Enhanced Damage-Resistant Optics for Spaceflight Laser Systems: Workshop findings and recommendations

NASA has defined a program to address critical laser-induced damage issues peculiar to its remote sensing systems. The Langley Research Center (LaRC), with input from the Goddard Space Flight Center (GSFC), has developed a program plan focusing on the certification of optical materials for spaceflight applications and the development of techniques to determine the reliability of such materials under extended laser exposures. This plan involves cooperative efforts between NASA and optics manufacturers to quantify the performance of optical materials for NASA systems and to ensure NASA's continued application of the highest quality optics possible for enhanced system reliability. A review panel was organized to assess NASA's optical damage concerns and to evaluate the effectiveness of the LaRC proposed program plan. This panel consisted of experts in the areas of laser-induced damage, optical coating manufacture, and the design and development of laser systems for space. The panel was presented information on NASA's current and planned laser remote sensing programs, laser-induced damage problems already encountered in NASA systems, and the proposed program plan to address these issues. Additionally, technical presentations were made on the state of the art in damage mechanisms, optical materials testing, and issues of coating manufacture germane to laser damage

An Unusual Ligand Coordination Gives Rise to a New Family of Rhodium Metalloinsertors with Improved Selectivity and Potency

Rhodium metalloinsertors are octahedral complexes that bind DNA mismatches with high affinity and specificity and exhibit unique cell-selective cytotoxicity, targeting mismatch repair (MMR)-deficient cells over MMR-proficient cells. Here we describe a new generation of metalloinsertors with enhanced biological potency and selectivity, in which the complexes show Rh–O coordination. In particular, it has been found that both Δ- and Λ-[Rh(chrysi)(phen)(DPE)]2+ (where chrysi =5,6 chrysenequinone diimmine, phen =1,10-phenanthroline, and DPE = 1,1-di(pyridine-2-yl)ethan-1-ol) bind to DNA containing a single CC mismatch with similar affinities and without racemization. This is in direct contrast with previous metalloinsertors and suggests a possible different binding disposition for these complexes in the mismatch site. We ascribe this difference to the higher pK_a of the coordinated immine of the chrysi ligand in these complexes, so that the complexes must insert into the DNA helix with the inserting ligand in a buckled orientation; spectroscopic studies in the presence and absence of DNA along with the crystal structure of the complex without DNA support this assignment. Remarkably, all members of this new family of compounds have significantly increased potency in a range of cellular assays; indeed, all are more potent than cisplatin and N-methyl-N′-nitro-nitrosoguanidine (MNNG, a common DNA-alkylating chemotherapeutic agent). Moreover, the activities of the new metalloinsertors are coupled with high levels of selective cytotoxicity for MMR-deficient versus proficient colorectal cancer cells

Glycyl-tRNA synthetase mutations in neurological disease : mechanisms and models

Charcot-Marie- Tooth disease type 2D (CMT2D) is a dominantly inherited axonal neuropathy caused by missense mutations in the glycyl-tRN A synthetase gene (CARS). Dominant mutations in tyrosyl-tRNA synthetase and alanyl-tRNA synthetase also cause CMT, suggesting a shared mechanism for all three diseases. The goal of this thesis was to investigate possible mechanisms and narrow the potential ways that mutations in CARS could lead to axon loss. GARS mutations are distributed throughout the protein in multiple functional domains. The localization, dimerization, and degradation of GARS were examined as in vitro measures of protein function. Dimer function was preserved in most mutants. Similarly, no differences in wild-type and mutant localization or degradation were seen. In vitro experiments did not show evidence of a loss of function in most GARS mutants. Progress has also been made towards the development of a Drosophila model of CMT2D. Overexpression of mutant Aats-gly, the Drosophila ortholog of CARS, was found to cause lethality in fruit flies, while overexpression of the wild-type did not reduce viability. Results suggest that CMT2D can be modeled in fly, that the toxicity of the mutant protein is tissue autonomous, and that mutations in CARS and YARS have similar effects in Drosophila, hinting at a shared mechanism. There are two murine models of CMT2D with different mutations in the Cars gene. While they have very different levels of severity, they are both reliable models of the human disease. Each disease model was crossed to mice ubiquitously overexpressing wild-type GARS in order to determine whether the disease phenotype is caused by a loss of function in GARS. Using behavioral, histological, and electrophysiological measures of nerve function, it was determined that overexpression of wild-type CARS cDNA mitigates, but does not dramatically improve neuromuscular function in either model. The wild-type transgenes were able to rescue compound heterozygous CarsC201RIXM256 mice from embryonic lethality proving that the protein product of the two transgenes is functional. In summary, my work in cells, fruit flies, and mice provides evidence that CARS mutations cause CMT2D primarily by a pathogenic gain of function.EThOS - Electronic Theses Online ServiceGBUnited Kingdo