Decline in insulin action with age in endurance-trained humans.

We tested the hypothesis that regular endurance exercise prevents the age-related decline in insulin action typically observed in healthy, sedentary adults. An index of whole body insulin sensitivity (ISI), obtained from minimal model analysis of insulin and glucose concentrations during a frequently sampled intravenous glucose tolerance test, was determined in 126 healthy adults: 25 young [27 +/- 1 (SE) yr; 13 men/12 women] and 43 older (59 +/- 1 yr; 20/13) sedentary and 25 young (29 +/- 1 yr; 12/13) and 33 older (60 +/- 1 yr; 20/13) endurance trained. ISI values were lower in the older vs. young adults in both sedentary (-53%; 3.9 +/- 0.3 vs. 7.0 +/- 0.7 x10(-4) x min(-1) x microU(-1) x ml(-1); P < 0.01) and endurance-trained (-36%; 7.9 +/- 0.6 vs. 12.4 +/- 1.0 x 10(-4) min(-1) x microU(-1) x ml(-1); P < 0.01) groups, but the value was 72-102% higher in the trained subjects at either age (P < 0.01). In subgroup analysis of sedentary and endurance-trained adults with similar body fat levels (n = 62), the age-related reduction in ISI persisted only in the endurance-trained subjects (12.9 +/- 1.9 vs. 8.7 +/- 1.2 x 10(-4) x min(-1) x microU(-1) x ml(-1); P < 0.01). The results of the present study suggest that habitual endurance exercise does not prevent the age-associated decline insulin action. Moreover, the age-related reduction in ISI in endurance-trained adults appears to be independent of adiposity.     

Localized Populations of CD8low/? MHC Class I Tetramer+ SIV-Specific T Cells in Lymphoid Follicles and Genital Epithelium

CD8 T cells play an important role in controlling viral infections. We investigated the in situ localization of simian immunodeficiency virus (SIV)-specific T cells in lymph and genital tissues from SIV-infected macaques using MHC-class I tetramers. The majority of tetramer-binding cells localized in T cell zones and were CD8⁺. Curiously, small subpopulations of tetramer-binding cells that had little to no surface CD8 were detected in situ both early and late post-infection, and in both vaginally and rectally inoculated macaques. These tetramer⁺CD8^low/− cells were more often localized in apparent B cell follicles relative to T cell zones and more often found near or within the genital epithelium than the submucosa. Cells analyzed by flow cytometry showed similar populations of cells. Further immunohistological characterization revealed small populations of tetramer⁺CD20⁻ cells inside B cell follicles and that tetramer⁺ cells did not stain with γδ-TCR nor CD4 antibodies. Negative control tetramer staining indicated that tetramer⁺CD8^low/− cells were not likely NK cells non-specifically binding to MHC tetramers. These findings have important implications for SIV-specific and other antigen-specific T cell function in these specific tissue locations, and suggest a model in which antigen-specific CD8+ T cells down modulate CD8 upon entering B cell follicles or the epithelial layer of tissues, or alternatively a model in which only antigen-specific CD8 T cells that down-modulate CD8 can enter B cell follicles or the epithelium.     

Preconditioning involves selective mitophagy mediated by Parkin and p62/SQSTM1

Autophagy-dependent mitochondrial turnover in response to cellular stress is necessary for maintaining cellular homeostasis. However, the mechanisms that govern the selective targeting of damaged mitochondria are poorly understood. Parkin, an E3 ubiquitin ligase, has been shown to be essential for the selective clearance of damaged mitochondria. Parkin is expressed in the heart, yet its function has not been investigated in the context of cardioprotection. We previously reported that autophagy is required for cardioprotection by ischemic preconditioning (IPC). In the present study, we used simulated ischemia (sI) in vitro and IPC of hearts to investigate the role of Parkin in mediating cardioprotection ex vivo and in vivo. In HL-1 cells, sI induced Parkin translocation to mitochondria and mitochondrial elimination. IPC induced Parkin translocation to mitochondria in Langendorff-perfused rat hearts and in vivo in mice subjected to regional IPC. Mitochondrial depolarization with an uncoupling agent similarly induced Parkin translocation to mitochondria in cells and Langendorff-perfused rat hearts. Mitochondrial loss was blunted in Atg5-deficient cells, revealing the requirement for autophagy in mitochondrial elimination. Consistent with previous reports indicating a role for p62/SQSTM1 in mitophagy, we found that depletion of p62 attenuated mitophagy and exacerbated cell death in HL-1 cardiomyocytes subjected to sI. While wild type mice showed p62 translocation to mitochondria and an increase in ubiquitination, Parkin knockout mice exhibited attenuated IPC-induced p62 translocation to the mitochondria. Importantly, ablation of Parkin in mice abolished the cardioprotective effects of IPC. These results reveal for the first time the crucial role of Parkin and mitophagy in cardioprotection.     

Evidence for Distinct 5-Hydroxytryptamine2 Binding Site Subtypes in Cortical Membrane Preparations

5-Hydroxytryptamine (5-HT) displays a sixfold higher affinity for 5-HT2 binding sites labeled by [3H]ketanserin in rat (IC50 = 200 +/- 40 nM) and human (IC50 = 190 +/- 50 nM) cortex than for 5-HT2 sites in bovine cortex (IC50 = 1,200 +/- 130 nM). The Hill slopes of the 5-HT competition curves are 0.67 +/- 0.04 in rat, 0.69 +/- 0.08 in human, and 0.96 +/- 0.02 in bovine cortex. Scatchard analysis of (+/-)-[3H]4-bromo-2,5-dimethoxyamphetamine ([3H]DOB) binding in the rat indicates a population of binding sites with a KD of 0.38 +/- 0.04 nM and a Bmax of 1.5 +/- 0.05 pmol/g tissue. In contrast, specific [3H]DOB binding cannot be detected in bovine cortical membranes. These data indicate that species variations exist in 5-HT2 binding site subtypes and that [3H]ketanserin appears to label a homogeneous population of 5-HT2 binding site subtypes in bovine cortex.     

Distribution,biology and hybridization of Scaphirhynchus albus and S. platorynchus in the Missouri and Mississippi rivers

Synopsis Scaphirhynchus albus and S. platorynchus were studied in Missouri during 1978–1979 to assess their distribution and abundance, to obtain information on their life histories, and to identify existing or potential threats to their survival. S. platorynchus was collected in substantial numbers (4355 specimens) at all 12 sampling stations in the Missouri and Mississippi rivers, while only 11 S. albus were captured from 6 stations. Twelve specimens identified in the field as hybrids between the two species were captured from 4 stations. Morphometric and meristic comparisons of presumed hybrids with the parent species, using cluster and principal components analyses, demonstrated intermediacy of most specimens identified in the field as hybrids. Aquatic insects comprised most of the diet of S. platorynchus and S. albus, but S. albus and the hybrids had consumed considerable quantities of fish. S. albus grew more rapidly than S. platorynchus, while the growth of hybrids was intermediate. Hybridization appears to be a recent phenomenon, resulting from man-caused changes in the big-river environment. Hybridization may be a threat to survival of S. albus in the study streams.     

Global patterns of geographic range size in birds

Large-scale patterns of spatial variation in species geographic range size are central to many fundamental questions in macroecology and conservation biology. However, the global nature of these patterns has remained contentious, since previous studies have been geographically restricted and/or based on small taxonomic groups. Here, using a database on the breeding distributions of birds, we report the first (to our knowledge) global maps of variation in species range sizes for an entire taxonomic class. We show that range area does not follow a simple latitudinal pattern. Instead, the smallest range areas are attained on islands, in mountainous areas, and largely in the southern hemisphere. In contrast, bird species richness peaks around the equator, and towards higher latitudes. Despite these profoundly different latitudinal patterns, spatially explicit models reveal a weak tendency for areas with high species richness to house species with significantly smaller median range area. Taken together, these results show that for birds many spatial patterns in range size described in geographically restricted analyses do not reflect global rules. It remains to be discovered whether global patterns in geographic range size are best interpreted in terms of geographical variation in species assemblage packing, or in the rates of speciation, extinction, and dispersal that ultimately underlie biodiversity.     

Structure-based optimization of 1H-imidazole-2-carboxamides as Axl kinase inhibitors utilizing a Mer mutant surrogate

Axl has been a target of interest in the oncology field for several years based on its role in various oncogenic processes. To date, no wild-type Axl crystal structure has been reported. Herein, we describe the structure-based optimization of a novel chemotype of Axl inhibitors, 1H-imidazole-2-carboxamide, using a mutated kinase homolog, Mer(I650M), as a crystallographic surrogate. Iterative optimization of the initial lead compound (1) led to compound (21), a selective and potent inhibitor of wild-type Axl. Compound (21) will serve as a useful compound for further in vivo studies.