α(1,3)-Fucosyltransferases FUT4 and FUT7 Control Murine Susceptibility to Thrombosis

The α(1,3)-fucosyltransferases, types IV and VII (FUT4 and FUT7, respectively), are required for the synthesis of functional selectin-type leukocyte adhesion molecule ligands. The selectins and their ligands modulate leukocyte trafficking, and P-selectin and its ligand, P-selectin glycoprotein ligand-1, can modulate hemostasis and thrombosis. Regulation of thrombosis by FUT4 and/or FUT7 activity was examined in mouse models of carotid artery thrombosis and collagen/epinephrine-induced thromboembolism. Mice lacking both FUT4 and FUT7 (Fut−/− mice) had a shorter time to occlusive thrombus formation in the injured carotid artery and a higher mortality due to collagen/epinephrine-induced pulmonary thromboemboli. Mice lacking P-selectin or P-selectin glycoprotein ligand-1 did not have a prothrombotic phenotype. Whole blood platelet aggregation was enhanced, and plasma fibrinogen content, clot weight, and clot strength were increased in Fut−/− mice, and in vitro clot lysis was reduced compared with wild type. Fut4−/−, but not Fut7−/−, mice had increased pulmonary thromboembolism-induced mortality and decreased thromboemboli dissolution in vivo. These data show that FUT4 and FUT7 activity regulates thrombosis in a P-selectin– and P-selectin glycoprotein ligand-1–independent manner and suggest that FUT4 activity is important for thrombolysis

Microbial Colonization Induces Dynamic Temporal and Spatial Patterns of NF-κB Activation in the Zebrafish Digestive Tract

The nuclear factor κ-light-chain enhancer of activated B cells (NF-κB) transcription factor pathway is activated in response to diverse microbial stimuli to regulate expression of genes involved in immune responses and tissue homeostasis. However, the temporal and spatial activation of NF-κB in response to microbial signals have not been determined in whole living organisms, and the molecular and cellular details of these responses are not well understood. We used in vivo imaging and molecular approaches to analyze NF-κB activation in response to the commensal microbiota in transparent gnotobiotic zebrafish

Carbon Monoxide and Heme Oxygenase-1 Prevent Intestinal Inflammation in Mice by Promoting Bacterial Clearance

Heme oxygenase-1 (HO-1) and its metabolic by-product, carbon monoxide (CO), protect against intestinal inflammation in experimental models of colitis, but little is known about their intestinal immune mechanisms. We investigated the interactions among CO, HO-1, and the enteric microbiota in mice and zebrafish

Microbiota Regulate Intestinal Absorption and Metabolism of Fatty Acids in the Zebrafish

SummaryRegulation of intestinal dietary fat absorption is critical to maintaining energy balance. While intestinal microbiota clearly impact the host’s energy balance, their role in intestinal absorption and extraintestinal metabolism of dietary fat is less clear. Using in vivo imaging of fluorescent fatty acid (FA) analogs delivered to gnotobiotic zebrafish hosts, we reveal that microbiota stimulate FA uptake and lipid droplet (LD) formation in the intestinal epithelium and liver. Microbiota increase epithelial LD number in a diet-dependent manner. The presence of food led to the intestinal enrichment of bacteria from the phylum Firmicutes. Diet-enriched Firmicutes and their products were sufficient to increase epithelial LD number, whereas LD size was increased by other bacterial types. Thus, different members of the intestinal microbiota promote FA absorption via distinct mechanisms. Diet-induced alterations in microbiota composition might influence fat absorption, providing mechanistic insight into how microbiota-diet interactions regulate host energy balance

Carbon Monoxide and Heme Oxygenase-1 Prevent Intestinal Inflammation in Mice by Promoting Bacterial Clearance

BACKGROUND & AIMS: Heme oxygenase-1 (HO-1) and its metabolic by-product, carbon monoxide (CO), protect against intestinal inflammation in experimental models of colitis, but little is known about their intestinal immune mechanisms. We investigated the interactions among CO, HO-1, and the enteric microbiota in mice and zebrafish. METHODS: Germ-free, wild-type, and Il10(−/−) mice and germ free zebrafish embryos were colonized with pathogen-free (SPF). Germ-free or SPF-raised wild-type and Il10(−/−) mice were given intraperitoneal injections of cobalt protoporphyrin (CoPP), which upregulates HO-1, the CO releasing molecule ALF186, or saline (control). Colitis was induced in wild-type mice housed in SPF conditions by infection with S. typhimurium. RESULTS: In colons of germ-free, wild-type mice, SPF microbiota induced production of HO-1 via activation of Nrf2–, IL-10–, and toll-like receptor–dependent pathways; similar observations were made in zebrafish. SPF microbiota did not induce HO-1 in colons of germ-free Il10(−/−) mice. Administration of CoPP to Il10(−/−) mice before transition from germ-free to SPF conditions reduced their development of colitis. In Il10(−/−) mice, CO and CoPP reduced levels of enteric bacterial genomic DNA in mesenteric lymph nodes (MLN). In mice with S. typhimurium-induced enterocolitis, CoPP reduced the numbers of live S. typhimurium recovered from the lamina propria, MLN, spleen, and liver. Knockdown of HO-1 in mouse macrophages impaired their bactericidal activity against E. coli, E. faecalis, and S. typhimurium, whereas exposure to CO or overexpression of HO-1 increased their bactericidal activity. HO-1 induction and CO increased acidification of phagolysosomes. CONCLUSIONS: Colonic HO-1 prevents colonic inflammation in mice. HO-1 is induced by the enteric microbiota and its homeostatic function is mediated, in part, by promoting bactericidal activities of macrophages

Physical Activity and Diabetes: Opportunities for Prevention Through Policy

Over the past decade, the prevalence of type 2 diabetes mellitus has reached epidemic levels in the United States and other developed countries. With a concomitant rise in obesity levels in the United States and advances in the treatment of diabetes and its complications, the prevalence of diabetes is expected to continue to rise through the year 2050. Despite strong evidence that regular physical activity can prevent or delay the onset of diabetes, too many Americans are not meeting the recommended levels of regular physical activity. Although most physical activity interventions to date have been focused on characteristics of the individual, more-recent studies have considered how changing characteristics of the social and physical environment in which people live may ultimately have a greater impact on increasing population levels of physical activity. Policy interventions are a way to make sustainable changes in the physical environment of a community and thus provide support for other intrapersonal and interpersonal behavioral change interventions. Policy changes also can affect the social norms that shape behavior. The purposes of this perspective article are: (1) to describe the rationale for population approaches to primary prevention of type 2 diabetes, (2) to discuss how policy interventions can increase physical activity levels within populations, and (3) to provide recommendations for the role of physical therapists in interventions that can increase the level of physical activity in communities. Public health approaches to curb the diabetes epidemic are urgently needed. Policy interventions to increase population levels of physical activity show promise for diabetes prevention. Physical therapists are uniquely suited to influence primary prevention efforts for diabetes. © 2008 American Physical Therapy Association

Type Ia supernova bolometric light curves and ejected mass estimates from the nearby supernova factory

We present a sample of normal type Ia supernovae from the Nearby Supernova Factory dataset with spectrophotometry at sufficiently late phases to estimate the ejected mass using the bolometric light curve. We measure $^{56}$Ni masses from the peak bolometric luminosity, then compare the luminosity in the $^{56}$Co-decay tail to the expected rate of radioactive energy re- lease from ejecta of a given mass. We infer the ejected mass in a Bayesian context using a semi-analytic model of the ejecta, incorporating constraints from contemporary numerical models as priors on the density structure and distribution of $^{56}$Ni throughout the ejecta. We find a strong correlation between ejected mass and light curve decline rate, and consequently $^{56}$Ni mass, with ejected masses in our data ranging from 0.9-1.4 $M_\odot$. Most fast-declining (SALT2 $x_1 < -1$) normal SNe Ia have significantly sub-Chandrasekhar ejected masses in our fiducial analysis.Comment: 20 pages, 10 figures, accepted to MNRA