David A. Grant - US grants

This proposal outlines the continued development of methodology and theory using carbon-13 magnetic resonance important in the study of biomedical problems. Theoretical work largely deals with diffusional motion of biomedical molecules and model systems required to verify the experimental methods. Spectroscopic developments include slowspinning director alignment of nematic solvents to simulate molecular orienting conditions observed in biologically ordered systems such as membranes. Spectroscopic research will use high magnetic fields to determine subtle conformational features associated with optical centers in isoprenoid molecules. Relaxation data on continuous chain alkanes, model polymers, and biomacromolecules is used to characterize molecular motions of the overall and segmental variety. Solid state NMR methods using both cross polarization (CP) and magic angle spinning (MAS) provide relatively high resolution spectra. Applications primarily to nitrogen-containing compounds, heterocycles, nucleosides, nucleic acid, etc., are planned. Subtle interactions which average in liquid samples can be frozen out in microcrystalline powders for study. Finally, work on site specific 2H/1H isotope ratios and their variations depending upon the compounds' chemical history will be pursued. The effect of various biosynthetic pathways will be explored.

This research project involves the development of experimental methods for detecting less receptive nuclei (13C, 15N and 2H) with special emphasis placed on 13C. The application of such methods to biologically important systems and their theoretical consequences are stressed. The value of chemical shifts in structure correlations of liquid samples has been very well documented and these concepts are to be expanded to the full shielding tensor. The three dimensional aspects of shielding tensors becomes one of the significant aspects of the proposal. Solid state work on either powders or single crystals is required to obtain the tensoral shieldings and their principal orientations in the molecular frame. The dipolar interactions, which average to zero in isotropic liquid, also is readily studied in the solid state and its inverse cubic distance dependance contributes valuable structural information. The relaxation of 13C spin multiplets in CH and CH2 groups provides information on molecular diffusional reorientation and these methods are priving to be beneficial in the study of segmental motion in flexible carbon chains. Measurement of deuterium resonance intensities provides a powerful, new method for studying biosynthetic pathway in biologically important systems. Site-specific 2H/1H ratios provide information on not only kinetic isotope effects but retain such historical events locked into the molecular structure for time periods corresponding to the molecules stability. Work will be directed towards the development of single crystal methods for biomolecules of a size not here-to-fore possible. Finally, the development of a high speed link from the spectrometer to a VAX computer is envisioned as a way to store larger (8 M words) free induction signals with a significant improvement in the quality of two dimensional, 2D, spectra. This development aids both our solid and liquid work. The use of 2D methods in NMR have significantly advanced the use of NMR methods in biomedical fields.

This grant from the Organic Dynamics Program provides support for the continuing research of Dr. David M. Grant at the University of Utah. This work will afford new insights into the structures of highly unstable molecular species that will be studied at very low temperatures. Dr. Grant will utilize infrared and nuclear magnetic resonance spectroscopy in combination with quantum mechanical calculations to measure previously inaccessible structural features of highly strained molecules and reactive intermediates. The investigation will focus on species that can only be isolated at cryogenic temperatures in an inert gas matrix. Appropriate doubly labeled precursors will be synthesized using both carbon and nitrogen isotopes in order to maximize the structural information obtained from the spectroscopic studies.

This award will support collaboration between the University of Utah Department of Chemistry (David Grant and Anita Orendt) and the Utah Supercomputing Institute (Julio Facelli), and the University of Buenos Aires Department of Organic Chemistry (Alicia Pomilio) and Department of Physics (Ruben Contreras). The aim of the project is to better understand the electronic structure of flavonoids and related compounds, using 17O NMR and quantum mechanical methods. Flavonoids are natural products of plants native to Argentina, known for their therapeutic effects. It is expected that research results from this project will lead to a rational understanding of the relevant structure-activity relationships of flavonoids and potentially to the discovery of new drugs. The isolation and synthesis of flavonoids and the confor- mational analysis and NMR parameters of these compounds will be done in Buenos Aires. The 0-17 NMR chemical shielding measurements and ab initio calculations of chemical shielding as a function of conformation will be done in Utah. The synthesis of 0-17 labeled flavonoids in Buenos Aires will make the solid state 0-17 NMR studies feasible.

Professor Grant will work on various aspects of the arithmetic of curves of genus two. He will study integer points on these curves, certain units arising from curves of genus two, and new methods for calculating the Mordell-Weil rank of such curves. This project falls into the general area of arithmetic geometry -a subject that blends two of the oldest areas of mathematics: number theory and geometry. This combination has proved extraordinarily fruitful - having recently solved problems that withstood generations. Among its many consequences are new error correcting codes. Such codes are essential for both modern computers (hard disks) and compact disks.

This award supports the research of Professor Grant to work in number theory, specifically, the theory of Gauss sums. Gauss sums are ubiquitous in number theory, playing a role in class field theory. The argument of the quadratic Gauss sum was found by Gauss himself in 1805 after a four-year search. No progress was made on the arguments of cubic Gauss sums for 170 years, when Cassels and Mathews related the argument to elliptic functions. Professor Grant proposes to study the argument of quintic Gauss sums using the arithmetic of curves of genus 2. Specifically, he plans to apply his previous work on the arithmetic of curves of genus 2 and their Jacobians. This is research in the field of number theory. Number theory starts with the whole numbers and questions such as the divisibility of one whole number by another. It is among the oldest fields of mathematics and it was originally pursued for purely aesthetic reasons. However, within the last half century, it hlas become an essential tool in developing new algorithms for computer science and new error correcting codes for electronics.

This research project involves the development of experimental methods for detecting less receptive nuclei (13C, 15N and 2H) with special emphasis placed on 13C. The application of such methods to biologically important system and their theoretical consequences are stressed. The value of chemical shifts in structure correlations of liquid samples has been very well documented and these concepts are now being developed in the full shielding tensor. The three dimensional aspects of shielding tensors becomes one of the significant aspects of the proposal. Solid state work on either powders or single crystals is required to obtain shielding tensors and their principal orientations in the molecular frame. Use of tensor data along with theory is advancing our understanding of the origins of chemical shielding and its use in shift structure correlations. The expansion from one isotropic shift to six tensor parameters in solids provides details unavailable in isotropic liquid shifts. Thus, work will be directed towards the development of single crystal methods for biomolecules of a size not here-to-fore possible. The dipolar interactions, which averages to zero in isotropic liquids, also is readily studied in the solid state and its inverse cubic distance dependence contributes valuable structural information. The relaxation of 13C spin multiplets in CH, CH2 and CH3 groups provides information on molecular diffusional reorientation and these methods are proving to be beneficial in the study of segmental motion in flexible molecular chains. the increased use of multidimensional NMR methods is increasing the need for coupled relaxation methods and analysis tools which properly account for complex relaxation effects arising in coupled spin systems. the detailed treatment of model systems has now advanced to the point where these concepts and methods may be applied to small peptides of biological importance to determine the importance of molecular motion on functionality. The use of 2D pattern recognition methods in NMR are significantly advancing the use of NMR methods in biomedical fields, and the use of these methods for characterizing important natural products is being investigated. Use of such methods in the 2D INADEQUATE experiment have reduced the required sample size requirements by better than ten fold.

9314428 Grant From 25 June to 1 July 1994, the University of Colorado will host on its Boulder campus a conference entitled: "Symposium on Diophantine Problems in honor of Wolfgang Schmidt's 60th Birthday." Diophantine Problems are of three types: 1)Diophantine equations, which ask how many and which whole numbers satisfy given polynomials equations with whole number coefficients; 2)Diophantine approximation, which at its base asks how well real numbers can be approximated by ratios of whole numbers; and 3)Diophantine geometry, which studies the number of regularly spaced points within certain geometric objects. Recently some remarkable results have been established in these fields, and it seems an appropriate time to bring together the leading mathematicians in these areas, so that they can interact with each other and disseminate ideas to young researchers. It is a happy coincidence that this era of rapid progress coincides with Schmidt's 60th birthday. ***

9601580 Loh, Eugene C. DeTar, Carleton University of Utah Academic Research Infrastructure: The Purchase of a Scaleable Parallel Computer to Complete the High End Computing Infrastructure This Academic Research Infrastructure award supports the acquisition of a high speed SMD computing systems operating at a peak speed of approximately 15 GFLops. The research projects supported by the equipment include: 1. Astrophysics research in simulation of cosmic ray cascades. 2. Numerical simulations of strong nuclear interactions. 3. Molecular structure simulations. 4. Quantum chemistry. 5. Applied seismology. 6. Advanced materials including nanostructures and electronic properties of solids. 7. Atmospheric physics.

This is an application for a planning grant of $10,000 to join and existing NSF Industry/University Cooperative Research Center for Pharmaceutical Processing, established at Purdue University with an affiliated site at the University of Connecticut. This application is from four faculty members in three departments, Pharmaceutics, Food Science and Nutrition, and Chemistry, at the University of Minnesota. This application stresses the fundamental understanding, at the molecular level, the effects of processing on critical quality attributes of pharmaceutical products and in minimizing validation requirements through improved process monitoring. The plan is to recruit six additional industrial companies to become members of the Center, to prepare a descriptive brochure, and to participate fully in the Center's activities.

The University of Minnesota-Twin Cities is joining the existing Industry/University Cooperative Research Center (I/UCRC) for Pharmaceutical Processing Research established at Purdue University with affiliated sites at the University of Connecticut and the University of Puerto Rico. The University has established expertise and industrial connections in several areas of pharmaceutical processing. This application stresses the fundamental understanding, at the molecular level, of the effects of processing on critical quality attributes of pharmaceutical products and in minimizing validation requirements through improved process monitoring.

With this award from the Major Research Instrumentation (MRI) Program, the Department of Chemistry at the University of Utah will acquire a wide-bore 600 MHz NMR Spectrometer. This equipment will enable researchers to carry out studies on a) measurements of chemical shift tensors in natural products, ionic compounds, aerosols and soots, b) quadrupolar interactions in shift tensors and couplings in biologically important molecules, and c) spin exchange in polarized noble gases.

Nuclear Magnetic Resonance (NMR) spectroscopy is the most powerful tool available to chemists for the elucidation of the structure of molecules. It is used to identify unknown substances, to characterize specific arrangements of atoms within molecules, and to study the dynamics of interactions between molecules in solution. Access to state-of-the-art NMR spectrometers is essential to chemists who are carrying out frontier research. The results from these NMR studies will have an impact in a number of areas including drug development and advanced materials.

This research is focused on developing enhanced plasma spray processing capabilities that will enable meeting the advanced materials and manufacturing requirements in two important areas: the emerging fuel-cell industry and advanced thermal barrier coatings (TBC) for engine and power applications. The research is directed at both expanding the science base needed to better understand the process-structure-property relationships critical for these applications, as well as utilizing this knowledge to develop an advanced real-time control system that more directly controls the process physics that determines the resulting microstructure. The benefit will be both in expanding the ability to engineer advanced coating systems as well as improving manufacturing capabilities. Our research approach is designed to bridge the gap between extensive parametric design of experiments studies and more fundamental studies of the process physics involving highly "idealized" conditions, such as single splats on smooth interfaces.
Plasma spray is a high-throughput, economical, low environmental impact process that can be used to custom engineer coating microstructure to meet specific performance requirements. However, fuel-cell and advanced TBC applications, important to improving energy efficiency and reducing environmental impact, require the ability to engineer coating structure and meet manufacturing requirements (yield and variation levels) that are beyond today's current plasma spray capabilities. We focus on these two applications not only because of their importance, but because they involve the same ceramic material (yitria stablized zirconia, YSZ) but with significantly different microstructural requirements. We believe that by basing our development effort on a deeper knowledge of the process-structure relations, we will develop a control system that is generalizable and widely applicable.
This research will be conducted by an interdisciplinary team of academic-industry researchers with expertise in materials, thermal-fluids, controls, manufacturing, and the application areas. We will take a combined modeling-experimental approach in order to better understand the complex process-structure issues under real processing conditions. Research areas include: a) developing a more complete understanding of the underlying physics that determines the process-structure relationships for critical coating features, b) developing non-dimensionalized models to relate the process physics and measurable process characteristics to production objectives such as coating thickness and deposition rate, c) investigating the distributed nature of the process in terms of its impact on coating structure and control requirements, and d) incorporating these elements explicitly into the architecture of an advanced control system. Guided by expertise from our industry co-PI's (GOALI Partners: Siemens-Westinghouse and Engelhard Surface Technologies), we will then evaluate these new capabilities in meeting the fuel-cell and TBC requirements. Building on our record over the past 9 years (50% of 38 undergraduate researchers were from underrepresented groups), we intend to continue actively involving underrepresented groups and undergraduate students in our research.

DESCRIPTION (provided by applicant): This research project involves the continued development (now entering its 5th decade) of basic methods and theory for advancing the use of NMR techniques in relevant biomedical areas for detecting less receptive nuclei with special emphasis placed on 13C and 15N. Earlier work stressed the chemical shift structure correlations of liquid samples and more recently these concepts are being developed in the shielding tensor. The 3D aspects of 13C and 15N shielding tensors and their applications to biological systems are well documented in the publications of our laboratory. Further developments of spectroscopic techniques and their correlation with theory continue to be significant aspects of this proposal. Major developments have been made in experimental techniques for determining shielding tensors on either powders or single crystals and their orientation on the molecular frame. Shift tensors, with their three principal values and three angular orientations, provide information on the symmetry and three dimensional structure of molecules not obtainable from isotropic shifts in liquids. Finished tensor work on aromatic systems and sugars is now being extended to relatively large natural products, nitrogen heterocycles, nucleosides, nucleotides, peptides and their related polymeric oligomers. Capabilities now exist to index and thoroughly analyze powdered samples containing dozens of non-equivalent carbons. Furthermore, theoretical methods have improved to the point where it is possible to discuss structural effects on 13C chemical shift changes under 2.5 ppm for neutral molecules with limited charge polarization present. Recent advances in the Utah NMR laboratory on Ewald potentials reveals a very promising way to treat long range charge polarization mechanisms that can also affect chemical shift components by as much as 50 ppm. This charge polarization mechanism is strongly perturbed by electrostatic fields characterized by long range electrostatic forces that give rise to shift perturbations in highly polar molecules. Calculating fields from interactions of monopolar arrays has long been known to require lattice sums that converge very slowly over long distances. New approaches to this problem are proposed in this renewal. Hence, the work at the Utah laboratory will continue to develop experimental and theoretical methods to be employed in the study of shift tensors in peptides, protein conformational analysis, correlations between biochemical structure and shift tensor data in biological complexes, natural products, and hydrogen bonded interactions.

[unreadable] DESCRIPTION (provided by applicant): The long-term objective of the research described in this application is to determine the physiological and clinical relevance of soluble epoxide hydrolase (sEH) polymorphisms in humans. Numerous studies have shown that sEH is involved in the metabolism of exogenous and endogenous epoxide substrates. Exogenous substrates include mutagenic and carcinogenic epoxides found in our diet. Endogenous substrates include fatty acid epoxides, which regulate vascular tone, and sEH knockout mice have significantly lower blood pressure than do wild-type mice. sEH activity in humans varies by more than 500-fold, however, the mechanisms that underlie this variability remain unknown. Preliminary studies described in this application reveal the existence of at least 6 amino acid variants in the human sEH protein. Based on heterologous expression experiments, we show that at least 2 of these variant amino acids significantly alter the specific activity of the human sEH protein in vitro. These results suggest that sEH activity variability in humans may be partially due to genetic polymorphisms in the sEH gene, and that these polymorphisms may influence an individual's susceptibility or response to exogenous or endogenous epoxides. Based on these preliminary results, the specific aims of this application are to: 1. Construct and further characterize human sEH variant proteins using a heterologous protein expression system, 2. Compare sEH genotypes with sEH enzyme activity and amount in human liver samples, and, 3. Compare sEH genotypes in a group of hypertensive and normotensive humans. These specific aims are designed to test the hypothesis that polymorphisms in the human sEH gene result in an altered sEH phenotype in vitro and in vivo. This work will provide a basis for understanding the mechanistic roles of sEH polymorphisms in determining human disease progression as related to exogenous and endogenous epoxide metabolism.

For this interdisciplinary grant in the mathematical sciences, Grant will spend August 2003-July 2004 visiting the Department of Electrical and Computer Engineering at the University of Colorado at
Boulder to collaborate with their research group in digital communications.

The primary goal is to design modulation techniques for systems with multiple transmit antennas. This modulation is also referred to as space-time coding, and requires the production of sets of complex matrices
which achieve maximal spatial diversity (that is, the difference of any of these matrices has maximal rank). The entries of these matrices are constrained to be so-called constellation points for the modulation scheme.

Grant hopes to build upon recent work of those who have used algebraic number theory to build sets of matrices with maximal spatial diversity whose entries are in constellations for BPSK, QPSK, and rectangular QAM modulation schemes, and to apply algebraic number theory to the design of
space-time codes for other constellations.

This IGMS project is jointly supported by the MPS Office of Multidisciplinary Activities (OMA) and the Division of Mathematical Sciences (DMS).

Abstract

It is expected that future generations of wireless communication
systems will provide a wide variety of services such as voice,
video, high speed data, and interactive multimedia for a variety
of users ranging from the stationary to the highly mobile --- with speeds
ranging from the pedestrian to high vehicular speeds --- and in a wide
range of outdoor (urban downtown to rural) as well as indoor
(homes, office buildings, factories, etc.) propagation environments
commonly encountered in everyday life. Battery limitations in
hand-held devices or laptops and the scarcity of bandwidth relative to the
ambitions of such services dictate the need for designing systems in which
these resources must be used as efficiently as possible.

This project will focus on developing a
mathematical theory of two-dimensional ``space-time'' codes based
on algebraic number theory for reliable, robust and
resource-efficient data transmission over multi-antenna wireless
communication links. Robustness of performance to a variety of
channel conditions will be emphasized by considering general code
design criteria as will problems related to efficient
decodability. Scalable, high performance space-time codes that can
be dynamically adapted to changing channel conditions due to
changes in propagation environments, scattering geometries, and user
mobility will be investigated. Questions of both existence
and construction will be pursued. A new level of generality is
introduced in this project so that knowledge acquired
for code design for one model can be applied to other models.
The long history of mathematics shows that the very level of
generality itself can be a guide to what good codes should look
like.

An award has been made to the University of Connecticut under the direction of Dr. David A. Knecht to acquire a spinning disc confocal microscope to be used for observing living cells in real time. The instrument will allow real-time, fast imaging of cells to study a variety of cellular processes, including motility, auxin transport, vesicular transport, and auxin localization in plants, slime molds, and fish. The microscope will increase viability of cells and allow observations to be made over long periods of time. The institution has strong record in several programs for recruiting underrepresented groups to science, and the instrument will enhance the experiences of students in these programs. Most of the users of the confocal microscope will be graduate students, and undergraduate and high school students will be given demonstrations with the instrument.

DESCRIPTION (provided by applicant): The long-term objective of the research described in this application is to develop analytical,computational and database tools that can be used to rapidly identify the chemical structure of compounds in human biofluids. These analytical and computational tools will be useful for: a) understanding disease mechanisms, b) enhancing the speed of disease diagnosis, and, c) enhancing the accuracy of disease prognosis. Our novel approach is to develop algorithms that predict physical/chemical properties of compounds contained in the PubChem database. The physical/chemical properties chosen are those that can be experimentally measured for any unknown compound by HPLC-mass spectrometry. Compounds in the PubChem database whose predicted properties most closely match experimental properties are returned as the most likely candidates for the unknown. We propose to then validate this system using an in vivo model of multiple sclerosis. Our preliminary data describe the validity of this approach using models developed for predicting retention indices, precursor ion survival curves and collision induced dissociation fragmentation spectra. Based on these promising preliminary data, we propose the following specific aims for this application: 1. Develop computational tools that predict physical/chemical properties for compounds in the PubChem (or similar) chemical database, 2. Integrate these computational tools into a software package (MolFind) that will allow rapid structural identification of unknown compounds in complex biofluids, and, 3. Validate the use of MolFind for global metabonomics using an animal model of multiple sclerosis. By facilitating the rapid structural identification of chemical compounds in clinically relevant biofluids, the tools described here will greatly enhance the ability of metabonomics studies to complement and synergize other areas of biomedical research and ultimately improve human health care.

Overwhelming evidence from education research has shown that active learning instructional techniques generate significantly greater student learning than traditional approaches in undergraduate science, technology, engineering, and mathematics (STEM) courses. To date, though, few college and university faculty employ active learning approaches in their introductory STEM classes. This disconnect between practices with established higher effectiveness and actual classroom teaching is particularly troublesome in mathematics because student success in all STEM disciplines relies on a strong mathematics foundation. This project will investigate environments at six institutions that have successfully improved student learning in the Precalculus-to-Calculus 2 (P2C2) sequence by employing active learning in mathematics (ALM). The results of this work will lead to important strategies for adapting, implementing, supporting, and assessing ALM in P2C2 courses. In order to meet the needs of institutions wishing to improve their mathematics instruction, the project will produce multiple options for implementation based upon case studies of the successful institutions. Overall, the project will benefit the mathematical sciences community by: improving student success in high-enrollment undergraduate courses, better preparing those students who go on to STEM majors, and improving the teaching of future faculty through the mentoring of graduate students. Faculty members at the University of Colorado at Boulder (1624628), San Diego State University (1624639), and the University of Nebraska-Lincoln (1624643) will collaborate with the Association of Public and Land-Grant Universities (APLU) (1624610) to research and advance how to influence and sustain educational change in mathematics departments--ultimately, at national scale.

A fundamental goal of the project is to develop a better understanding of how to enact and support institutional change for implementing ALM in undergraduate learning environments. The underlying research question is: What conditions, strategies, interventions and actions at the institutional, departmental and classroom levels contribute to the initiation, implementation, and institutional sustainability of ALM in the undergraduate P2C2 sequence across varied institutions? Project team members will work as part of APLU's ALM Research Action Cluster to advance understanding of the factors that influence and enhance institutional change as manifested through implementation of models of ALM in the P2C2 sequence. Research will follow a design research methodology linking qualitative and quantitative data collection and analysis to capture the iterative and cyclical processes of institutional change. The project will be carried out in two phases, with Phase 1 consisting of the aforementioned case studies at six institutions and Phase 2 consisting of longitudinal case studies of nine diverse institutions that set out to infuse and institutionalize ALM in the P2C2 sequence. Phase 1 will offer the field a retrospective account of ALM models of change that worked, and Phase 2 will develop theory and insights into the processes by which change focused on ALM can unfold over time, along with the affordances and constraints related to institutional change. The project will proactively disseminate its results and findings across APLU's large network of member institutions and beyond to promote adoption of ALM approaches.