Circulating Levels of Proprotein Convertase Subtilisin/Kexin Type 9 and Arterial Stiffness in a Large Population Sample: Data From the Brisighella Heart Study

Proprotein convertase subtilisin/kexin type 9 (PCSK9) circulating levels are significantly associated with an increased risk of cardiovascular events. This study aimed to evaluate the relationship between circulating levels of PCSK9 and arterial stiffness, an early instrumental biomarker of cardiovascular disease risk, in a large sample of overall healthy participants

PCSK9 induces a pro-inflammatory response in macrophages

Intraplaque release of inflammatory cytokines from macrophages is implicated in atherogenesis by inducing the proliferation and migration of media smooth muscle cells (SMCs). PCSK9 is present and released by SMCs within the atherosclerotic plaque but its function is still unknown. In the present study, we tested the hypothesis that PCSK9 could elicit a pro-inflammatory effect on macrophages. THP-1-derived macrophages and human primary macrophages were exposed to different concentrations (0.250\u2009\uf7\u20092.5\u2009\ub5g/ml) of human recombinant PCSK9 (hPCSK9). After 24\u2009h incubation with 2.5\u2009\ub5g/ml PCSK9, a significant induction of IL-1\u3b2, IL-6, TNF-\u3b1, CXCL2, and MCP1 mRNA, were observed in both cell types. Co-culture of THP-1 macrophages with HepG2 overexpressing hPCSK9 also showed the induction of TNF-\u3b1 (2.4\u2009\ub1\u20090.5 fold) and IL-1\u3b2 (8.6\u2009\ub1\u20091.8 fold) mRNA in macrophages. The effect of hPCSK9 on TNF-\u3b1 mRNA in murine LDLR-/- bone marrow macrophages (BMM) was significantly impaired as compared to wild-type BMM (4.3\u2009\ub1\u20091.6 fold vs 31.1\u2009\ub1\u20096.1 fold for LDLR-/- and LDLR+/+, respectively). Finally, a positive correlation between PCSK9 and TNF-\u3b1 plasma levels of healthy adult subjects (males 533, females 537) was observed (B\u2009=\u20098.73, 95%CI 7.54\u2009\uf7\u20099.93, p\u2009<\u20090.001). Taken together, the present study provides evidence of a pro-inflammatory action of PCSK9 on macrophages, mainly dependent by the LDLR

PCSK9 Expression in Epicardial Adipose Tissue : Molecular Association with Local Tissue Inflammation

Epicardial adipose tissue (EAT) has the unique property to release mediators that nourish the heart in healthy conditions, an effect that becomes detrimental when volume expands and proinflammatory cytokines start to be produced. Proprotein convertase subtilisin/kexin type 9 (PCSK9), a proinflammatory mediator involved in atherosclerosis, is also produced by visceral fat. Due to the correlation of inflammation with PCSK9 and EAT enlargement, we evaluated whether PCSK9 was expressed in EAT and associated with EAT inflammation and volume. EAT samples were isolated during surgery. EAT thickness was measured by echocardiography. A microarray was used to explore EAT transcriptoma. The PCSK9 protein levels were measured by Western Blot in EAT and ELISA in plasma. PCSK9 was expressed at both the gene and protein levels in EAT. We found a positive association with EAT thickness and local proinflammatory mediators, in particular, chemokines for monocytes and lymphocytes. No association was found with the circulating PCSK9 level. The expression of PCSK9 in EAT argues that PCSK9 is part of the EAT secretome and EAT inflammation is associated with local PCSK9 expression, regardless of circulating PCSK9 levels. Whether reducing EAT inflammation or PCSK9 local levels may have beneficial effects on EAT metabolism and cardiovascular risk needs further investigations

Adipokines and Sexual Hormones Associated with the Components of the Metabolic Syndrome in Pharmacologically Untreated Subjects: Data from the Brisighella Heart Study

We evaluated the association of the sex hormone pattern and the serum level of the main adipokines to metabolic syndrome (MS) and its components in 199 pharmacologically untreated subjects. Men and women included in the age-class subgroups were matched for body mass index, waist circumference, blood pressure, heart rate, fasting plasma glucose, and plasma lipids. Men without MS had significantly lower leptin/adiponectin ratio than men with MS. Women without MS had lower leptin and leptin/adiponectin ratio than women with MS but had significantly higher adiponectin, estrone, and dehydroepiandrosterone levels. In men, the leptin/adiponectin ratio is the main factor associated to MS diagnosis (OR: 3.36, 95% CI 1.40–8.08), while in women adiponectin alone appears to be a protective factor (OR: 0.87, 95% CI 0.79–0.95). In conclusion, in a sample of pharmacologically untreated subjects, leptin/adiponectin ratio seems to be the factor more strongly associated to MS and its components

A web analytics approach to map the influence and reach of CCAFS

This evaluation sought to understand CCAFS’ influence in motivating actors to tackle climate change. In CCAFS’ theory of change, a cross-cutting aim is to work with strategic partners to “foster policy and institutional change” that will enable large-scale CSA adoption. A conceptual framework was developed, and an innovative approach based on the Digital Methods epistemology was employed to explore the dynamics of knowledge dissemination and changes in attitude towards CSA among stakeholders at various levels. It considered online networks and narratives as evidence of “offline” program influence. Results show that CCAFS has inspired positive change in government policy; built a global community for climate adaption; and sparked public interest in “Climate Smart Agriculture”

CCAR2/DBC1 is required for Chk2-dependent KAP1 phosphorylation and repair of DNA damage

Cell cycle and apoptosis regulator 2 (CCAR2, formerly known as DBC1) is a nuclear protein largely involved in DNA damage response, apoptosis, metabolism, chromatin structure and transcription regulation. Upon DNA lesions, CCAR2 is phosphorylated by the apical kinases ATM/ATR and this phosphorylation enhances CCAR2 binding to SIRT1, leading to SIRT1 inhibition, p53 acetylation and p53-dependent apoptosis. Recently, we found that also the checkpoint kinase Chk2 and the proteasome activator REG\u3b3 are required for efficient CCAR2-mediated inhibition of SIRT1 and induction of p53-dependent apoptosis. Here, we report that CCAR2 is required for the repair of heterochromatic DNA lesions, as cells knock-out for CCAR2 retain, at late time-points after genotoxic treatment, abnormal levels of DNA damage-associated nuclear foci, whose timely resolution is reinstated by HP1\u3b2 depletion. Conversely, repair of DNA damages in euchromatin are not affected by CCAR2 absence. We also report that the impairment in heterochromatic DNA repair is caused by defective Chk2 activation, detectable in CCAR2 ablated cells, which finally impacts on the phosphorylation of the Chk2 substrate KAP1 that is required for the induction of heterochromatin relaxation and DNA repair. These studies further extend and confirm the role of CCAR2 in the DNA damage response and DNA repair and illustrate a new mechanism of Chk2 activity regulation. Moreover, the involvement of CCAR2 in the repair of heterochromatic DNA breaks suggests a new role for this protein in the maintenance of chromosomal stability, which is necessary to prevent cancer formation

Body composition and metabolic changes during a 520\u2011day mission simulation to Mars

Purpose The \u201cMars-500 project\u201d allowed to evaluate the changes in psychological/physiological adaptation over a prolonged confinement, in order to gather information for future missions. Here, we evaluated the impact of confinement and isolation on body composition, glucose metabolism/insulin resistance and adipokine levels. Methods The \u201cMars-500 project\u201d consisted of 520 consecutive days of confinement from June 3, 2010 to Nov 4, 2011. The crew was composed of six male subjects (three Russians, two Europeans, and one Chinese) with a median age of 31 years (range 27\u201338 years). Results During the 520-day confinement, total body mass and BMI progressively decreased, reaching a significant difference at the end (417 days) of the observation period ( 12 9.2 and 12 5.5%, respectively). Fat mass remained unchanged. A progressive and significant increase of fasting plasma glucose was observed between 249 and 417 days (+ 10/+ 17% vs baseline), with a further increase at the end of confinement (up to + 30%). Median plasma insulin showed a non-significant early increment (60 days; + 86%). Total adiponectin halved ( 12 47%) 60 days after hatch closure, remaining at this nadir ( 12 51%) level for a further 60 days. High molecular weight adiponectin remained significantly lower from 60 to 168 days. Conclusions Based on these data, countermeasures may be envisioned to balance the potentially harmful effects of prolonged confinement, including a better exercise program, with accurate monitoring of (1) the individual activity and (2) the relationship between body composition and metabolic derangement

Effect of soy on metabolic syndrome and cardiovascular risk factors : a randomized controlled trial

Background: Cardiovascular diseases are currently the commonest cause of death worldwide. Different strategies for their primary prevention have been planned, taking into account the main known risk factors, which include an atherogenic lipid profile and visceral fat excess. Methods: The study was designed as a randomized, parallel, single-center study with a nutritional intervention duration of 12 weeks. Whole soy foods corresponding to 30 g/day soy protein were given in substitution of animal foods containing the same protein amount. Results: Soy nutritional intervention resulted in a reduction in the number of MetS features in 13/26 subjects. Moreover, in the soy group we observed a significant improvement of median percentage changes for body weight ( 121.5 %) and BMI ( 121.5 %), as well as for atherogenic lipid markers, namely TC ( 124.85 %), LDL-C ( 125.25 %), non-HDL-C ( 127.14 %) and apoB ( 1214.8 %). Since the majority of the studied variables were strongly correlated, three factors were identified which explained the majority (52 %) of the total variance in the whole data set. Among them, factor 1, which loaded lipid and adipose variables, explained the 22 % of total variance, showing a statistically significant difference between treatment arms (p = 0.002). Conclusions: The inclusion of whole soy foods (corresponding to 30 g/day protein) in a lipid-lowering diet significantly improved a relevant set of biomarkers associated with cardiovascular risk

Influence of body variables in the development of metabolic syndrome : A long term follow-up study

Objectives. The body variable associated with the diagnosis of Metabolic Syndrome (MetS) is an elevated waist circumference (WC), although a number of other variables have been suggested. Among these, an elevated waist-to-height ratio (WHtR), ie a value higher than 0.5, that may identify abnormality, independently from height. An elevated WHtR provided the best correlation with MetS in a prior study in a large Italian population. In order to assess the validity of this conclusion, a long-term follow-up study re-examined this population, also in order to detect possible associations with cardiovascular (CV) risk. Methods and Results. 1,071 subjects with a complete follow-up of over 6 years were evaluated with a comparative assessment of the three anthropometric variables, namely WHtR, WC and body mass index (BMI). WHtR 65 0.5 had the highest sensitivity for the identification of MetS, both in males and females (94.1% and 86.7% respectively). WHtR was of reduced specificity, occurring, yet less frequently (17.7% in males and 30% in females), in patients without MetS. By contrast, enlarged WC occurred with a lower frequency in male patients who developed MetS (30.2%) whereas in females, frequency was higher than in males (69.3%). Finally, a BMI 65 25 kg/m2 had intermediate sensitivity and specificity regardless of gender. WC showed the highest odds ratio (2.62, 95%CI: 1.18-5.78) for the prediction of CV occurrence. Conclusion. The present study confirms WHtR as an excellent screening tool in identifying MetS carriers, but, different from reports in other countries, it shows a lower specificity in our population

Thermal diffusivity measurements of metastable austenite during continuous cooling

The thermal diffusivity of the metastable undercooled austenite is relevant for the quantitative analysis of the carbon and low-alloy steel quench. The standard laser-flash method requires prior thermal equilibrium between the sample and the furnace, which may not be possible to achieve without allowing the metastable phase to transform. Nevertheless, depending upon the steel's hardenability, the thermal transient due to a laser pulse may be much shorter than a cooling transient sufficiently steep to prevent the transformation of the austenite. In one such case, flash measurements were performed during continuous sample cooling and the thermal diffusivity of the metastable austenite was determined by using an extension of the standard analytical model. The adopted analytical model and data reduction procedure are described and the limitations and uncertainties of this method are discussed, also with the aid of a non-linear numerical simulation. The measured thermal diffusivity of the under cooled low-alloy austenite decreases linearly from 5.4•10−6 m2 s−1 at 1133 K to 4.3•10−6 m2 s−1 at 755 K; this trend is in broad agreement with one previous set of measurements upon a low-alloy undercooled austenite and with a large number of previous standard measurements upon stable (high-alloy) austenitic stainless steels