A search space “cartography” for guiding graph coloring heuristics

We present a search space analysis and its application in improving local search algorithms for the graph coloring problem. Using a classical distance measure between colorings, we introduce the following clustering hypothesis: the high quality solutions are not randomly scattered in the search space, but rather grouped in clusters within spheres of specific diameter. We first provide intuitive evidence for this hypothesis by presenting a projection of a large set of local minima in the 3D space. An experimental confirmation is also presented: we introduce two algorithms that exploit the hypothesis by guiding an underlying Tabu Search (TS) process. The first algorithm (TS-Div) uses a learning process to guide the basic TS process toward as-yet-unvisited spheres. The second algorithm (TS-Int) makes deep investigations within a bounded region by organizing it as a tree-like structure of connected spheres. We experimentally demonstrate that if such a region contains a global optimum, TS-Int does not fail in eventually finding it. This pair of algorithms significantly outperforms the underlying basic TS algorithm; it can even improve some of the best-known solutions ever reported in the literature (e.g. for dsjc1000.9).     

Thermo-oxidative aging of epoxy coating systems

The thermo-oxidative behavior of unformulated (unfilled) samples of epoxy coatings has been studied at five temperatures ranging from 70 °C to 150 °C. Two epoxy networks based on diglycidyl ether of bisphenol A (DGEBA), respectively, cured by jeffamine (POPA) or polyamidoamine (PAA) were compared. Infrared spectrophotometry (IR), differential scanning (DSC) and sol–gel analysis (SGA) were used to monitor structural changes.     

Heat of combustion of tantalum-tungsten oxide thermite composites

The heat of combustion of two distinctly synthesized stoichiometric tantalum-tungsten oxide energetic composites was investigated by bomb calorimetry. One composite was synthesized using a sol-gel (SG) derived method in which micrometric-scale tantalum is immobilized in a tungsten oxide three-dimensional nanostructured network structure. The second energetic composite was made from the mixing of micrometric-scale tantalum and commercially available (CA) nanometric tungsten oxide powders. The energetic composites were consolidated using the spark plasma sintering (SPS) technique under a 300 MPa pressure and at temperatures of 25, 400, and 500 °C. For samples consolidated at 25 °C, the density of the CA composite is 61.65 ± 1.07% in comparison to 56.41 ± 1.19% for the SG derived composite. In contrast, the resulting densities of the SG composite are higher than the CA composite for samples consolidated at 400 and 500 °C. The theoretical maximum density for the SG composite consolidated to 400 and 500 °C are 81.30 ± 0.58% and 84.42 ± 0.62%, respectively. The theoretical maximum density of the CA composite consolidated to 400 and 500 °C are 74.54 ± 0.80% and 77.90 ± 0.79%, respectively. X-ray diffraction analyses showed an increase of pre-reaction of the constituents with an increase in the consolidation temperature. The increase in pre-reaction results in lower stored energy content for samples consolidated to 400 and 500 °C in comparison to samples consolidated at 25 °C.     

Structure-based design of inhibitors specific for bacterial thymidylate synthase

Thymidylate synthase is an attractive target for antiproliferative drug design because of its key role in the synthesis of DNA. As such, the enzyme has been widely targeted for anticancer applications. In principle, TS should also be a good target for drugs used to fight infectious disease. In practice, TS is highly conserved across species, and it has proven to be difficult to develop inhibitors that are selective for microbial TS enzymes over the human enzyme. Using the structure of TS from Lactobacillus casei in complex with the nonsubstrate analogue phenolphthalein, inhibitors were designed to take advantage of features of the bacterial enzyme that differ from those of the human enzyme. Upon synthesis and testing, these inhibitors were found to be up to 40-fold selective for the bacterial enzyme over the human enzyme. The crystal structures of two of these inhibitors in complex with TS suggested the design of further compounds. Subsequent synthesis and testing showed that these second-round compounds inhibit the bacterial enzyme at sub-micromolar concentrations, while the human enzyme was not inhibited at detectable levels (selectivities of 100-1000-fold or greater). Although these inhibitors share chemical similarities, X-ray crystal structures reveal that the analogues bind to the enzyme in substantially different orientations. Site-directed mutagenesis experiments suggest that the individual inhibitors may adopt multiple configurations in their complexes with TS.     

Unrelated donor bone marrow transplantation for chronic myelogenous leukemia: a decision analysis

BACKGROUND: Chronic myelogenous leukemia (CML) is an indolent but ultimately fatal disease. Because the natural history of CML varies and quality of life with CML may be excellent until shortly before death, deciding whether and when to pursue unrelated donor bone marrow transplantation is often difficult. OBJECTIVE: To compare early transplantation, delayed transplantation, and no transplantation for patients with chronic-phase CML on the basis of discounted, quality-adjusted life expectancy. DESIGN: A markov model comparing different strategies was constructed. This model considers patient age, quality of life, risk aversion, and the competing risks for CML progression and transplant toxicity. SETTING: Therapeutic decision at the time of diagnosis of CML. PATIENTS: The base case is a 35-year-old patient with intermediate-prognosis CML. Younger and older patients with better and worse prognoses are also evaluated. INTERVENTION: Early transplantation, delayed transplantation, and no transplantation. MEASUREMENTS: Quality-adjusted, discounted life expectancy. RESULTS: For patients with newly diagnosed CML, transplantation within the first year provides the greatest quality-adjusted expected survival, although this benefit decreases with increasing patient age. For a 35-year-old patient with intermediate-prognosis CML, transplantation within the first year results in 53 more discounted, quality-adjusted years of life expectancy than does no transplantation. This finding is robust even with varying baseline assumptions. CONCLUSIONS: These results support the use of early unrelated donor bone marrow transplantation for most patients with CML.     

Time Course for the Development of Enzymes in Barley1

Barley (Hordeum distichon var. Harrington) was steeped, germinated and extracted to observe the order of enzyme development. Different parts of the barley kernel were extracted to observe the order of enzyme development during the malting process. Five enzymes were investigated: carboxypeptidase (EC 3.4.16.1), endo‐β1–3, 1–4‐glucanase (EC 3.2.1.73), endo‐B1‐4‐xylanase (EC 3.2.1.136), arabinofuranosidase (EC 3.2.1.55), and α‐amylase (EC 3.2.1.1). Early development of carboxypepti‐dase, followed by later development of β‐glucanase, then α‐amy‐lase, confirmed earlier reports concerning the sequence of synthesis for these activities. However, xylanase developed during the steeping of barley and early in germination, whereas other authors found this enzyme to develop much later in the malting process. Enzyme activities developed to higher levels in the proximal end of kernels for all enzymes except xylanase, which was evenly distributed throughout the kernel. Enzyme development was tested in sterile barley annuli [embryo‐less cross sections taken through the grain, and thus comprising rings of tissue with husk outermost and starchy endosperm innermost] under four effector conditions. Water controls mirrored the development pattern observed in whole barley kernels. Gibberellic acid (GA₃) promoted higher total enzyme activity and development of all enzymes at the same time. Abscisic acid (ABA) promoted earlier development of late developing enzymes (xylanase, arabinofuranosidase and α‐amylase) and significantly higher levels of xylanase than when treatment was with water alone. Mixtures of GA and ABA showed a non‐exclusive, combined response of higher activity levels and a shifting of the initiation of enzyme development. Treatment with a combination of GA and calcium chloride triggered signifycantly higher carboxy‐peptidase activity and significantly lower xylanase activity as compared to treatment with GA or with GA/ABA mixtures.     

Structural Investigation of the Binding of 5‐Substituted Swainsonine Analogues to Golgi α‐Mannosidase II

Golgi α‐mannosidase II (GMII) is a key enzyme in the N‐glycosylation pathway and is a potential target for cancer chemotherapy. The natural product swainsonine is a potent inhibitor of GMII. In this paper we characterize the binding of 5α‐substituted swainsonine analogues to the soluble catalytic domain of Drosophila GMII by X‐ray crystallography. These inhibitors enjoy an advantage over previously reported GMII inhibitors in that they did not significantly decrease the inhibitory potential of the swainsonine head‐group. The phenyl groups of these analogues occupy a portion of the binding site not previously seen to be populated with either substrate analogues or other inhibitors and they form novel hydrophobic interactions. They displace a well‐organized water cluster, but the presence of a C(10) carbonyl allows the reestablishment of important hydrogen bonds. Already approximately tenfold more active against the Golgi enzyme than the lysosomal enzyme, these inhibitors offer the potential of being extended into the N‐acetylglucosamine binding site of GMII for the creation of even more potent and selective GMII inhibitors.     

Distortion-free optical amplification of 20-80 GHz modelocked laser pulses at 1.3 /spl mu/m using quantum dots

Distortion-free amplification of modelocked laser pulses at 20, 40 and 80 GHz with a minimum pulse width of 710 fs is reported. The modelocked lasers and the semiconductor optical amplifiers are based on identical quantum dot material emitting at 1.3 /spl mu/m.