Integrated parallel performance views

The influences of the operating system and system-specific effects on application performance are increasingly important considerations in high performance computing. OS kernel measurement is key to understanding the performance influences and the interrelationship of system and user-level performance factors. The KTAU (Kernel TAU) methodology and Linux-based framework provides parallel kernel performance measurement from both a kernel-wide and process-centric perspective. The first characterizes overall aggregate kernel performance for the entire system. The second characterizes kernel performance when it runs in the context of a particular process. KTAU extends the TAU performance system with kernel-level monitoring, while leveraging TAU’s measurement and analysis capabilities. We explain the rational and motivations behind our approach, describe the KTAU design and implementation, and show working examples on multiple platforms demonstrating the versatility of KTAU in integrated system/application monitoring.

Plasma and urinary selenium in Saudi Arabian patients with dilated cardiomyopathy

We measured selenium (Se) levels in the urine and blood plasma samples of 72 Saudi Arabian patients with dilated cardiomyopathy (DCM) and 70 control subjects of the same origin. To correct for differences in the hydration state of the subjects, the selenium concentration for each urine sample was normalized by dividing it by the concentration of creatinine (CREAT) in the same sample. The median (and range) of the values found for the concentration of Se in plasma, urine, and normalized concentration in urine for the control subjects was 1.306 (0.66–2.50) μM, 0.478 (0.05–2.00) μM, and 56.7 (10.6–426.5) μM Se/M CREAT, respectively, whereas, for the patients, it was 1.246 (0.53–2.45) μM, 0.39 (0.05–1.90) μM, and 75.1 (4.9–656.2) μM Se/M CREAT, respectively. Additionally, the patients were separated into three subgroups according to the severity of their disease state as judged by NYHA procedure, and were then compared to the control group. Only group 4 (the most severe state of the disease) had a significantly lower concentration of urinary Se than the control group. However, the difference became nonsignificant when normalized for CREAT levels. There was no significant difference in the plasma Se levels between the controls and any of the patient groups. As the plasma Se in the control group and in the DCM patients both fell on the low end of the “normal” range, with the patients being marginally lower than the controls, there is no firm evidence from this study to suggest that Se is related to the high incidence rate of DCM found in Saudi Arabia.     

Adsorption of meloxicam on porous calcium silicate: Characterization and tablet formulation

The purpose of the present study was characterization of microparticles obtained by adsorption of poorly water soluble drug, meloxicam, on a porous silicate carrier Florite RE (FLR) and development of a tablet formulation using these microparticles, with improved drug dissolution properties. The study also reveals the use of FLR as a pharmaceutical excipient. Meloxicam was adsorbed on the FLR in 2 proportions (1∶1 and 1∶3), by fast evaporation of solvent from drug solution containing dispersed FLR. Drug adsorbed FLR microparticles were evaluated for surface topography, thermal analysis, X-ray diffraction properties, infrared spectrum, residual solvent, micromeritic properties, drug content, solubility, and dissolution studies. Microparticles showed bulk density in the range of 0.10 to 0.12 g/cm³. Dissolution of drug from microparticles containing 1∶3, drug∶FLR ratio was faster than microparticles containing 1∶1, drug∶FLR ratio. These microparticles were used for formulating directly compressible tablets. Prepared tablets were compared with a commercial tablet. All the prepared tablets showed acceptable mechanical properties. Disintegration time of prepared tablets was in the range of 18 to 38 seconds, and drug dissolution was much faster in both acidic and basic medium from prepared tablets as compared with commercial tablet. The results suggest that FLR provides a large surface area for drug adsorption and also that a reduction in crystallinity of drug occurs. Increase in surface area and reduction in drug crystallinity result in improved drug dissolution from microparticles. Published: December 7, 2005     

Pivotal role of AtSUVH2 in heterochromatic histone methylation and gene silencing in Arabidopsis

SU(VAR)3-9 like histone methyltransferases control heterochromatic domains in eukaryotes. In Arabidopsis, 10 SUVH genes encode SU(VAR)3-9 homologues where SUVH1, SUVH2 and SUVH4 (KRYPTONITE) represent distinct subgroups of SUVH genes. Loss of SUVH1 and SUVH4 causes weak reduction of heterochromatic histone H3K9 dimethylation, whereas in SUVH2 null plants mono- and dimethyl H3K9, mono- and dimethyl H3K27, and monomethyl H4K20, the histone methylation marks of Arabidopsis heterochromatin are significantly reduced. Like animal SU(VAR)3-9 proteins SUVH2 displays strong dosage-dependent effects. Loss of function suppresses, whereas overexpression enhances, gene silencing, causes ectopic heterochromatization and significant growth defects. Furthermore, modification of transgene silencing by SUVH2 is partially transmitted to the offspring plants. This epigenetic stability correlates with heritable changes in DNA methylation. Mutational dissection of SUVH2 indicates an implication of its N-terminus and YDG domain in directing DNA methylation to target sequences, a prerequisite for consecutive histone methylation. Gene silencing by SUVH2 depends on MET1 and DDM1, but not CMT3. In Arabidopsis, SUVH2 with its histone H3K9 and H4K20 methylation activity has a central role in heterochromatic gene silencing.     

Fluid shear- and time-dependent modulation of molecular interactions between PMNs and colon carcinomas

This study compares the effects offluid shear on the kinetics, adhesion efficiency, stability, andmolecular requirements of polymorphonuclear leukocyte (PMN) binding totwo colon adenocarcinoma cell-lines, theCD54-negative/sLe^x-bearing LS174T cells and theCD54-expressing/sLe^x-low HCT-8 cells. The efficiency ofPMN-colon carcinoma heteroaggregation decreases with increasing shear,with PMNs binding HCT-8 more efficiently than LS174T cells at low shear(50-200 s¹). In the low shear regime, CD11b issufficient to mediate PMN binding to LS174T cells. In contrast, bothCD11a and CD11b contribute to PMN-HCT-8 heteroaggregation, with CD54 onHCT-8 cells acting as a CD11a ligand at early time points. At highshear, only PMN-LS174T heteroaggregation occurs, which is initiated byPMN L-selectin binding to a sialylated, O-linked, protease-sensitiveligand on LS174T cells. PMN-LS174T heteroaggregation is primarilydependent on the intercellular contact duration (or shear rate),whereas PMN-HCT-8 binding is a function of both the intercellularcontact duration and the applied force (or shear stress). Cumulatively, these studies suggest that fluid shear modulates the kinetics andmolecular mechanisms of PMN-colon carcinoma cell aggregation.

     

Preferential binding of platelets to monocytes over neutrophils under flow

This study was undertaken to systematically investigate the binding kinetics of platelet recruitment by monocytes relative to neutrophils in bulk suspensions subjected to shear as well as the molecular requirements of leukocyte-platelet binding. Hydrodynamic shear-induced collisions augment the proportion of monocytes with adherent platelets more drastically than that of neutrophils with bound platelets. These heterotypic interactions are further potentiated by platelet activation with thrombin or to a lesser extent by monocyte stimulation with N-formyl-methionyl-leucyl-phenylalanine (fMLP). Monocyte-platelet heteroaggregation increases with increasing shear rate and shear exposure time. Platelet P-selectin binding to monocyte P-selectin-glycoprotein-ligand-1 is solely responsible for maximal platelet adhesion to unstimulated monocytes in shear flow. However, the enhanced platelet binding to fMLP-treated monocytes involves a sequential two-step process, wherein P-selectin-PSGL-1 interactions are stabilized by CD18-integrin involvement. Blocking platelet alpha(IIb)beta(3) or monocyte beta(1)-integrin function had no effect. This study underscores the preferential recruitment of platelets by monocytes relative to neutrophils in shear flow, and demonstrates that the shear environment of the vasculature coupled to the state of cell activation modulates the dynamics and molecular constituents mediating monocyte-platelet adhesion.     

Structural and functional roles of desmin in mouse skeletal muscle during passive deformation

Mechanical interactions between desmin and Z-disks, costameres, and nuclei were measured during passive deformation of single muscle cells. Image processing and continuum kinematics were used to quantify the structural connectivity among these structures. Analysis of both wild-type and desmin-null fibers revealed that the costamere protein talin colocalized with the Z-disk protein alpha-actinin, even at very high strains and stresses. These data indicate that desmin is not essential for mechanical coupling of the costamere complex and the sarcomere lattice. Within the sarcomere lattice, significant differences in myofibrillar connectivity were revealed between passively deformed wild-type and desmin-null fibers. Connectivity in wild-type fibers was significantly greater compared to desmin-null fibers, demonstrating a significant functional connection between myofibrils that requires desmin. Passive mechanical analysis revealed that desmin may be partially responsible for regulating fiber volume, and consequently, fiber mechanical properties. Kinematic analysis of alpha-actinin strain fields revealed that knockout fibers transmitted less shear strain compared to wild-type fibers and experienced a slight increase in fiber volume. Finally, linkage of desmin intermediate filaments to muscle nuclei was strongly suggested based on extensive loss of nuclei positioning in the absence of desmin during passive fiber loading.     

Evaluation of novel TGR5 agonist in combination with Sitagliptin for possible treatment of type 2 diabetes

TGR5 is a member of G protein-coupled receptor (GPCR) superfamily, a promising molecular target for metabolic diseases. Activation of TGR5 promotes secretion of glucagon-like peptide-1 (GLP-1), which activates insulin secretion. A series of 2-thio-imidazole derivatives have been identified as novel, potent and orally efficacious TGR5 agonists. Compound 4d, a novel TGR5 agonist, in combination with Sitagliptin, a DPP-4 inhibitor, has demonstrated an adequate GLP-1 secretion and glucose lowering effect in animal models, suggesting a potential clinical option in treatment of type-2 diabetes.     

Small molecule inhibitors reveal an indispensable scaffolding role of RIPK2 in NOD2 signaling

RIPK2 mediates inflammatory signaling by the bacteria‐sensing receptors NOD1 and NOD2. Kinase inhibitors targeting RIPK2 are a proposed strategy to ameliorate NOD‐mediated pathologies. Here, we reveal that RIPK2 kinase activity is dispensable for NOD2 inflammatory signaling and show that RIPK2 inhibitors function instead by antagonizing XIAP‐binding and XIAP‐mediated ubiquitination of RIPK2. We map the XIAP binding site on RIPK2 to the loop between β2 and β3 of the N‐lobe of the kinase, which is in close proximity to the ATP‐binding pocket. Through characterization of a new series of ATP pocket‐binding RIPK2 inhibitors, we identify the molecular features that determine their inhibition of both the RIPK2‐XIAP interaction, and of cellular and in vivoNOD2 signaling. Our study exemplifies how targeting of the ATP‐binding pocket in RIPK2 can be exploited to interfere with the RIPK2‐XIAP interaction for modulation of NOD signaling.     

Distribution of live and dead cells in pellets of an actinomycete Amycolatopsis balhimycina and its correlation with balhimycin productivity

Secondary metabolites such as antibiotics are typically produced by actinomycetes as a response to growth limiting stress conditions. Several studies have shown that secondary metabolite production is correlated with changes observed in actinomycete pellet morphology. Therefore, we investigated the correlation between the production of balhimycin and the spatio-temporal distribution of live and dead cells in pellets of Amycolatopsis balhimycina in submerged cultures. To this end, we used laser scanning confocal microscopy to analyze pellets from balhimycin producing and nonproducing media containing 0.2 and 1.0 g l^?1 of potassium di-hydrogen phosphate, respectively. We observed a substantially higher fraction of live cells in pellets from cultures yielding larger amounts of balhimycin. Moreover, in media that resulted in no balhimycin production, the pellets exhibit an initial death phase which commences from the centre of the pellet and extends in the radial direction. A second growth phase was observed in these pellets, where live mycelia are seen to appear in the dead core of the pellets. This secondary growth was absent in pellets from media producing higher amounts of balhimycin. These results suggest that distribution of live and dead cells and its correlation with antibiotic production in the non-sporulating A. balhimycina differs markedly than that observed in Streptomycetes.