Inhibition of the cardiac Na+ channel Nav1.5 by carbon monoxide

Sub-lethal carbon monoxide (CO) exposure is frequently associated with myocardial arrhythmias and our recent studies have demonstrated that these may be attributable to modulation of cardiac Na+ channels, causing an increase in the late current and an inhibition of the peak current. Using a recombinant expression system, we demonstrate that CO inhibits peak human Nav1.5 current amplitude without activation of the late Na+ current observed in native tissue. Inhibition was associated with a hyperpolarizing shift in the steady-state inactivation properties of the channels and was unaffected by modification of channel gating induced by anemone toxin (rATX-II). Systematic pharmacological assessment indicated that no recognised CO-sensitive intracellular signalling pathways appeared to mediate CO inhibition of Nav1.5. Inhibition was, however, markedly suppressed by inhibition of nitric oxide (NO) formation, but NO donors did not mimic or occlude channel inhibition by CO, indicating that NO alone did not account for the actions of CO. Exposure of cells to dithiothreitol immediately before CO exposure also dramatically reduced the magnitude of current inhibition. Similarly, L-cysteine and N-ethylmaleimide significantly attenuated the inhibition caused by CO. In the presence of DTT and the NO inhibitor L-NAME, the ability of CO to inhibit Nav1.5 was almost fully prevented. Our data indicate that inhibition of peak Na+ current (which can lead to Brugada-syndrome like arrhythmias) occurs via a mechanism distinct from induction of the late current, requires NO formation and is dependent on channel redox state.

Hydrology and climatology at Laguna La Gaiba, lowland Bolivia: complex responses to climatic forcings over the last 25,000 years

Diatom, geochemical and isotopic data provide a record of environmental change in Laguna La Gaiba, lowland Bolivia (17°450S, 57°350W), over the last ca. 25 000 years. High-resolution diatom analysis around the Last Glacial–Interglacial Transition provides new insights into this period of change. The full and late glacial lake was generally quite shallow, but with evidence of periodic flooding. At about 13 100 cal a BP, just before the start of the Younger Dryas chronozone, the diatoms indicate shallower water conditions, but there is a marked change at about 12 200 cal a BP indicating the onset of a period of high variability, with rising water levels punctuated by periodic drying. From ca. 11 800 to 10 000 cal a BP, stable, deeper water conditions persisted. There is evidence for drying in the early to middle Holocene, but not as pronounced as that reported from elsewhere in the southern hemisphere tropics of South America. This was followed by the onset of wetter conditions in the late Holocene consistent with insolation forcing. Conditions very similar to present were established about 2100 cal a BP. A complex response to both insolation forcing and millennial-scale events originating in the North Atlantic is noted.

Structure and magnetic properties of mono- and bi-dispersed ferrofluids as revealed by simulations

Using a Langevin molecular dynamics simulation, we show that the magnetic properties of a mono- and bi-dispersed ferrofluid system depend on the volume fraction and the dipolar coupling parameter. For the bi-dispersed system, most of the chains are formed by the large particles, but the aggregation behavior of the large particles is hindered by the presence of the small particles, which are predominantly attached to the end of the particle chain. To further elucidate the microscopic fluid structure, anisotropic structure factors are calculated.

Configurations institutionnelles de la protection de l’enfance: regards croisés de l’Afrique, de l’Europe et de l’Amérique du Nord

Cet article porte sur l’analyse de trois configurations institutionnelles de la protection de l’enfance : celle en place au Burkina Faso, en Belgique et au Québec. Pour chaque configuration, le texte explore les transformations qui ont marqué le passage de la prise en charge exclusive de l’enfant par la famille vers la présence accrue de l’État et la manière dont la Convention internationale des droits de l’enfant de 1989 a influencé ce passage. Il montre, au travers d’une lecture historique, que l’implication de l’État dans la protection des enfants a connu des formes et des modalités variables selon le temps et l’espace. L’approche actuelle en matière de protection de l’enfance au Nord et au Sud, approche largement inspirée de la perspective des droits, représente un défi tant pour les intervenants que pour les familles, car son application dépend à fois des ressources disponibles pour aider les enfants et les familles en difficulté, de la capacité d’action des institutions publiques et de l’efficacité des interventions. This article deals with the analysis of three institutional configurations of child protection: those in Burkina Faso, in Belgium, and in Québec. With respect to each configuration, the text explores the changes from situations in which the family had sole control of the child to those where the State played a greater role, and the manner in which the 1989 International Convention on the Rights of the Child has affected such changes. It shows, through a reading of history, that the involvement of the State in child protection has gone through different forms and stages over time and space. The current strategies as regards child protection in the North and in the South—an approach that is largely subject to a legal perspective—represent a challenge both for intervenors and for families, since their application depends on the resources available for helping children and families in difficulty, on the ability of the public institutions to intervene, and on the efficiency of such interventions.

Energy consistent discontinuous Galerkin methods for the Navier–Stokes–Korteweg system

We design consistent discontinuous Galerkin finite element schemes for the approximation of the Euler-Korteweg and the Navier-Stokes-Korteweg systems. We show that the scheme for the Euler-Korteweg system is energy and mass conservative and that the scheme for the Navier-Stokes-Korteweg system is mass conservative and monotonically energy dissipative. In this case the dissipation is isolated to viscous effects, that is, there is no numerical dissipation. In this sense the methods are consistent with the energy dissipation of the continuous PDE systems. - See more at: http://www.ams.org/journals/mcom/2014-83-289/S0025-5718-2014-02792-0/home.html#sthash.rwTIhNWi.dpuf

Search engine liability for autocomplete suggestions: personality, privacy and the power of the algorithm

This article is concerned with the liability of search engines for algorithmically produced search suggestions, such as through Google’s ‘autocomplete’ function. Liability in this context may arise when automatically generated associations have an offensive or defamatory meaning, or may even induce infringement of intellectual property rights. The increasing number of cases that have been brought before courts all over the world puts forward questions on the conflict of fundamental freedoms of speech and access to information on the one hand, and personality rights of individuals— under a broader right of informational self-determination—on the other. In the light of the recent judgment of the Court of Justice of the European Union (EU) in Google Spain v AEPD, this article concludes that many requests for removal of suggestions including private individuals’ information will be successful on the basis of EU data protection law, even absent prejudice to the person concerned.

Syk and Src family kinases regulate C-type lectin receptor 2 (CLEC-2)-mediated clustering of podoplanin and platelet adhesion to lymphatic endothelial cells

The interaction of C-type lectin receptor 2 (CLEC-2) on platelets with Podoplanin on lymphatic endothelial cells initiates platelet signaling events that are necessary for prevention of blood-lymph mixing during development. In the present study, we show that CLEC-2 signaling via Src family and Syk tyrosine kinases promotes platelet adhesion to primary mouse lymphatic endothelial cells at low shear. Using supported lipid bilayers containing mobile Podoplanin, we further show that activation of Src and Syk in platelets promotes clustering of CLEC-2 and Podoplanin. Clusters of CLEC-2-bound Podoplanin migrate rapidly to the center of the platelet to form a single structure. Fluorescence lifetime imaging demonstrates that molecules within these clusters are within 10 nm of one another and that the clusters are disrupted by inhibition of Src and Syk family kinases. CLEC-2 clusters are also seen in platelets adhered to immobilized Podoplanin using direct stochastic optical reconstruction microscopy. These findings provide mechanistic insight by which CLEC-2 signaling promotes adhesion to Podoplanin and regulation of Podoplanin signaling, thereby contributing to lymphatic vasculature development.

Molecular insights of p47phox phosphorylation dynamics in the regulation of NADPH oxidase activation and superoxide production

Phagocyte superoxide production by a multicomponent NADPH oxidase is important in host defense against microbial invasion. However inappropriate NADPH oxidase activation causes inflammation. Endothelial cells express NADPH oxidase and endothelial oxidative stress due to prolonged NADPH oxidase activation predisposes many diseases. Discovering the mechanism of NADPH oxidase activation is essential for developing novel treatment of these diseases. The p47phox is a key regulatory subunit of NADPH oxidase; however, due to the lack of full protein structural information, the mechanistic insight of p47phox phosphorylation in NADPH oxidase activation remains incomplete. Based on crystal structures of three functional domains, we generated a computational structural model of the full p47phox protein. Using a combination of in silico phosphorylation, molecular dynamics simulation and protein/protein docking, we discovered that the C-terminal tail of p47phox is critical for stabilizing its autoinhibited structure. Ser-379 phosphorylation disrupts H-bonds that link the C-terminal tail to the autoinhibitory region (AIR) and the tandem Src homology 3 (SH3) domains, allowing the AIR to undergo phosphorylation to expose the SH3 pocket for p22phox binding. These findings were confirmed by site-directed mutagenesis and gene transfection of p47phox_/_ coronary microvascular cells. Compared with wild-type p47phoxcDNAtransfected cells, the single mutation of S379A completely blocked p47phox membrane translocation, binding to p22phox and endothelial O2 . production in response to acute stimulation of PKC. p47phox C-terminal tail plays a key role in stabilizing intramolecular interactions at rest. Ser-379 phosphorylation is a molecular switch which initiates p47phox conformational changes and NADPH oxidase-dependent superoxide production by cells.

The lives and deaths of young medieval women: the osteological evidence

Written sources from the medieval period focus mainly on the activities of adults, particularly males and often those from the wealthier sections of society. Recent scholarship has attempted to redress this balance by giving attention to medieval women and children, but we are still limited by what we can learn about the daily lives of all members of medieval English society. Osteology, the study of human skeletal remains, suffers from no such bias and can provide substantial and detailed information on growth, health and daily life of the general population. This paper presents the results of a new analysis of the skeletal remains of over 300 medieval girls and young women aged at between 14 and 25 years from a number of English cemetery sites. We incorporate data from the published archaeological literature as well as documentary evidence to provide new insights into the lives and deaths of young medieval women.

An optimization problem concerning multiplicative functions

In this paper we study the problem of maximizing a quadratic form 〈Ax,x〉 subject to ‖x‖q=1, where A has matrix entries View the MathML source with i,j|k and q≥1. We investigate when the optimum is achieved at a ‘multiplicative’ point; i.e. where x1xmn=xmxn. This turns out to depend on both f and q, with a marked difference appearing as q varies between 1 and 2. We prove some partial results and conjecture that for f multiplicative such that 0

Self-concept clarity and compulsive Internet use: the role of preference for virtual interactions and employment status in British and North-American samples

Background and Aims Compulsive Internet Use (CIU) describes a maladaptive relationship with the Internet characterised by loss of control and conflict. Although also affecting adults, most studies use teenage samples, and theoretical development on risk factors is scarce. According to Davis (2001), the social connectivity function of the Internet is key in identifying traits associated with CIU. Since Self-Concept Clarity (SCC) is strongly related to social anxiety, and virtual interactions allow “self-edition”, we hypothesized that individuals low in SCC could choose virtual interactions as safer alternative to satisfy their social needs. This could in turn increase the risk of CIU. Building on a previous study, we also expected CIU to be more harmful in the unemployed. Methods We collected samples from the UK (N = 532) and US (N = 502) with equal distribution of employed and unemployed individuals. We ran Measurement Invariance tests to confirm that the constructs were equivalent across countries. Subsequently, we conducted mediation and moderation analysis to test our hypothesis with Multigroup Confirmatory Factor Analysis. Results Measurement Invariance was confirmed. The relationship between SCC and CIU was partially mediated by preference of virtual interactions in both countries. This preference was significantly related to lower social support. Short term unemployment seemed to accentuate the negative impact of CIU on life satisfaction in both countries, although only marginally significantly in the US. The unemployed reported significantly lower levels of life satisfaction. Conclusion We demonstrated that SCC is a key vulnerability factor to CIU in adults, and confirmed the additional risks for the unemployed.