• Studies of Classical and Quantum Effects in Gravity
  Awarded $32,198 for the period 4/2/07 to 6/30/08
  Source: National Science Foundation

  Current cosmological observations imply that the universe may have recently begun a second period of exponential expansion. This project addresses several questions with implications for accepted theory. First, it will study whether quantum fluctuations in the density and pressure of matter and radiation might be unstable during such a period, which would have serious consequences for the fate of the universe. The semi-classical approximation to quantum gravity, at the foundation of most models of inflation, would be invalid during at least part of this period and would have to be replaced by some more sophisticated theory.

  Second, the project will study whether quantum fluctuations would be large enough to invalidate the types of calculations that have previously predicted the amount of particles produced at the end of inflation in popular chaotic inflationary models. The amount of particle production determines the temperature to which the universe reheats after it finishes inflating, which largely determines its evolution.

  Third, the project will develop a new method to compute the self-force of a particle orbiting a nonrotating black hole and emitting scalar radiation. If successful, it could be generalized to the realistic case of a particle orbiting a rotating black hole and emitting gravitational radiation. One of the primary sources of gravitational waves for a space-based detector, like LISA, is a compact object spiraling into a super massive black hole. Its trajectory is necessary to get the waveform for the gravitational waves that are emitted and can be obtained by solving the radiation reaction problem in gravity. To date, the self-force has only been computed in cases of high symmetry, such as circular orbits or radial infall.

  Fourth, the project will investigate the important case of zero temperature black holes. Due to the Hawking effect, black holes radiate and can be assigned thermodynamic properties, such as temperature and entropy. Quantum effects can alter the spacetime geometry near the event horizon to change its temperature and entropy.If the project finds that zero temperature black holes cannot exist, results will have important consequences for black hole thermodynamics.

  Finally, the project supports undergraduate and graduate student training in both numerical and analytical research techniques.

Keith Bonin

• with Eugeny Budyain, Physiology
  Mathematical modeling of subsecond dopamine fluctuations in rat brain
  Awarded $12,500; $6,250 Reynolda campus, $6,250 Health Sciences
  Source: WFU Cross-Campus Collaborative Research Support Fund

  The origin and functional significance of phasic dopamine transmission in an intact mammalian brain is not clearly understood. This project aims, first, to develop a mathematical model for the patterns of subsecond dopamine fluctuations in brain areas that are essential to the circuitry involved in addiction. Second, a micromotor-driven manipulator with several significant advantages over current manual manipulators for obtaining data from ambulatory mammals will be developed. Results will offer critical insights into the neurobiology underlying drug abuse and inform the development of therapeutic agents for addicts.

• Optical Torquing and Nanofluidics
  Awarded: $49,771 for the period 1/1/05 to 12/31/06
  Source: Research Corporation

Research and technology are driving toward smaller scales in hope of creating faster and more powerful computers, more sensitive and accurate environmental and biological sensors, less invasive medical instruments, and more effective medicines. This project will use laser light to trap and to manipulate very small cylindrical rods or tubes, rotating them and placing them on specially prepared surfaces that will change their electrical properties. Watching how their rotation changes as they move close to a surface will elucidate surface interactions. The project will also study how the properties of the surrounding medium (water, dilute solutions of flexible rods) change the nanorods’ rotation. This research will aid novel nanodevice development, lead to a new understanding of nanofluidic flow near surfaces, and stimulate and guide experimental and computational work by others.

• Targeting the Glycocalyx (capsule/exopolysaccaride) to Reduce Bone/Implant
  Related Infections
  Awarded $39,696 for the period 7/1/06 to 6/30/08
  Source: Orthopaedic Research Education Foundation

  NANOTECH will collaborate with WFU Health Sciences’ Department of Orthopedic Surgery.

• Novel Carbon Nitride (CNW) Conjugates for Breast Cancer
  Awarded $91,055 for the period 8/15/06 to 8/14/07
  Source: Department of Defense, Congressionally Directed Medical Research Programs (CDMRP)

Recently, single-walled carbon nanotubes (SWNT) and Ag nanoshells have been shown effective in photo-ablating cultured cells. In both cases, penetrating infrared light generates heat in the nano-object to raise the temperature in surrounding cells. While promising, the applicability of these approaches to real therapeutics is limited because, in both cases, high amounts of light are required to initiate cell death in tissues. Further, these nanocarriers lack specificity or targeting modalities.

Carbon-based nanoparticles can be chemically modified to selectively target breast cancer cells, and when coupled to carbon nitride nanotube variants, the resulting conjugates can be activated to photo-ablate tumors with an extraordinarily small amount of power. This program will test the concept that carbon nitride nanowires (CNWs), conjugated to Herceptin, a therapy for certain breast cancers, can selectively target and photo-thermally ablate HER2-positive breast cancer tissues, using penetrating near-infrared radiation. Initial results suggest that CNWs are far superior to SWNTs or silver nanoshells due to their metallic nature and aspect ratio. This unique property of CNWs opens a new therapeutic application at depths more clinically relevant than the simple subcutaneous limits of previous approaches and with reduced dermal injury. They can also carry multiple functionalities, such as contracting agents, for imaging the target area, which will allow them to be locally activated.

• Assessment of Status and Opportunities in Nanophase Transition Metal Oxide Coatings for Air Pollution Control and Mitigation
  Awarded $15,000 for the period 7/20/06 to 11/21/06
  Source: Environmental Protection Agency (EPA)
  The project will generate a report on the state-of-the-art in nanoscale photocatalytic coatings based on transition metal oxides. This analysis of the literature and intellectual property should answer the following questions:
  • What advantages does nanotechnology offer in developing efficient photocatalysis of pollutants?
  • What mechanisms benefit from small size, surface proximity, high fields, defect exclusion, surface trapping, and extended coherence of excited states?
  • Can nanotechnology enhance cross-sections, separate charges, or mitigate well-known tendencies toward poisoning of the catalyst in realistic environments?
  • Can we conclude that current engineering technologies for broad area thin film fabrication are sufficient for practical implementation of such nanophase materials?
  The answers to these questions will identify both the opportunities and bottlenecks to implementing such technologies in air pollution control/mitigation. The project will significantly enhance EPA’s knowledge base in this important science field, and the product will serve the strategic planning process as a screening tool for future research and future NCER and SBIR solicitations.


• Self-Assembled Soft Optical NIMs
  Awarded $115,677 for the period 10/1/06 to 9/30/07
  Source: Air Force Office of Scientific Research (AFOSR), Multidisciplinary University Research Initiative (MURI)


Negative Index Materials (NIMs) promise a wide variety of exciting applications, such as flat, apertureless lenses; “perfect” lenses with subwavelength resolution; novel antennas; new beam-steering devices; sensor protection strategies; novel band-gap materials; and high-density optical storage. They do not occur in nature, but inherent obstacles have been overcome by the use of specially constructed resonant structures, such as split ring resonators, that have large negative magnetic susceptibility in the frequency range of interest. To avoid scattering, their linear dimensions must be smaller than a wavelength. Their tremendous scientific and technological potential has generated great interest in VIS NIMs, which operate in the visible range of the spectrum, but none have been yet realized, due to the difficulty of creating the appropriate resonant structures on the required nanometer lengths.

The multidisciplinary team aims to realize NIMs in the VIS-IR range. The materials will consist of oriented dispersions of metallic nanoparticles, forming a liquid crystal phase, in a host matrix that may also be liquid crystalline. They will be created via self-assembly of the nanoparticles with functionalized surfactant/tethers and processed to form large, thick, 3D films. This strategy will optimize the materials’ response to competing factors of index magnitude, loss, dispersion, and anisotropy. As liquid crystals, these NIMs will be soft and responsive, allowing easy processing and switching.

• Charge-Transfer Nanocomposites: The Effects of Scale Hierarchy
  Awarded $151,000 for the period 1/1/06 to12/31/06
  Source: AFOSR
  
  
  This research program will first quantify charge-transfer mechanisms and time scales relevant to nanoparticulite/electro-active polymer blends (charge-transfer nanocomposites). These features will be correlated with induced morphological modifications, modifications to optical absorption cross-sections, and localization effects. The program will then examine electronic and optical phenomena associated with degrees of matrix order and disorder, or scale hierarchy, to determine if nanotube/host interactions are modified when the nanoparticles are ordered over length scales commensurate with polarons/excitons or the wavelength of incident light. Finally, the program will integrate nanotube-based matrix composites into organic photovoltaic devices and organic optical sensing devices, such as CCDs (charge-coupled devices), which are used in digital and video cameras and optical scanners, and photodiodes.

• with Joel Stitzel, Biomedical Engineering, WFUSM
  Development of Electrospinning Apparatus for Tissue Engineering
  Awarded $ $14,700 for the period 5/6/05 to 5/15/06
  Source: WFU Cross-Campus Collaborative Research Support Fund

The team aims to purchase a negative pressure glove box with an antechamber and to fabricate an electrospinning apparatus for the development of vascular scaffolds. These vascular scaffolds, when seeded with endothelial or other appropriate cells, hold promise as vein and potential organ replacements. The investigators propose (1) to generate vascular scaffolds from several types of protein components by electrospinning; (2) to optimize the synthesis of these scaffolds; and (3) to test the mechanical strength, biocompatibility, and biochemical characteristics of the synthetic scaffolds compared to decellularized scaffolds or native vascular vessels.

• Agile Response Coatings
  Awarded $1,443,000 for the period 4/1/05 to 3/31/08
  Source: AFOSR

For twenty years, US forces have increasingly been required to respond to asymmetric situational threats, and Air Force technologies must perform multirole surveillance and tactical tasks. Reliance on slower, long-term, unmanned platforms with search-and-destroy capabilities like the Global Hawk system and stealth insertion using manned vehicles like the F-117 and B-2 demands agile coloration that can sense ambient thermal and lighting conditions; novel materials solutions to deterioration in aging and long-term deployed systems; and the ability to monitor all operational aspects of vehicle integrity, including structural and air frame components during flight.

The Agile Response Coatings (ARC) program aims to develop a single coating system that biomimetically responds to its surroundings and airframe integrity, using sensing and electromagnetic modulation technologies based on novel nanostructured materials. The program has four specific task areas:

1. Electromagnetic Modulation. Novel electrochromic polymers will be coupled with metamaterial functionalities, agile coloration, and reflective technologies to respond to ambient thermal, lighting, and threat conditions in real time.
2. Sensor Embed Technologies. Nano-engineered material will be used to create novel, high-sensitivity sensor systems with self-diagnostic functions, including the ability to sense strain, corrosion, and IR, locally and globally, and pressure transduction.
3. Macro-electronic, distributed connectivity. Organic macro-electronics will create a networked interconnectivity among sensors, allowing the coating system to respond autonomously to a wide variety of stimuli.
4. Tangential functionalities. Several tangential functionalities will be added to the coating system, including corrosion retardation and active vibration damping.

The program teams Dr. Carroll with investigators from the University of Florida and New Mexico State University and corporate partners Foster Miller, Inc., and International Technology Corporation. Coordinated through WFU, each site is responsible for developing and integrating a component into the final coating system. The “distributed” management structure will enhance synergistic and shared activities among team members and rapid response to scientific developments.

Gregory Brown Cook

• Quasi-equilibrium BH-BH and NS-BH binary Initial Data
  Awarded $35,000 for the period 11/1/07 to 10/31/08
  Source: National Science Foundation
  The collision of a pair of compact objects, either black holes or neutron stars, is a dramatic event that gravitational wave observatories, such as LISA and LIGO, hope soon to detect. The simulations to be performed in this project, starting from compact binary initial data, will provide the theoretical foundation for interpreting much of the data these observatories obtain. This work aims to improve the techniques and numerical tools for constructing compact binary initial data, to explore the space of interesting solutions, and to train undergraduate and graduate students.

  Aims include:
  1. to test current methods for constructing equal-mass binary black hole initial data sets and to extend them to the construction of unequal-mass initial-data sets;
  2. to construct a new, more efficient, and easier to use code for these initial data sets, adding the ability to deal with neutron stars as well as black holes;
  3. to develop the first consistent quasi-equilibrium initial data sets for binary systems containing a neutron star and a black hole; and
  4. to extend current initial data techniques to the computation of quasi-equilibrium “conformal three-geometry,” considered the last major obstacle in constructing astrophysically realistic compact binary initial data.

Jacquelyn Fetrow (see also Computer Science)

• Integrin Function in Cartilage
  Awarded $7,636 for the period 8/1/07-7/31/08
  Source: National Institutes of Health/WFU Health Sciences

  Results of these studies will provide new information needed to understand the molecular mechanisms by which signals generated by chondrocyte integrin receptors regulate the production of enzymes that cause excessive degradation of the cartilage matrix in arthritis and provide novel targets to inhibit the destruction.

• Integrated Process for Functional Site Feature Analysis
  Awarded: $167,800 for the period 8/1/07 to 7/31/08, Year 3
  Source: NSF

  Sequence and structural genomics projects have identified and predicted molecular functions in proteins, yet researchers still cannot determine the biological mechanisms of, for example, catalysis or substrate specificity or inhibitor binding, without detailed biochemical and biophysical analysis of each protein. While structural genomics projects are providing the necessary data, they are not being used to reveal the general principles underlying biological mechanism.

  This project uses sequence, structure, bioinformatics, and biophysical to characterize the molecular function sites of 6 protein superfamilies, with the following objectives: 1) characterizing the sequence and structure of functional site features and using the results to develop methods for clustering the peroxiredoxin family; 2) analyzing the electrostatics at peroxiredoxin functional sites and testing them experimentally; 3) integrating electrostatic, sequence, and structural information to create a robust profiling method that can identify peroxiredoxin subfamilies; and 4) using it to create active-site signatures and profiles for a well-studied and important set of protein superfamilies. The data will be made widely available.

  This detailed functional site analysis of 6 superfamilies will yield insights into biological mechanisms, leading to hypotheses that can be experimentally tested. In the long term, the methods will enable more accurate functional site identification from sequence. The development of general concepts for identifying and classifying molecular functional site features will advance the design of enzymes with improved, altered, or novel activity and inhibitors (or lead compounds), an early step in the drug-discovery process. Students involved in this project will gain cross-disciplinary molecular biophysics training that will fuel successful scientific careers. In addition, the project informs a new interdisciplinary molecular biophysics course in which students are introduced to computational methods and work to interpret data in terms of protein structure. Graduate and undergraduate students from biochemistry, biology, chemistry, and physics as well as researchers from a local biopharmaceutical company studied the peroxiredoxin family in this course and were introduced to the ideas and communication skills necessary in an interdisciplinary research project.

• with Elizabeth Hiltbold, Microbiology and Immunology, WFUHS
  Modeling Networks of Dendritic Cell Maturation Induced by Bacteria
  Awarded $20,000 for the period 5/06 to 5/07
  Source: WFU Cross-Campus Collaborative Research Support Fund

Dendritic cells (DCs) are uniquely qualified to activate naive T cells because of their ability to sense and to capture pathogens, to degrade them within the cell, and to present their antigens on the cell surface. In a process known as maturation, DCs are transformed from poor T cell stimulators to highly potent T cell activators through a series of morphological and functional changes. This process is tightly regulated at the transcriptional level, and while several aspects have been well characterized, the program that drives it remains unclear, especially in response to intact, live bacteria, a physiologically relevant stimulus.

Most bacteria express a variety of components that stimulate several pattern-recognition receptors, and many are able to access distinct groups of receptors at several intracellular sites, including the plasma membrane, phagosomes, and even cytoplasm. The PIs hypothesize that the interactions between multiple pattern-recognition receptors that are triggered by live Listeria are critical for maximal activation of antigen-presenting cells.

Microarray technology is a powerful methodology for systemically studying the time-course of global changes in many biological systems. The project couples this technology with computational biology to develop network models of functional classes of genes expressed when bacterial infection induces DC maturation. Completion of the two specific aims will provide the preliminary data and framework models of DC maturation necessary to develop a competitive R01 application.

• with Jason Grayson, Microbiology & Immunology, WFUHS
  Computational Modeling of Reactive Oxygen Intermediate Signaling in CD8+ T Cells
  Awarded $15,000 for the period 5/6/05 to 5/15/06
  Source: WFU Cross-Campus Collaborative Research Support Fund

  CD8+ T cells are critical for clearing viruses, tumors, and certain bacteria. Understanding the molecular mechanisms that control these cells’ proliferation and death is critical for optimizing HIV and cancer vaccines and developing treatments for autoimmunity. Recently, the team demonstrated that treatment with MnTBAP, an anti-oxidant, reduces both the expansion and contraction of antigen-specific CD8+ T cells in vivo during viral infection. With treatment, proliferation decreased ten-fold, while the contraction phase was almost completely blocked. This result demonstrates that increased immunological memory can be generated from a smaller expansion of virus-specific cells. Despite these intriguing results, the molecular mechanisms by which reactive oxygen intermediates (ROI) affect proliferation and death have not been determined.

  The team hypothesizes: (1) cellular proliferation pathways are very sensitive to ROI levels, but activating death pathways requires a higher and chronic level of stimulation; and (2) different levels of ROI induce different redox responses that can be identified as part of a biological network. These hypotheses will be tested by (1) identifying cellular proteins oxidized at cysteine residues by high- throughput proteomics following T cell activation in vitro; and (2) developing framework models of the proteins involved in redox signaling networks in antigen-specific CD8+ T cells and compaing their topologies for different incubation conditions and different segments of the culture cycle.

• with S. Bruce King, Chemistry
  Profiling of Redox-Sensitive Signaling Proteins
  Awarded $18,478.36 for the period 5/1/06 to 4/30/07
  Source: NIH

  Reynolds Professor Fetrow will direct the bioinformatics component of this ambitious project to devise large-scale methods to identify proteins that respond to cellular redox changes. The team aims to integrate analytical protein chemistry, cell biology, and bioinformatics to test the hypothesis that redox signaling affects the initiation of cell proliferation and transformation. Successful development of this technology will lead to future broad-scale research with implications for cancer prevention and treatment.

• Algebraic and Statistical Models of Redox Signaling
  Awarded $254,488 for the period 4/1/07 to 3/31/08, Year 3
  Source: NIH

  An interdisciplinary research group spanning the Reynolda and Health Sciences campuses aims to develop theory, algorithms, computational tools, and research methodologies for network modeling of redox-regulated events in human cells. Recent research indicates that redox-regulated networks are central to cellular communication under a variety of normal and diseased conditions, including cancer, neurodegenerative diseases, and aging. This project will (1) identify a comprehensive set of cellular proteins modified at cysteine residues as a result of redox-dependent signaling; (2) correlate the concentration of a given cellular perturbant and its associated redox signal; 3) associate networks with particular perturbants; and 4) produce both topological and dynamic models of the cellular network associated with these pathways. These models will then be compared to other data on protein/protein interactions and kinase cascades to produce a more comprehensive model of cellular regulation and its biological outcomes.

Martin Guthold

• Determining the Mechanical Properties of Single Fibrin Fibers
  Awarded $225,000 for the period 7/01/07 to 06/30/10
  Source: National Science Foundation

Blood clots perform the essentially mechanical task of stemming blood flow. However, the mechanical properties of clot constituents are largely unknown. Besides platelets, which initially aggregate at the site of a wound, the major structural component is a branched network of fibrin fibers. A novel technique, combining atomic force and fluorescence microscopy in a single instrument, will be used to systematically study the mechanical properties of single fibrin fibers and a variety of mutants under a variety of conditions.

• Viscoelastic properties of fibrin fibers
  Awarded $10,000, Spring 2007
  Source: Science Research Fund

  The mechanical properties of blood clot constituents are largely unknown, which has seriously hampered our full understanding of clotting and development of good models. Their major structural component is a network of fibrin fibers that critically depends on the fibers’ mechanical properties and the properties of the junctions between fibers. Little is known about these nanoscopic features because a good technique to study them has been lacking. This project aims to develop a novel technique, combining atomic force and fluorescence microscopy, to study the mechanical properties of single fibrin fibers. The tip of the atomic force microscope (AFM) will be used to laterally stretch fluorescently labeled fibrin fibers that are suspended across channels in a striated substrate, while the fluorescence microscope images this process. This experimental design yields a well-defined, easy-to-analyze geometry ideal for measuring stress-strain curves of fibrin fibers. The 16 viscoelastic characteristics of fibrin fibers that define their mechanical behavior will be quantified for several parameters, such as temperature and fiber radius. Fibrinogen variants will provide insights into their molecular mechanisms and the fibrin-fibrin interactions that affect them. This pioneering technique should apply to many biological and nonbiological fibers and provide an entirely new understanding of blood clots, heart attacks, strokes, and related diseases. The project will include two graduate and three undergraduate students.

George Holzwarth

• Kinesin Force-Velocity in Curves when 1, 2, or 3 Motors Transport a Single Load
  Awarded $5,013 for the period 8/1/07 to 7/31/08
  Source: National Institutes of Health (NIH)

  The project’s long-term objective is to elucidate, at the molecular level, how the motor protein kinesin transports vesicles from a neuron’s cell body to its axon tip, a distance of as much as 1 meter, in only 4 days. The velocity/force relation of one kinesin motor is well understood when the motor is in solution, and the viscous work load on it is small. However, within a cell, the viscolelastic drag force opposing the motor is at least 100 times greater, so 2-5 motors are probably required to pull a single vesicle. Quantitative velocity/force curves have been obtained for 1 kinesin but not for the 2, 3, or more active motors actually needed to pull a single load in vivo, and qualitative data on the effect of multiple motors are contradictory.

  The project will test the hypothesis that 2 or more motors pulling a single cargo will share the load equally. It aims to measure velocity/force curves for 1, 2, and 3 kinesins over a physiologically realistic force range. Using speckled microtubules to provide numerous fiduciary marks along the length of each microtubule will greatly improve the spatial precision of tracking over classical gliding assays, which use uniformly labeled microtubules, and the temporal precision will be 0.1s or better. If the gliding microtubule can be tracked for 5-10s, the pattern of velocity changes will reveal the number of active motors. Force will be generated by viscous drag and magnetic beads bound to the gliding microtubule.

  The exceptional length of some neurons places exceptionally stringent demands on their vesicle transport systems and suggests that some neuronal disease may originate in a transport system failure. Mutations in microtubule motor proteins have been shown to cause disease phenotypes in Drosophila and degenerative diseases of the human nervous system. A more quantitative analysis of multiple motor mechanics will expedite the identification of degenerative diseases associated with defective transport and facilitate rational intervention.

• Kinesin Force-Velocity Curves when 1, 2, or 3 motors transport a single load
  Awarded $20,000 for the period 1/27/06 to 1/26/07
  Source: Dreyfus Foundation

  Dr. Holzwarth is one of 14 national winners of the prestigious Senior Scientist Mentor Award for 2006. Faculty with emeritus status who maintain active research programs in the chemical sciences are awarded grants of $10,000 annually for two years to support undergraduate research under their guidance.

  The maximum force generated by 1 kinesin motor protein molecule in vitro is 7 pN. There is indirect evidence that in cells, several kinesin motors must cooperate to move a single vesicle, because the drag force that must be overcome is 5 pN. We will measure velocity-force curves for 2, 3, or 4 kinesin motors pulling a single load in vitro against a carefully measured viscous or magnetic force.

• Computational Study of Transition Metal Phosphate Materials
  Awarded $143,000 for the period 6/30/04 to 6/29/07
  Source: NSF

  This project will perform a systematic computational study of several crystalline transition metal phosphate materials exhibiting a wide range of interesting physical and chemical properties that are not completely understood. Several are naturally occurring minerals of geological interest; many have various polymorphic geometric and magnetic structures; and some, whose electrochemical properties show technological promise in the battery industry and catalysis applications, have recently generated a wealth of experimental results.

The proposed computer simulations will develop our qualitative and quantitative understanding of these materials' structural and magnetic transformations and properties of technological interest. Because of the special properties of transition metals in narrow band gap materials, some aspects of the proposed calculations will challenge the current state-of-the-art in computational formalism and coding. In particular, their electron/electron interactions are critical for determining the materials' properties but difficult to evaluate accurately. A tangential project will develop a new approach for examining many electron systems based on the knowledge of their electron pair states.

• Computational Tools for Detailed Simulations of Materials
  Awarded $336,000 for the period 7/1/04 to 6/30/09
  Source: NSF

This project aims to develop computational tools for accurate and efficient modeling of the bulk and surface properties of materials for fundamental studies and technological design. The main goals are:

(1) To investigate and to incorporate several new state-of-the-art optimization and iteration acceleration methods into the materials modeling codes, such as the use of surrogate functions and dynamic accuracy techniques;
(2) To develop algorithms and codes for the efficient solution of boundary value problems arising in the study of surfaces and interfaces of materials, incorporating input from bulk simulations;
(3) To share the codes and results with the research community, providing a forum for comparing the accuracy and efficiency of the leading computational methods.

Preliminary results on the use of surrogate functions for structural optimization and the development of surface algorithms are very encouraging. Based on the so-called projector augmented wave (PAW) method of Bloechl, a code for density functional calculations of periodic solids is shared with the electronic structure community from the website http://pwpaw.wfu.edu and through various collaborations. The PAW method combines the best features of pseudopotential and all-electron approaches.

• with Janice D. Wagner, Comparative Medicine
  Effects of Short-Term Hyperglycemia on Arterial and Liver Redox-Active Iron Concentrations
  Awarded $15,672; $6,900 Reynolda campus, $8,772 Health Sciences
  Source: WFU Cross-Campus Collaborative Research Support Fund

  Cardiovascular disease (CVD) is the primary cause of morbidity and mortality in both Type 1 and Type 2 diabetics, and CVD mortality rates are 2-8-fold higher in diabetics than nondiabetics. Only part of the problem can be explained by typical risk factors, such as plasma lipids and blood pressure. This project aims to explain how hyperglycemia influences production of oxygen free radicals in diabetic arteries and how it might contribute to atherosclerosis. Transition metal ions, such as iron or copper, are excellent catalysts for producing free radicals, and iron disturbances have been seen in diabetics. Preliminary results in diabetic monkeys show increases in transition metal-catalyzed aortic protein oxidation in parallel with an increase in atherosclerosis after six months. Using diabetic cynomolgus monkeys, the project will investigate how short-term hyperglycemia affects levels of redox-active iron species in arteries, to determine their involvement in atherosclerotic processes, and liver, which plays a central role in iron metabolism. Redox-active iron species will be measured in intact artery and liver tissues, snap-frozen in liquid nitrogen, and kept at -80°C, using electron paramagnetic resonance spectroscopy. Immunoblot analysis will measure relative amounts of proteins involved in iron storage (ferritin), iron transport, hemoglobin, and heme oxygenase-1 (heme breakdown).

• Effects of Nitrite in Sickle Cell Blood
  Awarded $343,920 for the period 12/1/06 to 11/30/07
  Source: National Institutes of Health

Sickle cell disease is caused by a mutant form of hemoglobin that polymerizes when exposed to low oxygen tension. Polymerization makes the red blood cells rigid so that they block some blood vessels, leading to significant morbidity and mortality. Nitric oxide (NO) is currently being tested as a treatment for sickle cell disease due to its role as a vasodilator among other things. NO is synthesized in blood vessel endothelial cells and diffuses to neighboring smooth muscle cells, where it acts as a signaling molecule, causing muscle relaxation and vasodilation. Sickle red blood cells are also fragile, rupturing during transit. For many years, this hemolytic anemia was not viewed as critical to the disease’sl pathophysiology. However, several groups have now begun to re-examine the consequences of hemolysis and the hypothesis that released cell-free hemoglobin efficiently scavenges NO, causing a deficiency.

This project aims to elucidate 4 mechanisms: 1) How does the hemoglobin mutation lead to increased red blood cell fragility? (2) How does the reduced NO scavenging by red cell-encapsulated hemoglobin compare to cell-free hemoglobin? (3) How does NO react in sickle cell blood compared to normal blood? (4) How can an effective NO response be restored in patients using the anion nitrite? The laboratories participating in this project have recently shown that, contrary to the existing paradigm, nitrite acts as a vasodilator in human circulation, possibly due to an allosterically controlled function of hemoglobin.

The study employs an array of biophysical techniques, including electron paramagnetic resonance spectroscopy, kinetic absorption spectroscopy, laser diffraction, and computational simulations. Techniques have been developed so that these studies can be made on whole blood, to assess physiologically relevant conditions.

• Nitrite and Nitric Oxide in Sickle Cell Blood
  Awarded $103,680 for the period 12/1/07 to 11/30/08
  Source: NIH, Independent Scientist Career Development Award

This career award will reduce Dr. Kim-Shapiro’s teaching and service load so that he can spend greater than 75% of his time on research, which focuses on the effects of nitric oxide (NO) in sickle cell blood. Patients with sickle cell anemia have been shown to have abnormal NO-related vasoactivity due to cell-free hemoglobin scavenging NO. NO therapy may restore normal NO vasoactivity. Recently published data also suggest that NO may upregulate fetal hemoglobin and thereby reduce sickling.

Dr. Kim-Shapiro is also a key collaborator on a study of the NO-donating properties of hydroxyurea, an FDA-approved drug for sickle cell disease. He has participated in some recent studies suggesting that nitrite is converted to NO by deoxygenated hemoglobin and thus serves as a reservoir for NO in the body and will expand his studies to investigate the effects of nitrite in sickle cell blood. Finally, he plans to develop noninvasive imaging tools to study pathology of the microcirculation in patients with sickle cell disease and the effects of therapeutics.

• Effects of Nitric Oxide in Sickle Cell Blood
  Awarded $306,206 for the period 5/1/06 to 4/30/07, Year 5 of 5
  Source: NIH

  The project’s goal is to elucidate the biochemistry and biophysics of nitric oxide (NO) in sickle cell blood and its use as a treatment for the disease. NO may benefit patients as a vasodilator, decreasing red blood cell sickling and sickle cell adherence and improving oxygen transport. However, much of NO biology in both sickle cell and normal blood is not well understood, and previous studies report contradictory results. Results from sickle blood will be compared to those in 1) normal blood, 2) preparations of isolated normal and sickle red blood cells, and 3) purified hemoglobins. A variety of spectroscopic and other biophysical tools, some developed specifically for this project, will include microscopy, ektacytometry, ultracentrifugation, stopped and quench-flow mixing, laser photolysis and diffraction, chemoluminescence, electron spin resonance, nuclear magnetic resonance, and absorption spectroscopy.

Jed Macosko
Generating DNA LOBOS: libraries of one-bead, one sequence using an anchored polymerase chain reaction
Awarded $10,000, Fall 2006
Source: WFU Science Research FundThis project will create libraries in which each “book” is a microscopic bead decorated with hundreds of copies of a unique DNA sequence. These DNA libraries of one-bead, one sequence (LOBOS) will enable a drug-screening method developed by Associate Professor Martin Guthold that uses folded DNA strands called aptamers. In this method, randomized DNA aptamers bind to a drug target, and the one that binds the tightest is amplified for future use. Hundreds of identical aptamers must be grouped together, so they can better bind the target and be properly amplified by PCR (the polymerase chain reaction). DNA LOBOS will satisfy these important requirements.

Richard T. Williams

• Scientific Exchange Program between Latvia and USA: Support of research visits between University of Latvia and Wake Forest University
  Source: US Embassy in Copenhagen

• Evaluation of Birefringence-based PTFE Film Inspection
  Awarded $12,500
  Source: The Gillette Company

  The first stage of this project looked at what light scattering can reveal about bare metal edges. The second will examine light reflected from edges having a Teflon (PTFE) coating. The study will use several techniques that are valuable for students to learn and will be conducted by two graduate students.