Synthesis and evaluation of new designed multiple ligands directed towards both peroxisome proliferator-activated receptor-γ and angiotensin II type 1 receptor

Because of the complex biological networks, many pathologic disorders fail to be treated with a molecule directed towards a single target. Thus, combination therapies are often necessary, but they have many drawbacks. An alternative consists in building molecules intended to interact with multiple targets, called designed multiple ligands. We followed such a strategy in order to treat metabolic syndrome, by setting up molecules directed towards both type 1 angiotensin II (AT1) receptor and peroxisome proliferator-activated receptor-γ (PPAR-γ). For this purpose, many molecules were prepared by merging both pharmacophores following three different strategies. Their ability to activate PPAR-γ and to block AT1 receptors were evaluated in vitro. This strategy led to the preparation of many new PPAR-γ activating and AT1 blocking molecules. Among them, some exhibited both activities, highlighting the convenience of this approach

Elongation of confined ferrofluid droplets under applied fields

Ferrofluids are strongly paramagnetic liquids. We study the behavior of ferrofluid droplets confined between two parallel plates with a weak applied field parallel to the plates. The droplets elongate under the applied field to reduce their demagnetizing energy and reach an equilibrium shape where the magnetic forces balance against the surface tension. This elongation varies logarithmically with aspect ratio of droplet thickness to its original radius, in contrast to the behavior of unconfined droplets. Experimental studies of a ferrofluid/water/surfactant emulsion confirm this prediction.Comment: 12 pages, 7 figures. Submitted to Phys. Rev.

The agency of liminality: army wives in the DR Congo and the tactical reversal of militarization

The inherently unstable boundaries between military and civilian worlds have emerged as a main object of study within the field of critical military studies. This article sheds light on the (re)production of these boundaries by attending to a group that rarely features in the debates on the military/civilian divide: army wives in a ‘non-Northern’ context, more specifically the Democratic Republic of the Congo (DRC). Drawing upon the ‘analytical toolbox’ of governmentality, we explore how civilian and military positionalities are called upon, articulated and subverted in the governing and self-governing of Congolese army wives. We show the decisive importance of these wives’ civilian-military ‘in betweenness’ both in efforts to govern them and in their exercise of agency, in particular The inherently unstable boundaries between military and civilian worlds have emerged as a main object of study within the field of critical military studies. This article sheds light on the (re)production of these boundaries by attending to a group that rarely features in the debates on the military/civilian divide: army wives in a ‘non-Northern’ context, more specifically the Democratic Republic of the Congo (DRC). Drawing upon the ‘analytical toolbox’ of governmentality, we explore how civilian and military positionalities are called upon, articulated, and subverted in the governing and self-governing of Congolese army wives. We show the decisive importance of these wives’ civilian–military ‘in-betweenness’ both in efforts to govern them and in their exercise of agency, in particular the ways in which they ‘tactically reverse’ militarization. The article also demonstrates the dispersed nature of the governing arrangements surrounding army wives, highlighting the vital role of ‘the civilian’ as well as the ‘agency of those being militarized’ within processes of militarization. By foregrounding the relevance of studying Congolese army wives and their militarization with an analytical toolbox often reserved for so called ‘advanced militaries/societies’, and by revealing numerous similarities between the Congolese and ‘Northern’ contexts, the article also sets out to counter the Euro/US-centrism and ‘theoretical discrimination’ that mark present-day (critical) military studies

ESA's Ice Sheets CCI: validation and inter-comparison of surface elevation changes derived from laser and radar altimetry over Jakobshavn Isbræ, Greenland – Round Robin results

In order to increase the understanding of the changing climate, the European Space Agency has launched the Climate Change Initiative (ESA CCI), a program which joins scientists and space agencies into 13 projects either affecting or affected by the concurrent changes. This work is part of the Ice Sheets CCI and four parameters are to be determined for the Greenland Ice Sheet (GrIS), each resulting in a dataset made available to the public: Surface Elevation Changes (SEC), surface velocities, grounding line locations, and calving front locations. All CCI projects have completed a so-called Round Robin exercise in which the scientific community was asked to provide their best estimate of the sought parameters as well as a feedback sheet describing their work. By inter-comparing and validating the results, obtained from research institutions world-wide, it is possible to develop the most optimal method for determining each parameter. This work describes the SEC Round Robin and the subsequent conclusions leading to the creation of a method for determining GrIS SEC values. The participants used either Envisat radar or ICESat laser altimetry over Jakobshavn Isbræ drainage basin, and the submissions led to inter-comparisons of radar vs. altimetry as well as cross-over vs. repeat-track analyses. Due to the high accuracy of the former and the high spatial resolution of the latter, a method, which combines the two techniques will provide the most accurate SEC estimates. The data supporting the final GrIS analysis stem from the radar altimeters on-board Envisat, ERS-1 and ERS-2. The accuracy of laser data exceeds that of radar altimetry; the Round Robin analysis has, however, proven the latter equally capable of dealing with surface topography thereby making such data applicable in SEC analyses extending all the way from the interior ice sheet to margin regions. This shows good potential for a~future inclusion of ESA CryoSat-2 and Sentinel-3 radar data in the analysis, and thus for obtaining reliable SEC estimates throughout the entire GrIS

MARINE-EXPRESS: taking advantage of high throughput cloning and expression strategies for the post-genomic analysis of marine organisms

Background: The production of stable and soluble proteins is one of the most important steps prior to structural and functional studies of biological importance. We investigated the parallel production in a medium throughput strategy of genes coding for proteins from various marine organisms, using protocols that involved recombinatorial cloning, protein expression screening and batch purification. This strategy was applied in order to respond to the need for post-genomic validation of the recent success of a large number of marine genomic projects. Indeed, the upcoming challenge is to go beyond the bioinformatic data, since the bias introduced through the genomes of the so called model organisms leads to numerous proteins of unknown function in the still unexplored world of the oceanic organisms. Results: We present here the results of expression tests for 192 targets using a 96-well plate format. Genes were PCR amplified and cloned in parallel into expression vectors pFO4 and pGEX-4T-1, in order to express proteins N-terminally fused to a six-histidine-tag and to a GST-tag, respectively. Small-scale expression and purification permitted isolation of 84 soluble proteins and 34 insoluble proteins, which could also be used in refolding assays. Selected examples of proteins expressed and purified to a larger scale are presented. Conclusions: The objective of this program was to get around the bottlenecks of soluble, active protein expression and crystallization for post-genomic validation of a number of proteins that come from various marine organisms. Multiplying the constructions, vectors and targets treated in parallel is important for the success of a medium throughput strategy and considerably increases the chances to get rapid access to pure and soluble protein samples, needed for the subsequent biochemical characterizations. Our set up of a medium throughput strategy applied to genes from marine organisms had a mean success rate of 44% soluble protein expression from marine bacteria, archaea as well as eukaryotic organisms. This success rate compares favorably with other protein screening projects, particularly for eukaryotic proteins. Several purified targets have already formed the base for experiments aimed at post-genomic validation

Integrated North Sea grids: The costs, the benefits and their distribution between countries

A large number of offshore wind farms and interconnectors are expected to be constructed in the North Sea region over the coming decades, creating substantial opportunities for the deployment of integrated network solutions. Creating interconnected offshore grids that combine cross-border links and connections of offshore plants to shore offers multiple economic and environmental advantages for Europe's energy system. However, despite evidence that integrated solutions can be more beneficial than traditional radial connection practices, no such projects have been deployed yet. In this paper we quantify costs and benefits of integrated projects and investigate to which extent the cost-benefit sharing mechanism between participating countries can impede or encourage the development of integrated projects. Three concrete interconnection case studies in the North Sea area are analysed in detail using a national-level power system model. Model outputs are used to compute the net benefit of all involved stakeholders under different allocation schemes. Given the asymmetric distribution of costs and benefits, we recommend to consistently apply the Positive Net Benefit Differential mechanism as a starting point for negotiations on the financial closure of investments in integrated offshore infrastructure

The Effects On Children Of Depressed Mothers' Remission And Relapse Over 9 Months

Background—The high rate of depression among children of depressed mothers is well known. Suggestions that improvement in maternal acute depression has a positive effect on the child have emerged. However, data on the mechanisms of change have been sparse. The aim was to understand how remission and relapse in the mother might explain the changes in the child’s outcome

The Shapes of Flux Domains in the Intermediate State of Type-I Superconductors

In the intermediate state of a thin type-I superconductor magnetic flux penetrates in a disordered set of highly branched and fingered macroscopic domains. To understand these shapes, we study in detail a recently proposed "current-loop" (CL) model that models the intermediate state as a collection of tense current ribbons flowing along the superconducting-normal interfaces and subject to the constraint of global flux conservation. The validity of this model is tested through a detailed reanalysis of Landau's original conformal mapping treatment of the laminar state, in which the superconductor-normal interfaces are flared within the slab, and of a closely-related straight-lamina model. A simplified dynamical model is described that elucidates the nature of possible shape instabilities of flux stripes and stripe arrays, and numerical studies of the highly nonlinear regime of those instabilities demonstrate patterns like those seen experimentally. Of particular interest is the buckling instability commonly seen in the intermediate state. The free-boundary approach further allows for a calculation of the elastic properties of the laminar state, which closely resembles that of smectic liquid crystals. We suggest several new experiments to explore of flux domain shape instabilities, including an Eckhaus instability induced by changing the out-of-plane magnetic field, and an analog of the Helfrich-Hurault instability of smectics induced by an in-plane field.Comment: 23 pages, 22 bitmapped postscript figures, RevTex 3.0, submitted to Phys. Rev. B. Higher resolution figures may be obtained by contacting the author