Local heuristic for the refinement of multi-path routing in wireless mesh networks

We consider wireless mesh networks and the problem of routing end-to-end traffic over multiple paths for the same origin-destination pair with minimal interference. We introduce a heuristic for path determination with two distinguishing characteristics. First, it works by refining an extant set of paths, determined previously by a single- or multi-path routing algorithm. Second, it is totally local, in the sense that it can be run by each of the origins on information that is available no farther than the node's immediate neighborhood. We have conducted extensive computational experiments with the new heuristic, using AODV and OLSR, as well as their multi-path variants, as underlying routing methods. For two different CSMA settings (as implemented by 802.11) and one TDMA setting running a path-oriented link scheduling algorithm, we have demonstrated that the new heuristic is capable of improving the average throughput network-wide. When working from the paths generated by the multi-path routing algorithms, the heuristic is also capable to provide a more evenly distributed traffic pattern

Substructural dynamics of the phase-I drug metabolizing enzyme, carbonyl reductase 1, in response to various substrate and inhibitor configurations

Purpose: To investigate the substructure and molecular dynamics change in the phase-I drug metabolizing enzyme, carbonyl reductase 1 (CBR1), in response to different substrate and inhibitor configurations, using a molecular dynamics approach. Methods: CBR1 structure and drug ligands, including 2,3-butanedione, prostaglandin E2 (PGE2), oracine, mitoxantrone, menadione, rutoside, barbital, and biochanin A, were retrieved and 3D optimized. Docking runs were performed using template docking into CBR1 active binding site with GSH. Molecular dynamic (MD) simulation was implemented for 100 ns. Results: The docking scores were positively correlated with the detected ligand’s affinities. Molecular dynamics simulation indicated that lower affinity ligands or weaker inhibitors produced less stable CBR1 with higher root mean square deviations (RMSD) of CBR1 backbone α-carbon atoms. Stronger inhibitors and substrates produced stable CBR1 structures with RMSD similar to or lower than CBR1- NADP complexes. Very low affinity ligands were unstable and were released from their sites within a few nanoseconds after commencing the simulation. Two flexible loops, LE92-PHE102 and VAL230- TYR251, were highly responsive to the nature of CBR1 ligands. Changes in the latter may be associated with lower CBR1 activity due to loss of stabilization of NADPH by the deviation of this loop’s residues. Conclusion: In this work, a model of CBR1 structural changes has been provided that can be used in the analysis of CBR1 future substrates and inhibitors. Docking followed by MD simulation and analysis of average backbone α-carbon RMSD and changes in ILE92-PHE102 and VAL230-TYR251 loops can be used in the model analysis of unknown or new drug candidates to predict their binding efficiencies

Metabolic syndrome influences cardiac gene expression pattern at the transcript level in male ZDF rats

Background: Metabolic syndrome (coexisting visceral obesity, dyslipidemia, hyperglycemia, and hypertension) is a prominent risk factor for cardiovascular morbidity and mortality, however, its effect on cardiac gene expression pattern is unclear. Therefore, we examined the possible alterations in cardiac gene expression pattern in male Zucker Diabetic Fatty (ZDF) rats, a model of metabolic syndrome. Methods: Fasting blood glucose, serum insulin, cholesterol and triglyceride levels were measured at 6, 16, and 25 wk of age in male ZDF and lean control rats. Oral glucose tolerance test was performed at 16 and 25 wk of age. At week 25, total RNA was isolated from the myocardium and assayed by rat oligonucleotide microarray for 14921 genes. Expression of selected genes was confirmed by qRT-PCR. Results: Fasting blood glucose, serum insulin, cholesterol and triglyceride levels were significantly increased, glucose tolerance and insulin sensitivity were impaired in ZDF rats compared to leans. In hearts of ZDF rats, 36 genes showed significant up-regulation and 49 genes showed down-regulation as compared to lean controls. Genes with significantly altered expression in the heart due to metabolic syndrome includes functional clusters of metabolism (e.g. 3-hydroxy-3-methylglutaryl-Coenzyme A synthase 2; argininosuccinate synthetase; 2-amino-3ketobutyrate-coenzyme A ligase), structural proteins (e.g. myosin IXA; aggrecan1), signal transduction (e. g. activating transcription factor 3; phospholipase A2; insulin responsive sequence DNA binding protein-1) stress response (e.g. heat shock 70kD protein 1A; heat shock protein 60; glutathione S-transferase Yc2 subunit), ion channels and receptors (e.g. ATPase, (Na+)/K+ transporting, beta 4 polypeptide; ATPase, H+/K+ transporting, nongastric, alpha polypeptide). Moreover some other genes with no definite functional clusters were also changed such as e. g. S100 calcium binding protein A3; ubiquitin carboxy-terminal hydrolase L1; interleukin 18. Gene ontology analysis revealed several significantly enriched functional inter-relationships between genes influenced by metabolic syndrome. Conclusions: Metabolic syndrome significantly alters cardiac gene expression profile which may be involved in development of cardiac pathologies in the presence of metabolic syndrome

The Effect of Sex and Background on Doxorubicin-Induced Cardiotoxicity in Carbonyl Reductase 1 +/- Mice: A Comparative Study

Doxorubicin has long been used clinically to treat a variety of cancers. Unfortunately, its success is limited due to its cardiotoxic side effects, restricting the cumulative dose that can be given to patients. It is known that the enzyme carbonyl reductase 1 (Cbr1) metabolizes this cancer drug in vivo, leading to the production of its toxic alcohol metabolite, doxorubicinol. A previous study has indicated that decreasing the expression level of carbonyl reductase 1 in male Cbr1+/- mice provided them with significant protection from doxorubicin-induced cardiotoxicity when compared to their wild type littermates. With the intent to identify whether the protection conferred by knocking out one copy of Cbr1 persists in a more diverse population, this subsequent study expanded the previous one to include female mice as well as mice of different genetic backgrounds. It was discovered that the protective effect conferred by a null Cbr1 allele is no longer present, that females significantly longer than males, and that survival is no longer significantly associated with cardiotoxicity. Western blotting, subclinical pathogen analysis, histology, and pedigree analysis were performed in an effort to discover an explanation for the unexpected results. It is believed that alternate acute toxicity such as leukopenia was responsible for mouse death, whereas such factors are controlled in human clinical trials. In the event that decreased Cbr1 levels provide significant cardiac protection, a Cbr1 inhibitor could be created to be taken simultaneously with doxorubicin

An Unbiased Cell Morphology–Based Screen for New, Biologically Active Small Molecules

We have implemented an unbiased cell morphology–based screen to identify small-molecule modulators of cellular processes using the Cytometrix (TM) automated imaging and analysis system. This assay format provides unbiased analysis of morphological effects induced by small molecules by capturing phenotypic readouts of most known classes of pharmacological agents and has the potential to read out pathways for which little is known. Four human-cancer cell lines and one noncancerous primary cell type were treated with 107 small molecules comprising four different protein kinase–inhibitor scaffolds. Cellular phenotypes induced by each compound were quantified by multivariate statistical analysis of the morphology, staining intensity, and spatial attributes of the cellular nuclei, microtubules, and Golgi compartments. Principal component analysis was used to identify inhibitors of cellular components not targeted by known protein kinase inhibitors. Here we focus on a hydroxyl-substituted analog (hydroxy-PP) of the known Src-family kinase inhibitor PP2 because it induced cell-specific morphological features distinct from all known kinase inhibitors in the collection. We used affinity purification to identify a target of hydroxy-PP, carbonyl reductase 1 (CBR1), a short-chain dehydrogenase-reductase. We solved the X-ray crystal structure of the CBR1/hydroxy-PP complex to 1.24 Å resolution. Structure-based design of more potent and selective CBR1 inhibitors provided probes for analyzing the biological function of CBR1 in A549 cells. These studies revealed a previously unknown function for CBR1 in serum-withdrawal-induced apoptosis. Further studies indicate CBR1 inhibitors may enhance the effectiveness of anticancer anthracyclines. Morphology-based screening of diverse cancer cell types has provided a method for discovering potent new small-molecule probes for cell biological studies and anticancer drug candidates

Kinetic features of carbonyl reductase 1 acting on glutathionylated aldehydes

The attempt to evaluate the human carbonyl reductase 1 (CBR1) activity on 3-glutathionylated-4-hydroxyalkanals through the classical spectrophotometric assay, in which NADPH oxidation is monitored at 340 nm, failed. This was due to the ability of the enzyme to catalyze the reduction of the free aldehyde form and at the same time the oxidation of the hemiacetal structure of this class of substrates, thus leading to the occurrence of a disproportion reaction sustained by a redox recycle of the pyridine cofactor. Making use of glutathionylated alkanals devoid of the 4 hydroxyl group, and thus unable to structurally arrange into a cyclic hemiacetal form, the susceptibility to inhibition of CBR1 to polyphenols was tested. Flavones, that were much more effective than isoflavones, resulted able to modulate the reductase activity of the enzyme on this new peculiar class of substrates