Tissue factor in cardiovascular disease pathophysiology and pharmacological intervention

Tissue factor (TF) is the major trigger of the coagulation cascade and thereby crucially involved in the maintenance of vascular hemostasis. By binding factor VIIa, the resulting TF:VIIa complex activates the coagulation factors IX and X ultimately leading to fibrin and clot formation. In the vessel wall, TF expression and activity is detectable in vascular smooth muscle cells and fibroblasts and, at a much lower level, in endothelial cells and can be induced by various stimuli including cytokines. In addition, TF is found in the bloodstream in circulating cells such as monocytes, in TF containing microparticles, and as a soluble splicing isoform. Besides its well-known extracellular role as a trigger of coagulation, TF also functions as a transmembrane receptor, and TF-dependent intracellular signaling events regulate the expression of genes involved in cellular responses such as proliferation and migration. TF indeed appears to be involved in the pathogenesis of neointima formation and tumor growth, and increased levels of TF have been detected in patients with cardiovascular risk factors or coronary artery disease as well as in those with cancer. Therefore, pharmacological or genetic inhibition of TF may be an attractive target for the treatment of cardiovascular disease and cancer. Different strategies for inhibition of TF have been developed such as inhibition of TF synthesis and blockade of TF action. Clinical applications of such strategies need to be tested in appropriate trials, in particular for evaluating the advantages of targeted versus systemic delivery of the inhibitors

Bosonic spectral density of epitaxial thin-film La1.83Sr0.17CuO4 superconductors from infrared conductivity measurements

We use optical spectroscopy to investigate the excitations responsible for the structure in the optical self-energy of thin epitaxial films of La1.83Sr0.17CuO4. Using Eliashberg formalism to invert the optical spectra we extract the electron-boson spectral function and find that at low temperature it has a two component structure closely matching the spin excitation spectrum recently measured by magnetic neutron scattering. We contrast the temperature evolution of the spectral density and the two-peak behavior in La2-xSrxCuO4 with another high temperature superconductor Bi2Sr2CaCu2O8+d. The bosonic spectral functions of the two materials account for the low Tc of LSCO as compared to Bi-2212

Constant effective mass across the phase diagram of high-Tc_{c} cuprates

We investigate the hole dynamics in two prototypical high temperature superconducting systems: La$_{2-x}$Sr$_{x}$CuO$_{4}$ and YBa$_{2}$Cu$_{3}$O$_{y}$ using a combination of DC transport and infrared spectroscopy. By exploring the effective spectral weight obtained with optics in conjunction with DC Hall results we find that the transition to the Mott insulating state in these systems is of the "vanishing carrier number" type since we observe no substantial enhancement of the mass as one proceeds to undoped phases. Further, the effective mass remains constant across the entire underdoped regime of the phase diagram. We discuss the implications of these results for the understanding of both transport phenomena and pairing mechanism in high-T$_{c}$ systems.Comment: 5 pages, 2 figure

First Evidence for Substrate Channeling between Proline Catabolic Enzymes \u3ci\u3eA VALIDATION OF DOMAIN FUSION ANALYSIS FOR PREDICTING PROTEIN-PROTEIN INTERACTIONS\u3c/i\u3e

Background: PRODH and P5CDH from Thermus thermophilus are monofunctional enzymes in proline catabolism. Results: Steady-state kinetics and intermediate trapping data show the PRODH and P5CDH reactions are coupled by a channeling step. Conclusion: Substrate channeling in monofunctional enzymes is achieved via weak interactions. Significance: Evidence for substrate channeling between monofunctional proline catabolic enzymes is shown and confirms the Rosetta Stone hypothesis

Urban agriculture and Anopheles habitats in Dar es Salaam, Tanzania.

A cross-sectional survey of agricultural areas, combined with routinely monitored mosquito larval information, was conducted in urban Dar es Salaam, Tanzania, to investigate how agricultural and geographical features may influence the presence of Anopheles larvae. Data were integrated into a geographical information systems framework, and predictors of the presence of Anopheles larvae in farming areas were assessed using multivariate logistic regression with independent random effects. It was found that more than 5% of the study area (total size 16.8 km2) was used for farming in backyard gardens and larger open spaces. The proportion of habitats containing Anopheles larvae was 1.7 times higher in agricultural areas compared to other areas (95% confidence interval = 1.56-1.92). Significant geographic predictors of the presence of Anopheles larvae in gardens included location in lowland areas, proximity to river, and relatively impermeable soils. Agriculture-related predictors comprised specific seedbed types, mid-sized gardens, irrigation by wells, as well as cultivation of sugar cane or leafy vegetables. Negative predictors included small garden size, irrigation by tap water, rainfed production and cultivation of leguminous crops or fruit trees. Although there was an increased chance of finding Anopheles larvae in agricultural sites, it was found that breeding sites originated by urban agriculture account for less than a fifth of all breeding sites of malaria vectors in Dar es Salaam. It is suggested that strategies comprising an integrated malaria control effort in malaria-endemic African cities include participatory involvement of farmers by planting shade trees near larval habitats

Neutral kaons in random media

The generalized dynamics describing the propagation of neutral kaons in randomly fluctuating media is derived and analyzed. It takes into account possible matter-induced effects leading to loss of phase coherence and dissipation. The study of selected neutral kaon observables indicates that these non-standard effects are amenable to a direct experimental analysis.Comment: 21 pages, plain-TeX, corrected typ

The Beagle 2 optical microscope

Introduction to the Beagle2 optical microscope

Association between bilirubin and cardiovascular disease risk factors: using Mendelian randomization to assess causal inference

Background: Elevated serum bilirubin has been associated with reduced risk of cardiovascular disease (CVD). However, serum bilirubin is also related with several potential confounders related to CVD, such as obesity. Mendelian randomization has been proposed as a method to address challenges to validity from confounding and reverse causality. It utilizes genotype to estimate causal relationships between a gene product and physiological outcomes. In this report, we demonstrate its use in assessing direct causal relations between serum bilirubin levels and CVD risk factors, including obesity, cholesterol, measures of vascular function and blood pressure. Methods: Study subjects included 868 asymptomatic individuals. Study subjects were genotyped at the UGT1A1*28 locus, which is strongly associated with bilirubin levels. Results: Serum bilirubin levels were inversely associated with levels of several cardiovascular disease risk factors, including body mass index (p = 0.003), LDL (p = 0.0005) and total cholesterol (p = 0.0002). In contrast, UGT1A1*28 genotype, a known cause of elevated bilirubin levels, was not significantly associated with any of these traditional CVD risk factors. We did observe an association between genotype and brachial artery diameter (p = 0.003) and cold pressor reactivity (p = 0.01). Conclusions: Our findings imply that the observed association of serum bilirubin levels with body mass index and cholesterol are likely due to confounding and suggest that previously established CVD benefits of increased bilirubin may in part be mediated by the early regulation of vascular structure and reactivity