Reduced leg blood flow during dynamic exercise in older endurance-trained men

It is currentlyunclear whether aging alters the perfusion of active muscles duringlarge-muscle dynamic exercise in humans. To study this issue, directmeasurements of leg blood flow (femoral vein thermodilution) andsystemic arterial pressure during submaximal cycle ergometry (70, 140, and 210 W) were compared between six younger (Y; 22-30 yr) and sixolder (O; 55-68 yr) chronically endurance-trainedmen. Whole body O₂uptake, ventilation, and arterial and femoral venous samples forblood-gas, catecholamine, and lactate determinations were alsoobtained. Training duration (min/day), estimated leg muscle mass(dual-energy X-ray absorptiometry; Y, 21.5 ± 1.2 vs. O, 19.9 ± 0.9 kg), and blood hemoglobin concentration (Y, 14.9 ± 0.4 vs. O, 14.7 ± 0.2 g/dl) did not significantly differ (P > 0.05) between groups. Leg bloodflow, leg vascular conductance, and femoral venousO₂ saturation were ~20-30%lower in the older men at each work rate (allP < 0.05), despite similarlevels of whole body O₂ uptake. At210 W, leg norepinephrine spillover rates and femoral venous lactateconcentrations were more than twofold higher in the older men.Pulmonary ventilation was also higher in the older men at 140 (+24%)and 210 (+39%) W. These results indicate that leg blood flow andvascular conductance during cycle ergometer exercise are significantlylower in older endurance-trained men in comparison to their youngercounterparts. The mechanisms responsible for this phenomenon and theextent to which they operate in other groups of older subjects deservefurther attention.

     

Gene silencing with RNA interference in the human pathogenic fungus Aspergillus fumigatus

Aspergillus fumigatus is an opportunistic pathogenic fungus which causes fatal invasive aspergillosis among immunocompromised patients. To obtain a better understanding of the key elements involved in A. fumigatus virulence and to identify possible drug targets, it is necessary to be able to generate gene-deletion strains. Unfortunately, the molecular techniques available do not include a rapid method to disrupt and identify essential genes. RNA interference, a process in which the presence of double-stranded RNA homologous to a gene of interest results in specific degradation of the corresponding message, has been successfully tested on A. fumigatus. We have shown that expression of double stranded RNA corresponding to portions of the ALB1/PKSP and FKS1 genes results in reduced mRNA levels for those genes, with phenotypic consequences similar to that of gene disruption. The two genes could also be subjected to simultaneous interference through expression of chimeric double-stranded RNA. Use of RNA interference in Aspergillus will allow easier examination of the phenotypic consequences of reducing expression of a gene of interest, especially for essential genes.     

Structure-activity relationships and docking studies of synthetic 2-arylindole derivatives determined with aromatase and quinone reductase 1

In our ongoing effort of discovering anticancer and chemopreventive agents, a series of 2-arylindole derivatives were synthesized and evaluated toward aromatase and quinone reductase 1 (QR1). Biological evaluation revealed that several compounds (e.g., 2d, IC₅₀?=?1.61?μM; 21, IC₅₀?=?3.05?μM; and 27, IC₅₀?=?3.34?μM) showed aromatase inhibitory activity with half maximal inhibitory concentration (IC₅₀) values in the low micromolar concentrations. With regard to the QR1 induction activity, 11 exhibited the highest QR1 induction ratio (IR) with a low concentration to double activity (CD) value (IR?=?8.34, CD?=?2.75?μM), while 7 showed the most potent CD value of 1.12?μM. A dual acting compound 24 showed aromatase inhibition (IC₅₀?=?9.00?μM) as well as QR1 induction (CD?=?5.76?μM) activities. Computational docking studies using CDOCKER (Discovery Studio 3.5) provided insight in regard to the potential binding modes of 2-arylindoles within the aromatase active site. Predominantly, the 2-arylindoles preferred binding with the 2-aryl group toward a small hydrophobic pocket within the active site. The C-5 electron withdrawing group on indole was predicted to have an important role and formed a hydrogen bond with Ser478 (OH). Alternatively, meta-pyridyl analogs may orient with the pyridyl 3′-nitrogen coordinating with the heme group.     

A meta-analysis and genome-wide association study of platelet count and mean platelet volume in african americans

Several genetic variants associated with platelet count and mean platelet volume (MPV) were recently reported in people of European ancestry. In this meta-analysis of 7 genome-wide association studies (GWAS) enrolling African Americans, our aim was to identify novel genetic variants associated with platelet count and MPV. For all cohorts, GWAS analysis was performed using additive models after adjusting for age, sex, and population stratification. For both platelet phenotypes, meta-analyses were conducted using inverse-variance weighted fixed-effect models. Platelet aggregation assays in whole blood were performed in the participants of the GeneSTAR cohort. Genetic variants in ten independent regions were associated with platelet count (N?=?16,388) with p<5×10(-8) of which 5 have not been associated with platelet count in previous GWAS. The novel genetic variants associated with platelet count were in the following regions (the most significant SNP, closest gene, and p-value): 6p22 (rs12526480, LRRC16A, p?=?9.1×10(-9)), 7q11 (rs13236689, CD36, p?=?2.8×10(-9)), 10q21 (rs7896518, JMJD1C, p?=?2.3×10(-12)), 11q13 (rs477895, BAD, p?=?4.9×10(-8)), and 20q13 (rs151361, SLMO2, p?=?9.4×10(-9)). Three of these loci (10q21, 11q13, and 20q13) were replicated in European Americans (N?=?14,909) and one (11q13) in Hispanic Americans (N?=?3,462). For MPV (N?=?4,531), genetic variants in 3 regions were significant at p<5×10(-8), two of which were also associated with platelet count. Previously reported regions that were also significant in this study were 6p21, 6q23, 7q22, 12q24, and 19p13 for platelet count and 7q22, 17q11, and 19p13 for MPV. The most significant SNP in 1 region was also associated with ADP-induced maximal platelet aggregation in whole blood (12q24). Thus through a meta-analysis of GWAS enrolling African Americans, we have identified 5 novel regions associated with platelet count of which 3 were replicated in other ethnic groups. In addition, we also found one region associated with platelet aggregation that may play a potential role in atherothrombosis.