David Clarke - US grants

Our aim is to classify and characterize peripheral effector receptors for 5-hydroxytryptamine (5-HT). A functional (pharmacological) approach to the problem is taken using isolated tissues set-up in vitro. Initial studies will be done on the isolated perfused rat kidney, the isolated rat vas deferens, and the isolated perfused rat mesenteric arteries. Subsequent experiments will be done with rat isolated atria, caudal arteries, and saphenous veins. The experiments will focus on peripheral receptors for 5-HT at sympathetic neuroeffector junctions at both prejunctional and postjunctional sites. Quantitative pharmacological analysis will be done with competitive antagonists, irreversible antagonists and a range of 5-HT-like agonists. The determination of pA2 values for competitive antagonists, agonist potency ratios, affinities and relative efficacies will be determined and used to classify and characterize the receptors. Criteria for defining three separate groups of 5-HT receptors ("5-HT1-like", 5-HT2, and 5-HT3) are given and will serve as the broad basis for receptor classification. The project represents a careful basic science pharmacological research investigation into receptor classification and characterization. Such research is a prerequisite for the full understanding of the biological and pathological effects of 5-HT and for the rational development of new serotonergic drugs.

This proposal examines the hypothesis that norepinephrine and related phenylethylamines (isoproterenol, epinephrine, etc.) can interact with a functional inhibitory site in isolated guinea-pig ileum distinct from currently defined alpha- and beta- adrenoceptors. The research objective is to characterize this putative adrenoceptor with regard to agonist and antagonist profiles. Quantitative pharmacological experiments are planned to measure pA2 values for competitive antagonists, the sensitivity of the putative site to irreversible antagonists, and agonist potency ratios, affinities, and efficacies. Characterization of the putative adrenoceptor in isolated guinea- pig ileum will lead to similar experimentation in isolated guinea- pig atria, rat atria, rabbit rectococcygeus muscle, rat stomach fundus, and rat vas deferens. (Evidence exists that an adrenoceptor, distinct from defined alpha- and beta-subtypes, exists in these tissues). The research project represents a basic science, pharmacological approach, to effector receptor classification and characterization. The results may have relevance to both physiological mechanisms and novel drug development.

9724254 Safinya Optical imaging instrumentation consisting of a laser scanning confocal microscope with real-time video-rate capability and a micromanipulation system will be acquired by the University of California at Santa Barbara. The instrument will support real- time studies of novel biomolecular materials, confined complex fluids, ceramics, alloys and composites. It will be housed within the Materials Research Laboratory at UCSB, where it will be accessible to all campus researchers. %%% Acquisition of this instrumentation will impact research and research training in an interdisciplinary program at UCSB in the general area of complex materials that involves about 30 graduate students, 15 post doctoral associates and 11 faculty. ***

Integrated experiments designed to incorporate concepts from physics, chemistry biology, and pharmaceutics into the laboratory components of general and organic chemistry have been developed. The specific integrated experiments require FTIR spectral analysis. Qualitative, quantitative and chemical kinetics analyses are incorporated into these laboratory experiments. These experiments are intended for the undergraduate pharmacy curriculum. Sets of experiments with a common theme focus on integrating basic science concepts with pharmacy relevant examples. These laboratory exercises emphasize independent learning and critical thinking. A strong basic science education incorporating exercises to develop thinking abilities is essential in the preparation of pharmacy practitioners who will use this knowledge to adapt and develop drug therapies for patients. The laboratory is an ideal environment for active learning activities that help students develop the thinking abilities necessary for the practice of pharmacy.

The long-term objectives of the application are to understand the structure, mechanism and biosynthesis of the human multidrug resistance P-glycoprotein (P-gp). This knowledge will then be used to develop strategies to shut off the transporter during cancer chemotherapy or treatment of AIDS. P-gp interferes in the treatment of cancer and AIDS by preventing anticancer drugs or HIV-1 protease inhibitors from reaching their targets. Efforts to develop effective inhibitory drugs that specifically bind to P-gp have been hampered by the lack of structural information about the drug-binding domain and the conformational changes that take place during transport. These issues will be addressed by testing the hypothesis that transmembrane segments 5, 6, 11 and 12 of P-gp form the drug-binding domain and that they undergo conformational changes during drug transport. These hypotheses will be tested using a Cys-less mutant of P-gp together with cysteine-scanning mutagenesis, thiol-reactive substrates and disulfide crosslinking. A new approach will also be developed to inhibit P-gp function by inhibiting folding and exit of P-gp from the endoplasmic reticulum. Preliminary evidence suggests that some compounds can block the conversion of a biosynthetic intermediate of P-gp into mature enzyme.

MICRO-MECHANICS ASSOCIATED WITH FRACTURE IN INTEGRATED MICROELECTRONICS


The research addresses two contemporary micro-mechanics issues concerning fracture in microelectronic devices. One is the mechanics of dielectric fracture produced by electromigration in constrained interconnect structures. The other is how stresses accumulate in packaged devices, particularly under thermal cycling conditions, with particular emphasis on conditions of mechanical "shakedown" and "ratcheting" (a condition favoring cracking). The principal experimental tool used in the proposed research will be optical piezospectroscopy, using Raman spectroscopy and photostimulated luminescence. Piezospectroscopy is a developing, non-destructive and non-contact method of strain measurement with a spatial resolution of ~ 1micron when implemented using an optical microprobe.

The scientific goal of the program is to learn how to manipulate the magnetic coupling between nanocrystalline particles to create soft magnetic materials in which the bulk magnetic properties, such as permeability in field, magnetization and coercive losses can be independently varied. In monolithic materials these properties are not independent. The approach being taken is to synthesize nanocrystalline magnetic oxide particles and manipulate their packing into a bulk material to alter, through composition, particle size, shape and volume fraction, the inter-particle magnetic coupling. Initially, nano-particles of ferrites and rare-earth oxides are being synthesized using inverse micelle processes and their spacing and packing varied through the choice of surfactants and solvents to form bulk material compatible with use in electrical power converters and related devices. The materials are characterized at different stages to determine how the bulk magnetic properties are related to the properties of the nanocrystalline particles and their magnetic coupling.

The overall justification of the program is to assess the potential for nanocrystalline-based materials in replacing existing magnetic materials in dc-dc electrical power converters by enhancing their performance and decreasing their physical size. Power converters are used throughout the electronics industry to provide a stable, low voltage power supply to almost all-digital electronics and microprocessors. Increasing demands for smaller, higher power, higher frequency dc-dc converters can only be realized with the development of magnetic materials having improved permeability and lower magnetic losses. The challenge being addressed is how to create new magnetic materials, using nanocrystalline particles, which can be fabricated into an integrated and functional power-converter whilst preserving their novel combination of magnetic properties. The collaboration with Rockwell Scientific Company provides students with experience in the design of the magnetic components of power devices as well as the opportunity to test their candidate materials as they are being developed.

This proposal was received in response to the Sensors and Sensor Networks Solicitation, NSF 04-522, category Individual Investigator Proposals.

Society today relies on gas turbine engines for both the generation of electricity and aircraft propulsion. To increase the overall energy efficiency as well as minimize maintenance, there is a drive to develop new coatings, sensors and controls. The focus of our research is on high-temperature thermal barrier coatings that provide thermal insulation to the turbine blades and combustion chambers allowing engines to be operated at higher temperatures, and hence higher efficiency, than uncoated engines. Specifically, we are developing an all-optical sensor for in-situ measurement of the temperature, and heat flux, across thermal barrier coatings, crucial heat transfer parameters for both "health monitoring" and design validation as well as reliability and life prediction.
As the life of the coating, the metal blades and vanes all depend on their maximum temperature, the temperature of the inner coating surface, which is in direct contact with the metal, is a vital but presently unknowable parameter. Likewise, the actual temperature of the coatings' outer surface, as distinct from the gas temperature at the surface, also affects coating life and durability. With measurements of the temperature difference across the thickness of the coating the heat flux can be determined.
The basis of our proposed sensor is the characteristic temperature-dependent luminescence from different rare-earth dopants that we incorporate within the crystal structure of existing thermal barrier coating materials. By placing the dopants at different levels in the coating it becomes a structured sensor whose signals come from the positions within the coating where the dopants are located, for instance at the inner and outer surfaces. Although the focus is on temperature measurement in thermal barrier coatings, the methodology, the protocols for selecting of dopants for high-temperature luminescence and the overall sensor design considerations are expected to be of value for other applications where it is important to measure high temperatures of materials and, in particular within structures of materials where optical pyrometer is not feasible or masked by thermal radiation.
An integral part of the program is that the graduate students will perform tests of the sensors at NASA Glenn Research Center using the laser-driven high heat flux test rig there, enabling them to also experience a different working environment and learning from research professionals and collaborators.

The proposal is being funded by the Thermal Transport and Thermal Processing Program of the Chemical and Transport Systems Division and the Sensors in Civil and Mechanical Systems Program in the Civil and Mechanical Systems Division.

This Materials World Network award is for a joint research and education program between participants in the US, China and England to use a combined experimental and simulation approach to discover materials with much lower thermal conductivity than those currently known, and to seek correlations with other phonon-dominated property measurements, such as elastic moduli and Raman spectra. In addition, to developing both experimental and simulation skills through research collaborations with the participating faculty in the network, an integral part of the education of the participating students is to give them a strong global perspective on science and its practice by performing part of their research studies in two other institutions, one in China and the other in England.

The basis of the scientific approach is to combine state-of-the art simulations with both traditional synthesis and processing of ceramics together with combinatorial approaches exploring compositional variations to provide a more rapid discovery path. The simulations will be carried out under the guidance of Professor Simon Phillpot at the University of Florida in conjunction with Professor Robin Grimes at Imperial College. The experimental portions of the research will be guided by Professor David Clarke, at the University of California, Santa Barbara and Professor W. Pan at Tsinghua University, Beijing. The emphasis will be on complex, fluorite-derived structures and perovskite-related layered structures because of their inherent ability to accommodate a wide range of different ions and ionic sizes and their crystalline anisotropy. Together these offer the prospect of very low and / or strongly anisotropic thermal conductivities. Initially, the research will focus on the pyrochlore and delta-phase compounds as well as on the Ruddleston-Popper phases and then use the findings to select more complex layered compounds.

This award is co-funded by the Office of International Science and Engineering

The research objective of this award is to establish the inter-relationship between dielectric breakdown and electric-field induced deformation of elastomeric materials. Integral to the research objective will be quantifying the role of defects as well as electric-field induced mechanical localization produced by conducting fibers and electrode geometry. The approach will be largely experimental with direct measurements of the deformation fields produced by pre-straining and applied voltages for different fiber electrode arrangements and for a variety of device geometries. The observations will be compared with and complemented by modeling studies based on theories of nonlinear electro-mechanical coupling of deformable dielectrics. Together, these will be used to design and construct proof-of-concept electrically controlled devices capable of extreme strains.

If successful, the benefits of this research will include simplified designs for utilizing dielectric elastomers in engineering applications including energy harvesting devices, linear actuators and displays. The project will also contribute to Harvard's existing outreach programs involving undergraduate research and local high-school outreach, other community outreach programs.

Abstract

This INSPIRE award is partially funded by Biological Oceanography Program in Division of Ocean Sciences, in the Directorate of Geosciences; the Electronic and Photonic Materials Program in the Division of Materials Research, Directorate of Mathematical and Physical Sciences.

A simple idea motivates this project: By characterizing the mechanisms underlying pyrite film deposition by subsurface microbes living at hydrothermal vents, can approaches be developed to controllably grow high-purity pyrite films that could be used to produce low-cost photovoltaic solar cells? Recent in situ studies at hydrothermal vents have found "subsurface" microbes associated with the deposition of large crystalline metal sulfides (up to 1.1 millimeters), including iron pyrite. In laboratory incubations, vent microbes specifically deposited pyrite (FeS2), devoid of Zn, Cu and other metals that were abundant in the liquid media. Abiotic incubations did not exhibit this specificity. The investigators hypothesize that, in situ, microbes deposit pyrite via a number of potential processes, including a physiological process called extracellular electron transfer (EET), wherein microbes shuttle electrons to/from minerals. In situ, EET-enabled microbes may use conductive minerals to electrically access oxidants, and deposit pyrite on these surfaces. Vents are thus natural bioelectrochemical cells, which grow metal sulfides via microbial and abiotic electrochemical processes, though the details and mechanisms remain to be determined. This project is aimed at elucidating the mechanisms underlying microbial FeS2 pyrite bio-deposition, and assessing how microbes might be used to deposit epitaxial films for solar cells absorbers. FeS2 pyrite has been identified as prospective low cost solar absorbers because of their abundance, suitable band-gap (~0.95 eV) and high optical absorbance. Microbial pyrite film deposition at lower temperatures (<100 C) might offer a radically new, low cost approach to creating large area PV solar cells. Nothing is currently known about the mechanisms underlying microbial pyrite growth, though the large crystal sizes suggest epitaxial deposition is favored over re-nucleation implying that, once nucleated, epitaxial growth can occur. A series of experiments using natural vent microbial communities and isolates will be conducted to determine: A) environmental factors that influence bio-deposition; B) potential molecular mechanisms; C) the microstructural and electrical properties of these films; and D) whether bio-deposition by single species or consortia yields films of highest purity, size and homogeneity.

Intellectual Merit: The project is both highly-integrated and transformative. It is relevant to our understanding of microbial sulfur cycling, as little is known about how microbes mediate crystalline pyrite formation and the degree to which this influences sulfur isotope geochemistry. Molecular studies will be used to interrogate relevant microbial metabolic processes and constrain the possible mechanisms of pyrite film growth, which is critical to advancing our ability to grow FeS2 films for device applications. Understanding the effects of substrate crystallography and electrical conductivity on the growth morphology will further inform our knowledge of microbial pyrite deposition. Notably, this research differ from existing biomimetic approaches. The studies are not focused on crystal growth via tethered peptides or synthetic extracellular matrices. Rather, they aim to advance our understanding of natural biodeposition, use the insights gained to grow pyrite materials and devices.

Broader Impacts: Apart from the exciting and possibly transformative impact on creating alternative photovoltaic solar cells, this activity offers an unusual opportunity to perform research across current intellectual boundaries of microbial sciences and electronic / engineering materials. Graduate students will be thoroughly engaged in both these areas, with extensive mentoring from the PIs and the postdoc. Via numerous Harvard and NSF programs, the investigators will engage undergraduates in the research. Moreover, Professors Girguis and Clarke will use this project to teach a new course to freshman, focused on understanding and communicating interdisciplinary science. In this course, and in collaboration with the Harvard Museum of Natural History, students would design a public exhibit on how microbes make minerals and electricity, which would be evaluated by the museum staff and the some of the ~200,000 annual visitors on its efficacy, thus enabling the Harvard students to learn firsthand about communicating science, and informing the public about the relationships between science and engineering.