The Interplay of SIRT1 and Wnt Signaling in Vascular Calcification

Vascular calcification is a major health risk and is highly correlated with atherosclerosis, diabetes, and chronic kidney disease. The development of vascular calcification is an active and complex process linked with a multitude of signaling pathways, which regulate promoters and inhibitors of osteogenesis, the balance of which become deregulated in disease conditions. SIRT1, a protein deacetylase, known to be protective in inhibiting oxidative stress and inflammation within the vessel wall, has been shown as a possible key player in modulating the cell-fate determining canonical Wnt signaling pathways. Suppression of SIRT1 has been reported in patients suffering with cardiovascular pathologies, suggesting that the sustained acetylation of osteogenic factors could contribute to their activation and in turn, lead to the progression of calcification. There is clear evidence of the synergy between β-Catenin and elevated Runx2, and with Wnt signaling being β-Catenin dependent, further understanding is needed as to how these molecular pathways converge and interact, in order to provide novel insight into the mechanism by which smooth muscle cells switch to an osteogenic differentiation programme. Therefore, this review will describe the current concepts of pathological soft tissue mineralization, with a focus on the contribution of SIRT1 as a regulator of Wnt signaling and its targets, discussing SIRT1 as a potential target for manipulation and therapy

Analysis of bolted flanged panel joint for GRP sectional tanks

Peer reviewedPublisher PD

Influence of the central-to-peripheral arterial stiffness gradient on the timing and amplitude of wave reflections

In individuals with compliant aortas, peripheral muscular artery stiffness exceeds central elastic artery stiffness. With ageing, central stiffness increases, with little change in peripheral stiffness, resulting in a reversal of the normal stiffness gradient. This reversal may reduce wave reflection amplitude, due to movement of the major “effective” reflection site further from the heart. To test this, we investigated the relationship among arterial stiffness gradients (normal and reversed), wave reflection amplitude and reflection site distance. Subjects aged ≥50years were recruited from the Anglo-Cardiff Collaborative Trial. Central stiffness was assessed by carotid-femoral pulse wave velocity (cfPWV). In study 1, peripheral PWV was also measured in the arm (carotid-radial, crPWV), and in study 2 in the leg (femoral- dorsalis pedis, fpPWV). Reflection site distance was calculated from cfPWV and reflected wave travel time. Subjects were dichotomized into those with a normal stiffness gradient (peripheral>central PWV), or a reversed gradient (peripheral<central PWV). In study 1, reflection site distance was greater in subjects with a reversed gradient (P<0.01), whereas time to reflection was lower (P<0.001). Both augmentation pressure (P<0.001) and augmentation index (P<0.05) were greater in subjects with a reversed gradient. In study 2, augmentation pressure, augmentation index and reflection site distance were greater in subjects with a reversed stiffness gradient (P<0.01, P<0.05 and P<0.01, respectively), and time to reflection was not different between groups. A reversed arterial stiffness gradient is associated with increased reflection site distance and a paradoxical increase in reflected wave amplitude, and augmentation index

Fin development in a cartilaginous fish and the origin of vertebrate limbs

Recent fossil finds and experimental analysis of chick and mouse embryos highlighted the lateral fin fold theory, which suggests that two pairs of limbs in tetrapods evolved by subdivision of an elongated single fin1. Here we examine fin development in embryos of the primitive cartilaginous fish, Scyliorhinus canicula (dogfish) using scanning electron microscopy and investigate expression of genes known to be involved in limb positioning, identity and patterning in higher vertebrates. Although we did not detect lateral fin folds in dogfish embryos, Engrailed-1 expression suggests that the body is compartmentalized dorso-ventrally. Furthermore, specification of limb identity occurs through the Tbx4 and Tbx5 genes, as in higher vertebrates. In contrast, unlike higher vertebrates, we did not detect Shh transcripts in dogfish fin-buds, although dHand (a gene involved in establishing Shh) is expressed. In S. canicula, the main fin axis seems to lie parallel to the body axis. 'Freeing' fins from the body axis and establishing a separate 'limb' axis has been proposed to be a crucial step in evolution of tetrapod limbs2, 3. We suggest that Shh plays a critical role in this process

Augmentation index assessed by applanation tonometry is elevated in Marfan Syndrome

<p>Abstract</p> <p>Background</p> <p>To examine whether augmentation index (AIx) is increased in Marfan syndrome (MFS) and associated with increased aortic root size, and whether a peripheral-to-central generalised transfer function (GTF) can be applied usefully in MFS.</p> <p>Methods</p> <p>10 MFS patients and 10 healthy controls (matched for sex, age and height) were studied before and after 400 μg sub-lingual GTN. Arterial waveforms were recorded using applanation tonometry. AIx and pulse pressure (PP) were determined for the radial and carotid arteries. Pulse wave velocity (PWV) was measured between carotid and femoral arteries. GTFs were generated to examine the relationship between radial and carotid waveforms.</p> <p>Results</p> <p>AIx was greater in MFS compared to controls at radial (mean -31.4 (SD 14.3)% v -50.2(15.6)%, p = 0.003) and carotid (-7.6(11.2)% v -23.7(12.7)%, p = 0.004) sites. Baseline PP at all measurement sites, and PWV, did not differ between subject groups. Multivariate analysis demonstrated that PWV and carotid AIx were positively correlated with aortic root size (p < 0.001 and p = 0.012 respectively), independent of the presence of MFS. PP was not associated with aortic root size. GTN caused similar decreases in AIx in both controls and patients. Significant differences were found in GTFs between MFS and control subjects, which changed following GTN administration. However, when an independent GTF was used to derive carotid waves from radial waves, no differences were found in the degree of error between MFS and controls.</p> <p>Conclusion</p> <p>AIx is sensitive to the vascular abnormalities present in MFS, and may have a role as an adjunct to measurement of central PP and PWV. Differences between MFS and controls in the nature of the peripheral-to-central GTF are present, although have little effect on the pulse contour.</p

Lack of basic and luxury goods and health-related dysfunction in older persons; Findings from the longitudinal SMILE study

<p>Abstract</p> <p>Background</p> <p>More so than the traditional socioeconomic indicators, such as education and income, wealth reflects the accumulation of resources and makes socioeconomic ranking manifest and explicitly visible to the outside world. While the lack of basic goods, such as a refrigerator, may affect health directly, via biological pathways, the lack of luxury goods, such as an LCD television, may affect health indirectly through psychosocial mechanisms. We set out to examine, firstly, the relevance of both basic and luxury goods in explaining health-related dysfunction in older persons, and, secondly, the extent to which these associations are independent of traditional socioeconomic indicators.</p> <p>Methods</p> <p>Cross-sectional and longitudinal data from 2067 men and women aged 55 years and older who participated in the Study on Medical Information and Lifestyles Eindhoven (SMILE) were gathered. Logistic regression analyses were used to study the relation between a lack of basic and luxury goods and health-related function, assessed with two sub-domains of the SF-36.</p> <p>Results</p> <p>The lack of basic goods was closely related to incident physical (OR = 2.32) and mental (OR = 2.12) dysfunction, even when the traditional measures of socioeconomic status, i.e. education or income, were taken into account. Cross-sectional analyses, in which basic and luxury goods were compared, showed that the lack of basic goods was strongly associated with mental dysfunction. Lack of luxury goods was, however, not related to dysfunction.</p> <p>Conclusion</p> <p>Even in a relatively wealthy country like the Netherlands, the lack of certain basic goods is not uncommon. More importantly, lack of basic goods, as an indicator of wealth, was strongly related to health-related dysfunction also when traditional measures of socioeconomic status were taken into account. In contrast, no effects of luxury goods on physical or mental dysfunction were found. Future longitudinal research is necessary to clarify the precise mechanisms underlying these effects.</p

Resistance training with soy vs whey protein supplements in hyperlipidemic males

<p>Abstract</p> <p>Background</p> <p>Most individuals at risk for developing cardiovascular disease (CVD) can reduce risk factors through diet and exercise before resorting to drug treatment. The effect of a combination of resistance training with vegetable-based (soy) versus animal-based (whey) protein supplementation on CVD risk reduction has received little study. The study's purpose was to examine the effects of 12 weeks of resistance exercise training with soy versus whey protein supplementation on strength gains, body composition and serum lipid changes in overweight, hyperlipidemic men.</p> <p>Methods</p> <p>Twenty-eight overweight, male subjects (BMI 25–30) with serum cholesterol >200 mg/dl were randomly divided into 3 groups (placebo (n = 9), and soy (n = 9) or whey (n = 10) supplementation) and participated in supervised resistance training for 12 weeks. Supplements were provided in a double blind fashion.</p> <p>Results</p> <p>All 3 groups had significant gains in strength, averaging 47% in all major muscle groups and significant increases in fat free mass (2.6%), with no difference among groups. Percent body fat and waist-to-hip ratio decreased significantly in all 3 groups an average of 8% and 2%, respectively, with no difference among groups. Total serum cholesterol decreased significantly, again with no difference among groups.</p> <p>Conclusion</p> <p>Participation in a 12 week resistance exercise training program significantly increased strength and improved both body composition and serum cholesterol in overweight, hypercholesterolemic men with no added benefit from protein supplementation.</p

An in silico model of the ubiquitin-proteasome system that incorporates normal homeostasis and age-related decline

BACKGROUND: The ubiquitin-proteasome system is responsible for homeostatic degradation of intact protein substrates as well as the elimination of damaged or misfolded proteins that might otherwise aggregate. During ageing there is a decline in proteasome activity and an increase in aggregated proteins. Many neurodegenerative diseases are characterised by the presence of distinctive ubiquitin-positive inclusion bodies in affected regions of the brain. These inclusions consist of insoluble, unfolded, ubiquitinated polypeptides that fail to be targeted and degraded by the proteasome. We are using a systems biology approach to try and determine the primary event in the decline in proteolytic capacity with age and whether there is in fact a vicious cycle of inhibition, with accumulating aggregates further inhibiting proteolysis, prompting accumulation of aggregates and so on. A stochastic model of the ubiquitin-proteasome system has been developed using the Systems Biology Mark-up Language (SBML). Simulations are carried out on the BASIS (Biology of Ageing e-Science Integration and Simulation) system and the model output is compared to experimental data wherein levels of ubiquitin and ubiquitinated substrates are monitored in cultured cells under various conditions. The model can be used to predict the effects of different experimental procedures such as inhibition of the proteasome or shutting down the enzyme cascade responsible for ubiquitin conjugation. RESULTS: The model output shows good agreement with experimental data under a number of different conditions. However, our model predicts that monomeric ubiquitin pools are always depleted under conditions of proteasome inhibition, whereas experimental data show that monomeric pools were depleted in IMR-90 cells but not in ts20 cells, suggesting that cell lines vary in their ability to replenish ubiquitin pools and there is the need to incorporate ubiquitin turnover into the model. Sensitivity analysis of the model revealed which parameters have an important effect on protein turnover and aggregation kinetics. CONCLUSION: We have developed a model of the ubiquitin-proteasome system using an iterative approach of model building and validation against experimental data. Using SBML to encode the model ensures that it can be easily modified and extended as more data become available. Important aspects to be included in subsequent models are details of ubiquitin turnover, models of autophagy, the inclusion of a pool of short-lived proteins and further details of the aggregation process

Phosphorylation-Independent Regulation of Atf1-Promoted Meiotic Recombination by Stress-Activated, p38 Kinase Spc1 of Fission Yeast

BACKGROUND:Stress-activated protein kinases regulate multiple cellular responses to a wide variety of intracellular and extracellular conditions. The conserved, multifunctional, ATF/CREB protein Atf1 (Mts1, Gad7) of fission yeast binds to CRE-like (M26) DNA sites. Atf1 is phosphorylated by the conserved, p38-family kinase Spc1 (Sty1, Phh1) and is required for many Spc1-dependent stress responses, efficient sexual differentiation, and activation of Rec12 (Spo11)-dependent meiotic recombination hotspots like ade6-M26. METHODOLOGY/PRINCIPAL FINDINGS:We sought to define mechanisms by which Spc1 regulates Atf1 function at the ade6-M26 hotspot. The Spc1 kinase was essential for hotspot activity, but dispensable for basal recombination. Unexpectedly, a protein lacking all eleven MAPK phospho-acceptor sites and detectable phosphorylation (Atf1-11M) was fully proficient for hotspot recombination. Furthermore, tethering of Atf1 to ade6 in the chromosome by a heterologous DNA binding domain bypassed the requirement for Spc1 in promoting recombination. CONCLUSIONS/SIGNIFICANCE:The Spc1 protein kinase regulates the pathway of Atf1-promoted recombination at or before the point where Atf1 binds to chromosomes, and this pathway regulation is independent of the phosphorylation status of Atf1. Since basal recombination is Spc1-independent, the principal function of the Spc1 kinase in meiotic recombination is to correctly position Atf1-promoted recombination at hotspots along chromosomes. We also propose new hypotheses on regulatory mechanisms for shared (e.g., DNA binding) and distinct (e.g., osmoregulatory vs. recombinogenic) activities of multifunctional, stress-activated protein Atf1

Search for Gravitational Waves from Primordial Black Hole Binary Coalescences in the Galactic Halo

We use data from the second science run of the LIGO gravitational-wave detectors to search for the gravitational waves from primordial black hole (PBH) binary coalescence with component masses in the range 0.2--$1.0 M_\odot$. The analysis requires a signal to be found in the data from both LIGO observatories, according to a set of coincidence criteria. No inspiral signals were found. Assuming a spherical halo with core radius 5 kpc extending to 50 kpc containing non-spinning black holes with masses in the range 0.2--$1.0 M_\odot$, we place an observational upper limit on the rate of PBH coalescence of 63 per year per Milky Way halo (MWH) with 90% confidence.Comment: 7 pages, 4 figures, to be submitted to Phys. Rev.