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Funded Research Abstracts

PI: Ramsburg, Andrew
Title: Exploring the Mechanisms Controlling Emulsion-Based Alkalinity Release during Subsurface Remediation
Abstract: At present, there is considerable interest within the geoenvironmental community to harness coupled physical, chemical and biological processes for remediation and stewardship of contaminated sites. Many of these processes require control of pH during treatment and, in some cases, long after. The central hypothesis of this proposal is that carefully designed oil-in-water emulsions can be effective tools for modulating alkalinity release during remediation. Emulsions have been employed to sequester contaminants and deliver remedial amendments, but controlling amendment release, both the extent and rate, remains highly empirical. This empiricism restricts our ability to realize the full potential that oil-in-water emulsions hold for controlling release of amendments within complex systems of porous media. The proposed project integrates experiments and modeling to elucidate the mechanisms controlling alkalinity release from oil-in-water emulsions during subsurface remediation.

Project objectives are:

  • assess mechanisms controlling the stability of CaCO3 and NaO2 nanoparticles suspended within soybean oil;
  • create and optimize critically stabilized oil-in-water emulsions containing alkalinity release particles within a dispersed soybean oil phase;
  • elucidate the influence of soybean oil composition on the rate of alkalinity release;
  • analyze the ability of oil-in-water emulsions to deliver and release alkalinity for control of groundwater pH.

PI: Reijmers, Leon
Title: Molecular Analysis of Functional Neural Circuits
Abstract:
A functional neural circuit consists of a group of connected neurons that collaborate to execute a specific function of the brain. The understanding of the molecular mechanisms that underlie the development, maintenance and experience-dependent modification of functional neural circuits is incomplete due to limitations of existing methods. I propose to generate a transgenic mouse that addresses these limitations by exploiting two recent methodological advances. The first advance is the TetTag mouse, which is a transgenic mouse that can be used to genetically tag a single functional neural circuit. This tag enables the selective molecular analysis of neurons that have a shared function. This method is more sensitive to changes within a single functional neural circuit than other available methods, which have to rely on spatial criteria and thereby include neurons that do not participate in the circuit of interest.

The second advance is the Translating Ribosome Affinity Purification (TRAP) method, which enables purification of actively translated messenger RNA from a genetically defined group of neurons. TRAP analysis reflects changes at both the transcriptional and translational level, while other available methods only detect transcriptional changes. I will combine TetTag and TRAP within a single transgenic mouse to generate the first tool that enables the comprehensive analysis of all translational events within a single functional neural circuit. Neurons tagged with the TetTag mouse during fear conditioning provide a stable neural correlate of the fear memory. I will use the TetTag/TRAP mouse to purify actively translated messenger RNA from these tagged neurons in order to detect the protein synthesis events that underlie the storage of a memory. The TetTag/TRAP mouse can be used for the molecular analysis of various functional neural circuits, including those involved in memory, addiction, epilepsy, circadian rhythms, spinal cord regeneration, pain, brain development, and neuronal cell death.

PI: Reijmers, Leon
Title: Tools for Genome-Wide Profiling of mRNA Translated in In-vivo Dendrites
Abstract: The brain processes and stores information by constantly adjusting the strength of connections between its neurons. In order to adjust the strength of these connections, called synapses, the neurons have to synthesize new proteins. Proteins can be synthesized in the soma of the neuron and then travel through dendrites to reach the synapses. Alternatively, proteins can be synthesized within the dendrites close to the synapses. This dendritic protein synthesis provides a rapid and efficient way of modifying the strength of single synaptic connections. Dendritic protein synthesis is important for normal brain development and cognitive functions. When dendritic protein synthesis is impaired, for example in Fragile X Syndrome, it causes severe neurodevelopmental and cognitive deficits. Despite its importance, there is an incomplete understanding of dendritic protein synthesis. A major remaining question is: which proteins can be synthesized in dendrites? This project will test and apply novel tools that can answer this question. The tools allow for the selective isolation of ribosome-bound messenger RNA (mRNA) from in-vivo dendrites. Since ribosomes bind to mRNA in order to synthesize proteins through a process called mRNA translation, the ribosome-bound translated mRNA directly reflects which proteins are being synthesized. In order to completely characterize dendritic translated mRNA, this project will use next-generation sequencing in order to sequence each mRNA molecule within the sample (RNA-Seq). Knowing the sequence of each dendritic translated mRNA molecule not only answers the question which proteins can be synthesized in dendrites, but also provides insights into the specific protein isoforms that are synthesized. The sequence data generated by this project can also be used to discover RNA motifs that are shared by groups of dendritic mRNA. Some of these motifs could regulate the transport of mRNA into the dendrite or the translation of mRNA within the dendrite. The insights into dendritic protein synthesis generated by this project will aid the development of treatments for brain disorders associated with impaired dendritic protein synthesis.  

PI: Ridge, Jack
Title: Collaborative Research: P2C2—Synchronizing the North American Varve Chronology and the Greenland Ice Core Record Using Meteoric 10Be Flux
Abstract:
The North American Varve Chronology (NAVC) is a nearly 6000-year-long sequence of annual sediment layers that was deposited in glacial lakes adjacent to the margin of the Laurentide Ice Sheet, which covered much of North America during the last ice age. At the time these sediments were deposited, between approximately 12,500 and 18,000 years ago, climate was warming and the Laurentide Ice Sheet was shrinking rapidly. The sediments that make up the NAVC are an annually resolved record of events that took place at the retreating ice margin, including the position and retreat rate of the ice margin, the flux of water derived from summer melting of the ice sheet, and large glacial-lake outburst floods that occurred periodically as ice-marginal lakes drained.

The goal of this proposal is to understand the relationship of these events to climate changes that were occurring at the same time and are recorded in ice core records from Greenland, which is important because i) it will help to understand how large ice sheets responded to rapid climate warming, and ii) because this time period is a potential analog for the current period of rapid warming and likely shrinkage of glaciers and ice sheets. The obstacle to comparing the NAVC with Greenland climate records is that, although both records have been independently dated, the precision of these dates is a few hundred years, which is not precise enough to accurately determine which climate changes are related to which glacial events.

This project will try to resolve this issue by comparing records of atmospherically-produced Beryllium-10 in both NAVC sediments and Greenland ice cores. Be-10 is a naturally occurring rare isotope of Beryllium that is created by cosmic-ray bombardment of the upper atmosphere and falls to earth in precipitation. Be-10 production changes through time due to changes in the Earth's magnetic field, and these changes occur everywhere on Earth at the same time. Be-10 is captured and preserved in sedimentary archives such as ice cores and lake sediments. Thus, Be-10 concentrations in the Greenland ice cores and in the NAVC lake sediments should show the same pattern of changes. By aligning these changes with each other, we can place the two records on a common timescale. Thus, even if we do not know the exact time that a particular climate change recorded in the Greenland ice cores took place, we will know exactly what ice-marginal events recorded in NAVC sediments were occurring at that time. We anticipate that we will be able to match these two records with a precision of several decades, which should be precise enough to determine the relationship between important climate changes and ice sheet change.

Mentor: Rife, Jason
Fellow: Kline, Amy
Title: Draper Lab Fellowship
Abstract:
The goal of the proposed research project is to develop new guidance, modeling and sensing technologies for unoccupied underwater vehicles (UUVs).

Mentor: Rife, Jason
Fellow: Alexander, Elizabeth
Title: Draper Lab Fellowship
Abstract:
The goal of the proposed research project is to develop models for a novel magnetometry device, a Heterogeneous Uncooled Magnetic Sensor (HUMS). This device is relatively inexpensive to manufacture and is much more sensitive than competing technologies, such as Superconducting Quantum Interference Devices (SQUIDs). Models will be used to assess the value of HUMS technology for several potential applications, such as magnetic imaging of the human brain.

PI: Rife, Jason
Title: Limit Cycle Control for Soft, Caterpillar-Inspired Robots
Abstract: The long-term goal of this work is to develop transformative technologies for the actuation and control of mobile, soft robots in challenging field applications, such as disaster relief. This project is an innovative, feedback-based solution for enhancing soft-robot mobility. This solution is inspired by the caterpillar Manduca sexta, a remarkable, multi-segmented invertebrate that crawls, climbs and burrows in many terrains. Our approach is aimed at controlling the caterpillar-like, periodic movements of a fluid-filled soft robot, in which the robot's deformable structure makes it difficult to sense or model body configuration on-the-fly.

The research has two specific research aims. Aim 1 will formulate a control design method for generating caterpillar-like gaits by exciting sustained oscillations (e.g., limit cycles) within a deformable, fluid-filled system. Aim 2 will quantify the in vivo kinematics of burrowing caterpillars to identify how they adapt their gait in response to rich patterns of tactile stimuli. New educational opportunities will be developed to foster interdisciplinary controls teaching for engineering and biology students.

PI: Rife, Jason
Title: Risk Analysis to Enhance GBAS Performance for NextGen Applications
Abstract:
As a first topic of investigation, we will study the impact of time-correlated noise on the GBAS Signal Deformation Monitor (SDM). In particular, we will investigate the impact of time-correlated errors on the integrity and continuity of this monitor. Our investigation will build on our prior research results, in which we demonstrated that traditional mechanisms for calculating continuity risk do not necessarily apply to the specific continuity risk requirements for GAST-D. Our research will result in the development of simulation tools to quantify whether the current SDM thresholds and Pmd analyses are consistent with the time correlation characteristics of actual SDM data.

As a second topic of investigation, we will study the impact of Excessive Acceleration (EA) faults on GBAS-enabled surface movement. Because of limited VHF Data Broadcast (VDB) coverage for surface movement, some taxiing aircraft may experience extended outages, as long as 10 seconds without receiving an updated set of differential corrections. Such extended outages can result in larger EA errors for surface movement than for precision approach. Hence, new methods are needed to ensure integrity for surface movement. To this end, we will propose two alternative algorithms aimed to reduce the impact of EA faults on DCPS-enabled surface movement. The first algorithm will be designed for implementation at the GBAS ground facility, the second for implementation in user avionics.

PI: Rios, Maribel
Title: BDNF and TrkB-Containing Neuronal Circuits Mediating Energy Balance
Abstract: Close to a third of the population in the United States is obese and over 60% is overweight. This is an alarming trend as obesity significantly increases susceptibility to type 2 diabetes, cardiovascular disease and other medical disorders. Mounting evidence indicates that the brain-derived neurotrophic factor (BDNF)/TrkB pathway plays a critical part in energy balance regulation and is a promising target for novel therapies. Accordingly, reduced BDNF signaling in mice and humans results in hyperphagic behavior and dramatic obesity. It remained unclear whether BDNF, which supports neuronal survival, differentiation and synaptic plasticity, acted as a required satiety factor in the adult brain or as a developmental facilitator of feeding neural circuits. As part of the previously funded project, we showed that BDNF acts in the adult animal to promote satiety and that the ventromedial hypothalamus (VMH) is a critical source of this neurotrophin. Supportive evidence includes the robust effects of energy status on expression of BDNF and TrkB in the VMH and the hyperphagia and obesity elicited by selectively deleting BDNF in the VMH of adult mice. The cellular and molecular mechanisms underlying the anorexigenic effects of BDNF in the VMH remain to be elucidated.

Our recent analysis of the transcriptome of cells laser-captured from the VMH of mice with central (BDNF2L/2LCk-cre) or VMH-specific depletion of BDNF revealed decreased expression of α2δ-1 and of two other genes associated with obesity susceptibility in a recent large-scale human study. Our preliminary studies show that BDNF's anorexigenic effects are mediated by α2δ-1, a high voltage-gated calcium channel subunit that enhances calcium currents and mediates excitatory synaptogenesis. We found that: i) selective α2δ-1 inhibition by chronic gabapentin infusion into wild type VMH increased food intake and body weight and ii) viral-mediated α2δ-1 delivery to the VMH of BDNF2L/2LCk-cre mutants ameliorated their hyperphagia and body weight gain.

This competitive renewal proposal seeks to build on these findings by ascertaining cellular mechanisms underlying the effects of BDNF and α2δ-1. Because calcium currents in VMH cells of BDNF mutants are normal, the satiety effects of α2δ-1 might be related to its ability to induce excitatory synaptogenesis in a calcium-independent manner. Thus, Aim 1 will investigate the role of BDNF and α2δ-1 in dynamic changes in VMH excitatory drive onto anorexigenic POMC neurons induced by nutritional cues using anatomical and electrophysiological approaches. In Aim 2, we will investigate whether BDNF and α2δ-1 also regulate excitatory drive onto anorexigenic VMH neurons. In Aim 3, we will test whether the reduced expression of two other gene candidates in the BDNF mutant VMH contributes to the emergence of hyperphagic behavior and obesity and whether they act in common pathways with α2δ-1in the VMH. These studies will provide a mechanistic understanding of anorexigenic actions of BDNF and reveal novel avenues for the treatment of obesity.

PI: Rogers, Chris
Title: Changing the Classroom: Building Student-Led Learning
Abstract:
Schools from kindergarten to college are talking about increasing the "technology in the classroom,'' implying that we need more projection systems, smart boards, and tablets. We propose the opposite; the technology “in the classroom” should redefine the idea of a classroom -supplying students with an environment to take risks, to collaborate with students of different expertise, and to give them a chance to drive their own learning. In our eyes, success in this new type of classroom is measured by the diversity of student solutions to the problem, rather than all students aiming for the one “right answer.” The work of Ron Berger (2003) and others demonstrates how students respond well to moving beyond “the test” to projects that do not have predefined right answers and that have some relevance to the students’ lives. In such cases, they found that the students performed well above expectation, were excited and motivated to learn, retained the information they learned, and were able to apply their knowledge to new situations.

So we propose to develop a balance between the conventional classroom, and this new, open ended style classroom for Tufts students. We will do this by growing our existing BotLAB, a robotics fabrication facility, both laterally by including more variation in student expertise, and vertically by bringing in expertise in product commercialization. In order to do this, we will collaborate with the Tufts Entrepreneurship Program (Hodgman and Liggero), Clarity Consulting (Frost) and the Tufts music department (Lehrman), child development department (Bers), human factors program (Hannon), computer science (Danahy), and engineering (Rogers and White).

Our goal is to use this proposal as a springboard to build the required collaborations and physical infrastructure within the university to result in student-led invention and commercialization. We will leverage two existing cross-disciplinary programs at Tufts in music instrument engineering and in educational product development to increase the diversity of student expertise. Building off of the existing infrastructure of the entrepreneurial leadership program and the BotLAB, we hope to demonstrate success within 3 years.

We will measure success by tracking:

  1. The number of student-led spin-off companies (and licensed intellectual property),
  2. Student involvement (numbers of students) and student team diversity (in expertise, race, and gender), and
  3. Alumni involvement through mentorship roles.

Our goal is to involve over 200 students from 10 different disciplines by the end of the 3 years. We hope to see at least 5 alumni actively involved and at least one student-led company started in this time period as well.

PI: Rogers, Chris
Title: Integrating Engineering and Literacy
Abstract:
The Integrating Engineering and Literacy (IEL) project is developing and testing curriculum materials and a professional development model designed to explore the potential for introducing engineering concepts in grades 3-5 through design challenges based on stories in popular children's literature. The project research and development team at Tufts University is working with pre-service teachers to design and test the curriculum modules for students and the teacher professional development model. Then the program is tested and refined in work with 100 in-service teachers and their students in a diverse set of Massachusetts schools. The research team hypothesizes that professional development for elementary teachers using an interdisciplinary method for combining literature with engineering design challenges will increase the implementation of engineering in 3-5 classrooms and have positive impacts on students.

The driving questions behind this proposed research are:

  1. How do teachers' engineering (and STEM) content knowledge, pedagogical content knowledge, and perceptions or attitudes toward engineering influence their classroom teaching of engineering through literacy?
  2. Do teachers create their own personal conceptions of the engineering design process, and what do these conceptions look like?
  3. What engineering/reading thinking skills are students developing by participating in engineering activities integrated into their reading and writing work?

The curriculum materials and teacher professional development model are being produced by a design research strategy that uses cycles of develop/test/refine work. The effects of the program are being evaluated by a variety of measures of student and teacher learning and practice.

The project will contribute materials and research findings to the ultimate goal of understanding how to provide elementary school students with meaningful opportunities to learn engineering and develop valuable problem solving and thinking skills.

PI: Rogers, Chris
Title: LEGO Engineering in NC
Abstract:
There are two main goals to the proposed work: (1) to help build a model K-5 Robotics/LEGO Engineering school at A.B. Combs and through that, (2) to better understand and document how a school goes through a system-wide change.

We have a unique opportunity to document how a highly successful school changes as engineering and robotics become part of every classroom and every child's education. Although it will be prohibitively expensive to lead a comprehensive research effort, we propose to investigate what catalyzes a teacher to bring open-ended problem solving into the classroom and go from being an expert to more of a coach and mentor. At the same time, we propose to use the Combs school to develop a gallery of activities and video snippets showing these activities in action.

Mentor: Romero, Michael
Fellow: Bauer, Carolyn
Title: Dissertation Research: Maternal Effects of Stress in a Plural-Breeding Rodent
Abstract:
The quality of parental care influences offspring fitness. In domesticated laboratory rodents, pups that have chronically stressed mothers receive low quality care, leading pups to develop highly reactive stress responses. Affected pups will have high stress hormone levels as adults, which can have severe consequences on their future survival and reproductive output. This research examines the relationship between stressed mothers, poor maternal care, and the offspring stress response and survival in the degu (Octodon degus), a wild, free-living rodent. Degus practice a unique reproductive tactic called "plural breeding with communal care" where multiple mothers cooperate to raise each other's pups. This research also will ask whether this unique social strategy can buffer the offspring against post-natal stress. By manipulating the stress levels of mothers and measuring stress hormone levels in pups in both field and laboratory experiments, this research will provide a comprehensive description of the links between stress, development, and, ultimately, survival. This link has never been demonstrated in a wild, free-living rodent. This research will have broader impacts because it will address the link between parental care and offspring survival, which is a major unsolved problem in ecology and stress physiology.

Mentor: Romero, Michael
Fellow: Lattin, Christine
Title: Evaluating the Stress Response of Wild Birds as a Bioindicator of Sub-Lethal Acute and Chronic Effects of Crude Oil Exposure
Abstract: One of the most important yet least understood of oil's biological impacts is on the stress response. Studies show petroleum can interact in an additive fashion with other stressors to cause increased mortality, but it is not clear exactly why – does petroleum change stress hormone receptor concentrations in the brain or peripheral tissues, does it disrupt feedback mechanisms or stress hormone production, or both? This study uses both lab and field components to systematically quantify the effects of Gulf of Mexico crude oil on the stress response and stress hormone receptors of wild birds. This will allow an evaluation of whether these physiological measures can be used as bioindicators of sub-lethal acute and chronic effects of crude oil exposure. Potentially this could allow us not only to identify exposure in wild shorebirds from contaminated areas, but also in humans.

PI: Romero, Michael
Title: Physiology and Behavior of Stress in Wild Animals
Abstract: All organisms are faced with challenges (such as predators or storms) from the environment. Animals mount a stress response in order to survive these challenges, but even after nearly 100 years of studying stress, there is only a basic understanding of how the stress response helps wild animals to survive. This lack of knowledge is of growing significance because man-made noxious events (such as habitat degradation or human disturbance) could cause chronic stress. Although a short-term stress response to a predator or storm is necessary for survival, chronic stress can be very harmful, and if it affects enough individuals, can cause population declines.

This project will use wild European starlings as a model to test two hypotheses: (1) That increased frequency of normal environmental events can result in chronic stress in wild animals; and (2) There will be long-term impacts on offspring whose mothers were exposed to chronic stress. Testing these hypotheses will require an integrated approach of laboratory and field studies on the physiology and behavior of both captive and free-living starlings. The ultimate goal is to create a physiological and endocrinological profile of chronically stressed wild animals. This will provide criteria for identifying chronically stressed individuals in the wild and determining the long-term impact on those individuals and their offspring.

PI: Rothbaum, Fred
Title: Child and Family WebGuide (Minnesota)
Abstract: The Child and Family WebGuide is a non-profit project coordinated by Fred Rothbaum, a Professor in the Eliot Pearson Department of Child Development at Tufts University. It is supported by the Child Development Department and the University. The goal of the WebGuide is to help parents, professionals, students and others interested in child development find trustworthy, research-based information about infants, children adolescents, and their families and communities. The WebGuide addresses one of the major concerns of the internet: how to obtain credible, research-based information. For example, when searching on the internet for the topic of spanking children, a user would instead find sites relating to personal opinion, pornography, and religious organizations. The WebGuide selects only those sites and videos that provide non-technical, user-friendly, research-based information. The information addresses specific medical conditions and treatments as well a broad range of child development information such as obesity, self-esteem, discipline, anxiety and sibling relationships. All sites and videos have undergone a rigorous evaluation process by graduate students who are supervised by faculty in Child Development. The evaluations are based on criteria that have been recommended by a panel of scholars and research practitioners as well as findings from focus groups and interviews with parents. Both modes of research indicated the need for credible and non-technical information, criteria that the WebGuide relies upon in selecting sites and videos. As a result of its Google powered search tool, the WebGuide can help visitors instantly find the specific information about children that they need.

PI: Rouhana, Nadim
Title: Religion, Nationalism and Human Suffering
Abstract:
Mainstream discourses across the globe often invoke religion as a major reason for the Israeli-Palestinian conflict. Religious differences between Muslims and Jews consistently find their way into populist explanations of the conflict's development and continuation. Inside Israel-Palestine, however, mainstream perceptions are counter if not antithetical to global understandings. For the majority of Israelis and Palestinians, the conflict is seen as fundamentally secular in nature, and rooted in competing national claims to self-determination in the same territory. Despite this, nevertheless, it is the case that we are witnessing an increasing creeping of religious claims into local understandings of the Israel-Palestinian conflict, and particularly into its nationalist dimensions. This creeping of religious claims into nationalist claims (and their potential future fusion) is a worrying dynamic for two, inter-related reasons. Firstly, it is apparent that should religious claims become fused to nationalism, the potential for increased future human suffering on both sides is exacerbated because the conflict will become more intense. Secondly, if religious claims and nationalism were to become fused in the Israeli-Palestinian conflict, then it is arguable that a possible resolution to the conflict becomes even more intractable.

To address this problem, the Fletcher School of Law and Diplomacy at Tufts University (in collaboration with Mada al-Carmel Arab Center for Applied Social Research in Haifa, Israel) proposes a three-year collaborative research program to better understand this trend and provide policy recommendations. There are three over-arching objectives of the research program. First, we aim to understand the role played by religion in the Israeli-Palestinian conflict, and in particular the forces driving a possible fusion between the religious and the national. Second, in order to better understand the possible fusion between religion and nationalism in Israel-Palestine and its potential consequences for the conflict, we aim to comparatively examine the intertwining of the religious and the national in other conflicts: namely, Sri Lanka, India, former Yugoslavia, and South Africa. Third, based on these findings, we will make policy recommendations for conflict resolution in Israel-Palestine, focusing in particular on negotiating and counteracting the potential fusion between religion and nationalism. The project will engage twelve scholars from Israel, Palestine and international locations, and will incorporate two international conferences and probe the development of a policy "think-tank" as a follow up to this project.

PI: Rozanski, Elizabeth
Title: Bloat Webinar: Advances in Prevention and Treatment
Abstract:
The goal of this project is to highlight recent developments in the prevention and treatment of bloat (Gastric dilatation-volvulus/GDV). Specifically, 30 minutes will be devoted to a review of relevant research and developments surrounding bloat and a single case of a dog with Bloat will be followed from admission and stabilization, surgical correction and recovery in the intensive care unit. Finally, a demonstration of two methods of surgical preventive approaches will be shown, including an open incisional gastropexy and a laproscopic-assisted gastropexy.

The specific goal of this project is educational, with the goal of educating the dog owner of an at-risk dog breed about this devastating condition. The secondary goal is to provide education to the veterinary clinician about surgical techniques to treat the dog with bloat as well as methods to prevent this life threatening disease.

This webinar plans to update and education dog owners and veterinarians on bloat. Discussion of preventative techniques that may be accomplished in clinical practice has tremendous opportunity to improve clinical practice, and to attempt to improve preventative measures. Bloat is a disease of high priority in many large breed dogs.

PI: Rozanski, Elizabeth
Title: Multiple Organ Dysfunction in Gastric Dilatation Volvulus (GDV); The Role of Cardiac Dysfunction and Coagulopathy
Abstract:

Hypothesis:

  1. Multiple organ dysfunction syndrome (MODS), including cardiac dysfunction and coagulopathy, is responsible for the death of dogs that do not survive an episode of GDV. A scoring strategy for dogs with GDV may be created and will be useful for stratifying affected dogs, as well as providing a springboard for future studies.

  2. Cardiac injury, as assessed by elevated cardiac troponin I (cTnI), and myocardial dysfunction, as assessed by echocardiography, blood pressure measurement, electrocardiography (ECG) and increased N-terminal B type natriuretic peptide (NT-proBNP) will be more common in non-survivors than survivors of GDV.

  3. Hypercoagulability at hospital presentation, as assessed by thromboelastography (TEG), will accurately predict the impending development of disseminated intravascular coagulation (DIC) and will be more common in non-survivors and in dogs with cardiac injury or myocardial dysfunction.

 Objectives:

  1. To retrospectively review the medical records of 200 cases of canine GDV seen at the Foster Hospital for Small Animals at Tufts University for determine of the prevalence of MODS and to create a scoring strategy (Functional Assessment of Bloat; FAB) for GDV.

  2. To determine the prevalence of cardiac injury and myocardial dysfunction in dogs with GDV by measurement of cTnI and a combination of echocardiography, ECG and NT-proBNP respectively.

  3. Documentation of the initial TEG in dogs with GDV and determination of the subsequent incidence of consumptive coagulopathy, as assessed by serial TEG and AT activity.

 PI: Rozanski, Elizabeth
Title: The Efficacy of Bosentan, a Mixed ETa ETb Receptor Antagonist, in Cats with Arterial Thromboembolism
Abstract: Heart disease (hypertrophic cardiomyopathy) is very common in cats and one of the most devastating complications of heart disease in cats is development of blood clots cutting off the blood supply to one or more limbs; termed feline aortic thromboembolism or ATE. Most cats that develop this complication have no known history of heart disease. ATE is associated with a survival rate of < 40% despite multiple efforts to try to improved outcome including clot dissolution with IV clot-busting drug, or clot removal with catheter-based methodology. However, no intervention to date has been a significant improvement over conservative (medical therapy). It is important to cats and their owners to be able to offer an intervention that improves survival with a good quality of life.

Cats are recognized to have "reactive" blood vessels, and this response may worsen the outcome as the vessels in cats suffering from ATE will release various chemicals, including one called endothelin (ET). Endothelin causes an increased tendency to form more clots, and promotes severe inflammation and narrowing (vasospasm) of collateral vessels supplying areas behind the site of the clot.

Bosentan is a drug used successfully in people to treat various diseases such as coronary artery disease, pulmonary hypertension and limb ischemia which are results of narrowing or blocking of blood vessels by either cell growth or blood clots. This study looks to determine the effectiveness of Bosentan in the treatment of cats with ATE.

PI: Ruskai, Mary Beth
Title: Quantum Information Theory
Abstract:
It was recently proved that there are situations in which the quantum phenomenon called entanglement can increase the capacity of a quantum channel used to transmit classical information. Such channels are called non-additive; however, no explicit examples are known. Even more recently, it was observed that the anti-symmetry associated with the Pauli exclusion principle can be used to give an example of a channel which is non-additive for a related quantity, called the minimal output Renyi entropy, when ρ > 2. This grant is intended to construct more examples of non-additive channels and clarify our understanding of this phenomenon. In connection with this, the PI will closely examine the role of permutational symmetry in quantum information theory. The PI will also study entropy inequalities and cones of entropy vectors for composite systems.

This highly interdisciplinary work will clarify the role of the Pauli exclusion principle, which is often suppressed in quantum information theory. It will also be of interest to quantum chemists and condensed matter physicists, particularly those who used reduced density matrices. The work should help identify situations in which quantum systems have advantages over classical ones for communication, as well as computation.

PI: Rutberg, Allen
Title: Crossing the Line: A Study of Bureau of Land Management Wild Horses Transitioning into Companion Horses
Abstract: Since the establishment of the Bureau of Land Management's (BLM) Adopt a Wild Horse or Burro Program in 1971, approximately 190,000 wild horses have been adopted by the public. However, beginning in 2000, the number of adoptions has not kept pace with the rate of removal. As a result, about 35,000 wild horses have ended up in BLM short- and long-term holding facilities, waiting to be adopted. The Unwanted Horse Coalition counts these horses as a significant proportion of the unwanted horse population. Some 2,000 horses are housed in Cañon City, CO, the location of the BLM's largest wild horse and burro holding facility and one of five Wild Horse Inmate Programs (WHIP). Since its creation in the mid 1980s, the WHIP in Cañon City has adopted out more than 5,000 gentled and trained horses or burros.

In recent years, both the United States Government Accountability Office and the proposed Restore Our American Mustang Act have made recommendations to the BLM for considerable changes in its adoption program to decrease the number of horses in holding facilities. Unfortunately, there is almost no research exploring the transition of wild horses to companion horses, and effective initiatives cannot be developed and implemented without more information about the factors that support or impede successful wild horse adoption. Our study will fill that gap.

PI: Rutberg, Allen
Title: Crossing the Line: Transitioning from Wild Horse to Companion Horse
Abstract: Between 1971 and 2009, the U.S. Bureau of Land Management (BLM) adopted out nearly 190,000 wild horses that were removed from public lands through its Adopt a Wild Horse or Burro Program. Although adoption mostly kept pace with removal in the early years of the program, in more recent years, the number of adoptions has decreased dramatically. The result, as of January 2011, is that approximately 35,000 horses are being kept in short- and long-term BLM holding facilities, raising both financial and welfare concerns. The inability of the BLM to adopt out wild horses as quickly as they are removed, and recurring reports that many wild horse adoptions fail, suggests that a better understanding of the adoption program is warranted. Unfortunately, little research has examined the transition of wild horses to companion horses. Using primarily in-depth interviews, this exploratory study will follow adopters of wild horses from two different geographical regions during their first year of adoption, a crucial time in determining adoption success/failure. The proposed study has the potential to improve the rate and success of adoptions by informing and educating those involved with wild horse adoption—the BLM, state equine welfare organization, adopters, and wild horse advocates. This study will also inform future research on wild horse adoption, including a longitudinal study or a more comprehensive study of regional challenges faced by wild horse adopters.

PI: Sacheck, Jennifer
Title: Impact of Vitamin D Supplementation on Cardiometabolic Risk in School Children
Abstract: Vitamin D deficiency has been linked to the development of cardiovascular disease and it is estimated that six million children are currently vitamin D deficient. As it is difficult for many children to consume the new recommended intake of 400 IU/d set forth by the American Academy of Pediatrics, many have suggested that vitamin D supplementation is necessary. Vitamin D deficiency is even more common in northern latitudes, amongst some minority groups with darker skin pigmentation, and in those who are overweight or obese. In these groups, higher supplemental doses may be needed to maintain optimal serum levels and to prevent cardiovascular risk. The overall objective of the proposed work is to determine the appropriate vitamin D supplementation requirements for children living at northern latitudes (above 42°) to maintain optimal serum levels of 25-hydroxyvitamin D [25(OH)D] and minimize cardiometabolic risk. We will also investigate for the first time in a randomized controlled trial what happens to serum 25(OH)D and cardiometabolic risk factors after supplementation is discontinued. Fourth-eight grade children from socioeconomically disadvantaged and racially diverse communities with high obesity rates in the northeastern U.S. will be randomized to 400 IU, 1000 IU, or 2000 IU/d for six months starting in the early winter. Serum 25(OH)D and cardiometabolic risk factors (blood lipids and glucose) will be measured at baseline prior to supplementation, at 3- and 6-months, and then again 6 months following the discontinuation of supplementation. Adiposity, physical activity, dietary intake of vitamin D, and sun exposure will also be assessed at these times. Results of this work will inform the development of evidence-based recommendations and guidelines regarding vitamin D supplementation to maintain optimal 25(OH)D levels and to reduce cardiometabolic risk. If vitamin D repletion has the potential to improve the cardiometabolic risk profile during childhood, then we will ultimately be able to lower a child's risk of developing cardiovascular disease in adulthood. 

PI: Sassaroli, Angelo
Title: Functional Near-Infrared Imaging Using the Phase of Hemodynamic Oscillations
Abstract: This project explores the potential of a novel approach to functional studies of the brain with near-infrared spectroscopy. We hypothesize that the phase relationship between oscillations of cerebral oxy-hemoglobin and deoxy-hemoglobin concentrations provides information about (1) the interplay of hemodynamic and oxygenation-related processes that are associated with brain activation, and (2) functional connectivity networks involving distinct cortical areas. Specifically, in this project we will perform a new analysis of data collected previously in a full-night sleep study using a novel phasor-based analysis and representation of hemodynamic oscillations. This new analysis will allow us to test the hypothesis that hemodynamic conditions associated with different sleep stages induce different phase relationship between spontaneous oscillations of oxy-hemoglobin and deoxy-hemoglobin concentrations at frequencies around 0.1 Hz (Mayer waves). We will also test the hypothesis that oxy-hemoglobin and deoxy-hemoglobin concentration changes have different relative phases depending on the cortical area activated and/or the stimulation protocol. Finally, we will perform pilot measurements to test the potential of this new phase-based method in studying functional connectivity networks in the brain. This project can lead to a novel approach to functional brain studies and explores signals that are not accessible with functional magnetic resonance imaging, involving both paramagnetic and diamagnetic hemoglobin species.

PI: Sauer, Anne
Title: Planning Approaches to Linked Archival Metadata (LiAM)
Abstract:
Despite the standardization and automation of archival description since the 1990s-primarily through the development and wide adoption of Encoded Archival Description (EAD)-archivists still struggle with the challenge of describing complex archival collections. In particular, most archival finding aids are not well suited for describing records produced by complex organizations or electronic records and digital objects created and managed in digital environments such as databases and social network sites. We believe the nature of the problem, however, describes the solution. The distributed and dynamic nature of contemporary archival materials mirrors the evolving network of documents that is the World Wide Web. With this in mind, the Digital Collections and Archives at Tufts University (DCA) is applying for a National Leadership Planning Grant to use the tools of linked data and the web to design a new approach to archival metadata that the archives community could implement.

PI: Schaffhausen, Brian
Title: Products of the Transforming Genes of Polyomavirus
Abstract: Polyomavirus middle T (MT) is responsible for murine polyomavirus (PyV) tumorigenesis. Otherwise wild type viruses that have mutant MT fail to induce tumors. Transgenic MT causes tumors in many tissues, providing valuable models for diseases such as breast cancer. Studies of MT led to the discovery of phosphoinositide 3-kinase (PI3K) and protein tyrosine phosphorylation. Much evidence suggests that continued study of MT will yield new insights into neoplastic transformation and tumorigenesis. Our central hypothesis is that MT promotes transformation by the modulation of specific steps in cell signaling that affect not only the tumor cell itself, but also associated stromal cells, to support tumor progression. 

We will focus on three areas where MT studies can offer novel insight into neoplastic transformation:

  1. Protein phosphatase 2A (PP2A): The role we have uncovered for the Aβ isoform of PP2A in activation of c-src by MT points to the importance of specific isoforms. We will examine the role of both A subunit isoforms of PP2A and loss of specific trimeric ABC complexes of PP2A in MT transformation. We have evidence for a new model whereby MT brings substrates to PP2A for dephosphorylation. The lipins, which are both enzymes of the lysophosphatidic acid (LPA) metabolism and also transcriptional coactivators, are examples of such substrates that point to novel PP2A-dependent signaling in transformation. We will test their role in transformation. Guided by a mutant defective in lipin binding, we will also use mass spectrometry of mutant and wild type (WT) MT to uncover additional substrates.

  2. PI3K: MT mutant E349K shows that there is a step, so far unappreciated, between PI3K recruitment to activated tyrosine kinases and signaling to activate downstream targets such as Akt. The nature of the defect will be determined in studies of PI lipids and protein localization. Using mass spectrometry comparing E349K to WT, we will seek to identify the cellular protein(s) responsible. Identification of a new intermediate in PI3K signaling would be paradigm shifting and offer new possibilities for therapeutic intervention.

  3. Cytokines: Although cytokine expression is well recognized to be an important part of tumorigenesis, little progress has been made in understanding the signals that control the patterns of cytokine expression. More importantly, the idea that cancer signaling alters responses to cytokines is largely unexplored.

Our evidence shows that MT both induces cytokine expression and at the same time alters the response of tumor cells to cytokines. We will determine the spectrum of effects on cytokine expression and response that MT has both in tumor cells and on stromal cells by gene array and protein analysis. Using genetic tools we will investigate the mechanisms MT uses to do this and carry out novel tests of how the genetic background of the host modulates responses. Finally, we will ask how these effects determine macrophage recruitment in vitro and tumorigenesis in vivo studies. Our work will thus close gaps in our knowledge of cytokines and determine their contribution to MT mammary tumorigenesis. 

PI: Scheutz, Matthias
Title: HCC: Large: Collaborative Research: Human-Robot Dialog for Collaborative Navigation Tasks
Abstract:
For humans and intelligent robots to collaborate on shared tasks, each agent must bring something useful to the partnership. In particular, the robot must have sufficiently rich knowledge of the domain to understand the requirements of the task, and that knowledge must be represented in a form that supports effective communication between the human and the robot.

We propose to address this problem, building on the Hybrid Spatial Semantic Hierarchy (HSSH), a human-inspired multi-ontology representation for knowledge of navigational space implemented on physical robots, and on our extensive experience in human-robot interaction (HRI). The domain of navigational space is distinctive because it is one of the few domains where the knowledge is sufficiently well understood for a physically embodied robot agent to be a useful collaborator, meeting genuine human needs.

The HSSH represents space within four different ontologies, representing different levels of abstraction of the spatial structure of the environment. The level represents local metrical knowledge of small-scale space (i.e., space within the sensory horizon of the agent), supporting efficient motion in the continuous environment, hazard detection and avoidance, and communication of local motion targets. The level abstracts continuous motion to discrete travel actions among decision points, the description of each decision point in terms of a small discrete set of choices for the next travel action, and supports communication like "Take the next left, and then the second right." The level represents environmental structure in terms of a graph of places, paths, and regions, and supports communication in terms of travel goals within the map. The level describes the environment in terms of locations within a single global frame of reference. This level of representation is useful to human navigators in the form of auxiliary cognitive aids, but it is neither necessary nor sufficient as part of the natural human cognitive map. These multiple levels make it possible to learn a sophisticated cognitive map by incremental assimilation of local travel experience. They also provide distinct representational targets for different types of communication acts.

Our project focuses on the basic issues of representation, inference, communication, and action in collaboration between a human and an intelligent robot, serving the needs of the human. To ensure generality, we will carry out this research with two different kinds of navigational robots. An intelligent robotic wheelchair carries the human driver to desired destinations. A telepresence robot transmits its perceptions to a remote human driver as it navigates within an environment, so the driver can achieve virtual presence and communicate with others within the environment. In both cases, the robot is an intelligent agent, learning from its travel experiences and building an increasingly sophisticated cognitive map. As the robot's cognitive map improves, the human can communicate with it at higher levels of abstraction.

PI: Scheutz, Matthias
Title: Toward an Integrated Cognitive Computational Architecture for Situated Natural Language Understanding and Reasoning
Abstract:
We propose to develop a novel probabilistic framework for situated natural language understanding and reasoning that integrates perceptual, task-based, goal-based and other pragmatic information in addition to lexical, syntactic, and semantic information in the construction of meaning. The theoretical probabilistic framework will be based on experimental results from psycholinguistic experiments about human ways of incremental information integration and inference as part of natural dialogues and will be able to handle situations with limited information about prior and joint distributions. Within this framework, we will develop novel incremental algorithms for parsing, semantic analysis and inference to deal with underspecified, fragmentary, and incomplete information. The effectiveness of the complete implemented architecture will be evaluated in human-robot interaction experiments using objective and subjective performance measures. The project will make significant contributions to computing in natural language in three ways:

  1. It will develop a novel theoretical framework of multi-level incremental information processing that will facilitate algorithm and architecture integration and thus the design of complete functional situated embodied intelligent agents;

  2. It will provide novel hybrid logical/probabilistic algorithms for incremental situated natural language understanding that will allow for unprecedented natural language interactions of intelligent agents with humans in natural environments; and

  3. It will provide a novel implemented cognitive computational architecture that will be evaluated in human subject experiments.

Specifically, we will utilize the strengths of statistical approaches to multi-modal information processing and integration, in particular, the Dempster-Shafer (DS) theory of evidence, to develop novel algorithms that will allow robots to interact with humans at unprecedented levels of naturalness. We will demonstrate the effectiveness and naturalness of our algorithms by implementing and evaluating them on a robotic system in human-robot interaction (HRI) experiments using subjective and objective performance measures. And while we will restrict logical forms in the semantic analysis to capture instructions so as to make the implementation and evaluation feasible within four years, the proposed DS-based framework together with all developed algorithms will be general enough to handle a large set of natural language interactions.

PI: Schwob, James
Title: Anatomical Bases of Human Olfactory Dysfunction
Abstract: Improvements in diagnosis and treatment of olfactory disease will require first, a more comprehensive analysis of the anatomical status of the olfactory periphery (the 1 cm2 areas on the nasal septum and the lateral nasal wall immediately inferior to the cribriform plate) with respect to the preservation of the olfactory epithelium (OE) and, second, a means of determining whether the OE's inherent capacity to reconstitute itself remains intact. We propose three specific aims designed to address our shortcomings with respect to the pathological bases of peripheral olfactory dysfunction. Aim 1: We observe a better than expected preservation of OE in the olfactory area of autopsy specimens, but immature neurons are abnormally prominent. We will test the hypothesis that areas in which immature neurons predominate are disconnected from the OB by using immunohistochemical analysis and DiI/DiO tracing of axons. Aim 2: The intermingling of OE and RE in the olfactory area and the occurrence of quiescent, aneuronal OE indicate that dysfunction of olfactory stem cells and progenitor cells contributes to peripheral olfactory pathology. Guided by our studies of the molecular profile of stem and progenitor cells in mouse and rat OE, we will identify markers for identifying neurocompetent stem and progenitor cells in human OE. We will screen for and analyze the expression of the human homologues of genes that are relevant in mouse using RT-PCR, IHC and in situ hybridization on human olfactory tissue collected by biopsy. We also plan open-ended gene profiling studies. The resulting panel can be used to assay for the stems and progenitors in human olfactory tissue. Aim 3: To test the usefulness of the stem/progenitor marker panel and the analysis of axon trajectory for the diagnosis of dysosmic patients. Guided by our studies of the olfactory area in Aim 1 we will harvest biopsies of the olfactory area from patients rendered dysosmic as a consequence of aging, chronic rhinosinusitis, or prior viral URI, and use our panel to analyze the status of stem and progenitor cells as well as the pattern of axonal growth within the tissue.

Mentor: Schwob, James
Fellow: Schnittke, Nikolai
Title: Olfactory Epithelial Stem Cell Regulation by the Transcription Factor p63
Abstract:
The mammalian olfactory epithelium (OE) is able to regenerate its cellular components (neurons, supporting cells, and duct/gland cells) throughout adult life under normal, maintenance conditions, as well as regenerative conditions after destruction of all differentiated cell types by exposure to the gas methyl bromide (MeBr). This ability together with its peripheral and therefore accessible location makes the CE an attractive system to utilize for purposes of regenerative medicine. Before such a potential can be realized one must first perform a complete structural, biochemical, and functional characterization of the cellular dynamics of the CE. At least two distinct populations of putative stem or progenitor cells have been identified among the basal cells of the epithelium that may be responsible for its regenerative capacity. Globose Basal Cells (GBCs) constitute a heterogeneous population of lineage committed and uncommitted progenitors situated below (basal to) the neuronal layer of the epithelium. Horizontal Basal Cells (HBCs) lie in the basalmost layer of the CE and correspond to an apparently homogeneous layer of cells in tight contact with the basement membrane of the CE. Both of these basal cell types have been shown by various methods to have the ability to generate all the differentiated cell types of the CE, however HBCs are not present until late in embryonic development whereas GBCs are the progenitor cells involved in the embryonic assembly of the tissue. The transcription factor p63, a member of the p53 family, is necessary for the embryonic appearance of HBCs and loss of p63 expression in the adult regenerative environment appears to be correlated with the ability of HBCs to give rise to differentiated CE cell types. The goal of the proposed research is to exhaustively characterize the functional role of p63 in HBC generation, quiescence, activation, and transdifferentiation.

First, nascent HBCs that express p63 but have not yet differentiated toward the HBC phenotype will be characterized based on expression of other markers previously identified in the lab as CE progenitor cell markers. Next, the sufficiency of p63 expression in HBC generation will be probed by forcing expression of p63 in the regenerative environment via retroviral infection. Finally the role of p63 loss will be assessed in the adult normal and post-lesion settings, via a conditional knock-out genetic approach. These studies will go a long way toward elucidating the nature of context dependent plasticity present in the CE specifically and adult stem cell systems in general, as well as provide a mechanistic framework in which to approach the therapeutic application of these cells.

Mentor: Schwob, James
Fellow: Donovan, Melissa
Title: Regulation of Epitheliopoiesis in the Olfactory Epithelium by Neuregulin Signaling
Abstract: The olfactory epithelium (OE) is unique in its ability to undergo regeneration of all cell types (both neurons and support cells) throughout mammalian life in response to both natural cell turnover, as well as environmental insult. Environmental injury can be easily induced in a laboratory setting through methyl bromide (MeBr) gas exposure, allowing for a controllable method to activate stem cells in vivo. The progenitor population responsible for regeneration has been identified as two classes of basal cells, globose basal cells (GBCs) and horizontal basal cells (HBCs). Together, the ease of acquiring activated stem cells along with knowledge of the identity of the progenitor population, makes the OE an ideal model in which to study regenerative medicine. In order to harness the potency of regenerative therapies, it is first necessary to dissect out the signaling pathways that govern stem cell differentiation. The olfactory epithelium contains an underlying mesenchymal compartment, the lamina propria (LP), which remains ill-defined. The importance of mesenchymal-epithelial communication is well-studied in other areas of stem cell biology, where factors secreted by mesenchymal cells signal via epithelial cells to drive differentiation. Understanding how this mesenchymal layer influences epithelial differentiation appears to be imperative in beginning to define signaling pathways that direct progenitor cells towards differentiation. The ErbB receptor family binding protein, Neuregulin1 (Nrg1), has been found to be secreted by LP cells and has been shown to be capable of inducing OE stem cell differentiation in a 3D culture model in vitro. The goal of this study is to understand the effects of Nrg1-induced differentiation.

First, a 3D culture model designed to allow for sphere growth and stem cell differentiation when in the presence of appropriate growth factors, will be studied for the ability of Nrg1 to stimulate sphere growth. Spheres stimulated to grow with Nrg1 will be analyzed through both Multisizer quantification of sphere number and size and confocal microscopy of spheres immunostained with markers for different OE cell types. This will provide a determination of the efficacy of Nrg1 to induce differentiation. Secondly, a knock out mouse for the Nrg1 receptor, ErbB4, will be used to study the effects of loss of Nrg1/ErbB4 signaling in vivo. These studies will focus on characterizing the knock out phenotype using immunohistochemistry, and performing 3D in vitro assays to determine the functional effect of ErbB4 loss on sphere growth and differentiation. Together, these studies will provide novel insight on the effects of a mesenchymal- secreted protein, Nrg1, on OE differentiation, and implicate a well-known developmental signaling pathway in OE differentiation.

PI: Schwob, James
Title: Regulation of Neurogenesis in Olfactory Epithelium
Abstract: Abnormalities of stem cell function and/or the destruction of stem cells leads to an olfactory epithelium (OE) that remains olfactory (including a full complement of sustentacular cells), but one that has no neurons, no globose basal cells, and no ongoing neurogenesis. Horizontal basal cells (HBCs) are still evident in aneuronal OE, but clearly are not functioning as multi potent progenitors/stem cells as they can and do under other circumstances. These and other data indicate that HBCs must be activated in some way by signals emanating from a damaged epithelium, in order to function as stem cells. Recently, we have shown that the transcription factor p63 is key to HBC differentiation and regeneration. We will test whether p63 is the key factor that regulates (prevents) HBC activation using a mouse genetic approach. In Aim 1 we will conditionally knock-out and conditionally over-express p63 selectively in HBCs, using K5 driver lines, and analyze clonal progeny from the targeted HBCs. Signaling via the Wnt and Notch pathways play antagonistic roles in regulating stem cells and their transition to more differentiated and shorter-lived progenitors. Moreover, both of them interface with p63 in that regulation. Accordingly, in Aims 2 and 3, we will assess how knock-out vs. constitutive activation of the Notch and Wnt pathways, respectively, affect HBC activation and function as progenitor. We will use the same kind of approach to achieve cell type- and temporal-control over the targeted genes. We expect that the results will show that p63 is the master regulator of HBC activation and that both Wnt and Notch pathways will participate in controlling both p63 and HBC activation. After completion of the experiments, we will be poised to apply small molecule inhibitors of p63 and the key signaling pathways to the problem of restoring neurogenesis to an aneuronal OE.

PI: Selhub, Jacob
Title: Assessment of Iron, Vitamin B12 and Vitamin D Status in Preschool Children Attending Day Care Centers in the CARITAS Archdiocesan System, Phase II
Abstract: The profile of micronutrient deficiencies vary from setting to setting related to environmental factors, dietary patterns and interventions already in place. Endemic deficiencies of riboflavin and iron were documented in Guatemala in a Central American nutrition survey conducted in the 1960s. Serial national nutrition surveys have continued to demonstrate anemia as a problem in young children and adult women. Inadequate vitamin B12 status in Guatemala and in Mexico has been documented in multiple studies. The unique environmental or even genetic circumstances in the MesoAmerican region possible contribute towards this deficiency. The subclinical deficiency of vitamin B12 in older individuals has long been associated with deterioration in cognitive function, and may have similar central nervous system effects in younger individuals, including children. In a survey of the elderly adults of Mayan descent, living in the Western Highlands of Guatemala, the majority of those surveyed had marginal or low vitamin D status. To address nutritional deficiencies, the general approach of "home fortification" has been developed over the last decade. This involves the direct addition of a concentrated source of micronutrients to usual meals served within the home or an institutional setting such as a day-care center. These have been primarily been focused on infant, toddlers and preschoolers, and have concentrated on the prevention of iron deficiency and iron deficiency anemia.

The Hormel Inc., has created a fortified, turkey-based meat paste (pate) called SPAMMY, which could enhance the macro- and micro-nutrient of institutional or home meals. One-half a can (43 g) is an individual daily ration, with a substantial contribution to energy, protein, vitamins, minerals and salts. Working with the international NGO, Food for the Poor, and the Archdiocesan CARITAS of the Roman Catholic Church of Guatemala, it was donated for distribution as a benefit to orphanages, day-care centers and woman's groups. A series of insights on its acceptability and its compatibility with household and institutional recipes were obtained. With a change in strategy, the product for Guatemala is to be reformulated to target the most important and relevant nutrient deficiencies. As a prelude to conducting a formal efficacy trial on the capacity of the food to improve nutrient status in the affiliated children, it was seen as necessary to evaluate the prevailing status of three nutrients of interest: iron, vitamin B12 and vitamin D and to allow for an effective fortification of the pate product. Measurement of plasma concentration of vitamin B12 and methyl malonic acid, the biomarker for vitamin B12 status will be conducted at the Vitamin Metabolism Laboratory at HNRC. This pilot study will provide information on the bioavailability of nutrients in a home fortification product and its efficacy in preventing malnutrition. Successful completion of this project will prove the feasibility of targeted fortification of subsets of populations at risk for deficiency without exposing the entire community to fortification. Vitamin B12 deficiency is highly prevalent in the elderly and the results from this project can be applied towards targeted fortification of the elderly who are at risk for vitamin B12 deficiency.

PI: Selhub, Jacob
Title: Improving Folate and Vitamin B12 Content of Fermented Whey Supplement
Abstract:
Currently synthetic forms of folate and vitamin B12 are used for fortification of foods. These forms have to be converted to biological forms by enzymes before they can participate in biological reactions. Due to slow activity and genetic variability, the conversion to biological forms is not efficient. To address this issue Bioforce AG, Switzerland has modified the fermentation process of whey to include precursors for folate and vitamin B12 which will be then converted to biological forms of these vitamins by the microbial action. The fermented whey products can be then used as a supplement to improve the vitamin status of the users.

Hypothesis: Addition of para amino benzoic acid (folate precursor) and vitamin B12 precursor during fermentation will increase the folate and vitamin B12 content of the fermented whey product.

Objective: To determine if the fermentation process with para amino benzoic acid and vitamin B12 precursor improves the content of biological forms of folate and vitamin B12 of fermented whey supplement. If the vitamin content of the whey supplement is improved as a result of this process, the bioavallability of the vitamins in humans will be tested in a future study.

During fermentation of whey, para amino benzoic acid which can be used as a precursor for folate and a precursor of vitamin B12 will be added to the fermentation medium. These precursors will be used by the microbes during fermentation to synthesize biological forms of folate and vitamin B12. Once the fermentation is complete the whey product will be tested for folate and vitamin B12 content. The vitamin analysis will be conducted at vitamin metabolism and aging laboratory at HNRC.

PI: Selker, Harry
Title: Tufts Clinical and Translational Science Institute (CTSI – UL1)
Abstract:
Leveraging Tufts University's excellent resources, traditions of multidisciplinary collaboration, generation of novel research methods, and academic innovation, including the first MS/PhD Clinical Research (CR) Program in a graduate school of biomedical sciences, we will establish the Tufts Clinical and Translational Science Institute (CTSI). This will unite eight Tufts Schools (Arts & Sciences, Citizenship and Public Service, Dental Medicine, Engineering, Graduate Biomedical Sciences, Medicine, Nutrition, and Veterinary Medicine), eight affiliated hospitals, the Tufts Center for the Study of Drug Development, the USDA Human Nutrition Research Center on Aging at Tufts, and the Tufts-New England Medical Center (Tufts-NEMC) Institute for Clinical Research and Health Policy Studies. This will:

  1. Create a new home for clinical and translational clinical research (CTR), a cross-University, cross-affiliate Tufts CTSI, headed by an international leader in CTR who will report to the University Provost

  2. Create eight research resource Components suggested by the CTSA RFA, plus four based on special Tufts strengths

  3. Enhance and expand the "CR Portal" at Tufts-NEMC into a Tufts-wide "CTSI Portal" that provides coordinated and mentored University- and affiliate-wide access to CTSI Components and other resources

  4. Create activities, processes, and new information systems that will support and promote collaborative cross-disciplinary full-spectrum translational research

  5. Enhance our MS/PhD CR Program by:
    1. Adding to the existing four Concentrations (Clinical Investigation, Epidemiology/Biostatistics, Health Services and Outcomes Research, and Medical Informatics), Concentrations in Bench-to-Bedside Translational Research and in Evidence-Based Medicine

    2. Developing distance learning to extend the Program to fellows, K12 scholars, and other faculty at Tufts affiliates across Massachusetts

    3. Creating the joint Pfizer Tufts Career Development Awards

    4. Preparing predoctoral tracks for Tufts MD, DMD, and DVM students to also get a CR MS or PhD

    5. Developing joint tracks for students to get an MS in Nutrition or in Biomedical Engineering with a PhD in CR

    6. Developing a program to generate interest in CTR among students from underrepresented minority group

In all aspects of training, research support, and organizational development, the Tufts CTSI will support and instill the culture of cooperative interdisciplinary research, a home without walls, for CTR Tufts-wide.

PI: Selker, Harry
Title: Tufts Clinical and Translational Science Institute (K12)
Abstract:
The objectives are to:

  • Provide training based on didactic curricula that provide solid grounding in basic biomedical sciences, the essential concepts and methods of CR, a working knowledge of research subjects' protections and the regulatory structures that underlie these protections, and an appreciation for the ethical norms that frame the responsible conduct of research.
  • Present the trainees with a series of research experiences, both in the laboratory and in the clinic that will demonstrate the interdisciplinary character of clinical and translational research at CTSI institutions and that will form the basis for development of their dissertation projects.
  • Provide a robust system of mentoring that will guide trainees in all stages of graduate training from early interdisciplinary courses through decisions about the immediate postdoctoral experience.
  • Train a cadre of researchers who can lead the translation of basic research into practice at the community level.
  • Strengthen CR collaborative ties between the Tufts CTSI and the affiliated hospitals.

PI: Selker, Harry
Title: Tufts CTSI Career Development Program in Comparative Effectiveness
Research
Abstract: From its inception in 2008, a major goal of the Tufts Clinical and Translational Institute (CTSI) has been to develop a comprehensive infrastructure for the efficient conduct of comparative effectiveness research (CER), the development of innovative CER methods, and the training of fellows and scholars in CER. Based on a long tradition in this area, the Tufts CTSI has linked an extraordinary array of disciplines, novel methods and collaborative research opportunities focused on "bedside-to-practice" and "practice-to-policy" translational research and, based on these assets and this focus, has played a leadership role in coordinating the response of the National CTSA Consortium. It has been clear that the need for CER to provide readily available and actionable information on the relative benefits and costs of competing treatment options far outstrips the collective capacity of academic research centers like the Tufts CTSI, where the nation's expertise and capacity for CER largely resides. A large national investment to train the next generation of CER researchers, as well as a commitment on the part of academic centers to prioritize CER training, is urgently needed. The Tufts CTSI is exquisitely well prepared to expand our role in training leaders and innovators in CER, to grow our core CER capacity, to help meet these critical needs. With this application, we aim to establish a Mentored Career Development Program in CER that builds on the breadth and depth of our research expertise across the full CER spectrum, as well as on our long history of training CER scholars and on our robust links to community and industry stakeholders. The purpose of this training program is: 1) to produce the leaders and innovators to help meet the nation's enormous CER challenges and workforce needs of the coming decade, and 2) (since CER is performed collaborative in teams) to further strengthen the Tufts CTSI as a Center of Excellence in CER. 

PI: Selsing, Erik
Title: Testing a Role for Activation-Induced Deaminase in Omenns Syndrome B-Cell Autoimmunity
Abstract: Omenn syndrome is a human disease that exhibits an unusual combination of immunodeficiency coupled with autoimmunity. Patients have few mature T cells or B cells, and have poor immune responses. On the other hand, patients show substantial serum antibodies with elevated levels of self-reactive antibodies. Hypomorphic mutations in recombination-activating genes (RAG) are some of the best-characterized genetic defects associated with Omenn syndrome. RAG proteins are critical for recombination of receptor genes during development of B and T lymphocytes and hypomorphic RAG mutations lead to limited generation of mature lymphocytes. However, the causes of autoimmunity in the disease are not clear. 

During the past several years, our research groups have collaborated on studies of B cell differentiation and tolerance during early B cell development. We have recently shown that isotype switching occurs even in immature B cells in the bone marrow, counter to the prevailing paradigm that switching was limited to activated mature B cells. We have also found that immature B cell switching is greatly elevated in a mouse strain (564Igi strain) that models human System Lupus Erythematosus (SLE), and develops autoimmune disease. Because isotype switched B cells respond more strongly to stimulation, we have hypothesized that isotype switching in immature B cells can lead to a breakdown of central tolerance checkpoints and can result in autoimmune disease. We have also developed mutant 564Igi variants that either can or cannot undergo isotype switching in immature B cells. Preliminary studies indicate that autoimmunity is greatly reduced in 564Igi mice that lack early B-cell isotype switching, supporting our hypothesis that early B-cell switching can circumvent tolerance and can lead to autoimmune disease. 

The SLE-like 564Igi mouse model effectively reproduces many features of human SLE, but the gene- targeted anti-RNA antibody genes in the 564Igi strain are a genetic construct that is not found in human SLE patients. We want to test the role of early B-cell switching in the development of autoimmunity arising from a genetic mutation known to be involved in human autoimmunity. 

Recent reports have described mouse models of the human Omenn syndrome disease. These have a gene-targeted hypomorphic RAG gene and, thereby, are analogous to patients with hypomorphic RAG. The mouse models replicate the lymphopenia, the serum antibody levels, and the autoimmunity of the human disease. Furthermore, some features of Omenn syndrome, such as anti-RNA, anti-chromatin and anti-DNA antibodies, as well as elevated serum cytokines that regulate isotype switching, are shared with SLE. We will use Omenn syndrome mouse model variants that cannot undergo isotype switching in immature B cells to test whether these exhibits reduced autoimmunity. Our tests will indicate whether or not tolerance breakdown through isotype switching might be a common feature of various B cell autoimmune diseases. 

PI: Shoemaker, Charles
Title: A Platform for Therapeutic Agents that Promote Rapid Recovery from Botulism
Abstract: Botulism is caused by exposure to toxins produced by Clostridium botulinum neurotoxin (BoNT), a CDC Category A biodefense threat agent for which no antidote currently exists. Seven different BoNT serotypes have been discovered to date (BoNT/A-G), many having numerous additional BoNT subtypes. To protect against all of these diverse BoNT bioterror threats, expensive conventional small molecule drug development would need to be separately performed for each of the seven different drug targets and perhaps others. This challenge, together with other extreme hurdles confronting BoNT small molecule drug development, particularly complicates efforts to develop small molecule drugs to treat botulism. New therapeutic paradigms are urgently needed to counter the enormous risks associated with these easy to obtain, easy to produce and extremely dangerous bioterror agents.

We have developed and then extensively optimized two distinct 'designer E3-ligase' agents that each accelerate the 'molecular cure' of neurons intoxicated by one of the two most dangerous Botulinum neurotoxins, serotypes A or B (BoNT/A, BoNT/B). These two lead agents consist of the F-box domain of TrCP fused to a camelid 'nanobody' domain with binding specificity for one of the BoNT proteases. These polypeptide agents, with a size less than 30 kDa, bind to the BoNT protease and cause its rapid, intraneuronal destruction leading to rapid recovery of the neuron. Because of the modular nature of this antidote, it will be simple and straightforward to develop similar agents to treat all other BoNT serotypes and subtypes simply by substituting the nanobody domains with another having the appropriate specificity.

In this proposal, we will develop a general delivery vehicle to deliver our two lead agents to the cytosol of intoxicated neurons within botulism patients and perform pre-clinical evaluation. As the vehicle, we propose to use an atoxic Clostridial toxin-based neuronal delivery vehicle (TNDV) due to its highly evolved capability to enter the body, survive in serum and deliver enzyme activities to the cytosol of targeted cells. We will develop three different and proven TNDV systems, each having unique and compelling features, and then select the best vehicle(s) for further development and animal testing. The three TNDV systems will be modified, atoxic forms of: 1) BoNT serotype C; 2) C. difficile toxin B and; 3) Clostridial C2 toxin. If successful, it is expected that similar agents could be developed to target the accelerated turnover of virtually any cytosolic neuronal protein for research or therapeutic applications.

PI: Shoemaker, Charles
Title: Motor Neuron-Targeted Adenovirus Antidotes for Botulism
Abstract:
Botulism is caused by Clostridium botulinum neurotoxin (BoNT), a CDC Category A biodefense threat agent for which no antidote exists. BoNT is the most potent toxin known and can be produced with relative ease. If large numbers of people were exposed to even a small dose of this toxin, they would become paralyzed and require assisted breathing which could easily overwhelm the limited supplies of respirators. We have developed small protein agents that, when expressed within intoxicated neurons, promote rapid degradation of BoNT proteases and improve rates of recovery from intoxication. We call these biomolecule agents "targeted F-boxes" (TFBs) because they consist of a 15 kDa F-box domain fused to a 14 kDa camelid VHH domain with binding specificity for a BoNT protease. Here we propose to develop adenovirus-based botulism antidotes that will specifically target motor neurons and lead to cytosolic expression of a TFB agent within intoxicated neurons.

Adenoviruses (Ads) are ideal vehicles for delivery of TFBs to motor neurons for several reasons. First, Ad does not integrate their genome into infected cells and Ad vectors have been produced that are non-replicating and safe for therapeutic use. Second, Ad can be modified to dramatically reduce the normal tropism (liver) while increasing infection of a selected cell population. Thirdly, Ad vectors can be modified to produce a transient burst of transgene expression lasting only a few weeks after which the infected cells revert to normal. Finally, Ads have been found to infect motor neurons leading to transgene expression and, surprisingly, BoNT intoxicated motor neurons are much more efficiently infected than normal neurons.

In this proposed project, we will develop an adapter protein that will block normal Ad tropism while imparting tropism for motor neurons by employing a neuron-specific receptor binding domain (RBD) that derives from BoNT. Recombinant Ad will be engineered to express a TFB agent that targets the protease from BoNT serotype A (BoNT/A) for degradation and will be pre-treated with the neuron-targeting adapter. This modified Ad will then be tested as a botulism antidote by local injection into BoNT/A intoxicated muscles in mice. If successful, in the R33 phase we will make additional modifications to the Ad vector to further improve specificity for motor neurons and obviate the need for an adapter protein. We will also engineer an Ad antidote for another BoNT serotype, BoNT/B. These Ad vectors will be tested for the ability to accelerate recovery from botulism paralysis in mice following a systemic administration of the therapeutic agent. If successful, similar agents can be readily developed for all seven known BoNT serotypes by simply replacing the VHH domain of the TFBs with others having specificity for different BoNT proteases. In addition, the neuron-targeted Ad vehicles we develop may have applications in other important neuronal pathologies.  

PI: Shultz, Mary Jane
Title: Collaborative Proposal: Students' Attempts at Understanding the Unobservable: A Multi-Method Approach to Visualization Analysis and Design (Empirical Contextual Research Strand)
Abstract:
Student comprehension of scientific concepts and principles presents a particular challenge when the phenomena are not directly observable. This issue has emerged as core to effective teaching and successful student learning in chemistry. The goal is to identify whether students' individual differences influence the effectiveness of visualizations for learning scientific concepts as measured with process and product-based metrics of evaluation. The investigators will also develop design principles for the use of visualizations as instructional tools in chemistry and STEM fields more broadly.

The central issues are: When and how students rely on visualizations while trying to comprehend unobservable chemistry content; whether reliance on visualizations varies as a function of student characteristics; and whether usage patterns inform instructional interventions. In a series of randomized, controlled experiments involving undergraduates at four institutions, investigators will: (a) determine baseline chemical knowledge, spatial ability, reasoning ability, and interest in learning; (b) use eye tracking to characterize the moment-by-moment scan and fixation processes that students rely on while viewing visualizations; (c) utilize concurrent interview protocols to assess learning strategies and knowledge acquisition; and (d) implement post-visualization tests to examine student memory for the visualization content and application of knowledge.

PI: Sims Gallagher, Kelly
Title: Climate Change Policy, with a US and China Focus
Abstract:
Kelly Sims Gallagher will have primary responsibility for U.S. and Chinese climate policy. This is a hugely dynamic and active area of policy in the USA and China currently and Gallagher has been and remains deeply involved in shaping the thinking and ideas around cooperation and collaboration between the USA and China on climate change. This work is directly related to Energy, Climate Change and National Security and is influenced by technology as well as impacting technology. Gallagher participates in a number of distinguished academic and government advisory panels, including PCAST and the American Academy for Arts and Science. Funds permitting, she will also collaborate on projects led by faculty at Harvard. In particular, she is committed to collaborate on the geopolitics research led by Meghan O'Sullivan. She will interact with Henry Lee on transportation and Wendy Jacobs on CCS, especially as their work pertains to U.S. or Chinese climate policy.

Gallagher served as the Director of ETIP from 2003-2009. Major accomplishments of the ETIP program between 2006-2009 included policy recommendations regarding tax incentives and loan guarantees for advanced energy technologies, annual analysis and policy recommendations regarding the U.S. Department of Energy's RDD&D budgets, analysis of the "real costs" of CCS in the United States, roadmaps for advanced coal and CCS in India and China, annual workshops convened with the Chinese government's Ministry of Science and Technology on clean and efficient transportation and advanced coal/CCS, conception of the idea of "Acting in Time on Energy Policy" (major conference, book published by Brookings) and, of course, including John Holdren's nomination to be President Barack Obama's Science Advisor at the end of 2008. ETIP's policy relevance, outstanding outreach, analytical rigor, and convening power were all demonstrated and proven during this initial period. Many of the ideas developed by ETIP have become policy during this time, in both the United States and China.

There are two primary objectives for the Climate Change Policy program. The first objective is to achieve substantial interaction between BP and the Climate Change Policy program so as to mutually inform each other's work. The substantive interactions will engage on climate change policy with a USA and China focus. The second objective is for the program to advance policy-relevant knowledge in these domains through excellent research, high-quality research products, outreach to policymakers, and the convening of meetings, conferences and events.

PI: Skeer, Margie
Title: A Brief Substance Use Preventive Intervention for Parents of Pre-Adolescents
Abstract:
The prevention of substance use and misuse among adolescents is a national public health priority. Universal prevention programs that include parents in this effort have been proven efficacious in preventing and reducing substance use problems among adolescents. However, the programs that have been most effective are resource and participant intensive. In addition, the majority of the current programs are not gender-specific and in some cases, long-term effects have been shown for one gender but not the other.

The proposed Stage 1 grant addresses this gap by evaluating the feasibility, acceptability, and preliminary efficacy of a novel, brief, gender-specific substance use and misuse preventive intervention for parents/guardians of pre-adolescents (aged 9-12) in an uncontrolled pilot and in a subsequent randomized controlled pilot. The brief intervention framework will comprise two components: an in-person session and a home-based element. For the in-person session, parents will meet for one-hour with an intervention specialist. One-to-two weeks prior to this session, parents will be provided with a handbook, specific to the gender of their child that emphasizes communication, monitoring, and talking with their child about the harms of substance use. During the in-person session, the main points in the handbook will be reviewed and parents will be given the opportunity to ask questions to increase their competencies around the suggestions in the handbook. A particularly innovative component is a focus on eating meals together as a primary intervention strategy to facilitate communication. For the home-based component, tips and reminders with content from the handbooks are to be sent via text messaging throughout the study period, and parents will fill out a weekly meal log.

Framed within the context of the Ecodevelopmental Theory, we hypothesize that over the study period, compared to parents who are randomized to the control condition, parents who receive the intervention will self-report an increase in the number of meals eaten together with their children per week, number of minutes spent per meal eaten with their children per week, frequency of conversations about substance use with their children, and frequency of parent-to-child communication and monitoring. Furthermore, we hypothesize that compared to children of parents randomized to the control condition, children of parents who are randomized to receive the intervention will self-report fewer intentions to use substances and increased negative attitudes and expectancies regarding substance use. Estimates of effect size and other information obtained from this pilot proposal will be used to design a larger, refined randomized controlled trial to test the efficacy of the intervention. Development of this intervention will follow the guidelines outlined by NIH for stage-wide development of interventions for substance use and will address the major goal of reducing rates of adolescent substance use and misuse put forth by NIDA and Healthy people 2020.

PI: Skelly, Patrick
Title: Functional Characterization of the Schistosome Tegument
Abstract:
Schistosomes are parasitic flatworms that cause a chronic, debilitating disease afflicting over 200 million people in over 70 countries. The parasites live for years, sometimes decades, in what should be a very hostile environment – the blood of vertebrates – yet they appear to solicit little if any protective reaction from two of the host’s major defensive systems: the hemostatic system and the immune system. We hypothesize that proteins at the host-interactive surface are central to the parasites ability to dampen host immunity and hemostasis while, at the same time, permitting metabolite exchange. In this competing renewal, we propose to use new molecular methods such as RNA interference that were first developed for use with schistosomes under our previous grant to test several key hypotheses concerning:

  1. The role of tegumental ecto-enzymes in hemostasis and immunomodulation

  2. The ability of tegumental sphingomyelinase to alter permeability properties at the parasite surface

  3. The molecular mechanisms of transtegumental metabolite exchange

The functional genomics approach we adopt here coupled with independent and direct, follow-up experiments employing more traditional cell biology and biochemistry techniques are designed to provide significant new information concerning the schistosome host interactive surface. In addition the work is designed to identify tegumental proteins critical for parasite survival in the host and subsequent screens will be undertaken to discover drugs that inhibit these molecules. In this way, our planned experiments have the potential to reveal novel and valid targets, as well as new treatments, for intervention in a parasite that remains a widespread and major cause of human disease.

PI: Sonenshein, Abraham
Title: Aerobic Growth of
Anaerobic Pathogens
Abstract:
Two very different bacterial pathogens, the Gram-negative Bacteroides fragilis and the Gram-positive Clostridium difficile, have been considered as textbook examples of strict anaerobes that inhabit the large intestine. B. fragilis is a normal inhabitant of the colon, but C. difficile is usually found in people whose normal microbiota has been compromised by antibiotic treatment. B. fragilis is an opportunistic pathogen mainly associated with escape from the intestine due to leakage into and formation of abscesses in the peritoneal cavity. C. difficile, on the other hand, is the primary cause of antibiotic-associated diarrhea and pseudomembranous colitis. Given that the normal habitat for these bacteria is the anaerobic environment of the large intestine, it is remarkable that our preliminary results have shown that mutants of B. fragilis and C. difficile arise that can grow in the presence of oxygen (up to 2%) and can survive exposure to even higher oxygen levels. Many of these mutants have oxe (oxygen-enabling) null mutations that lie in a gene called oxeA that is conserved in the two otherwise very dissimilar species. Moreover, many clinical isolates of B. fragilis derived from abscesses can grow in 1.5% oxygen and have oxeA mutations as well.

This application seeks to explain these unexpected findings by addressing a fundamental biological question: Why do anaerobic pathogens normally express genes whose products prevent them from growing aerobically? Our working hypothesis is that the wild-type product(s) of the oxe genes promote growth or survival in the anaerobic colon whereas the oxe mutations enhance some aspects of pathogenesis in animal hosts.

To test this hypothesis we will compare the colonization, virulence and transmission of B. fragilis and C. difficile wild-type and oxe mutant strains in animal models of disease. In addition, we will seek to uncover the biochemical mechanisms by which the oxe gene products prevent survival and growth in low levels of oxygen. The results are expected to reveal a novel and surprising aspect of anaerobic growth. 

Mentor: Sonenshein, Abraham
Fellow: Brinsmade, Shaun
Title: Integrating Global Responses to Nutrient Limitation in Gram-Positive Bacteria
Abstract: Expression of bacterial virulence genes often correlates with the exhaustion of nutrients, but how the signaling of nutrient availability and the resulting physiological responses are co- ordinated is unclear. Until this gap in knowledge is closed, metabolically diverse bacteria like Staphylococcus aureus will continue to cause perilous hospital-acquired infections. The applicant's long-term goal is to lead an independent academic research group studying how bacteria integrate and respond to information provided by intracellular metabolites (the metabolome) to reconfigure metabolism to adapt to environmental changes and cause disease.

The objective of this project is to augment existing genetic and biochemical expertise with high-throughput global techniques to analyze gene expression, intracellular metabolites and flux, and, in doing so, titrate the activity of the global regulator CodY and deduce its regulatory hierarchy in S. aureus. At the heart of this project is the hypothesis that fluctuations in the intracellular pools of branched-chain amino acids and GTP result in a spectrum of CodY activities that produce a graded response to nutrient limitation, culminating in metabolic adaptation and the development of virulence. This hypothesis is based on preliminary studies that identified the true intracellular metabolites that control CodY activit in living cells and revealed hierarchical organization for three genes.

The rationale for this project is that comprehensive knowledge of the co-regulation of metabolism and virulence is essential if we are to understand the physiological origins of bacterial pathogenesis. During the mentored (K99) phase at Tufts University School of Medicine, massively parallel sequencing, mass spectrometry-based metabolomics and chemostat cultivation will be mastered to map intersecting metabolic and virulence gene expression patterns in S. aureus, while gaining critical scholarly training needed to launch a successful independent academic career with guidance from a mentoring committee composed of experts in bacterial physiology, biochemistry and systems biology. Mastering the cultivation and genetic manipulation of pathogenic S. aureus along with high-throughput methods will enable efforts during the R00 phase to quantify changes in the S. aureus CodY regulon upon induction of physiological stress response systems. The approach is innovative, because continuous bacterial cultures mimic nutrient-limiting bacterial niches in the human body and the experiments will place virulence gene expression in the context of the normal behavior of S. aureus under the nutrient-limiting conditions of the host. Furthermore, correlations between global metabolite pools and CodY activity will provide a previously unattainable linkage of the transcriptome to the metabolome. The project is significant because it will increase our understanding of how the genetic pro- grams of metabolic adaptation and virulence gene expression are interrelated and interdependent. A more thorough understanding of these connections may also offer potentially novel therapeutic strategies. The Pathway to Independence Award will provide the time and resources needed to achieve these goals.  

PI: Sonenshein, Abraham
Title: Integration of Metabolism and Virulence in Gram-positive Bacteria
Abstract: Intracellular metabolism is a complex network of intersecting reactions in all living things. In Gram-positive bacteria, the CodY protein is a major integrator of diverse metabolic pathways and regulatory schemes, helping the cell to turn many pathways on or off in response to the intracellular pools of four metabolites, the three branched-chain amino acids (BCAAs; isoleucine, leucine and valine) and GTP. In pathogenic Gram-positive bacteria, CodY is also a major regulator of virulence genes. Depending on the organism and the role of a specific virulence gene product, CodY, may act as either a negative or a positive regulator and may either inhibit or stimulate pathogenesis. This property of CodY links pathogenesis in an important way to the physiological state of the cell by tying the bacterium's decision to cause damage to the host to the pools of just a few key metabolites. Not all CodY target genes, however, are equally sensitive to CodY-mediated regulation. That is, variations in the intracellular pools of the BCAAs and GTP due to variations in nutrient availability create situations in which different fractions of the total population of CodY molecules are active. As a result, some genes (e.g., those that have very high affinity targets for CodY) are fully repressed under conditions in which other genes (e.g., those with low affinity targets) are hardly repressed at all. Thus, CodY-regulated genes fall within a regulatory spectrum or hierarchy.

A major goal of the proposed project is to determine where each CodY-regulated gene in the model organism, Bacillus subtilis, falls within this spectrum, to couple the positioning of genes to the intracellular pools of the CodY effector molecules, to determine the molecular mechanisms that are responsible for establishing the spectrum of gene regulation, and to identify the metabolic pathways that are induced or repressed at different levels of nutrient availability. This analysis is expected to provide novel insight into how the cell prioritizes the usage of specific metabolic pathways in response to general nutrient limitation. Analogous studies with two important human pathogens, Staphylococcus aureus and Clostridium difficile, will reveal where within the CodY hierarchy various virulence genes fall. CodY is a major repressor of virulence in both species. The results will give an unprecedented view of the extent of specific metabolic limitation that causes a bacterium to turn from a commensal life style to a pathogenic life style. Moreover, for a complex pathogen, such as S. aureus, that expresses dozens of virulence factors that cause different extents of damage to the host, it will be possible to learn to what extent metabolite pools have to drop before the most damaging factors are induced.

PI: Sonenshein, Abraham
Title: Molecular Genetics of Basic Cell Functions
Abstract: Continued support is requested for five predoctoral trainees per year for five years for an interdepartmental training program in the molecular genetics of basic cell functions. The emphasis is on rigorous training using the power of genetic analysis to study basic cell processes, such as chromosome replication and segregation, regulation of gene expression, cellular differentiation, and host-parasite interactions. This training program has strongly benefited from continuous support from NIGMS since 1975. Supported students are almost exclusively in their first year, allowing them to have a broad exposure to the role of genetics as a science in itself and as a tool for solving important biological problems. The training faculty, from the Departments of Molecular Biology and Microbiology, Biochemistry, Pathology, and Medicine, is highly interactive and dedicated to close, joint supervision and mentoring of graduate students. Past trainees include leading researchers in academia and industry. The training program is administered by the Graduate Program in Molecular Microbiology. Starting with a pool of 80-115 applicants, the graduate program annually admits 5-7 new students, most or all of whom are eligible for training grant support. The program has been successful in attracting a significant number of students from underrepresented groups (including 8 of the 32 current students), nearly all of whom have been supported by this training grant. Nearly all graduates of the program have obtained high-quality postdoctoral appointments and are still active as researchers, as teachers, or in allied fields. Entering students take required courses in Genetics, Biochemistry and Microbiology and pursue 9-week rotation projects in four different laboratories. At the end of the first academic year, they choose a thesis supervisor and begin thesis research. In the second and third years, the students complete their coursework and prepare a research proposal (unrelated to the thesis topic) as a qualifying examination. All students are required to complete a seminar course in scientific ethics.  

PI: Sonenshein, Gail
Title: Lysyl Oxidase Propeptide: Breast Cancer Inhibitor
Abstract:
Breast cancer is the second leading cause of cancer deaths among American women, and thus additional, effective treatment protocols are needed. Lysyl oxidase (LOX) is an essential extracellular enzyme that controls matrix deposition. The LOX gene was isolated as the “ras recision” gene (rrg) with an ability to inhibit the transforming activity of the Ras oncogene in NIH 3T3 cells. Consistently many cancers display reduced LOX gene expression. The LOX gene encodes a 50 kDa pro-enzyme (termed Pro-LOX), which is secreted into the extracellular environment where it is processed by proteolytic cleavage to an 18 kDa amino terminal propeptide (LOX-PP) and a functional 32 kDa enzyme.

The PI’s group demonstrated that the rrg activity resides in the LOX-PP domain, whereas, the LOX enzyme itself has been found to promote a more aggressive phenotype and tumor metastasis under hypoxic conditions. Importantly, LOX-PP activity was shown by the PI’s group to effectively inhibit breast cancer cells, driven by Her-2/neu which signals via Ras. In culture, LOX-PP suppressed the PI3K/Akt and MEK/Erk pathways and NF-κB. Oncogenic Her-2/neu induces epithelial to mesenchymal transition (EMT) and this was reverted by LOX-PP. LOX-PP induced E-cadherin, decreased levels of Snail, tumor migration and formation of branching colonies in Matrigel, and reduced tumor formation in nude mice. A single nucleotide polymorphism (SNP) (rs1800449) G473A, resulting in an Arg158Gln substitution in a highly conserved region in the LOX-PP domain, occurs with an average 24.6% 473A minor allele carrier frequency in the HapMap database.

However when cancer cells were examined, the G473A SNP was present in the majority of lines and the LOX-PP Gln variant displayed substantially impaired tumor suppressor function in vitro and in vivo, and a reduced ability to oppose the pro-tumorigenic effects of LOX.
In a pilot study of African-American women, the minor 473A allele was associated with increased risk of ERα negative breast cancer. These findings lead to two related central hypotheses:

  1. Wildtype LOX-PP represents an important tumor suppressor, the activity of which is compromised by an Arg to Gln substitution.

  2. A G473A (rs1800449) SNP in the LOX gene leads to increased risk of more invasive cancers.

In this application, we propose to:

  • Aim 1: Elucidate the mechanisms whereby wild type LOX-PP mediates its action as a suppressor of Ras signaling in breast cancer cells and determine how these are affected by the Arg158Gln substitution;
  • Aim 2: Test the ability of LOX-PP to impede the tumor promoting effects of the LOX enzyme in culture and in an orthotropic mammary fat pad model;
  • Aim 3: Test the hypothesis that the rs1800449 SNP represents a risk factor for more invasive breast cancer using a knock-in mouse that will be prepared.

The proposed studies represent pre-clinical testing of LOX-PP as an inhibitor of Ras signaling and as a risk factor of disease progression. As the LOX-PP activity was also effective against lung and pancreatic cancers, our findings have broader implications for carcinomas driven by an activated Ras oncogene.

PI: Sonenshein, Gail
Title: Roles of NF-κB/Rel in the Pathogenesis of Breast Cancer
Abstract:
The incidence of breast cancer has been increasing over the past 50 years, and is now the second leading cause of death among American women. In an attempt to find the reasons for this steady increase in incidence, both genetic and environmental factors are being studied. The NF-κB family of transcription factors controls genes critical for neoplastic transformation, cell proliferation and survival. NF-κB factors are sequestered in the cytoplasm in an inactive complex in almost all non-B cells. Surprisingly, we observed that polycyclic aromatic hydrocarbon (PAH)-induced rat mammary tumors displayed constitutive NF-κB activation. Aberrant activation of NF-κB was also detected in ~90% of primary human breast cancer specimens. Inhibition of NF-κB induced apoptosis or slowed growth. More recently, we have:

  1. Shown that Her-2/neu overexpression activates NF-κB complexes, which promote transformed phenotype;

  2. Prepared an MMTV-c-rel mouse, which showed that c-Rel plays a causal role in mammary tumorigenesis;

  3. Demonstrated that PAH-induced mammary tumors in mice display activation of multiple NF-κB complexes;

  4. Identified a novel de novo RelB subunit synthesis pathway and shown RelB promotes Epithelial to Mesenchymal Transition (EMT) of breast cancer;

  5. Demonstrated induction of the IKK-i/IKKε kinase in human breast tumors and cell lines, and shown that it plays an important role in maintenance of NF-κB activity, and implicated CK2 in IKK-i/IKKε activation;
  6. Demonstrated that in vitro PAH treatment of c-Rel-driven mammary cancer cells further activates NF-κB, which promotes an invasive phenotype.

Here, we propose to test the central hypothesis that environmental carcinogens induce signaling cascades converge to constitutively activate multiple NF-κB complexes, which promote a more malignant phenotype of breast cancer cells; thus, inhibition of NF-κB will revert invasive phenotype. Cancer epidemiological studies have shown an inverse association between green tea consumption and breast cancer incidence. Green tea is rich in polyphenols with anti-oxidant and anti-carcinogenic properties; the most abundant GTP is epigallocatechin-3 gallate (EGCG). EGCG inhibits Her-2/neu signaling. Recently, green tea or EGCG was shown to reduce invasive phenotype of PAH-induced rat mammary tumors, and cells in culture and slow proliferation of Her-2/neu breast cancer cell lines resistant to trastuzumab, suggesting translational applications of EGCG.
In this application, three aims are proposed:

  1. We will elucidate the roles of NF-κB complexes in promoting transformation;

  2. Elucidate the functional roles of IKK-i/IKKε in PAH-induced mammary carcinogenesis and determine the mechanism of ikki promoter activation;

  3. Perform pre-clinical testing of the ability of green tea polyphenols to promote a more normal phenotype, and to inhibit Her-2/neu cancers resistant to therapy in animals.

These studies will provide important information on the roles of NF-κB factor complexes that are aberrantly activated by environmental carcinogens or oncogenes in promoting invasive breast cancer, and test a potential inhibitor that can readily be translated to the clinic in combinatorial therapies.

PI: Sonenshein, Gail
Title: Signaling Pathways in Stages of Mammary Tumorigenesis
Abstract:
Breast cancer is now the second most frequent cause of cancer death among women in the United States. Environmental chemical exposure and bioaccumulation throughout a women's lifetime are thought to play a substantial role in the rise in breast cancer incidence. The overarching hypothesis in our original application was that environmental carcinogens, which induce genetic and epigenetic events, set in motion interacting signaling cascades that promote a multistep process leading to mammary tumor formation. Three gene systems were the focus: the aromatic hydrocarbon receptor (AhR), the CK2 and GSK3 kinases, and the NF-κB family of transcription factors. This paradigm-shifting model has been confirmed, and a new hypothesis on the role of these critical regulatory pathways in tumorigenesis has been developed. The investigators now propose that the interactions among these three systems play key roles at several stages of the multistep signaling process that leads to altered cell morphology and invasive tumor formation. The individual hypotheses to be tested are: Project 1: As mammary epithelial cells progress from normal to immortalized cells and then to invasive tumors, AhR activity is modified through interactions with environmental chemicals, other transcription factors and cofactors to differentially regulate target gene transcription and to effect changes in cell growth and invasiveness. New information will be obtained on AhR function in normal as compared with malignant cells, and on the molecular and functional outcomes, particularly with regard to tumor invasiveness, of constitutively active as compared with environmental chemical-activated AhR. Project 2: Upregulation of CK2 and the Wnt pathway, resulting from environmental carcinogen exposure, contributes to epithelial to mesenchymal transition (EMT), which promotes tumor cell invasion and metastasis. Targets of CK2 in this process will be identified, and the mechanism by which 7,12-dimethylbenz(a)anthracene (DMBA) interacts with CK2 in tumorigenesis and promotes CK2 upregulation will be studied. Project 3: Genetic and epigenetic events initiated by environmental carcinogen exposure induce or enhance the activity of multiple NF-?B complexes, thereby promoting a more invasive phenotype of breast cancer. In particular, studies will focus on elucidating the roles of c-Rel, RelB, and IKKe/i kinase, and tumor inhibitory effects of green tea polyphenols. Thus, this application focuses on understanding signal transduction pathways impacted by environmental carcinogen exposure, which promote neoplastic transformation, with particular emphasis on elucidating the mechanisms that influence development of invasive breast disease. The investigators will employ innovative technologies, novel in vitro model systems, transgenic mice generated in the P01, and common cell lines and reagents. These studies will provide important information on the potential link between environmental factors and critical signaling pathways in the pathogenesis of breast cancer invasion and on the targeting of these interacting signaling pathways with novel prevention or treatment modalities. 

PI: Sonkusale, Sameer
Title: CAREER: Nanoelectrochemical Systems on Silicon
Abstract: The main objective of this research is the realization of nanoelectrochemical systems through a marriage of microelectronics and electrochemistry for low-cost, high-throughput bench-top nanofabrication. The PI proposes a highly unconventional yet powerful candidate to realize such nanoelectrochemical devices that of top-down fabricated silicon CMOS (Complementary Metal Oxide Semiconductor) die as functional substrate for controlled nanofabrication. This new paradigm extends the role of CMOS technology beyond conventional areas of computation, signal processing and communication towards directed nanoassembly and nanofabrication.

The proposed research will develop two approaches: (1) CMOS for Nanoassembly: Electric field manipulation and assembly of already synthesized nanostructures and (2) CMOS for Nanofabrication: Controlled electrochemical growth of different types of nanowires directly on CMOS. Built-in integrated circuits will facilitate real-time feedback control for assembly and growth, and can be reused as front-end circuits for sensing. The research provides a direct path for heterogeneous integration of multiple nanomaterials on same silicon chip. As a proof of concept, the PI plans to implement a nanoelectrochemical sensor for bioanalysis, primarily detection of neurotransmitters, and environmental sensing of trace heavy metal ions in actual samples.

PI: Sonkusale, Sameer
Title: Collaborative Research: Active Metamaterial/pHEMT Hybrid Devices for Terahertz Modulation and Detection
Abstract: The main objective of the proposed research is the demonstration of a suite of terahertz devices, specifically modulators and detectors based on the active control of metamaterial structures implemented in GaAs pHEMT processes. Metamaterials are engineered sub-wavelength metallic structures capable of achieving nearly any electromagnetic response at THz frequencies. Demonstrations of exotic electromagnetic response in metamaterials such as negative permittivity and permeability, and negative index of refraction, suggest that these new systems hold great promise for future technological applications. For active control of the metamaterial structures, we plan to use the resonant behavior of a gated two-dimensional electron gas (2DEG) in the channel of an HEMT transistor as a potentially selective and tunable terahertz solid-state detector. Compared with transit time limited (diffusive transport) of conventional field effect transistor devices, plasma wave devices (ballistic transport) can effectively detect and modulate terahertz frequency signals. However no practical THz monolithic integrated circuits have been realized yet because of the lack of efficient antennas and couplers of THz radiation into devices. The objectives of this proposal are to marry the outstanding propagation control and coupling of free-space THz waves using “metamaterial structures” and “plasma wave terahertz conductivity” of two dimensional electron gas in pHEMT devices. This will create a unique pHEMT-MM transistor array that collectively exhibits exceptionally attractive properties for the next generation of THz components.

PI: Sonkusale, Sameer
Title: Collaborative Research: IDBR: Metamaterial Enhanced Spectrometer for Terahertz Hyperspectral Imaging of Biological Specimens
Abstract: The objective of the proposed research is the development of novel instrumentation to facilitate highly sensitive, hyperspectral imaging of biological specimens, in the minimally explored yet information-rich electromagnetic spectrum of terahertz frequencies. This spectrum is broad in spectroscopic possibilities due to presence of the intermolecular vibrational, rotational and torsional modes, providing a distinct broadband molecular fingerprint and intrinsic contrast for biomolecular identification. However existing terahertz imaging approaches have limited sensitivity due to:

  1. Lack of efficient coupling of terahertz radiation in and out of the biological sample
  2. Higher level of signal loss due to unwanted scattering at sample/spectrometer interface
  3. Lack of efficient detectors in the terahertz frequency range, thus limiting their performance

Moreover the detectors are typically single pixel detectors that require scanning to obtain a 2D image and they fail to capture the spatiotemporal evolution of biomolecular dynamics.

To solve these issues, the proposed instrument brings two emergent technologies — (1) Metamaterials (MM) and (2) Plasma wave operation of GaAs pHEMT device. Metamaterials are artificial structures with subwavelength metallic inclusions that can be designed to exhibit exotic electromagnetic response such as negative permittivity and permeability, negative index, and ideal absorption or transmittance. Plasma wave operation of GaAs pHEMT device facilitates resonant detection of terahertz radiation with unparalleled sensitivity.

PI: Sonkusale, Sameer
Title: Metamaterial Embedded Terahertz Signal Processing: Novel Devices and Architectures
Abstract: Current electronics and photonics devices do not operate at the terahertz frequencies commonly referred to as the “terahertz gap” (0.1 - 10THz, 1 = 3mm - 30mm). This frequency range offers tremendous opportunities for sensing and communications. However, lack of efficient terahertz components for signal processing and computation has so far stunted any development in this field. There has been a renewed effort focused on the search for terahertz materials and novel processing techniques to enable the construction of device components at these frequencies, however no concrete solution has been found that will address the generation, processing, computation and detection of terahertz signals within a unified framework.

The vision of this research program is to perform fundamental research and to explore new ideas for terahertz signal processing and computation. This will be enabled using novel principles of precise dispersion engineering of surface electromagnetic waves (Goubau Lines) and free space electromagnetic waves, both made possible by metamaterials, and active electrical control of these waves using plasma wave properties of III-V transistor technology (e.g. GaAs pHEMT, InP and GaN HEMT technology). The synergistic combination of III-V technology and metamaterials facilitates control of terahertz propagation and processing and thereby provides a rich platform for fundamental theoretical and experimental investigations.

The specific objectives of the proposed three-year research effort are as follows:

Research Goal #1: Explore new fundamental modes of signal processing that are based on Maxwell’s equations for dispersion engineering on two platforms: surface (G-lines) and quasi-optical (free space). The goal is to perform computational and experimental investigation into phase-time encoding of terahertz pulses using these approaches.

Research Goal #2: Explore essentials of electromagnetic control of plasma wave response in III-V transistors. The research goal is to explore fundamental research in metamaterial enhanced Mach Zehnder Modulator for both surface waves (G-lines) and quasi-optical (free space) approach and realize a two-step delay line filter operating at terahertz frequencies.

Research Goal #3: Investigate the fundamentals for the realization of terahertz time encoded delta sigma time modulators based on the goals #1 and #2 above.

PI: Soto, Ana
Title: BPA as a Developmental Carcinogen
Abstract:
Developmental exposure to bisphenol-A (BPA) at doses within the range of human exposure causes a complex array of adverse effects in animals. These outcomes are also known to be present in human populations and the rise in their occurrence coincides with the massive use of BPA and other endocrine disrupting chemicals (EDCs) in consumer goods. The main hormonal activity of BPA is as an estrogen mimic. Exposure to estrogens throughout a woman's life, including the period of fetal development, is considered a main risk factor for breast cancer. The investigators found that developmental exposure to environmentally relevant doses of BPA altered mammary gland morphogenesis in rodents during the period of exposure and led to the development of pre-neoplastic and neoplastic lesions appearing in adulthood. These results justify adding mammary gland related end points to the large and well-controlled GLP NTP-FDA study.
The investigators propose to pursue the following Specific Aims:

  1. To test the hypothesis that pre-pubertal mammary gland morphology assessed by morphometries at PND21 is an excellent predictor of pathological outcomes which manifest during adulthood. This aim is based on data obtained independently in the investigator's laboratory and that of Dr. S. Fenton (NIEHS). The investigators will compare subjective scoring methods with morphometric ones, and determine which are the features that best predict neoplastic outcomes. The investigators will assess whole mounts of animals exposed until PND21.

  2. To test the hypothesis that DNA methylation profiles and concomitant alterations of gene expression in the mammary gland stroma and epithelium at PND21 are predictors of pathological outcomes that manifest during adulthood.

  3. To test the hypothesis that perinatal exposure to BPA induces the development of pre-neoplastic and neoplastic lesions.

The investigators will assess the development of intraductal hyperplasias, carcinomas in situ and microscopic tumors and the appearance of palpable tumors in animals exposed from i) GD6 until PND 21 and ii) continuously from GD6 to sacrifice.
The realization of these aims will definitively test the hypothesis that perinatal BPA exposure predisposes individuals to mammary cancer and reveal the dose-response pattern. Additionally, it will identify candidate molecular markers and morphological signs as predictors of neoplastic outcomes. This knowledge is crucial for the toxicological evaluation of BPA. The success of this project would suggest the addition of some of these mammary gland end points to the toxicological assessment of chemicals.

PI: Soto, Ana
Title: Mechanism of Developmental Toxicity of Bisphenol-A
Abstract:
Developmental exposure to bisphenol-A (BPA) at doses within the range of human exposure causes a complex array of adverse effects in animals. These outcomes are also known to be present in human populations and the rise in their occurrence coincides with the massive use of BPA and other endocrine disrupting chemicals in consumer goods. The main hormonal activity of BPA is as an estrogen mimic. Exposure to estrogens throughout a woman's life, including the period of fetal development, is considered a main risk factor for breast cancer. Developmental exposure to BPA altered mammary gland morphogenesis in rodents during the period of exposure and led to the development of pre-neoplastic and neoplastic lesions appearing in adulthood.

The goal of this proposal is to identify the molecular, cellular and morphogenetic mechanisms underlying BPA-driven altered mammogenesis that predisposes to neoplastic transformation. To achieve this goal, we will use innovative tools such as a fetal mammary gland explant culture model that allows testing for direct effects of hormones and real-time observation of organogenesis.
The specific aims of this proposal are to test three hypotheses, namely:

  1. That the direct effect BPA on mammary gland development is mediated by ER1 and/or 2.

  2. That BPA causes altered ductal morphogenesis i) by altering the composition and physical properties of the ECM and ii) by inducing adipogenesis.

  3. That the different mammary gland phenotypes resulting from gestational and gestational plus lactational BPA exposure are due to alterations at the hypothalamic level.

PI: Souvaine, Diane
Title: Geometric Data Structures
Abstract: A data structure is a repository of information; the goal is to organize the data so that it needs less storage (space) and so that information can be retrieved quickly (query). A geometric data structure handles data which has locations attached to it (e.g. addresses of fire stations in the state of Massachusetts). Geometric data structures have become pervasive and an integral part of life; and can be queried to produce driving directions or the name of the nearest Italian restaurant. Since the space and query time of a data structure depend upon the type of queries it has to support, it is important to study which tools and techniques are suitable for which data structures. The ongoing quest for better data structures sometimes results in improved methods and sometimes results in entirely new techniques. The goal is to determine optimal data structures with the best possible performance.

This research project focuses on creating new and efficient data structures for geometric queries and geometric decision problems that close the gaps between known lower and upper bounds. Particular problems include planar simplex emptiness queries, relative convex hull queries in dynamic subdivisions, and dynamic vertical ray shooting queries, and the implementation of the resulting data structures in both the real RAM and word RAM models. The project also addresses key problems in computational geometry such as computing spanning trees with low crossing number, constructing minimum size cuttings in 3-space, and generating convex subdivisions from disjoint line segments in such a way as to solve plane reconfiguration problems such as the compatible geometric matching problem. Solutions to these problems will contribute to the creation of efficient data structures for geometric queries such as multi-point location, ray shooting, and range searching. These data structures are fundamental to the field of computational geometry, and have broad applications in computer graphics, robotics, CAD/CAM, motion planning, collision detection, and geographic information systems.

PI: Sprague Martinez, Linda
Title: Nuestro Futuro: Applied Science Education to Engage Black and Latino Youth
Abstract:
This project is a curriculum based educational opportunity implemented in an after-school enrichment setting in a Boston, MA public middle school. The project builds on the active NIMHD funded research intervention study, Nuestro Futuro Saludable. This academic enrichment program is focused on inquiry-based science education, public outreach and community-based information campaigns to educate students, families, and their communities on health research topics within a health equity framework. The program is designed to (1) cultivate a deeper, contextualized understanding of scientific concepts related to health disparities and the social determinants of health in their community; (2) teach students to foster their ability to "think" like scientists from various disciplines (e.g.: epidemiology, biomedicine) as they study diseases that present disparities in their community (e.g.: asthma, diabetes, HIV/AIDS); and (3) provide an opportunity for students to use what they have learned about health, science, and disparities to develop and carry-out local advocacy and outreach efforts.

The project is designed to increase the scientific literacy of Latino and black students, as well as student interest in the sciences and enthusiasm for studying the sciences by providing research career awareness opportunities, mentoring and information dissemination to increase the representation of underrepresented minority groups in the sciences.

PI: Stadecker, Miguel
Title: Immunoregulation in Schistosomiasis
Abstracts: Schistosomiasis is a major neglected helminthic disease suffered by over 200 million people throughout the world. Critical to understanding schistosomiasis is the notion that it represents an immunologically mediated disease, that is, the damage to the affected tissues is inflicted by the host's own immune system, rather than by the parasite itself. Thus, morbidity and mortality are largely due to a pathogenic CD4 T lymphocyte-mediated immune response against parasite egg antigens. This results in granulomatous and fibrosing inflammation, which in the case of the species Schistosoma mansoni, takes place in the liver and intestines. The magnitude of disease varies greatly from individual to individual. In the majority of cases there is relatively limited immunopathology with good survival, however, in a minority of patients there is severe disease and death. S. mansoni infection in a mouse model similarly results in marked strain variation of immunopathology. In CBA mice, severe hepatic inflammation is associated a novel subset of pathogenic CD4 T cells producing IL-17 (Th17 cells), of which an expanded, clonally-restricted subpopulation is specific for the immunodominant epitope 234-246 of the major Sm-p40 schistosome egg antigen (Sm-p40234-246). In contrast, C57BL/6 mice develop milder lesions within the context of a largely anti-inflammatory immune response. The objective of the present application is to investigate the mechanisms that underlie the development of the severe form of immunopathology embracing the hypothesis that this is precipitated by a distinct, genetically determined innate antigen-presenting cell (APC) reaction to parasite products resulting in the development of a pathogenic adaptive Th17 cell response. Aim 1 of the proposal is to ascertain by gene profiling, and functionally test by gene knock- down, the lectin receptors on APC that recognize specific parasite egg-derived glycoproteins leading to pathogenic Th17 cell differentiation in CBA mice. Aim 2 is to understand the role of Sm-p40-reactive T cells in mediating severe pathology by making use of novel mice expressing a transgenic Sm-p40-specific T cell receptor, or rendered unresponsive to Sm-p40 by virtue of transgenic expression of this antigen in the thymus. Aim 3 is a forward genetic analysis to identify relevant quantitative trait loci taking advantage of unique congenic strains between BL/10 and BL/6 mice, which differ in only 5% of their genome, and yet exhibit significantly dissimilar IL-17 production and hepatic egg-induced inflammation. The proposed studies will provide new insights into the mechanisms leading to severe immunopathology in schistosomiasis. Their ultimate objective is the design of focused, realistic and practical strategies for amelioration of disease, which could be amenable for consideration and implementation in the human patient population.

PI: Staii, Cristian
Title: Combined Atomic Forces Microscopy/Fluorescence Spectroscopy Approach for Measuring Adhesion, Connectivity and Electrical Activity of Neurons Patterned on 2-Dimensional Protein Substrates
Abstract: The objective of this project is to gain a deeper understanding of the basic rules that neuronal cells use to form functional connections with one another. Understanding the brain is of tremendous fundamental importance, but it is immensely challenging because of the complexity of both its architecture and function. The central nervous system consists of many different spatially localized and yet highly interconnected regions. To date the processes involved in forming functional neuronal connections, the mechanisms of axonal navigation to their target region and their specific interactions with guidance factors such as chemical gradients and mechanical cues are still largely unknown.

The scientific goal of the current project is to understand the fundamental processes governing the development of connections and communications between neurons in living systems by studying the growth and interconnectivity of small numbers of neurons patterned in simplified, well-controlled geometries. The central hypothesis is that simplifying the neuronal growth environment by creating highly controlled neuronal circuits in vitro will allow the basic rules that underlie neuronal development and the formation of neural connections to be elucidated.

Simple neuronal networks will be created on two dimensional substrates, guiding the formation of synapses and measuring their electrical activity using a) atomic force microscope nanolithography; b) atomic force imaging and atomic force based electrical force microscopy; c) fluorescence spectroscopy.

Specifically, one aims to:

  1. pattern different types of proteins/growth factors at precise locations on surfaces and use them as growth templates for fluorescently labeled neurons;

  2. guide the formation of neuronal synapses by controlling the type and geometry of the underlying protein patterns;

  3. systematically investigate the adhesion and growth of neuronal processes using both atomic force and fluorescence spectroscopy measurements;

  4. map the electrical activity of the network by combined electrical force microscopy and fluorescence microscopy.

The crucial aspect for this last step is the use of a voltage-biased atomic force tip as a movable electrode to both stimulate and record the electrical activity of patterned neurons, both at the synapse level and along the neuronal pathway. Simultaneous fluorescence monitoring will identify the specific signaling molecules released during synapse formation as well as during the propagation of the electrical signal. By performing these experiments one seeks to a) quantify the role that different types of biochemical and geometrical cues play in neuronal growth and development; b) to measure under what conditions synaptic junctions are functional and c) to learn to control the formation of functional synapses in neuronal circuits having well-defined geometries.

PI: Starks, Philip
Title: REU Site: Integrative Approaches to Studying Recognition Systems in Cells, Organisms, and Populations
Abstract:
Our three main goals are:

  1. To educate the next generation of biological researchers,
  2. To facilitate undergraduate inclusion in high-quality, cross-disciplinary research, and
  3. To provide a research experience for qualified but underrepresented students.

The ability to recognize and respond is essential to the survival of organisms. Our REU students engage in cross-disciplinary research within the general field of recognition systems. Students design experiments, collect and analyze data, and present results for projects related to two recognition system topics: stress and signaling.While each student has an individual project, students also work in small and large groups to facilitate group cohesion, camaraderie, and collaboration. Through seminars and tutorials, students are exposed to research conducted by scientists within and outside the Biology Department. Students investigate a diversity of systems (plants & animals; invertebrates & vertebrates) using a large diversity of tools (from chemical to demographic analyses).

PI: Stites, Elizabeth
Title: Engaging Male Youth in Karamoja
Abstract:
Our research seeks to understand the ways in which customary mechanisms are addressing the rapidly changing social, political and economic order in Karamoja. We are seeking to understand the ways in which customary mechanisms are able to respond (or not respond) to these changes. In particular we are examining how these mechanisms mediate diversified livelihood systems, interact with new security structures, and address the protection gaps emerging in the absence of self-protection through weapons ownership. In parallel we are examining how different sectors of the population view and adhere to these customary mechanisms. We are working in multiple areas in Karamoja to capture the diversity of experiences in terms of livelihood change, relations to the military/state, and protection gaps.

PI: Sun, Xingmin
Title: Signaling Pathway of TNF-α Production and Clostridium difficle Infection (CDI)
Abstract:
My long-term career objective is to utilize knowledge acquired through my work and others to develop measures of prevention and therapy against CDI and other enteric pathogens-associated diseases. The object of this study is to elucidate the signaling pathway of C. difficile toxin-mediated TNF-α production and develop a novel therapy against CDI by targeted blocking TNF-α production. Three specific aims will be pursued.

  • Specific Aim 1: Identify subsets of immune cells that are major producer of TNF-α in response to C. difficile toxins in vivo, based on our hypothesis that intestinal dendritic cells (DCs) and macrophages are major TNF-α producer during the bacterial infection.
  • Specific Aim 2: Investigate the signaling events that lead to toxin-mediated TNF-α production in macrophages.
  • Specific Aim 3: Evaluate blocking TNF-α production as an adjunctive therapy against intestinal inflammation in both primary and recurrent CDI.

For specific aim1, TNF-α producing immune cells will be identified by immuofluorescence staining and immunohistochemistry in mouse ileal loop model and C. difficile infection in mice. To more precisely assess the roles of DCs and macrophages in TNF-α production, DC- or macrophage-depleted mice will be used.

For specific aim 2, multiple approaches including siRNA knockdown, Western-blot analysis, RT-PCR will be performed to identify the involvement of small Rho GTPases and dual specificity phosphatases (DUSPs) in C. difficile toxin-induced TNF-α production.

In specific aim 3, a novel glucan particle (GP)-dependent siRNA delivery system specifically targeting macrophages and DCs will be employed to evaluate blocking TNF-α production as an adjunctive therapy against intestinal inflammation in CDI.  

PI: Swan, Chris
Title: Collaborative Research: Engineering Faculty Engagement in Learning Through Service (EFELTS)
Abstract:
This project focuses on Learning Through Service (LTS), a pedagogical method that combines academic learning with service. Engaging investigators from five diverse institutions, the project is invoking a 4D Process (Discover, Distill, Design, Disseminate) to evaluate the impacts on faculty currently engaged in LTS efforts and to empower additional faculty to implement LTS. Major activities that are being undertaken include surveying and interviewing engaged faculty; convening a meeting of experts in LTS program/course designs, implementations, and assessments; conducting intensive faculty training workshops on LTS that lead to new LTS efforts at course and program levels; and sustaining faculty engagement via a continued dissemination of efforts. Assessment research methodologies (development and use) are being integrated throughout these activities. The project engages faculty through systemic implementation and support for LTS in engineering education. The project expands the use of LTS in engineering education and highlights LTS as a viable research endeavor and scholarly activity. The project identifies challenges and facilitators to LTS for different faculty and institution types.

PI: Swan, Chris
Title: Collaborative Research: The Impacts of Service on Engineering Students (ISES) – A Longitudinal Study
Abstract:
This engineering education research project will increase our understanding of learning through service (LTS) programs, specifically aiming to determine whether international service learning is a viable curricular approach with respect to developing desired engineering attributes. The research questions addressed in the proposal are timely since an increasing number of engineering students participate in international service projects at some personal and institutional expense. The project hypothesizes that LTS improves holistic thinking without detracting from technical ability, and this hypothesis is tested through a well-defined set of research questions.

The broader significance and importance of this project is to validate service learning as an effective educational strategy for engineering students. Although such programs are popular, they can potentially add costs to college education and some questions about their effectiveness remain unanswered. This study may develop insights into LTS and a set of "best practices" that can inform programs that wish to adopt this pedagogy. There is the potential to demonstrate improved recruitment and retention of under-represented groups.

PI: Swartz, Roger
Title: Community Innovations for Polio Eradication
Abstract: The Positive Deviance Initiative (PDI) at Tufts University proposes Community Innovations for Polio Eradication (CIPE), an operational research project designed to identify and address barriers to polio eradication in selected areas of Pakistan and Nigeria with persistent transmission of polio. Despite extraordinary efforts and a high degree of technical and logistical sophistication, polio eradication efforts in parts of these two countries (as well as several other nations) have faltered. While the will and the urgency exist, how to understand and respond to these local contexts and challenges seems out of reach. The "last inch" to eradication requires more attention to existing micro-innovations and a focus on the demand rather than the delivery side of the equation.

The Positive Deviance approach is the how.

Positive Deviance (PD) is an innovative approach designed specifically to address long-entrenched problems that have proven difficult to solve despite many previous efforts. By bringing together all the stakeholders in a process of data collection, discussion and discovery, PD enables the community to leverage the behavioral and technical innovations that already exist within the community. Because the strategies and resources come from within instead of being imposed from without, the outcomes are profound. The proposed CIPE study will bring together an experienced PDI team with national and community resources to rapidly identify existing successful behaviors and strategies within these communities and set the stage for piloting and disseminating the discovered solutions.

PI: Swartz, Roger
Title: Integrating the Positive Deviance Approach into Social Work Education and Practice in New York City
Abstract: Positive Deviance is based on the observation that in every community there are certain individuals or groups (the positive deviants), whose uncommon, but successful, behaviors or strategies enable them to find better solutions to a problem than their peers. These individuals or groups have access to exactly the same resources and face the same challenges and obstacles as their peers. The PD approach is a strength-based, problem-solving approach for behavior and social change, which enables the community to discover existing solutions to complex problems within the community. The PD approach thus differs from traditional "needs based" or problem-solving approaches in that it does not focus primarily on identification of needs and the external inputs necessary to meet those needs or solve problems. A unique process invites the community to identify and optimize existing, sustainable solutions from within the community, which speeds up innovation. PD is grounded in the belief that community transformation can be realized by the discovery of innovations and wisdom that already exists within a community.

The Positive Deviance Initiative, of the Friedman School of Nutrition Science and Policy at Tufts University, in partnership with the New York City Housing Authority (NYCHA), the Department for the Aging (DFTA), Children's Aid Society, and the Silberman School of Social Work at Hunter College, proposes a three-year project to increase the capacity of the Silberman School of Social Work to teach the theory and methodology of the Positive Deviance approach to students and faculty and to provide students with opportunities for applied learning through community-based placements.

Community-based placements will include two demonstration projects, one to increase school performance in adolescent male students in the Bronx, and another to improve the health and well-being of older adults in public housing by addressing the issue of social isolation. Integration of the PD approach into Silberman course work as well as participation in these two demonstration projects will provide students with the opportunity to understand how the PD approach can be integrated into social work practice. Development of the Silberman curriculum to teach the PD approach in the social work sector will increase the reach of the PD approach to a macro-level and may also be used as a model for including the approach more broadly in social work education.

PI: Sykes, Charles
Title: A Single-Molecule Approach for Understanding and Utilizing Surface and Subsurface Absorption to Control Chemical Reactivity and Selectivity
Abstract:
Heterogeneous hydrogenation reactions are among the most scientifically and technologically important chemistries and play a major role in the petrochemical, pharmaceutical, and food industries. While the reactions’ pathways themselves are often very complex, very basic steps often dictate important parameters like activity and selectivity. Recent research has hinted that the traditional picture of chemical reactions proceeding via only surface-bound species is totally inadequate in describing such systems. Evidence is gathering that subsurface species like hydrogen and carbon are sometimes more reactive and can even have a greater influence on the reaction outcome than surface-bound reactants. Therefore, elucidating the atomic-scale geometry, electronics and chemistry both on and under the surface of catalytically important metals and alloys will prove transformative in advancing current catalytic technology, cutting down on waste products, and helping facilitate more energy-efficient conversion to products.

This project will exploit and build on our recent findings that:

  1. Individual, isolated atoms like Pd in catalytically important alloys can be very active for key steps in hydrogenation chemistry
  2. Individual hydrogen atoms both on and under the surface of Pd metal can be imaged and manipulated at the atomic-scale and
  3. Single enantiomers of a chiral molecule can be distinguished based solely on scanning probe height measurements allowing enantiospecific reactions to be monitored in situ at the single-molecule level.

These unique capabilities will allow the roles of surface and subsurface hydrogen in both regular and enantioselective hydrogenation reactions to be interrogated at a new level of detail. The PI’s labs are well equipped with state of the art scanning probe and surface science instrumentation and the group has published twenty independent papers in the last four years.

The proposed work is aimed at:

  1. Quantifying hydrogen adsorption on and absorption in catalytically important Pd particles and alloys.
  2. Exploring the chemical reactivity and specificity of surface and subsurface hydrogen in a variety of industrially important hydrogenation reactions.
  3. Utilizing subsurface hydrogen to engineer a novel approach for asymmetric catalysis.

This work will be innovative in developing links between the atomic-scale composition, structure and electronic properties of catalytically important materials and their reactivity in industrially important reactions. The experiments will be the first to relate the atomic-scale details of subsurface reactants to the reactivity of the system as a whole. The work will also provide a framework for building theoretical models that predict reactivity trends. Knowledge garnered from these systems will address a critical need for structure-property-activity relationships that encompasses both the surface and near-surface regions of hydrogenation catalysts. As such, the results will have a significant impact on the chemical, clean energy and chiral catalysis fields.

PI: Sykes, Charles
Title: CAREER: Investigating and Controlling Molecular Rotation on Surfaces
Abstract: The term “molecular rotor” was coined during the inception of nanoscience and defines a system in which two parts of a molecule rotate relative to each other. Over the last fifteen years, organic chemists have synthesized many complex molecules with functionality that allows facile rotation. Very recently molecular rotors have been used to measure microviscosity in living cells, a property linked to disease and malfunction. Studying the rotation of molecules bound to surfaces offers the advantage that a single layer can be assembled and monitored using the tools of surface science. This approach opens up the possibility to engineer artificial molecular machinery that can respond to external stimuli and perform useful work such as driving fluid flow. Understanding and controlling the rotation of individual molecules on surfaces is a crucial step towards the development of future applications such as pumps, sensors, actuators and microwave signaling applications.

We have considerable recent experience with thioether self-assembly and have made significant progress in understanding the rotation of a simple set of thioether molecules. The unique properties of the low-temperature scanning tunneling microscope have allowed us to monitor the rotation of individual molecules as a function of temperature, applied electric field, and the proximity of neighboring molecules. We have measured the rotational energetic barriers and pre-exponential factors of a set of thioethers and can even discern the direction of rotation of individual molecules. Through a series of controlled manipulation experiments we have switched the rotation on and off reversibly by altering either the proximity of the tip or by moving the molecules towards or away from one another.

Our preliminary data demonstrates that the thioether backbone constitutes an excellent test bed for studying the details of molecular rotation at the single-molecule level. Our hypothesis is that the simplicity and tunability of this system will allow us to systematically investigate and control effects such as thermal fluctuations, lack of ordering, dipolar coupling and nanoscale friction that currently prevent molecular machines from doing useful work.
This proposal is aimed at:

  1. Elucidating the mechanism of thermally- and electrically-driven molecular rotation
  2. Chemically modifying the rotors to control the onset of these types of driven motion
  3. Designing and testing a system that exhibits electrically-driven unidirectional motion
  4. Building ordered arrays of dipolar rotors and elucidating their electrostatic coupling

PI: Sykes, Charles
Title: Collaborative Research: High Throughput Structure Sensitive Surface Chemistry
Abstract:
In this project will collaborate to develop and apply methods for high throughput study of structure sensitive surface chemistry. The core of the experimental program is the preparation, characterization and study of curved single crystal metal surfaces that expose continuous distributions of surface orientations; i.e. regions of the surface that expose different step and kink densities. Spatially resolved experimental tools such as STM, XPS, and LEIS will be used to characterize the local structures of these surfaces and to measure surface reaction kinetics at each point. This effort will resolve the role of step and kink density in several surface reactions. Complementary computational modeling tools will be used to understand the role of surface orientation in surface reaction kinetics. These methods will greatly accelerate the study of structure sensitive surface chemistry. The impact of this work will be development of a fundamental understanding of several catalytically important surface reactions.

PI: Sykes, Charles
Title: Turning Molecules into Motors and Mechanical Devices
Abstract:
Molecular motors are ubiquitous in nature; they perform tasks as varied as organizing the cellular cytoplasm by vesicle transport (e.g. kinesin or dynein) to powering the motion of cells (e.g. the bacterial flagellar motor) and even driving whole body locomotion through muscle contraction. In stark contrast to nature current manmade devices, with the exception of liquid crystals, make no use of nanoscale molecular motion. This is due in part to a gap in the understanding of how individual molecular components behave in the face of opposing forces such as friction, thermal fluctuations, coupling to neighbors and lack of inertia. Understanding and actuating the rotation of individual molecules on surfaces is a crucial step towards the development of nanoscale devices such as fluid pumps, sensors, delay lines, and microwave signaling applications. Recently the Sykes group has pioneered the use of a new, stable and robust molecular rotor system based on surface-bound thioethers (RSR) to attack these issues. The research aims to achieve the directed electrically powered rotation of single molecules, organize functional molecular rotors in ordered 2D arrays, and develop methods for coupling mechanical motion between neighboring molecules.

PI: Taylor, Allen
Title: Mechanistically Linking AMD, Glycemic Index and Protein Homeostasis
Abstract: Loss of sight is a major fear and significantly compromise to the quality of life among the elderly. Age-related macular degeneration (AMD) is the most common cause of irreversible blindness. There is no cure for this devastating disease. Costs associated with AMD are in the billions per year in the US alone. It is imperative that means to delay the onset or progress of AMD be found soon because the number of people afflicted is growing so rapidly. New information from three large human cohorts indicates that consuming lower glycemic index diets (GI) is associated with a lower risk for all grades of AMD as well as for delayed onset or progress of early AMD. This information suggests that slightly limiting intake of readily digested carbohydrate, or simulating such dietary practice, may provide a means to delay the onset and progress of all stages of AMD or even prevent it. Slowing AMD progression, particularly at early stages, by as little as 10-20% can delay vision loss for 5-10 years. Prior to initiating costly intervention trials, it is essential to replicate these findings in controlled animal trials and learn about the mechanism of how consuming lower GI diets protects the retina. Our pilot animal studies indicate that consuming lower GI diets results in delayed accumulation of early AMD-related retina lesions. This is also associated with less protein modification by sugars (glycation). Glycated proteins are toxic and related to AMD development. Furthermore, biochemical studies indicate that the cellular proteolytic capacities that normally eliminate cytotoxic proteins are compromised by glycation. In order to exploit these data, it is crucial to understand the patho-biochemical relationship between consuming higher GI diets, appearance of early AMD-related lesions, accumulation of cytotoxic glycated proteins, and the fidelity of the protein editing, proteolytic machinery. In this work we will test the hypothesis that early AMD-like lesions will be delayed, glycative stress diminished, and proteolytic functions that remove glycated proteins retained in mice that consume lower GI diets or when activators of the ubiquitin or lysosomal proteolytic pathways are employed. Such etiologic and mechanistic information will substantiate the benefit of lower GI diets and pave the way for intervention trials. The information is also essential for designing new interventions (dietary and pharmaceutical) that will diminish the AMD burden. The first Aim is to define the relationship between dietary GI, risk for early AMD lesions, and protein glycation. Because AMD is related to compromised protein quality in the RPE and its environs, the focus of Aim 2 will be novel experiments to define relationships between accumulation of glycated proteins and the fidelity of the protein quality control machinery, using RPE from the animal models and differentiated RPE. In Aim 3 we will try new drugs to diminish carbohydrate-induced stress and prolong retinal function. Due to the similarity of the response of many cells to glycative stress and the similar protein quality control in many cells it is anticipated that our observations and discoveries will impact many disciplines and have major health ramifications. This includes heart disease and type 2 diabetes, both of which have been related to dietary carbohydrate intake. 

PI: Taylor, Allen
Title: Ubiquitin Function in Eye Lens
Abstract:
Sight is our most valued sense. Cataract, or opacification of the lens afflicts virtually all the elderly and surgical extraction of the opacified lens is the most commonly performed surgery, accounting for among the largest line items in our Medicare budget. Fortunately, there is a successful procedure for removing cataracts. Unfortunately, the success is of limited duration because cells grow in the lens capsular bag that remains after cataract surgery causing re-opacification or "secondary cataract." It is essential to discover means to extend the duration of lens clarity after surgery and it would also be of invaluable benefit to delay cataract formation initially. To accomplish these objectives it is essential to understand how cell proliferation and differentiation are controlled in the lens. Cataract is due in part to production of abnormal genes and proteins. The ubiquitin proteolytic pathway (UPP) controls the expression of many genes and the levels of many proteins. We have shown that alteration of components of the UPP result in abnormal lens cell proliferation, differentiation and cataracts. Our findings clearly demonstrate a critical role for a fully functional UPP in regulation of lens formation, including cell proliferation and differentiation. There are many components to a ubiquitin pathway. Identifying essential components of UPPs and elucidating their function will identify specific molecules, the activity of which, if controlled, can be used to regulate proliferation and differentiation. The research proposed herein will identify functions of ubiquitin per se, and specific controllers (UbcH3, 7, 10) of lens cell proliferation and differentiation.

In accomplishing these objectives we will identify a myriad of new targets for pharmacologic intervention to delay formation of secondary cataract. Importantly, each of our hypotheses is testing a fundamental novel concept. Since much about the UPP is similar in many types of cells and tissues, the information we gather will provide understanding of how this pathway works in many other types of cells and tissue. Thus, our research will also inform about targets which should provide new therapeutics for many other tissues, in addition to lens, where controlled proliferation is desirable. This includes cornea, trabecular meshwork, retina and many cancers.

PI: Teixidor I Bigas, Monserrat
Title: The Poincaré Institute: A Partnership for Mathematics Education
Abstract:
The Poincaré Institute for Mathematics Education, led by Tufts University, in collaboration with TERC, with Dover, NH, School District as core partner, and partner districts in Massachusetts (Fitchburg, Leominster, Medford, and Somerville), New Hampshire (Dover, Sanborn, and Timberlane), and Maine (Portland), seeks to transform and improve the teaching and learning of mathematics in middle school and the connections between the elementary, middle, and high school curricula. One hundred eighty in-service and 24 new teachers and, each year, more than 2200 students benefit from the project’s work.
Building on successful NSF-funded collaborations between Tufts and TERC — the Fulcrum Institute, the Early Algebra, Early Arithmetic Project, and the Inquiry Project — the Institute leverages expertise from mathematicians, physicists, educational researchers, and school districts to:

  1. create graduate-level online courses on mathematical content, research in mathematics education, and mathematical knowledge for teaching, offered to three cohorts of in-service teachers (grades 5 to 9) from three states;

  2. use algebra and the mathematics of functions and modeling for promoting coherence among topics in the mathematics curriculum;

  3. implement permanent discussion forums where teachers plan, review (using video technology), and improve their lessons, drawing upon the critical mathematical topics and issues of learning and teaching;

  4. strengthen and expand partnerships with schools by preparing teachers and researchers in Tufts’ graduate programs in Mathematics and Education, through internships with teacher leaders and participation in educational research;

  5. conduct research on teacher development and student learning;

  6. support school districts’ efforts to improve their mathematics curriculum; and

  7. disseminate a teacher development model for adoption by other university-school partnerships.

Partners in this proposal recognize the importance of middle school, a period when many students lose interest in mathematics. The problem is acute not only in urban centers, where algebra has often served as an “engine of inequity” (Kaput, 1998) that widens the achievement gap between socio-economic, racial, and ethnic groups, but also a concern in rural areas and in areas of immigrant concentration. The project rests on the premise that to improve students’ learning one needs to broaden and deepen teachers’ understanding of mathematics, of how children think and learn, and of mathematics knowledge for teaching. The project’s research mathematicians and physicists identify and streamline a well-defined set of critical topics and physics phenomena for middle school mathematics, with input from mathematics education researchers and school districts. Mathematics education researchers identify issues of learning and teaching relevant to the chosen critical mathematics topics. Rather than re-teach the mathematics that the teachers already know or offer a set of pre-packaged lessons, the Institute offers them a broad, unified framework to re-envision the mathematics they already teach. Aided by online and face-to-face interactions with researchers, the schools create self-sustaining discussion groups focused on effective pedagogy for mathematics instruction. Experts in the use of software and classroom video in educational settings help bridge the Institute courses and teachers’ initiatives in the schools. Quantitative and qualitative measures are used to answer questions about impact and process.

PI: Terenzi, Gina
Title: Post-Doctoral Training in General, Pediatric and Public Health Dentistry
Abstract:
The purpose of this project is to create an Advanced Education in General Dentistry (AEGD) program at Tufts University School of Dental Medicine (TUSDM) and to enhance the general practice training opportunities of the TUSDM’s General Practice Residency (GPR) in Dentistry training program, and will expand dental workforce training activities as a result of this new oral health workforce program. The development and implementation of the AEGD will be in accordance with the American Dental Association’s recommendation for the Commission of Dental Accreditation for new program development in post graduate dental education. The proposed AEGD and enhanced GPR, along with affiliated Primary Care Providers in medicine, will provide increased access to care for populations at risk for oral health disease, defined as patients with developmental disabilities, HIV/AID’s, elderly, victims of domestic violence and substance abuse, the homeless and immigrants. Emphasis will be made on the importance of oral health and its impact on general health and quality of life through the newly created and enhanced curriculum in conjunction with the services the funds requested will provide. The development and implementation of an AEGD and the enhancement of the GPR at TUSDM will use the distance learning principles of Internet based curriculum to foster curriculum enhancement for faculty and resident training. The grant funded project to create faculty development will provide the framework for comprehensive, quality patient care utilizing community and dental school-based facilities as clinical sites for pre-doctoral student, resident, and faculty education, development, and practice.

PI: Tesco, Giuseppina
Title: Role of ADAM10 in the Pathogenesis of Alzheimer’s Disease after Head Trauma
Abstract:
Alzheimer's disease (AD) is a complex disease influenced by the actions of multiple genes, their interactions with each other and with the environment (Reitz et al. 2011). Traumatic brain injury (TBI) is one of the most robust environmental risk factors for AD (Johnson et al.). TBI has been suggested to accelerate the onset of AD and the severity of the injury positively correlates with increased risk (Jellinger 2004). Compelling evidence is mounting that a single TBI event is associated with increased levels of Aβ and amyloid deposition both in humans and animal models. Experimental TBI in rodents has been reported to increase levels of BACE1 (Blasko et al. 2004, Loane et al. 2009), suggesting that BACE1 elevation may be responsible for increased Aβ production following TBI. Increased β-secretase activity can result in adverse functional outcome post-injury not only from increased Aβ, but also from increased levels of APP-C99 (Neve et al. 1996, Berger-Sweeney et al. 1999) or decreased levels of APPsα (Vassar et al. 1999). More importantly, APPsα treatment reduces neuronal injury and improves functional outcome following diffuse traumatic brain injury in rats (Thorton et al. 2006).

ADAM10 has been identified as the major α-secretase in the brain. Overexpression of ADAM10 in the brain lowers the amyloid plaque load and leads to an improvement of cognitive performance in a mouse AD model (Postina et al. 2004). While transgenic mice expressing a dominant negative mutant form of ADAM10 (E384A enzyme site mutation) had greatly reduced levels of sAPPα, increased plaque load and learning deficits when measured by Morris Water Maze (MWM). More recently, our collaborator, Dr. Rudy Tanzi, has found evidence of a genetic association of ADAM10 with AD as well as two rare potentially disease-associated non-synonymous mutations, Q170H and R181G, in the ADAM10 prodomain. Functionally, both mutations significantly attenuated the α-secretase activity of ADAM10 (>70% decrease), and elevated Abeta levels (1.5-3.5-fold) in cell-based studies (Kim et al. 2009). Dr. Tanzi's group has confirmed these finding in transgenic mice.

We hypothesize that transgenic mice over expressing ADAM10 on an AD background (APPSwe, Tg2576) will demonstrate significant neuroprotection following experimental TBI through reduced Aβ production, improved plaque load, reduced lesion volume, improved motor performance and improved learning and memory when compared to transgenic mouse lines expressing dominant negative mutant forms of ADAM10 (E384A, enzyme site mutation; Q170H and R181G prodomain mutations identified in AD patients) which have reduced levels of sAPPα.

Specific Aims:

Hypothesis 1: Overexpression of wild type ADAM10 decreases Aβ levels and improves functional outcome, while overexpression of ADAM10 dominant negative mutations (E384ADN, Q170H or R181Q) potentiate Aβ increases and worsen functional outcome in the sub-acute phase post-TBI in Tg2576 mice.

Aim 1: Determine the extent to which overexpression of wild type ADAM10 or dominant negative mutants affects Aβ deposition and functional outcome following TBI in the sub-acute phase post-TBI in Tg2576 mice.

Hypothesis 2: Overexpression of wild type ADAM10 delays Aβ deposition and improves functional outcome, while overexpression of ADAM10 dominant negative mutations (E384ADN, Q170H or R181Q) accelerate Aβ accumulation and worsen functional outcome in the chronic phase post-TBI in Tg2576 mice.

Aim 2: Determine the extent to which overexpression of wild type ADAM10 or dominant negative mutants affect Aβ deposition and functional outcome following TBI in the chronic phase post-TBI in Tg2576 mice.

PI: Tesco, Giuseppina
Title: The Role of BACE in the Pathogenesis of Alzheimer's Disease after Head Trauma
Abstract: Traumatic brain injury (TBI) is the strongest environmental risk factor for Alzheimer's disease (AD). Clinical and experimental TBI is associated with accelerated beta-amyloid (Abeta) deposition, a hallmark of AD pathology. The Abeta peptide is derived by serial proteolysis of amyloid precursor protein (APP) by beta-secretase at the N-terminus followed by gamma-secretase at the C-terminus. Beta-site APP-cleaving enzyme (BACE) has been identified as beta-secretase. BACE levels are elevated in AD brain, and BACE is induced as a stress-related protease following cerebral ischemia and TBI in rodents. We recently reported that BACE and beta-secretase activity increase following cerebral ischemia in vivo and caspase activation in vitro due to post-translational stabilization of BACE protein. We also found that the impaired degradation of BACE is due to caspase- mediated depletion of GGA3, an adaptor protein involved in BACE trafficking. In the current proposal, we report that genetic ablation of GGA3 increases levels of BACE in the brain in vivo.

Furthermore, we have found that GGA3 is depleted following TBI while BACE protein levels increase with a pattern similar to the one observed following cerebral ischemia. These new findings indicate that GGA3 depletion, mediated by caspase cleavage, and consequent BACE upregulation may be the common underlying mechanism of increased Aβ production following cerebral ischemia and TBI. Since Abeta has been shown to impair synaptic transmission, increased Abeta levels may be responsible for impaired functional outcome after TBI. This mechanism may also explain how TBI leads to increased risk of developing AD over time. In support of our hypothesis, we have found that GGA3 levels are decreased in both temporal cortex and cerebellum from AD subjects, suggesting that subjects with lower levels of GGA3 could be at greater risk of developing AD. This may be particularly true for patients with stroke and TBI in which caspase activation occurs even in the chronic period after injury. The long-term goal of this proposal is to identify targets for novel treatments to prevent acute learning and memory deficits as well as development of AD following TBI.

We propose the following specific aims:

  1. Determine the extent to which depletion of GGA3 regulates levels and activity of BACE and causes behavioral changes in mice;

  2. Determine the extent to which decreased levels of GGA3 affect BACE levels and activity and functional outcome following TBI in mice;

  3. Determine the extent to which lack or low levels of GGA3 exacerbate Aβ deposition in a mouse model of AD pathology (Tg2576 transgenic mice expressing human APP with the "Swedish" mutation (KM670/671NL)) in normal conditions and following TBI.

PI: Theoharides, Theoharis
Title: Brain Mast Cells and Chronic Fatigue Syndrome
Abstract: Chronic Fatigue Syndrome (CFS) is a complex disease with a prevalence as high as 1%. CFS involves the nervous, hormonal and immune systems with symptoms that include fatigue, sleep disturbances, malaise, muscle aches, migraines, gastrointestinal complaints and cognitive problems. There may be some mitochondrial "dysfunction" in CFS patients. Many CFS patients demonstrate abnormal hypothalamic-pituitary- adrenal (HPA) axis activity, while stress worsens symptoms. Central and peripheral cytokines produced in response to viral infections or other inflammatory stimuli may be implicated, but there is no distinct pattern. CFS is often comorbid with other disorders that include fibromyalgia, interstitial cystitis (1C), irritable bowel syndrome (IBS), migraines and post-traumatic stress disorder. Neuroimmune interactions in CFS are still unknown creating a vacuum in diagnosis and treatment. Mast cells and their mediators have been implicated in all diseases that are comorbid with CFS. Brain mast cells are abundant in the median eminence where they are juxtaposed to corticotropin-releasing hormone (CRH)-positive neurons and CRH is secreted under stress and we showed that CRH activates mast cells through CRHR-1 leading to release of vascular endothelial growth factor (VEGF), increased vascular permeability and blood-brain-barrier (BBB) disruption. We recently showed an inverse relationship between expression of the mitochondrial uncoupling protein 2 (UCP2), which also regulates production of reactive oxygen species (ROS) and cytosolic calcium, and mast cell activation. There are no effective therapies for CFS. Tricyclic antidepressants have been reported to be beneficial, and our preliminary results indicate that only the tricyclic amitriptyline, and certain natural flavonoids can inhibit mast cell secretion and reduce intracellular calcium ion levels.

Our hypothesis is that external triggers, along with CRH secreted by stress, activate diencephalic centers and mast cells, leading to release of proinflammatory and fatigue producing molecules, and these can be inhibited by select flavonoids. We will investigate:

  1. The effect of CRH, viral poly(l:C), lipopolysaccharide (LPS), neurotensin (NT), substance P (SP) and thymus stromal lymphopoietin (TSMP) or restraint stress using female C57BL/6 mice on:

    1. Fatigue using the forced water immersion test,

    2. BBB disruption by measuring brain levels of the fluorescent marker AngioSense, as well as

    3. Brain expression of histidine decarboxylase (HDC), CRN, beta-endorphin, IL-6, IL- 8, IL-17, somatostatin, TNF, mouse mast cell protease (MMCP), urocortin 2, UCP2 and VEGF;

  2. The requirement for mast cells, for NT, SP, the CRHR involved, and the role of UCP2 in the endpoints studied in Aim 1 by using C57BL-derived WW mast cell deficient mice, NT -/- mice, SP -/- mice, CRHR-1; CRHR-2 -/- and UCP2 -/- mice,

  3. Inhibitory effect of a flavonoid formulation containing luteolin/quercetin/olive kernel oil on endurance and brain biomarkers. The proposed research is hypothesis-driven, is based on strong preliminary evidence, is innovative with high likelihood for novel findings with applicability to humans. 

PI: Thomas, Huw
Title: Inter-Professional Education Initiative
Abstract:
As the Institute of Medicine reported a decade ago, there are safety, quality, cost and access problems in the delivery of healthcare. Clearly, healthcare providers, across the professions, need to work together to improve the health of the population while controlling costs. To achieve this vision, we must bring these professions together at the very beginning: in the education of the next generation of healthcare providers. With an entirely new approach to health education, dentists, physicians, nurse practitioners, dental therapists, nutritionists, pharmacists, and others, can learn together how to function as inter-professional healthcare teams. It is only as collaborative teams that practitioners can provide the high-quality, cost effective care the public deserves.

Given our unique and long-standing experience in educating holistic caregivers in multi-disciplinary teams, Tufts University School of Dental Medicine (TUSDM) is prepared to take the lead in advancing Inter-professional Education (IPE) for healthcare providers nationwide. In partnership with Tufts Medical School and Tufts Medical Center, we will explore various models for an IPE program. A thorough and candid evaluation of our outcomes will enable us to recommend guidelines and standards for dissemination to other institutions of education.

The first step is to hire a Director of Inter-professional Education who will focus on laying the foundation for a new way of educating healthcare providers. Taking advantage of dental school curriculum revisions already underway, the Director will work to build training collaborations between dental and medical students and integrate the concept of the healthcare team across existing, discrete interdisciplinary collaborations.

PI: Thomas, Samuel
Title: CAREER: Control of Self-Assembly and Electrostatics with Photolabile Polymers
Abstract: Materials that respond to light have major technological importance, with applications ranging from human health (e.g. imaging agents and photochemical delivery of therapeutic agents) to microprocessor fabrication (e.g. high-resolution patterning of polymers in photolithography). The proposed interdisciplinary research will develop polymers that respond to light in new ways with both fundamental and applied implications. The proposed work also integrates this research with education through two new programs:

  1. encouraging STEM careers by involving a local community college in scientific research;
  2. a high school science fair mentoring program.

PI: Thorley-Lawson, David
Title: Epstein-Barr Virus Latency
Abstract:
Non-keratinizing nasopharyngeal carcinoma (NPC) is 100% associated with the presence of the oncogenic human herpesvirus Epstein-Barr virus. It is divided into two sub types: poorly differentiated (type II) and undifferentiated (type III). Type III is by far the most common form of the disease. Although a major world heath problem, NPC remains understudied. Furthermore, because it develops in an occult site and initially presents with symptoms associated with upper respiratory tract infection, it often remains undetected until it has reached an advanced stage. This is critical because early stage disease is readily treatable and potentially curable, whereas therapeutics for advanced stage disease result in high morbidity and relapse rates and there are no effective options for treating metastatic disease. Therefore there is a pressing need for the development of new therapies that target advanced disease.

In this study we are using systems biology techniques to identify candidate molecules and processes that contribute to NPC tumor growth and metastasis. The intent is to investigate underlying mechanisms that may also identify targets for new therapies. In this work in vitro and in vivo (mouse) models of NPC tumor growth and metastasis will be developed. In vitro, cultured primary epithelial cells, well characterized NPC cell lines and tumor cells cultured directly from NPC biopsies will be used. In vivo ectopic tumor growth and a newly developed orthotopic NPC metastasis model will be used employing xenotransplanted NPC cell lines and tumor biopsy samples. These models will allow the evaluation of how processes, already identified in preliminary studies, contribute to disease development and progression. These are:

  1. To test the idea that type II and type III NPC are distinct at the molecular genetic level based on preferential deregulation of the PI3kinase/Akt/mTOR signaling pathway in type III NPC. Does this deregulation make type III tumors more vulnerable to drugs that target this pathway and will such drugs impede the invasive and metastatic behavior of the tumors in vivo?

  2. To study the role of the chemokine CCL5 (RANTES) in mediating epithelial and NPC tumor cell migration, invasion and metastasis.

  3. Study the role of the EBV encoded latent proteins LMP1 and LMP2a in tumor growth and metastasis in vivo, activation of the PI3Kinase/Akt/mTOR signaling pathway and induction of RANTES dependent migration, invasion and metastasis.
  4. To develop quantitative profiles of EBV miRNA expression in EBV associated tumors with special emphasis on NPC. Apply clustering algorithms to these data sets to define miRNAs whose expression is up- or down-regulated in NPC in order to identify their target genes and ultimately assess the role of these genes in tumor growth and metastasis in vivo.

PI: Thorley-Lawson, David
Title: Host Immunity to EBV Infection In vitro and In vivo
Abstract:
Epstein-Barr virus (EBV) infects and persists in >95% of the human population but is also associated with important forms of lymphoma, carcinoma and possibly autoimmune disease. We now have a detailed model of how EBV establishes persistent infection based on the concept that it uses the normal biology of B lymphocytes to gain access to and persist within the memory B cell compartment. At the heart of this model is the idea that EBV uses the germinal center (GC) reaction to convert latently infected B cells into memory cells. The GC reaction is the mechanism by which antigen activated B cells proliferate and undergo affinity maturation of their antibody molecules to become memory cells. EBV encodes proteins, LMP1 and LMP2a, that potentially have the signaling capacity to drive a latently infected cell through a GC into memory and their expression has been detected in tonsil cells bearing the GC marker CD10. However it is not known if these cells are functional GC cells or even reside within a GC. To resolve this issue we will:

  1. Use flow cytometry matched with highly sensitive quantitative PCR to show that GC cells, latently infected with EBV and expressing LMP1 and LMP2a, also express specific functional markers of the GC reaction. These include chemokine receptors, bcl-6, c-myc, p53 and AID.

  2. Dissect whole GCs and test if they contain EBV+ B cells expressing LMP1 and LMP2a.

  3. Use laser capture microdissection to isolate individual infected cells from GCs and test if they express functional GC markers.

These studies will reveal whether and to what extent EBV+ cells participate in the GC reaction. This is crucial for understanding the mechanism of EBV persistence and its role in Hodgkin’s disease and Burkitt’s lymphoma both of which are thought to arise from GC or post GC cells.

For the second goal we will analyze how EBV interacts with the host to produce latently infected memory cells. EBV has long been postulated to have a role in autoimmune diseases, including SLE and MS, because of its potential capacity to rescue autoreactive B cells. Previously this question could not be addressed, but our approach now makes this possible. We will ask if EBV+ memory B cells are antigen specific and, if so, are they autoreactive? We will use sensitive single cell RTPCR to identify the expressed immunoglobulin from EBV+ and EBV- memory cells isolated from the same individual. The PCR products will be cloned and expressed in bacterial or mammalian systems to produce the original immunoglobulins. These will be tested for autoreactivity by ELISA and immunofluorescence techniques on standard sources of autoantigens. This will answer the question of whether or not EBV promotes the survival of autoreactive B cells in vivo.

Mentor: Tickle-Degnen, Linda
Fellow: Bogart, Kathleen
Title: Compensatory Expressive Behavior for Social Functioning with Facial Paralysis
Abstract:
Although facial paralysis (FP) is a relatively common condition, affecting 127,000 Americans each year, there is a serious gap in understanding social functioning for people with this socially disabling disorder. My long-term goal is to develop interventions to improve social functioning for people with FP. The overall objective of this project, which is the next step toward attainment of my long-term goal, is to identify the compensatory expressive behaviors (i.e. gestures and prosody) that people with FP use to communicate and how other people interpret these behaviors to form impressions about their emotions and other attributes. My central hypothesis is that people with FP can compensate by using other expressive channels (body and voice) and that perceivers can improve the accuracy of their impressions of people with FP by focusing on their bodies and voices. The rationale that underlies the proposed research is that once compensatory expressive behaviors are identified and a perceiver training is tested, these can be used to develop interventions to improve social functioning.
The specific aims of the proposed research project are to:

  1. Identify the expressive behaviors that people with FP use to communicate their emotions and attributes;

  2. Determine the accuracy of perceivers' impressions of the emotions and attributes of people with FP and examine the relative contribution of different channels to accuracy;

  3. Examine whether training perceivers to attend to channels other than the face improves accuracy of impressions.

The proposed research consists of three social perception studies. In Study 1, adults with various types of FP (targets), including both congenital and acquired conditions are videotaped while being interviewed about their experiences living with FP. Trained research assistants will rate the expressive behaviors and severity of paralysis of the targets. In Studies 2–3, participants without FP (perceivers) will view 1 minute clips of the Study 1 targets and rate their impressions of the targets' emotions and attributes. In Study 2, perceivers will be given one or more expressive channels to observe: voice only, body only, face only, body and voice, or all channels. In Study 3, which tests a training intervention to improve accuracy, some participants will be trained to attend to the body and voice when rating their impressions of targets with FP, and others will not receive training.

The proposed research is significant because it is expected to vertically advance understanding of how people with FP can use compensatory expressive behavior and how perceivers can form impressions based on this behavior. Ultimately, such knowledge will inform development of interventions that will improve social functioning for people with FP.

PI: Trimmer, Barry
Title: IGERT: Soft Material Robotics
Abstract:
This Integrative Graduate Education and Research Traineeship (IGERT) award creates an interdisciplinary graduate program to develop advances in the field of soft robotics. These machines, inspired by animals, will be capable of complex tasks that are difficult to achieve with conventional robots, suitable for close interactions with humans, and able to work in environmentally sensitive locations. The research will cross traditional disciplinary boundaries, employing novel biomaterials, exploiting cellular processes and tissue engineering methods, and using control strategies derived from evolutionary principles approaches that are comparatively rare in conventional robotics.

PI: Trimmer, Barry
Title: Neuromechanics of Soft-bodied Locomotion
Abstract: Animals can move through the world in remarkably complex and effective ways that are still difficult or impossible to replicate in machines. This is particularly evident in soft animals such as octopus, worms and caterpillars which can change shape as they move. A long-term goal of this research is to understand how boneless animals control their bodies and to apply this knowledge in the design and fabrication of entirely new types of robot. In effect, soft animals are working prototypes for all sorts of new devices. Using a well-established model animal (the caterpillar, Manduca sexta) these experiments will simultaneously collect data on the mechanical performance and neural signals driving behavior. New measuring devices (e.g., flexible electrode arrays, micro-force beams) and computational methods have been developed to carry out these studies. Working with engineers, these data will be used to build mathematical models that control and simulate soft animal movements. One outcome will be the first explanation of how a massively deformable structure can be controlled using a few simple commands.

PI: Utz, Arthur
Title: Energy Resolved Studies of Dynamics, Reactivity and Mechanisms at the Gas-Surface Interface
Abstract:
In this project supported by the Chemical Structure Dynamics and Mechanisms Program of the Division of Chemistry, Prof. Arthur Utz of Tufts University will study how the motions (dynamics) of atoms and molecules can promote chemical reactivity at the gas-surface interface. Gas-surface reactions underlie industrial processes ranging from heterogeneous catalysis to materials deposition and semiconductor fabrication. The proposed studies will combine quantum state-resolved laser excitation of a gas phase reagent with ultra-high vacuum surface science techniques to show how specific molecular motions (bond stretches, bends, and surface vibrations) promote reactivity. Another line of inquiry will explore the rates and pathways for energy redistribution processes that dictate reactivity. The experiments will reveal how vibrational energy in the gas-phase reagent and in the surface impact reactivity. The study of surface vibrations will be a particularly significant focus as it has the potential to inform our understanding of the unique catalytic activity of nanoparticles. The ultimate goal of this work is to develop a better understanding of the important variables that influence gas-surface reactivity, with an aim towards designing better theories, identifying new strategies for chemical control, and revealing new practical applications. The results of this study will provide theorists with much useful data to test the latest theories.

The results of this research will also provide important guidance in designing practical catalytic reaction schemes, which are important to industry. Students and postdoctoral research associates who participate in this research acquire new knowledge and skills in preparation for advanced studies or entrance into the scientific/technological job market. The PI will also guide departmental efforts to incorporate active citizenship into the undergraduate and graduate curriculum at Tufts. These efforts will better prepare Tufts students to engage in public discourse, participate in outreach activities, and incorporate the principles of active citizenship in their professional careers.

PI: Utz, Arthur
Title: MRI: Acquisition of a Single Crystal X-Ray Diffractometer
Abstract:
With this award from the Major Research Instrumentation Program that is co-funded by the Chemistry Research Instrumentation and Facilities (CRIF) Program and the Office of Multidisciplinary Activities (OMA), Professor Arthur Utz from Tufts University and colleagues Terry Haas, Elena Rybak-Akimova, Clay Bennett and Samuel Thomas will acquire a single crystal X-ray diffractometer equipped with a CCD detector. The proposal is aimed at enhancing research training and education at all levels, especially in areas such as:

  1. mechanism-based design of selective, efficient, switchable receptors and catalysts for oxidations and other small molecule activation reactions;
  2. design of functional organic materials;
  3. design and development of catalysts for regioselective and enantioselective synthetic methods;
  4. design of nanomaterials and nanocatalysts;
  5. intermolecular interactions and self-assembly in fluorinated biomolecules;
  6. functional polymer materials;
  7. single molecules on surfaces;
  8. biomimetic protein-based materials; and
  9. design of cyclic peptides with enhanced affinity and selectivity of binding to their targets.

An X-ray diffractometer allows accurate and precise measurements of the full three dimensional structure of a molecule, including bond distances and angles, and provides accurate information about the spatial arrangement of a molecule relative to neighboring molecules. The studies described here will impact a number of areas, including organic and inorganic chemistry, materials chemistry and biochemistry. This instrument will be an integral part of teaching as well as research not only at Tufts University but also in a series of Boston area primarily undergraduate institutions that include Bridgewater State University, Emmanuel College and Suffolk University. Outreach to Braintree High School students and to deaf undergraduate students is being planned.

PI: Utz, Arthur
Title: Training Tomorrow's Innovators: A GAANN Program for Interdisciplinary Doctoral Studies in Chemistry
Abstract:
All fellowships will be used to support students pursuing a doctoral degree. Training will include coursework in core areas of chemistry and will be complemented by interdisciplinary research in the laboratory, supervised teaching experience, and community outreach. The interdisciplinary training that the GAANN fellows will receive at Tufts will broaden their horizons by enabling them to enter other fields with fresh approaches to problem-solving that are rooted in chemistry.

Our department presents a special opportunity for a GAANN award to have significant long-term impact. GAANN support will attract an influx of highly qualified Ph.D. students at a crucial point in the department's growth. GAANN fellows will explore new directions of inquiry that will attract external funding and lead to a permanent increase in the department's capacity to train doctoral students. It will also increase the diversity of our graduate student body and enhance our ability to recruit students from traditionally underrepresented groups through partnerships with selected undergraduate institutions. In short, a GAANN program at Tufts will increase the number of Ph.D. chemists trained – both in the short- and long-term.

Mentor: Uvin, Peter
PI: Chindea, Irina
Title: Power and Underworld Alliances: Understanding Cooperation Agreements Forged by Criminal Groups
Abstract: Based on the three phases of the evolutionary stage approach to organized criminal groups (i.e., predatory, parasitical, and symbiotic), this dissertation project aims to investigate to what extent the power differential within dyads in which at least one actor is a criminal group impacts the cooperation agreements they forge with other non-state armed groups and the form these agreements embrace (e.g., one off, tactical or strategic partnerships, symmetric or asymmetric alliances). To answer these questions, the dissertation embraces a mixed-methods approach based on building an original dataset of cooperation agreements entered by crime groups, and on five case studies which trace the evolution of “pure” and “hybrid” criminal groups and of their alliances in strong, weak and failing states: 1) the Cuntrera-Caruana mafia family in Canada; 2) a within case comparison of the Mara Salvatrucha gangs (MS 13) in the United States and El Salvador; 3) the alliances forged by the Mexican drug cartels since the early 1990s to the present; and 4) the cooperation/conflict patterns in which the Mahdi Army in Iraq and the Haqqani network in the Afghanistan-Pakistan border region have engaged after the US intervention in the region.

PI: Vandervelde, Thomas
Title: CAREER: Metamaterial-Enhanced Thermal Energy Harvesters
Abstract: The objective of this research is to create a new class of thermophotovoltaic cells that convert thermal radiation (heat) into electricity that harness wide-ranging heat temperatures frequently occurring in home appliances, factories, and during electricity generation. The approach is to use recent advances in infrared photodetectors, developed in part by the PI, which maximize conversion of light into electrical current.

PI: Vandervelde, Thomas
Title: High Operating Temperature Quantum-Based Infrared Photodetectors
Abstract:
This work is an expansion on the work the PI, Tom Vandervelde, did as an IC Post-doc with Sanjay Krishna at The Center for High Technology Materials (CHTM) at the University of New Mexico (UNM) on high operating temperature infrared photodetectors. Through this research the PI helped to develop the beginnings of what could be a revolutionary technology – the monovalent-barrier photodiode. As a new faculty member, Professor Vandervelde has been exploring its uses on two fronts, far-infrared photodetectors and for high-efficiency thermophotovoltaics for efficient power generation where and when you want it.

IR photodetectors of the type discussed here have a multitude of uses beyond the standard low-light/night vision, missile tracking, and calorimetry; including, chemical detection, material identification, identify friend or for systems, and medical diagnosis to name only a few. These novel IR camera systems could find use from field agents to satellite systems. They could have a transformative effect once they are field deployable. These photodetectors would have better performance characteristics than existing IR camera technologies, because they are built in a more reliable materials system (III-V versus II-VI). This partially means that focal plane arrays could also be fabricated in to larger elements with more pixels with a higher yield.

The thermophotovoltaic (TPV) power generators we intend to create could convert power from sources as cold as 15°C and as hot as 6000°C (e.g. the Sun). These TPV systems efficiently convert the heat into high-grade electricity silently with mean-time-between-failure metrics measured in decades. These systems when combined with microcombustors could be used to power personal electronics, unmanned aerial vehicles, and mobile campsite energy needs. They can also be paired with native heat sources (e.g. body heat, hot water pipes, etc.) to power more covert electronics.

PI: Vilenkin, Alexander
Title: Fundamental Physics and Cosmology
Abstract:
Recent developments in cosmology suggest that much of the universe is in a state of explosive accelerated expansion, called inflation. We live in a "bubble" where inflation has ended, and other bubbles with diverse properties are constantly being formed. A major unresolved problem in this theory of eternal inflation is the problem of calculating relative probabilities of different measurements. In the course of eternal inflation, any event having a nonzero probability will happen an infinite number of times, and comparing infinities is an inherently ambiguous task. The challenge is to formulate a compelling probability measure prescription. This will put the theory on a much firmer footing and will (at least in principle) allow its observational tests. Another major topic of this research is the evolution and observational signatures of cosmic strings. Strings can be formed as high-energy linear defects in the early universe and can produce a variety of observational effects at the present time. A detection of cosmic strings would be of great importance, as it would open a unique window into the physics of very high energies and into the early history of the universe.

PI: Walsh, Genevieve
Title: The Geometry and Topology of Groups Generated by Involutions
Abstract:
The PI will work on problems regarding the geometry and topology of groups generated by involutions. The first problem involves a new geometric criterion for when a Coxeter group is a Kleinian group. Specifically, if the defining graph of a right-angled Coxeter group can be realized as the 1-skeleton of an acute triangulation of the 2-sphere, is the Coxeter group hyperbolic? This relates the techniques of geometric group theory and classical 3-dimensional hyperbolic geometry to combinatorial problems concerning triangulations. As part of this study, the PI will investigate the moduli space of an acute triangulation of the 2-sphere. In particular, is this space connected? A second question asks when a group generated by reflections in hyperbolic 3-space contains a knot group. This is deeply related to understanding commensurability of knot complements. More broadly, the PI seeks to address the conjecture that there are at most three hyperbolic knot complements in any given commensurability class. Boileau, Boyer, Cebanu, and the PI have made significant progress on the conjecture in recent work, and this project aims to address the remaining case. In a third project, the PI seeks a CAT(0) space for the group of outer automorphisms of the free product of four copies of the integers mod 2. This group of outer automorphisms is particularly pleasing and related to the proposal as it is generated by involutions.

Groups generated by involutions have long been guiding examples in furthering the understanding of the geometry of groups. They are inherently geometric and relevant to the modern theory of orbifolds. These groups have been studied in various ways by Coxeter, Thurston, Davis, and Moussong, as well as by many other celebrated mathematicians, and they continue to inform current research. Imposing some condition, such as the presence of a reflection, allows one to gain traction on a difficult problem and eventually see the whole picture. The projects proposed here have potential impact in other fields. For example, the study of triangulations, particularly acute triangulations, is important in computer-aided design and scientific computing.

PI: Walt, David
Title: Bioinformatics Inquiry through Sequencing (BIOSEQ)
Abstract: The overall goal for the Bioinformatics Inquiry through Sequencing (BIOSEQ) project is to provide opportunities for a broad audience of people to learn about the field of bioinformatics through inquiry-based research.

Three main activities will support this goal:

  1. Increase knowledge of and participation in inquiry-based bioinformatics research among students and educators by establishing a sequencing center at Tufts University's Medford Campus for educational use.

    This sequencing center will be available to college students and high school students through college-level research courses, and will also be available to educators and students who wish to integrate sequencing into classroom projects, science fair projects, college level theses, and graduate-level research through an application process.

  2. Introduce bioinformatics to college students and high school students through entry level, semester-long research-based courses designed to teach students laboratory skills, computer skills and research skills in the context of student designed projects.

    The high school student course will happen during the summer session, students will be able to receive college credit. Scholarships will be available for underrepresented minorities and those of low socioeconomic status to participate in the course.

  3. Increase teacher knowledge of bioinformatics and inclusion of bioinformatics concepts in their courses by developing modular activities and curricular units to describe bioinformatics concepts, including the impact of bioinformatics on scientific and medical research.

    Some of these activities and units will be integrated into existing high school biology and computer science courses, and will include understanding of how bioinformatics and genomics have influenced individual and public health through innovations such as Genome Wide Association studies (GWAs) and Direct to Consumer (DTC) genetic testing.

This five year project will involve faculty, staff, graduate students, and undergraduate students from Tufts' Chemistry and Computer science departments, faculty and students from Bunker Hill Community College, and teachers and high school students from four diverse, urban partner school districts.

PI: Walt, David
Title: Development of New Tools for Single Cell Analysis
Abstract: Single cell analysis is becoming increasingly important as it is clear that ensemble measurements mask the diversity of the biology in cell populations. Single cell genotyping and phenotyping are necessary to define functional heterogeneity in varying cell types including diseased vs. normal cells. The overall goal of this project is to develop new bioanalytical tools for performing high resolution single cell analysis. This interdisciplinary project involves Chemistry, Molecular Biology, Biochemistry, Genetics, and Bioengineering and will be conducted by a team including a senior Principal Investigator, one postdoctoral associate, and two graduate students.

Specific Aim 1-Develop a high fidelity single DNA molecule genotyping approach for analyzing thousands of molecules simultaneously and with the ability to interrogate multiple SNPs. We plan to employ fiber optic microwell arrays to develop a robust, efficient, fast, and affordable method of simultaneously genotyping single DNA molecules from thousands of individual cells. Specific Aim 2-Develop an approach to isolating single cells, capturing genomic DNA, and genotyping the captured DNA. In this Aim, we will apply the methods developed in Specific Aim 1 to whole cells. Thousands of single E. coli cells will be captured in individual wells, lysed, genomic DNA fragmented, the DNA captured on the surface of the individual wells, and then genotyped. Specific Aim 3-Develop a high resolution single molecule analysis method for analyzing the contents of single cells. We will develop methods for performing high resolution single molecule counting of the contents of individual cells. Single cells will be isolated, lysed, and their contents will be captured in microwell arrays such that individual mRNA and protein molecules are isolated. We will then use a variety of methods that enable us to count the individual molecules.

Success of these aims will provide a powerful new technology broadly applicable to multiple areas of biological research. For biologists, it provides the ability to describe the complex genetics of cell populations, providing clinicians with improved opportunities for diagnostics, and relating population genetics with responses to therapy and clinical outcomes. For experimentalists, it provides new ways to study phenomena such as tumor progression and responses to experimental therapies. For researchers on aging, it provides the ability to monitor changes in somatic genetics with age and the factors influencing them. For geneticists, it provides a low cost ability to construct genetic maps, to identify trans-acting elements controlling recombination, and to monitor the molecular structure of recombination products with high resolution. Our long term goal is to apply the developed technology to a variety of cell types to study fundamental cell biology and to understand how cell-to-cell and cell population differences may lead to different cell fates and may define disease.

PI: Walt, David
Title: Development of Technologies for Early Detection and Stratification of Breast Cancer
Abstract:
In the field of Chemistry, the fundamental unit is the molecule. In the field of Biology, the fundamental unit is the cell. Collections of molecules form pathways and systems; collections of cells form tissues and organisms. In order to understand Biology at its most fundamental level, it is essential to measure tissues with single cell resolution. Furthermore, if one could interrogate these tissues by literally counting the numbers of molecules of each protein, RNA transcript, and metabolite present in each cell, while also having a complete genetic profile of each and every individual cell in the tissue, one would likely have a much clearer picture than one does today. My vision is to develop the tools to enable the highest level understanding of biology in general and breast cancer in particular. If we can use our single cell and single molecule tools to detect molecules and measure cell populations with unprecedented resolution, we should uncover new biomarkers and indicators with diagnostic and predictive value. Breast cancer offers an important challenge because it is a serious medical problem that has the potential to be addressed by technologies that can get at the single cell level.

PI: Wanke, Christine
Title: Nutrition and HIV Progression
Abstract:
There are more than 40 million individuals infected with HIV living throughout the world, the majority of these live within the resource-limited world. It has been clear throughout the HIV epidemic that the nutritional status of the host plays an important, independent role in HIV-associated outcomes particularly progression of HIV disease and mortality. Although it would appear to be intuitive that maintenance of or improvement in nutritional status would lead to improved outcomes in HIV infected individuals, few data are available to demonstrate the potential benefits of maintaining nutrition status at normal. There are data that suggest that the use of micronutrients could reduce CD4 count decline and delay death, however micronutrients alone will not support or maintain nutritional status. The overall hypothesis of this application is that the consumption of a nutrient dense protein supplement (NDPS) early in HIV infection will slow disease progression, and that the time from infection with HIV to the initiation of HAART will be prolonged.

If this hypothesis is proven to be correct, this type of intervention will result in benefit to the individual, as the need for the use of HAART would be delayed. It would also benefit the health systems, as cost savings would result from a delay in the initiation of HAART. Specifically we propose to enroll 740 HIV infected women in Kenya, with CD4 counts between 350 cells/µL and 500 cells/µL and no symptoms, opportunistic infections or AIDS defining illnesses or malnutrition (BMI<18.5 kg/m2) that would require the initiation of HAART. These individuals with early disease will be randomized to a group that will be provided with the nutrient dense protein supplement (NDPS) or standard of care (SOC) and followed until the initiation of HAART is necessary or a total of 2 years. Outcomes in this study will include the need for the initiation of HAART, the rate of decline of CD4 cell count, overall nutritional status as measured by BMI and lean body mass, and quality of life. We will determine the cost effectiveness of this intervention strategy.

In order determine if the dietary intake and the nutritional status (BMI) of the HIV-infected women with early disease is within the community norm, we need to evaluate the dietary intake and nutritional status of similar but non HIV-infected women in the local community. We propose to collect data on 200 women who are documented to be HIV-negative from Voi Division at a single visit, the Division that will also provide the HIV-infected women for the intervention study.

PI: Wanke, Christine
Title: The Impact of Omega-3 Fatty Acids on Vascular Function and cIMT in HIV Infected Individuals
Abstract:
There is convincing evidence that there is an increased risk of cardiovascular disease in patients infected with HIV. There are multiple potential risks for CVD in HIV infected patients; atherogenic lipid profiles have long been associated with increased risk of cardiovascular disease; elevations in total and LDL cholesterol have been demonstrated to be associated with such increased risk in the general population. More recent data suggest that elevations in levels of triglycerides and decreased levels of HDL cholesterol may be equally important markers of CVD risk. There is also emerging data that CVD is an inflammatory disease, and that HDL-C levels and subprofiles are mediated by inflammation; in HIV-infected individuals these changes may be exacerbated by the HIV infection. While treatment of atherogenic lipid profiles is desirable, attempts to treat these abnormalities in HIV infection are complex in HIV infected individuals. In studies done in populations with and without HIV, intake of high doses of omega three fatty acids is demonstrated to decrease triglycerides and may have a beneficial effect on HDL-cholesterol levels. Intake of omega three fatty acids alters lipid metabolism and may decrease inflammation by decreasing production of arachidonic acid. At present, there are no data that extend these observations to determine whether intake of omega three fats over a more prolonged time period will also have a beneficial impact on vascular function and surrogate markers of CVD in HIV infected patients.

We propose a randomized, double blind trial of purified omega three fatty acids in HIV infected individuals with elevated levels of triglycerides. While the impact of omega three fatty acids on lipid profiles should be evident within 12 weeks, we propose to conduct this trial for a full 24 months to test our overall hypothesis that this intervention will not only improve triglyceride and HDL-C levels, improve subprofiles and membrane phospholipids and decrease inflammation, but will also improve brachial artery reactivity as a measure of vascular function at 24 weeks and lead to a reduced rate of progression of cIMT as a surrogate marker of CVD at 24 months when compared to controls. The specific aims of this proposal include:

  1. To conduct a randomized, placebo controlled trial of omega three fatty acids over 24 months in HIV-infected individuals with elevated levels of triglycerides (>150mg/dl).

  2. To demonstrate the impact of omega three fatty acid intake on TG levels and on HDL-C levels, HDL subprofiles, composition of membrane phospholipids, chronic inflammation as measured by CRP, sPLA2 and by levels of arachidonic acid.

  3. To demonstrate the impact of omega three fatty acid intake on brachial artery reactivity at 24 weeks and on cIMT at 24 months.

PI: Webb, Patrick
Title: Food Aid Quality Review Phase II
Abstract:
The overarching goal of the USAID P.L. 480 Title II food aid program is to reduce the food insecurity of vulnerable populations around the world. An important part of that program and effort deals with malnutrition and its negative impact on health, learning, and productivity. The Title II program seeks to combat the root causes of food insecurity, improve nutrition, and, through the direct distribution of food aid commodities, provide for the immediate dietary needs of needy and vulnerable people.

As part of its ongoing efforts to improve the quality and efficiency of U.S. food aid operations, in 2009 the USAID Office of Food for Peace tasked the Friedman School of Nutrition Science and Policy of Tufts University (Contract AFP-C-00-09-000 16-00) to review the state of science as it relates to the nutrition-related needs of traditionally vulnerable groups, including vitamin and mineral enrichment and technologies of fortification of food aid commodities and methods for the delivery of micronutrients in the form of supplements or powders.

The objective of that two-year review by Tufts, commonly referred to as the Food Aid Quality Review (FAQR), was to produce recommendations on how to cost-effectively meet the nutrition needs of Title II beneficiary populations with U.S. food aid commodities. The main deliverable of the work was to be a report on the following topics:

  • Review of past recommendations from efforts to improve nutrition quality of US food-aid efforts and their implementation to date.

  • Provide recommendations on USAID programs, processes and guidance to implementing partners.

  • Recommendations to improve Title II enrichment and fortification formulations.

  • Review the state of science and program experience on food aid and nutritional support for people living with HIV and provide recommendations.

  • Implement a consultative process to engage stakeholder participation, input and feedback, including the establishment of a website (wikipage) for the posting of findings and papers, soliciting comments and the exchange of ideas with a broader community.

PI: Weiss, Lawrence
Title: Fletcher Sportsman’s Club
Abstract:
Our mission is to increase student membership by introducing new students and student athletes to the shooting sports, a sport and a passion they can enjoy for a lifetime. In many cases these student athletes have never enjoyed exposure or opportunity to firearms or shooting sports. The athlete can participate recreationally and/or competitively. We seek to offer this opportunity to as many participants as possible.

Our goal is to provide opportunities for safe, informed participation in shooting sports. Through club activities we will promote firearm responsibility and develop clubs and teams that will foster ongoing relationships within the college community and beyond. Minute Man sportsmen's Club and trained coaching staff will provide safe instruction and specific shooting skills in all 5 shotgun shooting disciplines: American Trap, American Skeet, Sporting Clays, International Skeet and International Trap. In addition, our team will be offered the opportunity to participate in local, state and National shooting sports events, including: The New England Clay Cup, New England Collegiate Shotgun Championships, ACUI Championships, MA ATA State Championships.

We will cultivate a team spirit that promotes and supports shooting sports. We believe that we are in an optimal position to do so for two reasons: 1) Because of The Fletcher School's tightknit and supportive community and, 2) the camaraderie between Fletcher school students who are more experienced shooters and students who are willing to step outside of their comfort zone and experience a new activity.

A final goal is to investigate opportunities for expansion into rifle and pistol competition sporting events. We hope to develop a partnership with a club and draw on expertise from their staff, as well as existing membership (military fellows). Finally, we hope to compete in regional or university shooting events.

Objectives:

  • Build a team of at least 40 active shooters
  • Hold team practices on a bi-weekly to tri-weekly basis
  • Conduct ongoing safety classes for new shooters and current members
  • Promote league shooting between other collegiate teams
  • Introduce and train shooters on all shooting disciplines
  • Cultivating lifetime interest in shooting sports to ultimately grow the sport for generations to follow

PI: Weiss, Richard
Title: Buildings and the Exceptional Groups
Abstract: Bruhat-Tits buildings are geometric objects that play a fundamental role at the intersection of group theory, number theory, and geometry. They were introduced and classified by Jacques Tits and François Bruhat. This classification rests on Tits's earlier work on spherical buildings. The P.I. has written four books about these classification results. The first of these books describes the classification of Moufang polygons which the P.I. completed in collaboration with Tits and which opened up a new “rank 2” approach to the earlier classification results.

The aim of the present project is to apply these results to the investigation of the structure of the residues of Bruhat-Tits buildings and to a variety of related problems involving Moufang sets (i.e. buildings of rank 1), the structure of the automorphism group of a spherical building, bounded generation of the Ree groups, the structure of convex subsets of a spherical building and the existence of Bruhat-;Tits buildings for the exceptional quadrangles of type E8.

The principal goal of this activity is to reach a deeper understanding of the structure of spherical and Bruhat-Tits buildings and to widen the bridge between the methods of algebraic groups and the geometric/combinatorial approach inherent in the theory of buildings.

PI: Wilkerson-Jerde, Michelle
Title: EXP: SiMSAM: Bridging Student, Scientific, and Mathematical Models with Expressive Technologies
Abstract:
The purpose of this project is to shed light on two important questions in science education and cyberlearning: (1) How can we study and support the ways in which students learn to use simulation and data analysis technologies as tools of scientific discourse? (2) What is the pedagogical potential of such an approach? The project explores the feasibility of a novel web-based modeling environment, SiMSAM, that will allow students in grades 5-8 to easily produce dynamic Stop-Action Motion animations that illustrate scientific events using everyday materials (e.g., construction paper, cotton balls, drawing, etc.) with which they are already familiar; analogous computer simulations using a novel visual interface that allows them to import and "give instructions" to images from their original animations; collect, analyze, and graph data generated by their simulations; and share, trade, and test their creations. Students use SiMSAM to explore kinetic molecular phenomena by completing activities that invite them to represent "unseen" events involving air pressure, sound propagation, and evaporation. Analysis focuses on new forms of learning afforded by the tool (especially the adoption of simulation and data analysis as tools of scientific discourse) and identifying potential shifts in students' reasoning about causal mechanism in the modeled phenomena, their adoption of kinetic molecular theory as a conceptual model, and their understanding of the nature of scientific models in STEM disciplines. The project integrates contemporary learning theory regarding the value of students' productive resources for reasoning about scientific and mathematical topics, model-based approaches in science and mathematics education, and the importance of computational simulation as a pedagogical and professional tool.

This project will prototype new technologies that will allow middle-school students to learn science through scientific modeling, an approach with potential for promoting deep understanding of the mechanisms underlying phenomena in the world. The software, called SimSAM, allows students to create animations and simulations of phenomena related to molecular kinetics – an important content area across grades K-16. The technology uses cross-platform, web-based technologies that do not require a special device or download and will thus be easily usable in schools without the need to download specialized software applications. The project's products will include curriculum materials for promoting learning the particle theory of matter and software that can eventually become a robust toolkit for students to engage with a wide variety of dynamic scientific phenomena across the science curriculum.

PI: Wilson, Kimberley
Title: Fletcher School Leadership Program for Financial Inclusion
Abstract:
The Fletcher School Leadership program for Financial Inclusion aims to give regulators from emerging and frontier markets the skills, knowledge, and confidence they need to lead innovative policy and regulatory reform. The program selects "rising stars" in banking regulation and financial inclusion policy to become fellows and participate in a two-week residency, grooming them to think in fresh ways about the challenges they face and equipping them to lead the charge for solutions.

PI: Wilson, Nancy
Title: Moving the Needle: The Impact of Online and Residentiality-Based Foundations for Student-Community Engagement on Psychosocial Flourishing
Abstract:
We will prepare students to take advantage of courses and extracurricular activities in ways that benefit their communities and their own psychosocial well-being, by developing and evaluating two scalable and innovative preparation modules: one online gaming model, the other a face-to-face First Year Experience in residence halls facilitated by peer leaders.

PI: Wilson, Nancy
Title: The Goldberg Initiative: Mitigating Obesity in Boston's Immigrant Communities
Abstract:
The project will develop, pilot, evaluate and disseminate strategies that lead to more physical activity and improved nutrition across Boston's largest immigrant populations—Chinese, Haitian, Dominican and Vietnamese. This three-year initiative will include a strong research element, multiple intervention strategies, policy work and a communications plan, which will allow us to translate research into evidenced-based community programs and influence policy. All of this will be conducted using a trans-disciplinary, cross-sector team, with balanced participation from immigrant serving organizations alongside Tufts University faculty, staff and students. This process of co-creation between community partners and the university has been the cornerstone of the successful nutrition and obesity mitigation projects already undertaken by the principal investigators in this project, in other communities or on other health topics.

The Goldberg Initiative will produce results in four areas:

  1. Improved individual level health awareness and behavior for participants in direct intervention programs;
  2. Increased capacity to incorporate obesity mitigation strategies into the work of immigrant-serving organizations;
  3. Implemented and evaluated practices for obesity mitigation in immigrant communities that can be shared widely; and
  4. Influencing policymakers and the policy agenda.

PI: Wise, Timothy
Title: China in Latin America: Environmental and Developmental Dimensions
Abstract:
This two-year project will track and analyze the investment activities of China's 'development banks' in Latin America and form a working group on China and Sustainable Development in Latin America that can document and track China's footprint in the region on an ongoing basis. The goal of this project is twofold:

  • First is to gain an empirical-based understanding of the environment and development impacts of China in Latin America.

  • Second, and perhaps more importantly, is to draw on this empirical record and work with policy-makers and stakeholders to identify and exploit the relevant policy levers in the region and beyond that can maximize the benefits of Chinese economic activity in Latin America while mitigating the social and environmental costs.

To achieve these goals, the principal effort will be to establish channels where research can be shaped by, communicated to, and used by civil society organizations and policy-makers in Latin America seeking to improve livelihoods in a sustainable manner. Secondly, the establishment of a standing working group of in-country experts that can monitor Chinese investment and embed more closely with the advocacy community will build capacity and lay a foundation for more comprehensive analysis and policy action.

PI: Wise, Timothy
Title: Global Economic Governance and Sustainable Development
Abstract:
Over the next two years (July 2009-June 2011), GDAE will build on its impressive range of collaborations with researchers in the global South to ground the debate over policy space and alternative national development strategies. The goal is to contribute accessible, empirically-based research on the social, economic, and environmental impacts of globalization to shape a more sustainable economic future and promote a rights-based approach to international development in a climate-constrained world. The project has two principal areas of research. “New Models for Global Economic Governance” focuses on broad international trade, development and governance issues. “Sustainable Hemispheric Integration” deepens GDAE’s work on Mexico and Latin America.

PI: Wong, Peter
Title: Collaborative Research: Microscale Joining Using Nanoheater Structure
Abstract:
This grant provides funding for a multi-institution, multi-disciplinary project to understand the processing-structure-property relationships of composite nanoheater-joining-material structures. The focus is on joining applications at the microscale level where spatial and temporal control of temperature profiles is important in complex geometries and heterogeneous devices with temperature sensitive parts. This research aims to understand (1) the fabrication of nanoheater composites of nanoheaters and joining materials, including the effect of mixing on proper distribution of heat output; (2) the deposition of the nanoheater-joining material composite onto flexible substrates; (3) the controlled, non-contact ignition of the nanoheaters; and (4) the functionality and reliability of the joining/interconnects. Both metal-based structures and polymer adhesives will be investigated. Fabrication and deposition of the composite joining system will be done by both ultrasonic powder consolidation and printing or direct electrospinning/electrospraying. Ignition experiments and modeling of self-ignition will be conducted. Finally, joint quality and robustness will be characterized.

If successful, this research will enable new ways of joining materials in conventional applications that increase productivity, reduce energy and material usage, lower costs, and broaden the range of products. This research is anticipated to lead to new ways to build microscale devices such as Lab-On-Chips, flexible electronics, micro-optical devices, sensors, medical devices, and energy and information storage devices. The project will also contribute to human resource development (especially women and minorities) and increased public understanding of STEM through collaborations with the Urban Massachusetts Louis Stokes Alliance for Minority Participation (UMLSAMP), local K-12 schools, the Museum of Science, and international partners (University of Cyprus).

PI: Wortis, Henry
Title: Babesiosis as a Model of Age-Related Immunosenescence
Abstract:
As people age, a greater number becomes susceptible to infections. Because the aged represent an ever-growing segment of the populations in the western world, morbidities due to infection are significant. We are interested in identifying alleles that underlie this age-acquired susceptibility. We developed a mouse model of human babesiosis due Babesia microti, an emerging infection particularly severe in the aged. We observed that young DBA/2 mice experience significant parasitemia but young C57BL/6, B10.D2 and BALB/c mice do not. In DBA/2 mice an early phase characterized by an intense and transient parasitemia is followed by a late phase of low grade, but persistent parasitemia. As age advances, both acute and chronic parasitemia become greater in DBA/2, but not in C57BL/6, B10.D2 or BALB/c mice. Using B10.D2 x DBA/2 (BXD) and BALB/c x DBA/2 (CXD) crosses as well as chromosome substitution mice, we have established that i) resistance is a complex trait in young and old mice, and ii) acute resistance in young mice maps to QTL that differ from those of old mice. We conclude that the greater susceptibility of old DBA/2 mice maps to age-restricted QTL.

We now propose to identify resistance and susceptibility alleles and to uncover how they modulate the response to B. microti infection. In Aim 1, we will identify the major genetic determinants of acute resistance in old mice of the BXD cross. In Aim 2, we will identify the major genetic determinants of acute resistance in old mice of the CXD cross. Both aims combine a positional cloning approach with bioinformatic analyses and gene expression studies. In Aim 3, we will identify the cells that contribute to resistance and are affected by the polymorphisms underlying the major QTL. Strain differences in cell function will be studied and used to guide the genetic analysis. We are hopeful that the identification of age-sensitive polymorphisms that modulate immune resistance of old mice to babesiosis may inform the search of alleles that predispose aged individuals to infection.

PI: Wortis, Henry
Title: Immunologic Aspects of Disease
Abstract: This is a renewal application to support a well-established pre-doctoral training program in immunology at the Sackler School of Graduate Biomedical Sciences located on the Tufts University Health Sciences Campus in downtown Boston. Currently, 21 faculty members are training 34 students of whom seven receive direct support from this grant. Highly qualified students are selected from a pool of over 100 applicants based on research experience, recommendations, coursework/grades, interviews, and GRE scores. Training is designed to provide an appreciation of clinical problems together with the technical expertise and scientific insight to successfully perform research on important immunological questions. It aims to stimulate originality, curiosity and the use of rational reasoning to understand biological mechanisms. The didactic component consists of required courses: Biochemistry, Introduction to Immunology, Immunogenetics, Immunochemistry, Immunological Mechanisms in Disease and an elective. These courses provide the foundation for required participatory courses: Journal Club, Advanced Journal Club, Seminars and Student Workshop. Students take four first year laboratory rotations and pass a qualifying examination before entering a thesis laboratory. Thesis research, considered the core of the Ph.D. training, is overseen by individual thesis advisory committees that meet with the student each semester. It is the thesis committee's role to critique the project proposal and to assess the student's progress towards producing an original and substantive contribution to scientific knowledge. While publication is not a formal requirement, graduates are expected to be first authors of peer-reviewed papers. Students are explicitly trained in oral and written presentation of scientific ideas and data and have opportunities to present their research findings at the weekly Student Workshop as well as the annual retreat and mini-symposium. Students also routinely attend and present at national and international meetings. A Program Student Adviser acts as student consultant and advocate. Requirements and expectations are established in writing and the Student Adviser keeps students well informed of their progress. The program successfully graduates a high proportion of all entering students (89%). In the past 10 years there have been 65 graduates, three are in transition, twelve are in clinical training or service and of the remaining 53, a high proportion, 45 (85%), are actively engaged in research, including four in tenure track positions. The program has benefited from a recently increased University commitment of resources to graduate biomedical education, new research facilities and the hiring of new faculty members.

Mentor: Wortis, Henry
Fellow: Shapiro, Michael
Title: Light Weight Modeling of Epstein-Barr Virus
Abstract: Eipstein-Barr virus (EBV) infects more than 90% of all humans, usually without symptoms. It can also be responsible for acute infectious mononucleosis (AIM) and is associated with fatal malignancies including immunoblastic lymphoma, Hodgkin's lymphoma, Burkitt's lymphoma, nasopharyngeal carcinoma and X-linked proliferative disorder (XLP). Our long-term goal is to understand these processes in sufficient detail to guide clinical intervention. Our overall model of normal and malignant EBV biology puts us in a good position to build computer models of EBV infection. Our specific aims include the following: Evaluate the relative impacts of various factors known to play a role in EBV biology. Assess the probability of the varying fates of a cell once it has entered a particular infected state. Understand the overall dynamics of these models as dynamical systems. This includes distinguishing possible long-term behaviors and the transitory states that lead to them. We will pursue these goals by building and analyzing multiple light weight computer models of EBV infection. By "light weight" we mean that these models are easy to write, modify and run. This will allow investigations not possible with larger agent-based computer models. Epstein-Barr Virus is widespread in the human population. While it is usually asymptomatic, it is also associated with fatal malignancies. Computer simulation is a way to study the normal asymptomatic course of this infection and the ways in which this turns malignant. We hope that a better understanding of these processes will show us how they can be controlled. 

PI: Wortis, Henry
Title: Tufts Post-Baccalaureate Research Education Program
Abstract: This is a program designed to increase the number of post-baccalaureates from currently under-represented groups who become leading biomedical research scientists. It is based on the idea that an enriched hands-on experience in research is the best preparation for PhD training. The training typically consists of a one year academic research laboratory apprenticeship pursuing a hypothesis-driven research project. This core experience is complemented with interactive training to increase skills in scientific writing, oral presentation and the critical reading and interpretation of scientific literature. Trainees will be offered additional elective didactic training appropriate to their research project. Collegiality and cooperation will be fostered. The Sackler School of Graduate Biomedical Sciences and Tufts University School of Medicine propose a training plan that will be built on the foundation of well funded and highly regarded research laboratories; highly successful experiences in PhD training in biomedical research and several successful training programs that target underrepresented groups. Assessment of the trainees' understanding of their own research, their bench skills, writing skills, presentation technique and leadership skills will be conducted regularly. Evaluation instruments are in place that will provide measurements for improving the training experience. The ultimate success of this PREP training program will be measured by outcomes: the aim is to have more than 80% of entering trainees go on to obtain an MD/PhD or PhD from a research-intense school.  

PI: Wu, Dayong
Title: Effect of the White Button Mushroom Supplementation on Resistance to Salmonella Infection and Immune Response in an Animal Model
Abstract:
Food borne pathogen-caused infection is a global health concern. As immune function decreases with age, an efficient immune response to the pathogens, including both innate and adaptive immunity, as well as the cross-talk bridging both arms of immunity, is important in both preventing infection and reducing the severity and duration of infection. Components in commonly consumed mushrooms (including white button mushrooms), such as beta-glucans, and the extracts of certain mushrooms, have been shown to enhance innate immunity and the process bridging innate to adaptive immunity. Therefore, we hypothesize that consumption of white button mushrooms may positively impact the host’s resistance to local and systemic infection caused by food borne pathogens through enhancing the appropriate immune functions. We propose to test this hypothesis using an animal model of salmonella infection already developed in our laboratory. Mice will be fed two doses of mushrooms or control diet for 2-months and then subjected to use two infection models for localized and systemic infections, respectively, to determine the effect of mushroom consumption on the clearance of bacteria as well as selected markers for the host’s immune response. Two studies are designed to use localized and systemic infection model respectively as described below.

Study One: This study is designed to determine the impact of mushroom supplementation on acute enterocolitis caused by Salmonella (S. typhimurium) using streptomycin pretreated C57BL/6 mouse model 3. It will provide evidence for whether mushroom supplementation affects host resistance in early stages of S. typhimurium infection as indicated by bacterial loading in the gut, Peyer’ s patches (PP), and mesenteric lymph nodes (MLN) as well as the associated pathological changes. C57B/6L (3-mo) mice will be fed diets containing 0 (control), 2%, or 10% mushroom for 2 months. After the feeding period, mice will be pretreated with streptomycin 24 hours prior to inoculation with S. typhimurium and killed on days 0, 1, 4 post-infection (15 mice/time point). One group of mice fed the control diet and without streptomycin treatment will serve as control to determine any confounding effect that may be introduced by using the antibiotic. Fifteen mice will be needed for each diet group and time point based on previous studies. Thus, a total of 180 mice (15 mice/diet x 4 diet groups x 3 time points) will be needed for this study. The severity of infection will be assessed by bacterial colonization in the gut and other gut-associated lymphoid tissues, and pathological changes in cecum. Gene expression and production of the cytokines involved in the innate immune and inflammatory responses (IL-6, IL-I-beta, TNF-α, IL-12, IFN-g) and chemokines (IL-8, MCP-1) will be determined by RT-PCR and ELISA, immune cell phenotype in PP and MLN by FACS, and the neutrophil function by myeloperoxidase (MPO) assay.

Study Two: This study is designed to determine the effect of mushroom supplementation on systemic infection caused by S. typhimurium using a systemic infectious typhoid mouse model without pretreatment with streptomycin. Animal numbers in each group and feeding regime will be the same as those in Study One. Mice without streptomycin pretreatment will be infected with S. typhimurium and killed on day 0, 4, 7, 14 day post-infection. Selected indicators of the adaptive immune response will be determined, e.g., lymphocytes isolated from MLN and spleen will be re-challenged with the specific pathogen antigen (heat-killed Salmonella) in vitro and their proliferation and capacity to produce cytokines will be analyzed. The cytokines to be measured include inflammatory cytokines (TNF-α, IL-6, IL-I-beta, and T cell cytokines (IL-α, IFN-g, IL-l2). These cytokincs are involved in inducing adaptive immune response to eradicate Salmonella. A total of 180 mice (15 mice/diet x 3 diet groups x 4 time points) will be needed for this study. In addition to the mice needed for the two studies, 60 extra mice will be needed to conduct preliminary tests to confirm the optimal doses and time course established from the previous studies before the proposed study is conducted.

Successful completion of the proposed study will enable the identification of a new health benefit of consuming mushrooms as a functional food. Positive outcome would open a potential application of consumption of mushrooms as a nutritional approach to complement the preventive and therapeutic strategies in fighting food borne pathogen-induced infection.

PI: Xu, Jun
Title: X-linked Genes, Histone Modifications and Behavior
Abstract:
Jarid1c is an X-linked gene expressed more highly in females than in males, suggesting that it may contribute to the effect of sex chromosome complement (XX vs. XY) on behaviors such as aggression. Jarid1c encodes a histone demethylase that represses expression of specific genes. The JARID1C enzyme plays an important role in brain development and function; patients with JARID1C mutations suffer from symptoms including mental retardation, elevated aggression, defective social interaction, language development, and seizure.

We hypothesize that Jarid1c is implicated in the sex chromosome effect on aggression. Three related aims are proposed to test this hypothesis. Aim 1 will identify genes that are differentially expressed between XX and XY mice, and genes that show different chromatin modifications in specific brain regions. These genes are candidates for causing the behavioral differences between XX and XY mice. Aim 2 will examine the effects of aggression on gene expression and chromatin modifications. Aim 3 will test the effects of knocking down Jarid1c expression in specific brain regions on behavior, gene expression, and chromatin modifications. The feasibility of siRNA treatment has been confirmed in our pilot study which detected changes in behaviors and gene expression. Hippocampal Jarid1c k/d mice were deficient in their performance in the object recognition test; furthermore, prefrontal cortical Jarid1c k/d mice were more anxious than controls in the open field test. Gene expression arrays indicated genes involved in GABAergic neurotransmission were regulated in both hippocampal and cortical Jarid1c k/d mice, suggesting GABA receptor signaling as a candidate mediating Jarid1c’s effects on brain and behavior.

A better understanding of Jarid1c’s involvement in brain function and behavior will provide insights in novel molecular mechanisms underlying brain sexual differentiation, aggression regulation, as well as behaviors and emotions (e.g. episodic memory and anxiety).

PI: Yang, Yongjie
Title: Regulation of Astrocyte Heterogeneity and Developmental Maturation in the CNS
Abstract: Astrocytes are now recognized as active components of mature synapses; they structurally ensheath synapses and modulate neurotransmission in the central nervous system (CNS). Astrocyte dysfunction has been implicated in various neurological disorders and has been shown to actively modulate disease progression. Although astrocytes undergo a developmental maturation process in which subtypes form unique and elaborate morphologies and express overlapping but distinct molecular signatures, it is unknown how astrocyte heterogeneity arises during development of the CNS and how astrocyte development is regulated, in part because of a lack of appropriate tools for such studies. We propose to use integrated molecular and genetic approaches in Drosophila and mouse to define factors that distinguish astrocyte subtypes and regulate their developmental maturation. In particular, this project will focus on these aims: 1) Molecularly define astrocyte subtypes within the cortex and in different CNS regions using FACS and TRAP approaches; 2) Perform dEAAT1-based genetic screens to identify regulators of astrocyte development; 3) Develop new cre recombinase mice for studying astrocyte heterogeneity and function in vivo. We have generated a large amount of preliminary data demonstrating feasibility for the three aims summarized above. By characterizing molecular signatures of astrocyte subtypes in the CNS and identifying regulators of astrocyte development, this project will provide markers for astrocyte subtypes in the cortex and novel insights about how astrocyte maturation occurs. The development of a new cre recombinase driver mouse line will facilitate the selective deletion/activation of genes in astrocytes of the cortex, a region for which an existing astrocyte cre driver line is not very effective. Knowledge of astrocyte heterogeneity and new tools for studying it are critical for understanding how astrocytes become dysfunctional and how distinct classes of astrocytes contribute to the pathogenesis of psychiatric disorders.  

PI: Yang, Yongjie
Title: Role of Astrocytic Glutamate Transporter GLT1 in Fragile X
Abstract:
Fragile X syndrome (FXS) is the most common form of inherited mental retardation and one of the leading causes of autism. FXS is caused by a mutation in the fmr1 gene resulting in loss of fragile X mental retardation protein (FMRP), a selective RNA-binding protein which regulates mRNA translation at the synapse. FMRP's role in neuronal synaptic plasticity has been studied in depth; however, the effect of the astrocytic glutamate transporter EAAT2 (Rodent analog GLT1) function in FXS has never been studied. This transporter plays a crucial role in extracellular glutamate uptake to support normal synaptic function. Recently, we discovered cortical fmr1-/- astrocytes were associated with multiple defects in induction and maintenance of the astrocytic GLT1 expression pathway. Moreover, fmr1-/- astrocytes have functional glutamate uptake deficits during their development and after maturation. The results suggest fmr1-/- astrocytes have lost the ability to properly regulate glutamate homeostatic mechanisms in the brain. In light of this finding, we hypothesize that the lack of expression and function of GLT1 in fmr1-/- astrocytes prevents proper clearance of glutamate at the synaptic cleft resulting in excessive activation of extra-synaptic mGluRS5 receptors at postsynaptic sites. In FXS, loss of FMRP results in excessive activation of mGluR5 leading to aberrant synaptic protein synthesis which ultimately enhances excitatory post-synaptic activity. Many of the abnormalities seen in fmr1-/- mice can be rescued by decreasing mGluR5 signaling. We are therefore proposing to significantly up-regulate astrocytic GLT1 expression and function in fmr1-/- animals to restore normal glutamate uptake and mGiuRS activity. By utilizing pharmacological tools and genetic manipulation we will examine region-specific excitatory and inhibitory neuronal activity by enhancing GL T1 function in fmr1-/- animal. We will also compare the molecular characteristics of fmr1-/- astrocytes and controls in in vitro and in vivo by re-establishing proper GLT1 function.

PI: Yee, Amy
Title: Epilepsy and the Wnt Signaling Pathways
Abstract:

  • Aim 1: Generate time course of Wnt activation following a prolonged seizure, status epilepticus (SE).
  • Aim 2: To identify the role of Wnt signaling in two potential mechanisms of early epileptogenesis following SE.
  • Aim 3: Animal Clinical Trail: Determine if Wnt inhibition modulates cell death and delays the onset to epilepsy in a whole animal model of SE.

PI: Yelick, Pamela Crotty
Title: Dental Stem Cells and Tooth Tissue Engineering
Abstract:
The ultimate goal of this research project is to develop novel biologically based, dental and craniofacial skeletal repair and regeneration therapies in humans. We hypothesize that improved knowledge of dental stem cell (DSC) properties, and characteristics, combined with improved knowledge of tissue engineering strategies to reliably generate mineralized dental and craniofacial tissues of predictable size and shape, will result in the development of novel and effective, clinically relevant therapies for humans. To address this hypothesis, four specific aims are proposed, all of which will exclusively use human DSCs harvested from extracted human teeth. First, we will characterize the properties of individually harvested human dental tissues, to establish the normal range of DSC properties, to correlate DSC properties with the age and overall health of the donor, and to correlate these properties with the ability to successfully use harvested dental stem cells for dental tissue regeneration therapies. Next, we will test four different scaffold materials, carefully chosen for their defined physical properties, for their ability to generate bioengineered human tooth crowns of predictable size and shape. Third, we will expand upon our results demonstrating that silk scaffolds can be used to generate osteodentin of predicted size and shape, to bioengineer full sized, functional human tooth root equivalents that can support a synthetic or bioengineered tooth crown. Silk scaffold fabrication methods, porosity, degradation rates, and added growth factor peptides, will be systematically evaluated. As recommended in prior review, Aims 2 and 3 will be performed in both subcutaneous and minipig mandibular implant models. Finally, in Aim 4, we will combine our tooth crown, root, and craniofacial skeletal regenerative strategies, again using the Yucatan mini pig mandibular implant model, to generate successive 1st, 2nd and 3rd generation replacement teeth. For each of the proposed aims, detailed developmental analyses of bioengineered dental implant tissues will be performed in order to better understand, and devise strategies to improve dental tissue regeneration.

Our novel approach to tooth repair and regeneration, using human DSCs, and state of the art scaffold fabrication methods, combined with our extensive expertise in Developmental Biology and Tissue Engineering, have the potential to provide new and improved, biologically based repair and regeneration strategies, using autologous tissues. The successful accomplishment of the proposed studies would dramatically alter the field of dentistry as it currently exists, extending clinically relevant dental repair therapies to include biologically based dental materials with properties closely matching those of naturally formed dental tissues.

PI: Yeum, Kyung-Jin
Title: Biological Functions of Rice Bran on Metabolic Syndrome: A Randomized Cross-Over Pilot Study
Abstract:
The rapid increase in prevalence of metabolic syndrome, which is associated with a state of elevated systemic oxidative stress, is projected to future increase in diabetes and cardiovascular diseases. Due to the electrophilic nature of reactive carbonyl species (RCS) produced by oxidation of polyunsaturated fatty acids and sugars, they react with nucleophilic site of proteins and DNA, and lead to cellular dysfunction. Therefore, an effective RCS sequestering agent will protect such cellular dysfunction. Phytochemicals in rice bran such as γ-oryzanol and vitamin E arenot only potent antioxidants but also reported to control blood sugar and lipid in animal models.

Hypothesis:
We hypothesize that brown and purple rice bran rich in γ-oryzanol, α-tocopherol, α-tocotrienols and anthocyanidine will alleviate the metabolic disorders by quenching protein carbonyls and reducing systemic oxidative stress. We believe that the current study will provide us essential information for establishing dietary defense strategies preventing the progression of metabolic syndrome.

Objectives:
The long term goal of this study is to understand the mechanism underlying metabolic syndrome to develop dietary strategies reduce the prevalence of chronic diseases such as diabetes and cardiovascular disease. A strong research team with combined expertise in human physiology, mass spectrometry, and human nutritional biochemistry will work in concert to achieve our specific aims: to determine the ability of brown and purple rice bran to 1) reduce the protein carbonylation and DNA damage in vivo and 2) alleviate selected metabolic risk factors.

Approach:
Fifteen men and women (>50 yr) with metabolic syndrome will be recruited for the study. Qualified subjects will randomized to receive either brown and purple rice bran power (20g/d) or placebo (colored rice powder, 20g/d) during each 4 wk intervention phase with a 4 wk washout between phases. Subjects will visit our research center before and after intervention of each phase (baseline, wk 4, wk 8 and wk 12) for blood drawing, urine collection, physical examination and an interview with a research dietician. Blood and urine samples will be analyzed for:

  1. reactive carbonyl species and albumin cys34 modification using LC-ESI-MS/MS and immunoistochemistry

  2. systemic oxidative stress

  3. oxidative DNA damage and

  4. metabolic risk factors (plasma glucose, lipid profiles, blood pressure, adiponectin, Hemoglobin A1c, C-reactive protein).

PI: Yi, Hyunmin
Title: CDI-Type I: Geometric Algorithms for Staged Nanomanufacturing
Abstract: Efficient nanomanufacturing of arbitrary structures is a major scientific challenge and a major technological opportunity. This concept of this proposal is that computational thinking will bootstrap any technology for constructing basic building blocks and glues into a general methodology for manufacturing arbitrary structures. A host of such results has the potential to revolutionize the field of nanomanufacturing and bring the societal benefits much closer to feasibility.

The project approach is to understand the extent to which high-level algorithmic control, combined with nano self-assembly as the low-level machine, can be used to manufacture arbitrary two- and three-dimensional structures with desired interfaces using very few types of glues and basic units. The theoretical approach is to begin with mathematical models of the assembly process from basic units, small rigid units (rods, squares, cubes, etc.) with glues (binding sites) of different types at specific locations, proceeding to view the sequence of steps by which these units are created, mixed in a solution, and filtered as a geometric algorithm in a novel computational model. The modeling component will develop novel models for viewing nanomanufacturing as a sequential or parallel computation system, where computational steps are either precisely controlled physical manipulations or self-assembly procedures. The primary computational novelty is to consider both of these aspects in one cohesive model, while the chemical innovation is the control and manipulation of viral nanobuilding blocks for higher-order architecture construction. For comparison, complex, large-scale architectures will be assembled by DNA hybridization using building blocks of tobacco mosaic virus, analogous to the theoretical approach. The unique combination of nanobiofabrication and two computational models - sequential and parallel algorithms with self-assembly manufacturing is intended to enable more efficient solutions to general nanomanufacturing.           

In additional to the technological benefits, the project will also train graduate and undergraduate students to take practical challenges outside computer science and develop mathematical and computational perspectives into the problems, a cornerstone for the success of computational thinking. The proposed research will also be widely disseminated through course and lecture exchanges, visual art projects, and outreach activities.

PI: Yi, Hyunmin
Title: Collaborative Research: Hierarchically Assembled Viral-Synthetic Hybrid Microentities
Abstract:
This award by the Biomaterials program in the Division of Material Research for a Collaborative proposal from Tufts University (Lead) and Massachusetts Institute of Technology (non Lead) is to develop and understand a new method for manufacturing of biomaterial-based microscale entities with biosensing capabilities. This project is based on the hierarchical, high-throughput assembly of functionalized tobacco mosaic virus (TMV) nanotemplates with hydrogel microparticles via nucleic acid hybridization. This approach enables seamless integration of nano-, bio- and synthetic materials with unprecedented density, selectivity, programmability and orientational control. The significance of the project is that the new multiplexed sensing platforms will integrate hydrogel particles with the biofunctionality of TMV via highly programmable biochemical interactions to achieve features and performances beyond what is possible with individual technologies or mere addition of the two. Furthermore, the research will pave the way for moving beyond 2D patterning of viruses on surfaces and move this into 3D particle environments. The broad impact of this project is further enhanced by strong educational components such as extensive recruitment and exchange of undergraduate researchers, exchange lectures and shared research experience between MIT and Tufts University. As a part if this project, educational videos on nanotechnology and self-assembly for K-12 students and teachers will be available online via a public radio station in the area as part of the National Science Digital Library.

The ability to simultaneously assay for multiple target molecules in a complex mixture in a high-throughput capacity is an unmet challenge. This project will tackle this by integrating harmless viral templates and polymer microparticles to create multiplexed sensing systems by nucleic acid hybridization. This research is important for the general health and safety of the public in that the technology will pave new ways to rapidly monitor food pathogens, biological threats and environmental hazards. The research will also lead to ways in designing new methods to process viruses for use as high-value added materials. The education of the public will further benefit from this project by exposing a large number of undergraduate and K-12 students to cutting-edge research projects. In addition, educational video clips will be freely available to students and science teachers at grade schools from National Science Digital Library.

PI: Zeng, Li
Title: Muscle Cell-Enhanced Cartilage Tissue Engineering
Abstract: Arthritis is a leading cause of disability in the United States. Despite its prevalence in our ever-aging society, effective treatment options for arthritis are still limited. Arthritis is caused by the destruction of joint cartilage, which is accompanied by inflammation and pain. Cartilage tissue engineering offers a promising solution to regenerate cartilage and restore tissue function. However, the presence of pro-inflammatory cytokines at the host site inevitably leads to matrix degradation, causing the engineered cartilage to be unstable. Therefore, for this technology to be applied clinically there is a critical need to engineer stable cartilage that is resistant to pro-inflammatory cytokine-induced degradation. 

Our long-term goal is to gain critical knowledge of cartilage regulation and enhance the technology of cartilage tissue engineering for clinical applications. We are developing a novel strategy that integrates concepts and approaches from developmental biology with those of tissue engineering. During embryogenesis, muscle is one of the tissues that develop alongside the presumptive cartilage tissue. Our extensive preliminary studies indicate a role of muscle cells in regulating cartilage homeostasis and inflammatory stimuli. Our central hypothesis is that muscle cells and optimal scaffold selection can be used to enhance the stability of engineered cartilage by enhancing cartilage matrix production and the resistance to pro-inflammatory cytokines. We plan to test this hypothesis by using primary human articular chondrocytes and mesenchymal stem cells seeded in 3D silk scaffolds. We plan to: 1) investigate the role of muscle cells in regulating cartilage matrix production, 2) investigate the role of muscle cells in regulating the response to pro-inflammatory cytokines, and 3) investigate the effect of scaffold material on muscle cell regulation of cartilage matrix production and the response to pro-inflammatory cytokines. 

Our research team consists of experts in the fields of developmental biology, tissue engineering, immunology and orthopaedics. We believe that our synergistic efforts and interdisciplinary approach will result in deeper understanding of the regulation of cartilage homeostasis and the response to pro- inflammatory stimuli, providing the fundamental knowledge for modeling and treating arthritis. Thus, our study aspires to meet the critical need of improving tissue engineering technology, and may lead to the development of a novel strategy to engineer stable cartilage for clinical applications. 

PI: Zeng, Li
Title: Novel Strategies in Cartilage Tissue Engineering: Enhancing Cartilage Stability Using Muscle-Derived Factors and Scaffold Selection
Abstract:
This interdisciplinary research combines the expertise of developmental biology with tissue engineering. It aims at solving key issues in the technology of cartilage tissue engineering by testing the central hypothesis that muscle cells and scaffolding selection can enhance the stability of regenerated cartilage in terms of cartilage matrix production and inflammatory cytokine resistance. A comprehensive battery of biochemical and biomechanical analyses are planned to test this hypothesis. Very little is known regarding the mechanism by which muscle cells regulate cartilage gene expression, and the role of muscle cells or scaffolding materials on cytokine response has never been reported. Thus in addition to advancing cartilage tissue engineering technology, completing this research will also lead to a deeper and more complete understanding of the biology of cartilage regulation.

The strategy described in this proposal was inspired by concepts from animal development, when tissues develop alongside each other (such as cartilage and muscle) play crucial roles in cell-cell signaling between adjacent tissues and their subsequent differentiation and proliferation. Thus, cartilage formation involves not just cartilage cells, but cells of multiple surrounding tissues. Thus our idea of mimicking embryo development may inspire the creation of novel strategies to engineer other tissue types as well.

PI: Zimmerman, Michael
Title: High Frequency RF Materials and Devices
Abstract:
A new thermotropic Liquid Crystal Polymer material is being developed for the purpose of multilayer interconnects for extremely high frequency device operation (up to 100 GHz). A process is also in development to provide thin films for multilayer circuits. Critical in the manufacturing process is developing a process which provides for more isotropic materials properties, which is critical for operation of devices at high frequencies. Extrusion die design has a large impact on alignment of molecules in machine and transverse direction during extrusion. This work focuses on research in the area of developing computational models to determine molecular alignment in the extrusion process. Previously, modeling methods have focused on modeling die designs and process parameters, only. The research work will focus on the structure and rheological properties of a nematic thermotropic Liquid Crystal Polymer, and the correlation of process parameter to solidification, and orientation of the polymer chains. Finite element techniques will both be used to model the state of the polymer in both the die, and outside (free surface) and appropriate rheological models will be developed for incorporation into the numerical model.

In addition to the modeling work, we will expand our work at the Harvard Center for Nanoscience (CNS). We will continue to develop appropriate procedures to evaluate the morphology and structure of thin film polymers. The goal is to be able to completely characterization crystalline domains of polymers which include sizes, anisotropy, molecular length scale, orientation, and surface characteristics. Procedures that will be developed will include preparation of soft materials for TEM studies, proper methods for SEM characterization and standards and methods for FTIR.

 

 

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