Advanced modeling and simulation to design and manufacture high performance and reliable advanced microelectronics and microsystems.

An interdisciplinary team of scientists and engineers having broad expertise in materials processing and properties, materials characterization, and computational mechanics was assembled to develop science-based modeling/simulation technology to design and reproducibly manufacture high performance and reliable, complex microelectronics and microsystems. The team's efforts focused on defining and developing a science-based infrastructure to enable predictive compaction, sintering, stress, and thermomechanical modeling in ''real systems'', including: (1) developing techniques to and determining materials properties and constitutive behavior required for modeling; (2) developing new, improved/updated models and modeling capabilities, (3) ensuring that models are representative of the physical phenomena being simulated; and (4) assessing existing modeling capabilities to identify advances necessary to facilitate the practical application of Sandia's predictive modeling technology

Mixed -metal oxide nanopowders for structural and photonic applications.

This dissertation uses liquid feed flame spray pyrolysis (LF-FSP) to synthesize and process mixed-metal nano oxides with well-defined structural and photonic properties. LF-FSP combusts a metal oxide precursor solution and oxygen aerosol to produce nanoparticles with the same metal ratio as the precursor solution. The ability to tailor compositions and morphologies of the resultant nanopowders through the use of multiple liquid based metal-oxide precursors lends itself to combinatorial studies of composition and morphology, which is highly useful in property optimization. We first chose to investigate the effects of different aluminum oxide precursors on the morphology of the resulting alumina nanoparticles. This study showed that the metal ligand strongly influences the particle morphology based on the mechanisms of ligand decomposition. We successfully applied flame spray pyrolysis for the first time to synthesize combinatorially MgO:Al 2O3 with MgO concentrations in the range 0.005--50 mol%. The investigation provide a complete picture of the physical phase structure and associated native defect content over the full concentration range allowed by thermodynamics, but controlled by kinetics resulting in novel metastable phase formation and optimization the novel UV emission behavior. To demonstrate how the choice of ligand depends on the desired property, two different ceria ligands were used to alter the ceria doping mechanism of the alumina nanoparticles. The use of combustible, cerium propionate increased in the theta-alumina phase stability through increased dopant homogeneity and nano-domain development compared to the nitrite derived nanopowder. While the inorganic, cerium nitrate appears to favor Ce3+ in the Ce3+/4+ redox couple providing novel incoherent lasing. Previous combinatorial upconversion emission studies on co-doped yttria (Y0.86Yb0.11Er0.03)2O3 provided nanopowders that could be densified to give the first example of a submicron transparent upconversion ceramic sintered at 1400°C with unprecedented dopant concentrations of > 10 mol% allowing new photonic application to be realized. In addition, these sintering studies demonstrated the exceptional sinterability of LF-FSP powders. In toto, this dissertation demonstrates many experimental firsts that have only been predicted previously; including, the furthest extension of the magnesium spinel phase field, incoherent lasing, submicron transparent upconversion ceramics and reduced sintering parameters due to unaggregated nanocrystalline powders.Ph.D.Applied SciencesMaterials scienceUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/125663/2/3208467.pd

Finding Spinel in All the Wrong Places We thank the Air Force Office of Scientific Research for support of this work through Contract No. F49620-03-1-0389. Supporting Information is available online from Wiley InterScience or from the author.

No Abstract.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/58573/1/1373_ftp.pd

Identification of a New Class of Glucokinase Activators through Structure-Based Design

Glucose flux through glucokinase (GK) controls insulin release from the pancreas in response to high glucose concentrations. Glucose flux through GK also contributes to reducing hepatic glucose output. Because many individuals with type 2 diabetes appear to have an inadequacy or defect in one or both of these processes, compounds that can activate GK may serve as effective treatments for type 2 diabetes. Herein we report the identification and initial optimization of a novel series of allosteric glucokinase activators (GKAs). We discovered an initial thiazolylamino pyridine-based hit that was optimized using a structure-based design strategy and identified <b>26</b> as an early lead. Compound <b>26</b> demonstrated a good balance of in vitro potency and enzyme kinetic parameters and demonstrated blood glucose reductions in oral glucose tolerance tests in both C57BL/6J mice and high-fat fed Zucker diabetic fatty rats

Discovery of 2‑Pyridylureas as Glucokinase Activators

Glucokinase (GK) is the rate-limiting step for insulin release from the pancreas in response to high levels of glucose. Flux through GK also contributes to reducing hepatic glucose output. Since many individuals with type 2 diabetes appear to have an inadequacy or defect in one or both of these processes, identifying compounds that can allosterically activate GK may address this issue. Herein we report the identification and initial optimization of a novel series of glucokinase activators (GKAs). Optimization led to the identification of <b>33</b> as a compound that displayed activity in an oral glucose tolerance test (OGTT) in normal and diabetic mice

Novel Series of Potent Glucokinase Activators Leading to the Discovery of AM-2394

Glucokinase (GK) catalyzes the phosphorylation of glucose to glucose-6-phosphate. We present the structure–activity relationships leading to the discovery of <b>AM-2394</b>, a structurally distinct GKA. <b>AM-2394</b> activates GK with an EC₅₀ of 60 nM, increases the affinity of GK for glucose by approximately 10-fold, exhibits moderate clearance and good oral bioavailability in multiple animal models, and lowers glucose excursion following an oral glucose tolerance test in an <i>ob/ob</i> mouse model of diabetes

C5-Alkyl-2-methylurea-Substituted Pyridines as a New Class of Glucokinase Activators

Glucokinase (GK) activators represent a class of type 2 diabetes therapeutics actively pursued due to the central role that GK plays in regulating glucose homeostasis. Herein we report a novel C5-alkyl-2-methylurea-substituted pyridine series of GK activators derived from our previously reported thiazolylamino pyridine series. Our efforts in optimizing potency, enzyme kinetic properties, and metabolic stability led to the identification of compound <b>26</b> (<b>AM-9514</b>). This analogue showed a favorable combination of <i>in vitro</i> potency, enzyme kinetic properties, acceptable pharmacokinetic profiles in preclinical species, and robust efficacy in a rodent PD model