Selective Sirt2 inhibition by ligand-induced rearrangement of the active site.

Sirtuins are a highly conserved class of NAD(+)-dependent lysine deacylases. The human isotype Sirt2 has been implicated in the pathogenesis of cancer, inflammation and neurodegeneration, which makes the modulation of Sirt2 activity a promising strategy for pharmaceutical intervention. A rational basis for the development of optimized Sirt2 inhibitors is lacking so far. Here we present high-resolution structures of human Sirt2 in complex with highly selective drug-like inhibitors that show a unique inhibitory mechanism. Potency and the unprecedented Sirt2 selectivity are based on a ligand-induced structural rearrangement of the active site unveiling a yet-unexploited binding pocket. Application of the most potent Sirtuin-rearranging ligand, termed SirReal2, leads to tubulin hyperacetylation in HeLa cells and induces destabilization of the checkpoint protein BubR1, consistent with Sirt2 inhibition in vivo. Our structural insights into this unique mechanism of selective sirtuin inhibition provide the basis for further inhibitor development and selective tools for sirtuin biology

The silence of self-knowledge

Gareth Evans famously affirmed an explanatory connection between answering the question whether p and knowing whether one believes that p. This is commonly interpreted in terms of the idea that judging that p constitutes an adequate basis for the belief that one believes that p. This paper formulates and defends an alternative, more modest interpretation, which develops from the suggestion that one can know that one believes that p in judging that p

A prospective, blinded evaluation of a video-assisted ‘4-stage approach’ during undergraduate student practical skills training

BACKGROUND: The 4-stage approach (4-SA) is used as a didactic method for teaching practical skills in international courses on resuscitation and the structured care of trauma patients. The aim of this study was to evaluate objective and subjective learning success of a video-assisted 4-SA in teaching undergraduate medical students. METHODS: The participants were medical students learning the principles of the acute treatment of trauma patients in their multidiscipline course on emergency and intensive care medicine. The participants were quasi- randomly divided into two groups. The 4-SA was used in both groups. In the control group, all four steps were presented by an instructor. In the study group, the first two steps were presented as a video. At the end of the course a 5-minute objective, structured clinical examination (OSCE) of a simulated trauma patient was conducted. The test results were divided into objective results obtained through a checklist with 9 dichotomous items and the assessment of the global performance rated subjectively by the examiner on a Likert scale from 1 to 6. RESULTS: 313 students were recruited; the results of 256 were suitable for analysis. The OSCE results were excellent in both groups and did not differ significantly (control group: median 9, interquantil range (IQR) 8–9, study group: median 9, IQR 8–9; p = 0.29). The global performance was rated significantly better for the study group (median 1, IQR 1–2 vs. median 2, IQR 1–3; p < 0.01). The relative knowledge increase, stated by the students in their evaluation after the course, was greater in the study group (85% vs. 80%). CONCLUSION: It is possible to employ video assistance in the classical 4-SA with comparable objective test results in an OSCE. The global performance was significantly improved with use of video assistance

Privacy as a Human Right

The right to privacy seems to occupy an entirely natural place within the structure of human rights; for many years now there has been an established jurisprudence on the right to privacy coming from the European Court of Human Rights in Strasbourg. At the same time, there have been fundamental conceptual (Thomson, Geuss) and normative (McKinnon) criticisms of the right to privacy. Against these critics, I argue, first, that it is possible to articulate a systematic normative conception of privacy, which explains and supports a general right to privacy; and second, that the right to privacy lies at the very heart of a human right to freedom and autonomy. Without reference to a right to privacy, many other rights to freedom are not realizable. I first develop a normative conception of privacy and its different dimensions, and in a second step take a closer look at the jurisprudence of the ECHR by considering some examples, in order to understand what role the right to privacy plays in the Court's decisions. The right to privacy, far from being reducible to other rights or detrimental to the rights and needs of women, occupies a central place on the list of human rights

Comparison of established and emerging biodosimetry assays

Rapid biodosimetry tools are required to assist with triage in the case of a large-scale radiation incident. Here, we aimed to determine the dose-assessment accuracy of the well-established dicentric chromosome assay (DCA) and cytokinesis-block micronucleus assay (CBMN) in comparison to the emerging &gamma;-H2AX foci and gene expression assays for triage mode biodosimetry and radiation injury assessment. Coded blood samples exposed to 10 X-ray doses (240 kVp, 1 Gy/min) of up to 6.4 Gy were sent to participants for dose estimation. Report times were documented for each laboratory and assay. The mean absolute difference (MAD) of estimated doses relative to the true doses was calculated. We also merged doses into binary dose categories of clinical relevance and examined accuracy, sensitivity and specificity of the assays. Dose estimates were reported by the first laboratories within 0.3-0.4 days of receipt of samples for the &gamma;-H2AX and gene expression assays compared to 2.4 and 4 days for the DCA and CBMN assays, respectively. Irrespective of the assay we found a 2.5-4-fold variation of interlaboratory accuracy per assay and lowest MAD values for the DCA assay (0.16 Gy) followed by CBMN (0.34 Gy), gene expression (0.34 Gy) and &gamma;-H2AX (0.45 Gy) foci assay. Binary categories of dose estimates could be discriminated with equal efficiency for all assays, but at doses &ge;1.5 Gy a 10% decrease in efficiency was observed for the foci assay, which was still comparable to the CBMN assay. In conclusion, the DCA has been confirmed as the gold standard biodosimetry method, but in situations where speed and throughput are more important than ultimate accuracy, the emerging rapid molecular assays have the potential to become useful triage tools

Immunoblot analysis of the seroreactivity to recombinant Borrelia burgdorferi sensu lato antigens, including VlsE, in the long-term course of treated patients with Erythema migrans

Objective: We evaluated whether immunoblotting is capable of substantiating the posttreatment clinical assessment of patients with erythema migrans ( EM), the hallmark of early Lyme borreliosis. Methods: In 50 patients, seroreactivity to different antigens of Borrelia burgdorferi sensu lato was analyzed by a recombinant immunoblot test (IB) in consecutive serum samples from a minimum follow-up period of 1 year. Antigens in the IgG test were decorin- binding protein A, internal fragment of p41 (p41i), outer surface protein C (OspC), p39, variable major protein-like sequence expressed (VlsE), p58 and p100; those in the IgM test were p41i, OspC and p39. Immune responses were correlated with clinical and treatment-related parameters. Results: Positive IB results were found in 50% before, in 57% directly after therapy and in 44% by the end of the follow-up for the IgG class, and in 36, 43 and 12% for the IgM class. In acute and convalescence phase sera, VlsE was most immunogenic on IgG testing 60 and 70%), and p41i (46 and 57%) and OspC (40 and 57%) for the IgM class. By the end of the follow-up, only the anti-p41i lgM response was significantly decreased to 24%. Conclusions: No correlation was found between IB results and treatment-related parameters. Thus, immunoblotting does not add to the clinical assessment of EM patients after treatment. Copyright (c) 2008 S. Karger AG, Basel