticity in the VTA.

Specific Aim III: Test the hypothesis that gliotransmission is essential for cocaine-induced behavioral response.

Systematically evaluating the role of gliotransmission in synaptic plasticity and behavioral responses to drugs of abuse promises to offer new insights into the cellular mechanisms underlying addiction. Since astrocytes express unique receptors that could be targeted therapeutically, success in this project may offer a new approach to prevent and treat addictions.

Mentor: Haydon, Philip
Fellow: McIver, Sally
Title: The Role of Gliotransmission in Mediating the Central Effects of Alcohol
Much attention has been given to the neurochemical and synaptic changes that influence the behavioral effects of alcohol, with emphasis placed on neuronal mechanisms of action. The potential role of astrocytes as targets or mediators of the central effects of alcohol is largely unknown, and is the major focus of this proposal. The rationale behind the proposed studies is in part based on two key findings from the literature: that acute alcohol exposure causes increased extracellular adenosine via blockade of the equilibrative nucleoside transporter 1, and that sensitivity to and consumption of alcohol can be mediated by activation of the src family kinases (SFK) and a known substrate, the NR2B subunit of the NMDAR. Using an astrocyte-specific transgenic mouse, called dnSNARE, we have shown that an astrocytic source of adenosine acting on A1 receptors (A1R) influences NMDAR-mediated synaptic activity and membrane expression of NR2B. In preliminary studies, dnSNARE mice exhibited increased sensitivity to the acute effects of alcohol and decreased alcohol consumption, supporting the involvement of astrocytes in alcohol behaviors. Collectively, this evidence led to the hypothesis that an astrocytic source of adenosine acting on A1Rs contributes to the synaptic and behavioral changes occurring in response to alcohol exposure.

The proposed experiments are designed to establish the potential link between astrocytes and the effects of alcohol on A1R activation and NMDAR-mediated synaptic activity. In the first aim, dnSNARE mice will be tested to determine sensitivity to the hypnotic and motor impairing effects of alcohol, and for consumption of and preference for alcohol. The second aim will employ pharmacology in dnSNARE and control mice to examine whether these characteristic alcohol behaviors involve A1R activation, independently and/or in concert with downstream changes in activation of SFK and the NR2B subunit of the NMDAR. In the third aim, electrophysiology will be used to compare the effects of alcohol on synaptic transmission in brain slices from dnSNARE and control mice, and to test whether astrocyte-regulated activation of A1Rs, SFK, and NR2B mediates alcohol-induced changes in synaptic transmission. By identifying a novel astrocytic target of alcohol, results from these studies have a unique potential to impact the development of therapies for treatment of alcohol abuse and dependence.

Mentor: Haydon, Philip
Fellow: Blutstein, Tamara
Title: The Role of Gliotransmission in Sleep Homeostasis
Over ten years ago the idea of a tripartite synapse, which suggested that synaptic transmission involved three components, a presynaptic terminal, a postsynaptic terminal and a glial cell, was put forth to the scientific community. Since then tremendous advances have been made in the field of glial biology, and it is now well-accepted that glial cells are active participants in synaptic transmission and can release chemical transmitters, in a process called gliotransmission, which can influence synaptic activity and behavior. Our lab has developed a transgenic mouse model which specifically impairs gliotransmitter release in astrocytes via the inducible expression of a dominant negative SNARE (dnSNARE) protein driven by a GFAP promoter. Using this model we have shown that gliotransmission is involved in the modulation of sleep homeostasis. More specifically, astrocytic SNARE dependent gliotransmitter release is necessary for the accumulation of sleep pressure and contributes to the impairment of working memory following sleep deprivation in an A1R dependent manner.

The goal of this proposal is to further explore the role of gliotransmission in sleep homeostasis and cognition. First, we propose to determine the identity of the gliotransmitter. The effects we observe are A1R dependent which has led us to propose that astrocytic release of ATP, which is converted extracellularly to adenosine, is the putative gliotransmitter. Thus, we will directly measure extracellular adenosine levels in wild-type and dnSNARE animals during sleep deprivation. Next, we will seek to identify the activating signal for gliotransmitter release. Nitric oxide (NO) is also involved in sleep homeostasis and has been shown to increase extracellular adenosine levels, making it an intriguing potential candidate molecule for the initiation of gliotransmitter release. Thus, we will test whether NO can induce an astrocytic SNARE sensitive increase in extracellular adenosine and sleep pressure. Finally, we will assess whether the increased adenosine tone contributes to the cognitive deficits seen after sleep deprivation. The proposed experiments will take advantage of my existing skills in in vivo microdialysis and molecular biology while allowing me to gain skills in EEG/EMG recordings, electrophysiology and behavior. Sleep is important to overall health and affects all aspects of human behavior. This makes it imperative to understand the homeostatic mechanisms that underlie sleep and wakefulness and identify new regulatory targets, such as glial cells.

PI: Heldwein, Ekaterina
Title: Structural and Mechanistic Studies of Herpesvirus Entry into Host Cells
Herpesviruses are human pathogens that infect their hosts for life, causing cold sores, genital herpes, blindness, encephalitis, cancers, and life-threatening conditions in immuno-compromised individuals. The goal of my research is to understand in atomic-level detail how herpesviruses enter host cells. Such information will be invaluable in designing anti-herpesvirus therapeutics to combat both viral infections and cell-cell spread.

The herpesvirus cell-entry mechanism is very complex. Whereas other enveloped viruses use a single protein to effect cell entry, all herpesviruses require at least three proteins: gB, gH, and gL. These three proteins are thought to accomplish the fusion of viral and cell membranes – a pivotal step in viral entry – but their exact functions are obscure. I aim to determine how the gB and gH/gL proteins of Herpes Simplex Virus (HSV) work together to accomplish membrane fusion and how the signal from the receptor-binding protein, gD, triggers the membrane-fusion machinery. Uncovering how these proteins work in HSV infection will also reveal their functions in other herpesviruses because the membrane-fusion machinery, i.e., gB, gH, and gL, is highly conserved. My approach will combine the power of x-ray crystallography to determine the structures of individual proteins with the rigor of other biophysical and biochemical techniques to study their interactions. The outcome of this research will be a thoroughly determined and finely detailed picture of the herpesvirus-mediated fusion of the viral and cell membranes.

Previous studies of virus-mediated membrane fusion in single-component systems have provided many crucial insights into the general mechanism of membrane fusion, involved in many normal cellular processes. But the complex multiprotein fusion machinery of herpesviruses is a better model for the regulated, multi-component cellular membrane fusion. Therefore, if we establish how herpesvirus glycoproteins interact to drive membrane fusion during cell entry, we will advance fundamentally our mechanistic understanding of membrane fusion.

PI: Heldwein, Ekaterina
Title: Structural Mechanism of Herpesvirus Egress
Herpesviruses are a family of human pathogens that infect their hosts for life, whereby they establish a latent state from which viruses periodically reactivate causing a number of ailments ranging from cold sores to blindness, encephalitis, and cancers. Assembly of progeny virions and their release from the infected cells, termed egress, is an important stage in the herpesvirus lifecycle. Therefore, a thorough knowledge of the egress mechanism may lead to successful therapeutic interventions based on stopping successfully the production of new virions. The basic mechanism of egress is common to all herpesviruses. Nascent capsids containing viral genomes first bud into the inner nuclear membrane, a step called primary envelopment. Once in the perinuclear space, these primary virions fuse their membranes with the outer nuclear membrane, releasing capsids into the cytoplasm, a step called de-envelopment. These cytoplasmic capsids next travel along microtubules to the Trans Golgi-derived vesicles where a second, and final, round of envelopment takes place. The cell's own secretory machinery then transports these mature virions out of the cell. Thus, herpesvirus egress involves a complex network of protein-protein interactions among multiple viral and cellular proteins. All of these interactions represent potential targets for development of new antivirals, particularly ones designed to prevent viral reactivation. Although several protein-protein interactions have been identified, critical mechanistic details are lacking.

Our long-term goal is to elucidate the egress "interactome" at atomic-level detail, and to use this knowledge for antiviral drug design. This proposal focuses on several known interactions that are critical for viral egress, i.e., those between UL31 and UL34, between UL36 and UL25, and between UL36 and UL37. The objective of this proposal is to obtain an atomic-level view of these interactions, and characterize them using structural, biochemical, and functional approaches. Our central hypothesis is that herpesvirus egress proteins have unique structures that underlie the novel mechanisms they use to mediate herpesvirus egress. Some of these proteins may prove to share structural similarities with other viral or host proteins and mimic some known processes.

Our specific aims are:

Aim 1 – To develop an atomic model of the nuclear egress complex UL31/UL34 and to characterize its membrane interactions. We hypothesize that UL31 and UL34 interact through multiple domains and that the UL31/UL34 complex binds membranes and reshapes them. We hypothesize that UL31/UL34 may be sufficient to mediate membrane budding and fission.

Aim 2 – To investigate interactions between UL36 and UL25 and between UL36 and UL37 using biochemical and structural approaches. The first interaction is necessary to attach tegument proteins to capsids. The second interaction is necessary for efficient transport of capsids along microtubules. A detailed picture of how these proteins interact will help elucidate fully (lead to a better understanding of how) the function during egress.

If successful, this research will yield finely detailed pictures of several key viral complexes, which will provide mechanistic insight into their roles in herpesvirus egress. For both aims, the structures will be used to develop testable hypotheses regarding the functions of specific proteins. Approaches will include mutagenesis, biochemical characterization, interactions with model membranes and functional assays of virus egress.

PI: Hodes, Marc
Title: Galinstan-Based Liquid Cooling of Microelectronics
Galinstan, a gallium, indium and tin eutectic, possesses unique thermophysical properties which may be exploited for enhanced cooling of microelectronics. At atmospheric conditions, it is a liquid with a thermal conductivity of 28 times that of water; however, its volumetric heat capacity (ρc) and dynamic viscosity are 0.6 and 2.4 times those of water, respectively. A critical evaluation of the cooling potential of Galinstan has not been undertaken and it is the objective of the proposed advanced study. Specifically, analytical and, subsequently, more accurate numerical models (applicable to both indirect and direct liquid cooling configurations) will be developed to optimize Galinstan-based cooling. The geometry considered will be minichannel heat sinks, i.e., those possessing a large number of millimeter-scale rectangular channels to obtain the surface area enhancement necessary to minimize total thermal resistance. A major experimental program would be undertaken to validate the modeling effort. Then the cooling potential of Galinstan relative to other options relevant for the cooling of military electronics may be evaluated on an application specific basis.

Mentor: Holcomb, Phillip
Fellow: Krendl, Anne
Title: Effects of Age-Related Cognitive Decline on Attitudes Toward the Stigmatized
As I begin the third year of my training, I will continue my dual collaborations with Elizabeth Kensinger (a consultant on my NRSA) and Nalini Ambady. I will also borrow from the expertise of Dr. Holcomb, who is an expert in neuroimaging techniques. Dr. Kensinger and I are currently analyzing the results of the fMRI studies I conducted with older adults in Year 2. In addition to the methods proposed in my NRSA, I have also begun training in ERP methods in Dr. Kensinger's lab. Dr. Holcomb is also an expert in ERP methods and will be an excellent resource to enhance my training in learning this technique. As part of my collaboration with Dr. Kensinger, I have been attending weekly lab meetings at Boston College, and have also been meeting with her at least once a week to discuss ongoing research projects. The main focus of Year 3 will be to finish analyzing the studies I conducted in Year 2 and write them up for publication. I also plan to conduct any follow-ups that may be necessary based on my research findings from Year 2. Dr. Ambady will play a central role in helping me identify the follow-ups that should be conducted and offering guidance on how to best execute them. One question that has already arisen in my analyses is whether there are temporal differences in the manner in which older adults with various levels of cognitive decline engage the processes that lead to regulating stereotypes effectively. The latter question could be investigated using event-related potentials, a technique both Drs. Kensinger and Holcomb have the resources and expertise to advise me in using.

PI: Holcomb, Phillip
Title: The Neuro-cognition of Word Comprehension
The mental and underlying neural (neuro-cognitive) operations involved in the comprehension of words are fundamental to language based communication. Understanding how the brain identifies individual words from around fifty thousand or so possibilities in less than half a second, has been a continuing challenge for theorists in psychology, neuroscience and education. Finding the answer to this and related questions would represent a major step forward in basic language science, but also would provide a framework for helping isolate the neuro-cognitive locus of deficits in certain developmental language disorders. The overall goal of the proposed research is to continue our study of word comprehension processes from a neuro-cognitive perspective. The experiments outlined in this proposal are focused on providing answers to questions about the temporal dynamics (ERPs) and now the spatial organization (MEG and fMRI) of the neural networks that underlie the comprehension of words.

The proposed research has four specific aims. In Aim 1 we propose to test a series of predictions about the temporal dynamics of visual word comprehension derived from our recently elaborated Bi-modal Interactive Activation Model (BIAM) of word processing. Experiments are proposed that use our well understood ERP masked priming paradigm, as well as two new novel experimental techniques. We will also extend the scope of our research in three new directions. In Aim 2 we propose a novel series of ERP studies designed to expand our study of comprehension to the auditory modality using our newly developed dichotic priming task. These studies will allow us to better elaborate the auditory side of the BIAM. In Aim 3 we propose experiments that test predictions from the BIAM at the interface between visual and spoken word processing, a level we hypothesize is critical to the process of learning to read. Finally, in Aim 4 we propose to augment our work on the temporal dynamics of word comprehension by using multi-modal imaging techniques. This will provide much needed information about the spatial organization of the neural networks involved in word comprehension and will allow us to add an anatomical component to our BIAM of word comprehension.

Our long term goal is to extend these studies to normal children as well as those with word processing deficits including dyslexia and SLI.

PI: Hollander, Justin
Title: A Spatial Analysis of Housing Vacancy in the United States – 2000-2011
Housing vacancy has been recognized to decrease the quality of life in neighborhoods. Recently, researchers and policymakers have reframed this problem as an opportunity for adaptive redevelopment. This study is the second stage of a research effort to identify vacancy hot spots, analyze why these areas have declined, and tailor policy recommendations to planners and policymakers for encouraging neighborhood revitalization. It utilizes GIS technologies to analyze housing occupancy data provided by the United States Postal Service to show how housing occupancy patterns changed during the recent foreclosure crisis. It also utilizes Global Moran's I and Local Indicators of Spatial Autocorrelation (LISA) spatial analysis techniques to identify clusters of declining zip codes. It is found that formerly expanding regions in the South, West, and northern Midwest were heavily impacted by the foreclosure crisis. Suburban areas recorded a higher net increase in declining zip codes during the foreclosure period relative to other areas.

PI: Hollister, Robert
Title: Talloires Network Leaders Conference
The Talloires Network requests a grant to defray the travel and accommodations expenses of the heads of African universities so that they can attend the Network's global conference in Madrid June 13-16, 2011. The conference will be hosted by the Universidad Autónoma de Madrid with support from Santander Bank and the Pearson Foundation. The conference has good potential to reinforce the work of the Carnegie Corporation's Higher Education and Libraries in Africa Program, and in particular its strategic investment in Africa's next generation of academic and university leaders. 29 African universities are members of the Talloires Network. Many only will be able to participate if they receive financial assistance for air travel and accommodations.

The Talloires Network (TN) is an international association of institutions of higher education committed to strengthening their civic roles and social responsibilities. Our growing coalition numbers over 190 members from 59 countries with a combined student enrollment of 5½ million. The network promotes educating future leaders for change, mobilizing university professors and students to address pressing societal challenges (with an emphasis on combating poverty and improving public health), and adopting socially and environmentally responsible institutional policies and practices. TN is guided by a Steering Committee of 11 international leaders in higher education chaired by Tufts University President Lawrence Bacow. Tufts University and Innovations in Civic Participation (Washington, DC) serve as secretariat for the Talloires Network.

The Network works to raise public awareness of, and support for, the expanding global civic engagement movement in higher education. We help member institutions to strengthen their civic engagement work through building organizational capacity, providing institutional assessment and planning tools, cultivating financial resources, and providing a global communication platform. We broker joint projects among members and organize conferences for them to share ideas and foster collective action.

The Talloires Network Leaders Conference will bring together higher education leaders from every corner of the world: rectors, vice-chancellors, presidents, ministers of education, regional network leaders, as well as philanthropic leaders. Together they will discuss and sharpen their strategies with respect to the future of civic engagement, community outreach, and social responsibility in higher education.

Over two and a half days, the conference will explore how to deepen the impact of community engagement in the higher education sector. Internationally renowned speakers will share their visions for institutional civic action, the role of universities in tackling pressing social needs, and partnership with the NGO and business sectors. Session topics will cover leadership strategies, technology and online organizing, creating policy environments to support community engagement, program design and evaluation, and community partnerships. Plenary and breakout sessions will be organized around these subjects. In addition, participants will share the experience and plans of their individual universities, and engage with their peers in major regions around the world.

Conference goals are to reinforce the civic engagement work of member institutions; strengthen the leadership of university rectors, vice-chancellors and presidents in the area of civic engagement and social responsibility; recruit additional institutions to join the Network; strengthen working ties among participants; foster collaboration and broker joint projects; strengthen the support activities of the Talloires Network itself, and of higher education and civic engagement networks; elevate public awareness of, and support for, this global movement; and amplify the efforts of partner organizations, including the Carnegie Corporation.

PI: Hopwood, Jeffrey
Title: Instabilities in Nonthermal Atmospheric Pressure Plasma
Large-area glow discharges at atmospheric pressure are plagued by ionization instabilities. The full, three-dimensional challenge of understanding atmospheric instability is currently untenable, so this proposal will study these instabilities in a reduced-dimension test bed.

The test bed consists of a linear array of micromachined quarter-wave microstripline resonators. A resonantly ballasted microplasma is sustained in a 200 micron gap between the end of each resonator and ground. The experiment is easily fabricated using printed circuit board technology which allows rapid reconfiguration at essentially no cost. Although each resonator delivers energy to an individual microplasma, the closely-coupled array of resonators creates a quasi-1D linear plasma consisting of overlapping microplasmas. Strong coupling among the resonators allows a single microwave generator to drive all microplasmas in the array. Instability propagation can be initiated within the array by pulsing the microwave energy to a local resonator. Microwave and optical diagnostics will measure and track the growth of the induced instability. The work will elucidate the role of photoionization, electron, ion, and thermal instabilities through the use of optical isolation of microplasmas, potential barriers created by DC biasing of any single resonator, and thermal conductivity control using resonator geometry, respectively.

Intellectual Merit: The successful completion of this study is potentially transformative of our understanding of glow discharge instabilities in large volume, atmospheric pressure plasmas. By reducing the dimensionality of the plasma, growth and propagation mechanisms are constrained to one dimension. This dimensional reduction allows one to isolate and control various instability triggers including optical, electrostatic, and thermal instabilities.

Broader Impact: This work will support the scientific infrastructure through the support of a PhD student and undergraduate research. The results from these studies will naturally be published in the peer-reviewed literature. In addition, the test bed is sufficiently simple and inexpensive that it will be duplicated and made available to other laboratories so that a more extensive suite of plasma diagnostics may be employed in the understanding of nonthermal plasma uniformity and instabilities.

The fundamental experimental science of this program will not only improve the scientific understanding of nonthermal atmospheric plasmas, but will also enable the generation of uniform, stable, large-area plasmas with densities approaching the glow-to-arc transition boundary. Dense, large-area plasmas operating at one atmosphere open the field of plasma processing to many new applications, including atmospheric roll-to-roll thin film deposition, etching, and surface modification on low-cost substrates such as plastics. Stability is essential for industrial applications. The generation of dense atmospheric plasma is anticipated to improve the quality of thin film deposition by increasing the energy flux to the film, thereby enhancing adatom surface diffusion of the film.

PI: Huber, Brigitte
Title: HERV-K18 as a Risk Factor for CFIDS
The etiology of Chronic Fatigue Syndrome (CFS) is far from understood and is likely due to multiple genetic components. Infection with EBV and treatment with IFN-α have been implicated in the pathogenesis. Our laboratory has shown that EBV-infection, as well as exogenous IFN-α, activate transcription of the env gene of a Human Endogenous Retrovirus, HERV-K18. This provirus is normally silent, but when induced it encodes a superantigen (SAg), which is a class of proteins that is capable of deregulating the immune system. Three alleles of HERV-K18 env have been documented, K18.1, K18.2, K18.3, whose gene products have SAg activity, but are predicted to differ biochemically and functionally.

Our working hypothesis is that HERV-K18 is a risk factor for CFS. In a pilot study, the allele and genotype distributions of the HERV-K18 env gene were compared between various groups of CFS patients and healthy controls. Although only a limited number of samples were available in the various cohorts, the odds ratios that were obtained were statistically significant. The most intriguing interpretation of these data is that they provide genetic evidence for the unique etiology of at least one group of CFS patients. Thus, it may be possible to delineate different subtypes of CFS, depending on the clinical history of the patients.

It is now proposed to substantiate these pilot results, using a much larger cohort of 400 CFS patients associated with EBV that has been assembled by the co-investigator, Dr. Renee Taylor. Dr. Ben Katz, board certified in both Pediatrics and Pediatric Infectious Diseases, will clinically evaluates the patient cohort, and Dr. Inga Peter, a genetic epidemiologist and biostatistician, will oversee the statistical analyses. In addition, the expression pattern of the HERV-K18 SAg during active disease versus intermission will be measured.

Furthermore, T cell stimulatory activity of this SAg, expressed on peripheral blood lymphocytes of patients during the course of the disease, will be tested ex vivo, using a T cell hybridoma reporter assay that has been developed in our lab. Since SAg-activated T cells produce massive quantities of chemokines, lymphokines and neurokines, the expression of the HERV-K18 SAg could influence not only the immune system, but other organs as well. A positive association between CFS and either HERV-K18 alleles or expression patterns would open new avenues for the development of clinical treatments of this chronic disease.

PI: Hynes, Morgan
Title: Preparing Engineers to Educate Now
The Tufts University Noyce capacity building project aims to bolster Tufts' newly instituted Master of Arts in Teaching Engineering program that prepares engineers as grades 5-12 engineering teachers. The project team composed of faculty from Mechanical Engineering, Computer Science, and Education recognizes the need for a multi-faceted approach:

  1. Attract and recruit engineering undergraduates and practicing professionals to become engineering teachers,
  2. Build partnerships with local schools and engineering teachers to serve as M.A.T. in Engineering candidates cooperating teachers, and
  3. Effectively prepare M.A.T. in Engineering candidates through innovative coursework, engineering faculty advisors, and other programmatic supports.

The approach includes new course development where engineering faculty work with education faculty to incorporate education themes and ideas in graduate level engineering content courses and year-round programming with all stakeholders (undergraduate engineering students, M.A.T. candidates and graduates, cooperating in-service teachers, and engineering and education faculty).

The intellectual merit of the project rests upon the pioneering endeavor of preparing engineers and K-12 engineering teachers. Integrating engineering into the K-12 classroom has become a popular notion and the Prepare Engineers to Educate Now project looks to address one of the major hurdles in making this happen more broadly creating highly qualified engineering teachers.

The broader impacts rest on the communities served by Tufts and its graduates, but the goal is to inform other institutions through the evaluation of the project includes measuring the effectiveness of recruiting strategies, partnership strategies, and courses in developing teachers' knowledge and practices.

PI: Imanishi-Kari, Thereza
Title: The Effect of Innate Immunity on B Cell Tolerance
Recent evidence increasingly points to the importance of antibodies specific for RNA antigens in the pathogenesis of SLE. Using a novel mouse model in which RNA-specific B cells are generated and easily tracked, and in which clinical SLE pathologies are recapitulated, new and critical information on the pathogenesis of SLE will be obtained. The mouse line to be used, 564lgi, was generated in our laboratory and has already made an important contribution to the emerging understanding of the role played by TLRs, in particular TLR7, in the development of SLE. In this system, on the non-autoimmune C57BL/6 background, most RNA-reactive B cells undergo receptor editing, while those that retain their RNA-specificity become anergic by multiple criteria. Yet class-switched pathogenic autoantibodies are produced by a T-independent, but TLR7-dependent mechanism. Thus, either anergic RNA-specific lgM+ B cells are capable of activation and differentiation into lgG producing cells in response to self-antigen, or a subpopulation of these cells is able to evade anergy, namely those that have undergone CSR in the bone marrow during B cell development in response to self-antigen encounter. In the current proposal, these two models will be tested in detail. In either case, the signals required for differentiation into antibody producing cells and the extent to which there are contributions from non-B cells will be determined. Finally, the effect of autoimmune-prone backgrounds on the regulation of RNA-specific B cells in the 564lgi system will be studied. These experiments will help unravel the mechanisms by which RNA-specific B cells become activated and produce pathogenic autoantibodies in SLE.

PI: Isberg, Ralph
Title: Molecular Analysis of Microbial Pathogens
This application requests support for continuation of a rigorous predoctoral training Program that focuses on the molecular analysis of microbial pathogens. The Program is interdepartmental and is centered around the Department of Molecular Biology and Microbiology, with members being drawn from the Departments of Biochemistry, Medicine, Infectious Diseases, and Pathology. All investigators have either a common interest in pathogenic microorganisms, restriction of pathogens in cell or animal models, in basic processes performed by such microorganisms, or have complementary expertise in molecular biology. The varied research interests of the group include:

  1. Bacterial pathogenesis, including the study of colonization, intracellular growth, toxin expression and development of tools to study microbial genes expressed during animal infections;
  2. Viral pathogenesis and replication;
  3. Sporulation as model regulatory and pathogenic system;
  4. Protein secretion and the analysis of microbial surfaces, including those of pathogenic bacteria and yeast;
  5. Regulation of gene expression and cell growth in microbial model systems;
  6. Analysis of developmental stages in fungal pathogens;
  7. Mouse models of innate immunity.

The members of this program use genetic and biochemical strategies to analyze microbial pathogens, as well as animal infection models. This program has a long history of having a strong collaborative spirit of learning and research among faculty and students. Recruitment and admission strategies have been highly successful, with an excellent minority recruitment program, with 20% of the students being members of underrepresented minority groups, as defined by NIH guidelines. The overwhelming majority of the 140 Ph.D. graduates of the department since 1964 are currently employed in research positions in academics and industry, with approximately 50% of the graduates who have finished postdoctoral training currently holding faculty positions.

PI: Isberg, Ralph
Title: Molecular Basis of Yersinia-Host Cell Interaction
The long-term objective of these studies is to determine how an enteropathogenic bacterium is able to enter within host cells and to evaluate the role of mammalian cell receptors in promoting uptake. As a model system, Yersinia pseudotuberculosis is being studied in order to gain detailed information on the function of bacterial- and host-encoded internalization factors. Specifically, Y. pseudotuberculosis invasin-integrin interaction will be studied, and host-encoded factors that modulate receptor-mediated bacterial internalization will be identified. Uptake promoted by invasin depends upon high affinity binding to its receptors, regulated by the concentration of receptor available to participate in uptake.

To further investigate the molecular mechanism of uptake, the following experiments will be performed:

  1. A model for the binding of a single invasin molecule to multiple host receptors will be tested, by analyzing the subunit structure of invasin and determining the stoichiometry of invasin-receptor interaction;

  2. The region of the integrin heterodimer involved in invasin binding will be determined by performing two novel mutant selection for altered receptor interaction;

  3. The role in bacterial uptake of the beta-1 integrin will be investigated by analyzing the binding of mammalian cell cytoplasmic components to hybrid protein harboring this domain;

  4. Functional studies on the role of mammalian cytoplasmic components will be performed using a newly-developed perforated cell assay, allowing evaluation of the biological roles of factors identified in other Aims; and

  5. The role of invasin in intestinal infections will be analyzed, using invasin mutations resulting in partially functional proteins.

Bacterial uptake by host cells is a common step in establishing disease by a number of bacterial pathogens. Investigation of this process will result in important information on how enteric diseases are initiated, and provide a potential source for the development of new chemotherapies that block this step in the infection process. In addition, identification of the components that allow a simple organism to enter an animal cell could result in new techniques to introduce therapeutic agents that would otherwise not be able to enter the host cell.

Mentor: Isberg, Ralph
Fellow: Crimmins, Gregory
Title: Spatial Control of Host Cell Signaling by a Bacterial Pathogen
The secreted virulence factors of pathogenic microorganisms and their role in manipulating host cells have been the subject of intense study. However, almost nothing is known regarding the manipulation of host protein localization by pathogens and how this alters innate immune function. The Isberg lab recently showed that YopT, a secreted Yersinia virulence factor that removes the prenylated tail of host Rho family GTPases, promotes relocalization of Raci from the cytoplasm to the nucleus. Raci is associated with control of a number of immune signaling pathways, including direct binding to the transcription factor STAT3. In this application, I hypothesize that the YopT-induced Raci nuclear accumulation shifts immune cells to a state having a lowered inflammatory response, allowing pathogenic Yersinia to establish a persistent bacterial infection. To test this hypothesis I will first determine the consequences of YopT-induced Raci nuclear localization on STAT3 localization, nuclear export, and phosporylation. I will then determine the effect of Raci nuclear localization on host immune cell function, including the transmission of signals through the IL-10 and IL-6 receptors and the induction of inflammatory immune responses upon infection with Yersinia pseudotuberculosis. Finally, I will examine the role this manipulation of host protein localization plays in Yersinia pseudotuberculosis pathogenesis. These experiments will provide detailed information on how a pathogen controls the balance between states of lower and higher virulence by forcing altered compartmentalization of a host protein.

PI: Islam, Shafiqul
Title: IGERT: Water Across Boundaries – Integration of Science, Engineering and Diplomacy
This Integrative Graduate Education and Research Training (IGERT) award supports the development of an interdisciplinary graduate training program at Tufts University, focused on water diplomacy. The goal is to prepare students who can think across natural and societal boundaries and generate actionable knowledge to help resolve water problems with competing needs.

The origin of many water problems is a dynamic consequence of competition, interconnections, and feedback among variables in the natural and societal domains. While scientific formulation and engineering solutions are necessary to address these needs, societal and political contexts must be an integral part of long-term solutions. Formulation and framing of water problems are intricately linked; consequently, variables in natural and societal domains cannot be treated independently. A main feature of this IGERT is the synthesis of these viewpoints — through integration of knowledge from science, engineering, policy and diplomacy—critical to effective water management solutions. This IGERT will prepare a new cadre of water professionals with strong disciplinary grounding and experience as problem solvers with interdisciplinary expertise and negotiation skills. Strong institutional support and proposed innovations—e.g., integrating scientific assessment and policy relevance to create actionable knowledge, exploratory research experience in real world settings, opportunities for national and international field work, and engaging students in synergistic interdisciplinary activities—will transform this IGERT project into a process that will continue to produce a new generation of water professionals with the skills and aptitude to cross boundaries and create an impact far beyond this grant.

PI: Islam, Shafiqul
Title: Water Diplomacy Workshop: Strengthening Science and Enhancing International Partnerships in a Globalized World
This project supports participation of three foreign experts in a meeting: Water Diplomacy Workshop, Strengthening Science and Enhancing International Partnership in a Globalized World scheduled to be held in Medford, MA on June 13-17, 2011. The workshop is organized by Dr. Shafiqul Islam, Department of Civil and Environmental Engineering at Tufts University, with participation by faculty from MIT and Harvard University. The objective of the three-day workshop is to bring experts in water issues in the physical sciences (e.g. civil and environmental engineering and geological sciences), with experts in water issues in social and economic sciences (e.g. economics, sociology, anthropology, political science) to identify issues and solutions that can be provided to decision-makers. A major objective is to facilitate and encourage collaborations between researchers in physical sciences and in social sciences in identifying solutions to problems of water resources and use in the US and other countries. The foreign participants will be from Egypt, Sudan and Pakistan, countries with significant water-related border disputes.




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