Telomerase Inhibition by Everolimus Suppresses Smooth Muscle Cell Proliferation and Neointima Formation Through Epigenetic Gene Silencing

Proliferation of smooth muscle cells (SMCs) during neointima formation is prevented by drug-eluting stents. The replicative capacity of mammalian cells is enhanced by telomerase expression; however, the contribution of telomerase to the proliferative response underlying neointima formation and its potential role as a pharmacological target are unknown. The present study investigated the mechanisms underlying the mitogenic function of telomerase, and tested the hypothesis that everolimus, which is commonly used on drug-eluting stents, suppresses SMC proliferation by targeting telomerase. Inhibition of neointima formation by everolimus was lost in mice overexpressing telomerase reverse transcriptase (TERT), indicating that repression of telomerase confers the anti-proliferative efficacy of everolimus. Everolimus reduced TERT expression in SMC through an Ets-1-dependent inhibition of promoter activation. The inhibition of TERT-dependent SMC proliferation by everolimus occurred in the absence of telomere shortening but rather as a result of a G1→S-phase arrest. Although everolimus failed to inhibit phosphorylation of the retinoblastoma protein as the gatekeeper of S-phase entry, it potently repressed downstream target genes. Chromatin immunoprecipitation assays demonstrated that TERT induced E2F binding to S-phase gene promoters and supported histone acetylation. These effects were sensitive to inhibition by everolimus. These results characterize telomerase as a previously unrecognized target for the antiproliferative activity of everolimus, and further identify a novel mitogenic pathway in SMC that depends on the epigenetic activation of S-phase gene promoters by TERT

Oxidative Stress Accumulates in Adipose Tissue during Aging and Inhibits Adipogenesis

Aging constitutes a major independent risk factor for the development of type 2 diabetes and is accompanied by insulin resistance and adipose tissue dysfunction. One of the most important factors implicitly linked to aging and age-related chronic diseases is the accumulation of oxidative stress. However, the effect of increased oxidative stress on adipose tissue biology remains elusive. In this study, we demonstrate that aging in mice results in a loss of fat mass and the accumulation of oxidative stress in adipose tissue. In vitro, increased oxidative stress through glutathione depletion inhibits preadipocyte differentiation. This inhibition of adipogenesis is at least in part the result of reduced cell proliferation and an inhibition of G1→S-phase transition during the initial mitotic clonal expansion of the adipocyte differentiation process. While phosphorylation of the retinoblastoma protein (Rb) by cyclin/cdk complexes remains unaffected, oxidative stress decreases the expression of S-phase genes downstream of Rb. This silencing of S phase gene expression by increased oxidative stress is mediated through a transcriptional mechanism involving the inhibition of E2F recruitment and transactivation of its target promoters. Collectively, these data demonstrate a previously unrecognized role of oxidative stress in the regulation of adipogenesis which may contribute to age-associated adipose tissue dysfunction

Osteopontin Mediates Obesity-Induced Adipose Tissue Macrophage Infiltration and Insulin Resistance in Mice

Obesity is associated with a state of chronic, low-grade inflammation characterized by abnormal cytokine production and macrophage infiltration into adipose tissue, which may contribute to the development of insulin resistance. During immune responses, tissue infiltration by macrophages is dependent on the expression of osteopontin, an extracellular matrix protein and proinflammatory cytokine that promotes monocyte chemotaxis and cell motility. In the present study, we used a murine model of diet-induced obesity to examine the role of osteopontin in the accumulation of adipose tissue macrophages and the development of insulin resistance during obesity. Mice exposed to a high-fat diet exhibited increased plasma osteopontin levels, with elevated expression in macrophages recruited into adipose tissue. Obese mice lacking osteopontin displayed improved insulin sensitivity in the absence of an effect on diet-induced obesity, body composition, or energy expenditure. These mice further demonstrated decreased macrophage infiltration into adipose tissue, which may reflect both impaired macrophage motility and attenuated monocyte recruitment by stromal vascular cells. Finally, obese osteopontin-deficient mice exhibited decreased markers of inflammation, both in adipose tissue and systemically. Taken together, these results suggest that osteopontin may play a key role in linking obesity to the development of insulin resistance by promoting inflammation and the accumulation of macrophages in adipose tissue

Evaluation of the LSA-SAF gross primary production product derived from SEVIRI/MSG data (MGPP)

The objective of this study is to describe a completely new 10-day gross primary production (GPP) product (MGPP LSA-411) based on data from the geostationary SEVIRI/MSG satellite within the LSA SAF (Land Surface Analysis SAF) as part of the SAF (Satellite Application Facility) network of EUMETSAT. The methodology relies on the Monteith approach. It considers that GPP is proportional to the absorbed photosynthetically active radiation APAR and the proportionality factor is known as the light use efficiency ε. A parameterization of this factor is proposed as the product of a εmax, corresponding to the canopy functioning under optimal conditions, and a coefficient quantifying the reduction of photosynthesis as a consequence of water stress. A three years data record (2015–2017) was used in an assessment against site-level eddy covariance (EC) tower GPP estimates and against other Earth Observation (EO) based GPP products. The site-level comparison indicated that the MGPP product performed better than the other EO based GPP products with 48% of the observations being below the optimal accuracy (absolute error < 1.0 g m−2 day−1) and 75% of these data being below the user requirement threshold (absolute error < 3.0 g m−2 day−1). The largest discrepancies between the MGPP product and the other GPP products were found for forests whereas small differences were observed for the other land cover types. The integration of this GPP product with the ensemble of LSA-SAF MSG products is conducive to meet user needs for a better understanding of ecosystem processes and for improved understanding of anthropogenic impact on ecosystem services.The objective of this study is to describe a completely new 10-day gross primary production (GPP) product (MGPP LSA-411) based on data from the geostationary SEVIRI/MSG satellite within the LSA SAF (Land Surface Analysis SAF) as part of the SAF (Satellite Application Facility) network of EUMETSAT. The methodology relies on the Monteith approach. It considers that GPP is proportional to the absorbed photosynthetically active radiation APAR and the proportionality factor is known as the light use efficiency epsilon. A parameterization of this factor is proposed as the product of a epsilon(max), corresponding to the canopy functioning under optimal conditions, and a coefficient quantifying the reduction of photosynthesis as a consequence of water stress. A three years data record (2015-2017) was used in an assessment against site-level eddy covariance (EC) tower GPP estimates and against other Earth Observation (EO) based GPP products. The site-level comparison indicated that the MGPP product performed better than the other EO based GPP products with 48% of the observations being below the optimal accuracy (absolute error <1.0 g m(-2) day(-1)) and 75% of these data being below the user requirement threshold (absolute error <3.0 g m(-2) day(-1)). The largest discrepancies between the MGPP product and the other GPP products were found for forests whereas small differences were observed for the other land cover types. The integration of this GPP product with the ensemble of LSA-SAF MSG products is conducive to meet user needs for a better understanding of ecosystem processes and for improved understanding of anthropogenic impact on ecosystem services.Peer reviewe

Fertility Control Options for Management of Free-roaming Horse Populations

The management of free-roaming horses (Equus ferus) and burros (E. asinus) in the United States has been referred to as a “wicked problem” because, although there are population control options, societal values will ultimately determine what is acceptable and what is not. In the United States, free-roaming equids are managed by different types of organizations and agencies, and the landscapes that these animals inhabit vary widely in terms of access, size, topography, climate, natural resources, flora, and fauna. This landscape diversity, coupled with contemporary socioeconomic and political environments, means that adaptive management practices are needed to regulate these free-roaming populations. The Bureau of Land Management (BLM) currently manages free-roaming equids on 177 herd management areas in the United States by applying fertility control measures in situ and/or removing horses, which are either adopted by private individuals or sent to long-term holding facilities. The BLM off-range population currently includes \u3e50,000 animals and costs approximately $50 million USD per year to maintain; on-range equid numbers were estimated in March 2022 to be approximately 82,384. On-range populations can grow at 15–20% annually, and current estimates far exceed the designated appropriate management level of 26,715. To reduce population recruitment, managers need better information about effective, long-lasting or permanent fertility control measures. Because mares breed only once a year, fertility control studies take years to complete. Some contraceptive approaches have been studied for decades, and results from various trials can collectively inform future research directions and actions. Employing 1 or more fertility control tools in concert with removals offers the best potential for success. Active, iterative, cooperative, and thoughtful management practices can protect free-roaming horses while simultaneously protecting the habitat. Herein, we review contraceptive vaccines, intrauterine devices, and surgical sterilization options for controlling fertility of free-roaming horses. This review provides managers with a “fertility control toolbox” and guides future research

Squirrelpox virus: assessing prevalence, transmission and environmental degradation

Red squirrels (Sciurus vulgaris) declined in Great Britain and Ireland during the last century, due to habitat loss and the introduction of grey squirrels (Sciurus carolinensis), which competitively exclude the red squirrel and act as a reservoir for squirrelpox virus (SQPV). The disease is generally fatal to red squirrels and their ecological replacement by grey squirrels is up to 25 times faster where the virus is present. We aimed to determine: (1) the seropositivity and prevalence of SQPV DNA in the invasive and native species at a regional scale; (2) possible SQPV transmission routes; and, (3) virus degradation rates under differing environmental conditions. Grey (n = 208) and red (n = 40) squirrel blood and tissues were sampled. Enzyme-linked immunosorbent assay (ELISA) and quantitative real-time polymerase chain reaction (qPCR) techniques established seropositivity and viral DNA presence, respectively. Overall 8% of squirrels sampled (both species combined) had evidence of SQPV DNA in their tissues and 22% were in possession of antibodies. SQPV prevalence in sampled red squirrels was 2.5%. Viral loads were typically low in grey squirrels by comparison to red squirrels. There was a trend for a greater number of positive samples in spring and summer than in winter. Possible transmission routes were identified through the presence of viral DNA in faeces (red squirrels only), urine and ectoparasites (both species). Virus degradation analyses suggested that, after 30 days of exposure to six combinations of environments, there were more intact virus particles in scabs kept in warm (25°C) and dry conditions than in cooler (5 and 15°C) or wet conditions. We conclude that SQPV is present at low prevalence in invasive grey squirrel populations with a lower prevalence in native red squirrels. Virus transmission could occur through urine especially during warm dry summer conditions but, more notably, via ectoparasites, which are shared by both species

Intakes of fruits and vegetables, carotenoids and vitamins A, E, C in relation to the risk of bladder cancer in the ATBC cohort study

We examined the relation between dietary fruit and vegetables, carotenoids and vitamin intakes and the risk of bladder cancer among male smokers in a prospective cohort study. Over a median of 11 years, we followed 27 111 male smokers aged 50–69 years who were initially enrolled in the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study. During this period, 344 men developed bladder cancer. All of these men had completed a 276-food item dietary questionnaire at baseline. Cox proportional hazards models were used to estimate the relative risks and 95% confidence intervals and to simultaneously adjust for age, smoking history, energy intake and intervention group. Consumption of fruits and vegetables was not associated with the risk of bladder cancer (relative risk=1.28; 95% confidence intervals CI: 0.89–1.84, for highest vs lowest quintile). Similarly, no associations were observed for groups of fruits or vegetables (berries and cruciferous vegetables), or for specific fruits and vegetables. Dietary intakes of alpha-carotene, beta-carotene, lycopene, lutein/zeaxanthin, beta-cryptoxanthin, vitamins A, E, and C, and folate were not related to the risk of bladder cancer. These findings suggest that fruit and vegetable intakes are not likely to be associated with bladder cancer risk. However, these results may not be generalisable to non-smokers

An Integrated Decision Making Approach for Adaptive Shared Control of Mobility Assistance Robots

© 2016, Springer Science+Business Media Dordrecht. Mobility assistance robots provide support to elderly or patients during walking. The design of a safe and intuitive assistance behavior is one of the major challenges in this context. We present an integrated approach for the context-specific, on-line adaptation of the assistance level of a rollator-type mobility assistance robot by gain-scheduling of low-level robot control parameters. A human-inspired decision-making model, the drift-diffusion Model, is introduced as the key principle to gain-schedule parameters and with this to adapt the provided robot assistance in order to achieve a human-like assistive behavior. The mobility assistance robot is designed to provide (a) cognitive assistance to help the user following a desired path towards a predefined destination as well as (b) sensorial assistance to avoid collisions with obstacles while allowing for an intentional approach of them. Further, the robot observes the user long-term performance and fatigue to adapt the overall level of (c) physical assistance provided. For each type of assistance a decision-making problem is formulated that affects different low-level control parameters. The effectiveness of the proposed approach is demonstrated in technical validation experiments. Moreover, the proposed approach is evaluated in a user study with 35 elderly persons. Obtained results indicate that the proposed gain-scheduling technique incorporating ideas of human decision-making models shows a general high potential for the application in adaptive shared control of mobility assistance robots

Differential Roles of Cardiomyocyte and Macrophage Peroxisome Proliferator–Activated Receptor γ in Cardiac Fibrosis

OBJECTIVE—Cardiac fibrosis is an important component of diabetic cardiomyopathy. Peroxisome proliferator–activated receptor γ (PPARγ) ligands repress proinflammatory gene expression, including that of osteopontin, a known contributor to the development of myocardial fibrosis. We thus investigated the hypothesis that PPARγ ligands could attenuate cardiac fibrosis

Vanin-1 Pantetheinase Drives Smooth Muscle Cell Activation in Post-Arterial Injury Neointimal Hyperplasia

The pantetheinase vanin-1 generates cysteamine, which inhibits reduced glutathione (GSH) synthesis. Vanin-1 promotes inflammation and tissue injury partly by inducing oxidative stress, and partly by peroxisome proliferator-activated receptor gamma (PPARγ) expression. Vascular smooth muscle cells (SMCs) contribute to neointimal hyperplasia in response to injury, by multiple mechanisms including modulation of oxidative stress and PPARγ. Therefore, we tested the hypothesis that vanin-1 drives SMC activation and neointimal hyperplasia. We studied reactive oxygen species (ROS) generation and functional responses to platelet-derived growth factor (PDGF) and the pro-oxidant diamide in cultured mouse aortic SMCs, and also assessed neointima formation after carotid artery ligation in vanin-1 deficiency. Vnn1−/− SMCs demonstrated decreased oxidative stress, proliferation, migration, and matrix metalloproteinase 9 (MMP-9) activity in response to PDGF and/or diamide, with the effects on proliferation linked, in these studies, to both increased GSH levels and PPARγ expression. Vnn1−/− mice displayed markedly decreased neointima formation in response to carotid artery ligation, including decreased intima:media ratio and cross-sectional area of the neointima. We conclude that vanin-1, via dual modulation of GSH and PPARγ, critically regulates the activation of cultured SMCs and development of neointimal hyperplasia in response to carotid artery ligation. Vanin-1 is a novel potential therapeutic target for neointimal hyperplasia following revascularization