Stephen Smith - US grants

In the past, we developed an assay which supports the growth of malignant colonies from children with acute lymphoblastic leukemia and non-Hodgkin's lymphoma. Our methodology differs from in vitro culture techniques reported by others in that (albeit sporadically) long term cell growth and cell line establishment from passage of a single colony could be accomplished. Cell line establishment, however, is important because cell lines provide an unlimited, stable source of cells for in vitro studies. Cell lines established in our laboratory have been shown to have the same immunophenotype, biochemical enzyme profile, immunogenotype and karyotype as the patient's tumor. We have recently determined that different subtypes of malignant lymphoblasts possess unique profiles for receptors to peptide hormones. While each of 9 immature T-lymphoblast cell lines possess IGF-I receptors and lack insulin receptors, 19 of 20 immature B-lymphoblast cell lines possess insulin receptors and lack IGF-I receptors. We have shown that T-lymphoblasts proliferate in response to nanogram concentrations of IGF-I but not insulin in serum-free media. Moreover, supplemental IGF-I has proven to be a key growth factor necessary in the development of a reproducible, standardized method for the establishment of T-lymphoblast cell lines in vitro. Based on these data, we hypothesize that peptide hormones such as insulin and IGF-I may be critical growth factors necessary for the proliferation of malignant hematopoietic cells and that peptide receptor function blockage may severely limit cellular proliferation. The objective of this proposal is to study the biologic function of specific peptides (I, IGF-I, IGF-II, CH) on malignant hematopoietic cells which possess (or lack) specific peptide receptors, and to determine the specificity, kinetics, structure and function on specific peptide receptors by binding studies, chemical cross-linking on SDS-PAGE, receptor phosphorylation and by polyclonal and monoclonal antireceptor antibodies. These studies will augment our understanding of peptide/peptide receptor function in malignant cells, will help establish standard methodologies for cell line establishment, and may provide the foundation for antipeptide receptor therapy for hematopoietic malignancies in the future.

This project marks the beginning of a long time series hydrographic station north of Hawaii, which will constitute a contribution to both the World Ocean Circulation Experiment (WOCE), and the Global Ocean Flux Study (GOFS). Hydrographic observations, and current meter and tracer data will be collected, analysed, and disseminated to the community. The data collected will provide information for the Pacific similar to those now collected near Bermuda at what has come to be called the Panulirus Station.

This project is concerned with the theory of modular representations of the finite groups of Lie type, in which case the natural geometry is the Tits building. Earlier work has established techniques for describing important modules via generators and relations determined by the geometry. This research will extend the class of modules to which the methods apply. These techniques will be used to study the modular representations of the highly exceptional sporadic simple groups. The study of groups arises from consideration of the symmetry of physical and theoretical objects. The expression of these symmetry transformations by means of matrices leads to group representation theory. This project will develop representation theory by exploiting techniques from combinatorics and discrete geometry.

This award supports five U.S. mathematicians for collaborative research in group theory with a number of German mathematicians at several universities in the Federal Republic of Germany (FRG). The collaborative framework was organized by Professor Stephen D. Smith of the University of Illinois at Chicago and Professors Franz G. Timmesfeld of the University of Geissen and Gernot Stroth of the Free University, Berlin. The proposed visits will permit continuation of some highly productive collaborative relationships previously supported by the U.S.-FRG Program, while also introducing some new participants. Reciprocal visits by the Germans to several U.S. universities are being supported by the DFG (the German equivalent of NSF.) The various partnerships among the two groups will focus on several closely related problems: axiomatization and classification of geometries for simple groups, universal covers of finite geometries, the theory of trees and more general amalgams for geometric groups; and the application of such results to the study of maximal subgroups and representation of simple groups. Most of the leaders in this area of mathematics are working in the U.S. and West Germany, so fruitful collaboration is expected. Both geometry and group theory have important applications in twentieth century science - for example, geometry in the physics of relativity, and group theory in physics and chemistry at the quantum and particle levels. Natural interrelations between the two theories have long been studied. The use of techniques from discrete geometry in problems of finite group theory is a particularly vigorous area of modern mathematical research.

The coastal bays play a critical role in the transport and transformation of land runoff to the ocean. Drs. Hollibaugh and Smith will consider the role of bays and estuaries in the net flux of carbon, nitrogen, and phosphorous between the land and ocean. The system of interest (Tomales Bay, California) is hydrographically simple, has a long water residence time, is sufficiently compact that it can be studied as a single unit, and has low inorganic nutrient pollution. The system functions metabolically like numerous other coastal marine ecosystems. External sources of organic matter which support food chains in this system are simple to characterize and have strong seasonal and interannual signals. These investigators will address the following questions by means of a multi-investigator field and laboratory program: 1) What is the relative importance of coastal upwelling versus terrigenous runoff in delivering oxidizable organic matter and nutrients to this system? 2) What are the responses of system metabolism and the metabolism of major system components to seasonal and interannual variations in these forcing functions? 3) What is the relationship between net system metabolism and non-conservative fluxes of nitrogen? 4) Can rates derived from stoichiometric arguments be validated by "direct" biochemical assays. It is anticipated that the outcome of this research can be extrapolated to other systems which may be applicable to management of the nations resources. This effort is being funded as a Land Margins Ecosystem Research project in a program which is jointly supported by the Directorates of Geosciences and Biotic Systems and Resources.

This project is a one year continuation of the PI's long term study of Tomales Bay, California. It will complete his ongoing hydrographic and nutrient survey. Tomales Bay is unique because of its hydrgraphic simplicity and because of the long residence time of its water. These factors greatly facilitate mass and flux calculations for the water, salt, and nutrients within the Bay, itself. In addition, the Bay is optimum for studying the exchange of material between the land, the estuary and the coastal ocean. It is a "net heterotrophic system," meaning that it consumes more organic matter than it consumes. It is also a denitrifying system where nitrogen gas is released to the atmosphere as the microbes decompose organic matter. The PI seeks to answer the following question. Is the heterotrophy of this and similar systems fueled by material from the land or by material from the coastal ocean? A great deal of organic matter is delivered to the Bay from the coastal ocean, but when upwelling is weak terrestrial runoff is strong and may contribute even more organic matter. With this additional year of sampling the PI will resolve the relative importance of these potential sources. The results of this study may force a recalculation of the global carbon and nitrogen budget because other estuarine systems may also be net heterotrophic rather than net autotrophic as previously thought.

This is a request for partial funding for a workshop on "Ultrasound Transducers: The Next Generation". The workshop is to take place on the Duke campus on Sept. 10- 11, 1990. The workshop is to include leading researchers both from the U.S. and foreign countries, and will examine those areas where transducers still hamper full utilization of ultrasound technology in biomedical applications. The workshop is co-sponsored by the Duke ERC.

9309677 Smith This grant will support research to improve 2-D ultrasonic transducers by using opto-electronic transmitter technology to replace power amplifiers and coaxial cables. Low power diode lasers, optical fibers and photo conductive switches will be used in the new system. This research will be aimed at determining if the photo-conductive switches can be optimized for this application. This research is important since it has the potential to eliminate the bulky transducer cables now used with high density ultrasonic arrays and thus allow the systems to be more flexible and to consist of more transmit channels. ***

This award will provide essential computational resources, to several on-going research projects in number theory, algebra, and algebraic geometry. These projects cover the related areas of representation theory; modular forms and elliptic curves; the topology of algebraic varieties and Picard-Fuchs, differential equations; and Arakelov theory, K-theory, and arithmetic geometry. The investigators plan variously to apply symbolic algebra programs, such as REDUCE, Maple, Macaulay, to these problems; to develop packages of procedures in these languages; and to develop programs in lower level languages such as FORTRAN and C. In addition, the equipment will be used to support graduate students working in these areas.

9414558 Casey A major practical limitation to the application of high resolution two-dimensional ultrasonic imaging is the size and flexibility of the cable linking the transmitter/receive transducer element with the powering and processing electronics. The PI's have successfully fabricated a prototype based on a combination of a fiber optics and integrated optoelectronics, which would replace the cumbersome coaxial cable currently used to excite the transmit pulses for relatively small linear transducer arrays. They propose the use of the Electronics and Power Sources Directorate (EPSD) facility for assistance in the design and fabrication of the photoconductive semiconductor switch (PCSS) which is the critical element of our approach. Support of the proposed research would be in direct support of advanced biomedical ultrasound techniques already being partially supported by the National Science Foundation as well as Army interests in the application of high resolution ultrasonic non-destructive evaluation (NDE) to materials and structures of military significance. ***

9523466 Smith The coastal bays play a critical role in the transport and transformation of land runoff to the ocean. Drs. Hollibaugh and Smith will consider the role of bays and estuaries in the net flux of carbon, nitrogen, and phosphorous between the land and ocean. The system of interest (Tomales Bay, California) is hydrographically simple, has a long water residence time, is sufficiently compact that it can be studied as a single unit, and has low inorganic nutrient population. The system functions metabolically like numerous other coastal marine ecosystems. External sources of organic matter which support food chains in this system are simple to characterize and have strong seasonal and interannual signals. These investigators will address the following questions by means of a multi-investigator field and laboratory program: 1) What is the relative importance of coastal upwelling versus terrigenous runoff in delivering oxidizable organic matter and nutrients to this system? 2) What are the responses of system metabolism and the metabolism of major system components to seasonal and interannual variations in these forcing functions? 3) What is the relationship between net system metabolism and non-conservative fluxes of nitrogen? 4) Can rates derived from stoichimetric arguments be validated by "direct" biochemical assays. It is anticipated that the outcome of this research can be extrpolated to other systems which may be applicable to management of the nations resources. This effort is being funded as a Land Margins Ecosystem Research project in a program which is jointly supported by the Directorates of Geosciences and Biotic Systems and Resources.

Over the past decade, artificial intelligence concepts and techniques have been productively applied to diverse aspects of manufacturing decision-making, ranging from product and process development, to production management, to process diagnosis and quality control. Artificial intelligence techniques will continue to impact design and manufacturing. In fact, they are an important - even necessary - part of the dreams shared by concepts such as lean manufacturing, agile manufacturing, virtual manufacturing, computer-integrated manufacturing and design. Because artificial intelligence is still a field in which there is much fundamental research required to bring to fruition exciting developments that will prove useful in these fields and because this research might as well be focused on the most productive areas, it is a good time to bring together experts and practitioners in both artificial intelligence and manufacturing, to bridge gaps between problem and solution perspectives, build better mutual understanding of important research challenges and technical potential in the field, break down cultural barriers that now exist, and foster future interaction and collaboration between the two communities. Together, manufacturing and artificial intelligence researchers and practitioners will work to facilitate the realization of truly intelligent manufacturing systems.

DESCRIPTION (Adapted from Applicant's Abstract): Although intra-luminal ultrasound scanning has been developed with some degree of success for the imaging of the cardiovascular system, the circular side scanning geometry of the catheter ultrasound transducer is intrinsically unsuitable for many diagnostic applications. The objective of this application is the improvement of real time intra-luminal scanning via the development of a new generation of miniature forward looking mechanical sector scanners incorporating high frequency transducers above 20 MHz to enable improved guidance of cardiac interventional procedures. Each piezoelectric transducer is driven by a tiny linear actuator operating electrostatic forces combined with pivoting hinges to produce a sector scan. The linear actuator is an example of a microelectromechanical system (MEMS), now one of the most important research fields of microelectronics. The transducer / MEMS assembly will be totally housed within a cardiac catheter. Applications may include: 1) real time intra-luminal sector scanning of the heart at 20-40 MHz; 2) real time intra-vascular sector scanning at 20-50 MHz; 3) real time intra-luminal volumetric scanning; 4) the combination of cardiac intra- ventricular ultrasound imaging with electrophysiological endocardial mapping; 5) the combination of intra-luminal ultrasound imaging and intra-luminal radio-frequency or ultrasound thermal ablation.

Triple immunosuppressant therapy with cyclosporine (CsA), prednisone, and azathioprine has been the mainstay of initial maintenance immunosuppression for renal transplantation in the U.S. These drugs have different mechanisms of action and different toxicities. CsA causes scarring of the transplanted kidney in many patients. Many patients do well with only two immunosuppressant agents late after renal transplantation, however, there are no controlled comparative trials of the withdrawal of immunosuppressant agents. Mycophenolate mofetil (MMF) when used with CsA and steroids in two large randomized trials reduced the rate of acute rejection in the first year post transplant to about half the rate obtained when CsA/azathioprine/steroids were used. Thus the rate of acute rejection following withdrawal of CsA or steroids will likely be lower with the substitution of MMF for azathioprine. This is an open label, randomized, controlled, therapeutic comparison trial, limited to patients at low risk for acute rejection following a decrease in immunosuppression. The primary hypothesis is that withdrawal of cyclosporine in stable renal allograft recipients 12 months or more after transplantation results in a slower decline in renal function and less kidney scarring than withdrawal of either mycophenolate or prednisone.

The Department of Mathematics, Statistics and Computer Science at the University of Illinois at Chicago will purchase computational equipment which will be dedicated to the support of research in the mathematical sciences. The equipment will be used for several research projects, including in particular research in Geometric Group Theory (Paul R. Brown); Topology of 3-Manifolds (Marc Culler); Algebraic Geometry (Anatoly Libgober); Theory of Finite Groups (Stephen Smith); and Number Theory (Jeremy Teitelbaum). Most of these projects are data-intensive and amenable to distributed computing techniques.

Abstract

IIS-9900298
Veloso, Manuela
Carnegie Mellon University
$150,000 - 36 mos. (joint funding with CISE CNPq and International Program)

NSF-CNPq Collaborative Research: Multi-Agent Collaborative and Adversarial
Perception, Planning, Execution, and Learning

This is a three-year standard award. This project aims to investigate a concrete spectrum of issues of relevance to the development of teams of complete robot agents in dynamic, real-time, and adversarial environments. The proposed research will investigate and develop agents that are: (1) autonomous - with on-board sensing, planning, and acting, (2) efficient - capable of achieving specific goals under time and resource constraints through the integration of deliberative and reactive planning, (3) cooperative - capable of collaborating with each other to accomplish tasks that are beyond individual's capabilities, and (4) adaptive - capable of learning from experience by refining their individual and collaborative action selection preferences.This multi-agent robotic research will be carried within the context of robotic soccer. The robotic soccer domain introduces many specific research topics, including: (i) complete integration of perception, action, and cognition in a team of multiple robotic agents; (ii) definition of a set of robust reactive planning behaviors for individual agents (each agent should be equipped with skills that enable it to effectively perform individual and collaborative actions); (iii) reliable, real-time and active visual perception, including tracking of multiple moving objects and prediction of object movement; (iv) multi-agent strategic reasoning. The proposed work will build upon the research experience of the
U.S. research group on planning and learning and on the Brazilian research group on real-time perception.

DESCRIPTION (the applicant?s description verbatim): The overall objective of this proposal is to provide post-doctoral training in the context of testing the hypothesis that the length dependence of cardiac myofilament Ca2+ activation occurs independently of interfilament lattice spacing (ILS). The first aim is to compare effects of protein kinase A (PKA) phosphorylation on ILS and length dependence of Ca2+ activation in skinned mouse cardiac trabeculae containing either the adult cardiac troponin I (cTnI) isoform or the embryonic, neonatal isoform slow skeletal troponin I (ssTnl). X-ray diffraction, the most accurate method to measure actin-myosin distance, is used to measure ILS at various sarcomere lengths and Ca2+ concentrations prior to and following PKA phosphorylation. The second aim of this proposal is to identify the regions of cTnI that are important determinants of length-dependent Ca2+ sensitivity in cardiac myofilaments. Five different chimeras of TnI are constructed from the various domains of cTnI and ssTnl. These chimeras are then placed into skinned mouse cardiac trabeculae using a reconstitution protocol and pCa-force curves are generated. Our data will provide new insights into our understanding of integrated cardiac function, and will be important in formulating new strategies to fight heart disease and dysfunction.

DESCRIPTION (provided by applicant): Ion channel activity at the nerve terminal determines presynaptic action potential shape and Ca2+ entry and thus plays a pivotal role in the regulation of synaptic transmission. This is particularly important in the presynaptic terminals of the neocortex, due to this brain region's role in mediating higher neurological function under normal conditions and during disease states. We have recently developed a technique that permits electrophysiological recording from single, acutely isolated rat neocortical nerve terminals. The long-term objective of the laboratory is to answer questions about the physiological and pathophysiological regulation of synaptic transmission by directly studying neocortical, presynaptic ion channels with this technique. An increase in intracellular [Ca2+] ([Ca2+]i) is a critical signal at the synapse where it triggers exocytosis, plasticity and gene expression. Much more is known about signaling downstream of changes in intracellular Ca2+ than about the impact of changes in extracellular [Ca2+] ([Ca2+]o). Yet [Ca2+]o is likely to undergo significant changes as a result of electrical activity. The driving hypothesis for this proposal is that a decrease in synaptic cleft [Ca2+] is an important signal which regulates synaptic efficacy. We have recently discovered a novel, Ca2+-based signaling pathway in neocortical nerve terminals, comprised of a voltage sensitive non-specific cation (NSC) channel activated by decreases in [Ca2+]o. This interesting finding poses a number of questions: what is the mechanism by which changes in [Ca2+]o are detected and transduced to alterations in membrane conductance? Is the Ca2+ sensor-NSC channel signaling pathway modulated by other agents at the nerve terminal? What is the physiological impact of Ca2+ sensor-NSC channel signaling pathway on synaptic transmission? To answer these questions we plan to use a combination of electrophysiological, pharmacological and immunochemical techniques to: 1. Identify the constituents of the Ca2+ sensor-NSC channel signaling pathway. 2. Determine physiological modulators of Ca2+ sensor-NSC channel signaling pathway. 3. Determine the role of the Ca2+ sensor-NSC channel signaling pathway in synaptic transmission. The goals of this proposal are to understand the mechanism by which [Ca2+]o modulates ion channel activity in the synapses of the cortical nerve terminals and to determine how this Ca2+ sensor-NSC channel signaling pathway impacts synaptic transmission in the neocortex.

[unreadable] DESCRIPTION (provided by applicant): [unreadable] Real time trans-thoracic volumetric scanning, using 2-D array transducers based on Duke University designs, offers potential to increase the accuracy of cardiac measurements such as ventricular volumes and improve the diagnosis of coronary heart disease. The objective of this proposal is to extend the advances of real time volumetric scanning to transesophageal endoscopes, surgical endoscopes for applications in minimally invasive cardiac surgery. In this research, we will develop new 2D array transducers including cylindrical and hemispherical curvilinear probes operating from 5-10 MHz which produce a panoramic 3-D field of view approaching 1800. We will also develop an intracardiac catheter which combines 3-D ultrasound imaging and endocardial ultrasound thermal ablation system integrated within a single catheter delivery device for applications to the cardiac arrhythmias and interventional cardiology. [unreadable] [unreadable]

This FRG (focused research group) project addresses materials science and biomedical engineering issues in research on new generation, high performance pMUT (piezoelectric micromachined ultrasound transducer) arrays using Pb(Mg1/3Nb2/3)-PbTiO3 (PMN-PT) heterostructures on silicon for real-time 3-D medical ultrasound imaging. The aim is for more sensitive, broader bandwidth, less expensive transducer arrays compared with conventional technologies. The approach is to gain understanding of phenomena governing electromechanical coupling in epitaxial piezoelectric films in pMUT device structures, and to achieve epitaxial piezoelectric heterostructure fabrication directly on silicon with superior piezoelectric response. By integrating PMN-PT films with silicon, use is made of well-developed device fabrication processes for patterning/micromachining of silicon, the availability of large-area substrates, and integration with high performance electronic circuits. Research activities include: (1) growth of epitaxial SrRuO3 conductive oxide bottom electrodes directly on silicon by MBE; (2) growth of epitaxial piezoelectric PMN-PT films by sputtering; (3) macroscale and nanoscale characterization of the electromechanical properties of PMN-PT films; (4) examination of the microstructure and interface atomic structure of pMUT devices using high resolution transmission electron microscopy and analytical electron microscopy at locations defined by focused ion beam etching; (5) design and fabrication of pMUT arrays using epitaxial PMN-PT heterostructures on silicon; and (6) evaluation of the pMUT for medical ultrasound imaging using the Duke University real-time ultrasound scanner. The required expertise is assembled in a multidisciplinary team with members working in materials science and biomedical engineering.
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Education and outreach efforts are integrated into the research program, introducing graduate students to modern, multidisciplinary science and technology through use of sophisticated research instrumentation, and research interactions and approaches across disciplines. Undergraduate students will also be involved with laboratory research activities. Additionally, direct interaction with high school students and science teachers is a part of the project. High school teachers will participate in a summer laboratory research experience at U. Wisconsin and Argonne National Laboratory. This research experience will be coordinated with an existing curriculum-development program, in order to integrate it into the high-school curriculum. The project is co-supported by the MPS/DMR/EM and ENG/BES/BME-RAPD Programs.
***

0423076
Smith
The goal of this project is the design of a novel implantable brain imaging device called an IOS sensor. Based on a microscale integrated array of intermingled GaAs NIR emitters and detectors, this device will be optimized to image the intrinsic optical signal (IOS), a diffuse optical reflectance correlate of brain electrical activity rich in detail about sensory and motor information processing in mammalian cortex. The neurobiological utility of IOS imaging is already very well established, but all previous IOS imaging has used bulky, benchtop-scale instruments that require subjects to be immobilized and, almost always, anesthetized. Because of its small size, the IOS sensor will allow unprecedented imaging of cortical activity patterns in unanaesthetized and freely behaving subjects. Applications of the implantable IOS sensor will include neuroscience research, prosthetics for neurological injury patients, and drug discovery.

vitamin B12; vitamin B6; folate; human therapy evaluation; dietary supplements; kidney transplantation; dosage; diet therapy; homocysteine; patient oriented research; human subject; clinical research;

This award supports the participation of doctoral students from U.S. universities in the Doctoral Consortium of the 16th International Conference on Automated Planning and Scheduling (ICAPS) to be held June 6-10, 2006, Ambleside, England. ICAPS is the premier conference for research in artificial intelligence planning and scheduling. This Doctoral Consortium will provide participants with the opportunity to interact with established researchers as well as fellow doctoral students. The overall goals of the ICAPS Doctoral Consortium include providing participants with valuable feedback and exposure to additional perspectives on their work at a critical time in their doctoral research projects as well as providing helpful career advice at a critical time in their professional development. Participants will receive feedback and advice from mentors and fellow participants through activities and discussions at the Consortium as well as through a Poster Session of the main ICAPS conference. Participants in the Doctoral Consortium will be invited to publish their research abstracts on the conference web site and in a stand-alone proceedings that will be distributed to all conference attendees

DESCRIPTION (provided by applicant): There is growing evidence of the clinical benefits of real-time 3-D ultrasound for transthoracic cardiovascular applications using 2-D array transducers as originally developed in our laboratories at Duke University. More recently we have achieved a number of significant advances by expanding real time 3D echocardiography to intra-cardiac (3D-ICE), intra-vascular (3D-IVUS), transesophageal (3D-TEE) and thoracoscopic and laparoscopic (3D-LUS) applications by developing 2D array transducers at the tips of catheters and endoscopic probes for the guidance of minimally invasive cardiovascular procedures. The last decade has also seen tremendous breakthroughs in the development and application of interventional medical devices including vascular stents, aortic aneurysm stent grafts, vena cava filters, vascular occluders, cardiac occluders, prosthetic cardiac valves, and catheter and needle delivery of radio frequency ablation. Each minimally invasive procedure involves extensive real time imaging to guide the deployment of these devices currently requiring long periods of x-ray fluoroscopy with its inherent disadvantages of ionizing radiation exposure, poor tissue contrast and requirement for nephrotoxic contrast agents in angiography. Our hypothesis is that we can develop new generations of miniature 2D array transducers integrated into the deployment kits for these interventional devices to enable real time 3D ultrasound scanning for improved guidance of minimally invasive procedures. Thus in our specific aims we will extend our previous advances in cardiovascular real time 3D ultrasound by developing integrated catheter array transducers to guide the implantation of two important interventional cardiovascular devices from those listed above. We propose: (1) To investigate 3D ultrasound guidance of the deployment of the vena cava filter which prevents a venous thrombus from embolizing to the pulmonary circulation. (2) To investigate 3D ultrasound guidance of the aortic stent graft which isolates a weakened abdominal aortic aneurysm wall from the arterial circulation. (3) To conduct in vitro and in vivo evaluation of integrated catheter arrays for the aortic aneurysm stent graft and vena cava filter. Our long term goals are to significantly reduce exposure to ionizing radiation and x-ray contrast agents during these procedures while working toward the possibility of bedside implantation of vena cava filters and evaluating the patency of the aortic stent graft and its associated vasculature.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The goal of this collaborative project is to leverage and help drive NCMIR research and development activities in areas of specimen preparation for correlated light microscopy (LM) and electron microscopy (EM) that preserve antigenicity and microstructure in ways that contribute to the further development of our new array tomography reconstruction technology. We also plan to integrate our project data about microchemistry of multiple synapses in neuropil with the multi-scale, federated data environment of the NCMIR Cell Centered Database.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Human immunodeficiency virus type 2 (HIV-2) emerged following cross-species transmission of SIV from sooty mangabeys to humans several decades ago in West Africa. The epidemic groups of HIV-2 are HIV-2 Group A and Group B. These 2 groups have been established in the human population for at least 50 years. However, it is likely that new divergent strains of SIV can infect humans and lead to new outbreaks. We isolated characterized a new HIV-2 group F, HIV2-NWK08F, in 2008 from an immunodeficient person from Sierra Leone who immigrated to the USA in 2007. Health care providers in Sierra Leone and elsewhere need to be alerted that a strain of HIV-2, which is not detected by PCR for epidemic HIV-2 strains, exists and can lead to immunosuppression. This is the first HIV-2 to emerge from an Anglophone African country.

Recent developments in molecular neuroscience allow scientists to both optically record neuronal activity and to cause neurons to fire by stimulating them with light. In genetic model organisms like zebrafish and mice, these technologies can be used to observe and manipulate the activity patterns of thousands of neurons at once using non-invasive all-optical methods. While such techniques promise to revolutionize how we look at brain circuits, neural circuits are fundamentally three-dimensional structures. As a result, optical tools able to both image and selectively stimulate 3D volumes of brain tissue must be developed.

This project will develop a device that can record a volume of neurons at each camera exposure, extract information from thousands of these neurons over time, and then use this information to choose which groups of individual neurons in the volume to stimulate with light. This feedback loop will allow scientists to test causal hypotheses about brain network function and its relationship to behavior in a fast and powerful way, leveraging feedback-control technologies currently used in robotics and aeronautics to build and refine dynamical models of the brain online. At the core of this device are new developments in computational microscopy: the light field microscope (LFM), which can computationally reconstruct an entire volume from a single snapshot, and the light field illuminator (LFI), which can create (nearly) arbitrary patterns of light in three dimensions. The project will couple these two devices and accelerate their performance using commercial graphics cards (GPUs) to allow real-time control of biological neural networks in behaving animals.

Project outcomes, including scientific findings resulting from the application of the device to biological specimens, detailed directions on how to construct the physical device, and free, open-source software to run the device, will be provided online at http://graphics.stanford.edu/projects/lfmicroscope/.

DESCRIPTION (provided by applicant): Cannabis is one of the most widely used psychotropic drugs and it has been linked with numerous serious adverse effects including dependence, psychiatric disorders, and cardio-respiratory disease. Detailed knowledge about the mechanisms by which this drug acts is crucial to understand its many effects, and may greatly assist the design of drugs to facilitate treatment of cannabis dependence and withdrawal. Identification of all the cannabinoid receptors is central to this problem. In addition to the two well-characterized classical cannabinoid receptors three other receptors have recently been identified. Based on its distribution and function in the brain it has also been suggested that the extracellular Ca-sensing receptor (CaSR) would be a suitable target for cannabinoids. In preliminary experiments we found that cannabinoids activate CaSR, a G-protein coupled receptor (GPCR), that is localized in the majority of nerve terminals in the brain, and decreases synaptic transmission when activated. These preliminary findings, coupled with the abundance of CaSR in the brain, may fundamentally change our understanding of the mechanism of action of cannabinoids. The objective of this proposal is to determine if CaSR is an important pathway in the action of cannabinoids and our hypothesis is that brain CaSR is activated directly by cannabinoids. We are ideally suited to perform this project because of our expertise in CaSR function in nerve terminals and expression systems. The sensitivity of CaSR to cannabinoids and the prevalence of CaSR in the brain will open up a new view of cannabinoid action, substantially changing thinking in the field. Successful completion of these specific aims will characterize the response of CaSR to cannabinoids, shedding light on the broader range of influence of CaSR. This work will define the tools necessary to dissect the relative contributions of CaSR and CB1 to cannabinoid modulation of synaptic transmission in the brain. Future proposals would combine pharmacological and genetic approaches to ascertain the impact of cannabinoids via CB1 and CaSR at central synapses. Our rationale is that the identification and characterization of a novel and prevalent cannabinoid receptor will facilitate our understanding of the behavioral actions of the commonly used drug cannabis. Moreover, distinguishing the various actions of cannabinoids may translate into the identification of a novel class of drugs that facilitate treatment of cannabis addiction and withdrawal. PUBLIC HEALTH RELEVANCE: Cannabis is a commonly used drug that is associated with drug dependence and serious psychiatric, cardiovascular and pulmonary diseases. New treatments are needed to help people stop using cannabis but this requires improved understanding of how cannabis works. We have discovered a new pathway in the brain that is activated by cannabis-like drugs. By studying this new pathway we will discover more about how cannabis works and so improve the chances of designing new treatments to help stop cannabis use.

This award supports the participation (travel, lodging, registration) of doctoral students from U.S. universities in the Doctoral Consortium of the 22nd International Conference on Automated Planning and Scheduling (ICAPS-12) to be held June 25-29, 2012, in Sao Paulo, Brazil. The Doctoral Consortium will be comprised of two parts: (1) a one-day session the day before the conference begins that will include invited talks on research skills and career development, student presentations, and mentor-led focus groups; and (2) a poster session to be held during the conference. The objective of the Doctoral Consortium is to provide an opportunity for Ph.D. students who are doing dissertation research on topics related to AI Planning and Scheduling to present their research and to receive feedback on it from established researchers as well as other students and conference attendees. It is intended to give participants valuable exposure to outside perspectives at a critical time in their research and to provide a setting in which to explore career objectives. This award will support the participation of approximately 8 U.S.-based students. Participants will be selected through an application process that includes review of submitted materials including an extended dissertation abstract and CV; an assessment of the benefit of participation to the applicant; and the stage of the participant's doctoral research. The travel stipends will allow the selected students to present their research results and participate in valuable discussions that will likely shape the future of this critically important field. The technical program is complemented with an array of workshops, tutorials, and other events. The wide variety and significance of the topics typically presented at ICAPS, in the technical and other programs, provides opportunities for students to share, exchange, and learn from each other.

DESCRIPTION (provided by applicant): Cannabis is the most widely used illegal drug and it has been linked with numerous serious adverse effects. Cannabis has also been proposed as useful therapy for several neurological conditions including chronic pain, AIDS-related muscle wasting, and movement disorders. Detailed knowledge about the mechanisms by which this drug acts is crucial to understanding its many effects, and may greatly assist in the design of drugs to facilitate treatment of cannabis dependence and the above diseases. In addition to the two well-characterized classical cannabinoid receptors three other receptors have recently been identified. Based on the distribution and function in the brain of the extracellular Ca-sensing receptor (CaSR) it has been suggested that it a potential target for cannabinoids. In preliminary experiments we found that cannabinoids activate CaSR, a G-protein coupled receptor (GPCR), localized in the majority of nerve terminals in the brain, and activation of CaSR modulates synaptic transmission. These preliminary findings, coupled with the abundance of CaSR in the brain, may fundamentally change our understanding of the mechanisms of cannabinoid action. The objective of this proposal is to determine if CaSR is an important pathway in the action of cannabinoids and whether brain CaSR is activated directly by cannabinoids. We are ideally suited to perform this project because of our expertise in CaSR function in nerve terminals and expression systems. Successful completion of these specific aims will characterize the response of CaSR to cannabinoids, shedding light on the broader range of influence of CaSR and substantially change the thinking in this field. Our rationale is that the identification and characterization of a novel and prevalent cannabinoid receptor will facilitate our understanding of the behavioral actions of the commonly used drug cannabis. Moreover, distinguishing the various actions of cannabinoids may translate into the identification of a novel class of drugs that facilitate treatment of cannabis addiction and several neurological diseases.

The tree of life links all biodiversity through a shared evolutionary history. This project will produce the first online, comprehensive first-draft tree of all 1.8 million named species, accessible to both the public and scientific communities. Assembly of the tree will incorporate previously published results, with strong collaborations between computational and empirical biologists to develop, test and improve methods of data synthesis. This initial tree of life will not be static; instead, we will develop tools for scientists to update and revise the tree as new data come in. Early release of the tree and tools will motivate data sharing and facilitate ongoing synthesis of knowledge.

Biological research of all kinds, including studies of ecological health, environmental change, and human disease, increasingly depends on knowing how species are related to each other. Yet there is no single resource that unites knowledge of the tree of life. Instead, only small parts of the tree are individually available, generally as printed figures in journal articles. This project will provide the global community of scientists who study the tree of life with a means to share and combine their results, and will enable large-scale studies of Earth's biodiversity. It will also create a resource where students, educators and citizens can go to explore and learn about life's evolutionary history.

Biologists have long known that traits and gene sequences evolve at different rates in different lineages of organisms, but it has been difficult to understand the causes for these shifts in evolutionary rate. For example, the Caryophyllales contain ~6% of all flowering plant species and exhibit extreme life history diversity, including tropical trees, temperate herbs, long-lived succulent cacti, and a diverse array of carnivorous plants. The rate of DNA sequence evolution among these lineages differs greatly. This project will leverage recent advances in genome sequencing technologies and computational methods to evaluate the extent to which changes in life history and ecophysiology in plants are correlated with changes in the evolutionary rate over the entire genome. In collaboration with researchers worldwide, key traits will be characterized and >10,000 genes will be sequenced for 300 representative species of Caryophyllales. Analyses of evolutionary rate shifts in both traits and the genome will be used to assess how life history and ecophysiology have influenced genomic evolution, and vice versa.

This project provides the first rigorous assessment of the relationship between shifts in ecology and life history and genome-wide changes in evolutionary rate. It will yield unprecedented insight into the evolution of several genetic pathways of fundamental importance in flowering and crop plants, including those associated with flower development, photosynthesis, and pigmentation. Furthermore, this research will include the development of new and refined bioinformatic tools of broad use to biologists. The project will support the mentorship and training of a postdoctoral researcher, graduate students, and numerous undergraduates on all aspects of the project, and will fund professional development workshops for high school teachers and plant biologists.

Extracting biological knowledge from complex datasets such as those now being compiled requires integration of powerful computational tools. Recent developments in computational biology as well as rich new data sources provide novel opportunities for integrating massive amounts of biological data. This perfect storm of new data and advanced data acquisition, management, and integration afford the unique opportunity to drive the discovery of new, complex patterns in biology. The project will leverage NSF's considerable investment in biodiversity tools provided by Open Tree of Life (the framework for the project), Lifemapper (which handles geospatial data), iDigBio (data from~1 billion museum specimens that carry locality data and their ecological information), and Arbor (computer tools that permit new analyses from the sources noted). It will create much needed computational connections among these tools. It will then build upon these new linkages and tools, enabling novel research in biodiversity. These linkages will provide researchers the opportunity to rapidly synthesize datasets and use them to address diverse evolutionary questions. The tools and infrastructure the project will build will connect species relationships with species distribution models, climate projections, genes and traits. The project will transform future studies of biodiversity; it will provide a global integration of powerful tools that will permit new data-driven discovery in "next generation" biodiversity science. It will provide interdisciplinary post-doc and graduate student training in bioinformatics, use of digitized specimen data, and complex analyses (e.g. ecological analyses), preparing the biodiversity scientists of the future. The project will recruit underrepresented students and women and develop an undergrad course that will help train students with the integrative skills (field biology to computational biology) needed in the workforce. We will further develop this module for wider classroom use. We will introduce an annual week-long course at University of Florida (UF) for students and post-docs on the use of the resources developed. With education specialists at UF, the project will produce video materials and a coordinated display for general audiences on the importance of digitized specimen data, and their utility for studies of climate change.

The project will develop a computational framework linking diverse data (trees of species relationships, morphology, ecology, fossils, geography, and climate) across research tools used by the biological community, including Open Tree of Life, which will serve as the framework to which all other biological data - traits, genes, genomes, and especially specimens - will be linked, as well as Lifemapper, iDigBio, and Arbor. Use of the large, hyper-diverse plant group Saxifragales will provide precisely what is needed to drive the development of these tools--a comprehensive dataset that covers morphology, ecology, geography, fossils, and climate provides a test case for refining the tools the project will develop and their integration. The project will: 1. Facilitate new synergistic research of broad utility at the interface of phylogenetics, ecology, evolutionary biology, biogeography and biodiversity science, enabling scientists to address novel questions relating phenotypic and ecological biodiversity, spatial and temporal variation, community assembly, and diversification across landscapes and through time. 2. Increase visibility and accessibility of iDigBio, Open Tree of Life, Arbor, and Lifemapper resources by linking them together and making them available through multiple access points (e.g., pre-existing tools associated with Arbor and Lifemapper) in a variety of appropriate formats. 3. Develop a complete, multifaceted species-level dataset for a large clade (Saxifragales), which will not only fill in this branch on the ToL, but will produce a resource of great utility for the scientific community to explore. 4. Demonstrate the utility of iDigBio, Open Tree, Lifemapper, and Arbor resources with a comprehensive analysis using near complete sampling of Saxifragales, for which we will add the following data layers: DNA sequences, morphology, fossils, ontologies, geospatial and environmental data, digitized voucher specimens, and link to the Encyclopedia of Life (EOL). The project will: 1) provide interdisciplinary post-doc and graduate student training in bioinformatics, large-scale phylogeny reconstruction, use of digitized specimen data, and complex post-tree analyses (e.g. niche modeling, niche diversification), preparing the integrative biodiversity scientists of the future; 2) recruit underrepresented students and women; 3) developed an undergrad course that uses field collection, herbarium specimens, digitized data (iDigBio), and niche modeling (with climate change; 4) introduce an annual week-long course (UF) for students and post-docs on the use of the resources produced; 5) produce video materials and a coordinated display for general audiences on the importance of digitized specimen data, their utility for modeling niche evolution through time and implications for climate change. The project will provide a platform that will enable other researchers to take the same integrated approach in other groups. It will also establish web links to EOL and 1) build species pages; 2) place morphological and other trait data on TraitBank, making these widely available; 3) work with EOL and iNaturalist to engage citizen scientists.

Why are some school districts able to sustain school desegregation while others are not? Although social scientists have been active in studying the effects of school racial composition on student achievement, relatively neglected is the inclusion of variation among districts in the social factors that lead to school district segregation itself. Using five case studies and public opinion polls, the research team will study the relationship between citizen characteristics and their attitudes and values supporting (or failing to support) school desegregation. This study increases the value of five strategically chosen case studies including those of Wake County, NC (Raleigh); Davidson County, TN (Nashville); Jefferson County, KY (Louisville); Charlotte-Mecklenburg, NC and Rock Hill, SC by fielding an opinion poll in each location, where the polls contain mostly common questions across sites. These polls will reveal similarities and differences in adult attitudes that track to differences in how long these districts have sustained desegregated schools. Study findings have implications for other school districts beyond the five studied here in terms of formulating policy that will better support socioeconomic mixing of students, which enhances diversity by promoting educational attainment and upward mobility in society, especially for at-risk students.

Some school districts sustain desegregation over many years while others do not. Existing research is largely based on case studies. Case studies have limited external validity and are often heterogeneous in approach because researchers frame questions and invoke theory differently. The data obtained from in-depth interviews, participant observation, and document analyses are rarely triangulated with data from theoretically-driven surveys of the school district's adult population. These attitudes and values play an important part in explaining districts' current school assignment policies and inform future policies as well. This study addresses gaps in existing social science literature on desegregation by using a common theoretical perspective and fielding a largely common questionnaire via Interactive Voice Response, supplemented by cell phone samples, across five school districts. The research will produce poll data on a minimum of 5000 adult respondents. Analysis will (1) embed each poll within the existing qualitative data on each case; and (2) use the poll data to analyze both commonalities and differences in values and attitudes across sites.

One of the important, long standing events that is held annually in conjunction with the International Conference on Automated Planning and Scheduling (ICAPS) is the ICAPS Doctoral Consortium (ICAPS DC). The ICAPS DC is a primary method for broadening participation and improving retention of doctoral researchers in the field of automated planning and scheduling, which is essential to ensuring the continued vibrancy of research and scientific advancement in this area. This travel grant will enable travel awards to be provided to US doctoral students to support their participation of in the ICAPS 2016 DC. The ICAPS 2016 DC will be the fourteenth inception of the event, and will take place in June 2016 at London, England UK.

The objective of the DC is to provide a forum where doctoral students, in any phase of their training, can receive career and research advice from peers and mentors, present preliminary results and plans for their dissertations, and build professional relationships. A popular component of past ICAPS DCs that will be included in the 2016 edition is the formation of several small focus groups where students and assigned mentors meet to discuss each student's dissertation topic. To broaden the feedback that students receive, students will also prepare posters that they will present during a social event open to all conference attendees. To support career development, two invited speakers will address the students, discussing research skills and the process of transitioning to the workplace after graduation. Finally, students will have the opportunity to attend to all ICAPS conference events, including the technical program, workshops and tutorials.

? DESCRIPTION (provided by applicant): The major technological and analytical advances in human brain imaging achieved as part of the Human Connectome Projects (HCP) enable examination of structural and functional brain connectivity at unprecedented levels of spatial and temporal resolution. This information is proving crucial to our understanding of normative variation in adult brain connectivity. It is now timely to use the tools and analytical approaches developed by the HCP to understand how structural and functional wiring of the brain develops. Using state-of-the art HCP imaging approaches will allow investigators to push our currently limited understanding of normative brain development to new levels. This knowledge will critically inform prevention and intervention efforts targeting well known public health concerns (e.g., neurological and psychiatric disorders, poverty). The majority of developmental connectivity studies to date have used fairly coarse resolution, have not been multi-modal in nature, and few studies have used comparable methods to assess individuals across a sufficiently wide age range to truly capture developmental processes (e.g., early childhood through adolescence). Here we propose a consortium of five sites (Harvard, Oxford, UCLA, University of Minnesota, Washington University), with extensive complimentary expertise in brain imaging and neural development, including many of the investigators from the adult and pilot lifespan HCP efforts. Our synergistic integration of advances from the HARVARD-MGH and WU-MINN-OXFORD HCPs with cutting edge expertise in child and adolescent brain development will enable major advances in our understanding of the normative development of human brain connectivity. The resultant unique resource will provide rich, multimodal data on several biological and cognitive constructs that are of critical importance to health and well-being across this age range and allow a wide range of investigators in the community to gain new insights about brain development and connectivity. Aim 1 will be to optimize existing HCP Lifespan Pilot project protocols on the widely available Prisma platform to respect practical constraints in studying healthy children and adolescents over a wide age range and will also collect a matched set of data on the original Skyra and proposed Prisma HCP protocols to serve as a linchpin between the past and present efforts. Aim 2 will be to collect 1500 high quality neuroimaging and associated behavioral datasets on healthy children and adolescents in the age range of 5-21, using matched protocols across sites, enabling robust characterization of age-related changes in network properties including connectivity, network integrity, response properties during tasks, and behavior. Aim 3 will be to collect and analyze longitudinal subsamples, task, and phenotypic measures that constitute intensive sub-studies of inflection points of health-relevant behavioral changes within specific developmental phases. Aim 4 will capitalize on our success in sharing data in the HCP, and use established tools, platforms and procedures to make all data publically available through the Connectome Coordinating Facility (CCF).

? DESCRIPTION (provided by applicant): The major technological and analytical advances in human brain imaging achieved as part of the Human Connectome Projects (HCP) enable examination of structural and functional brain connectivity at unprecedented levels of spatial and temporal resolution. This information is proving invaluable for enhancing our understanding of normative variation in young adult brain connectivity. It is now timely to use the tools and analytical approaches developed by the HCP to understand how structural and functional wiring of the brain changes during the aging process. Using state-of-the art HCP imaging approaches will allow investigators to push our currently limited understanding of normative brain aging to new levels. We propose an effort involving a consortium of five sites (Massachusetts General Hospital, University of California at Los Angeles, University of Minnesota, Washington University in St. Louis, and Oxford University), with extensive complementary expertise in human brain imaging and aging and including many investigators associated with the original adult and pilot lifespan HCP efforts. This synergistic integration of advances from the MGH and WU-MINN-OXFORD HCPs with cutting-edge expertise in aging provides an unprecedented opportunity to advance our understanding of the normative changes in human brain connectivity with aging. Aim 1 will be to optimize existing HCP Lifespan Pilot project protocols to respect practical constraints in studying adults over a wide age range, including the very old (80+ years). Aim 2 will be to collect high quality neuroimaging, behavioral, and other datasets on 1200 individuals in the age range of 36 - 100+ years, using matched protocols across sites. This will enable robust cross-sectional analyses of age-related changes in network properties including metrics of connectivity, network integrity, response properties during tasks, and behavior. Aim 3 will be to collect and analyze longitudinal data on a subset of 300 individuals in three understudied and scientifically interesting groups: ages 36-44 (when late maturational and early aging processes may co-occur); ages 45-59 (perimenopausal, when rapid hormonal changes can affect cognition and the brain); and ages 80 - 100+ (the `very old', whose brains may reflect a `healthy survivor' state). The information gained relating to these important periods will enhance our understanding of how important phenomena such as hormonal changes affect the brain and will provide insights into factors that enable cognitively intact function into advanced aging. Aim 4 will capitalize on our success in sharing data in the Human Connectome Project (HCP), and will use these established tools, platforms, and procedures to make this data publicly available through the Connectome Coordination Facility.

This goal of this project is to optimize processes for remote delivery of meals to persons in need. The COVID-19 pandemic has fundamentally disrupted processes of food delivery to economically depressed and vulnerable segments of the US population. With the closing of schools and the advent of social distancing practices, over 13 million low-income students who have historically relied on their school to provide daily meals are now without important nutritional support, and centralized school summer meal distribution programs are no longer viable. Similarly, low-income adults and seniors that depend on centralized distribution of meals at shelters and food banks are now being forced to cope with virus mitigation procedures that severely limit their access. Both short and long term solutions to food security for all in this new normal depend on greater reliance on remote food delivery, and although vehicle routing and pickup/delivery problems have been studied for close to 50 years, the constraints imposed by contemporary public health and social distancing concerns present new optimization challenges. This research will contribute new problem formulations and solutions to these important classes of remote food delivery problems, and through existing relationships with the Allegheny County Department of Human Services, Southwestern Pennsylvania United Way, Allies for Children and the Greater Pittsburgh Food Bank, the project will apply research results to inform their ongoing pilot food delivery efforts. More broadly, these results will stimulate future research on these problems and influence remote food delivery problems nationwide.

To realize these results and impact, this project aims to develop new algorithms and heuristics that address the unique constraints and objectives presented by these geographically-dispersed food delivery problems, to provide a theoretical basis for more efficient operational practice. With respect to school bus student meal delivery, algorithms and heuristics for solving several problems will be developed and analyzed. First, the project will consider the coupled problem of assigning stops to students requiring meals and generating efficient routes to accommodate these students within a global meal time window, while enforcing social distance constraints on number of students that can be assigned to any one bus stop. Second, the research will investigate an extended formulation that additionally allows the use of smaller passenger vehicles or vans, to better service students that have difficult access to bus stops and/or long walk times. To ensure relevance, the project will utilize demand and bus route data from selected school districts in Allegheny County, PA to evaluate performance. Finally, with respect to remote distribution of food to low-income seniors, the algorithms and heuristics developed for student meal delivery will be extended and adapted to this more capacity constrained setting, where food must be moved exclusively in smaller volunteer passenger vehicles. Data obtained from the Greater Food Bank of Pittsburgh will be used to evaluate these extended research results. All data sets used and solutions results obtained will be made available to stimulate future research in this area.

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.

Voltage-gated sodium channels (VGSCs) are essential for action potential generation. Furthermore, drugs that directly target VGSCs are widely used to treat common diseases, such as pain, mood disorders, muscle spasms, seizures, and cardiac arrhythmias. However, side effects arise because of the widespread distribution of VGSCs and cross-sensitivity of the various VGSC subtypes to blockers. In addition, these drugs are not completely effective, underlining a substantial need for new drugs that target VGSCs. This has motivated us to identify and characterize new mechanisms by which VGSC function can be regulated. Regulation of voltage- gated ion channel function is an important pathway by which neuronal signaling and brain function is regulated, and G-protein coupled receptors (GPCRs) form a major element of the endogenous transduction mechanisms by which this occurs. However, unlike other ion channels, VGSCs have been assumed to be relatively insensitive to modulation by GPCR signaling. We have recently identified a pathway that is modulated by agents known to interact with the CaSR (calcium-sensing receptor). This pathway is widespread, present in the vast majority of neocortical neurons, and strong enough to completely and reversibly block VGSC currents when maximally stimulated. This novel, dynamic signaling pathway is positioned to substantially modulate neuronal excitability and brain function. Detailed knowledge about the underlying mechanisms is crucial to understand its many effects. The objectives of this proposal are to determine how CaSR modulators regulate VGSCs. Using a combination of electrophysiology and unbiased biochemical approaches we will identify the receptors mediating the inhibition of VGSC currents, measure the relative sensitivity to block of different VGSC isoforms, and determine if the pathway differentially regulates action potentials at nerve terminals and soma. These specific aims will test the hypothesis that CaSR modulators actions via VGSCs represent important new pathways for modulating neuronal excitability. We are ideally suited to perform this project because of our preliminary data and expertise. Our rationale is that the identification and characterization of a novel and prevalent receptor(s) and downstream pathway will facilitate our understanding of a prevalent and potentially powerful neurobiological signaling pathway. Successful completion of these specific aims will characterize new drug targets and eventually will lead to new therapeutics to improve control of pain, seizures, muscle spasm, and arrhythmias.

Understanding complex activity due to humans and vehicles in a large environment like a city neighborhood or even an entire city is one of the main goals of smart cities. The activities are heterogeneous, distributed, vary over time and mutually interact in many ways, making them hard to capture and understand and mitigate issues in a timely manner. While there has been tremendous progress in capturing aggregate statistics that helps in traffic and city management as well as personal planning and scheduling, much of this work ignores anomalous patterns. Examples include protests, erratic driving, near accidents, construction zone activity, and numerous others. Discovering and resolving anomalies is challenging for many reasons as they are complex and rare, depend on the context and depend on the spatial and temporal extent over which they are observed. There are potentially a large number of anomalies or anomalous patterns, so they are impossible to label and describe manually.

The PIs will conduct research to address automatic discovery and resolution of anomalous patterns in smart city visual data. The PIs will leverage the large amount of visual data they have access to ranging from cameras at many intersections in Pittsburgh, around the Carnegie Mellon University neighborhood, cameras installed on public buses, and physical distribution networks in the city. The project will include the following four closely integrated research thrusts: (1) Extracting anomalies in the presence of noise due to visual processing algorithms, (2) Automatically discover anomalies at different spatial and temporal scales with intelligent coordinated and distributed planning, (3) discovering the relationship with anomalies and context, and (4) Resolving Anomalies through Hard and Soft Actuation using both automatic and human-in-the-loop methods.

The work will enable the following applications: Safer and more efficient roads, monitoring the roadway infrastructure and roadside, maximizing the distribution services and informing decisions on health policy (including COVID-19). The project will be conducted in collaboration with several stakeholders - multiple infrastructure and traffic management startups and local city government - in a comprehensive transition to practice program designed to deploy the research in the real world.

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.

The physical attributes and behaviors of species are shaped by evolution. These traits determine how individuals interact with their environment (ecology) which then influences the course of evolution. Thus, ecology and evolution are inextricably intertwined. Bridging the fields of evolution and ecology is challenging because the processes involved can operate on similar, or very different, time scales. African savanna acacia trees have evolved to survive and reproduce under harsh conditions not tolerated by many other tree species. Acacias can tolerate fires, droughts, herbivory by giraffes and elephants, and competition from other plants. But how acacias have adapted to these conditions in the past will influence their response to the current changing environment on the African continent. The goal of this study is to develop a comprehensive understanding of the evolutionary history and ecological distribution of African acacias and to explore how species traits and distributions changed over time in response to change in the savanna climate. Ultimately, this knowledge will inform predictions about how acacia habitats will be affected by ongoing climate change. This project not only has broader societal benefit but also it will train undergraduate and graduate students and postdoctoral fellows in evolutionary biology, ecology, plant physiology, and molecular genomics. In addition, the project will expand the content and reach of a successful undergraduate teaching module of ecology and evolution featuring Serengeti National Park and will begin a new bioinformatics training course in partnership with universities in Africa.

This project will bridge phylogenetic approaches to diversification with direct ecological field measurement of trait responses and gene expression. The activities include: (1) constructing new, detailed models of the phylogenetic history and ecological distribution of species and traits in the African Acacia Clade, (2) using phylogenomic analyses to study selection, introgression, and gene family expansion in relation to the Savanna Syndrome, (3) measuring acacia trait responses to Savanna Syndrome components (drought, fire, herbivory, grass competition) in a common garden experiment in Arusha, Tanzania, and (4) analyzing the molecular aspects of the phenotypic response through analysis of acacia transcriptomic profiles collected both on site in Tanzania and in controlled greenhouse experiments. Collectively, these linked lines of evidence will provide crucial information about the past evolution of the savanna community, the rapid rise of savannas across Africa that occurred in the Miocene, and its likely response to present ecological change.

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.

PROJECT SUMMARY Voltage-gated sodium channels (VGSCs) are essential for action potential generation. Furthermore, drugs that directly target VGSCs are widely used to treat common diseases, such as pain, mood disorders, muscle spasms, seizures, and cardiac arrhythmias. However, side effects arise because of the widespread distribution of VGSCs and cross-sensitivity of the various VGSC subtypes to blockers. In addition, these drugs are not completely effective, underlining a substantial need for new drugs that target VGSCs. This has motivated us to identify and characterize new mechanisms by which VGSC function can be regulated. Regulation of voltage- gated ion channel function is an important pathway by which neuronal signaling and brain function is regulated, and G-protein coupled receptors (GPCRs) form a major element of the endogenous transduction mechanisms by which this occurs. However, unlike other ion channels, VGSCs have been assumed to be relatively insensitive to modulation by GPCR signaling. We have recently identified a pathway that is modulated by agents known to interact with the CaSR (calcium-sensing receptor). This pathway is widespread, present in the vast majority of neocortical neurons, and strong enough to completely and reversibly block VGSC currents when maximally stimulated. This novel, dynamic signaling pathway is positioned to substantially modulate neuronal excitability and brain function. Detailed knowledge about the underlying mechanisms is crucial to understand its many effects. The objectives of this proposal are to determine how CaSR modulators regulate VGSCs. Using a combination of electrophysiology and unbiased biochemical approaches we will identify the receptors mediating the inhibition of VGSC currents, measure the relative sensitivity to block of different VGSC isoforms, and determine if the pathway differentially regulates action potentials at nerve terminals and soma. These specific aims will test the hypothesis that CaSR modulators actions via VGSCs represent important new pathways for modulating neuronal excitability. We are ideally suited to perform this project because of our preliminary data and expertise. Our rationale is that the identification and characterization of a novel and prevalent receptor(s) and downstream pathway will facilitate our understanding of a prevalent and potentially powerful neurobiological signaling pathway. Successful completion of these specific aims will characterize new drug targets and eventually will lead to new therapeutics to improve control of pain, seizures, muscle spasm, and arrhythmias.

The Tree of Life is marked by short periods of rapid innovation where groups emerge with dramatically altered forms and diversify quickly. This has happened multiple times throughout geologic history including with the rise of birds, mammals, the transition of plants from water to land, and the origination of flowering plants. The rapid emergence and diversification of flowering plants in particular represents one of the most remarkable episodes in the history of life on earth. However, while fundamental to understanding the ecology and evolution of modern ecosystems, this episode remains unexplained and leads to one of the grand challenges in the biological sciences – determining what processes may be responsible for such rapid changes in form and function across the Tree of Life. A major impediment to addressing this question is the availability of data and methods for analyzing those data. The goal of this study is to use and develop new machine learning approaches to gathering data for both fossil and living plant species and to use these data to help develop new techniques. These techniques will help identify what contributed to the rapid change in plants that resulted in their dominance in the environment today. This project will train undergraduates, graduate students, and postdoctoral fellows in machine learning methods, evolutionary biology, and techniques for working with both fossil and living specimens. The project will also include resource development and training for middle schoolers, high schoolers, undergraduates, and the broader research community.<br/><br/>This project aims to evaluate the evolutionary processes underlying the emergence of innovation, using flowering plants as a case study. Specifically, the project will examine Cretaceous radiations of flowering plants characterized by rapid evolution, a rich fossil record, and the origin of innovations and lineages of great ecological significance. The central goals of the proposed research are to (a) generate a large morphological dataset for flowering plants using novel machine learning methods, (b) develop new statistical methods for modeling evolution, and (c) use these advances in data collection and methods to identify the processes that led to the episodic and rapid emergence of novelty across the Tree of Life. Collectively, these new developments in machine learning techniques, morphological data collection, and analytical techniques for addressing evolutionary processes will be potentially transformative to several fields including the biological sciences, computational biology, and machine learning. The large scope and scale of this project, together with its highly integrative nature, creates the potential to address one of the most important standing questions in evolutionary biology.<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.