Reappraising the cardiosafety of dihydroartemisinin-piperaquine

The arsenal of efficacious drugs for the treatment of malaria remains small and is clearly insufficient to tackle the global burden of malaria, with more than 216 million clinical episodes and nearly half a million deaths annually.1 Among the new antimalarials that have been developed in the past decade, the artemisinin-based combination dihydroartemisinin–piperaquine is one of the most promising, on account of its good efficacy and tolerability, simplified dose schedule (ie, once daily for 3 days), and long post-treatment prophylactic effect.2 The only brand of dihydroartemisinin–piperaquine that has been registered under stringent regulatory authority is Eurartesim (licensed by the European Medicines Agency [EMA] in 2011), although at least three other brands exist: Duo-cotecxin (also prequalified by WHO), D-ARTEPP, and Arterakine. Dihydroartemisinin–piperaquine is not only used as a treatment of uncomplicated malaria but also has been proposed as an alternative to sulphadoxine–pyrimethamine for intermittent preventive treatment of malaria during pregnancy,3 or as a suitable drug for the mass treatment of entire populations as part of malaria-elimination endeavours

L’identité britannique au miroir de l’empire

Le déclin de l’Empire britannique après la Seconde Guerre mondiale, la montée en puissance des nationalismes écossais et gallois dans les années 1970 ainsi que l’intégration européenne de la Grande-Bretagne et la récente crise du modèle multiculturel ont abouti à une redéfinition de l’identité nationale britannique. Cet article est consacré aux évolutions historiographiques relatives à l’interaction entre cette identité et les recherches sur l’empire et le Commonwealth à partir de la fin des années 1980. Depuis lors, les historiens ont eu tendance à privilégier une interprétation de l’aventure impériale en termes d’histoire culturelle. De surcroît, ils se sont davantage intéressés aux répercussions de l’empire sur la société de la métropole que sur l’influence de la civilisation britannique sur les dominions et les colonies. Ces approches se distinguent par l’exploitation de nouvelles sources, en particulier iconographiques, une conception plurielle de l’identité nationale mais aussi la critique de concepts tels que celui d’impérialisme. Des historiens tels que Linda Colley, Andrew Thompson et Bernard Porter se sont efforcés de répondre de façon pragmatique et critique à la question particulièrement épineuse de l’intégration de l’héritage impérial à l’histoire nationale dans un contexte post colonial. Ils en appellent enfin au développement de recherches permettant de comparer les différentes histoires impériales.The decline of the British Empire following the end of the Second World War, the rise of Scottish and Welsh nationalisms in the 1970s as well as Britain integration into Europe and the recent crisis in the multicultural model contributed to a redefinition of Britishness. This article reviews historiographical developments regarding the interaction between imperial and Commonwealth studies and British national identity from the late 1980s. Since then, historians have tended to focus much more on a cultural interpretation of imperial history. Besides, they have been more interested in the impact of empire on British society than on the influence of British civilization on dominions and colonies. These approaches are remarkable for the use of new sources, especially visual ones, a plural conception of British identity and the criticism of such concepts as imperialism. Historians such as Linda Colley, Andrew Thompson and Bernard Porter have tried to work out a pragmatic and critical answer to the much debated question of the integration of imperial history to British history in a post-imperial context. Lastly, they advocate a development of comparative approaches of the different imperial histories

L’Histoire en représentation dans le dessin de presse britannique d’après 1945

Cet article est consacré au dessin d’actualité politique britannique de la seconde moitié du XXe au début du XXIe siècle siècles. Son appartenance au champ de l’histoire des représentations est explicitée, notamment dans la perspective d’une réflexion sur la tendance des dessinateurs de presse à réinterpréter les événements historiques contemporains. A cet effet, un certain nombre de cartoons de Michael Cummings, Nicholas Garland et Steve Bell sont analysés afin de montrer la remarquable plasticité de ce média hybride, mais aussi sa capacité à revisiter inlassablement le patrimoine visuel de la Grande-Bretagne. Afin de commenter l’instant présent, les dessinateurs sollicitent la mémoire des lecteurs de journaux, tant s’agissant de la Deuxième Guerre mondiale que d’autres événements marquants de l’histoire nationale.This article deals with British political cartoons published between the second half of the 20th and the early 21st centuries. There is a case for arguing that this media belongs to the field of cultural history, especially if we try to consider the tendency for cartoonists to give their personal interpretation of contemporary historical events. Consequently, a number of cartoons by Michael Cummings, Nicholas Garland and Steve Bell are analyzed in order to pinpoint the plasticity of this hybrid of picture and text, but also its huge potential for tirelessly revisiting Britain’s visual heritage. Indeed, in order to comment topical events, cartoons appeal to newspaper readers’ memory whether by reinterpreting the Second World War or other defining moments in British history

Dynamics of receptor and protein transducer homodimerisation

<p>Abstract</p> <p>Background</p> <p>Signalling pathways are complex systems in which not only simple monomeric molecules interact, but also more complex structures that include constitutive or induced protein assemblies. In particular, the hetero-and homo-dimerisation of proteins is a commonly encountered motif in signalling pathways. Several authors have suggested in recent times that dimerisation relates to a series of physical and biological outcomes used by the cell in the regulation of signal transduction.</p> <p>Results</p> <p>In this paper we investigate the role of homodimerisation in receptor-protein transducer interactions. Towards this end, mathematical modelling is used to analyse the features of such kind of interactions and to predict the behaviour of the system under different experimental conditions. A kinetic model in which the interaction between homodimers provokes a dual mechanism of activation (single and double protein transducer activation at the same time) is proposed. In addition, we analyse under which conditions the use of a power-law representation for the system is useful. Furthermore, we investigate the dynamical consequences of this dual mechanism and compare the performance of the system in different simulated experimental conditions.</p> <p>Conclusion</p> <p>The analysis of our mathematical model suggests that in receptor-protein interacting systems with dual mechanism there may be a shift between double and single activation in a way that intense double protein transducer activation could initiate and dominate the signal in the short term (getting a fast intense signal), while single protein activation could control the system in the medium and long term (when input signal is weaker and decreases slowly). Our investigation suggests that homodimerisation and oligomerisation are mechanisms used to enhance and regulate the dynamic properties of the initial steps in signalling pathways.</p

Effect of ionic strength and salt type on humic acid fouling of forward osmosis membranes

The effect of ionic strength and salt type on humic acid (HA) fouling of forward osmosis membranes was systematically investigated. A permeation cell was used to produce an osmotic flow of working solution from the dilute HA feed solution to the concentrated draw solution. Two forward osmosis membranes were tested to determine the dependence of fouling on membrane type. A nanocapillary array membrane with nominal pore size of 10 nm was also used but did not produce an osmotic flow due to the diffusion of salts through the larger membrane pores. 0.5 mM and 5.0 mM KCl and CaCl2 feed solutions were used to determine the effect of ionic strength and salt type on humic acid fouling. Average flux data from baseline experiments with zero HA was compared to average flux data from experiments containing 10 mg/L of HA, with no measurable effect observed. Ionic strength of the feed solution was shown to affect the average trans-membrane water flux with higher average fluxes found for the 0.5 mM feed solution compared to the 5.0 mM feed solution. Salt type was shown to affect the average trans-membrane water flux and was found to be dependent on the membrane type. Internal concentration polarization was determined to be the primary cause for decreased average fluxes at high ionic strengths, while HA fouling was determined to depend on the composition of the working solution. Despite not always having higher initial average fluxes, CaCl2 working solutions always resulted in larger percent reductions of average flux which could be evidence of increased HA fouling in the presence of Ca2+ ions. This result agrees with previous findings of HA fouling in membrane processes.The Ohio State University College of EngineeringThe Ohio State University Engineering Experiment StationThe Microsystems and Nanosystems Lab, Dept. of Mechanical Engineering, The Ohio State UniversityHydration Technology InnovationsNo embarg

Satire graphique et enracinement national : le dessin de presse britannique

À la fin du XXe siècle, l’art du dessin de presse fut tardivement reconnu comme partie intégrante de la culture visuelle britannique. Dans cet article, on le considère comme l’hériter légitime de la satire graphique du XVIIIe siècle, que représentent notamment les œuvres de James Gillray et George Cruikshank. L’analyse de ‘Substance and Shadow’, un dessin de John Leech portant la mention ‘Cartoon n° I’ montre sa pertinence dans le cadre d’une réflexion sur les relations entre art et nation. Par leur longévité, des allégories telles que Britannia et John Bull attestent de la permanence de l’engouement nationaliste dans la satire graphique. Enfin, on soutient qu’à travers les emprunts fréquents à la tradition du XVIIIe siècle, les dessins de presse jettent un pont entre la culture visuelle du présent et les maîtres du passé. Bien que les dessinateurs aient tendance à recourir à l’exaltation patriotique en temps de guerre, ils contribuent à nous faire revisiter des siècles de culture britannique sans chauvinisme manifeste.By the late 20th century, cartoon art received belated recognition as part and parcel of British visual culture. This article argues that it can be regarded as the legitimate heir of 18th century graphic satire such as the works of James Gillray and George Cruikshank. An analysis of ‘Substance and Shadow’ by John Leech, which was suitably labelled ‘Cartoon n° I’, is presented as a relevant contribution to the theme of the relationships between art and nation. The careers of allegories like Britannia and John Bull testify to the permanence of nationalistic fervour in graphic satire. It is finally argued that through repeated borrowing from 18th century tradition, cartoons build bridges between current visual culture and earlier masters. Even if, in times of war, cartoonists have been apt to resort to patriotic exaltation, they help us revisit centuries of British culture without any noticeable jingoism

COS cell expression studies of P86L, P86R, P480L and P480Q Hunter's disease-causing mutations

AbstractThree missense mutations identified in the IDS gene of our Hunter's disease patients (P86L, P480L and P480Q) and the previously described P86R mutation were expressed in COS cells to evaluate their functional consequence on iduronate-2-sulfatase (IDS) activity and processing. The 86-proline residue belongs to the highly conserved pentapeptide C-X-P-S-R in which cysteine modification to a formylglycine is required for sulfatase activity. The substitution of the 86-proline residue led to a severe mutation as no mature form was targeted to the lysosome in agreement with the severe phenotype observed in patients carrying P86L and P86R mutations. Expression studies with P480L and P480Q mutant cDNAs showed the presence of a small amount of 55 kDa mature form in the lysosomes of transfected COS cells. IDS activity of the P480L and P480Q mutants in cell extracts represents 16.6% and 5.4% of the wild-type, respectively