Fucoidan is a novel platelet agonist for the C-type lectin-like receptor 2 (CLEC-2)

Fucoidan, a sulfated polysaccharide from Fucus vesiculosus, decreases bleeding time and clotting time in hemophilia, possibly through inhibition of tissue factor pathway inhibitor. However, its effect on platelets and the receptor by which fucoidan induces cellular processes has not been elucidated. In this study, we demonstrate that fucoidan induces platelet activation in a concentration-dependent manner. Fucoidan-induced platelet activation was completely abolished by the pan-Src family kinase (SFK) inhibitor, PP2, or when Syk is inhibited. PP2 abolished phosphorylations of Syk and Phospholipase C-γ2. Fucoidan-induced platelet activation had a lag phase, which is reminiscent of platelet activation by collagen and CLEC-2 receptor agonists. Platelet activation by fucoidan was only slightly inhibited in FcRγ-chain null mice, indicating that fucoidan was not acting primarily through GPVI receptor. On the other hand, fucoidan-induced platelet activation was inhibited in platelet-specific CLEC-2 knock-out murine platelets revealing CLEC-2 as a physiological target of fucoidan. Thus, our data show fucoidan as a novel CLEC-2 receptor agonist that activates platelets through a SFK-dependent signaling pathway. Furthermore, the efficacy of fucoidan in hemophilia raises the possibility that decreased bleeding times could be achieved through activation of platelets.

Critical role for an acidic amino acid region in platelet signaling by the HemITAM (hemi-immunoreceptor tyrosine-based activation motif) containing receptor CLEC-2 (C-type lectin receptor-2)

CLEC-2 is a member of new family of C-type lectin receptors characterized by a cytosolic YXXL downstream of three acidic amino acids in a sequence known as a hemITAM (hemi-immunoreceptor tyrosine-based activation motif). Dimerization of two phosphorylated CLEC-2 molecules leads to recruitment of the tyrosine kinase Syk via its tandem SH2 domains and initiation of a downstream signaling cascade. Using Syk-deficient and Zap-70-deficient cell lines we show that hemITAM signaling is restricted to Syk and that the upstream triacidic amino acid sequence is required for signaling. Using surface plasmon resonance and phosphorylation studies, we demonstrate that the triacidic amino acids are required for phosphorylation of the YXXL. These results further emphasize the distinct nature of the proximal events in signaling by hemITAM relative to ITAM receptors.

Mesh adaptation on the sphere using optimal transport and the numerical solution of a Monge-Ampère type equation

An equation of Monge-Ampère type has, for the first time, been solved numerically on the surface of the sphere in order to generate optimally transported (OT) meshes, equidistributed with respect to a monitor function. Optimal transport generates meshes that keep the same connectivity as the original mesh, making them suitable for r-adaptive simulations, in which the equations of motion can be solved in a moving frame of reference in order to avoid mapping the solution between old and new meshes and to avoid load balancing problems on parallel computers. The semi-implicit solution of the Monge-Ampère type equation involves a new linearisation of the Hessian term, and exponential maps are used to map from old to new meshes on the sphere. The determinant of the Hessian is evaluated as the change in volume between old and new mesh cells, rather than using numerical approximations to the gradients. OT meshes are generated to compare with centroidal Voronoi tesselations on the sphere and are found to have advantages and disadvantages; OT equidistribution is more accurate, the number of iterations to convergence is independent of the mesh size, face skewness is reduced and the connectivity does not change. However anisotropy is higher and the OT meshes are non-orthogonal. It is shown that optimal transport on the sphere leads to meshes that do not tangle. However, tangling can be introduced by numerical errors in calculating the gradient of the mesh potential. Methods for alleviating this problem are explored. Finally, OT meshes are generated using observed precipitation as a monitor function, in order to demonstrate the potential power of the technique.

Noether-type discrete conserved quantities arising from a finite element approximation of a variational problem

In this work, we prove a weak Noether-type Theorem for a class of variational problems that admit broken extremals. We use this result to prove discrete Noether-type conservation laws for a conforming finite element discretisation of a model elliptic problem. In addition, we study how well the finite element scheme satisfies the continuous conservation laws arising from the application of Noether’s first theorem (1918). We summarise extensive numerical tests, illustrating the conservation of the discrete Noether law using the p-Laplacian as an example and derive a geometric-based adaptive algorithm where an appropriate Noether quantity is the goal functional.

The effects of lipoic acid and alpha-tocopherol supplementation on the lipid profile and insulin sensitivity of patients with type 2 diabetes mellitus: A randomized, double-blind, placebo-controlled trial

Antioxidants probably play an important role in the etiology of type 2 diabetes (DM2). This study evaluated the effects of supplementation with lipoic acid (LA) and alpha-tocopherol on the lipid profile and insulin sensitivity of DM2 patients. A randomized, double-blind, placebo-controlled trial involving 102 DM2 patients divided into four groups to receive daily supplementation for 4 months with: 600 mg LA (n = 26); 800 mg alpha-tocopherol (n = 25); 800 mg alpha-tocopherol + 600 mg LA (n = 25); placebo (n = 26). Plasma alpha-tocopherol, lipid profile, glucose, insulin, and the HOMA index were determined before and after supplementation. Differences within and between groups were compared by ANOVA using Bonferroni correction. Student`s t-test was used to compare means of two independent variables. The vitamin E/total cholesterol ratio improved significantly in patients supplemented with vitamin E + LA and vitamin E alone (p <= 0.001). There were improvements of the lipid fractions in the groups receiving LA and vitamin E alone or in combination, and on the HOMA index in the LA group, but not significant. The results suggest that LA and vitamin E supplementation alone or in combination did not affect the lipid profile or insulin sensitivity of DM2 patients. (C) 2011 Elsevier Ireland Ltd. All rights reserved.

Association of genetic variants in the adiponectin encoding gene (ADIPOQ) with type 2 diabetes in Japanese Brazilians

Aim: The objective of this study is to assess the contribution of ADIPOQ variants to type 2 diabetes in Japanese Brazilians. Methods: We genotyped 200 patients with diabetes mellitus (100 male and 100 female, aged 55.0 years [47.5-64.0 years]) and 200 control subjects with normal glucose tolerant (NGT) (72 male and 128 female, aged 52.0 years [43.5-64.5 years]). Results: Whereas each polymorphism studied (T45G, G276T, and A349G) was not significantly associated with type 2 diabetes mellitus, the haplotype GGA was overrepresented in our diabetic population (9.3% against 3.1% in NGT individuals, P=.0003). Also, this haplotype was associated with decreased levels of adiponectin. We also identified three mutations in exon 3: I164T, R221S, and H241P, but, owing to the low frequencies of them, associations with type 2 diabetes could not be evaluated. The subjects carrying the R221S mutation had plasma adiponectin levels lower than those without the mutation (2.10 mu g/ml [1.35-2.55 mu g/ml] vs. 6.68 mu g/ml [3.90-11.23 mu g/ml], P=.015). Similarly, the I164T mutation carriers had mean plasma adiponectin levels lower than those noncarriers (3.73 mu g/ml [3.10-4.35 mu g/ml] vs. 6.68 mu g/ml [3.90-11.23 mu g/ml]), but this difference was not significant (P=.17). Conclusions: We identified in the ADIPOQ gene a risk haplotype for type 2 diabetes in the Japanese Brazilian population. (C) 2010 Elsevier Inc. All rights reserved.

Relationship Between Expression of Voltage-Dependent Anion Channel (VDAC) Isoforms and Type of Hexokinase Binding Sites on Brain Mitochondria

Voltage-dependent anion channels (VDAC) are pore-forming proteins found in the outer mitochondrial membrane of eukaryotes. VDACs are known to play an essential role in cellular metabolism and in early stages of apoptosis. In mammals, three VDAC isoforms have been identified. A proteomic approach was exploited to study the expression of VDAC isoforms in rat, bovine, and chicken brain mitochondria. Given the importance of mitochondrially bound hexokinase in regulation of aerobic glycolysis in brain, we studied the possibility that differences in the relative expression of VDAC isoforms may be a factor in determining the species-dependent ratio of type A/type B hexokinase binding sites on brain mitochondria. The spots were characterized, and the signal intensities among spots were compared. VDAC1 was the most abundantly expressed of the three isoforms. Moreover the expression of VDAC1 plus VDAC2 was significantly higher in bovine than in rat brain. Chicken brain mitochondria showed the highest VDAC1 expression and the lowest of VDAC2. Bovine brain mitochondria had the highest VDAC2 levels. We concluded that the nature of hexokinase binding site is not determined by the expression of a single VDAC isoform.

Biodegradable Films Based on Blends of Gelatin and Poly (Vinyl Alcohol): Effect of PVA Type or Concentration on Some Physical Properties of Films

The aim of this work was to develop biodegradable films based on blends of gelatin and poly (vinyl alcohol) (PVA), without a plasticizer. Firstly, the effect of five types of PVA with different degree of hydrolysis (DH) on the physical properties of films elaborated with blends containing 23.1% PVA was studied. One PVA type was then chosen for the study of the effect of the PVA concentration on the mechanical properties, color, opacity, gloss, and water solubility of the films. The five types of PVA studied allowed for films with different characteristics, but with no direct relationship with the DH of the PVA. Therefore, the PVA Celvol (R) 418 with a DH = 91.8% was chosen for the second part, because they produced films with greater tensile strength. The PVA concentration affected all studied properties of films. These results could be explained by the results of the DSC and FTIR analyses, which showed that some interactions between the gelatin and the PVA occurred depending on the PVA concentration, affecting the crystallinity of the films.

Global properties of `ordinary` early-type galaxies: photometry and spectroscopy of stars and globular clusters in NGC 4494

We present a comprehensive analysis of the spatial, kinematic and chemical properties of stars and globular clusters (GCs) in the `ordinary` elliptical galaxy NGC 4494 using data from the Keck and Subaru telescopes. We derive galaxy surface brightness and colour profiles out to large galactocentric radii. We compare the latter to metallicities derived using the near-infrared Calcium Triplet. We obtain stellar kinematics out to similar to 3.5 effective radii. The latter appear flattened or elongated beyond similar to 1.8 effective radii in contrast to the relatively round photometric isophotes. In fact, NGC 4494 may be a flattened galaxy, possibly even an S0, seen at an inclination of similar to 45 degrees. We publish a catalogue of 431 GC candidates brighter than i(0) = 24 based on the photometry, of which 109 are confirmed spectroscopically and 54 have measured spectroscopic metallicities. We also report the discovery of three spectroscopically confirmed ultra-compact dwarfs around NGC 4494 with measured metallicities of -0.4 less than or similar to [Fe/H] less than or similar to -0.3. Based on their properties, we conclude that they are simply bright GCs. The metal-poor GCs are found to be rotating with similar amplitude as the galaxy stars, while the metal-rich GCs show marginal rotation. We supplement our analysis with available literature data and results. Using model predictions of galaxy formation, and a suite of merger simulations, we find that many of the observational properties of NGC 4494 may be explained by formation in a relatively recent gas-rich major merger. Complete studies of individual galaxies incorporating a range of observational avenues and methods such as the one presented here will be an invaluable tool for constraining the fine details of galaxy formation models, especially at large galactocentric radii.