Materials science experiments in space

The criteria for the selection of the experimental areas and individual experiments were that the experiment or area must make a meaningful contribution to the field of material science and that the space environment was either an absolute requirement for the successful execution of the experiment or that the experiment can be more economically or more conveniently performed in space. A number of experimental areas and individual experiments were recommended for further consideration as space experiments. Areas not considered to be fruitful and others needing additional analysis in order to determine their suitability for conduct in space are also listed. Recommendations were made concerning the manner in which these materials science experiments are carried out and the related studies that should be pursued

Crossover Scaling in Dendritic Evolution at Low Undercooling

We examine scaling in two-dimensional simulations of dendritic growth at low undercooling, as well as in three-dimensional pivalic acid dendrites grown on NASA's USMP-4 Isothermal Dendritic Growth Experiment. We report new results on self-similar evolution in both the experiments and simulations. We find that the time dependent scaling of our low undercooling simulations displays a cross-over scaling from a regime different than that characterizing Laplacian growth to steady-state growth

Extending the scope of microscopic solvability: Combination of the Kruskal-Segur method with Zauderer decomposition

Successful applications of the Kruskal-Segur approach to interfacial pattern formation have remained limited due to the necessity of an integral formulation of the problem. This excludes nonlinear bulk equations, rendering convection intractable. Combining the method with Zauderer's asymptotic decomposition scheme, we are able to strongly extend its scope of applicability and solve selection problems based on free boundary formulations in terms of partial differential equations alone. To demonstrate the technique, we give the first analytic solution of the problem of velocity selection for dendritic growth in a forced potential flow.Comment: Submitted to Europhys. Letters, No figures, 5 page

Influence of external flows on crystal growth: numerical investigation

We use a combined phase-field/lattice-Boltzmann scheme [D. Medvedev, K. Kassner, Phys. Rev. E {\bf 72}, 056703 (2005)] to simulate non-facetted crystal growth from an undercooled melt in external flows. Selected growth parameters are determined numerically. For growth patterns at moderate to high undercooling and relatively large anisotropy, the values of the tip radius and selection parameter plotted as a function of the Peclet number fall approximately on single curves. Hence, it may be argued that a parallel flow changes the selected tip radius and growth velocity solely by modifying (increasing) the Peclet number. This has interesting implications for the availability of current selection theories as predictors of growth characteristics under flow. At smaller anisotropy, a modification of the morphology diagram in the plane undercooling versus anisotropy is observed. The transition line from dendrites to doublons is shifted in favour of dendritic patterns, which become faster than doublons as the flow speed is increased, thus rendering the basin of attraction of dendritic structures larger. For small anisotropy and Prandtl number, we find oscillations of the tip velocity in the presence of flow. On increasing the fluid viscosity or decreasing the flow velocity, we observe a reduction in the amplitude of these oscillations.Comment: 10 pages, 7 figures, accepted for Physical Review E; size of some images had to be substantially reduced in comparison to original, resulting in low qualit

Type II Kinase Inhibitors Show an Unexpected Inhibition Mode against Parkinson’s Disease-Linked LRRK2 Mutant G2019S

A number of well-known type II inhibitors (ATP-noncompetitive) that bind kinases in their DFG-out conformation were tested against wild-type LRRK2 and the most common Parkinson’s disease-linked mutation, G2019S. We found that traditional type II inhibitors exhibit surprising variability in their inhibition mechanism between the wild type (WT) and the G2019S mutant of LRRK2. The type II kinase inhibitors were found to work in an ATP-competitive fashion against the G2019S mutant, whereas they appear to follow the expected noncompetitive mechanism against WT. Because the G2019S mutation lies in the DXG motif (DYG in LRRK2 but DFG in most other kinases) of the activation loop, we explored the structural consequence of the mutation on loop dynamics using an enhanced sampling method called metadynamics. The simulations suggest that the G2019S mutation stabilizes the DYG-in state of LRRK2 through a series of hydrogen bonds, leading to an increase in the conformational barrier between the active and inactive forms of the enzyme and a relative stabilization of the active form. The conformational bias toward the active form of LRRK2 mutants has two primary consequences. (1) The mutant enzyme becomes hyperactive, a known contributor to the Parkinsonian phenotype, as a consequence of being “locked” into the activated state, and (2) the mutation creates an unusual allosteric pocket that can bind type II inhibitors but in an ATP-competitive fashion. Our results suggest that developing type II inhibitors, which are generally considered superior to type I inhibitors because of desirable selectivity profiles, might be especially challenging for the G2019S LRRK2 mutant

Universal Dynamics of Phase-Field Models for Dendritic Growth

We compare time-dependent solutions of different phase-field models for dendritic solidification in two dimensions, including a thermodynamically consistent model and several ad hoc models. The results are identical when the phase-field equations are operating in their appropriate sharp interface limit. The long time steady state results are all in agreement with solvability theory. No computational advantage accrues from using a thermodynamically consistent phase-field model.Comment: 4 pages, 3 postscript figures, in latex, (revtex

Efficient Computation of Dendritic Microstructures using Adaptive Mesh Refinement

We study dendritic microstructure evolution using an adaptive grid, finite element method applied to a phase-field model. The computational complexity of our algorithm, per unit time, scales linearly with system size, rather than the quadratic variation given by standard uniform mesh schemes. Time-dependent calculations in two dimensions are in good agreement with the predictions of solvability theory, and can be extended to three dimensions and small undercoolingsComment: typo in a parameter of Fig. 1; 4 pages, 4 postscript figures, in LateX, (revtex

Enzymatic Characterization of ER Stress-Dependent Kinase, PERK, and Development of a High-Throughput Assay for Identification of PERK Inhibitors

PERK is serine/threonine kinase localized to the endoplasmic reticulum (ER) membrane. PERK is activated and contributes to cell survival in response to a variety of physiological stresses that affect protein quality control in the ER, such as hypoxia, glucose depravation, increased lipid biosynthesis, and increased protein translation. Pro-survival functions of PERK are triggered by such stresses, suggesting that development of small-molecule inhibitors of PERK may be efficacious in a variety of disease scenarios. Hence, we have conducted a detailed enzymatic characterization of the PERK kinase to develop a high-throughput-screening assay (HTS) that will permit the identification of small-molecule PERK inhibitors. In addition to establishing the Km of PERK for both its primary substrate, eIF2?, and for adenosine triphosphate, further mechanistic studies revealed that PERK targets its substrate via either a random/steady-state ordered mechanism. For HTS, we developed a time-resolved fluorescence resonance energy transfer–based assay that yielded a robust Z? factor and percent coefficient of variation value, enabling the successful screening of 79,552 compounds. This approach yielded one compound that exhibited good in vitro and cellular activity. These results demonstrate the validity of this screen and represent starting points for drug discovery efforts