ABC transporters and scavenger receptor BI : important mediators of lipid metabolism and atherosclerosis

Excessive accumulation of cholesterol by macrophage-derived foam cells is one of the characteristic features of atherosclerotic lesion development. Macrophages not only play an important role in the initiation of the early atherosclerotic lesion, during further progression of the lesions macrophages also contribute to the formation of a necrotic core, thereby affecting the stability of the atherosclerotic plaque. Especially in the initiation of atherosclerosis the balance between cholesterol influx and efflux in macrophages is of prime importance. This balance is maintained by scavenger receptors and ATP-binding cassette (ABC) transporters, which are key mediators for macrophage cholesterol homeostasis as they facilitate the influx and efflux of lipids. Macrophages are incapable of limiting the uptake of cholesterol by scavenger receptors, including scavenger receptor class A (SR-A) and CD36. Therefore, prevention of lipid accumulation in macrophages largely depends on cholesterol efflux pathways, mainly mediated by ABC transporters. Gaining more knowledge on macrophage lipid homeostasis is of prime importance for the development of new therapeutic strategies to prevent atherosclerotic lesion development or induce regression of existing lesions. The aim of the studies described in this thesis was investigation of the role of several ABC transporters and SR-BI in (macrophage) lipid metabolism and atherogenesis.- LACDR - Leiden University - Chiron Development ConsultancyUBL - phd migration 201

Intergenerational transmission of child problem behavior

In the present thesis, the intergenerational transmission of child problem behavior will be investigated. In this introduction, we will explain why it is important to study transmission of problem behavior from parents to their offspring. In addition, we will describe the study design that is suitable for this type of research, and give a description of its methodological advantages and difficulties. We will summarize previous studies that have used this type of design, and made an important contribution to the research in intergenerational transmission of child problem behavior. Two factors that are thought to be important in the intergenerational transmission of problem behavior, parenting and parental psychopathology, will also be described. In addition, we will describe the possible relevance of developmental trajectories of problem behavior displayed by parents during their childhood, in predicting offspring problem behavior. Finally we will describe the aims, methods and structure of the present thesis

Towards sex-specific osteoarthritis risk models: evaluation of risk factors for knee osteoarthritis in males and females

Objectives The aim of this study was to identify sex-specific prevalence and strength of risk factors for the incidence of radiographic knee OA (incRKOA). Methods Our study population consisted of 10 958 Rotterdam Study participants free of knee OA in one or both knees at baseline. One thousand and sixty-four participants developed RKOA after a median follow-up time of 9.6 years. We estimated the association between each available risk factor and incRKOA using sex stratified multivariate regression models with generalized estimating equations. Subsequently, we statistically tested sex differences between risk estimates and calculated the population attributable fractions (PAFs) for modifiable risk factors. Results The prevalence of the investigated risk factors was, in general, higher in women compared with men, except that alcohol intake and smoking were higher in men and high BMI showed equal prevalence. We found significantly different risk estimates between men and women: high level of physical activity [relative risk (RR) 1.76 (95% CI: 1.29–2.40)] or a Kellgren and Lawrence score 1 at baseline [RR 5.48 (95% CI: 4.51–6.65)] was higher in men. Among borderline significantly different risk estimates was BMI ≥27, associated with higher risk for incRKOA in women [RR 2.00 (95% CI: 1.74–2.31)]. The PAF for higher BMI was 25.6% in women and 19.3% in men. Conclusion We found sex-specific differences in both presence and relative risk of several risk factors for incRKOA. Especially BMI, a modifiable risk factor, impacts women more strongly than men. These risk factors can be used in the development of personalized prevention strategies and in building sex-specific prediction tools to identify high risk profile patients

The laminin β1-competing peptide YIGSR induces a hypercontractile, hypoproliferative airway smooth muscle phenotype in an animal model of allergic asthma

Background: Fibroproliferative airway remodelling, including increased airway smooth muscle (ASM) mass and contractility, contributes to airway hyperresponsiveness in asthma. In vitro studies have shown that maturation of ASM cells to a (hyper)contractile phenotype is dependent on laminin, which can be inhibited by the laminin-competing peptide Tyr-Ile-Gly-Ser-Arg (YIGSR). The role of laminins in ASM remodelling in chronic asthma in vivo, however, has not yet been established. Methods: Using an established guinea pig model of allergic asthma, we investigated the effects of topical treatment of the airways with YIGSR on features of airway remodelling induced by repeated allergen challenge, including ASM hyperplasia and hypercontractility, inflammation and fibrosis. Human ASM cells were used to investigate the direct effects of YIGSR on ASM proliferation in vitro. Results: Topical administration of YIGSR attenuated allergen-induced ASM hyperplasia and pulmonary expression of the proliferative marker proliferating cell nuclear antigen (PCNA). Treatment with YIGSR also increased both the expression of sm-MHC and ASM contractility in saline-and allergen-challenged animals; this suggests that treatment with the laminin-competing peptide YIGSR mimics rather than inhibits laminin function in vivo. In addition, treatment with YIGSR increased allergen-induced fibrosis and submucosal eosinophilia. Immobilized YIGSR concentration-dependently reduced PDGF-induced proliferation of cultured ASM to a similar extent as laminin-coated culture plates. Notably, the effects of both immobilized YIGSR and laminin were antagonized by soluble YIGSR. Conclusion: These results indicate that the laminin-competing peptide YIGSR promotes a contractile, hypoproliferative ASM phenotype in vivo, an effect that appears to be linked to the microenvironment in which the cells are exposed to the peptide

Role of contractile prostaglandins and Rho-kinase in growth factor-induced airway smooth muscle contraction

Background: In addition to their proliferative and differentiating effects, several growth factors are capable of inducing a sustained airway smooth muscle (ASM) contraction. These contractile effects were previously found to be dependent on Rho-kinase and have also been associated with the production of eicosanoids. However, the precise mechanisms underlying growth factor-induced contraction are still unknown. In this study we investigated the role of contractile prostaglandins and Rho-kinase in growth factor-induced ASM contraction.Methods: Growth factor-induced contractions of guinea pig open-ring tracheal preparations were studied by isometric tension measurements. The contribution of Rho-kinase, mitogen-activated protein kinase ( MAPK) and cyclooxygenase ( COX) to these reponses was established, using the inhibitors Y-27632 ( 1 mu M), U-0126 ( 3 mu M) and indomethacin ( 3 mu M), respectively. The Rho-kinase dependency of contractions induced by exogenously applied prostaglandin F-2 alpha (PGF(2 alpha)) and prostaglandin E-2 (PGE(2)) was also studied. In addition, the effects of the selective FP-receptor antagonist AL-8810 (10 mu M) and the selective EP1-antagonist AH-6809 (10 mu M) on growth factor-induced contractions were investigated, both in intact and epithelium-denuded preparations. Growth factor-induced PGF(2 alpha)- and PGE(2)-release in the absence and presence of Y-27632, U-0126 and indomethacin, was assessed by an ELISA-assay.Results: Epidermal growth factor (EGF)- and platelet-derived growth factor ( PDGF)- induced contractions of guinea pig tracheal smooth muscle preparations were dependent on Rho-kinase, MAPK and COX. Interestingly, growth factor-induced PGF(2 alpha)- and PGE(2)-release from tracheal rings was significantly reduced by U-0126 and indomethacin, but not by Y-27632. Also, PGF2a- and PGE(2)-induced ASM contractions were largely dependent on Rho-kinase, in contrast to other contractile agonists like histamine. The FP-receptor antagonist AL-8810 ( 10 mu M) significantly reduced ( approximately 50 %) and the EP1-antagonist AH-6809 ( 10 mu M) abrogated growth factor-induced contractions, similarly in intact and epithelium-denuded preparations.Conclusion: The results indicate that growth factors induce ASM contraction through contractile prostaglandins - not derived from the epithelium - which in turn rely on Rho-kinase for their contractile effects.</p

Black Hole Mass, Velocity Dispersion and the Radio Source in AGN

The recent discovery of a correlation between nuclear black hole mass, M_bh, and the stellar velocity dispersion (Gebhardt et al. 2000, Ferrarese and Merritt 2000), in elliptical galaxies and spiral bulges, has raised the question whether such a relationship exists for AGN. Estimates of M_bh for many AGN, made using reverberation mapping techniques, allow exploration of the relationship between black hole mass, the host galaxy and the energetics of nuclear emission. However, since only a few AGN have both M_bh and velocity dispersion measurements, we use the [OIII] 5007 emission line widths on the assumption that for most AGN the forbidden line kinematics are dominated by virial motion in the host galaxy bulge. We find that a relation does exist between M_bh and [OIII] line width for AGN which is similar to the one found by Gebhardt et al. 2000, although with more scatter as expected if secondary influences on the gas kinematics are also present. Our conclusion is that both active and inactive galaxies follow the same relationship between black hole mass and bulge gravitational potential. We find no compelling evidence for systematic differences in the mass estimates from reverberation mapping and stellar dynamics. We also find that for radio quiet AGN the radio power and black hole mass are highly correlated linking emission on scales of kiloparsecs with the nuclear energy source.Comment: 4 pages, uses emulateapj5.sty and aastex, 2 figures, 1 table accepted for publication in the Astrophysical Journa

Epidemiological Interactions between Urogenital and Intestinal Human Schistosomiasis in the Context of Praziquantel Treatment across Three West African Countries

© 2015 Knowles et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. The attached file is the published version of the article

Rectification of thermal fluctuations in ideal gases

We calculate the systematic average speed of the adiabatic piston and a thermal Brownian motor, introduced in [Van den Broeck, Kawai and Meurs, \emph{Microscopic analysis of a thermal Brownian motor}, to appear in Phys. Rev. Lett.], by an expansion of the Boltzmann equation and compare with the exact numerical solution.Comment: 18 page

Tomographic Separation of Composite Spectra. IX. The Massive Close Binary HD 115071

We present the first orbital elements for the massive close binary, HD 115071, a double-lined spectroscopic binary in a circular orbit with a period of 2.73135 +/- 0.00003 days. The orbital semiamplitudes indicate a mass ratio of M_2/M_1 = 0.58 +/- 0.02 and yet the stars have similar luminosities. We used a Doppler tomography algorithm to reconstruct the individual component optical spectra, and we applied well known criteria to arrive at classifications of O9.5 V and B0.2 III for the primary and secondary, respectively. We present models of the Hipparcos light curve of the ellipsoidal variations caused by the tidal distortion of the secondary, and the best fit model for a Roche-filling secondary occurs for an inclination of i = 48.7 +/- 2.1 degrees. The resulting masses are 11.6 +/- 1.1 and 6.7 +/- 0.7 solar masses for the primary and secondary, respectively, so that both stars are very overluminous for their mass. The system is one of only a few known semi-detached, Algol-type binaries that contain O-stars. We suggest that the binary has recently emerged from extensive mass transfer (possibly through a delayed contact and common envelope process).Comment: Submitted to Ap

Statistical Properties of Radio Emission from the Palomar Seyfert Galaxies

We have carried out an analysis of the radio and optical properties of a statistical sample of 45 Seyfert galaxies from the Palomar spectroscopic survey of nearby galaxies. We find that the space density of bright galaxies (-22 mag <= M_{B_T} <= -18 mag) showing Seyfert activity is (1.25 +/- 0.38) X 10^{-3} Mpc^{-3}, considerably higher than found in other Seyfert samples. Host galaxy types, radio spectra, and radio source sizes are uncorrelated with Seyfert type, as predicted by the unified schemes for active galaxies. Approximately half of the detected galaxies have flat or inverted radio spectra, more than expected based on previous samples. Surprisingly, Seyfert 1 galaxies are found to have somewhat stronger radio sources than Seyfert 2 galaxies at 6 and 20 cm, particularly among the galaxies with the weakest nuclear activity. We suggest that this difference can be accommodated in the unified schemes if a minimum level of Seyfert activity is required for a radio source to emerge from the vicinity of the active nucleus. Below this level, Seyfert radio sources might be suppressed by free-free absorption associated with the nuclear torus or a compact narrow-line region, thus accounting for both the weakness of the radio emission and the preponderance of flat spectra. Alternatively, the flat spectra and weak radio sources might indicate that the weak active nuclei are fed by advection-dominated accretion disks.Comment: 18 pages using emulateapj5, 13 embedded figures, accepted by Ap