Myeloperoxidase-derived oxidants inhibit sarco/endoplasmic reticulum Ca2+-ATPase activity, and perturb Ca2+ homeostasis in human coronary artery endothelial cells

The sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) plays a critical role in Ca2+ homeostasis via sequestration of this ion into the sarco/endoplasmic reticulum. The activity of this pump is inhibited by oxidants and impaired in ageing tissues and cardiovascular disease. We have shown previously that the myeloperoxidase- (MPO) derived oxidants HOCl and HOSCN target thiols and mediate cellular dysfunction. As SERCA contains Cys residues critical to ATPase activity, we hypothesized that HOCl and HOSCN might inhibit SERCA activity, via thiol oxidation, and increase cytosolic Ca2+ levels in human coronary artery endothelial cells (HCAEC). Exposure of sarcoplasmic reticulum vesicles to pre-formed or enzymatically-generated HOCl and HOSCN resulted in a concentration-dependent decrease in ATPase activity; this was also inhibited by the SERCA inhibitor thapsigargin. Decomposed HOSCN and incomplete MPO enzyme systems did not decrease activity. Loss of ATPase activity occurred concurrently with oxidation of SERCA Cys residues and protein modification. Exposure of HCAEC, with or without external Ca2+, to HOSCN or HOCl, resulted in a time- and concentration-dependent increase in intracellular Ca2+ under conditions that did not result in immediate loss of cell viability. Thapsigargin, but not inhibitors of plasma membrane or mitochondrial Ca2+ pumps/channels, completely attenuated the increase in intracellular Ca2+ consistent with a critical role for SERCA in maintaining endothelial cell Ca2+ homeostasis. Angiotensin II pre-treatment potentiated the effect of HOSCN at low concentrations. MPO-mediated modulation of intracellular Ca2+ levels may exacerbate endothelial dysfunction, a key early event in atherosclerosis, and be more marked in smokers due to their higher SCN− levels

Hydroclimate Variability and Change in the Prairie Pothole Region, the “Duck Factory” of North America

The Prairie Pothole Region (PPR) of the northern Great Plains is a vital ecosystem responsible each year for producing 50%–80% of new recruits to the North American duck population. Climate variability and change can impact the hydrology and ecology of the region with implications for waterfowl populations. The historical relationship between PPR wetlands, duck populations, and seasonal hydroclimate are explored. Model experiments from phase 5 of the Coupled Model Intercomparison Project are used to determine whether a recent wetting trend is due to natural variability or changing climate and how PPR hydroclimate will change into the future. Year-to-year variations in May duck populations, pond numbers, and the Palmer drought severity index are well correlated over past decades. Pond and duck numbers tend to increase in spring following La Niña events, but the correlation is not strong. Model simulations suggest that the strengthening of the precipitation gradient across the PPR over the past century is predominantly due to natural variability and therefore could reverse. Model projections of future climate indicate precipitation will increase across the PPR in all seasons except summer, but this gain for surface moisture is largely offset by increased evapotranspiration because of higher temperatures and increased atmospheric evaporative demand. In summer, the combined effects of warming and precipitation changes indicate seasonal surface drying in the future. The presented hydroclimate analyses produce potential inputs to ecological and hydrological simulations of PPR wetlands to inform risk analysis of how this North American waterfowl habitat will evolve in the future, providing guidance to land managers facing conservation decisions

Climatology, Variability, and Trends in the U.S. Vapor Pressure Deficit, an Important Fire-Related Meteorological Quantity

Unlike the commonly used relative humidity, vapor pressure deficit (VPD) is an absolute measure of the difference between the water vapor content of the air and its saturation value and an accurate metric of the ability of the atmosphere to extract moisture from the land surface. VPD has been shown to be closely related to variability in burned forest areas in the western United States. Here, the climatology, variability, and trends in VPD across the United States are presented. VPD reaches its climatological maximum in summer in the interior southwest United States because of both high temperatures and low vapor pressure under the influence of the northerly, subsiding eastern flank of the Pacific subtropical anticyclone. Maxima of variance of VPD are identified in the Southwest and southern plains in spring and summer and are to a large extent driven by temperature variance, but vapor pressure variance is also important in the Southwest. La Niña–induced circulation anomalies cause subsiding, northerly flow that drives down actual vapor pressure and increases saturation vapor pressure from fall through spring. High spring and summer VPDs can also be caused by reduced precipitation in preceding months, as measured by Bowen ratio anomalies. Case studies of 2002 (the Rodeo–Chediski and Hayman fires, which occurred in Arizona and Colorado, respectively) and 2007 (the Murphy Complex fire, which occurred in Idaho and Nevada) show very high VPDs caused by antecedent surface drying and subsidence warming and drying of the atmosphere. VPD has increased in the southwest United States since 1961, driven by warming and a drop in actual vapor pressure, but has decreased in the northern plains and Midwest, driven by an increase in actual vapor pressure

Glucose challenge metabolomics implicates medium-chain acylcarnitines in insulin resistance

Insulin resistance (IR) predisposes to type 2 diabetes and cardiovascular disease but its causes are incompletely understood. Metabolic challenges like the oral glucose tolerance test (OGTT) can reveal pathogenic mechanisms. We aimed to discover associations of IR with metabolite trajectories during OGTT. In 470 non-diabetic men (age 70.6 ± 0.6 years), plasma samples obtained at 0, 30 and 120 minutes during an OGTT were analyzed by untargeted liquid chromatography-mass spectrometry metabolomics. IR was assessed with the hyperinsulinemic-euglycemic clamp method. We applied age-adjusted linear regression to identify metabolites whose concentration change was related to IR. Nine trajectories, including monounsaturated fatty acids, lysophosphatidylethanolamines and a bile acid, were significantly associated with IR, with the strongest associations observed for medium-chain acylcarnitines C10 and C12, and no associations with L-carnitine or C2-, C8-, C14- or C16-carnitine. Concentrations of C10- and C12-carnitine decreased during OGTT with a blunted decline in participants with worse insulin resistance. Associations persisted after adjustment for obesity, fasting insulin and fasting glucose. In mouse 3T3-L1 adipocytes exposed to different acylcarnitines, we observed blunted insulin-stimulated glucose uptake after treatment with C10- or C12-carnitine. In conclusion, our results identify medium-chain acylcarnitines as possible contributors to IR

Ground deformation analysis at Campi Flegrei (Southern Italy) by CGPS and tide-gauge network

Campi Flegrei caldera is located 15 km west of the city of Naples, within the central-southern sector of a large graben called Campanian Plain. It is an active volcanic area marked by a quasi-circular caldera depression, formed by a huge ignimbritic eruption occurred about 37000 years ago. This caldera was generated by several collapses produced by strong explosive eruptions (the last eruption, occurred in 1538, built an about 130 m spatter cone called Mt. Nuovo). Campi Flegrei area periodically experiences significant deformation episodes, with uplift phenomena up to more than 3.5 m in 15 years (from 1970 to 1984), which caused during 1983-84 the temporary evacuation of about 40000 people from the ancient part of Pozzuoli town. The deformation field obtainable by CGPS and tidegauge stations plays an important role for the modelling and interpretation of volcanic phenomena, as well as for forecasting purposes. The structural complexity of the Campi Flegrei area, together with the evidence of a strong interaction between magmatic chamber and shallow geothermal system, calls for a detailed characterization of the substructure and of magma-water interaction processes. The incoming experiment of deep drilling, down to about 4 km, will give detailed structural and physical constraints able to resolve the intrinsic ambiguities of geophysical data and in particular geodetic ones. In this poster we describe the recent ground deformations at Campi Flegrei area by means of GPS technique and tide gauge stations, discussing the possible interpretations also in light of further constraints likely coming from the next CFDDP (Campi Flegrei Deep Drilling) deep drilling experiment

Dynamical and Thermodynamical Causes of Large-Scale Changes in the Hydrological Cycle over North America in Response to Global Warming

The mechanisms of model-projected atmospheric moisture budget change across North America are examined in simulations conducted with 22 models from phase 5 of the Coupled Model Intercomparison Project. Modern-day model budgets are validated against the European Centre for Medium-Range Weather Forecasts Interim Re-Analysis. In the winter half year transient eddies converge moisture across the continent while the mean flow wets the west from central California northward and dries the southwest. In the summer half year there is widespread mean flow moisture divergence across the west and convergence over the Great Plains that is offset by transient eddy divergence. In the winter half year the models project drying for the southwest and wetting to the north. Changes in the mean flow moisture convergence are largely responsible across the west but intensified transient eddy moisture convergence wets the northeast. In the summer half year widespread declines in precipitation minus evaporation (P-E) are supported by mean flow moisture divergence across the west and transient eddy divergence in the Great Plains. The changes in mean flow convergence are related to increases in specific humidity but also depend on changes in the mean flow including increased low-level divergence in the U.S. Southwest and a zonally varying wave that wets the North American west and east coasts in winter and dries the U.S. Southwest. Increased transient eddy fluxes occur even as low-level eddy activity weakens and arise from strengthened humidity gradients. A full explanation of North American hydroclimate changes will require ex- planation of mean and transient circulation changes and the coupling between the moisture and circulation fields

Ernst Freund as Precursor of the Rational Study of Corporate Law

Gindis, David, Ernst Freund as Precursor of the Rational Study of Corporate Law (October 27, 2017). Journal of Institutional Economics, Forthcoming. Available at SSRN: https://ssrn.com/abstract=2905547, doi: https://dx.doi.org/10.2139/ssrn.2905547The rise of large business corporations in the late 19th century compelled many American observers to admit that the nature of the corporation had yet to be understood. Published in this context, Ernst Freund's little-known The Legal Nature of Corporations (1897) was an original attempt to come to terms with a new legal and economic reality. But it can also be described, to paraphrase Oliver Wendell Holmes, as the earliest example of the rational study of corporate law. The paper shows that Freund had the intuitions of an institutional economist, and engaged in what today would be called comparative institutional analysis. Remarkably, his argument that the corporate form secures property against insider defection and against outsiders anticipated recent work on entity shielding and capital lock-in, and can be read as an early contribution to what today would be called the theory of the firm.Peer reviewe

Patch-augmented rotator cuff surgery (PARCS) study-protocol for a feasibility study

Background: A rotator cuff tear is a common disabling shoulder problem. Symptoms include pain, weakness, lack of shoulder mobility and sleep disturbance. Many patients require surgery to repair the tear; however, there is a high failure rate. There is a pressing need to improve the outcome of rotator cuff surgery and the use of patch augmentation to provide support to the healing process and improve patient outcomes holds new promise. Patches have been made using different materials (e.g. human/animal skin or intestine tissue, and completely synthetic materials) and processes (e.g. woven or a mesh). However, clinical evidence on their use is limited. The aim of the patch-augmented rotator cuff surgery (PARCS) feasibility study is to determine, using a mixed method approach, the design of a definitive randomised trial assessing the effectiveness and cost-effectiveness of a patch to augment surgical repair of the rotator cuff that is both acceptable to stakeholders and feasible. Methods: The objectives of this six-stage mixed methods feasibility study are to determine current practice, evidence and views about patch use; achieve consensus on the design of a randomised trial to evaluate patch-augmented rotator cuff surgery; and assess the acceptability and feasibility of the proposed design. The six stages will involve a systematic review of clinical evidence, two surveys of surgeons, focus groups and interviews with stakeholders, a Delphi study and a consensus meeting. The various stakeholders (including patients, surgeons, and representatives from industry, the NHS and regulatory bodies) will be involved across the six stages. Discussion: The PARCS feasibility study will inform the feasibility and acceptability of a randomised trial of the effectiveness and cost-effectiveness of a patch-augmented rotator cuff surgery. Consensus opinion on the basic design of a randomised trial will be sought. Trial registration: Not applicable

Invasive non‐native species likely to threaten biodiversity and ecosystems in the Antarctic Peninsula region

The Antarctic is considered to be a pristine environment relative to other regions of the Earth, but it is increasingly vulnerable to invasions by marine, freshwater and terrestrial non‐native species. The Antarctic Peninsula region (APR), which encompasses the Antarctic Peninsula, South Shetland Islands and South Orkney Islands, is by far the most invaded part of the Antarctica continent. The risk of introduction of invasive non‐native species to the APR is likely to increase with predicted increases in the intensity, diversity and distribution of human activities. Parties that are signatories to the Antarctic Treaty have called for regional assessments of non‐native species risk. In response, taxonomic and Antarctic experts undertook a horizon scanning exercise using expert opinion and consensus approaches to identify the species that are likely to present the highest risk to biodiversity and ecosystems within the APR over the next 10 years. One hundred and three species, currently absent in the APR, were identified as relevant for review, with 13 species identified as presenting a high risk of invading the APR. Marine invertebrates dominated the list of highest risk species, with flowering plants and terrestrial invertebrates also represented; however, vertebrate species were thought unlikely to establish in the APR within the 10 year timeframe. We recommend (a) the further development and application of biosecurity measures by all stakeholders active in the APR, including surveillance for species such as those identified during this horizon scanning exercise, and (b) use of this methodology across the other regions of Antarctica. Without the application of appropriate biosecurity measures, rates of introductions and invasions within the APR are likely to increase, resulting in negative consequences for the biodiversity of the whole continent, as introduced species establish and spread further due to climate change and increasing human activity

A meta-analysis of individual participant data reveals an association between circulating levels of IGF-I and prostate cancer risk

The role of insulin-like growth factors (IGF) in prostate cancer development is not fully understood. To investigate the association between circulating concentrations of IGFs (IGF-I, IGF-II, IGFBP-1, IGFBP-2, and IGFBP-3) and prostate cancer risk, we pooled individual participant data from 17 prospective and two cross-sectional studies, including up to 10,554 prostate cancer cases and 13,618 control participants. Conditional logistic regression was used to estimate the ORs for prostate cancer based on the study-specific fifth of each analyte. Overall, IGF-I, IGF-II, IGFBP-2, and IGFBP-3 concentrations were positively associated with prostate cancer risk (Ptrend all ≤ 0.005), and IGFBP-1 was inversely associated weakly with risk (Ptrend = 0.05). However, heterogeneity between the prospective and cross-sectional studies was evident (Pheterogeneity = 0.03), unless the analyses were restricted to prospective studies (with the exception of IGF-II, Pheterogeneity = 0.02). For prospective studies, the OR for men in the highest versus the lowest fifth of each analyte was 1.29 (95% confidence interval, 1.16-1.43) for IGF-I, 0.81 (0.68-0.96) for IGFBP-1, and 1.25 (1.12-1.40) for IGFBP-3. These associations did not differ significantly by time-to-diagnosis or tumor stage or grade. Aftermutual adjustment for each of the other analytes, only IGF-I remained associated with risk. Our collaborative study represents the largest pooled analysis of the relationship between prostate cancer risk and circulating concentrations of IGF-I, providing strong evidence that IGF-I is highly likely to be involved in prostate cancer development.</p