Frank Brown - US grants

The major goals of the Clinical Mental Health Academic Award for Dr. Brown are: l) development into an independent researcher in geriatric psychiatry specifically late-life schizophrenic disorder; 2) additional research training and skills necessary to function as a resource person in geriatric psychiatry, especially for the development of other researchers including geriatric psychiatry fellows; 3) development as a primary geriatric educator for medical students, residents and allied health care providers at Emory University School Of Medicine; 4) development of a research program in geriatric psychiatry that will facilitate Dr. Brown's role as a research mentor to younger researchers;. 5) initial pilot studies necessary for longitudinal research projects through RO1 funding; and 6) development of collaborative relationships with research faculty at Emory and at Johns Hopkins School of Medicine. The research design will use a multidomain, neurobiological strategy that will utilize neurobehavioral and neuromorphology to characterize elderly schizophrenics with specific focus on the early-onset versus late-onset schizophrenics; subjects (elderly early-onset and elderly late-onset schizophrenics) will be administered a neuropsychological battery and will have brain magnetic resonance imaging. The research project has been designed to characterize the fundamental differences in the neuropsychological and neuromorphological expressions of schizophrenia in elderly late-onset schizophrenics when compared to elderly early-onset schizophrenics. The specific aims of the research project are: l) enhance the development of the nominee, 2) establish referral network and core procedures that future work will build upon and 3) characterize study sample.

9401021 Ambler This award provides support for the establishment of the Design Technologies Laboratory, or DesignLab. The laboratory will stimulate experimental research in technologies fundamental to building design support tools. Many such design support technologies are inherently nonprocedural and ill-suited to von Neumann uni-processor architectures. Efficient implementation strategies demand parallel and distributed computing environments with large shared memories and/or ultra high-speed interconnections. The requested equipment includes a 16-processor SGI Challenge and a very high speed network. The research topics to be explored include intelligent information databases for multimedia and 3D drawings; computer vision, modeling and visualization; declarative design specification languages; collaborative multi- agent design; meta-languages for defining reasoning systems; implementation strategies for non-procedural design technologies; and applied design technologies.

The major goals of the Clinical Mental Health Academic Award for Dr. Brown are: l) development into an independent researcher in geriatric psychiatry specifically late-life schizophrenic disorder; 2) additional research training and skills necessary to function as a resource person in geriatric psychiatry, especially for the development of other researchers including geriatric psychiatry fellows; 3) development as a primary geriatric educator for medical students, residents and allied health care providers at Emory University School Of Medicine; 4) development of a research program in geriatric psychiatry that will facilitate Dr. Brown's role as a research mentor to younger researchers;. 5) initial pilot studies necessary for longitudinal research projects through RO1 funding; and 6) development of collaborative relationships with research faculty at Emory and at Johns Hopkins School of Medicine. The research design will use a multidomain, neurobiological strategy that will utilize neurobehavioral and neuromorphology to characterize elderly schizophrenics with specific focus on the early-onset versus late-onset schizophrenics; subjects (elderly early-onset and elderly late-onset schizophrenics) will be administered a neuropsychological battery and will have brain magnetic resonance imaging. The research project has been designed to characterize the fundamental differences in the neuropsychological and neuromorphological expressions of schizophrenia in elderly late-onset schizophrenics when compared to elderly early-onset schizophrenics. The specific aims of the research project are: l) enhance the development of the nominee, 2) establish referral network and core procedures that future work will build upon and 3) characterize study sample.

The mental process of predicting the reasonable consequences of a change in the design of an artifact is an important step in the design process. This research addresses issues in developing a theory of design change. The premise is that the incremental changing of the geometric design of an artifact may be formally explained by logical and mathematical theories, similar to those in automated planning and simulation systems which are used in many fields. Topics being investigated are representation of designs, designer intentions, and constraints. A computational model of the deductive process of changing a design is being developed. The model uses frame laws and default constraints expressed in the modal quantificational logic Z. Other work includes exploring problems of automated deduction of facts in three dimensional geometry, consistency analysis, and developing a taxonomy of appropriate engineering design actions and intents.

9818341
Brown, Frank M.
Agah, Arvin
University of Kansas

Ambiguity Resolution for Intelligent Systems Using a Cognitive Robot

This research instrumentation contributes to the acquisition, by the Departments of Electrical Engineering and Computer Science, Psychology, and Speech Language and Hearing, of a Cognitive Robot (base system, arm and hand manipulator, binocular color vision, laser ranger, sound reception and interpretation, and sound generation) enabling research projects in:

- Ambiguity Resolution in Spoken Language Understanding,
- Ambiguity Resolution in Context Driven Active Robot Vision,
- Ambiguity Resolution within the Memory System, and
- Ambiguity Resolution in Robot Reasoning and Actuation.

The Cognitive Robot, with visual, speech, movement, and hand/arm manipulation capabilities, will enable research plausible interactions among the processes of ambiguity resolution in multiple cognitive subsystems including subsystems for speech and natural language understanding, scene interpretation, the retrieval of appropriate memory context, and robot planning and action execution. The research methodology is to integrate together computational models of these various ambiguity resolution processes of these subsystems into the Cognitive Robot and to test them in an integrated fashion by observing the behavior of the Cognitive Robot. The significance of this research lies in the fact that ambiguity in one subsystem can often only be resolved by the ambiguity resolution capabilities of the other subsystems. Thus, the study of ambiguity resolution in each of the four research projects using the Cognitive Robot will be enhanced by its integration with the ambiguity resolution capabilities of the others. Since the human capability for effortlessly resolving ambiguity seems to be a fundamental aspect of intelligence, an explication of the interactions among the ambiguity resolution capabilities of these subsystems may be highly significant.

EIA-9972843
Minden, Gary J.
Brown, Frank M.
University of Kansas Center for Research, Inc.

RI: Ambient Computational Environments

The University of Kansas (KU) will conduct research on Ambient Computational Environments (ACE) in which computational resources are available in offices, conference rooms, and other places and users are able to co-opt the use of these resources through authorization. User sessions are long lived and move among locations. To enable transitions and shared use, the ACE will include multiple interaction modes such as visual recognition, voice, gesture, etc. Research in techniques for access and interaction with environments, languages and run-time systems to support long-lived, mobile sessions, task negotiation among multiple user workspaces, context sensitive information retrieval, and disambiguation of speech and gestures will be performed. The PI team will work to increase recruiting of women and minorities at both the faculty and student levels.

The research builds upon previous work in the area of protein diffusion on the surface of erythrocytes. The investigator will develop numerical algorithms to efficiently evolve the shape of the cell membrane as a function of time. Thermal fluctuations insure that the membrane's dynamics will be stochastic and it is anticipated, on the basis of preliminary results, that these fluctuations will be sufficiently large in amplitude and sufficiently long in duration to account for the escape of band 3 protein from the cytoskeletal "corrals "on the surface of the red blood cell. The simulations may provide a microscopic justification for the choice of empirical parameters in earlier studies, or, it may prove necessary to include the dynamics of the cytoskeleton to achieve agreement with experiments. In either eventuality, the investigation will quantify the relative importance of membrane fluctuations and cytoskeletal dynamics on protein mobility. The algorithms developed will be of use in future studies of cell motility and other biological behavior that is dependent upon dynamic membrane fluctuations.

With support from the Major Research Instrumentation (MRI) Program, the Department of Chemistry and Biochemistry at the University of California in Santa Barbara will acquire a Beowulf cluster. This equipment will enhance research in a number of areas including a) simulation of biomaterial microstructures; b) simulation and interpretation of single molecule spectroscopy experiments; c) field-theoretic computer simulations of polymers and complex fluids; and d) modeling and computation of flow-structure interaction in multi-phase and complex fluids.

A cluster of fast, modern computer workstations is vital to serving the computing needs of active research departments. Such a "computer network" also serves as a development environment for new theoretical codes and algorithms, provides state-of-the-art graphics and visualization facilities, and supports research in state-of-the-art applications of parallel processing. These studies will have a significant impact in a wide number of areas, including materials science and physics.

Prof. Frank L. Brown of the University of California Santa Barbara is supported by this CAREER award to develop a dynamic elastic model for lipid bilayers which is used in simulating complex biochemical and biophysical phenomena. The research involves the development of Fourier Space Brownian Dynamics, or FSBD, for stochastically evolving these surfaces. This method will allow the modeling of cellular motility and membrane protein diffusion. A second project supported by this award is the development of theoretical and computational approaches to single molecule spectroscopy. The results of these simulations are used to interpret photon counting experiments.

This research has a broad impact on the field of biology, particularly the biophysics of membranes. Professor Brown is involved with the Computational Science and Engineering program on the UCSB campus and is working to incorporate computational chemistry into the program. Courses in atomic and mesoscale simulation techniques are being developed by Professor Brown as part of this project.

This project is supported by the Theoretical and Computational Chemistry Program in a co-funding arrangement with both Molecular Biophysics of Molecular and Cellular Biology and the Materials Theory Program of the Division of Materials Research.

Frank Brown of the University of California, Santa Barbara is supported by an award from the Chemical Theory, Models and Computational Methods program within the Division of Chemistry (MPS/CHE) and the Division of Molecular and Cellular Biology (BIO/MCB) for the development of theoretical tools to model lipid bilayers and biomembranes for use in simulating complex biochemical and biophysical phenomena. Dr. Brown's algorithms allow hydrodynamically and thermodynamically consistent modeling of inhomogeneous membrane surfaces over a range of "mesocopic" length scales (tens of nanometers to tens of microns) and time scales (tens of nanoseconds to tens of seconds and longer).

The research is having a broad impact on the interpretation of experiments that enhance our understanding of biological phenomena such as the diffusion of membrane proteins in complex cellular environments and the structure and dynamics of human red blood cells. Dr. Brown communicates the excitement and importance of science to grade school children through his participation in the Physics Circus and Chemistry Outreach programs at UCSB. Dr. Brown also serves as co-director of the UCSB center for scientific computing, which oversees and maintains shared scientific computing facilities for the UCSB campus, for use in both research and classroom teaching.

"This award is funded under the American Recovery and Reinvestment Act of 2009 (Public Law 111-5)."
Proposal #: 09-60316
PI(s): Brown, Frank, L.; Fredrickson, Glenn, H.; Garcia-Cervera, Carlos; Gilbert, John, R.; Van de Walle, Christian, G.
Institution: University of California-Santa Barbara
Title: MRI-R2: Acquisition of a High Performance Central Computing Facility at UCSB
Project Proposed:
This project, acquiring of a computational cluster to replace a six-year-old system, allows access to fast mid-sized parallel computation to dozens of researchers and serves as the institution's primary resource for parallel computation. The system is structured for a variety of uses. Standard MPI computation is carried out with a tightly coupled cluster of quad core processors, while 'fat nodes' with 256 GB of RAM as well as local high speed disk storage service jobs that require large shared memory. Researchers actively developing codes can take advantage of the unique performance characteristics of GPU (graphics processing) nodes. The system will have several NVidia Tesla nodes.
The users of the system are drawn from all five departments of the College of Engineering (Chemical Engineering, Computer Science, Electrical & Computer Engineering, Materials, and Mechanical Engineering), seven departments of the Division of Mathematical, Life and Physical Sciences (Chemistry & Biochemistry, Earth Science, Ecology Evolution & Marine Biology, Mathematics, Molecular Cellular & Developmental Biology, Physics, and Psychology), as well as the departments of Economics, Geography, and Media Arts & Technology from the Division of Humanities and Social Sciences. In addition, the system supports research in eight campus centers: Allosphere Research Facility, the California NanoSystems Institute, the Center for Polymers and Organic Solids, the Institute for Crustal Studies, the Kavli Institute for Theoretical Physics, the Materials Research Laboratory, the National Center for Ecological Analysis & Synthesis, and the Neuroscience Research Institute.
The new system will be housed in the same location as the previous one where the same successful administrative and maintenance procedures used for the past six years will be applied. The proposed cluster will be accessible via the UC Grid, a web portal interface that makes high performance computing resources easy to use from desktop machines (PCs or Macs). The acquired system will come with a three-year warranty. Prior experience has shown that only a small number of nodes are expected to malfunction during the useful lifetime (> 3 years) of the cluster.
Broader Impacts:
The research enabled by the campus-wide facility, interdisciplinary and collaborative in nature, is available to the broad research community. The large majority of users, roughly 75%, consists of postdocs, graduate students, and undergraduates (5%), allowing this award to accomplish NSF's longstanding goal of integrating research and education. Outreach to K-12 takes place via a new initiative, The School for Scientific Thought (SST), an extension to the Let's Explore Physical Sciences (LEAPS) Program. Under the SST Program UCSB science and engineering graduate students design and teach a course for an audience of high school students on Saturdays. In addition, many of the faculty associated with this proposal participate in the UC Leadership Excellence through the Advanced Degrees program that has increased the number of underrepresented students in science and engineering at UCSB.

The Chemistry of Life Processes Program in the Division of Chemistry is supporting Professor Norbert Reich of University of California Santa Barbara to investigate how cellular proteins locate specific positions on DNA. It is well known that DNA stores genetic information that is transcribed and translated within cells in other biological molecules and that underscores the life of every cell. The "reading and interpretation" of the DNA information require and are modulated by interactions with other molecules in the cell, particularly proteins. The search by proteins of specific locations on DNA is challenging because DNA appears very uniform. This proposal focuses on how the proteins identify specific locations on DNA to bind to and then how they translocate on the DNA to which they are bonded. This work will have a broader impact on scientists' ability to determine how the information stored in DNA is productively interpreted, which is a process common to all cells. It is having further impact on the education of the next generation of scientists, both undergraduate and graduate students, capable of recognizing and addressing scientific issues relevant for human health. Furthermore, Professor Reich and his students actively engage in activities aimed at explaining to broad audiences how science works and what benefits science brings to society.

Proteins that act on DNA are responsible for the vast majority of the functions of DNA. The overarching goal of this proposal is to provide a deeper understanding of one such protein, the bacterial DNA adenine methyltransferase (Dam, modifies 5'-GATC-3'). The ability of Dam and related enzymes to carry out multiple cycles of catalysis (processive catalysis) is critical to their biological roles. Yet, current models of processive catalysis are based largely on enzymes faced with entirely different biological challenges and do not account for the characteristics of these enzymes. For example, DNA methyltransferases efficiently modify multiple recognition sites with highly variable intersite distances, and this processivity is modulated by interacting proteins and DNA sequences that flank the target sites. The aims of the research are to investigate the mechanism, regulation, and in vivo importance of processive catalysis by Dam. Several strategies will be pursued to address broadly relevant and unanswered questions of how Dam and other proteins act processively with DNA substrates over intersite distances beyond the ones predicted by conventional models, how some proteins, such as Dam, rely on intra-segment transfer to efficiently move large distances, and what is the mechanism whereby the monomeric Dam modifies both strands of DNA without leaving the DNA.

Frank Brown of the University of California - Santa Barbara is supported by an award from the Chemical Theory, Models and Computational Methods program of the Chemistry Division for research that is helping us understand the structure and function of the molecules that make up the membranes that enclose all the cells in our bodies. These membranes, a combination of fat-like molecules, cholesterol and proteins, are complex entities across which food and other substances enter our cells while wastes and cellular products exit them. The investigators are studying the ways these events occur at a fundamental physical and chemical level. They are, thus, promoting the progress of science and having an impact on a wide array of scientific topics involving the healthy functioning of living things. The research is having a further broad impact through the training of the next generation of scientists, both in the investigator's research laboratory and through the distribution of software that results from this work. In addition, the investigators are helping to coordinate outreach programs at the UCSB institution that seek to involve elementary school students in science and encourage them to consider careers in the STEM disciplines.

The investigators are developing theoretical models, numerical methods and simulation algorithms for the study of lipid bilayers, lipid and surfactant monolayers and DNA-modifying enzymes. In particular, field-theoretic models for membrane structure are being refined at two different levels of description suited to long-wavelength undulations and short-wavelength lipid tilt/thickness deformations. The investigators are generalizing the interfacial regularized Stokeslet methodology previously developed by this group to incorporate compressibility and viscoelastic effects. In a third project, the investigators are extending their analysis methods to the development of improved kinetic schemes to analyze enzymatic turnover in DNA-modificication. A number of applications of this work are expected, including: (1) extracting quantitatively accurate values of membrane bending moduli from molecular simulations; (2) interpreting NMR measurements on lipid bilayers; (3) interpreting interfacial microbutton rheology measurements; (4) relating membrane elastic properties determined via measurements taken at vastly different length scales; (5) quantifying the influence of periodic boundary conditions on simulated dynamics in lipid bilayers; (6) elucidating the kinetics and processivity of DNA modifying enzymes; and (7) understanding thickness fluctuations in lipid bilayers and their influence on neutron scattering experiments.

The Biophysics Program in the Division of Molecular and Cellular Biolosciences (MCB) in Biosciences Directorate (BIO) and the Condensed Matter and Materials Theory Program in the Division of Materials Research (DMR) contribute to this award.

This project, acquiring a computer cluster (mini-supercomputer) to replace the old one, aims to serve the computational needs facilitating scientific research and education in multiple areas. The machine includes 120 node Infiniband interconnected cluster for efficient message passing interface (MPI) parallel processing, four shared memory "fat nodes" with 1 Terabyte (TB) of memory/node, four graphic processing unit (GPU) nodes built around NVIDIA Tesla P100 1 Gigabyte (GB) GPUs, and four Intel Knight's Landing nodes. This blended system will serve the computational needs of the vast majority of campus researchers. This system will also service users needing large-scale resources by allowing development, prototyping, and benchmarking calculations locally, prior to production runs at supercomputer centers.

The research enabled spans multiple departments and supports research in many campus centers including AlloSphere Research Facility, the California Nanosystems Institute, the Center of Polymers and Organic Solids, the Earth Research Institute, the Kavli Institute of Theoretical Physics, the Marine Science Institute, the Materials Research Laboratory, and the National Center for Ecological Analysis and Synthesis. This interdisciplinary and mainly collaborative research will be facilitated by the presence of an available local facility, without the administrative hurdles and delays associated with application to supercomputing centers.

Broader Impacts:
The cluster is expected to play a prominent role in educating the next generation of scientists, engineers, and mathematicians. The NSF Integrated Graduate Education and Research Traineeship (IGERT) program in Network Science and Big Data will also employ the cluster that will additionally be utilized by undergraduates, high school, and community college students and K-12 teachers via existing sponsored programs. It will also contribute to attract others students and researchers. Furthermore the facility will service graduate participants in the University of California Leadership Excellence through Advanced Degrees (UCLEADS) and the Bridges to Doctorate programs. These programs help increase the number of under-represented students involved.

With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding Dr. Norbert Reich from the University of California at Santa Barbara to understand how proteins scan DNA in order to find specific sites for action. This process is essential to all known cellular systems. A new idea about how this happens is that enhanced motion over large distances requires DNA looping. This highly efficient approach is investigated and modeled using a newly developed theoretical approach. The implications of this work are quite broad as this means of movement is likely to be used by various proteins. This project also supports the development of a university course focused on teaching STEM students how to design experiments through extensive lab work as well as lectures and discussions. Furthermore, the expansion of a large outreach program is proposed (SciTrek) which reaches thousands of K-12 students by bringing trained university students into the classroom for several weeks to guide self-directed investigations on diverse topics.

In studying the bacterial DNA adenine methyltransferase (Dam, modifies 5'-GATC-3'), it was noted that the ability to rapidly modify two or more sites is enhanced when the sites are separated up to 500 bp. Furthermore, current models of processive and distributive DNA modification fail to fully account for the efficient search processes by Dam and other proteins. A new understanding of the underlying mechanism is needed. Aim 1 attempts to answer the question: Do proteins relying on different mechanisms display distinct trajectories away from the DNA? Sliding, hopping, intersegmental transfer and intersegmental hopping mechanisms predict distinct protein movements away from the DNA and anovel experimental approach to address this is proposed. The second aim attempts to answer the question: What is the mechanism of intrasite processivity? How widespread is this activity? Dam as well as several other DNA modifying enzymes modifies both strands of DNA within the same recognition site, without dissociating (intrasite processivity). The third aim attempts to answer the question: Is efficient multisite DNA modification important in vivo? The fourth aim develops and applies quantitative theoretical/numerical tools for analyzing activity-based kinetic assays of DNA modifying enzymes. Particular emphasis is placed on elucidating the behavior of Dam, but additional systems (CcrM, uracil DNA glycosylase) are also studied to test and validate the approach more generally.

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.