Richard Martin - US grants

This project is in the general area of analytical and surface chemistry and in the subfields of photochemistry and surface reaction dynamics. The research continues the Principal Investigator's studies of the photofragmentation, via internally repulsive states excited by an ultraviolet laser, of molecules adsorbed on metal and semiconductor surfaces. Photofragmentation, which generates radicals important in surface reactions, can proceed on these surfaces even in the presence of very fast (250 - 2500 femtoseconds) quenching of the excited states by energy transfer to the substrate. The role of faster charge transfer processes (5 - 50 fs) will be investigated by measuring the cross- sections, photofragment velocity and angular distributions, and polarization dependence for a series of small adsorbate molecules. Ultraviolet laser surface photochemistry is an important new area of fundamental research which has potentially broad applications in diverse technological fields such as semiconductor processing, solar energy conversion, chemical catalysis, and eye surgery. However, little is known about the fundamental mechanisms underlying the photochemical reactions. Both charge transfer and electron attachment have been identified as important reaction channels. Studies of the photofragmentation of adsorbed molecules will provide a highly specific probe of the dynamics of energy and charge transfer at interfaces.

0104399
Ceperley
The long range goal of this research program is to develop practical, efficient theoretical methods to accurately predict the properties of many-electron systems. The methods and computational algorithms so generated can be applied to important idealized systems, such as the homogeneous electron gas, as well as to realistic problems in condensed matter. The rapid development of these computational quantum methods will have a qualitative impact upon the course of many fields of science including physics, materials science, chemistry and even biology.

The approach is a combination of quantum Monte Carlo (QMC) simulations and density functional theory (DFT). QMC can provide exact results for some many-body problems, the principle goal is to extend the range of problems for which the method can be applied. On the other hand, DFT is the only current method feasible for accurate large-scale simulations of real systems. The research concerns both the basic theory, as well as tests of approximate forms using QMC.

Continued development of QMC methods, with emphasis upon more accurate wavefunctions and improved boundary conditions and upon developing new methods able to use much larger computational facilities will be undertaken. Applications of QMC methods to physical problems will include nanoscale quantum devices and two-dimensional electron systems in the presence of disorder, where there is much experimental and theoretical controversy concerning the possible metal-insulator transition. General theoretical methods for studying dielectric polarization and functionals in correlated systems will be developed. We will extend the lattice model calculations to continuum systems that can serve as the basis for improved universal density-polarization functionals. We will also continue work started recently using time-dependent DFT to predict excitation spectra of materials, nanostructures and quantum dots. The first system studied will be silicon clusters, where intense blue light emission has been recently discovered. A long range goal is to develop both many-body methods and imporved functionals that can go beyond DFT approximations for ground state energies and excitation spectra.
%%%
The long range goal of this research program is to develop practical, efficient theoretical methods to accurately predict the properties of many-electron systems. The methods and computational algorithms so generated can be applied to important idealized systems, such as the homogeneous electron gas, as well as to realistic problems in condensed matter. The rapid development of these computational quantum methods will have a qualitative impact upon the course of many fields of science including physics, materials science, chemistry and even biology.
***

Electronic Structure of Condensed Matter - The proposed research is aimed at the development of computational methods for studying electronic states in condensed matter and the use of those methods to study the electronic properties of solids and liquids. The primary techniques to be used are quantum Monte Carlo and density- functional theory. Two primary improvements for QMC are contemplated: finding accurate and efficient representations for the many-electron wave function and development of pseudopotentials suitable for elimination of the effects of core electrons. Such improved QMC techniques can be used to provide an improved exchange-correlation energy for DFT which would include the effects of structural inhomogeneity. These improved DFT methods can then be directly compared to the QMC results for tests of accuracy. When the new DFT methods are tested, they can be used to generate trial functions to make QMC analysis more efficient. This coupling between different computational approaches is seen as central to the proposed research. The potential benefit of using massively- parallel computers on this class of problems will also be investigated. Concurrent with their development, these techniques will be applied to the study of a wide range of condensed systems, ranging from jellium to highly correlated materials %%% The proposed research is part of a long-term effort to understand and to predict the properties of real-world materials. They propose to develop complementary computational methods for determining the electronic structure (and hence the physical properties) of a wide range of solids and liquids. The emphasis is to refine and simplify existing techniques, so that the resulting methods are practical for use on complex materials. This research will include development and evaluation of algorithms for massively parallel computers. As improved computational techniques are developed, they will be applied to problems with direct connections to experimental physics and materials science - both to test the methods and to understand and predict experimentally relevant properties. Such materials as silicon, condensed states of hydrogen metal surfaces, and liquid and amorphous systems will be studied.

9352362 Martin The enormous progress in computational technology has generated a new methodology, computational science, for learning and advancing the traditional sciences such as physics and chemistry. We are initiating fundamental change in undergraduate science education by providing a model for computational-science laboratory instruction in physics and chemistry. We are setting up a seed laboratory devoted to computational science and developing a curriculum for computational degree options in undergraduate physics and chemistry. The faculty involved are developing the necessary courses and course materials and the computer hardware to implement the courses has been obtained. The project personnel consist of interdisciplinary teams of faculty with expertise in computational physics and chemistry education and research, and computer science. We anticipate that results of the project will be transferable to the national scene in science education. ***

9350641 Skadron Accelerating innovations in computer technology have changed the nature of the discovery process in physics and have created opportunities to rethink the undergraduate physics curriculum. The present project is a product of such an effort. The goal is to create a modern computational facility for the entire undergraduate physics program. Majors moving through the physics sequence are learning computational techniques alongside the physics and are using these techniques to enhance their understanding of the physics. Students are gaining several distinct benefits from the modernized curriculum: a). the computational component of the curriculum broadens each course by enabling students to examine realistic effects usually neglected when only analytical methods are used; b). newly gained computational skills enable undergraduates to make meaningful contributions to the Department's undergraduate research participation programs; and c). students carry powerful problem-solving tools to graduate school or the work force. ***

This two-year award will support U.S.-France cooperative research in atmospheric and space physics between Richard F. Martin of Illinois State University and Dominique Delcourt of the French Center for the Study of Earth and Planetary Environments. The project addresses the physics of the aurora borealis (aurora substorms) in response to solar wind variations. The magnetotail region behind the earth is where aurora substorms are triggered and energized. The investigators propose three computational/theoretical projects that address: (1) basic nonlinear dynamics of substorms; (2) applications of the model to the near-Earth magnetotail; and (3) consequences of the model on ions of ionosphere origin entering the magnetotail. These studies are relevant to understanding of space storms, which cause commercial spacecraft anomalies and failures, interruptions of power distribution and of communications. The U.S. investigator brings to this collaboration background in basic nonlinear dynamics and magnetotail dynamical modeling. This is complemented by the French investigator's expertise in ionospheric and near-Earth particle dynamics. The project will further understanding of space storms and extend the work on predicting space weather.

clarithromycin; human therapy evaluation; respiratory disorder chemotherapy; asthma; drug screening /evaluation; Mycoplasma; species difference; clinical trials; clinical research; human subject;

To determine if there is a difference in pulmonary function in mild to moderately severe asthma when inhaled corticosteroids are administered as a single daily dose at 8am or 5:30pm versus four times a day dosing at 7am, noon, 7pm, and 10pm. To compare the magnitude of systemic and local effect of the three treatment schedules. To compare the effect on asthma symptoms of the three treatment schedules.

9976550
Martin
This Focused Research Group award supports research and education in computational materials theory and associated algorithm development. It assists in establishing a Materials Computation Center at the University of Illinois at Urbana-Champaign for interdisciplinary materials research. The award is jointly funded by the Divisions of Materials Research, Chemistry, Physics, Mathematical Sciences and the Office of Multidisciplinary Activities in the Directorate for Mathematical and Physical Sciences, and by the Division of Advanced Computational Infrastructure and Research in the Directorate for Computer and Information Science and Engineering. The Center will provide a stimulating environment for state-of-the-art computational materials research and for development of new algorithms and computational approaches. The intellectual thrust of the research will be organized around broad research themes that will be coupled to experiment. The PIs will develop and maintain well-structured modular codes, educate students in the most modern computational materials science techniques, and apply computational methods to important materials problems. Algorithmic developments will span the range from programs for teaching to forefront programs for research. Included are programs for molecular dynamics and Monte Carlo simulations, density functional theory calculations, and linear-scaling algorithms for large complex systems. The PIs aim to work toward defining common analysis tools, input/output data structures, and well-defined interfaces between programs written by different people. This helps enable compatibility and coupling in multi-scale applications, as well as heterogeneous computing via portable browser-type interfaces. The PIs intend to benchmark results on test problems and compare results with experiments. The Center will have a core group of faculty from different disciplines committed to a program of collaborative research with shared postdoctoral associates and students. The Center will provide educational training and thesis research themes that address national needs for computational scientists with experience in applications to real problems and materials research. In conjunction with the Computational Science and Engineering program at UIUC, students will acquire comprehensive computer science experience as well as basic science and engineering training, and they will gain valuable experience working in teams across disciplines.

This award supports research and education in computational materials theory and associated algorithm development. It assists in establishing a Materials Computation Center at the University of Illinois at Urbana-Champaign for interdisciplinary materials research. The award is jointly funded by the Divisions of Materials Research, Chemistry, Physics, Mathematical Sciences and the Office of Multidisciplinary Activities in the Directorate for Mathematical and Physical Sciences, and by the Division of Advanced Computational Infrastructure and Research in the Directorate for Computer and Information Science and Engineering. The Center will provide a stimulating environment for state-of-the-art computational materials research and for development of new algorithms and computational approaches. The intellectual thrust of the research will be organized around broad research themes that will be coupled to experiment. The PIs will develop and maintain well-structured modular codes, educate students in the most modern computational materials science techniques, and apply computational methods to important materials problems. Algorithmic developments will span the range from programs for teaching to forefront programs for research. Included are programs for molecular dynamics and Monte Carlo simulations, density functional theory calculations, and linear-scaling algorithms for large complex systems. The PIs aim to work toward defining common analysis tools, input/output data structures, and well-defined interfaces between programs written by different people. This helps enable compatibility and coupling in multi-scale applications, as well as heterogeneous computing via portable browser-type interfaces. The PIs intend to benchmark results on test problems and compare results with experiments. The Center will have a core group of faculty from different disciplines committed to a program of collaborative research with shared postdoctoral associates and students. The Center will provide educational training and thesis research themes that address national needs for computational scientists with experience in applications to real problems and materials research. In conjunction with the Computational Science and Engineering program at UIUC, students will acquire comprehensive computer science experience as well as basic science and engineering training, and they will gain valuable experience working in teams across disciplines.

EIA-9986046
Thu D. Nguyen
Rutgers University

CISE Research Instrumentation: System Support for Scalable, Fault-Tolerant Computing and Service on PC Clusters

A high-end PC cluster is the crucial computing infrastructure for research in the recently established Distributed Computing Laboratory (DISCO Lab) in the Department of Computer Science at Rutgers University. The requested cluster consists of 8 quad-processor PCs, a 16-port Alteon Gb/s Ethernet LAN with layer 4 switching capabilities and a 16 NICs, and a 16-port Myrinet Gb/s LAN with 8 NICs. This cluster will support research in several projects that jointly, are intended to improve the state-of-the-art in cluster computing, moving towards the realization of a robust and efficient distributed computing environment for clusters of PCs. In particular, this proposal describes four projects: (i) developing a robust software distributed shared-memory environment to support emerging cluster applications, (ii) building system support for efficient global utilization of cluster resources (iii) exploring the construction of highly available operating systems, and (iv) implementing distributed applications such as data mining, scalable servers, and interactive continuous media applications and system mechanisms and policies to support them efficiently on clusters.

EIA-0103722
Thu D. Nguyen
Rutgers University

System and Compiler Support for Component-Based Construction of Scalable Internet Services

The principal investigators propose to investigate system and compiler support for an emerging class of Scalable Internet Service (SIS) applications. This proposed work will be motivated by the emergence of the Internet as the global, ubiquitous networking infrastructure, and its accompanying computing model where much of the computing takes place on servers rather than local machines. SIS applications provide a rich set of services such as on-line auctions, stock exchanges, and instant messaging to diverse clients worldwide.

DESCRIPTION (Adapted from the Applicant's Abstract): Ascariasis and hookworm infections are carried by 1.6 billion people throughout the world and in 2 percent of cases cause loss of life. Anthelmintics, including levamisole and related drugs (pyrantel and oxantel), are used to combat nematode parasites, but the development of resistance is a concern. The long-range objective is to improve and protect human health by protecting the efficacy of anthelmintic drugs by controlling and reversing resistance. The objective of the application is to identify mechanisms that regulate the sensitivity of the response of nematode parasite levamisole receptor channels. Our central hypothesis is that competing processes (phosphorylation-dephosphorylation) modulate levamisole responses, and that modification of the processes can produce a decrease or increase in resistance. We developed this hypothesis on the basis of: 1) analysis showing consensus regulatory phosphorylation sites on levamisole receptors; 2) our published and preliminary data showing reduced patency of levamisole receptor channels in resistant nematodes; 3) strong preliminary data that shows levamisole responses are reduced by inhibition of protein kinases. The rationale for the research is that, once mechanisms for regulating levamisole receptor channels are known, pharmacological approaches can be formulated to prevent or overcome resistance, and to maintain the efficacy of levamisole and related anthelmintics. In most experiments we will use electrophysiological techniques on Ascaris suum to examine the properties of the receptor channel. Muscle-flap preparations with current- and voltage-clamp techniques will be used for screening drug effects. We will use muscle-vesicle preparations and patch-clamp technology to measure effects on gating kinetics of levamisole receptor channels of nematode parasites. We will pursue two specific aims to accomplish our current objective: 1) determine mechanisms by which nematode parasites limit their response (P-open) of receptors, and become resistant to levamisole; 2) determine mechanisms that increase P-open values of receptors, in order to reverse resistance to levamisole. We will test our hypothesis that levamisole resistance can be reversed by increased receptor phosphorylation in different species of resistant nematodes. The research is innovative because few groups carry out parasite electrophysiology and others have not developed nematode parasite muscle-vesicle preparations for patch-clamp recordings from levamisole receptor channels. We expect the research to identify mechanisms that decrease levamisole responses (reduce P-open) so parasites become resistant to levamisole and to demonstrate how this resistance can be reversed. The research is significant because application of the results is expected to lead towards methods that will control and overcome resistance to anthelmintics of the levamisole class.

This award was made on a 'medium' category proposal submitted in response to the ITR solicitation, NSF-02-168. The Division of Materials Research, the Advanced Computational Infrastructure and Research Division, and the Chemistry Division contribute funds to this award. It supports interdisciplinary computational and theoretical research and education at the Materials Computation Center (MCC). The MCC will foster a stimulating intellectual and interactive environment in a facility for students, teachers and researchers focused on research, software development, and education in computational materials research. The MCC has three major Thrusts: (1) collaborations/networking, (2) education and knowledge-transfer, and (3) materials research, computational tools and algorithms. Key projects are currently in the themes of quantum simulations, complex systems and phase transformations, and computer science and scaleable parallel methods for materials modeling. Through these projects, advances will be made in important areas and advanced codes/algorithms and tools, based on modern software engineering, will be provided for the computational materials science community. Research activities include genetic algorithms and programs applied to multiple time scale simulations for materials dynamics and to reaction chemistry; MatSimViz simulation/visualization tools; block, parallel iterative methods for parallel electronic structure algorithms; Quantum Monte Carlo workbench; and a PlayStation2 parallel supercomputer for quantum chemistry.
The MCC will engage research problems and algorithm development at the forefront of scientific computing and aims to develop new approaches for understanding complex materials using advanced computational methods. The MCC will expand and maintain updated libraries of codes in a Software Archive (http://www.mcc.uiuc.edu) and it will actively collaborate with similar efforts in Europe (broad collaborations such as III, PSI-k and CECAM), with National laboratories, and other Centers. The MCC will expand its previous efforts on Summer School and Workshop activities and graduate training. As a center activity, graduate-level training modules will be developed on various topics in computational materials research and will be distributes through the Software Archive and the web.
Apart from education and outreach activities outlined above, MCC contributes to the broad advance of Computational Materials Research which has impact on the advance of fundamental science and the potential impact on a wide range of technologies. Its activities contribute to education of future computational materials scientists, knowledge-transfer activities associated with active research, networking of researchers and students with the world-wide community, creation and distribution of useful tools for research and applications to challenging problems in materials research.
%%%
This award was made on a 'medium' category proposal submitted in response to the ITR solicitation, NSF-02-168. The Division of Materials Research, the Advanced Computational Infrastructure and Research Division, and the Chemistry Division contribute funds to this award. It supports interdisciplinary computational and theoretical research and education at the Materials Computation Center (MCC). The MCC will foster a stimulating intellectual and interactive environment in a facility for students, teachers and researchers focused on research, software development, and education in computational materials research. The MCC has three major Thrusts: (1) collaborations/networking, (2) education and knowledge-transfer, and (3) materials research, computational tools and algorithms. Key projects are currently in the themes of quantum simulations, complex systems and phase transformations, and computer science and scaleable parallel methods for materials modeling. Through these projects, advances will be made in important areas and advanced codes/algorithms and tools, based on modern software engineering, will be provided for the computational materials science community. Research activities include genetic algorithms and programs applied to multiple time scale simulations for materials dynamics and to reaction chemistry; MatSimViz simulation/visualization tools; block, parallel iterative methods for parallel electronic structure algorithms; Quantum Monte Carlo workbench; and a PlayStation2 parallel supercomputer for quantum chemistry.
The MCC will engage research problems and algorithm development at the forefront of scientific computing and aims to develop new approaches for understanding complex materials using advanced computational methods. The MCC will expand and maintain updated libraries of codes in a Software Archive (http://www.mcc.uiuc.edu) and it will actively collaborate with similar efforts in Europe (broad collaborations such as III, PSI-k and CECAM), with National laboratories, and other Centers. The MCC will expand its previous efforts on Summer School and Workshop activities and graduate training. As a center activity, graduate-level training modules will be developed on various topics in computational materials research and will be distributes through the Software Archive and the web.
Apart from education and outreach activities outlined above, MCC contributes to the broad advance of Computational Materials Research which has impact on the advance of fundamental science and the potential impact on a wide range of technologies. Its activities contribute to education of future computational materials scientists, knowledge-transfer activities associated with active research, networking of researchers and students with the world-wide community, creation and distribution of useful tools for research and applications to challenging problems in materials research.
***

The long-range goal of this research is to develop theoretical and computational methods to predict accurately
the properties of many-electron systems and then to apply the methods to important condensed matter
systems. The focus of this research is primarily on the development and application of quantum
Monte Carlo (QMC) methods. However, part of the research attempts to tie these approaches to other
theoretical issues such as the fundamental distinction between metals and insulators in terms of the manybodyelectron wave function.

QMC can provide very accurate results for electronic systems: the most well-known example is the homogenous electron gas where QMC has provided the benchmark upon which are based most density functional (DFT) calculations. DFT-based methods are the only current method feasible for accurate large-scale simulations of realistic systems; however, even the improved functionals have well-known defects. The past few years have seen substantial progress in coupling the simulation of ions at a finite temperature with QMC simulation of the electrons (the CEIMC method). In addition to being more accurate, in cases where other averaging must be performed, the QMC approach can be as efficient as DFT-
based approaches. Applications to extended systems of hydrogen are now in production. In the near future
there will be development of QMC methods, with emphasis upon more accurate wave functions, improved
boundary conditions, and new methods able to use much larger computational facilities efficiently.
The research will enable applications to elements with core electrons using more accurate pseudopotentials.
Methods to calculate electronic forces will enable dynamical calculations of ionic systems.

Applications of the methods will include hydrogen throughout the whole phase diagram of temperature
and pressure. Although there have been numerous previous QMC and DFT simulations, the CEIMC
method removes most of their limitations. The connection between the insulator-metallic transition, the
atomic molecular-transition and temperature and zero point effects is still lacking in current approaches.
The simulations should clarify the situation, especially under conditions where experiment is non-existent
or unreliable. A further challenge is the microscopic simulation of water from first principles, which is
absolutely fundamental to many scientific questions and which appears to be within reach of QMC simulation.
The power of this approach can be applied to other problems, for example, new methods to simulate
electrons and their spin states in real nanostructure devices, potentially more accurately and efficiently
than with existing grid-based approaches. The entire device can be simulated by coupling two
random walks-one to solve the electrostatic equations in a complicated structure and another for the Nbody
quantum equation for the electrons.

The computational complexity of the simulation of the basic equations of matter (on
classical not quantum computers) is a very important and fundamental issue. The challenge is to solve
accurately problems with many interacting particles, including strongly interacting systems and cooperative
phenomena. QMC methods have made it possible to compute the thermodynamic properties of bosonic
systems, including superfuidity. However, the fermion sign problem is a critical issue limiting
present work, and steps toward solving or minimizing the sign problem are among the outstanding challenges
in computational science. In addition, development of new computational approaches frequently
leads to new theoretical understanding as well as algorithms useful in other disciplines.

The development of these computational quantum methods will have a qualitative impact
upon the course of many fields of science including physics, materials science, chemistry and even
biology, by enabling much more accurate, and potentially faster, simulation of a broad range of systems.
The calculations will resolve questions about the properties of hydrogen at high temperatures and pressures,
the basis of models for the formation of Jovian planets; the microscopic properties of water and
solutions; and properties of nanoscale systems. The research is carried out primarily by graduate students
and postdocs who often go later to industry, thus transferring the latest computational methods. Algorithms
and software developed as a result of the research will be made available to the general research
community through the Materials Computation Center and used in undergraduate courses, graduate
courses, and summer schools at the University of Illinois and elsewhere.

Internet services are rapidly becoming an integral part of people's work and leisure all over the world. With such popularity and importance comes the need for 24x7 availability. Yet, recent research suggests that, at best, Internet services are achieving only 99-99.9% availability, implying 8 to 80 hours of downtime per year.

This project addresses a major source of unavailability: operator mistakes. Specifically, the PIs seek to reduce the impact of mistakes by guiding and validating operator actions, focusing specifically on cluster-based Internet services. This approach involves three efforts: (1) to explore the nature of operator mistakes and their impact on the performance and availability of Internet services by interviewing and surveying experienced operators, running experiments with volunteer operators, and running several operator contests; (2) to develop operator models that can be used to guide operator actions based on the likelihood of mistakes; and (3) to design and prototype a validation infrastructure that is part of the online system, yet allows operators to check the correctness of their actions before they can impact the live service.

The main expected outcome of the project is a demonstration that systems that guide and validate operator actions can significantly reduce the impact of operator mistakes on service availability. Valuable artifacts for other research efforts relating to availability (and manageability) will include: (1) extensive data on operator mistakes and their impact on service performance and availability; (2) models of operator behavior for guiding actions; and (3) a prototype validation infrastructure.

Spatial localization is a prerequisite for a range of sensor network tasks, such as monitoring, tracking, routing and security services. Currently, a variety of approaches are employed in providing critical positioning information to sensor nodes. Although these approaches provide a rich environment for innovation, their diversified strategies introduce problems of standardization and inefficient resource use. For example, many techniques require unique infrastructures, and among different localization technologies, little is understood about cost performance tradeoffs in the presence of systematic distortions and noise. This research addresses the need to construct a scalable, unified family of localization services over a variety of sensor node types. The algorithmic methodology centers on Bayesian networks. These networks allow for a systematic way to manage signal distortion and noise and enable the integration of the spectrum of current sensor network positioning modalities: signal strength to distance, angle of arrival, time difference of arrival, and fingerprinting. This research will result in a universal localization infrastructure capable of integrating location information into any computing device and provide new benchmarks that describe the limits of localization performance in the presence of distortion and noise.

These findings will allow designers to select the localization modalities that maximize their application's performance goals given their cost constraints and will promote the ubiquitous use of low-cost sensor nodes. Through dissemination of the results in both archival publications and new curricula, this project will advance the development of sensor applications by enabling scalable localization services for a diverse range of sensor networks.

[unreadable] DESCRIPTION (provided by applicant): Ascariasis and hookworm infection affect 1.6 billion people across the world. Anthelmintics, including levamisole and related drugs (pyrantel), are used to combat nematode parasites, and resistance is a threat. Our long-range objective is to improve human health by increasing the efficacy of anthelmintic drugs by identifying approaches to reverse resistance. The objective of this application is to test single-channel properties of levamisole receptors and a model that describes changes in the sensitivity of nematodes to levamisole and alters potency. Our central hypothesis is that the structure and pore of the L-subtype acetylcholine receptor ion-channel on nematode muscle makes it more sensitive to levamisole and more permeable to Ca; and the increased response of acetylcholine channels (modulation) produced by the neuropeptide, AF2, involves cAMP, Ca entry and kinase activity. The rationale for the research is that, as the mechanisms for modulating responses to levamisole activated receptor channels become known, pharmacological approaches can be formulated to overcome resistance. We will use muscle preparations of A. suum, C. elegans and null-mutants with current-clamp, voltage-clamp and patch-clamp technology to test the Ca permeability and subunit composition of L-subtype acetylcholine channels and to test a model for AF2 modulation. We will pursue 3 aims: 1) determine the Ca permeability of N-, L- and B- subtypes of A. suum muscle acetylcholine receptors and thereby identify a preferred target site; 2) determine in patch-clamp experiments in C. elegans, the subunit requirements of the L-subtype acetylcholine channel; 3) characterize, n A. suum muscle, the mechanism & pharmacology by which calcium and AF2 affect the opening of different AChR channel subtypes, in order to increase responses and potency of cholinergic anthelmintics. The research is innovative because we are combining new knowledge from C. elegans with advanced electrophysiology of nematode parasites including muscle-vesicle preparations for patch-clamp recordings. We expect the research to identify additional strategies that increase the potency of cholinergic anthelmintics. The research is significant because application of the results will to lead to new approaches to control and overcome resistance to anthelmintics of the levamisole class. [unreadable] [unreadable] [unreadable]

Proposal Number: 0627032
PI: Marco Gruteser
Institution: Rutgers University
Title: NeTS-FIND: A Geometric Stack for Location-Aware Networking


Abstract

This project addresses the challenge of integrating location information into the network architecture through a multi-resolution distributed location service, combined with trajectory-based forwarding as a key routing primitive. The location service that will be developed under this project builds a hierarchy of servers on the location registries available in wireless networks to keep track of associated nodes. Each node is associated with a home area, so that the location-service only needs to track nodes away from home. In addition, each level stores position information at progressively lower resolution, which improves both scalability (less updates) and privacy (less sensitive information). The trajectory-based forwarding mechanisms also allows for efficient coordinate system ranslations at routers.

Project results are expected to provide guidance for handling location information in a future comprehensive network architecture. They may also influence the evolution of current Internet architecture. For example, geographic routing could improve manageability through smaller routing tables or the geocast concept may be incorporated into layer 2.5 designs for future vehicular networks. Similarly, the results of the location-service design may inform interested users of the possibilities of low-cost tracking services for large numbers of objects, for example at the FEMA for disaster management. The experimental and design components of this project will also enhance Rutger's graduate education.

CRISP; Cells; Computer Retrieval of Information on Scientific Projects Database; Funding; Grant; Institution; Investigators; NIH; National Institutes of Health; National Institutes of Health (U.S.); Research; Research Personnel; Research Resources; Researchers; Resources; Source; Steroid Compound; Steroid Resistance; Steroid Resistant; Steroid-resistant asthma; Steroids; United States National Institutes of Health

(RS)-11beta,16alpha,17,21-Tetrahydroxypregna-1,4-diene-3,20-dione cyclic 16,17-acetal w/ butyraldehyde; Adrenal Cortex Hormones; Asthma; Beclometasone; Beclomethasone; Beclovent; Beconase; Bronchial Asthma; Budesonide; CRISP; Computer Retrieval of Information on Scientific Projects Database; Consensus; Corticoids; Corticosteroids; Drugs; FDA; Food and Drug Administration; Food and Drug Administration (U.S.); Frequencies (time pattern); Frequency; Funding; Grant; Guidelines; INFLM; Inflammation; Inhalators; Inhaler; Institution; Intervention; Intervention Strategies; Investigators; Lung; Measures; Medication; NIH; National Institutes of Health; National Institutes of Health (U.S.); Patients; Pharmaceutic Preparations; Pharmaceutical Preparations; Physicians; Pregna-1,4-diene-3,20-dione, 9-chloro-11,17,21-trihydroxy-16-methyl-, (11beta,16beta)-; Pregna-1,4-diene-3,20-dione,16,17-(butylidenebis(oxy))-11,21-dihydroxy-, (11beta,16alpha)-; Purpose; Research; Research Personnel; Research Resources; Researchers; Resources; Respiratory System, Lung; Respiratory physiology; S-(Fluoromethyl) 6a,9-difluoro-11b,17-dihydroxy-16a-methyl-3-oxoandrosta-1,4-diene-17b-carbothioate; SCHED; Schedule; Source; Symptoms; Therapeutic Corticosteroid; Time; USFDA; United States Food and Drug Administration; United States National Institutes of Health; Vancenase; Vanceril; Week; base; drug/agent; fluticasone; interventional strategy; irritation; lung function; pulmonary; respiratory function

This award is funded under the American Recovery and Reinvestment Act of 2009 (Public Law 111-5).
Many studies have shown that human mistakes are an important source of system failures. Further, repairing mistakes is often time consuming, leading to high unavailability. In this project, we will explore a novel approach to dealing with human mistakes called operator-proof systems management. In an operator-proof system, an omnipresent management infrastructure will enable the system to defend itself against operator mistakes. The infrastructure will constantly monitor operator actions and the system state to decide when and how the system should defend itself. Possible defensive measures include blocking operator actions that could lead to a mistake and/or limiting operator access to prevent mistakes from spreading throughout the system. Blocks are later lifted if the system can test the correctness of the operator actions.
To explore our ideas, we will design and implement two very different prototype operator-proof systems: an Internet service and an enterprise system. We will explore the design space and evaluate the overall approach by running a large set of experiments, where volunteer operators of different levels of experience are asked to perform a variety of tasks on the prototype systems.
Broader impacts. Our research will provide a concrete step toward the realization of a model where large computer systems can be operated at lower cost by less skilled individuals. Our investigation will also expose a large number of students (acting as volunteer operators) to system management issues and our proposed solutions.

The objective of this research project is to perform high-resolution sensing of surface charges and ionic currents of living cells. Both these measurements will provide important information about the cell membrane and underlying proteins. Understanding the pivotal role of membrane proteins in clinical diagnostics requires measurement tools with high-resolution and distributed sensing. Thus, this project is motivated by the need to miniaturize bioassays with higher resolution and the present lack of integrated measurement tools for advanced cellular studies. The following research tasks will be undertaken (i) electronic sensors to monitor vesicle trafficking and intercellular communication electronically and at real-time, (ii) electrophysiology sites to simultaneously record ionic currents in parallel, (iii) ultra low-noise amplifier with correlated-double-sampling (CDS) sensitive signal readout to process ionic currents, and (iv) a new hybrid approach to model physiological changes within a single ion-channel, cell or cellular assembly.

The integrated system will provide an unprecedented level of spatial and temporal resolution for cellular studies. The integrated education and out-reach components proposed investigation are expected to greatly improve the representation of female students in electrical engineering and open avenues of biotechnology research for engineers.

This project is aimed at the design and experimental validation of a comprehensive clean-slate future Internet architecture. The proposed MobilityFirst architecture is motivated by the ongoing paradigm shift of Internet usage from today?s fixed PC/host (client)?server model to emerging mobile data services and pervasive computing applications. The major design goals of the architecture are: mobility as the norm with dynamic host and network mobility at scale; robustness with respect to intrinsic properties of the wireless medium; trustworthiness in the form of enhanced security and privacy; usability features such as support for context-aware services, evolvability, manageability and economic viability. The key components of the MobilityFirst network design are: (1) separation of naming and addressing, implemented via a fast global dynamic name resolution service; (2) self-certifying public key network addresses to support strong authentication and security; (3) generalized delay-tolerant routing with in-network storage for packets in transit; (4) flat-label internetwork routing with public key addresses; (5) hop-by-hop transport protocols operating over segments rather than an end-to-end path; (6) a separate network management plane that provides enhanced visibility; (7) optional privacy features for user and location data; and (8) an integrated computing and storage layer to support programmability. The project?s scope includes architectural design, validation of key protocol components, testbed prototyping of the MobilityFirst architecture as a whole, and real-world protocol deployment on the GENI experimental infrastructure. The results of this project will provide architectural guidance for cellular-Internet convergence, and are expected to influence future technical standards in the networking industry.

DESCRIPTION (provided by applicant): 'Membrane Ion-channels in Helminth Parasites: Resistance and Sites of Action for Anthelmintics'The Neglected Tropical Diseases include the Soil-Transmitted Nematode (STN) parasites (ascariasis, hookworm, and trichuriasis), filariasis (river blindness and lymphatic filariasis) and schistosomiasis. These diseases are caused by Clade I, III and V parasitic nematodes and the trematodes S. mansoni, S. haematobium and S. japonicum. Ascariasis is caused by the large intestinal roundworm, Ascaris lumbricoides. Worldwide, it occurs in 1.4 billion people. Lymphatic filariasis (elephantiasis) threatens over a billion people in 83 countries and is caused by filarial nematodes like Wuchereria bancrofti and Brugia malayi. Schistosomiasis threatens over 1 billion people and infects some 300 million individuals. These infections are both caused by, and cause, poverty. Prophylaxis and treatment of these parasitic diseases relies on the use of anthelmintic drugs because no effective vaccines are available;but, there are real concerns that mass chemotherapy will lead to development of resistance. Single-dose Mass Drug Administration [MDA] is preferable for prevention and treatment, and is used by current control and elimination programs, but is not effective with most (all) anthelmintics. The emergence of resistance to any of the drugs currently used in MDA would deal a devastating blow to the control of these debilitating diseases. No current anthelmintic has optimal properties so there is an urgent need for new lead compounds, together with a better grounding of basic science to improve the use of existing drugs and new drug development. Ion-channels in helminths are major, validated, sites of action for existing and for potential novel anthelmintics. Our conference is planned as a Pre-meeting of the American Society of Tropical Medicine, in Philadelphia at the Downtown Marriot Hotel, Dec 1-3, 2011. The symposium is timely and will facilitate spread of knowledge and foster research interest in this important and expanding area of research by our program of speakers, interactions between delegates, discussions of strategic directions and publication of the meeting's papers. There will be an open registration to national and international attendees. Our current estimated number of attendees is 100. The field is expected to be of most interest to parasitologists and public health interests. The planning and location will allow accommodation for disabilities and actively seek input and contribution from minorities. The conference will include invited expert speakers from the field and to seek submissions from interested participants to present papers and/or posters. The intention of the conference is to encourage research and knowledge of ion-channel drug targets in helminths;to encourage collaborative research;to improve recognition and support for the field of research. The planned outcome is publication of papers in a special edition of the Journal Invertebrate Neuroscience. Each speaker will review their area of expertise and be invited to comment on how the community should organize itself to advance the field of study. An important aim is to invigorate the research area and to raise the level of interest in basic research for drug development of neglected tropical diseases. We have four aims at our conference: Aim #1: To review recent progress in understanding the actions of anthelmintics at ion channels, and how resistance to those drugs can emerge. Aim #2: To publish a special issue of a learned journal summarizing current knowledge in this area. Aim #3: To encourage the formation of new cross-disciplinary international collaborations that will recruit established workers in other fields to study parasitic helminths. Aim #4: To identify and pursue opportunities for increased funding for projects in this area. The overall impact will be a powerful influence on: Odispersion and expansion of the knowledge base of membrane and ligand gated ion-channels as helminth drug targets;Oan increase in the number of active scientists supporting the field;Oidentification of strategic directions for the development of the field;O within 24 months, two or more significant (R01 or similar) proposals and two or more collaborative projects between US and international researchers will be formed. PUBLIC HEALTH RELEVANCE: Nematode parasites and flatworm parasites affect more than 1.5 billion people world- wide;these diseases are not a focus of interest in developed countries and part of a group of diseases known as the neglected tropical diseases. These helminth parasites reduce growth, health, cause lost work productivity and contribute to poverty. There are no effective vaccines and so in the absence of adequate sanitation, treatment and prophylaxis relies on anthelmintic drugs. There are concerns that Mass Drug Administration required for helminth control will produce resistance. To counter this real concern new drugs, new drug target sites and the necessary supporting basic research is required. Membrane and ligand-gated ion-channels are major, validated, anthelmintic drug target sites. The 2-day open symposium will bring together national and international experts in the field of membrane ion-channels of helminths as drug targets, will foster communication of the new knowledge base of the field, and identify strategic directions for the development of the field. It will also recruit new interest to this developing and important research topic.

Objective: The objective of the program is to develop an integrated droplet-based microfluidic system for parallel screening of phenotypic changes in nematode worms within droplet microenvironments of varying chemical compositions. This work aims to provide a radical translation from existing low-throughput worm motility assays to a truly high-throughput, whole-organism assay for testing multi-drug compounds against nematodes.

Intellectual Merit: The intellectual merit is to provide a powerful lab-on-a-chip assay system for biological studies on whole-animal models with unprecedented high throughput. The system will uniquely combine automated generation and modulation of drug-coded pharmacological droplet libraries, guided movement stimulation, locomotion assay, and electrophysiological recording for single organisms inside droplets. This research is transformative because the system can provide unique details of neurophysiological changes in nematodes with drug exposures, facilitating experiments that are impossible by current techniques. The proposed technology is generic because the system can be adapted to test a wide range of important nematodes and drug compounds.

Broader Impacts: The proposed research will help answer fundamental questions in diagnosing, controlling and predicting drug resistance in nematode parasites, thereby unraveling complex mechanisms of host-parasite interactions. This research will generate broad educational opportunities for both undergraduate and graduate students, and benefit curriculum development for a new Undergraduate Bioengineering Minor Program of the Iowa State. Women and minority students, and middle school students will be attracted into science and engineering through open-lab tours, and in-class presentations. High school science teachers will be collaborated to develop K-12 instructional materials in the topics of micro/nanotechnology and bioengineering.

Project Summary 1. The Neglected Tropical Diseases include ascariasis and lymphatic filariasis. These diseases are caused by parasitic nematodes that are grouped in Clade III because of their molecular similarities. Ascariasis is caused by the large intestinal roundworm, Ascaris lumbricoides. Worldwide, it occurs in 1.4 billion people. Lymphatic filariasis (elephantiasis) threatens over a billion people in 83 countries and is caused by filarial nematodes like Brugia malayi. Control of these nematode parasites relies on a limited number of anthelmintic drugs. There are concerns that mass chemotherapy will lead to the development of resistance. There is a significant and urgent need for more basic science that will facilitate the use of existing drugs and the development of new drugs. 2. Recently, several novel nematode selective cholinergic anthelmintics, including tribendimidine and derquantel, have been introduced and increased the significance of cholinergic anthelmintics. Tribendimidine has potential for single-dose Mass Drug Administration. Derquantel has [unreadable]resistance busting[unreadable] actions against worms that are resistant to other cholinergic anthelmintics. The pharmacology of nematode nicotinic receptors (nAChRs) is more complex than has been appreciated. The nAChR, referred to as the levamisole receptor, is divided into N-, L- and B-subtypes in the Clade III nematode Ascaris suum. The pharmacology of Clade III levamisole receptors may be plastic and modulated by receptor subunit stoichiometry. The therapeutic importance of the subtypes and the modulation demands further investigation in parasitic nematodes. We have three aims. 3. Our approach will use muscle contraction assays, current-clamp, voltage-clamp, patchclamp, cloning &Xenopus oocyte expression and pharmacological agents, to distinguish the subtypes. Aim #1 will test the hypothesis that tribendimidine is or is not an nAChR agonist that is either N-, L- or B-subtype selective in A. suum and if it is an open-channel blocker. Aim #2 will express specific nicotinic receptor subunits from A. suum in different combinations to test the hypothesis that modulation of subunit stoichiometry reproduces the pharmacological diversity of native levamisole receptors. Aim #3 will characterize nAChR responses and receptors in B. malayi, to test the hypothesis that the subtypes are functionally similar to the Clade III nematode, A. suum. 4. The proposal is innovative, exploring unknown modulatory, plastic and important pharmacological properties of Clade III nAChRs and extending, to the Brugia malayi parasite preparation, the methods that this group of investigators has developed. 5. The overall impact will be a powerful influence on: expansion &logical use of tribendimidine, a potential single-dose MDA;a significant impact on understanding of modulation &pharmacological diversity of nicotinic anthelmintic target sites in Clade III nematodes;a powerful influence on development of a novel B. malayi preparation for studying ion-channel drug targets;new knowledge allowing development of improved anthelmintic combinations of nAChR receptor subtype selective drugs.

DESCRIPTION (provided by applicant): 1. The Neglected Tropical Diseases include ascariasis and lymphatic filariasis. These diseases are caused by parasitic nematodes that are grouped in Clade III because of their molecular similarities. Ascariasis is caused by the large intestinal roundworm, Ascaris lumbricoides. Worldwide, it occurs in 1.4 billion people. Lymphatic filariasis (elephantiasis) threatens over a billion people in 83 countries; it is caused by filaria nematodes like Brugia malayi. Control of these nematode parasites (adults or larvae) relies on a limited number of anthelmintic drugs. There are concerns that mass chemotherapy will lead to the development of resistance. There is a significant and urgent need for research that will allow better use of existing drugs, including combinations, to preserve their value, and to develop new drugs. 2. Recently, several novel nematode selective cholinergic anthelmintics, like tribendimidine and derquantel (now synergized with abamectin), have been introduced and increased the significance of cholinergic anthelmintics. Tribendimidine has potential for single-dose Mass Drug Administration. Derquantel has 'resistance busting' actions against worms that are resistant to other cholinergic anthelmintics. The pharmacology of nematode nicotinic receptors (nAChRs) is more complex than has been appreciated. The muscle nAChRs are divided into N-, L- and B-subtypes in the Clade III nematode Ascaris suum. The pharmacology of Clade III muscle receptors (levamisole receptors) are modulated by receptor subunit composition. The therapeutic importance of subtypes and modulation demands further investigation in parasitic nematodes. We have three aims. 3. Our approach will use muscle contraction assays, current-clamp, voltage-clamp, patch- clamp, cloning & Xenopus oocyte expression and pharmacological agents, to characterize actions of cholinergic anthelmintics and the subtypes of their receptors. Aim #1 will characterize the mode of action and subtype selectivity of tribendimidine in A. suum. It will test the hypothesis that tribendimidine is not selective for the L-subtype of nAChR but another type in A. suum and determine if its action as an open-channel blocker limits efficacy. Aim #2 will examine the effects of subunit arrangements and stoichiometry on pharmacology of Ascaris nAChRs. It will express four specific nicotinic receptor subunits from A. suum in different combinations to test the hypothesis that different subunit compositions reproduce the pharmacological diversity of native muscle receptors (levamisole receptors). Aim #3 will characterize nAChR responses and receptors in B. malayi, to test the hypothesis that the subtypes are functionally similar to the Clade III nematode, A. suum. 4. The proposal is innovative, exploring unknown drug effects and effects of subunit arrangements on the pharmacological properties of Clade III nAChRs. We also extend, to the Brugia malayi parasite preparation, the methods that this group of investigators has developed. 5. The overall impact will be a powerful influence on: expansion & informed use of tribendimidine, a potential single-dose MDA; the expansion and informed use of the pharmacological diversity of nicotinic anthelmintic target sites in Clade III nematodes; use of a novel B. malayi preparation for studying ion-channel targets for future drug development; development or informed use of combinations (e.g. derquantel with avermectins; or combinations of subtype selective cholinergic anthelmintics).

This platform presents a hardware-neutral way of developing sensing and ubiquitous computing applications. It is focused on making sensing application available to a larger community of users and developers. It is centered around 2 core concepts: a layered approach to system design, and a set of simple network APIs and data abstractions. The design and simple programming model make it possible for novice developers to rapidly design and develop new and creative applications. The project focuses on lowering the knowledge and skill required of application developers that wish to integrate sensor information. It does this through a combination of simple data structures and information models, and a layered network-based API that hides unnecessary details from developers, freeing them to focus on specific tasks.

While commodity sensors and software are becoming more readily available every day, the programming interfaces exported by those systems are tightly bound to the sensors the system supports. Researchers believe that this platform presents a positive first step toward sensing systems that are flexible and general-purpose enough to support a wider array of sensors than is possible in competing systems.

The Next-Phase MobilityFirst (MF) project aims to have a major impact on the architecture of the future Internet by re-architecting it to address the needs of emerging mobile platforms and applications. Adoption of technologies arising from this project may be expected to provide improved efficiency, security and robustness that would benefit both network operators and end-users of the Internet. This project, originally funded as a collaborative research effort under the NSF Future Internet Architecture (FIA) program (2010-13) in which the MF architecture was designed over the past 3 years, is centered on a new name-based service layer which serves as the narrow-waist of the protocol; this name-based services layer makes it possible to build advanced mobility-centric services in a flexible manner while also improving security and privacy properties. The architecture incorporates novel storage-aware routing techniques which provide significant improvements in mobile network capacity and functionality. The next phase of the MobilityFirst project is aimed at making the transition from early-stage architecture and prototyping to advanced real-world services and trial network deployments. The research and experimental trials agenda is aimed at validating and refining the core name service, routing, security and management components of the MF architecture, while also responding to emerging trends in network technology and services such as the cellular mobile data explosion, the growth of content, the emergence of cloud computing, and software-defined network (SDN) technology.

Intellectual Merit: This project includes several research thrusts aimed at transitioning the MobilityFirst architecture to advanced services and field deployable technology. These include: (1) advanced name-based network services and development of enhanced global name service (GNS) technology; (2) network security and privacy designs and enhancements; (3) design of advanced content services; (4) application of MobilityFirst protocols to next-generation mobile cloud computing; (5) design of advanced context-aware services; (6) technical and economic study of cellular-Internet convergence; (7) software-defined network (SDN) ready protocol design; and (8) technology platforms, router implementation and deployment strategies. These research thrusts will be informed by three distinct real-world network environment trials: a "mobile data services" trial with a wireless ISP (5Nines) in Madison; WI; a "content production and delivery network" trial involving several public broadcasting stations in Pennsylvania connected by a greenfield optical network called PennREN; and a "context-aware public service" weather emergency notification system (CASA) with end-users in the Dallas/Fort Worth area. These network environment trials are the centerpiece of the proposed project, and are expected to provide a firm basis for validation of the MobilityFirst protocol stack and its usefulness for developing advanced mobile, content, context and cloud applications, while also advancing the technology to the field-deployment stage. Expected outcomes from the project include research results on security, privacy, content/context/cloud services and SDN; MobilityFirst protocol stack software revisions; router technology implementations; multiple real-world trial deployments of the technology; and experimentally supported evaluations of the architecture. This project is a collaborative effort involving Rutgers, UMass, MIT, Duke, U Michigan, U Wisconsin, and U Nebraska with the participation of several industrial research and network environment trial partners.

Broader Impacts: The MobilityFirst project will have impact as a new approach to a future Internet that by design addresses mobility and mobile platforms, and as an enabler of new mobile Internet applications of social value such as context-aware emergency notification services. The release of open source protocol software may be expected to help to stimulate further experimental research on future Internet architectures across the networking community. The project also contributes to education and training in the key areas of Internet and mobile network technology.

To date, safety services are typically constructed as dedicated stovepipe systems focusing on high reliability and a specific area of risk (e.g., automotive safety systems). Usage of
 such services remains limited since they require a dedicated investment for each system. This project trades off the ultra-high reliability of dedicated systems for the much more 
rapid adoption of safety services that comes with integrating them directly into mobiles and wearables. By demonstrating the feasibility of this approach, this project can contribute to saving lives, such as some of the more than 30,000 traffic fatalities in the United States each year. It can also inform regulatory policy for safety services 
at the CPSC, NHTSA, or FCC. Moreover, the PIs will not only train graduate students to conduct the research but also actively include undergraduates and high school students through research internship programs. Results will be disseminated through scholarly publications, active outreach to the wireless and mobile industry through WINLAB's industry events and connections.

This project seeks to demonstrate that the mobile devices we carry and wear can provide effective safety services. This is particularly relevant where our devices contribute to dangers by causing distractions for drivers and pedestrians. This project therefore pursues the vision of a system that offsets such unsafe use by continually sensing our activities and surroundings, identifying potentially dangerous situations, and mitigating them through appropriate interventions. At a technical level, the primary challenge lies not only in designing precise sensing techniques but in understanding and managing the level of confidence provided by these techniques. A key observation is that there are usually multiple possible interventions of varying levels of intrusiveness and tolerance to false positives. It is therefore important to match interventions to the confidence level provided by the sensors. To address this challenge, the project develops system support and a toolkit to help developers track and manage mobile
 sensing uncertainty. It explores crowdsourcing failure and relevance data
 from a large user population and automatically estimating the confidence provided
 by internal sensing and activity recognition components. The toolkit can further use the obtained metrics to help adapt sensing or application behavior. The system might conserve energy by switching one context sensor to a fallback mode from a diversity mode; or, the system could
 switch to a different intervention if the level of confidence has changed. System validation includes prototyping two application use cases, which sense and mitigate mobile device distractions for drivers and pedestrians. Together, these techniques form the system, which supports development of many other effective safety services on mobile devices.

Project Summary 1. Cholinergic anthelmintics, including levamisole and pyrantel, are used for the control of nematode parasites. We have found that cholinergic anthelmintics are not a homogenous functional class of drugs. These anthelmintics select for different subtypes of acetylcholine- gated ion-channel receptors (nAChRs) in muscle of parasitic nematodes. The different nAChR subtypes are produced by varied combinations of five subunit proteins: each subunit may be produced by a different gene. We will exploit our advances with RNAi, quantitative motility studies, molecular pharmacology and patch-clamp to study the diversity and dynamic nature of nAChR subtypes of Brugia malayi: a parasite that causes lymphatic filariasis. This parasite is an excellent specific and general nematode parasite model. It is tractable to study with techniques that permit functional studies of genes that produce the different subunits of the nAChR subtypes involved in parasite neuromuscular transmission. 2. The classic cholinergic anthelmintic, levamisole, selectively activates muscle L-subytpe nAChRs, producing spastic contraction in parasitic nematodes. In Brugia adults, responses to levamisole decline over an hour, but responses to other cholinergic anthelmintics do not. Why is there this loss of anthelmintic effect (tachyphylaxis) and why is there a difference between cholinergic anthelmintics? Here we will identify the dynamic functions and interactions of different nAChR genes and a mechanistic explanation for anthelmintic tachyphylaxis. 3. Our approach in Aim #1 will be to characterize, molecularly and pharmacologically, the four or more nAChRs subtypes present on Brugia somatic muscle. In Aim #2, we will identify the functions of nAChR subunit genes by using RNAi on Brugia adults to produce different phenotypes and to alter muscle responses to different cholinergic anthelmintics. In Aim #3, we will test the hypothesis that populations of receptor subtypes are dynamic, compensating for the effects of anthelmintic exposure; we will determine how the L-subtype nAChRs behave during tachyphylaxis. 4. The proposal is innovative, using a combination of techniques for the study of functional properties of filarial nAChR ion-channels genes. To our knowledge, we are the only lab that has been able to combine these techniques successfully for the study of nematode parasites. 5. The overall impact, by an innovative combination of techniques, we will discover important new information on: ?the functional properties of filarial nAChR genes sensitive to anthelmintics; ?the dynamic nature of different receptor subtypes and; ?the loss of functional receptors and expression of genes associated with anthelmintic tachyphylaxis

Wireless networks have grown enormously during the past 30 years, impacting numerous industries, including telecommunications, emergency response, and entertainment. Wireless advances could radically change several industries in the near future, including manufacturing, the automotive industry, healthcare, assisted living, public events, home automation, and utilities. However, each industry has different, often opposing, wireless demands. Manufacturing often requires a low data rate, ultra-low latency closed loop communication between machines, while emerging augmented reality interactions between people have much larger large data volumes, but can tolerate higher latency. Today, applications and services are constrained to a handful of wireless technologies, such as 4G, Wi-Fi and Bluetooth, because developing and modifying new radio protocols requires many man-years. The challenge for the wireless community is to enable wireless networks the same flexibility as regular computing devices, such as laptops or phones, where the same hardware supports a near infinite variety of behaviors realized in software. Flexibility at the wireless level has lagged as radios have been implemented as fixed-function circuits, in order to minimize marginal cost, energy use, and network latency. Enabling such flexibility would open opportunities for new wireless functions in diverse application domains.

While the emerging field of Software-Defined Radio (SDR) has made progress toward this vision, recent results have shown that traditional SDRs suffer serious limitations. The main problem is the slower sequential execution, even when using multicore central processing units (CPUs) or graphics processing units (GPUs), in contrast to the fast execution and high parallelization in application-specific integrated circuits (ASICs)or field-programmable gate arrays (FPGAs). This research will explore and evaluate a new software abstraction, Dynamic Blocks (DB), which will realize many software abstractions in an SDR FPGA, including procedure calls, recursion, queuing, dynamic routing, shared memory and matrix algebra. Realizing these abstractions in FPGAs will allow developers to rapidly try new designs or modify existing ones while meeting real-time latency and low energy requirements. The project will use millimeter-wave (mmWave) scenarios to evaluate real-time SDRs programmed using DBs. The SDRs available in the ORBIT testbed at Rutgers University, and the future mmWave capable equipment from the recently-funded COSMOS platform and European Union partners would be the target platforms for this research.

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 Filariasis is a group of neglected tropical diseases produced by infection with microfilaria of Clade III parasitic nematodes that ae transmitted by biting insects. River Blindness caused by Onchocerca volvulus, and Lymphatic Filariasis produced by Brugia malayi are examples of these diseases. River Blindness is caused by parasites that produce scaring of the cornea as well as severe itching and dermatitis; it infects 17 million people in West and Central Africa. Lymphatic filariasis is a debilitating and disfiguring disease, which occurs in 120 million people worldwide. Control of these nematode parasites relies on a small number of anthelmintic drugs, which have a limited spectrum of action. There are no practical macrofilaricides, which kill the adult parasites in the host; and there are concerns that mass microfilaricide chemotherapy will lead to the development of resistance. Diethylcarbamazine is a mainstay for the treatment of lymphatic filariasis in most parts of the world, except in areas where onchocerciasis is present because it is contra-indicated by risks of blindness. It produces rapid clearance of microfilaria and causes ~40% mortality of adult parasites (macrofilaricide). It is striking however, that 68 years after its introduction, we have no proven understanding of the molecular mechanism of its action. Here, we propose to re-invigorate this investigation by studying its effects on filarial ion-channels, including effects on SLO-1 K channels. Emodepside is an emerging and important cyclooctadepsipeptide class of anthelmintic that also has effects on microfilaria and adult filaria. Single emodepside treatments could allow a major advance over existing mass drug administration (MDA) programs which require regular treatments to kill adult parasites. One of the putative sites of action of emodepside is on nematode SLO-1 K channels where opening of the channels inhibits motility, but it is not effective against all filaria. Here we propose to examine filarial SLO-1 K channels as sites of action of emodepside. Our approach will focus on Brugia malayi but we will also use include studies on Onchocerca and human channels. We will use patch-clamp, dsRNA knock down, Worminator motility assays and Xenopus expression to characterize the functional properties of innate SLO-1 K channels from Brugia malayi. In Aim #1, we will test the hypothesis that Brugia malayi SLO-1 K channels are the only target sites of diethylcarbamazine and emodepside. We will use patch-clamp recordings of SLO-1 K channels from Brugia muscle cells and examine effects of knock down of putative targets. We propose, in , to express Onchocerca, human and Brugia SLO-1 K channels splice variants in Xenopus oocytes to test the hypothesis that different species of filaria and human SLO-1 K channels are pharmacologically separable using emodepside and K channel agonists. Aim #2 The proposal is innovative, using a combination of techniques to test the effects of diethylcarbamazine and emodepside on their putative target sites, SLO-1 K channels of filarial. The overall impact of using this mixture of techniques, will be the discovery of effects of diethylcarbamazine and emodepside on filarial SLO-1 K channel splice variants, and an improved characterization of the modes of action of diethylcarbamazine and emodepside. Knowledge of the molecular sites of action of these drugs is required for: a) molecular detection of resistance; b) designing new drugs and combination therapies; c) predicting and understanding sensitivities of different nematode parasite species; and d) predicting host toxicity

Project Summary Filariases are a group of neglected tropical diseases produced by infection with microfilaria of Clade III parasitic nematodes that are transmitted by biting insects. One example is the lymphatic filariasis produced by Brugia malayi. Lymphatic filariasis is a debilitating and disfiguring disease which occurs in 120 million people worldwide. Other filarial diseases are River Blindness produced by Onchocerca volvulus and loiasis produced by Loa loa. Prevention and treatment of these nematode parasite diseases relies on the use of anthelmintic drugs because no effective vaccines are available. Prophylaxis using Mass Drug Administration [MDA] programs are limited by the efficacy of existing anthelmintics. Diethylcarbamazine is a mainstay for the treatment of lymphatic filariasis and loiasis in most parts of the world, except in areas where onchocerciasis is present because it is contra-indicated by risks of blindness. Diethylcarbamazine produces rapid clearance of microfilaria and causes ~40% mortality of adult parasites (macrofilaricide). A number of studies have suggested that diethylcarbamazine has an indirect host- mediated mode of action and that diethylcarbamazine acts by changing host arachidonic acid pathways. We have observed that diethylcarbamazine has direct effects on filarial nematodes. We present preliminary observations that show that diethylcarbamazine increases the opening of TRP-2 channels in Brugia malayi, and opening of calcium-activated SLO-1 K channels. The effect is a rapid, transient inhibition of motility followed by recovery: the response accommodates. Emodepside is an emerging and important cyclooctadepsipeptide class of anthelmintic that also has effects on microfilaria and adult filaria. Emodepside treatments could allow a major advance over existing mass drug administration (MDA) programs which require regular treatments to kill adult parasites. One of the sites of action of emodepside is on nematode SLO-1 K channels where opening of the channels inhibits motility, but it is not effective against all filaria. Here we propose to compare effects on filarial SLO- 1 K channels from Brugia, Onchocerca and Loa and to examine actions and interactions of these two drugs to explore their mode of action. We have 3 aims: Aim #1: Characterize, in vitro, the concentration motility-inhibition-response relationships of diethylcarbamazine and emodepside and their combination on: A) Brugia microfilaria; B) Brugia adult females; C) Brugia adult males. We will test the hypothesis that effects of diethylcarbamazine and emodepside are additive, synergistic or antagonistic and dependent of life-cycle stage and sex. Aim #2 Characterize the SLO-1 K channel current responses to diethylcarbamazine and emodepside in isolated Brugia malayi muscle flaps under patch-clamp We will test the hypotheses: a) that the effects of emodepside and diethylcarbamazine interact; b) that the interactions of diethylcarbamazine and emodepside are dependent on the presence of TRP-2 by knockdown of TRP-2 channels; and c) that TRP-2 and SLO-1 channel message & channel opening accommodates during prolonged exposure to diethylcarbamazine or emodepside. Aim #3: Characterize the comparative molecular pharmacology of: a) different SLO-1 K channels of Brugia malayi, Onchocerca volvulus and Loa loa and; b) TRP-2 channels of Brugia malayi and Loa loa expressed in oocytes. We will test the hypothesis that the pharmacology and potencies of emodepside and diethylcarbamazine on SLO-1 K channels and TRP-2 channels of, Brugia, Onchocerca and Loa are different and also different to a human channel homologue. We will examine channel desensitization. The proposal is innovative, using a combination of techniques to test the effects of diethylcarbamazine and emodepside on their putative target sites, SLO-1 K channels of filarial. The overall impact of using our mixture of techniques, will be discovery and comparison of effects of diethylcarbamazine and emodepside on different species of filarial TRP-2 channels and SLO-1 K channels. Knowledge of the molecular actions of these drugs is required for: a) molecular detection of sensitivity of different filarial species and resistance; b) designing new drugs and combination therapies; c) predicting and understanding sensitivities of different nematode parasite species; and d) predicting possible host toxicity.