Vascular smooth muscle Sirtuin-1 protects against aortic dissection during Angiotensin II-induced hypertension

BACKGROUND: Sirtuin-1 (SirT1), a nicotinamide adenine dinucleotide(+)-dependent deacetylase, is a key enzyme in the cellular response to metabolic, inflammatory, and oxidative stresses; however, the role of endogenous SirT1 in the vasculature has not been fully elucidated. Our goal was to evaluate the role of vascular smooth muscle SirT1 in the physiological response of the aortic wall to angiotensin II, a potent hypertrophic, oxidant, and inflammatory stimulus. METHODS AND RESULTS: Mice lacking SirT1 in vascular smooth muscle (ie, smooth muscle SirT1 knockout) had drastically high mortality (70%) caused by aortic dissection after angiotensin II infusion (1 mg/kg per day) but not after an equipotent dose of norepinephrine, despite comparable blood pressure increases. Smooth muscle SirT1 knockout mice did not show any abnormal aortic morphology or blood pressure compared with wild-type littermates. Nonetheless, in response to angiotensin II, aortas from smooth muscle SirT1 knockout mice had severely disorganized elastic lamellae with frequent elastin breaks, increased oxidant production, and aortic stiffness compared with angiotensin II-treated wild-type mice. Matrix metalloproteinase expression and activity were increased in the aortas of angiotensin II-treated smooth muscle SirT1 knockout mice and were prevented in mice overexpressing SirT1 in vascular smooth muscle or with use of the oxidant scavenger tempol. CONCLUSIONS: Endogenous SirT1 in aortic smooth muscle is required to maintain the structural integrity of the aortic wall in response to oxidant and inflammatory stimuli, at least in part, by suppressing oxidant-induced matrix metalloproteinase activity. SirT1 activators could potentially be a novel therapeutic approach to prevent aortic dissection and rupture in patients at risk, such as those with hypertension or genetic disorders, such as Marfan's syndrome.R01 HL098028 - NHLBI NIH HHS; HL098028 - NHLBI NIH HHS; HL105287 - NHLBI NIH HHS; T32 HL07224 - NHLBI NIH HH

Assessing indicators of runoff and erosion by rain simulation in the Ben Ahmed watershed (Central Morocco)

The objective of this study was to investigate the risks of runoff and erosion of soils in the Ben Ahmed watershed, it's located in the region of casa-settat, 70 km south-east of Casablanca, and characterized by a semi-arid climate. The study consists of measuring on 1 m2 plot, the volumes of runoff and sediments, under the influence of rainfall generation (60mm/30 min). Soil samples were collected from each plot to determine texture, organic matter and humidity. Results obtained show that the detachability varies between 19 and 34 g/l, infiltrability oscillate between 15 and 37 mm.h-. Pearson correlation test shows that infiltration was negatively correlated with runoff and soil detachability (R=-0.99, R=-0.87 respectively). It‘s significantly correlated with the proportions of sand(R=0.69), silt (R= -0.98) an clay (R= 0.92), however, is weakly correlated with organic matter (R=-0.32). Infiltration and detachability were significantly correlated with humidity (R = -0.99, R = -0.63respectively)

Bounded and unitary elements in pro-C^*-algebras

A pro-C^*-algebra is a (projective) limit of C^*-algebras in the category of topological *-algebras. From the perspective of non-commutative geometry, pro-C^*-algebras can be seen as non-commutative k-spaces. An element of a pro-C^*-algebra is bounded if there is a uniform bound for the norm of its images under any continuous *-homomorphism into a C^*-algebra. The *-subalgebra consisting of the bounded elements turns out to be a C^*-algebra. In this paper, we investigate pro-C^*-algebras from a categorical point of view. We study the functor (-)_b that assigns to a pro-C^*-algebra the C^*-algebra of its bounded elements, which is the dual of the Stone-\v{C}ech-compactification. We show that (-)_b is a coreflector, and it preserves exact sequences. A generalization of the Gelfand-duality for commutative unital pro-C^*-algebras is also presented.Comment: v2 (accepted

The link between job satisfaction and organizational commitment:differences between public and private sector employees

Employees in the public and private sectors experience different working conditions and employment relationships. Therefore, it can be assumed that their attitudes toward their job and organizations, and relationships between them, are different. The existing literature has identified the relationship between organizational commitment and job satisfaction as interesting in this context. The present field study examines the satisfaction–commitment link with respect to differences between private and public sector employees. A sample of 617 Greek employees (257 from the private sector and 360 from the public sector) completed standardized questionnaires. Results confirmed the hypothesized relationship differences: Extrinsic satisfaction and intrinsic satisfaction are more strongly related to affective commitment and normative commitment for public sector employees than for private sector ones. The results are discussed, limitations are considered, and directions for future research are proposed

Effects of a Composite Endomycorrhizal Inoculum on Olive Cuttings under the Greenhouse Conditions

This study was carried out in a nursery to evaluate the impact of mycorrhizal fungi on the cutting's root growth, and root colonization of a Moroccan olive variety ‘Picholine Marocaine' under greenhouse conditions during 2 years of cultivation. The results revealed that the inoculation with a composite inoculum of arbuscular mycorrhizal fungi (AMF) stimulated an early root formation and high development of vegetative shoots in inoculated cuttings respectively, 35 days (50 days in the control plots) and 40 days (60 days in the control plots) after their culture. The progressive establishment of mycorrhizal symbiosis in the roots of the inoculated plants showed that the root and vegetative masses were respectively 24 g and 19.5 g two years after inoculation. The average height and the leave's number of the inoculated plants relative to the control were respectively s 42/ 12 cm and 145/12. The newly formed roots were mycorrhizal and present different structures characteristic of AMF: arbuscules, vesicles, hyphae and spores, whose frequency and intensity reached 90% and 75% two years after cuttings cultivation. The arbuscular and vesicular contents and the number of spores were 67%, 96% and 212 spores/ 100 g of soil respectively. The fourteen species of mycorrhizal fungi isolated from the rhizosphere belong to 4 genera (Glomus, Acaulospora, Gigaspora, and Scutellospora) and three families (Glomaceae, Acaulosporaceae and Gigasporacea).The Glomus genus was the most dominant (65%) followed by the Gigaspora genus (22%). Glomus intraradices, Gigaspora sp.2, Glomus versiformes are the most abundant species, their frequency of occurrence are respectively 30%, 21% and 16%

A Phase II Trial of AZD6244 (Selumetinib, ARRY-142886), an Oral MEK1/2 Inhibitor, in Relapsed/Refractory Multiple Myeloma

AZD6244 is a MEK1/2 inhibitor with significant preclinical activity in multiple myeloma (MM) cells. This phase 2 study used a two-stage Simon design to determine the AZD6244 response rate in patients with relapsed or refractory MM

Sustained antiproliferative mechanisms by RB24, a targeted precursor of multiple inhibitors of epidermal growth factor receptor and a DNA alkylating agent in the A431 epidermal carcinoma of the vulva cell line

Recently, with the purpose of enhancing the potency of epidermal growth factor receptor (EGFR)-based therapies, we designed a novel strategy termed ‘Cascade-release targeting’ that seeks to develop molecules capable of degrading to multiple tyrosine kinase (TK) inhibitors and highly reactive electrophiles, in a stepwise fashion. Here we report on the first prototype of this model, RB24, a masked methyltriazene, that in addition to being an inhibitor on its own was designed to degrade to RB14, ZR08, RB10+a DNA alkylating methyldiazonium species. The cascade degradation of RB24 requires the generation of two reactive electrophiles: (a) an iminium ion and (b) a methyldiazonium ion. Thus, we surmise that these species could alkylate the active site of EGFR, thereby irreversibly blocking its action and that DNA damage could be induced by the methyldiazonium. Using the EGFR-overexpressing human epidermoid carcinoma of the vulva cell line, A431, we demonstrate herein that (a) RB24 and its derived species (e.g. RB14, ZR08) irreversibly inhibit EGFR autophosphorylation, (b) RB24 induced significant levels of DNA strand breaks, (c) sustained inhibition of EGFR by RB24 was associated with blockade of MAPK activation and c-fos gene expression, (d) RB24 induced irreversible cell growth inhibition with a 100-fold greater potency than Temodal™, a clinical methyltriazene. The pronounced growth inhibitory potency of RB24 was attributed to its ability to simultaneously damage DNA and irreversibly block EGFR TK activity