Inhibition of tumor necrosis factor α–stimulated monocyte adhesion to human aortic endothelial cells by AMP-activated protein kinase

<b>Objective</b>— Proatherosclerotic adhesion of leukocytes to the endothelium is attenuated by NO. As AMP-activated protein kinase (AMPK) regulates endothelial NO synthesis, we investigated the modulation of adhesion to cultured human aortic endothelial cells (HAECs) by AMPK. <b>Methods and Results</b>— HAECs incubated with the AMPK activator, AICAR, or expressing constitutively active AMPK demonstrated reduced TNF α-stimulated adhesion of promonocytic U-937 cells. Rapid inhibition of TNF α-stimulated U-937 cell adhesion by AICAR was NO-dependent, associated with unaltered cell surface adhesion molecule expression, and reduced MCP-1 secretion by HAECs. In contrast, inhibition of TNF α-stimulated U-937 cell adhesion by prolonged AMPK activation was NO-independent and associated with reduced cell surface adhesion molecule expression. <b>Conclusions</b>— AMPK activation in HAECs inhibits TNF α-stimulated leukocyte adhesion by a rapid NO-dependent mechanism associated with reduced MCP-1 secretion and a late NO-independent mechanism whereby adhesion molecule expression, in particular E-selectin, is suppressed. We investigated the functional effects of AMPK activation in cultured human endothelial cells. Stimulation of AMPK inhibited TNF α-stimulated monocyte adhesion by two distinct mechanisms: a rapid NO-dependent mechanism associated with a reduction in chemokine release and a late NO-independent mechanism whereby adhesion molecule expression is suppressed

MONOID RINGS AND STRONGLY TWO-GENERATED IDEALS

This paper determines whether monoid rings with the two-generator property have the strong two-generator property. Dedekind domains have both the two-generator and strong two-generator properties. How common is this? Two cases are considered here: the zero-dimensional case and the one-dimensional case for monoid rings. Each case is looked at to determine if monoid rings that are not PIRs but are two-generated have the strong two-generator property. Full results are given in the zero-dimensional case, however only partial results have been found for the one-dimensional case

Heavy Quark Parameters and Vcb from Spectral Moments in Semileptonic B Decays

We extract the heavy quark masses and non-perturbative parameters from the Delphi preliminary measurements of the first three moments of the charged lepton energy and hadronic mass distributions in semileptonic B decays, using a multi-parameter fit. We adopt two formalisms, one of which does not rely on a 1/mc expansion and makes use of running quark masses. The data are consistent and the level of accuracy of the experimental inputs largely determines the present sensitivity. The results allow to improve on the uncertainty in the extraction of Vcb.Comment: 13 pages, 2 figure

Cephalosporinases associated with outer membrane vesicles released by Bacteroides spp. protect gut pathogens and commensals against beta-lactam antibiotics

Objectives: To identify β-lactamase genes in gut commensal Bacteroides species and to assess the impact of these enzymes, when carried by outer membrane vesicles (OMVs), in protecting enteric pathogens and commensals. Methods: A deletion mutant of the putative class A β-lactamase gene (locus tag BT_4507) found in the genome of the human commensal Bacteroides thetaiotaomicron was constructed and a phenotypic analysis performed. A phylogenetic tree was built from an alignment of nine Bacteroides cephalosporinase protein sequences, using the maximum likelihood method. The rate of cefotaxime degradation after incubation with OMVs produced by different Bacteroides species was quantified using a disc susceptibility test. The resistance of Salmonella Typhimurium and Bifidobacterium breve to cefotaxime in liquid culture in the presence of B. thetaiotaomicron OMVs was evaluated by measuring bacterial growth. Results: The B. thetaiotaomicron BT_4507 gene encodes a β-lactamase related to the CepA cephalosporinase of Bacteroides fragilis. OMVs produced by B. thetaiotaomicron and several other Bacteroides species, except Bacteroides ovatus, carried surface-associated β-lactamases that could degrade cefotaxime. β-Lactamase-harbouring OMVs from B. thetaiotaomicron protected Salmonella Typhimurium and B. breve from an otherwise lethal dose of cefotaxime. Conclusions: The production of membrane vesicles carrying surface-associated β-lactamases by Bacteroides species, which constitute a major part of the human colonic microbiota, may protect commensal bacteria and enteric pathogens, such as Salmonella Typhimurium, against β-lactam antibiotics

Borrowed alleles and convergence in serpentine adaptation

ACKNOWLEDGMENTS. We thank members of the L.Y. and K.B. laboratories for helpful discussions. This work was supported through the European Research Council Grant StG CA629F04E (to L.Y.); a Harvard University Milton Fund Award (to K.B.); Ruth L. Kirschstein National Research Service Award 1 F32 GM096699 from the NIH (to L.Y.); National Science Foundation Grant IOS-1146465 (to K.B.); NIH National Institute of General Medical Sciences Grant 2R01GM078536 (to D.E.S.); and Biotechnology and Biological Sciences Research Council Grant BB/L000113/1 (to D.E.S.)Peer reviewedPublisher PD

High-resolution genome-wide scan of genes, gene-networks and cellular systems impacting the yeast ionome

Peer reviewedPublisher PD

Vegetarianism

Ethical vegetarians maintain that vegetarianism is morally required. The principal reasons offered in support of ethical vegetarianism are: (i) concern for the welfare and well-being of the animals being eaten, (ii) concern for the environment, (iii) concern over global food scarcity and the just distribution of resources, and (iv) concern for future generations. Each of these reasons is explored in turn, starting with a historical look at ethical vegetarianism and the moral status of animals

Executive abilities in children with congenital visual impairment in mid-childhood.

The role of vision and vision deprivation in the development of executive function (EF) abilities in childhood is little understood; aspects of EF such as initiative, attention orienting, inhibition, planning and performance monitoring are often measured through visual tasks. Studying the development and integrity of EF abilities in children with congenital visual impairment (VI) may provide important insights into the development of EF and also its possible relationship with vision and non-visual senses. The current study investigates non-visual EF abilities in 18 school-age children of average verbal intelligence with VI of differing levels of severity arising from congenital disorders affecting the eye, retina, or anterior optic nerve. Standard auditory neuropsychological assessments of sustained and divided attention, phonemic, semantic and switching verbal fluency, verbal working memory, and ratings of everyday executive abilities by parents were undertaken. Executive skills were compared to age-matched typically-sighted (TS) typically-developing children and across levels of vision (mild to moderate VI [MVI] or severe to profound VI [SPVI]). The results do not indicate significant differences or deficits on direct assessments of verbal and auditory EF between the groups. However, parent ratings suggest difficulties with everyday executive abilities, with the greatest difficulties in those with SPVI. The findings are discussed as possibly reflecting increased demands of behavioral executive skills for children with VI in everyday situations despite auditory and verbal EF abilities in the typical range for their age. These findings have potential implications for clinical and educational practices

Improving Mitochondrial Function Protects Bumblebees from Neonicotinoid Pesticides

Global pollination is threatened by declining insect pollinator populations that may be linked to neonicotinoid pesticide use. Neonicotinoids over stimulate neurons and depolarize their mitochondria, producing immobility and death. However, mitochondrial function can be improved by near infrared light absorbed by cytochrome c oxidase in mitochondrial respiration. In flies, daily exposure to 670nm light throughout life increases average lifespan and aged mobility, and reduces systemic inflammation. Here we treat bumble bees with Imidacloprid a common neonicotinoid. This undermined ATP and rapidly induced immobility and reduced visual function and survival. Bees exposed to insecticide and daily to 670nm light showed corrected ATP levels and significantly improved mobility allowing them to feed. Physiological recordings from eyes revealed that light exposure corrected deficits induced by the pesticide. Overall, death rates in bees exposed to insecticide but also given 670nm light were indistinguishable from controls. When Imidacloprid and light exposure were withdrawn, survival was maintained. Bees and insects generally cannot see deep red light so it does not disturb their behaviour. Hence, we show that deep red light exposure that improves mitochondrial function, reverses the sensory and motor deficits induced by Imidacloprid. These results may have important implications as light delivery is economic and can be placed in hives/colonies

Insulin-stimulated phosphorylation of endothelial nitric oxide synthase at serine-615 contributes to nitric oxide synthesis

Insulin stimulates endothelial NO (nitric oxide) synthesis via PKB (protein kinase B)/Akt-mediated phosphorylation and activation of eNOS (endothelial NO synthase) at Ser-1177. In previous studies, we have demonstrated that stimulation of eNOS phosphorylation at Ser-1177 may be required, yet is not sufficient for insulin-stimulated NO synthesis. We therefore investigated the role of phosphorylation of eNOS at alternative sites to Ser-1177 as candidate parallel mechanisms contributing to insulin-stimulated NO synthesis. Stimulation of human aortic endothelial cells with insulin rapidly stimulated phosphorylation of both Ser-615 and Ser-1177 on eNOS, whereas phosphorylation of Ser-114, Thr-495 and Ser-633 was unaffected. Insulin-stimulated Ser-615 phosphorylation was abrogated by incubation with the PI3K (phosphoinositide 3-kinase) inhibitor wortmannin, infection with adenoviruses expressing a dominant-negative mutant PKB/Akt or pre-incubation with TNFα (tumour necrosis factor α), but was unaffected by high culture glucose concentrations. Mutation of Ser-615 to alanine reduced insulin-stimulated NO synthesis, whereas mutation of Ser-615 to aspartic acid increased NO production by NOS in which Ser-1177 had been mutated to an aspartic acid residue. We propose that the rapid PKB-mediated stimulation of phosphorylation of Ser-615 contributes to insulin-stimulated NO synthesis