An efficient new route to dihydropyranobenzimidazole inhibitors of HCV replication.

A class of dihydropyranobenzimidazole inhibitors was recently discovered that acts against the hepatitis C virus (HCV) in a new way, binding to the IRES-IIa subdomain of the highly conserved 5' untranslated region of the viral RNA and thus preventing the ribosome from initiating translation. However, the reported synthesis of these compounds is lengthy and low-yielding, the intermediates are troublesome to purify, and the route is poorly structured for the creation of libraries. We report a streamlined route to this class of inhibitors in which yields are far higher and most intermediates are crystalline. In addition, a key variable side chain is introduced late in the synthesis, allowing analogs to be easily synthesized for optimization of antiviral activity

Exklusivitets- och trohetsskapande rabatter - En åtskillnad utan skillnad

Sedan avgörandet i Hoffmann-La Roche, som meddelades 1979, har EU-domstolen framhållit att rabatter som är villkorade med exklusivitet utgör missbruk av dominerande ställning i den mening som avses i artikel 102 FEUF. I Hoffmann-La Roche tillämpades ett formbaserat angreppssätt genom vilket exklusivitetsrabatterna presumerades inneha konkurrensbegränsande ändamål till sin natur och var därför otillåtna. Med andra ord medförde exklusivitetsrabatterna inga konkurrensfördelar, utan syftade till att utesluta konkurrenter. För rabatter som inte till sin natur ansågs inneha konkurrensbegränsande ändamål, skulle en prövning av konkurrensbegränsande effekt genomföras. I Michelin I etablerades att rabatter som inte var formellt villkorade med exklusivitet skulle samtliga omständigheter beaktas för att konstatera huruvida det förelåg konkurrensbegränsande effekter. Det vill säga huruvida rabatterna hade trohetsskapande effekter. Sedan Hoffmann-La Roche har genom ekonomisk forskning visats att premisserna vilket det formbaserade angreppssättet härleds, inte håller i praktiken. Rättsutvecklingen har därför gått mot ett mer verkningsbaserat angreppssätt som utreder omständigheter som har en faktisk påverkan på marknaden vad gäller negativ inverkan på effektivitet och konsumenternas välfärd. För att utreda konkurrensbegränsande effekt har därför kommissionen tagit fram det vägledande dokumentet vilket utgår från att kommissionen endast ingriper om rabatten hämmar konkurrensen för konkurrenterna som anses vara lika effektiva som det dominerande företaget. En sådan prövning kallas för det verkningsbaserade angreppssättet och inkluderar lika-effektiv-konkurrent-testet. I Intel-avgörandet implementerade EU-domstolens det verkningsbaserade angreppssättet på exklusivitetsrabatter och stärkte lika-effektiv-konkurrent-testets ställning vid en prövning av exklusivitetsrabatter. Slutsatsen från avgörandet är att EU-domstolen klargör tillämpningen av det verkningsbaserade angreppssättet på exklusivitetsrabatter vilket är ett steg mot en starkare rättssäkerhet. Vad gäller lika-effektiv-konkurrent-testet utgör testet endast en av flera möjliga metoder att utreda konkurrensbegränsande förmåga, även om testet ställning förstärks i missbruksmål.In Hoffmann-La Roche, delivered in 1979, the CJEU held that rebates conditional upon exclusivity were abusive within the meaning of Article 102 TFEU. The CJEU applied a rule-based approach in which the exclusivity rebate was presumed to serve an anticompetitive purpose. Put differently, there was no plausible explanation other than the aim to eliminate competitors. Where a rebate was not deemed to be abusive by its very nature, it became necessary to establish that it had anticompetitive effects. Michelin I established that, where a rebate scheme was not formally conditional upon exclusivity, it was necessary to consider all the circumstances to establish whether it amounted to an abuse of a dominant position. In other words, the question was whether the scheme had a ‘loyalty-inducing’ effect. The experience acquired since Hoffmann-La Roche, revealed in line with contemporary economic research, that the effects that were presumed regarding exclusivity rebates did not reflect reality. Therefore, an increasing consensus arose against the application of rule-based approach to exclusivity rebates. The Commission in its ‘Guidance on Article 102’ considered that it should enforce against rebates only where practices were likely to have anti-competitive effects on the market. To assess anticompetitive effects the ‘Guidance on Article 102’ stated that it only intervenes where the abuse was capable of hampering competition from competitors which were considered to be as efficient as the dominant undertaking. This is assessed under the ‘effects-based’ approach which also included the ’as efficient competitor test’. In the Intel case, the CJEU supported the ‘effects-based’ approach and highlighted the ’as efficient competitor test’. The conclusion deriving from the case is that the CJEU’s clarification is a step towards legal certainty. However, the ’as efficient competitor test’ is only but a mere proxy depending on the specific context of the case

Chapter Supporting Inclusive Design of Mobile Devices with a Context Model

Embedded system

Supporting Inclusive Design of Mobile Devices with a Context Model

The aim of inclusive product design is to successfully integrate a broad range of diverse human factors in the product development process with the intention of making products accessible to and usable by the largest possible group of users. However, the main barriers for adopting inclusive product design include technical complexity, lack of time, lack of knowledge and techniques, and lack of guidelines. Although manufacturers of consumer products are nowadays more likely to invest efforts in user studies, consumer products in general only nominally fulfill, if at all, the accessibility requirements of as many users as they potentially could. The main reason is that any user-centered design prototyping or testing aiming to incorporate real user input, is often done at a rather late stage of the product development process. Thus, the more progressed a product design has evolved - the more time-consuming and costly it will be to alter the design. This is increasingly the case for contemporary mobile devices such as mobile phones or remote controls

Kinneyia: a flow-induced anisotropic fossil pattern from ancient microbial mats

Kinneyia is the commonly used term to describe a class of trace fossil that is strongly associated with microbial mats. The appearance of Kinneyia (or wrinkle structures) in the fossil record has recently led to a number of possible mechanisms being proposed to explain its formation. Here, we outline, and critically compare, three of these models, involving formation of the characteristic ripple structures (i) in mats over liquefied sediment, (ii) by oscillatory flow of microbial aggregates, and (iii) by a Kelvin–Helmholtz instability of the mat surface. Of these models, our study shows that the hydrodynamic instability compares most favorably with the corresponding structures in the fossil record. Implications for the conditions under which the fossils formed are then further discussed

Lead exposure in adult males in urban Transvaal Province, South Africa during the apartheid era

Human exposure to lead is a substantial public health hazard worldwide and is particularly problematic in the Republic of South Africa given the country’s late cessation of leaded petrol. Lead exposure is associated with a number of serious health issues and diseases including developmental and cognitive deficiency, hypertension and heart disease. Understanding the distribution of lifetime lead burden within a given population is critical for reducing exposure rates. Femoral bone from 101 deceased adult males living in urban Transvaal Province (now Gauteng Province), South Africa between 1960 and 1998 were analyzed for lead concentration by Inductively Coupled Plasma Mass Spectrometry (ICP-MS). Of the 72 black and 29 white individuals sampled, chronic lead exposure was apparent in nearly all individuals. White males showed significantly higher median bone lead concentration (ME = 10.04 µg·g−1), than black males (ME = 3.80 µg·g−1) despite higher socioeconomic status. Bone lead concentration covaries significantly, though weakly, with individual age. There was no significant temporal trend in bone lead concentration. These results indicate that long-term low to moderate lead exposure is the historical norm among South African males. Unexpectedly, this research indicates that white males in the sample population were more highly exposed to lead

Gender Differences in Public and Private Drinking Contexts: A Multi-Level GENACIS Analysis

This multi-national study hypothesized that higher levels of country-level gender equality would predict smaller differences in the frequency of women’s compared to men’s drinking in public (like bars and restaurants) settings and possibly private (home or party) settings. GENACIS project survey data with drinking contexts included 22 countries in Europe (8); the Americas (7); Asia (3); Australasia (2), and Africa (2), analyzed using hierarchical linear models (individuals nested within country). Age, gender and marital status were individual predictors; country-level gender equality as well as equality in economic participation, education, and political participation, and reproductive autonomy and context of violence against women measures were country-level variables. In separate models, more reproductive autonomy, economic participation, and educational attainment and less violence against women predicted smaller differences in drinking in public settings. Once controlling for country-level economic status, only equality in economic participation predicted the size of the gender difference. Most country-level variables did not explain the gender difference in frequency of drinking in private settings. Where gender equality predicted this difference, the direction of the findings was opposite from the direction in public settings, with more equality predicting a larger gender difference, although this relationship was no longer significant after controlling for country-level economic status. Findings suggest that country-level gender equality may influence gender differences in drinking. However, the effects of gender equality on drinking may depend on the specific alcohol measure, in this case drinking context, as well as on the aspect of gender equality considered. Similar studies that use only global measures of gender equality may miss key relationships. We consider potential implications for alcohol related consequences, policy and public health