Potential peptidic proteasome inhibitors by incorporation of an electrophilic trap based on amino acid derived α-substituted sulfonyl fluorides

Peptido sulfonyl fluoride derivatives were designed and synthesized containing a substituent on the alpha position (αPSFs) with respect to the sulfonyl fluoride electrophilic trap. The chemical reactivity of these α-substituted amino sulfonyl fluorides was studied and compared with the previously described β-substituted amino sulfonyl fluorides in order to get a deeper insight into the importance of the immediate structural environment of the sulfonyl fluoride moiety. Unfortunately, the poor solubility of the resulting αPSFs precluded a proper evaluation of their biological activity

Proteasome inhibition by new dual warhead containing peptido vinyl sulfonyl fluorides

The success of inhibition of the proteasome by formation of covalent bonds is a major victory over the long held-view that this would lead to binding the wrong targets and undoubtedly lead to toxicity. Great challenges are now found in uncovering ensembles of new moieties capable of forming long lasting ties. We have introduced peptido sulfonyl fluorides for this purpose. Tuning the reactivity of this electrophilic trap may be crucial for modulating the biological action. Here we describe incorporation of a vinyl moiety into a peptido sulfonyl fluoride backbone, which should lead to a combined attack of the proteasome active site threonine on the double bond and the sulfonyl fluoride. Although this led to strong proteasome inhibitors, in vitro studies did not unambiguously demonstrate the formation of the proposed seven-membered ring structure. Possibly, formation of a seven-membered covalent adduct with the proteosomal active site threonine can only be achieved within the context of the enzyme. Nevertheless, this dual warhead concept may provide exclusive possibilities for duration and selectivity of proteasome inhibition

Costs of compliance with EU regulations and competitiveness of the EU dairy sector

The introduction of cross-compliance mechanism in the European Union with its 2003 CAPreform might affect the costs of production and thus competitiveness of the EU. Little evidence is available to asses the costs of compliance with regulations and it implication for trade. In this study a farm level competitiveness analysis of the impacts of the Nitrate Directive and the Identification & registration Directive focuses on the dairy sector in Germany, France, Italy, Netherlands and UK (within EU), and the US and New Zealand (outside EU). The findings from this study are integrated into a trade analysis which assesses the impact of compliance costs on competitiveness of the various trading nations in global trade. Representative farm studies were used as a basis for the cost increase calculations. Best-estimates of compliance are used from the existing literature and expert judgements. The negative impact of these measures (for nitrates, and animal identification and registration) on EU imports and exports are less than 3 percent. If a smaller increase in compliance takes place, these already relatively small trade impacts will be further diminished. When the standards for nitrate pollution taken by the US and New Zealand are taken into account along with full compliance assumption in all countries analysed, this would only slightly improve the EU exports. The trade impacts obtained when no changes are assumed to happen in key competitor countries can thus be argued as providing the upper bound of the likely trade impacts

The risk linked to ionizing radiation: an alternative epidemiologic approach.

Radioprotection norms have been based on risk models that have evolved over time. These models show relationships between exposure and observed effects. There is a high level of uncertainty regarding lower doses. Recommendations have been based on the conservative hypothesis of a linear relationship without threshold value. This relationship is still debated, and the diverse observations do not allow any definitive conclusion. Available data are contradictory, and various interpretations can be made. Here we review an alternative approach for defining causation and reconciling apparently contradictory conclusions. This alternative epidemiologic approach is based on causal groups: Each component of a causal group is necessary but not sufficient for causality. Many groups may be involved in causality. Thus, ionizing radiation may be a component of one or several causal groups. This formalization reconciles heterogeneous observations but implies searching for the interactions between components, mostly between critical components of a causal profile, and, for instance, the reasons why specific human groups would not show any effect despite exposure, when an effect would be expected

Predicting bilingual preschoolers' patterns of language development: Degree of non-native input matters

While numerous studies have recently shown that variation in input quantity predicts children’s rate of acquisition across a range of language skills, comparatively little is known about the impact of variation in input quality on (bilingual) children’s language development. This study investigated the relation between specific quality-oriented properties of bilingual children’s input and measures of children’s language development across a number of skills while at the same time taking family constellation into account. Participants were bilingual preschoolers (n = 50) acquiring Dutch alongside another language. Preschoolers’ receptive and productive vocabulary and morphosyntax in Dutch were assessed. Parental questionnaires were used to derive estimates of input quality. Family constellation was first operationalized as presence of a native-speaker parent and subsequently in terms of patterns of parental language use. Results showed that proportion of native input and having a native-speaker parent were never significant predictors of children’s language skills, whereas the degree of non-nativeness in the input, family constellation in terms of parental language use, and language richness were. This study shows that what matters is not how much exposure bilingual children have to native rather than non-native speakers, but how proficient any non-native speakers are

The assessment of efforts to return to work in the European Union

Background: Assessment of efforts to promote return-to-work (RTW) includes all efforts (vocational and non-vocational) designed to improve the work ability of the sick-listed employee and increase the chance to return to work. Aim of the study was to investigate whether in 13 European countries these RTW efforts are assessed and to compare the procedures by means of six criteria. METHODS: Data were gathered in the taxonomy project of the European Union of Medicine in Assurance and Social Security and by means of an additional questionnaire. RESULTS: In seven countries RTW efforts are subject of the assessment in relation to the application for disability benefits. Description of RTW efforts is a prerequisite in five countries. Guidelines on the assessment of RTW efforts are only available in the Netherlands and no countries report the use of the ICF model. Based on the results of the additional questionnaire, the assessor is a social scientist or a physician. The information used to assess RTW efforts differs, from a report on the RTW process to medical information. A negative outcome of the assessment leads to delay of the application for disability benefits or to application for rehabilitation subsidy. Conclusion: RTW efforts are assessed in half of the participating European countries. When compared, the characteristics of the assessment of RTW efforts in the participating European countries show both similarities and differences. This study may facilitate the gathering and exchange of knowledge and experience between countries on the assessment of RTW efforts