Abstracts

PI: Ackerman, Frank
Title: The True Cost of REACH
Abstract: Debate over REACH pits industry analysts against advocates for protection of human health and environmental quality. Industry-sponsored analyses suggest that the economic implications of REACH will be dramatic and negative; these studies have received considerable attention, and have influenced the debate over REACH. To date, there have been only a few progressive studies of the economics of REACH. An analysis of the monetary value of the likely health benefits of REACH, written by David Pearce for the World Wildlife Fund (WWF), is largely inaccessible to those outside the economics profession, and is incomplete in several key respects. A shorter and more accessible critique of industry arguments published jointly by WWF and the European Environment Bureau (EEB) is a helpful starting point, but far from making the complete case for REACH in any detail. Our report will build on and substantially expand the information and analysis available to counter industry claims.

PI: Ambady, Nalimi
Title: Effects of Perceived Gaze Direction on Emotion Processing
Abstract: The primary goal of the proposed research is to examine the effect that perceived eye gaze direction has on the processing of facial affect. Previous research efforts examining gaze and facial affect perception have been conducted independently. However, there is good reason to believe that these cues share an underlying signal value of either approach or avoidance. Specifically, it is hypothesized that direct eye gaze will facilitate the perception and detection of facially communicated anger, whereas averted eye gaze will facilitate the perception and detection of facially communicated fear. Four phases of research are proposed. Using reaction time and memory paradigms, Phase 1 investigates the notion that direct and averted eye gaze can facilitate or inhibit the processing of anger and fear expressions. Phase 2 utilizes a visual search paradigm to explore the possibility that the combined processing of these cues is innately prepared. Phase 3, investigates the role of the amygdala in processing facially communicated anger and fear combined with direct versus averted eye gaze. Finally, Phase 4 extends a pre-existing literature on joint attention by addressing the role of facial affect. Broadly, this research will 1) help resolve 1ong standing controversies in the field of facial affect perception, 2) tie together two seemingly disparate lines of research (visual1y mediated attention and facial affect), and 3) help theorists better understand psychopathological disorders such as autism and schizophrenia and localized brain lesions such as amygdalotomy that are marked by problems in the processing of nonverbal facial cues.

PI: Bachovchin, William
Title: Structure and Function of the SV40 T-AG DNA Binding Domain
Abstract: We are interested in trying to understand initiation of DNA replication processes at the molecular level. To achieve this goal, we are studying initiation at the Simian Virus 40 (SV40) origin of replication. Initiation of SV40 replication requires a single viral protein termed T-antigen (T-ag). Recognition of the SV40 origin of replication is primarily the function of a domain of T-ag termed the T-ag origin binding domain (T-ag-obd). Having recently solved the solution structure of the T-ag-obd, we are anxious to provide a molecular description of the interaction of this domain with the SV40 origin. Furthermore, using a slightly larger version of the T-ag-obd, we will initiate molecular studies of how the cell cycle regulates the critical events during the initiation of DNA replication. The following are the specific aims of this proposal: 1) To determine the solution structure of the complex formed between the origin binding domain (131-260) of SV40 T antigen (T-ag-obd) and a GAGGC containing oligonucleotide. 2) To determine the solution structures of cdk-T-ag-OBD in both the phosphorylated and unphosphorylated forms. 3) To use various biochemical techniques to support the structure studies. The health related significance of the proposed experiments stems from the fact that initiation of DNA replication is a fundamental process that takes place in all cells. We must understand how this process normally occurs prior to describing how it malfunctions in disease states. Moreover, SV40 T-ag is highly homologous to the T-ags encoded by the BK and JC viruses. These viruses induce a number of diseases in humans, including cancer. For example, JC virus induces progressive multifocal leukoencephalopathy, a disease present in many AIDS patients. Therefore, our studies may help to control the proliferation of these viruses.

PI: Bullock, Peter
Title: Initiation of SV40 DNA Replication and Its Regulation
Abstract: Many DNA tumor viruses encode "initiators" proteins that site specifically bind to viral origins of DNA replication. Upon binding to their respective origins, the initiators assemble into DNA helicases that are capable of melting duplex DNA. Initiators also recruit cellular proteins required for synthesis of nascent DNA. We are attempting to understand these processes by characterizing in depth an initiator encoded by Simian Virus 40, termed T-antigen (T-ag). Using the Simian Virus 40 system and simple band shift experiments, a fundamental question in biology will be addressed: "how does the cell cycle machinery control the assembly of initiators on viral origins of replication?" Recent experiments with T-ag derived peptides, whose ability to bind to DNA is regulated by phosphorylation of Thr 124, are providing significant insights into this process. Experiments are proposed to determine if similar mechanisms are operating in the context of T-ag. Related aspects of T-ag assembly and regulation will be considered, such as locating a site on T-ag whose interactions with the flanking sequences in the core origin is necessary for T-ag binding. Collectively, these studies will provide information that may allow us to solve the mechanism of DNA unwinding. Once the SV40 origin is unwound, the pol alpha-primase complex initiates the synthesis of nascent DNA strands. Exactly what sequences constitute the initiation sites for the pol alpha-primase complex is the topic of an additional series of experiments. Given that many basic processes are conserved throughout evolution, we are confident that the information we obtain from these studies will be pertinent to the initiation of DNA replication at other viral origins of replication. Furthermore, they may help us to understand how the cell cycle machinery controls initiation events at cellular origins. Given that uncontrolled DNA replication is thought to be a component of many diseases, including cancer, it is very important to understand how DNA replication is initiated and how it is controlled.

PI: Camilli, Andrew
Title: Study of Vibrio Intestinal Physiology and Pathogenecity
Abstract: Vibrio cholerae is a facultative pathogen and is the causative agent of the severe secretory diarrheal disease cholera. Virtually all cholera at present is caused by El Tor biotype strains which differ biochemically and phenotypically from strains of the better-characterized classical biotype. The goal of the proposed work is to understand the pathogenicity and physiology of El Tor V. cholerae during intestinal infection. Laboratory manipulation of virulence factor expression in El Tor strains is difficult, and this has hampered their study. Moreover, knowledge of which genes are expressed by V. cholerae during infection is rudimentary, and virtually nothing is known about the patterns of expression of such genes within the gastrointestinal tract. Advanced genetic approaches will be used to identify and analyze El Tor infection-induced genes within the suckling mouse model of cholera, and during colonization of a natural plankton host. The regulation and spatiotemporal patterns of expression of genes in the ToxR regulon, and newly identified virulence genes, will be determined in vivo using an enhanced recombinase-based in vivo expression technology (RIVET). Factors which are non-essential for in vitro growth but are essential for colonization of the small bowel of suckling mice, will be comprehensively identified using a modified Signature-Tagged Mutagenesis (STM) procedure. As a complementary approach, RIVET will be used to identify genes induced transcriptionally during infection, some of which may be essential for in vitro growth. These methods will also be used to identify and characterize V. cholerae genes important for colonizing the plankton host Anabaena variabilis. The importance of select genes for colonization of each host will be determined by constructing specific gene mutations followed by colonization studies. The broad specificity of RIVET, combined with the focused specificity of STM, will allow identification of an unprecendented number and variety of genes that play roles in the physiology and virulence of V cholerae in these animal and environmental host systems. These studies will not only establish a basis for understanding the dynamics of virulence gene expression during infection of an intact host, but will aid in the development of new cholera vaccines and suggest new approaches for the prevention of the dissemination of this lethal organism.

PI: Cao, Caroline
Title: CAREER: Adapting to technology in minimally invasive surgery
Abstract: Advances in robotics and computer-based technology have enabled much complex work to be performed via remote control. One example of this development is minimally invasive surgery (MIS). Successful minimally invasive surgery (MIS) relies on innovative technology that allows surgery to be performed remotely, and effective integration of this technology into the surgical process. Technology can improve the performance of the system with increased reliability and precision. However, it can also create unexpected interactions and new forms of errors (Reason, 1990; Cook & Woods, 1994). High error rates in surgery, in particular those associated with technology in minimally invasive surgery, have been documented (Leape et al, 1991; Shea et al, 1996; Wu et al, 2000). There is a great need to improve system performance and patient safety (Bogner, 1994; Kohn et al, 1999), but relatively little systematic research conducted to this end. Our long-term goal is to enhance human performance with enabling technology in minimally invasive surgery through effective human-machine interface design and training systems. This requires that we understand the system requirements, constraints, and the interactions between various system components upon the introduction of new technology.

PI: Chapra, Steve
Title: Improved Science for Managing Watershed Nutrient Loads
Abstract: This proposal focuses on four major gaps that presently impede the effective management of nutrients in watersheds: (1) inadequate knowledge of mechanisms controlling sediment- nutrient interactions, (2) inability of current receiving water models to accurately simulate nutrient-sediment-water interactions and fixed plants, (3) lack of decision-oriented optimization frameworks for managing nutrient loads to achieve multiple water quality objectives, and (4) ineffective communication of technical information with stakeholders. We propose to address these gaps by developing a decision support system (DSS). The DSS will integrate scientific models of watershed nutrient loads and receiving water quality into a decision-oriented optimization framework to allow stakeholders to define and prioritize nutrient management objectives.

PI: Coffin, John
Title: Retrovirus Evolution
Abstract: Retroviruses display a remarkable variety of interactions with their hosts, well beyond that known for any other virus group. This variety is a consequence of special features of the virus life cycle, including a high mutation rate during replication, the unique ability (and necessity to integrate their DNA at every replication cycle, and special features of certain parts of the genome, including the envelope gene and the LTR, that allow rapid adaptation to host cells displaying different surface receptors and in different transcription programs. For a number of years, our laboratory has been studying a number of different aspects of the evolutionary interaction of retroviruses with their host. These areas include: the mechanisms and role of genetic variation - point mutation, homologous and illegitimate recombination in genetic variation in vitro, the way in which LTR and env sequences are able to vary their patterns of expression and receptor usage; the nature and evolution of endogenous proviruses. Future studies will continue along the same lines. Our aims are: To study mutation and selection, we will continue development of our approach toward quantitation of very low-frequency; use these approaches to test models for retrovirus evolution (accumulation of point mutations and recombination) in simple culture; and develop and extend mathematical models for retrovirus variation and short-term evolution. To study evolution of env genes, we will analyze avian retrovirus env gene variants isolated by in vitro selection for extended host range; we will determine the evolutionary pathway by which such variants; we will determine the functional properties of "ancestral" env genes in endogenous; and we will test the possibility of evolution of env genes from normal cellular genes. We will study the evolution of endogenous proviruses by continuing to dissect the coevolution of endogenous MLV's and wild mice; using se sequences of endogenous human proviruses to test models of primate evolution; and testing why the large numbers of human endogenous proviruses do not give rise to infectious virus.

PI: Colati, Gregory
Title: Collaborative Research: Managing Authority Lists for Customized Linking and Visualization: a Service for the National SMETE Digital Library
Abstract: We propose two broad classes of service to the NSDL. First, we will provide automatic linking services that automatically bind key words and phrases to supplementary information. Such automatic linking services are already in place in the Perseus Digital Library. These services will help students, professionals outside a particular discipline, and the interested public to read documents full of unfamiliar technical terms and concepts. Astronomy students and curious amateurs may need to see expansions of some acronyms -e.g., MACHO: massive compact halo object, such as neutron stars and brown dwarfs -or pictures of "Kuiper belt objects." These services can be of particular help to undergraduates as they shift from textbooks to scientific literature: the student struggling with research papers on bioluminescence, for example, will be able to locate information about particular chemical processes or relevant species of echinoderms. Second, we will base automatic linking on authority control of names and terms and on links among different authority lists such as thesauri, glossaries, encyclopedias, subject hierarchies, and object catalogues.

PI: Freeman, Lisa
Title: Interdisciplinary Research Training for Veterinarians
Abstract: Well-trained comparative medical scientists are needed to meet the research needs of the 21st Century. Veterinarians currently are underrepresented in biomedical research but can make a unique contribution because of their expertise in clinical practice and fundamental biology, as well as their knowledge of spontaneous animal models of human disease. The goal of the proposed education program is to attract veterinarians to NIDDK-relevant research. This program is focused primarily on veterinary residents, a highly motivated group for which research training usually is not provided. This program is designed to first create the desire to pursue research and then to nurture these candidates with strong mentoring and programs, as well as by providing readily accessible research opportunities. Finally, common barriers to research will be addressed. A major aspect of the program will be biannual symposia on spontaneous animal models of human disease to disseminate information to the scientific community on the vast array of models available and to create new opportunities for collaboration. This program will utilize the strengths and resources of Tufts University to develop an untapped resource for research scientists. This will be achieved under the mentoring of a program faculty that has been recruited specifically to provide an interdisciplinary team of collaborative scientists in a variety of disciplines and that provides experienced and positive role models. The program faculty consists of 17 faculty from 9 departments on three different campuses, providing a network of research training in nutrition and endocrine, digestive, kidney, urologic, and hematologic diseases. Veterinary residents will be actively recruited, with particular attention paid to minority candidates. The program will consist of six parts: 1) Biannual symposia on spontaneous animal models of human disease to provide greater interaction with researchers from other disciplines and to increase opportunities for collaborative research; 2) A multi-function website to facilitate research, including two web-based courses on laboratory techniques and applied statistical methods; 3) A resident research and development (R&D) seminar series that will include topics to foster an interest in research and to facilitate research training; 4) Short-term introductory research electives; 5) Intensive research training electives; and 6) An active mentoring program. The inclusion of a specialist in outcomes assessment on the program faculty will ensure timely and accurate assessment of the program. Short-term evaluations will be used to guide development in the early stages of the program. Mid-range impact of the program will be evaluated by the number of participants, research presentations, grants, and papers. Long-term outcomes will be assessed by the number of Tufts-trained residents that do postdoctoral training and pursue research careers, and by using existing and novel outcomes assessment instruments. These evaluations, continued refinement, and the commitment of the program faculty will help to ensure that this becomes a self-sustaining program.

PI: Gorbach, Sherwood
Title: Impact of Micronutrients on Progression of SIV
Abstract: Studies in HIV-infected patients have revealed that serum micronutrient levels are often below normal levels, particularly for vitamins A, B about2, and E, as well as for selenium and zinc. Some studies have correlated low micronutrient levels with more rapid progression of HIV infection. Our initial studies in SIVmac239-infected rhesus monkeys have shown low serum levels of Vitamins B12 and E and selenium. Ongoing studies with a highly supplemented (HS) vitamin/micronutrient intervention in SIV-infected animals show a decrease in the rate of loss of weight and body fat compared to placebo controls. For this competitive renewal, we plan to conduct two phases of investigations: 1) single interventions over 36 months of observation in this SIV- infected model with intramuscular Vitamin B 12 and oral selenium, the two most promising micronutrients in human studies; and 2) Conduct an HS vitamin/micronutrient intervention over 36 months in SIV-infected macaques receiving an antiretroviral regimen of HAART (PMPA, ddI, hydroxyurea), which has been shown to produce undetectable SIV viral loads. Primary end points for both studies are time of death and changes in body weight. Secondary end points are measurements of serum micronutrients; changes in lean body mass (by DEXA, bioelectric impedance [BIA], and somatometric measurements); SIV viral load; CD4 cell count; and development of opportunistic infections. Study 1 will show if a single micronutrient such as B 12 or selenium can produce similar effects on end points as the combined HS preparations. Study 2 will simulate the situation of using HAART in HIV/AIDS patients who may have continued weight loss despite suppression of plasma viral load, in order to see if the HS vitamin/micronutrient intervention can maintain weight and improve nutritional status.

PI: Gordon, Leslie
Title: The Progeria Research Foundation Cell and Tissue Bank
Abstract: PRF is the only organization dedicated to the rare disorder Hutchinson-Gilford Syndrome, a premature aging syndrome. Its mission includes initiating, accelerating and funding promising areas of research, which could provide information about the root causes, potential treatments and cure for Hutchinson-Gilford Syndrome, also often referred to as Progeria. Patients die prematurely of cardiovascular disease or stroke at an average age of thirteen years. The syndrome is very rare, with an incidence of approximately 1/8,000,000 live births. Hence, there is a severe lack of resources with which to conduct scientific research on HGPS. A potential consequence of our mission is the increased need for biological samples for research. We at PRF also want to protect affected individuals from being asked to donate to multiple research projects and from a loss of confidentiality when donating. By centralizing, coding, and making confidential the samples from affected individuals and their relatives, there will be a substantial asset for the initiation and support of research projects. In addition, many researchers could have access to samples they might not otherwise have the resources to collect. Molecular studies, mutation analysis, genotype/phenotype correlations and animal model research would all benefit from increased availability of cell lines and DNA samples.

PI: Greenblatt, David
Title: Chronic Benzodiazepines: Behavior and Neurochemistry
Abstract: Benzodiazepine agonists continue to be the principal pharmacologic option available for the treatment of anxiety, panic disorders, and insomnia. Despite an overall record of efficacy and safety that is generally favorable, concerns regarding tolerance, dependence, withdrawal syndromes, and abuse of benzodiazepines remain issues of medical and public health importance. Also of concern is the usage of these agents by the elderly, who may have increased susceptibility to adverse CNS depressant effects. There is continuing need for basic mechanistic data on the causes and consequences of tolerance and withdrawal; such data can form the basis for strategies to identify patients at highest risk, or to develop other pharmacologic interventions to minimize the risk of tolerance and dependence. We propose to continue and broaden our ongoing research program having this overall objective. The core of the model involves male CD-1 mice that receive continuous infusions of benzodiazepine agonists, or vehicle control, for up to 14 days via implanted osmotic pumps. During the period of infusion, and in the 7-day post-infusion withdrawal period, the following outcomes are determined: computerized ambulatory activity; pentylenetetrazole seizure threshold; in vivo benzodiazepine receptor occupancy; in vitro receptor binding; GABA(A) receptor function; receptor autoradiography; receptor subunit mRNA expression; and plasma and brain concentrations of infused substances. The principal research questions to be addressed include the following: a. Do benzodiazepine agonists with relative selectivity for the BZ1 receptor subtype have reduced liability to produce tolerance, dependence and withdrawal? b. Does the protein kinase C second messenger pathway have a modulatory role in benzodiazepine-associated tolerance? c. Does the excitatory amino acid (EAA) receptor system co-modulate the development of tolerance and withdrawal associated with benzodiazepine agonists, and does pharmacologic antagonism of specific EAA receptor systems modify these phenomena? d. Do aging organisms have differential patterns of benzodiazepine tolerance and withdrawal? Are such differences explained by protein kinase C or EAA regulatory systems? These studies should continue to provide mechanistic data relevant to the clinical management and prevention of tolerance and dependence problems associated with therapeutic use of benzodiazepine agonists.

PI: Griffiths, Jeffrey
Title: An Ecological Analysis of Cryptosporidium in Kenya
Abstract: This research will be done in Kenya as an extension of NIH grant 1 R01 AI 43415-01A1. The first and third specific aims of this parent grant, entitled "Waterborne Emerging Diarrheal Diseases Study (WEDDS)," have as their underlying goals the identification of any linkages between the ingestion of drinking Water and human cryptosporidiosis. The WEDDS study is being conducted in Massachusetts, where exposure to Cryptosporidium parvum (CP) is moderate compared to developing world environments. Cryptosporidium is an opportunistic pathogen in people with AIDS, and is very common in children. We propose to expand the sites, populations studied, and range of exposures to CP studied by the Parent grant, by replicating specific portions of the study in Greater Meru, Kenya. The site we have chosen is a complex ecosystem with significant human and game park animal interactions. Meru town is adjacent to Meru National Park, the third largest conservation area in Kenya, and Meru town and a number of rural villages share their water supply with the animals of the National Park. Recent studies have shown that humans can be infected with many genotypes of Cryptosporidium, including those from birds (C. meleagridis) and from cats (C. fells) as well as from humans and cattle ("genotypes 1 and 2") and other animals. Human volunteer information has shown that some C. parvum (e.g. the TAMU strain studied in Texas) is both highly virulent and infectious, whereas other strains are orders of magnitude less infectious. The Meru region offers an unusual opportunity to study the connection between human and animal sources of exposure, and to gain some insight into any differences in the severity of disease that may relate to these different genotypes. Our aims are: 1. Conduct a prospective clinical and molecular assessment of Cryptosporidium infecting humans in a region expected to have high exposure to multiple genotypes of Cryptosporidium via its water supply. 2. Isolate, and if possible characterize the genotypes of, Cryptosporidium in waters used by the human population, focusing on (1) Meru town, and (2) rural villages and pastoral areas in the region. 3. Via time-series and geographical information systems (GIS) statistical analysis, delineate the linkage between drinking water exposure and human disease over time.

PI: Griffiths, Jeffrey
Title: Vitamin A and Zinc: Prevention of Pneumonia (VAZPOP) Study
Abstract: The Vitamin A and Zinc - Prevention of Pneumonia (VAZPOP) Study. Linking Vitamin A and Zinc Deficiencies, Immunity, Growth, and the Prevention of the Leading Cause of Childhood Death. The objective is to delineate how vitamin A and zinc supplementation interact in improving immunity, fostering growth, and preventing infection, in populations at risk for malnutrition and vitamin A and zinc deficiency. Malnutrition is involved in half of the global deaths in children less than 5. Acute respiratory infection (ARI), especially acute lower respiratory infection (ALRI) or pneumonia, is the leading cause of death in children. The investigators propose to conduct a randomized, placebo controlled, double blind, nutritionally stratified study of low dose vitamin A, 10 mg/day elemental zinc, both, or placebo in 2,400 children in Quito Ecuador. They will test the hypotheses that: a) low-dose vitamin A has paradoxically positive and negative effects on ALRI in underweight and well nourished children; b) zinc will protect against ALRI and diarrhea while boosting cell mediated immunity; c) growth will be fostered by zinc (and potentially by vitamin A) in deficient children; and d) misclassification of ALRI cases can mask the benefits or risks of vitamin A. The investigators will use state-of- the-art field techniques to assess body composition and growth, and utilize sophisticated techniques to assess vitamin A and zinc deficiency. In addition, they will use rigorous definitions of ALRI/pneumoma to avoid misclassification and ascertainment bias, which may have affected prior studies.

PI: Hassoun, Soha
Title: Tools for Designing and Integrating Configurable Components
Abstract: To address the need of creating and utilizing low power configurable and adaptable components within a single System-On-Chip or within a distributed heterogeneous environment, this research proposes novel synthesis, evaluation, and integration tools of future configurable components. Key to our tools will be the use of an abstract configure-ability model that separates configuration capabilities from the underlying configurable implementation or architecture. Based on this model; the PI will develop design automation tools that will allow designers from different application domains to automatically craft their own configurable components and related compilation tools and integration interferes under their system design constraints. To assess the quality of the de- signs, the PI will investigate techniques to quickly estimate various metrics such as power, area, and performance. To truly investigate the architectural design space, the PI proposes tools for creating power-conscience ASIC reconfigurable components. In addition, the research will investigate tools to facilitate the design of distributed communication configurable components that would be suitable for future network technologies.
The educational plans of this CAREER proposal include integrating different aspects of system design into the Computer Engineering curriculum at Tufts University. In addition, the PI proposes a variety of activities for enhancing students' learning experiences. Finally, the PI outlines plans of developing valuable educational programs in CAD at the national level.

PI: Holcomb, Phillip
Title: Plausibility and Synatic Processing Load
Abstract: The focus of this study is the process that underlies sentence comprehension. Sentences convey information about how the meanings of words are related to one another --which entities are performing which actions, which entities are having which actions performed on them, what properties hold of which entities etc. This information, known as the "propositional content" of a sentence, is largely determined by the syntactic structure of the sentence. For instance, instance in the sentence The boy who chased the girl fell down, it is the boy, not the girl, who fell down, because the boy is the subject of fell, whereas the girl has no syntactic relation to fell.