Tetramethoxystilbene-loaded liposomes restore reactive-oxygen-species-mediated attenuation of dilator responses in rat aortic vessels Ex vivo

The methylated analogue of the polyphenol resveratrol (RV), 2,3',4,5'-tetramethoxystilbene (TMS) displays potent antioxidant properties and is an effective cytochrome P450 (CYP) 1B1 inhibitor. The bioavailability of TMS is low. Therefore, the use of liposomes for the encapsulation of TMS is a promising delivery modality for enhanced uptake into tissues. We examined the effect of delivery of TMS in liposomes on the restoration of vasodilator responses of isolated aortic vessels after acute tension elevation ex vivo. Aortic vessels from young male Wistar rats were isolated, and endothelial-dependent (acetylcholine, ACh) and -independent (sodium nitroprusside, SNP) responses assessed. Acute tension elevation (1 h) significantly reduced ACh dilator responses, which were restored following incubation with superoxide dismutase or apocynin (an NADPH oxidase inhibitor). Incubation with TMS-loaded liposomes (mean diameter 157 ± 6 nm; PDI 0.097) significantly improved the attenuated dilator responses following tension elevation, which was sustained over a longer period (4 h) when compared to TMS solution. Endothelial denudation or co-incubation with L-NNA (Nω-nitro-l-arginine; nitric oxide synthase inhibitor) resulted in loss of dilator function. Our findings suggest that TMS-loaded liposomes can restore attenuated endothelial-dependent dilator responses induced by an oxidative environment by reducing NADPH-oxidase-derived ROS and potentiating the release of the vasodilator nitric oxide. TMS-loaded liposomes may be a promising therapeutic strategy to restore vasodilator function in vascular disease

Challenging the challenge: handling data in the Gigabit/s range

The ALICE experiment at CERN will propose unprecedented requirements for event building and data recording. New technologies will be adopted as well as ad-hoc frameworks, from the acquisition of experimental data up to the transfer onto permanent media and its later access. These issues justify a careful, in-depth planning and preparation. The ALICE Data Challenge is a very important step of this development process where simulated detector data is moved from dummy data sources up to the recording media using processing elements and data-paths as realistic as possible. We will review herein the current status of past, present and future ALICE Data Challenges, with particular reference to the sessions held in 2002 when - for the first time - streams worth one week of ALICE data were recorded onto tape media at sustained rates exceeding 300 MB/s.Comment: Talk from the 2003 Computing in High Energy and Nuclear Physics (CHEP03), La Jolla, Ca, USA, March 2003, 9 pages, PDF. PSN MOGT00

Internal Mammary Arteries as a Model to Demonstrate Restoration of the Impaired Vasodilation in Hypertension, Using Liposomal Delivery of the CYP1B1 Inhibitor, 2,3′,4,5′-Tetramethoxystilbene

A significant number of patients with severe cardiovascular disease, undergoing coronary artery bypass grafting (CABG), present with hypertension. While internal mammary arteries (IMAs) may be a better alternative to vein grafts, their impaired vasodilator function affects their patency. Our objectives were to (1) determine if inhibition of the cytochrome P450 enzyme CYP1B1, using liposome-encapsulated 2,3′,4,5′-tetramethoxystilbene (TMS), can potentiate vasodilation of IMAs from CABG patients, and (2) assess mechanisms involved using coronary arteries from normal rats, in an ex vivo model of hypertension. PEGylated liposomes were synthesized and loaded with TMS (mean diameter 141 ± 0.9 nm). Liposomal delivery of TMS improved its bioavailability Compared to TMS solution (0.129 ± 0.02 ng/mL vs. 0.086 ± 0.01 ng/mL at 4 h; p < 0.05). TMS-loaded liposomes alleviated attenuated endothelial-dependent acetylcholine (ACh)-induced dilation in diseased IMAs (@ACh 10−4 M: 56.9 ± 5.1%; n = 8 vs. 12.7 ± 7.8%; n = 6; p < 0.01) for TMS-loaded liposomes vs. blank liposomes, respectively. The alleviation in dilation may be due to the potent inhibition of CYP1B1 by TMS, and subsequent reduction in reactive oxygen species (ROS) moieties and stimulation of nitric oxide synthesis. In isolated rat coronary arteries exposed to a hypertensive environment, TMS-loaded liposomes potentiated nitric oxide and endothelium-derived hyperpolarization pathways via AMPK. Our findings are promising for the future development of TMS-loaded liposomes as a promising therapeutic strategy to enhance TMS bioavailability and potentiate vasodilator function in hypertension, with relevance for early and long-term treatment of CABG patients, via the sustained and localized TMS release within IMA

A therapeutic antibody targeting osteoprotegerin attenuates severe experimental pulmonary arterial hypertension

Abstract: Pulmonary arterial hypertension (PAH) is a rare but fatal disease. Current treatments increase life expectancy but have limited impact on the progressive pulmonary vascular remodelling that drives PAH. Osteoprotegerin (OPG) is increased within serum and lesions of patients with idiopathic PAH and is a mitogen and migratory stimulus for pulmonary artery smooth muscle cells (PASMCs). Here, we report that the pro-proliferative and migratory phenotype in PASMCs stimulated with OPG is mediated via the Fas receptor and that treatment with a human antibody targeting OPG can attenuate pulmonary vascular remodelling associated with PAH in multiple rodent models of early and late treatment. We also demonstrate that the therapeutic efficacy of the anti-OPG antibody approach in the presence of standard of care vasodilator therapy is mediated by a reduction in pulmonary vascular remodelling. Targeting OPG with a therapeutic antibody is a potential treatment strategy in PAH

Computing at the Petabyte scale with the WLCG

The Worldwide LHC Computing Grid provides and operates the Grid infrastructure used by the experiments of the Large Hadron Collider at CERN for their data processing. The huge amount of data to be distributed and analysed, the number of collaborating centres and users and the diversity of the underlying resources make the WLCG the largest and most complex research Grid currently in operation. In this paper we describe how the WLCG successfully provides a scalable system for the LHC experiments and its recent successes during data challenges and data taking

The CREAM-CE: First experiences, results and requirements of the four LHC experiments

In terms of the gLite middleware, the current LCG-CE used by the four LHC experiments is about to be deprecated. The new CREAM-CE service (Computing Resource Execution And Management) has been approved to replace the previous service. CREAM-CE is a lightweight service created to handle job management operations at the CE level. It is able to accept requests both via the gLite WMS service and also via direct submission for transmission to the local batch system. This flexible duality provides the experiments with a large level of freedom to adapt the service to their own computing models, but at the same time it requires a careful follow up of the requirements and tests of the experiments to ensure that their needs are fulfilled before real data taking. In this paper we present the current testing results of the four LHC experiments concerning this new service. The operations procedures, which have been elaborated together with the experiment support teams will be discussed. Finally, the experiments requirements and the expectations for both the sites and the service itself are exposed in detai