Computational Screening of Tip and Stalk Cell Behavior Proposes a Role for Apelin Signaling in Sprout Progression

Angiogenesis involves the formation of new blood vessels by sprouting or splitting of existing blood vessels. During sprouting, a highly motile type of endothelial cell, called the tip cell, migrates from the blood vessels followed by stalk cells, an endothelial cell type that forms the body of the sprout. To get more insight into how tip cells contribute to angiogenesis, we extended an existing computational model of vascular network formation based on the cellular Potts model with tip and stalk differentiation, without making a priori assumptions about the differences between tip cells and stalk cells. To predict potential differences, we looked for parameter values that make tip cells (a) move to the sprout tip, and (b) change the morphology of the angiogenic networks. The screening predicted that if tip cells respond less effectively to an endothelial chemoattractant than stalk cells, they move to the tips of the sprouts, which impacts the morphology of the networks. A comparison of this model prediction with genes expressed differentially in tip and stalk cells revealed that the endothelial chemoattractant Apelin and its receptor APJ may match the model prediction. To test the model prediction we inhibited Apelin signaling in our model and in an \emph{in vitro} model of angiogenic sprouting, and found that in both cases inhibition of Apelin or of its receptor APJ reduces sprouting. Based on the prediction of the computational model, we propose that the differential expression of Apelin and APJ yields a "self-generated" gradient mechanisms that accelerates the extension of the sprout.Comment: 48 pages, 10 figures, 8 supplementary figures. Accepted for publication in PLoS ON

Electronic excited state of protonated aromatic molecules: protonated Fluorene

The photo-fragmentation spectrum of protonated fluorene has been recorded in the visible spectral region, largely red shifted as compared to the first excited state absorption of neutral fluorene. The spectrum shows two different vibrational progressions, separated by 0.19 eV that are assigned to the absorption of two isomers. As in protonated linear PAHs, comparison with ab-initio calculations indicates that the red shift is due to the charge transfer character of the excited state

Oral treatment with Eubacterium hallii improves insulin sensitivity in db/db mice

F.B. is supported by Swedish Research Council, Swedish Diabetes Foundation, Swedish Heart Lung Foundation, Swedish Foundation for Strategic Research, Knut and Alice Wallenberg foundation, Göran Gustafsson Foundation, Ingbritt and Arne Lundberg’s foundation, Swedish Heart Lung Foundation, Torsten Söderberg’s Foundation, Ragnar Söderberg’s Foundation, NovoNordisk Foundation, AFA insurances, and LUA-ALF grants from Västra Götalandsregionen and Stockholm County Council. F.B. is a recipient of ERC Consolidator Grant (European Research Council, Consolidator grant 615362—METABASE). W.M.d.V. is supported by the Finland Academy of Sciences (grants 137389, 141140 and 1272870 ), the Netherlands Organization for Scientific Research (Spinoza Award and SIAM Gravity Grant 024.002.002) and the European Research Council (ERC Advanced Grant 250172 MicrobesInside). M.N. is supported by a ZONMW-VIDI grant 2013 (016.146.327).Peer reviewe

A functional polymorphism in the glucocorticoid receptor gene and its relation to cardiovascular disease risk in familial hypercholesterolemia

Context: Individuals with the functional ER22/23EK variant in the glucocorticoid receptor gene are relatively resistant to the downstream consequences of glucocorticoids. Evidence suggests that carriers have a more favorable cardiovascular risk profile, but the relationship between this ER22/23EK variant and cardiovascular disease has not been hitherto assessed. Objective: We, therefore, determined whether carriership of the ER22/23EK improves cardiovascular disease risk in patients with severe hypercholesterolemia. Design, Setting, and Participants: In a multicenter cohort study, 2024 patients with heterozygous familial hypercholesterolemia, aged 18 yr and older, were genotyped for the ER22/23EK polymorphism. Patients were identified at lipid clinics throughout The Netherlands between 1989 and 2002. Main Outcome Measures: The primary outcome measure was cardiovascular disease. Results: Seventy-six (7.8%) of 977 men and 72 (6.9%) of 1047 women were carriers of the ER22/23EK variant. A total of 395 men and 247 women had a cardiovascular event. In contrast to expected results, we observed no significant association of the ER22/23EK variant with cardiovascular disease risk (men: relative risk, 0.75; 95% confidence interval, 0.50-1.14; P = 0.2; women: relative risk, 1.37;95%confidence interval, 0.82-2.28;P = 0.2). However, we found a significant interaction between gender and the polymorphism on cardiovascular disease (P = 0.02). Conclusions: In this large cohort of individuals with very high risk of cardiovascular disease, the association between the functional ER22/23EK polymorphism and cardiovascular risk was not significant overall, although it varied significantly by gender. Copyrigh

Cholesteryl ester transfer protein decreases high-density lipoprotein and severely aggravates atherosclerosis in APOE*3-Leiden mice

OBJECTIVE - The role of cholesteryl ester transfer protein (CETP) in the development of atherosclerosis is still undergoing debate. Therefore, we evaluated the effect of human CETP expression on atherosclerosis in APOE*3-Leiden (E3L) mice with a humanized lipoprotein profile. METHODS AND RESULTS - E3L mice were crossbred with human CETP transgenic mice. On a chow diet, CETP expression increased plasma total cholesterol (TC) (+43%; P<0.05). To evaluate the effects of CETP on the development of atherosclerosis, mice were fed a Western-type diet containing 0.25% cholesterol, leading to 4.3-fold elevated TC levels in both E3L and CETP.E3L mice (P<0.01). On both diets, CETP expression shifted the distribution of cholesterol from high-density lipoprotein (HDL) toward very-low-density lipoprotein (VLDL)/low-density lipoprotein (LDL). Moreover, plasma of CETP.E3L mice had reduced capacity (-3

The efficacy of lower limb screening tests in predicting PlayerLoad within a professional soccer academy

Context: Training exposure has been associated with injury epidemiology in elite youth soccer, where lower limb musculoskeletal screening is commonly used to highlight injury risk. However, there has been little consideration of the relationship between lower limb screening and the loading response to soccer activities. Objective: To quantify the efficacy of using screening tests to predict the loading elicited in soccer-specific activities, and to develop a hierarchical ordering of musculoskeletal screening tests to identify test redundancy and inform practice. Design: Correlational. Setting: Professional soccer club academy. Participants: 21 elite male soccer players aged 15.7 ± 0.9 years. Intervention: Players completed a battery of five screening tests (knee to wall, hip internal rotation, adductor squeeze, single leg hop, anterior reach), and a 25min standardised soccer session with a GPS unit placed at C7 to collect multi-planar PlayerLoad data. Main Outcome Measures: Baseline data on each screening test, along with uni-axial PlayerLoad in the medio-lateral, anterio-posterior and vertical planes. Results: Stepwise hierarchical modelling of the screening tests revealed that dominant leg knee to wall distance was the most prevalent and powerful predictor of multi-planar PlayerLoad, accounting for up to 42% of variation in uni-axial loading. The adductor squeeze test was the least powerful predictor of PlayerLoad. Of note, one player who incurred a knee injury within three weeks of testing had shown a 20% reduction in knee to wall distance compared with peers, and elicited 23% greater PlayerLoad, supporting the hierarchical model. Conclusions: There was some evidence of redundancy in the screening battery, with implications for clinical choice. Hierarchical ordering and a concurrent case study highlight dominant leg knee to wall distance as the primary predictor of multi-axial loading in soccer. This has implications for the design and interpretation of screening data in elite youth soccer

Fasting and postprandial remnant-like particle cholesterol concentrations in obese participants are associated with plasma triglycerides, insulin resistance, and body fat distribution

Elevated plasma concentrations of remnant-like particle cholesterol (RLP-C) are atherogenic. However, factors that determine RLP-C are not fully understood. This study evaluates which factors affect RLP-C in the fasting and postprandial state, using multiple regression analyses in a large cohort of lean and obese participants. All participants (n = 740) underwent a test meal challenge containing 95 energy % (en%) fat (energy content 50% of predicted daily resting metabolic rate). Fasting and postprandial concentrations of circulating metabolites were measured over a 3-h period. Obese participants (n = 613) also participated in a 10-wk weight loss program (-2510 kJ/d), being randomized to either a low-fat or a high-fat diet (20-25 vs. 40-45en% fat). Postprandial RLP-C was associated with fasting RLP-C, waist:hip ratio (WHR), HOMA(IR) (homeostasis model assessment index for insulin resistance) (P < 0.001), and age, independently of BMI and gender [adjusted R(2) (adj. R(2)) = 0.70). These factors were also related to fasting RLP-C (P < 0.010), along with gender and physical activity (adj. R(2) = 0.23). The dietary intervention resulted in significantly lower fasting RLP-C concentrations, independently mediated by weight loss, improvements in HOMA(IR), and the fat content of the prescribed diet. However, after inclusion of plasma triglyceride (TG), HDL-cholesterol, and FFA concentrations in the models, HOMA(IR) and WHR no longer significantly predicted fasting RLP-C, although WHR remained a predictor of postprandial RLP-C (P = 0.002). Plasma TG was strongly associated with both fasting and postprandial RLP-C (P < 0.001). In conclusion, plasma RLP-C concentrations are mainly associated with plasma TG concentrations. Interestingly, the high-fat diet was more effective at decreasing fasting RLP-C concentrations in obese participants than the low-fat diet