Density functional theory and modified embedded-atom method: applications to steel, magnesium alloys, and semiconductor surfaces

We performed atomistic modeling to study structural and mechanical properties of materials. We used density functional theory (DFT) for all the studies presented and constructed a method for quickly optimizing semi-empirical modified embedded atom method (MEAM) potentials. In our first study, we show that the reconstruction model in the literature for GaSb(001) is not predicted to have the lowest surface reconstruction energy. A modification was proposed that improves the energy. The second study tries to validate a crystal structure for the Φ Phase of Al-Mg-Zn. The third study deals with plain carbon steel, including some microalloying of Vanadium and vacancy assisted diffusion of Fe in Cementite(Fe3C). In the fourth study, we show a method for optimizing a MEAM potential. The code written is specific to hexagonal closed packed structures and was applied to a Magnesium potential

Density functional theory and modified embedded-atom method: applications to steel, magnesium alloys, and semiconductor surfaces

We performed atomistic modeling to study structural and mechanical properties of materials. We used density functional theory (DFT) for all the studies presented and constructed a method for quickly optimizing semi-empirical modified embedded atom method (MEAM) potentials. In our first study, we show that the reconstruction model in the literature for GaSb(001) is not predicted to have the lowest surface reconstruction energy. A modification was proposed that improves the energy. The second study tries to validate a crystal structure for the Φ Phase of Al-Mg-Zn. The third study deals with plain carbon steel, including some microalloying of Vanadium and vacancy assisted diffusion of Fe in Cementite(Fe3C). In the fourth study, we show a method for optimizing a MEAM potential. The code written is specific to hexagonal closed packed structures and was applied to a Magnesium potential

Structural, elastic and thermal properties of cementite (Fe3_3C) calculated using Modified Embedded Atom Method

Structural, elastic and thermal properties of cementite (Fe$_3$C) were studied using a Modified Embedded Atom Method (MEAM) potential for iron-carbon (Fe-C) alloys. Previously developed Fe and C single element potentials were used to develop an Fe-C alloy MEAM potential, using a statistically-based optimization scheme to reproduce structural and elastic properties of cementite, the interstitial energies of C in bcc Fe as well as heat of formation of Fe-C alloys in L$_{12}$ and B$_1$ structures. The stability of cementite was investigated by molecular dynamics simulations at high temperatures. The nine single crystal elastic constants for cementite were obtained by computing total energies for strained cells. Polycrystalline elastic moduli for cementite were calculated from the single crystal elastic constants of cementite. The formation energies of (001), (010), and (100) surfaces of cementite were also calculated. The melting temperature and the variation of specific heat and volume with respect to temperature were investigated by performing a two-phase (solid/liquid) molecular dynamics simulation of cementite. The predictions of the potential are in good agreement with first-principles calculations and experiments.Comment: 12 pages, 9 figure

AMG 837: A Novel GPR40/FFA1 Agonist that Enhances Insulin Secretion and Lowers Glucose Levels in Rodents

Agonists of GPR40 (FFA1) have been proposed as a means to treat type 2 diabetes. Through lead optimization of a high throughput screening hit, we have identified a novel GPR40 agonist called AMG 837. The objective of these studies was to understand the preclinical pharmacological properties of AMG 837. The activity of AMG 837 on GPR40 was characterized through GTPγS binding, inositol phosphate accumulation and Ca2+ flux assays. Activity of AMG 837 on insulin release was assessed on isolated primary mouse islets. To determine the anti-diabetic activity of AMG 837 in vivo, we tested AMG 837 using a glucose tolerance test in normal Sprague-Dawley rats and obese Zucker fatty rats. AMG 837 was a potent partial agonist in the calcium flux assay on the GPR40 receptor and potentiated glucose stimulated insulin secretion in vitro and in vivo. Acute administration of AMG 837 lowered glucose excursions and increased glucose stimulated insulin secretion during glucose tolerance tests in both normal and Zucker fatty rats. The improvement in glucose excursions persisted following daily dosing of AMG 837 for 21-days in Zucker fatty rats. Preclinical studies demonstrated that AMG 837 was a potent GPR40 partial agonist which lowered post-prandial glucose levels. These studies support the potential utility of AMG 837 for the treatment of type 2 diabetes

Efficacy of AMG 837 in Zucker fatty (<i>fa/fa</i>) rats following a single dose.

<p>8-week old Zucker fatty rats were administered a single bolus of AMG 837 (at 0.3, 1 and 3 mg/kg, n = 6/group) by oral gavage 30-minutes prior to an intraperitoneal glucose challenge at t = 0 minutes. (A) Blood glucose during the IPGTT (black circle = vehicle, blue triangle = 0.3 mg/kg AMG 837, green diamond = 1 mg/kg AMG 837 and purple square = 3 mg/kg AMG 837) (B) Glucose AUC (from −30 to 120 minutes) during the IPGTT. (C) Plasma insulin levels during the IPGTT (black circle = vehicle, blue triangle = 0.3 mg/kg AMG 837, green diamond = 1 mg/kg AMG 837 and purple square = 3 mg/kg AMG 837). Statistical significance compared to vehicle treated animals is denoted by * (p<0.5), ** (p<0.01), *** (p<0.001) and **** (p<0.001) as determined by one-way or two-way ANOVA and colors match the corresponding groups in the figure legend.</p

<i>In vitro</i> characterization of AMG 837.

<p>(A) The chemical structure of AMG 837 is shown. (B–D) The activity of AMG 837 in various GPCR assays was assessed as described in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0027270#s4" target="_blank">Materials and Methods</a>. Dose response relationships of AMG 837 in GTPγS binding (B), inositol phosphate accumulation (C) and aequorin Ca²⁺ flux assays (D) in cell lines overexpressing GPR40/FFA1 were determined. (D–G) In order to compare the activity of AMG 837 to fatty acids, plasmid titration experiments where either 5000 ng (D), 500 ng (E), 50 ng (F) or 5 ng (G) of GPR40 expression plasmid was co-transfected with aequorin expression plasmids into CHO cells. Activity of AMG 837 (blue diamond) was compared to the naturally occurring GPR40/FFA1 ligand docosahexaenoic acid (DHA, green square) in aequorin Ca²⁺ flux. (H) The activity of AMG 837 in the aequorin Ca²⁺ flux assays in the presence of 0.01% (v/v) purified human serum albumin (HSA, blue diamond), 0.625% (w/v) HSA (green square) or human serum (100% v/v, black circle) was determined.</p

Aequorin Ca²⁺ Flux Activity (EC₅₀, nM) of AMG 837 on Various Receptors.

<p>CHO cells were co-transfected with expression plasmids of a given receptor along with the Ca²⁺ sensitive bioluminescent reporter aequorin, as described in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0027270#s4" target="_blank">Materials and Methods</a>. Response to AMG 837 was measured with a luminometer and the EC₅₀ (nM) ± SEM was determined.</p

AMG 837 Potentiates Insulin Secretion from Islets.

<p>Islets were isolated from mice and the activity of AMG 837 on insulin secretion was determined. (A) The dose response relationship of AMG 837 and insulin secretion on mouse islets at 16.7 mM glucose was evaluated. (B) In order to determine whether the activity of AMG 837 was GPR40/FFA1 dependent, islets were isolated from GPR40 null mice (<i>gpr40^−/−</i>). AMG 837 potentiated glucose stimulated insulin secretion from wild type islets (black bar), but not <i>gpr40^−/−</i> islets (blue bar). (C) Glucose dependence of AMG 837 on glucose stimulated insulin secretion was determined by incubating islets in buffer containing either 0.1% DMSO (black bar) or 1 µM AMG 837 in 0.1% DMSO (blue bar) in the presence of increasing concentrations of glucose. Statistical significance is denoted by * (p<0.5), ** (p<0.01) and *** (p<0.001) as determined by one-way or two-way ANOVA.</p

Improvement in glucose tolerance and potentiation of insulin secretion in Sprague-Dawley rats treated with AMG 837.

<p>8-week old Sprague-Dawley rats were treated with a single bolus of AMG 837 (at 0.03, 0.1 and 0.3 mg/kg, n = 6/group) by oral gavage 30-minutes prior to an intraperitoneal glucose challenge at t = 0 minutes. (A) Blood glucose measurements were taken during prior to and following glucose challenge. Black circle = vehicle, blue triangle = 0.03 mg/kg AMG 837, green diamond = 0.1 mg/kg AMG 837 and purple square = 0.3 mg/kg AMG 837 (B) The glucose AUC (from −30 to 120 minutes) during the course of the experiments were calculated. (C) Plasma insulin levels were measured using ELISA. Black circle = vehicle, blue triangle = 0.03 mg/kg AMG 837, green diamond = 0.1 mg/kg AMG 837 and purple square = 0.3 mg/kg AMG 837 (D–D) Two successive glucose challenges were conducted in Sprague-Dawley rats following a single oral dose of vehicle (n = 4, black circle) or AMG 837 at 0.3 mg/kg (n = 4, purple diamond). AMG 837 was dosed at −30 minutes, and glucose was administered by <i>ip</i> injection at 0 and 180 minutes. Blood glucose (D), calculated glucose AUC (from 0–60 minutes following glucose challenge (E, black bars = vehicle, purple bars = 0.3 mg/kg AMG 837) and plasma insulin (F) were determined. Statistical significance is denoted by * (p<0.5), ** (p<0.01) and *** (p<0.001) as determined by one-way or two-way ANOVA.</p