A new class of glycomimetic drugs to prevent free fatty acid-induced endothelial dysfunction

Background: Carbohydrates play a major role in cell signaling in many biological processes. We have developed a set of glycomimetic drugs that mimic the structure of carbohydrates and represent a novel source of therapeutics for endothelial dysfunction, a key initiating factor in cardiovascular complications. Purpose: Our objective was to determine the protective effects of small molecule glycomimetics against free fatty acid­induced endothelial dysfunction, focusing on nitric oxide (NO) and oxidative stress pathways. Methods: Four glycomimetics were synthesized by the stepwise transformation of 2,5­dihydroxybenzoic acid to a range of 2,5­substituted benzoic acid derivatives, incorporating the key sulfate groups to mimic the interactions of heparan sulfate. Endothelial function was assessed using acetylcholine­induced, endotheliumdependent relaxation in mouse thoracic aortic rings using wire myography. Human umbilical vein endothelial cell (HUVEC) behavior was evaluated in the presence or absence of the free fatty acid, palmitate, with or without glycomimetics (1µM). DAF­2 and H2DCF­DA assays were used to determine nitric oxide (NO) and reactive oxygen species (ROS) production, respectively. Lipid peroxidation colorimetric and antioxidant enzyme activity assays were also carried out. RT­PCR and western blotting were utilized to measure Akt, eNOS, Nrf­2, NQO­1 and HO­1 expression. Results: Ex vivo endothelium­dependent relaxation was significantly improved by the glycomimetics under palmitate­induced oxidative stress. In vitro studies showed that the glycomimetics protected HUVECs against the palmitate­induced oxidative stress and enhanced NO production. We demonstrate that the protective effects of pre­incubation with glycomimetics occurred via upregulation of Akt/eNOS signaling, activation of the Nrf2/ARE pathway, and suppression of ROS­induced lipid peroxidation. Conclusion: We have developed a novel set of small molecule glycomimetics that protect against free fatty acidinduced endothelial dysfunction and thus, represent a new category of therapeutic drugs to target endothelial damage, the first line of defense against cardiovascular disease

Development of a new experimental method for studies of muon capture in hydrogen

A new experiment is under preparation with the aim to improve considerably the present knowledge of the rate Lambda(s), which should be measured on a level of 1% or better, for the basic electroweak capture reaction of a negative muon on the free proton mup(1s) --> n + nu(mu). The capture rate will be determined by measuring the lifetime of mu(-) stopped in ultra pure hydrogen at 10 bar pressure and comparing it with the lifetime of the unbound mu(+). A new experimental method was developed for this project which should allow measuring the mu(-) lifetime with at least 10 ppm precision. The basic element of the detector is operating in the hydrogen gas time projection chamber (TPC) surrounded by multi-wire proportional chambers (MWPCs) and scintillator counters. The arrival times and trajectories of the incoming muons and the outgoing decay electrons are measured with this device providing effective suppression of background. Using the TPC as an active target, we can monitor on-line the protium contamination by impurities with a sensitivity better than 10(-8). This can be done by detecting the charged products of the muon capture reaction on these impurities. It was demonstrated that the TPC and MWPCs can operate in pure hydrogen under 10 bar pressure providing gas gain up to 10 000

Precise measurement of muon capture on the proton

The aim of the muCap experiment is a 1% measurement of the singlet capture rate Lambda(S) for the basic electro-weak reaction mu + p --> n + nu(mu). This observable is sensitive to the weak form-factors of the nucleon, in particular to the induced pseudoscalar coupling constant g(p). It will provide a rigorous test of theoretical predictions based on the Standard Model and effective theories of QCD. The present method is based on high precision lifetime measurements of mu(-) in hydrogen gas and the comparison with the free mu(+) lifetime. The mu(-) experiment will be performed in ultra-clean, deuterium-depleted H-2 gas at 10 bar. Low density compared to liquid H-2 is chosen to avoid uncertainties due to ppmu formation. A time projection chamber acts as a pure hydrogen active target. It defines the muon stop position in 3D and detects rare background reactions. Decay electrons are tracked in cylindrical wire-chambers and a scintillator array covering 75% of 4pi

Electroweak parameters of the z0 resonance and the standard model

Contains fulltext : 124399.pdf (publisher's version ) (Open Access

Species diversification – which species should we use?

Large detector systems for particle and astroparticle physics; Particle tracking detectors; Gaseous detectors; Calorimeters; Cherenkov detectors; Particle identification methods; Photon detectors for UV. visible and IR photons; Detector alignment and calibration methods; Detector cooling and thermo-stabilization; Detector design and construction technologies and materials. The LHCb experiment is dedicated to precision measurements of CP violation and rare decays of B hadrons at the Large Hadron Collider (LHC) at CERN (Geneva). The initial configuration and expected performance of the detector and associated systems. as established by test beam measurements and simulation studies. is described. © 2008 IOP Publishing Ltd and SISSA