Nuclear Dbf2-related protein kinases (NDRs) in isolated cardiac myocytes and the myocardium: activation by cellular stresses and by phosphoprotein serine-/threonine-phosphatase inhibitors

The nuclear Dbf2-related protein kinases 1 and 2 (NDR1/2) are closely-related AGC family kinases that are strongly conserved through evolution. In mammals, they are activated inter alia by phosphorylation of an hydrophobic domain threonine-residue [NDR1(Thr-444)/NDR2(Thr-442)] by an extrinsic protein kinase followed by autophosphorylation of a catalytic domain serine-residue [NDR1(Ser-281)/NDR2(Ser-282)]. We examined NDR1/2 expression and regulation in primary cultures of neonatal rat cardiac myocytes and in perfused adult rat hearts. In myocytes, transcripts for NDR2, but not NDR1, were induced by the hypertrophic agonist, endothelin-1. NDR1(Thr-444) and NDR2(Thr-442) were rapidly phosphorylated (maximal in 15-30 min) in myocytes exposed to some phosphoprotein Ser-/Thr-phosphatase 1/2 inhibitors (calyculin A, okadaic acid) and, to a lesser extent, by hyperosmotic shock, low concentrations of H(2)O(2), or chelerythrine. In myocytes adenovirally-transduced to express FLAG-NDR2 (which exhibited a mainly-cytoplasmic localisation), the same agents increased FLAG-NDR2 activity as assessed by in vitro protein kinase assays, indicative of FLAG-NDR2(Ser-282/Thr-442) phosphorylation. Calyculin A-induced phosphorylation of NDR1(Thr-444)/NDR2(Thr-442) and activation of FLAG-NDR2 were inhibited by staurosporine, but not by other protein kinase inhibitors tested. In ex vivo rat hearts, NDR1(Thr-444)/NDR2(Thr-442) were phosphorylated in response to ischaemia-reperfusion or calyculin A. From a pathological viewpoint, we conclude that activities of NDR1 and NDR2 are responsive to cytotoxic stresses in heart preparations and this may represent a previously-unidentified response to myocardial ischaemia in vivo.

'The Elements' and Hobbesian moral thinking

It is easy to read Hobbes's moral thinking as a deviant contribution to 'modern' natural law, especially if Leviathan (1651) is read through a lens provided by De Cive (1642). But The Elements of Law (1640) encourages the view that Hobbes's argument is 'physicalist', that is, that it requires no premises beyond those required by his physics of matter in motion. The Elements included a draft De Homine and its argument is intimately connected with De Cive's; it shows how such concepts as 'reason', 'right', 'natural law' and 'obligation' can be understood in physicalist terms. But Hobbes's decision to print the latter work in isolation has led to serious misunderstandings

Grey-box radial basis function modelling

A fundamental principle in data modelling is to incorporate available a priori information regarding the underlying data generating mechanism into the modelling process. We adopt this principle and consider grey-box radial basis function (RBF) modelling capable of incorporating prior knowledge. Specifically, we show how to explicitly incorporate the two types of prior knowledge: (i) the underlying data generating mechanism exhibits known symmetric property, and (ii) the underlying process obeys a set of given boundary value constraints. The class of efficient orthogonal least squares regression algorithms can readily be applied without any modification to construct parsimonious grey-box RBF models with enhanced generalisation capability.

Policy interventions to promote healthy eating: a review of what works, what does not and what is promising

Unhealthy diets can lead to various diseases, which in turn can translate into a bigger burden for the state in the form of health services and lost production. Obesity alone has enormous costs and claims thousands of lives every year. Although diet quality in the European Union has improved across countries, it still falls well short of conformity with the World Health Organization dietary guidelines. In this review, we classify types of policy interventions addressing healthy eating and identify through a literature review what specific policy interventions are better suited to improve diets. Policy interventions are classified into two broad categories: information measures and measures targeting the market environment. Using this classification, we summarize a number of previous systematic reviews, academic papers, and institutional reports and draw some conclusions about their effectiveness. Of the information measures, policy interventions aimed at reducing or banning unhealthy food advertisements generally have had a weak positive effect on improving diets, while public information campaigns have been successful in raising awareness of unhealthy eating but have failed to translate the message into action. Nutritional labeling allows for informed choice. However, informed choice is not necessarily healthier; knowing or being able to read and interpret nutritional labeling on food purchased does not necessarily result in consumption of healthier foods. Interventions targeting the market environment, such as fiscal measures and nutrient, food, and diet standards, are rarer and generally more effective, though more intrusive. Overall, we conclude that measures to support informed choice have a mixed and limited record of success. On the other hand, measures to target the market environment are more intrusive but may be more effective.

Daily precipitation statistics in regional climate models: evaluation and intercomparison for the European Alps

An evaluation is undertaken of the statistics of daily precipitation as simulated by five regional climate models using comprehensive observations in the region of the European Alps. Four limited area models and one variable-resolution global model are considered, all with a grid spacing of 50 km. The 15-year integrations were forced from reanalyses and observed sea surface temperature and sea ice (global model from sea surface only). The observational reference is based on 6400 rain gauge records (10–50 stations per grid box). Evaluation statistics encompass mean precipitation, wet-day frequency, precipitation intensity, and quantiles of the frequency distribution. For mean precipitation, the models reproduce the characteristics of the annual cycle and the spatial distribution. The domain mean bias varies between −23% and +3% in winter and between −27% and −5% in summer. Larger errors are found for other statistics. In summer, all models underestimate precipitation intensity (by 16–42%) and there is a too low frequency of heavy events. This bias reflects too dry summer mean conditions in three of the models, while it is partly compensated by too many low-intensity events in the other two models. Similar intermodel differences are found for other European subregions. Interestingly, the model errors are very similar between the two models with the same dynamical core (but different parameterizations) and they differ considerably between the two models with similar parameterizations (but different dynamics). Despite considerable biases, the models reproduce prominent mesoscale features of heavy precipitation, which is a promising result for their use in climate change downscaling over complex topography.

Cannabidivarin is anticonvulsant in mouse and rat in vitro and in seizure models

Summary Background and purpose: Phytocannabinoids in Cannabis sativa have diverse pharmacological targets extending beyond cannabinoid receptors and several exert notable anticonvulsant effects. For the first time, we investigated the anticonvulsant profile of the phytocannabinoid cannabidivarin (CBDV) in vitro and in in vivo seizure models. Experimental approach: The effect of CBDV (1-100μM) on epileptiform local field potentials (LFPs) induced in rat hippocampal brain slices by 4-AP application or Mg2+-free conditions was assessed by in vitro multi-electrode array recordings. Additionally, the anticonvulsant profile of CBDV (50-200 mg kg-1) in vivo was investigated in four rodent seizure models: maximal electroshock (mES) and audiogenic seizures in mice, and pentylenetetrazole (PTZ) and pilocarpine-induced seizures in rat. CBDV effects in combination with commonly-used antiepileptic drugs were investigated in rat seizures. Finally, the motor side effect profile of CBDV was investigated using static beam and gripstrength assays. Key results: CDBV significantly attenuated status epilepticus-like epileptiform LFPs induced by 4-AP and Mg2+-free conditions. CBDV had significant anticonvulsant effects in mES (≥100 mg kg-1), audiogenic (≥50 mg kg-1) and PTZ-induced seizures (≥100 mg kg-1). CBDV alone had no effect against pilocarpine-induced seizures, but significantly attenuated these seizures when administered with valproate or phenobarbital at 200 mg kg-1 CBDV. CBDV had no effect on motor function. Conclusions and Implications: These results indicate that CBDV is an effective anticonvulsant across a broad range of seizure models, does not significantly affect normal motor function and therefore merits further investigation in chronic epilepsy models to justify human trials.

Croig Cave: a late Bronze Age ornament deposition and 3,500 years of coastal foraging in NW Mull, Scotland

Activity within caves provides an important element of the later prehistoric and historic settlement pattern of western Scotland. This contribution reports on a small-scale excavation within Croig Cave, on the coast of north-west Mull, that exposed a 1.95m sequence of midden deposits and cave floors that dated bewteen c 1700 BC and AD 1400. Midden analysis indicated the processing of a .... 950 BC, a penannular copper bracelet a discrete ritual episode within the cycle of otherwise potentially mundane activities. Lead isotope analysis indicates an Irish origin for the copper ore. A piece of iron slag within later midden deposits, dated to c 400 BC, along with high frequencies of wood charcoal, suggest that smithing or smelting may have occurred within the cave. High zinc levels in the historic levels of the midden c AD 1200 might indicate intensive processing of seaweed.

Enhancement of buffer strips can improve provision of multiple ecosystem services

Farmland invertebrates play a pivotal role in the provision of ecosystem services, i.e. services that benefit humans. For example, bumblebees, solitary bees and honeybees, are crucial to the pollination of many of the world's crops and wildflowers, with over 70% of the world's major food crops dependent on the pollination services provided by these insects. The larvae of some butterfly species are considered to be pests; however, together with moth and sawfly larvae, they represent a key dietary component for many farmland birds. Spiders and ground beetles predate on crop pests including aphids, whilst soil macrofauna such as earthworms are vital for soil fertility services and nutrient recycling. Despite their importance, population declines of invertebrates have been observed during the last sixty years in the UK and NW Europe. For example, seven UK bumblebee species are in decline, and in the last 20 years, the species Bombus subterraneus (short-haired bumblebee) has become extinct, whilst there was a 54% decline in honeybee colony numbers in England from 1985 to 2005. Comparable trends have been documented for butterflies with a 23% decline in UK farmland species such as Anthocharis cardamines (orange tip) between 1990 and 2007. These declines have been widely attributed to the modern intensive arable management practices that have been developed to maximise crop yield. For example, loss and fragmentation of foraging and nesting habitats, including species-rich meadows and hedgerows, have been implicated in the decline of bees and butterflies. Increased use of herbicides and fertilisers has caused detrimental effects on many plant species with negative consequences for predatory invertebrates such as spiders and beetles which rely on plants for food and shelter.

Predictability of the Arctic sea ice edge

Skillful sea ice forecasts from days to years ahead are becoming increasingly important for the operation and planning of human activities in the Arctic. Here we analyze the potential predictability of the Arctic sea ice edge in six climate models. We introduce the integrated ice-edge error (IIEE), a user-relevant verification metric defined as the area where the forecast and the “truth” disagree on the ice concentration being above or below 15%. The IIEE lends itself to decomposition into an absolute extent error, corresponding to the common sea ice extent error, and a misplacement error. We find that the often-neglected misplacement error makes up more than half of the climatological IIEE. In idealized forecast ensembles initialized on 1 July, the IIEE grows faster than the absolute extent error. This means that the Arctic sea ice edge is less predictable than sea ice extent, particularly in September, with implications for the potential skill of end-user relevant forecasts.

Gaze stabilization testing: The efficiency and test-retest reliability of user operated control versus the parameter estimation (PEST) algorithm

The primary objective of this research study is to determine which form of testing, the PEST algorithm or an operator-controlled condition is most accurate and time efficient for administration of the gaze stabilization test

Mixed multiplicities and the minimal number of generator of modules

Let (R, m) be a d-dimensional Noetherian local ring. In this work we prove that the mixed Buchsbaum-Rim multiplicity for a finite family of R-submodules of R(p) of finite colength coincides with the Buchsbaum-Rim multiplicity of the module generated by a suitable superficial sequence, that is, we generalize for modules the well-known Risler-Teissier theorem. As a consequence, we give a new proof of a generalization for modules of the fundamental Rees` mixed Multiplicity theorem, which was first proved by Kirby and Rees in (1994, [8]). We use the above result to give an upper bound for the minimal number of generators of a finite colength R-submodule of R(p) in terms of mixed multiplicities for modules, which generalize a similar bound obtained by Cruz and Verma in (2000, [5]) for m-primary ideals. (C) 2009 Elsevier B.V. All rights reserved.