Richard T. Williams - US grants

They propose subpicosecond investigations of the lattice relaxation in certain materials when electron-hole pairs are created by linear or nonlinear absorption of light. Techniques to be used are ultrafast optical spectroscopy and short pulse photoelectron spectroscopy. Problems to be investigated (7 in all) include self-trapping of holes in silver halides and in SiO2.

Desorption of atoms from surfaces is being investigated with ultrafast spectroscopic techniques and surface microscopy. The work should lead to real-time visualization of desorption phenomena down to time scales of 10-13 sec in selected systems. The atomic force microscope is employed to image surfaces of ionic insulators eroded by desorption of substrate atoms. The work seeks to correlate atomically resolved surface defects on compound semiconductors, such as gallium phosphide, with special desorption sites identified in sub-gap laser-induced sputtering. Two-photon ultrafast spectroscopy is used to obtain dynamic data on surface defect states in insulators. Desorption from insulator material surfaces induced by electronic excitation is an important concern in application areas such as component survivability in earth orbit, intense pulsed ion sources for accelerators, sputter erosion and deposition of films, laser ablation, and laser cleaning.

9510297 Williams The program combines femtosecond lasers with atomic force microscopy (AFM) to study the energy conversion of light into atomic displacements in bulk solids and surfaces. Time and space resolved detection of electronic excitation of insulator surfaces by induced change in chemical interaction potentials between the surface and the AFM tip will be investigated. Synchronized short laser pulses with the tip scan are expected to improve aspects of nanomachining with features that introduce chemical specificity into AFM. In addition, high energy, six electron-volt photon pulses of two hundred femtoseconds duration, are used to conduct ultrafast spectroscopy and supporting studies on technologically useful classes of materials that exhibit self-localization of excitations in pure crystals. Materials which have the additional technological advantage of being the best new fast scintillator crystals for high-energy electromagnetic calorimeters and medical imaging will also be investigated. %%% This is a multidisciplinary proposal which spans a broad area of research such as basic studies of the interaction of atoms with light in bulk solids and surfaces, photochemistry, micromachining, and medical imaging. The program combines femtosecond lasers with atomic force microscopy to study the energy conversion of light into atomic discplaments in solids and surfaces. The program has a strong university-industry component and provides opportunity for training students in the basic sciences as well as applied research. The core industrial research collaboration is with AMP Incorporated. ***

9510390 Williams The 13th International Conference on Defects in Insulating Materials will be held July 15-16, 1996 at Wake Forest University. The Conference will focus on wide-gap materials and their defects in bulk and interface regions. A wide range of scientific and technological topics will be covered. The scientific sessions will feature theoretical (computational) methods and experimental techniques for understanding defect physics. Ferroelectric memory materials, gate insulators, blue diode laser materials, and fiber optics are some of the technological problems to be discussed. %%% The 13th International Conference on Defects in Insulating Materials will be held July 15-16, 1996 at Wake Forest University. The Conference will focus on wide-gap materials and their defects in bulk and interface regions. A wide range of scientific and technological topics will be covered. The scientific sessions will feature theoretical (computational) methods and experimental techniques for understanding defect physics. Ferroelectric memory materials, gate insulators, blue diode laser materials, and fiber optics are some of the technological problems to be discussed. ***

9732023 Williams This proposal by Professor Richard T. Williams of the Department of Physics of Wake Forest University describes a research program for the characterization of materials based on far-field optical microscopy. The goal is atomic scale identification and characterization of local and extended defects in inorganic materials. Specific phenomena which will be observed and studied by this technique include local diffusion of adsorbates in zeolites, single molecule imaging of fluorescent dyes in organic host matrices, Cesium 3+ clustering at interfaces of fluoride hosts, 3D mapping GaN/AlN films, and characterization of desorption -induced defects in ionic and semiconducting systems. The proposed work involves new, high-risk, high-payoff research. %%% This proposal by Professor Richard T. Williams of the Department of Physics of Wake Forest University describes a research program for the characterization of materials based on far-field optical microscopy. The goal is atomic scale identification and characterization of local and extended defects in inorganic materials. Specific phenomena which will be observed and studied by this technique include local diffusion of adsorbates in zeolites, single molecule imaging of fluorescent dyes in organic host matrices, Cesium 3+ clustering at interfaces of fluoride hosts, 3dimensional mapping Gallium-Nitride/Aluminum-Nitride films, and characterization of desorption -induced defects in ionic and semiconducting systems. The proposed work involves new, high-risk, high-payoff research. ***

An award has been made to Wake Forest University under the direction of Dr. Anita K. McCauley for the acquisition of a laser scanning confocal microscope that will be used in research and education in biology and physics. The instrument will allow fluorescent imaging in thick tissues in biological samples, and of nanoparticles in various studies in physics. This provides a more three-dimensional view of the samples than available with conventional microscopes. Research projects that will be enhanced include studies of gene regulation of plant proteins, gene expression in bee brains, cellular behavior in insects, and excitable nanostructures in thin films. The institution will establish collaborations with several nearby colleges, including a historically Black college.

DESCRIPTION (provided by applicant): Despite the dramatic impact of rationally-developed, single-agent, 'targeted'therapy with the tyrosine kinase inhibitor imatinib (GleevecTM) in chronic myelogenous leukemia (CML), resistance to targeted therapies is still a significant clinical problem for patients with advanced phase CML and Ph+ ALL, a related but genetically- distinct BCR-ABL-dependent, high-risk lymphoid leukemia. This proposal describes a plan to develop cell-based assays for the systematic identification of drugs and small molecules that synergize with dasatinib, an FDA-approved, second generation, targeted BCR-ABL kinase inhibitor. In this approach, we seek to adapt our well characterized, robust pre-clinical murine leukemia model system to develop methodologies for the rational design of truly synergistic combination therapies. One of the underlying principles is that synergistic agents have different cellular target(s) and mechanism(s) of action, often acquire alternate mechanism of drug resistance, have distinct pharmacokinetic, pharmacodynamic and side-effect profiles, and yet dramatically enhance each other's therapeutic impact. In the context of leukemia therapy, we propose that synergistic drug combinations dramatically enhance initial eradication of leukemic cells, which directly reduces the pool of incipient drug-resistant cells to subsequently emerge during the course of continuous therapy. The central goal of this proposal is to further develop and configure cell-based assays for High-Throughput Screening (HTS) studies, with the goal of identifying known FDA-approved drugs and novel small molecules that will both overcome cytokine-dependent 'protection'and synergize with dasatinib to efficiently induce killing of engineered leukemia cells. Specifically, by incorporating our unique insights of cytokine-dependent, cell- extrinsic drug resistance into our innovative assay design, we aim to characterize existing drugs and discover novel small molecules that pheno-revert leukemogenic cells to their prior dasatinib-sensitive state. Conceptually, novel small molecules discovered in these studies represent unique pharmacological probes targeting pathways that may never have previously been implicated in the acquisition or maintenance of a drug-resistant phenotype. Our specific aims of this proposal include 1) the development of a cell-based, HTS- ready, primary screening assay that will reliably detect synergistic leukemic cell killing , and 2) The development of an efficient and systematic approach for evaluation, validation, and prioritization of active compounds identified in pilot and large-scale cell-based, synergy screening studies. PUBLIC HEALTH RELEVANCE: Despite the success with which modern chemotherapy is able to control many cancers, resistance of even a few residual cancer cells to therapy ultimately leads to clinical relapse and death of many cancer patients. Using well-defined experimental systems, we seek to develop reliable and robust methodologies to efficiently test or 'screen'thousands of existing drugs and new chemicals for their ability to effectively kill cancer cells.

The objective of this program is to strengthen the fabrication capabilities at Wake Forest University (WFU) by acquisition of an electron-beam evaporation system. This instrument will be unique in northwest North Carolina, provide a comprehensive fabrication-characterization infrastructure, and allow investigators to improve the quality and expand the scope of their research and training endeavors.

Intellectual merit: The system will enable researchers to grow single and multilayered non-magnetic, ferromagnetic and organic metals, (doped metal) oxides, nitrides and a wide range of semiconductors. It will advance several nanoscience, nanotechnology, biotechnology and energy programs with the potential to yield transformative applications in organic electronics and spintronics, solid oxide fuel cells, solid electrolytes for Li-ion batteries, high-performance scintillators for homeland security, photocatalytic membranes for water splitting and CO2 reduction, and the study of cell mechanics and protein mobility during neoplastic transformation. Crucial fabrication tasks to realize these advances are limited or impossible due to the current lack of infrastructure.

Broader impacts: The instrument will significantly enhance multidisciplinary cross-departmental research collaborations among groups from WFU, neighboring institutions and small companies. Over 50 students and postdoctoral fellows from WFU, Appalachian State University, Winston-Salem State University, and Forsyth Technical Community College will use this instrument for over 15 research projects. The system will support curricular improvement by allowing new experiments that will expand Physics and Chemistry syllabi. About 150 graduate and undergraduate students will receive formal training in the 7 courses and a summer workshop that will use the instrument.

1348361 (Williams), 1348139 (Burger), and 1348341 (Biswas). The Global Nuclear Detection Architecture (GNDA) is intended to detect illicit and unregulated nuclear and radiological materials worldwide. Wide deployment calls for quick and accurate detection technology with sensitivity and resolution close to current state-of-the-art scintillators but at much lower cost. The basic premise of this approach is that there are already inorganic scintillators with light yield and proportionality close to the limits that can be achieved in their ~5 eV band gap range; and that this group haswe developed a predictive model that describes why there is a sweet spot of material parameters defining the current group of highest performance scintillators. This is used to narrow the scope of theoretical, crystal-growth, and evaluative searches in this project so that they can be targeted farther into ternary and quaternary compositions and at the same time deeper into parameters that affect cost and performance. Some of the best new scintillator hosts are in fact composed of abundant (cheap) elements. The reason for their current high cost is not materials, but low yield of growing large single crystals. This project will pursue four research avenues to solve or side-step the crystal growth problems on the way to realizing an economical detector from materials in the sweet spot of structures, compositions, and physical parameters identified from the design rules developed by Wake Forest, Fisk, LBNL, and others since about 2010. One of the approaches to reduce cost examines how to improve the proportionality of segmented index-matched assemblies of smaller crystal blocks that are difficult to grow in large sizes. Such segmented detectors combined with wavelength shifting also provide flexibility to deal with self-absorption (photon diffusion) that currently limits the size of SrI2:Eu detectors. The group will measure and model how the peripheries of blocks in segmented scintillators contribute to nonproportionality, and what can be done to improve it. One ultra-lowcost but high-risk possibility involves index-matched granular scintillators using pre-doped SrI2:Eu beads supplied in bulk by chemical manufacturers. Starting with an excellent scintillator like SrI2:Eu, guided by experience with the segmented scintillators and their modeling, and applying thermal and chemical processing to the beaded material, the group will investigate the physics of what limits the resolution of granular detectors and how to advance performance beyond prior index-matched granular scintillators. A third approach to cost reduction will raise the yield of crystal growth by hardening and toughening existing excellent scintillators while taking care that the hardening measures do not degrade proportionality and light yield. A fourth targets theoretical and experimental searches toward new ternary and quaternary crystals with cubic structures and other properties favoring large crystal growth as well as slow electron thermalization, poor hot electron mobility, good thermalized electron mobility, and low Auger rates leading to best proportionality and light yield. Three university teams bring to this quest their complementary expertise and facilities in (1) crystal growth and characterization, (2) ultrafast laser probes of scintillation and associated numerical modeling of transport, trapping, and nonlinear quenching, and (3) electronic structure calculations on candidate crystals, defects, and dopants. The intellectual merit lies in applying this complementary three university array of experimental and theoretical techniques guided by predictive physical models to attack the cost problem treated in terms of physical parameters alongside those determining proportionality and light yield in both gamma and neutron detectors. The results, positive or negative, will inform the whole field on the models and methods employed. The broader impacts will be to increase national and global security by making possible improved, affordable deployment of nuclear monitoring; increasing the pool of U.S. university graduates trained in the materials technologies necessary to build and deploy such systems widely; and instituting a 3- university bridge system of interacting undergraduate, M.S., and Ph.D. programs and opportunities among the participating universities in three southeastern states to provide a path into the nuclear detection workforce for under-represented and economically disadvantaged students.