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Nanostructured materials are of widespread interest because of the unique properties they offer. Well-proven techniques, such as ball milling, exist for preparing powders with nanocrystalline microstructures. Nevertheless, consolidation of nanocrystalline powders is challenging and presents an obstacle to the use of nanocrystalline metals. This work demonstrates that nanocrystalline aluminum powders can be consolidated using the cold spray process. Furthermore, transmission electron microscopy (TEM) analysis of the nanocrystalline cold spray coatings reveals that the cold spray process can cause significant grain refinement. Inert gas atomized 6061 and 5083 aluminum powders were ball milled in liquid nitrogen resulting in micron-sized powder containing 250-400 nm grains. Cold spray coatings prepared using these feed stock materials exhibited homogenous microstructures with grain sizes of 30-50 nm. TEM images of the as-received powders, ball-milled powders, and cold spray coatings are shown.

Copper powder was sprayed by the cold gas-dynamic method. In-flight particle velocities were measured with a laser two-focus system as a function of process parameters such as gas temperature, gas pressure, and powder feed rate. Mean particle velocities were uniform in a relatively large volume within the plume and agreed with theoretical predictions. The presence of a substrate was found to have no significant effect on in-flight particle velocities prior to impact. Cold-spray deposition efficiencies were measured on aluminum substrates as a function of particle velocity and incident angle of the plume. Deposition efficiencies of up to 95% were achieved. The critical velocity for deposition was determined to be about 640 m/s for the system studied.

Cold spray, a new member of the thermal spray process family, can be used to prepare dense, thick metal coatings. It has tremendous potential as a spray-forming process. However, it is well known that significant cold work occurs during the cold spray deposition process. This cold work results in hard coatings but relatively brittle bulk deposits. This work investigates the mechanical properties of cold-sprayed aluminum and the effect of annealing on those properties. Cold spray coatings approximately 1 cm thick were prepared using three different feedstock powders: Valimet H-10; Valimet H-20; and Brodmann Flomaster. ASTM E8 tensile specimens were machined from these coatings and tested using standard tensile testing procedures. Each material was tested in two conditions: as-sprayed; and after a 300 DGC, 22 h air anneal. The as-sprayed material showed high ultimate strength and low ductility, with < 1% elongation. The annealed samples showed a reduction in ultimate strength but a dramatic increase in ductility, with up to 10% elongation. The annealed samples exhibited mechanical properties that were similar to those of wrought 1100 H14 aluminum. Microstructural examination and fractography clearly showed a change in fracture mechanism between the as-sprayed and annealed materials. These results indicate good potential for cold spray as a bulkforming process.

In large part, antimicrobial drug discovery is driven by the breadth and quality of both potential drug targets and available chemical libraries to screen. Traditionally, targets have been few in number and have been limited to those with known function, from which biochemical assays could be implemented into drug screens. Iterations of this same basic approach, applied to a few biochemically-defined targets have identified a limited set of novel antibiotics and even fewer antifungal agents. Indeed, in the last 50 years less than 30 antimicrobial targets have been exploited commercially. Within infectious disease, the industry was driven largely by chemistry-based approaches, simply making new analogs to existing drugs to overcome the growing problem of drug resistance. Elitra Pharmaceuticals approach has been to enable true functional genomics on a genome-wide scale. Elitras vision has been to identify all of the essential genes directly in the key pathogenic organisms. Having moved rapidly towards the completion of this goal, we are now faced with the enviable challenge of prioritizing enormous target sets and developing novel sensitive screens for those best suited as definitive drug targets. These highly sensitive, cell-based screening paradigms enable re-screening of even well screened chemical libraries to reveal new chemical entities displaying novel modes of action against new targets. In parallel, we have also begun to shift the paradigm from screening targets singly, towards genome-wide approaches to drug screening.

Here, we review the 'target-centric' genomic strategy to antimicrobial discovery and share our perspective on identification, validation and prioritization of potential antimicrobial drug targets in the context of emerging chemical biology, genomics and phenotypic screening strategies. We propose that coupling the dual processes of antimicrobial small-molecule screening and target identification in a whole-cell context is essential to empirically annotate 'druggable' targets and advance early stage antimicrobial discovery. We also advocate a systems-level approach to annotating synthetic-lethal genetic interactions comprehensively within yeast and bacteria models. The resulting genetic interaction networks provide a landscape to rationally predict and exploit drug synergy between cognate inhibitors. We posit that synergistic combination agents provide an important and largely unexploited strategy to 'repurpose' existing chemical space and simultaneously address issues of potency, spectrum, toxicity and drug resistance in early stages of antimicrobial drug discovery.

In large part, antimicrobial drug discovery is driven by the breadth and quality of both potential drug targets and available chemical libraries to screen. Traditionally, targets have been few in number and have been limited to those with known function, from which biochemical assays could be implemented into drug screens. Iterations of this same basic approach, applied to a few biochemically-defined targets have identified a limited set of novel antibiotics and even fewer antifungal agents. Indeed, in the last 50 years less than 30 antimicrobial targets have been exploited commercially. Within infectious disease, the industry was driven largely by chemistry-based approaches, simply making new analogs to existing drugs to overcome the growing problem of drug resistance. Elitra Pharmaceutical s approach has been to enable true functional genomics on a genome-wide scale. Elitra s vision has been to identify all of the essential genes directly in the key pathogenic organisms. Having moved rapidly towards the completion of this goal, we are now faced with the enviable challenge of prioritizing enormous target sets and developing novel sensitive screens for those best suited as definitive drug targets. These highly sensitive, cell-based screening paradigms enable re-screening of even well screened chemical libraries to reveal new chemical entities displaying novel modes of action against new targets. In parallel, we have also begun to shift the paradigm from screening targets singly, towards genome-wide approaches to drug screening.

The KRE6 gene product is required for synthesis of the major beta-glucans of the yeast cell wall, as mutations in this gene confer reduced levels of both the (1 leads to 6)- and (1 leads to 3)-beta-D-glucan polymers. Cloning and sequencing of KRE6 reveals a gene encoding a predicted 80-kDa protein with a central transmembrane domain and the topology of a type II membrane protein. Null mutants of KRE6 grow slowly, have larger cells, and show a reduction in alkali-insoluble wall glucans. The mutants show good viability and are not osmotically sensitive, but they are more susceptible to beta-glucanase digestion and mechanical stress than wild-type cells. The specific activity of the GTP-dependent, membrane-associated, in vitro (1 leads to 3)-beta-glucan synthase is reduced 50% in kre6 null mutants, and this reduction correlates with the mutation in meiotic tetrads. Transformants of kre6 null mutants with a KRE6 gene expressed from a centomere-based vector show a 4- to 5-fold increase in vitro (1 leads to 3)-beta-glucan synthase activity over transformants with the vector alone. The phenotype and structure of the KRE6 product, Kre6p, suggest that Kre6p may be a beta-glucan synthase, and if so, it implies that beta-glucan synthases are functionally redundant in yeast. Alternatively, Kre6p may be part of a single multiprotein glucan synthase or modulate its activity. Use of KRE6 should permit a genetic analysis of eukaryotic (1 leads to 3)-beta-glucan synthesis.

This research addresses two common tools for reducing product development lead times: overlapping of development stages and crashing of development times. For the first time in the product development literature, a formal model addresses both tools concurrently, thus facilitating analysis of the interdependencies between overlapping and crashing. The results exhibit the necessity of addressing overlapping and crashing concurrently, and exhibit general characteristics of optimal overlapping/crashing policies. The impact of different evolution/sensitivity constellations on optimal policies is investigated, and comprehensive guidelines for structuring development processes are provided. For the special case of linear costs, an efficient procedure is presented that generates the efficient time-cost trade-off curves and determines the corresponding optimal overlapping/crashing policies. The impact of key parameters and the robustness regarding their estimates is illustrated with a simple two-stage example.

The concurrent open shop problem is a relaxation of the well known open job shop problem, where the components of a job can be processed in parallel by dedicated, component specific machines. Recently, the problem has attracted the attention of a number of researchers. In particular, Leung et al. (2005) show, contrary to the assertion in Wagneur and Sriskandarajah (1993), that the problem of minimizing the average job completion time is not necessarily strongly NP-hard. Their finding has thus once again opened up the question of the problem's complexity. This paper re-establishes that, even for two machines, the problem is NP-hard in the strong sense. [PUBLICATION ABSTRACT]

Increasingly shorter product life cycles impel firms to design, develop, and market more products in less time than ever before. Overlapping of design and development stages is commonly regarded as the most promising strategy to reduce product development times. However, overlapping typically requires additional resources and can be costly. Our research addresses the trade-off between product development time and costs and introduces an algorithm to determine an appropriate overlapping strategy under different scenarios. The methodology developed was successfully employed at Rocketdyne Division of Rockwell International.