β1-Integrin-Mediated Uptake of Chondrocyte Extracellular Vesicles Regulates Chondrocyte Homeostasis.

Osteoarthritis (OA) is the most prevalent age-related degenerative disorder, which severely reduces the quality of life of those affected. Whilst management strategies exist, no cures are currently available. Virtually all joint resident cells generate extracellular vesicles (EVs), and alterations in chondrocyte EVs during OA have previously been reported. Herein, we investigated factors influencing chondrocyte EV release and the functional role that these EVs exhibit. Both 2D and 3D models of culturing C28I/2 chondrocytes were used for generating chondrocyte EVs. We assessed the effect of these EVs on chondrogenic gene expression as well as their uptake by chondrocytes. Collectively, the data demonstrated that chondrocyte EVs are sequestered within the cartilage ECM and that a bi-directional relationship exists between chondrocyte EV release and changes in chondrogenic differentiation. Finally, we demonstrated that the uptake of chondrocyte EVs is at least partially dependent on β1-integrin. These results indicate that chondrocyte EVs have an autocrine homeostatic role that maintains chondrocyte phenotype. How this role is perturbed under OA conditions remains the subject of future work

Efferocytes release extracellular vesicles to resolve inflammation and tissue injury via prosaposin-GPR37 signaling.

Macrophages release soluble mediators following efferocytic clearance of apoptotic cells to facilitate intercellular communication and promote the resolution of inflammation. However, whether inflammation resolution is modulated by extracellular vesicles (EVs) and vesicular mediators released by efferocytes is not known. We report that efferocyte-derived EVs express prosaposin, which binds to macrophage GPR37 to increase expression of the efferocytosis receptor Tim4 via an ERK-AP1-dependent signaling axis, leading to increased macrophage efferocytosis efficiency and accelerated resolution of inflammation. Neutralization and knockdown of prosaposin or blocking GRP37 abrogates the pro-resolution effects of efferocyte-derived EVs in vivo. Administration of efferocyte-derived EVs in a murine model of atherosclerosis is associated with an increase in lesional macrophage efferocytosis efficiency and a decrease in plaque necrosis and lesional inflammation. Thus, we establish a critical role for efferocyte-derived vesicular mediators in increasing macrophage efferocytosis efficiency and accelerating the resolution of inflammation and tissue injury

A review of climate change and the implementation of marine biodiversity legislation in the United Kingdom

1. Marine legislation, the key means by which the conservation of marine biodiversity is achieved, has been developing since the 1960s. In recent decades, an increasing focus on ‘holistic’ policy development is evident, compared with earlier ‘piecemeal’ sectoral approaches. Important marine legislative tools being used in the United Kingdom, and internationally, include the designation of marine protected areas and the Marine Strategy Framework Directive (MSFD) with its aim of meeting ‘Good Environmental Status’ (GES) for European seas by 2020. 2. There is growing evidence of climate change impacts on marine biodiversity, which may compromise the effectiveness of any legislation intended to promote sustainable marine resource management. 3. A review of key marine biodiversity legislation relevant to the UK shows climate change was not considered in the drafting of much early legislation. Despite the huge increase in knowledge of climate change impacts in recent decades, legislation is still limited in how it takes these impacts into account. There is scope, however, to account for climate change in implementing much of the legislation through (a) existing references to environmental variability; (b) review cycles; and (c) secondary legislation and complementary policy development. 4. For legislation relating to marine protected areas (e.g. the EC Habitats and Birds Directives), climate change has generally not been considered in the site-designation process, or for ongoing management, with the exception of the Marine (Scotland) Act. Given that changing environmental conditions (e.g. rising temperatures and ocean acidification) directly affect the habitats and species that sites are designated for, how this legislation is used to protect marine biodiversity in a changing climate requires further consideration. 5. Accounting for climate change impacts on marine biodiversity in the development and implementation of legislation is vital to enable timely, adaptive management responses. Marine modelling can play an important role in informing management decisions

Diagnosis, therapeutic advances, and key recommendations for the management of factor X deficiency.

Factor X deficiency is a rare coagulation disorder that can be hereditary or acquired. The typology and severity of the associated bleeding symptoms are highly heterogeneous, adding to the difficulties of diagnosis and management. Evidence-based guidelines and reviews on factor X deficiency are generally limited to publications covering a range of rare bleeding disorders. Here we provide a comprehensive review of the literature on factor X deficiency, focusing on the hereditary form, and discuss the evolution in disease management and the evidence associated with available treatment options. Current recommendations advise clinicians to use single-factor replacement therapy for hereditary disease rather than multifactor therapies such as fresh frozen plasma, cryoprecipitate, and prothrombin complex concentrates. Consensus in treatment guidelines is still urgently needed to ensure optimal management of patients with factor X deficiency across the spectrum of disease severity

Thermoelectric properties of Ca0.8Dy0.2MnO3 synthesized by solution combustion process

High-quality Ca0.8Dy0.2MnO3 nano-powders were synthesized by the solution combustion process. The size of the synthesized Ca0.8Dy0.2MnO3 powders was approximately 23 nm. The green pellets were sintered at 1150-1300°C at a step size of 50°C. Sintered Ca0.8Dy0.2MnO3 bodies crystallized in the perovskite structure with an orthorhombic symmetry. The sintering temperature did not affect the Seebeck coefficient, but significantly affected the electrical conductivity. The electrical conductivity of Ca0.8Dy0.2MnO3 increased with increasing temperature, indicating a semiconducting behavior. The absolute value of the Seebeck coefficient gradually increased with an increase in temperature. The highest power factor (3.7 × 10-5 Wm-1 K-2 at 800°C) was obtained for Ca0.8Dy0.2MnO3 sintered at 1,250°C. In this study, we investigated the microstructure and thermoelectric properties of Ca0.8Dy0.2MnO3, depending on sintering temperature

Absence of influence of gender and BMPR2 mutation type on clinical phenotypes of pulmonary arterial hypertension

<p>Abstract</p> <p>Background</p> <p>Previous studies indicate that patients with pulmonary arterial hypertension (PAH) carrying a mutation in the bone morphogenetic protein receptor type 2 (<it>BMPR2</it>) gene, develop the disease 10 years earlier than non-carriers, and have a more severe hemodynamic compromise at diagnosis. A recent report has suggested that this may only be the case for females and that patients with missense mutations in <it>BMPR2 </it>gene have more severe disease than patients with truncating mutations.</p> <p>Methods</p> <p>We reviewed data from all patients with PAH considered as idiopathic and patients with a family history of PAH, who underwent genetic counselling in the French PAH network between January, 1^st2004 and April, 1^st2010. We compared clinical, functional, and hemodynamic characteristics between carriers and non-carriers of a <it>BMPR2 </it>mutation, according to gender or <it>BMPR2 </it>mutation type.</p> <p>Results</p> <p>PAH patients carrying a <it>BMPR2 </it>mutation (n = 115) were significantly younger at diagnosis than non-carriers (n = 267) (35.8 ± 15.4 and 47.5 ± 16.2 respectively, p < 0.0001). The presence of a <it>BMPR2 </it>mutation was associated with a younger age at diagnosis in females (36.4 ± 14.9 in <it>BMPR2 </it>mutation carriers and 47.4 ± 15.8 in non-carriers, p < 0.0001), and males (34.6 ± 16.8 in <it>BMPR2 </it>mutation carriers and 47.8 ± 17.1 in non-carriers, p < 0.0001). <it>BMPR2 </it>mutation carriers had a more severe hemodynamic compromise at diagnosis, but this was not influenced by gender. No differences in survival and time to death or lung transplantation were found in male and female PAH patients carrying a <it>BMPR2 </it>mutation. No differences were observed in clinical outcomes according to the type of <it>BMPR2 </it>mutations (missense, truncating, large rearrangement or splice defect).</p> <p>Conclusion</p> <p>When compared to non-carriers, <it>BMPR2 </it>mutation carriers from the French PAH network are younger at diagnosis and present with a more severe hemodynamic compromise, irrespective of gender. Moreover, <it>BMPR2 </it>mutation type had no influence on clinical phenotypes in our patient population.</p

How the risk of liver cancer changes after alcohol cessation: A review and meta-analysis of the current literature

<p>Abstract</p> <p>Background</p> <p>It is well established that drinking alcohol raises the risk of liver cancer (hepatocellular carcinoma). However, it has not been sufficiently established as to whether or not drinking cessation subsequently reduces the risk of liver cancer and if it does reduce the risk how long it takes for this heightened risk to fall to that of never drinkers. This question is important for effective policy design and evaluation, to establish causality and for motivational treatments.</p> <p>Methods</p> <p>A systematic review and meta-analysis using the current available evidence and a specific form of Generalised Least Squares is performed to assess how the risk of liver cancer changes with time for former drinkers.</p> <p>Results</p> <p>Four studies are found to have quantified the effect of drinking cessation on the risk of liver cancer. The meta-analysis suggests that the risk of liver cancer does indeed fall after cessation by 6-7% a year, but there remains a large uncertainty around this estimate both statistically and in its interpretation. As an illustration it is estimated that a time period of 23 years is required after drinking cessation, with a correspondingly large 95% confidence interval of 14 to 70 years, for the risk of liver cancer to be equal to that of never drinkers.</p> <p>Conclusion</p> <p>This is a relatively under researched area and this is reflected in the uncertainty of the findings. It is our view that it is not possible to extrapolate the results found here to the general population. Too few studies have addressed this question and of the studies that have, all have significant limitations. The key issue amongst the relevant studies is that it appears that current drinkers, abstainers and former drinkers are not composed of, or effectively adjusted to be, similar populations making inferences about risk changes impossible. This is a very difficult area to study effectively, but it is an important topic. More work is required to reduce both statistical uncertainty and tackle the various study limitations this paper highlights and until this is done, the current result should be considered preliminary.</p

Bioassay design and length of time in the laboratory affect intercolonial interactions of the Formosan subterranean termite (Isoptera, Rhinotermitidae)

This study examined the effect of diet, experimental design, and length of time in the laboratory on intercolonial agonism among Formosan subterranean termite, Coptotermes formosanus Shiraki, colonies. In pairings of 12 C. formosanus Shiraki colonies collected in an urban forest, there was no significant reduction in survival of termites in 30 out of 59 colony pairs compared to colony controls, but there was <50% survival in 18 colony pairs and <10% survival in six colony pairs. There was no correlation between the level of aggressive behavior and the laboratory diet of the termites. Effect of bioassay design and length of time in the laboratory was evaluated in three colony pairs where tests were first conducted on the day of field collection, then colony pairs were retested every 7 days. Aggressive behavior decreased over time in both bioassays, but it tended to decrease more rapidly in the Petri dish tests. The rapid loss of agonism in groups of termites kept in the laboratory demonstrates that changes in environmental factors affect intercolonial agonism

Entrepreneurs’ age, institutions, and social value creation goals: a multi-country study

This study explores the relationship between an entrepreneur's age and his/her social value creation goals. Building on the lifespan developmental psychology literature and institutional theory, we hypothesize a U-shaped relationship between entrepreneurs’ age and their choice to create social value through their ventures, such that younger and older entrepreneurs create more social value with their businesses while middle age entrepreneurs are relatively more economically and less socially oriented with their ventures. We further hypothesize that the quality of a country’s formal institutions in terms of economic, social, and political freedom steepen the U-shaped relationship between entrepreneurs’ age and their choice to pursue social value creation as supportive institutional environments allow entrepreneurs to follow their age-based preferences. We confirm our predictions using multilevel mixed-effects linear regressions on a sample of over 15,000 entrepreneurs (aged between 18 and 64 years) in 45 countries from Global Entrepreneurship Monitor data. The findings are robust to several alternative specifications. Based on our findings, we discuss implications for theory and practice, and we propose future research directions