Donald Smith - US grants

The Tuberculosis Prevention Trial in progress in the Chingelput District in south India (Chingelput Trial) is providing an extensive data base for answering questions of major importance about the pathogenesis and epidemiology of tuberculosis as it exists today in a rural tropical area in a developing country. Thus far, the Chingelput Trial has revealed two major and unexpected findings: (1) the absence of a protective effect of BCG, (2) the number of Chingelput patients undergoing an early progression from infection to disease was only 10% of that observed in similar active case finding studies in other areas of the world. Another unique observation about tuberculosis in south India, made 20 years earlier and of potential relevance to the Chingelput Trial, was that 70% of isolates of tubercle bacilli from patients in MadrAS were of low virulence for guinea pigs. In preliminary studies of the virulence of Chingelput isolates in aerosol infected guinea pigs, we demonstrated a significant reduction in the extent of hematogenous spread to lung and spleen. We propose to utilize the Chingelput Data Bank, a research resource of international importance, to answer the question, "Does the tendency for hematogenous spread in aerosol infected guinea pigs have predictive value for the occurrence of hematogenous forms of tuberculosis in Chingelput patients. Isolates to be studied for their ability to spread hematogenously in aerosol infected guinea pigs include those recovered from urine, bone, or cerebrospinal fluid." If tubercle bacilli obtained from Chingelput patients do exhibit a reduced tendency to spread via the blood in guinea pigs and if this is reflected in a reduced frequency of hematogenous forms of tuberculosis in such patients, these data would provide the first laboratory evidence obtained on a large number of patients supporting a role for exogenous reinfection tuberculosis. If exogenous reinfection is shown to be a significant factor in the pathogenesis and epidemiology of tuberculosis in the Chingelput district, it not only explains both of the major unexpected Chingelput Trial observations, it also has important implications for the tuberculosis control strategy to be stressed in Chingelput and in other areas where similar circumstances exist.

The broad long-tenn objectives of this proposed project are to identify actors contributing to increased lead exposures that are specific to postmenopausal females, and to examine effects of lead on the aged skeleton as a target organ of toxicity. This study will investigate the role of the skeleton as an endogenous source of lead exposure, as well as effects of lead on the skeleton as a target organ of toxicity, using a sensitive stable lead isotope (204Pb) tracer technique and the ovariectomized rat model of human hormone depletion-induced osteopenia and bone lead toxicity. The specific aims of this study are: (l) Determine the magnitude of lead remobilized from the skeleton back into the circulation as a result of experimentally induced osteopenia in rats with low and elevated bone lead levels: (2) Examine the effects of bone lead levels. and treatments with estrogen. parathyroid hormone and bisphosphonate (risedronate) on the mobilization of lead from bone. and on bone physiology: and (3) Determine whether skeletal lead is redistributed to other target organs. specifically the brain and kidney. as a result o induced osteopenia. Rats with low and elevated bone lead levels will be ovariectomized or sham-ovariectomized, and then undergo therapeutic interventions with vehicle, estrogen, PTH, and risedronate (bisphosphonate) to evaluate the effects of ovariectomy and these treatments on bone lead and mineral loss. Under the conditions proposed here, the skeleton will be labeled with the bone-specific tracer 3H- tetracycline and a lead 204Pb isotopic tracer distinguishably different from the soft tissues at the beginning of the therapeutic treatments. The primary outcome measures of this study are (i) the levels of 204Pb in skeletal and soft tissues, and urine as a tracer of bone lead, (ii) changes in total lead concentrations in soft tissues resulting from bone lead mobilization or its prevention, (iii) the levels of 3H-tetracycline in bone, serum, and urine as a tracer of bone mineral status, (iv) the calcium content of bone and urine, and (v) osteocalcin, alkaline phosphatase, and pyridinoline crosslinks levels in serum and urine as markers of bone physiology. The rationale for this study is based on the need to elucidate the magnitude and possible risk(s) of elevated lead exposure from remobilized skeletal lead in postmenopausal women, as well whether elevated bone lead levels alter the osteogenic response of bone to hormonal stimuli and the efficacy of therapeutic treatments to reduce the development of osteopenia.

Java is designed to be a mature, object-oriented programming languagemainly for Web-based programming. However, Java can support general stand-alone applications as well, such as scientific codes that consist of independent components using exceptions as a control mechanism between components. Although Java is too new to have been used extensively in applications, it is clear that user-defined exceptions will be ubiquitous in Java programs, causing them to exhibit distinctive control flow, different from previous object-oriented languages. The proposed research concentrates on combining new analysis techniques with two optimization strategies, namely speculative and non- speculative, using a testbed of scientific applications for validation. Exceptions pose new challenges to optimizing compilers since they introduce implicit control flow and their semantics requires access to user-visible state at any raised exception. Optimization strategies may either preserve exceptions and their visible states, or perform speculative optimizations by ignoring exceptions, and restore the visible state if an exception is raised. New static analyses are needed to provide an accurate estimate of control flow within and across method boundaries, including concrete type inference and subsequent def-use analyses. The resulting information is crucial for the effectiveness of many optimizations, including code specialization, code motion, register allocation, and instruction scheduling.

Prop: AST-0105221
PI: Smith, Donald


Dr. Smith is awarded an NSF Astronomy and Astrophysics Postdoctoral Fellowship to carry out a program of research and education at the University of Michigan. He will work with the Robotic Optical Transient Search Experiment (ROTSE) project, a program to distribute and operate at least four small, automatic telescopes at widely separated points on Earth in order to capture the early optical emission from an extensive sample of gamma-ray bursts (GRBs). Early observations will yield constraints on characteristics of the burst origins. The telescope design allows GRB observations during the important window between five and forty seconds after the onset of the event, which no other current or planned experiment will be able to achieve. Dr. Smith will develop the operational and analysis software, use existing instruments to respond to alerts, install units at the international sites, and train collaborators in the use of the system. The ROTSE project also provides a large database of all-sky observations for student projects and his work will involve undergraduate students in the research. He also intends to develop a course in observational astronomy and presentations at a local museum using the ROTSE database, as well as an interactive tool providing access for the public and researchers alike.
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DESCRIPTION (provided by applicant): Recent studies have shown that chronic exposures to manganese (Mn) are associated with an increased risk for the development of neurodegenerative diseases, such as Parkinsonism. Concern over the potential neurotoxicity of low but chronic Mn exposure has increased in light of the incorporation of MMT into gasoline. The effects of Mn exposure in in vivo rodent models has focused on Mn-induced depletion of striatal dopamine, whereas non-human primate studies have more commonly shown gliosis in the globus pallidus. Also, most studies have utilized relatively high Mn exposures, while only a few have investigated the effects of chronic low-level Mn exposures. Here we are proposing that the locus of Mn toxicity may depend on the total cumulative Mn dose, such that more sensitive GABAergic systems of the globus pallidus are targeted at lower relative doses, while dopaminergic systems of the nigro-striatal pathway become involved at higher doses. To validate this, there is a need to investigate the effects of Mn on specific brain nuclei and neurotransmitter systems as a function of Mn exposure regimens in order to better characterize the overall susceptibility of the basal ganglia to Mn effects. Moreover, there is justified concern that increased chronic low-level Mn exposure may further undermine the functionality of the basal ganglia in susceptible populations in the early stages of neurodegenerative disease, and accelerate the emergence of neuromotor dysfunction. The specific aims of this study are to: (1) Determine the progression of Mn effects on brain regional Mn distribution, and neurochemical and neuromotor function, across different durations and low level doses of Mn exposures in a whole animal rodent model. And (2) Determine the effect(s) and underlying interaction(s) of Mn exposure on neurotoxicity and neuromotor performance in a rodent model of asymptomatic Parkinsonism, as a model of a susceptible population. These Aims will be pursued through several sub-aims focusing on the following major outcomes: (i) A Functional Observational Battery (FOB) of neuromotor performance; (ii) Particle induced X-ray emission (PIXE) analyses of in situ brain regional Mn levels; (iii) Neurochemical measures of GABAergic and dopaminergic metabolism/status in specific brain regions, and; (iv) Investigation of specific mechanisms underlying the Mn - GABAergic effect using cell culture models. These proposed studies will significantly extend our knowledge of chronic low level Mn neurotoxicity, by pursuing a unifying hypothesis of action of low-level chronic Mn exposure, and by investigating neurochemical and neuromotor outcomes of Mn exposure in conjunction with a moderate degree of sub-threshold Parkinsonism.

A grant has been awarded to the University of California, Santa Cruz for the purchase of an Electron Paramagnetic Resonance (EPR) spectrometer. The goal of this research program is to develop a deeper understanding of how metals, especially those found in the environment, influence living systems. Metals such as iron, copper, manganese and lead are found throughout our environment. Some of these metals are found as natural components of living systems, such as plants and bacteria, while others are contaminants. This research program centered on the new EPR spectrometer will provide critical new information at the molecular level as to how living systems store metals, utilize metals for natural biological processes and respond to metal imbalances.
This research program brings together four interdisciplinary research groups from the Departments of Chemistry & Biochemistry and Environmental Toxicology. Working together, these research groups will examine the roles metals play in the prion diseases which include mad cow disease and Creutzfeldt-Jakob Disease in humans, how metals are used in microbial metabolism, how cellular structures are chemically modified by metals and how metals such as manganese distribute in living systems and contribute to environmental diseases. This latter project is motivated, in part, by the Canadian Government's recent approval of manganese as a gasoline additive. In all of these projects, the molecular centers containing the metals will be directly studied with unprecedented detail using the EPR spectrometer.
Our fundamental goal is to reveal important new molecular insights into how organisms use metals and respond to metal imbalances. The specific research projects will significantly expand our understanding of the basic biochemistry of metals. In addition, the findings will identify potential toxic metal species that could ultimately damage ecosystems. By identifying such species before they are widely distributed in the environment, such as manganese as a gasoline additive, we may help prevent a repeat of previous environmental catastrophes such as those experienced from lead, PCBs and asbestos. The instrument will be used primarily in research laboratories. From an educational perspective, having a new EPR spectrometer will allow us to train our future undergraduate and graduate students with this modern technique. We also plan to devote about 5% of the spectrometer time to class laboratories so as to enhance education and expose a new generation of chemists and environmental scientists to the fundamental technique of EPR.

This project combines hands-on experiential discovery laboratory exercises with computer-aided instruction into computer aided laboratory instruction (CALI). The goal of the project is to enhance laboratory learning and understanding while significantly reducing the time, equipment, staffing and space requirements. A generalized, interactive software application is being developed which presents the laboratory problem, guides students through setup of the experiment and physical apparatus, monitors the experimental effort, provides feedback during the laboratory exercise, and evaluates student performance. An existing prototype CALI experiment is being modified, based on experience to date, and two new experiments are being developed.
The efficacy of the CALI system is being evaluated by having randomly selected experimental groups perform the CALI experiments and comparing their short and long term learning with control groups performing conventional laboratory experiments with similar apparatus without the CALI interface. This evaluation procedure is being replicated at another institution for one of the experiments. Resources are being tracked to estimate potential savings. CALI details and the evaluation results will be disseminated by conference presentations and through testing of the system at the second institution.

DESCRIPTION (provided by applicant): Epidemiological and case study reports in children have provided compelling evidence for significant neurobehavioral deficits associated with elevated environmental and dietary manganese (Mn) exposure. However, these studies have not established a causal relationship between Mn exposure and neurobehavioral deficits, nor have they provided a detailed understanding of the specific nature of the cognitive deficits (i.e., learning, attention, emotionality, etc.), or underlying neurochemical alterations. Aim 1 will determine whether pre-weaning or continuous postnatal Mn exposure produces neurobehavioral deficits in young adults, using a rodent model of Mn neurotoxicity. Aim II will explore the molecular and neurochemical mechanisms underlying the cognitive deficits induced by pre-weaning or continuous postnatal Mn exposure. Aim III will determine the relationship of pre-weaning or continuous postnatal Mn exposures with biological markers of exposure, and the extent that these exposure biomarkers are associated with neurobehavioral and neurochemical alterations. We will test the overarching hypotheses that (1) neonatal Mn exposure causes lasting dysfunction in various aspects of cognitive (i.e., learning, memory, attention and/or inhibitory control) and affective (arousal and/or emotion) functioning, and (2) that these changes are linked to developmental alterations in dopaminergic and glutamatergic systems in brain regions which subserve these functions (i.e., the prefrontal cortex, striatum, and hippocampus). We will measure cellular and neurochemical parameters of dopaminergic and glutamatergic system function by microdialysis/biosensor, receptor binding, and immunohistochemistry in the same animals that underwent cognitive testing, in order to provide information about Mn-induced changes in systems that subserve these behavioral functions, and to determine whether one or more of these neural changes correlate with behavioral deficits. Further, we will directly test whether alteration of the dopaminergic system due to Mn exposure plays a role in the resulting behavioral deficits by determining whether Mn exposure alters the dose- response relationship of methylphenidate (Ritalin), a dopamine transporter (DAT) inhibitor, and whether the drug alleviates behavioral deficits due to Mn exposure. These studies will be the most comprehensive assessments to date on the neurological consequences of early life exposure to levels of manganese that infants and children are likely to encounter in their environment. This knowledge will inform public health policies and guidelines on suitable levels of Mn exposure to children. PUBLIC HEALTH RELEVANCE: The proposed studies will address a significant gap in our understanding of the health risks posed by elevated manganese exposure in children by defining in detail the link between early life or continuous postnatal manganese exposure and lasting cognitive deficits, the neurochemical alterations underlying those deficits, and biomarkers that best predict exposure and effects, using a rodent model of childhood Mn exposure. These studies will be the most comprehensive assessments to date on the neurological consequences of early life exposure to levels of manganese that infants and children are likely to encounter in their environment. This knowledge will inform public health policies and guidelines on suitable levels of Mn exposure to children.

DESCRIPTION (provided by applicant): Emerging evidence demonstrates that elevated environmental manganese (Mn) exposure is associated with cognitive and behavioral deficits in children. However, up to now, studies in children have only been focused on exposure via ingestion pathways, although occupational research in adults has established that Mn exposure via inhalation poses a more significant risk for cognitive and motor effects than exposure via ingestion. We will assess the neurodevelopmental effects of airborne Mn exposure in 11-13 year old children living in areas impacted by current or past ferroalloy industries. We will examine 750 children across three well- characterized study sites in the province of Brescia, Italy, that differ in history of ferroalloy plant activity: 1) Bagnolo Mella, a community with an active ferroalloy plant that produces very elevated air Mn levels;2) Valcamonica, a region with slightly elevated air Mn levels due to a history of ferroalloy plant activity that ended in 2001, and;3) Garda Lake, a reference region with background air Mn levels and no history of ferroalloy plant activity. The project will build upon the existing EU-funded PHIME (Public Health Impact of Mixed element Exposure in susceptible populations) study that has already examined a total of 300 children from Valcamonica and Garda Lake;we propose to enroll 450 more to achieve our aims. A strength of our proposal is the emphasis on environmental exposure assessment, utilizing measures of airborne Mn with 24 hr personal air monitors, Mn levels in home deposited dust, tap water, soil, and a detailed food frequency questionnaire, coupled with comprehensive cognitive, behavioral, motor, and sensory assessments, along with exposure biomarker measures (blood, urine, hair, nails) and Mn in shed deciduous teeth to assess early life and cumulative lifetime exposures. Preliminary results show changes in motor-coordination, odor identification and IQ among the residents in the historically exposed area of Valcamonica are associated with air Mn levels. This study will offer the unique opportunity to compare effects of Mn at distinct developmental time periods by evaluating children with three exposure histories 1) continuous high airborne Mn exposure since birth (Bagnolo Mella), 2) exposure to high air Mn levels over the first 3 - 5 postnatal years, but reduced current exposure (Valcamonica), and 3) no history of elevated airborne Mn exposure (Garda Lake). We will also address the role of genetic susceptibility to Mn via genetic variation in iron metabolism pathways genes. This will be the first study on Mn neurotoxicity in children supported by a profound characterization of environmental Mn exposure levels. PUBLIC HEALTH RELEVANCE: The proposed studies will address a significant gap in our understanding of the health risks posed by elevated environmental manganese exposure in children by defining in detail the link between early life or continuous exposure and cognitive, behavioral, motor, and sensory deficits in children age 11-13 years. This research will also investigate how genetic polymorphisms influence exposure risk. Such findings will surely be powerful influences on future research initiatives and public policy directed at minimizing the morbidity associated with manganese exposure, especially when associated with iron deficiency, lead exposure and other covariates. Given the potential use of MMT in gasoline, this study will also contribute to understanding the potential risk from airborne manganese that may be increased by the introduction of this manganese-based fuel worldwide. This knowledge will inform public health policies and guidelines on suitable levels of manganese exposure to children worldwide.

This project is to provide 126 scholarships over a 5-year period for academically-talented, financially-needy students in Engineering, Computer Information Systems, Computer Aided Design and Drafting, and Robotics Technology at Baltimore City Community College (BCCC). The project builds on strong existing student support services at BCCC and develops new interventions such as invited speakers, field trips, peer tutoring, innovative mathematics workshops, engineering/technology competition and family involvement. The project includes a strong evaluation process with feedback loops to ensure continuous improvement. The mathematics-centered advising and workshops should improve mathematics skills and overall program success. Professional development opportunities will also enhance the educational benefit to the students.

The project has strong collaboration and support from local universities and industry, a commitment from industry for internships, and support from political leaders. Project partners include Morgan State University, Capitol College, Carnegie Mellon University, Lockheed Martin, Baltimore Gas & Electric, Amtek Company, and Juxtopia LLC. The demographic data support the project's objective of increasing African American enrollment in the engineering technology related programs. The project's strong advising and mentoring programs and family involvement should contribute to retention and success. The project will contribute to broadening participation of underrepresented groups and producing a highly-qualified workforce in STEM fields.

Advanced computing and data cyberinfrastructure (ACI) is playing an increasingly important role in all areas of computational and data-enabled science and engineering (CDS&E), and has become a key enabler of scientific insights and innovation. As a result, it is critical that researchers and students have access to adequate campus ACI (e.g., computing and data resources). However, it is also critical that such a campus ACI aligns and is integrated with national initiatives, to connect with and share advanced computing/data resources and expertise, enable collaborative and end-to-end science, and build upon and leverage existing federal investments in high end infrastructure. This EAGER focus on three main thrusts: (1) develop the expertise and experience at Rutgers for establishing a campus ACI for CDS&E research, and to align it with the national ACI by integrating this campus ACI as part of a national resource, i.e., Open Science Grid (OSG); (2) develop the necessary research partnerships based on the OSG federated ACI to address important research problems in an end-to-end manner and lead to significant insights; and (3) document processes, experiences, and lesson learnt during this process to share these findings with the broader community, providing a "cook- book".

Establishing campus ACI ecosystems is a common practice that Universities follow in order to support their research and education missions. However, these campus ACI ecosystems typically operate in isolation, restricting the access to resources and therefore the potential impact that they can offer to the community beyond their own campuses. The outcomes of this research will provide important insights into the feasibility of leveraging national investments to create resource pools where the whole is greater than the sum of its parts. As a result, it can have significant impact on the mindset of faculty, campus IT, and administrators, and on the overall ability of campus IT groups to support the advanced computing needs of researchers. The resulting models for collaboration will be seeded through shared ACI to incentivize resource and expertise sharing that can enable faculty and students to leverage a much larger and more robust set of resources. It will also help foster the creation of necessary support teams to support science and scholarship.

Project Summary Studies in children/adolescents have linked developmental environmental manganese (Mn) exposure to inattention, impulsivity, hyperactivity, oppositional behaviors, and fine motor deficits, though these studies are limited by their cross-sectional designs and limited control of confounding that make it impossible to demonstrate that Mn causes these deficits. Our recent studies have shown that developmental Mn exposure causes lasting deficits in attention, impulse control, and fine motor function, providing the first causal evidence supporting the human studies. Our initial studies of the potential benefits of chronic oral methylphenidate (Ritalin) treatment revealed that the one dose studied alleviated the Mn-induced impulse control and fine motor dysfunctions, but impaired attentional performance in the Mn animals. We propose to build upon these findings to elucidate the neural mechanisms underlying the lasting attentional, impulse control, and fine motor dysfunction caused by developmental Mn exposure, and test potential therapeutic interventions (methylphenidate, guanfacine), in our established rodent model of childhood Mn exposure. Our testable hypotheses are 1) Oral MPH and/or guanfacine treatment will alleviate the lasting fine motor, attention and impulse control deficits caused by developmental Mn exposure; and 2) These lasting deficits caused by Mn exposure are due to changes levels of catecholaminergic system proteins in the pre-frontal cortex - striatal pathway. We will test these hypotheses via the following aims: Aim 1 will (i) Identify a clinically-relevant therapeutic regimen of MPH for the Mn deficits in attention, impulse control, and fine motor function by determining the dose-response relationship with MPH in male and female control vs Mn animals, and (ii) Determine involvement of DA D1, D2, and ?2A adrenoreceptors in the Mn deficits and in the therapeutic efficacy of MPH, using administration of selective receptor antagonists during behavioral testing. Aim 2 will use PET neuroimaging and quantitative immunohistochemistry to further elucidate changes in catecholaminergic system proteins implicated in the attention/impulse control/fine motor Mn deficits, and the association of these measures with the attention/impulse control/fine motor outcomes. Aim 3 will test the hypotheses that guanfacine alleviates the attention/impulse control deficits produced by Mn. These studies will be the first to identify potentially efficacious therapies for the treatment/prevention of attentional and co-morbid fine motor deficits due to developmental Mn exposure, and to elucidate their neural mechanisms.

This Major Research Instrumentation (MRI) program award will support the acquisition of a modern triple-quadrupole inductively coupled plasma mass spectrometer (TQ-ICP-MS) and three dedicated sample processing and introduction systems for research and teaching in the Institute of Marine Science’s Marine Analytical Laboratory at the University of California, Santa Cruz. This suite of instruments will enable novel multidisciplinary analytical work by faculty, researchers, and students that will contribute to a more refined understanding of diverse processes in Earth, ocean, and planetary sciences, and environmental toxicology. The new facility will amplify the campus commitment to student social mobility and increased diversity in STEM by providing state-of-the-art instrumentation for practical training in the context of undergraduate and graduate coursework and research. Laboratory PIs actively engage with the AGU Bridge program (Ocean Sciences), NSF-ICER GEOPAths - IMPACT (Earth and Planetary Sciences), and the UCSC STEM Diversity Program, which fund cutting-edge research opportunities for underrepresented students. <br/><br/>TQ-ICP-MS systems combine the sensitivity, scan speed, and dynamic range of modern single quadrupole ICP-MS with a quadrupole - reaction cell - quadrupole configuration that enables unambiguous chemical and physical resolution of many of the most challenging isobaric interferences. The three dedicated sample introductions systems include: (1) a gas chromatograph speciation analysis of organometallics (e.g., Hg) in the marine and terrestrial environments; (2) an ESI prepFAST IC for high-throughput metal speciation (e.g. As, Cr, Se) and total metal analysis for environmental toxicology research; and (3) an ESI seaFAST for automated analysis of ultra-trace elements in seawater. The TQ-ICP-MS will be integrated with an existing Teledyne Analyte Excite laser ablation system and Thermo Element XR high-resolution magnetic sector ICP-MS. The laser can be operated with either ICP-MS or with both for split-stream analysis of geological and meteoritic materials for geochemical and petrochronologic research.<br/><br/>This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.