Probable Innocence Revisited

International audienceOften we wish to ensure that the identity of the user performing a certain action is maintained secret. This property is called anonymity. Examples of situations in which we may wish to provide anonymity include: publishing on the web, retrieving information from the web, sending a message, etc. Many protocols have been designed for this purpose, for example, Crowds [15], Onion Routing [23], the Free Haven [7], Web MIX [1] and Freenet [4]

Drug target optimization in chronic myeloid leukemia using innovative computational platform.

Chronic Myeloid Leukemia (CML) represents a paradigm for the wider cancer field. Despite the fact that tyrosine kinase inhibitors have established targeted molecular therapy in CML, patients often face the risk of developing drug resistance, caused by mutations and/or activation of alternative cellular pathways. To optimize drug development, one needs to systematically test all possible combinations of drug targets within the genetic network that regulates the disease. The BioModelAnalyzer (BMA) is a user-friendly computational tool that allows us to do exactly that. We used BMA to build a CML network-model composed of 54 nodes linked by 104 interactions that encapsulates experimental data collected from 160 publications. While previous studies were limited by their focus on a single pathway or cellular process, our executable model allowed us to probe dynamic interactions between multiple pathways and cellular outcomes, suggest new combinatorial therapeutic targets, and highlight previously unexplored sensitivities to Interleukin-3.We would like to thank the members of the Fisher laboratory, in particular to Gavin Smyth and Caroline Dahl for their help with the BMA development, and Alex Hajnal for valuable comments on the manuscript and insightful discussions. Research in BG laboratory is supported by the Medical Research Council, Leukaemia and Lymphoma Research, The Leukemia and Lymphoma Society, Microsoft Research and core support grants by the Wellcome Trust to the Cambridge Institute for Medical Research and Wellcome Trust-MRC Cambridge Stem Cell Institute.This is the final published version. It was originally published in Scientific Reports 5: 8190. DOI: 10.1038/srep08190

Branching on multi-aggregated variables

open5siopenGamrath, Gerald; Melchiori, Anna; Berthold, Timo; Gleixner, Ambros M.; Salvagnin, DomenicoGamrath, Gerald; Melchiori, Anna; Berthold, Timo; Gleixner, Ambros M.; Salvagnin, Domenic

The Tim54p–Tim22p Complex Mediates Insertion of Proteins into the Mitochondrial Inner Membrane

We have identified a new protein, Tim54p, located in the yeast mitochondrial inner membrane. Tim54p is an essential import component, required for the insertion of at least two polytopic proteins into the inner membrane, but not for the translocation of precursors into the matrix. Several observations suggest that Tim54p and Tim22p are part of a protein complex in the inner membrane distinct from the previously characterized Tim23p-Tim17p complex. First, multiple copies of the TIM22 gene, but not TIM23 or TIM17, suppress the growth defect of a tim54-1 temperature-sensitive mutant. Second, Tim22p can be coprecipitated with Tim54p from detergent-solubilized mitochondria, but Tim54p and Tim22p do not interact with either Tim23p or Tim17p. Finally, the tim54-1 mutation destabilizes the Tim22 protein, but not Tim23p or Tim17p. Our results support the idea that the mitochondrial inner membrane carries two independent import complexes: one required for the translocation of proteins across the inner membrane (Tim23p–Tim17p), and the other required for the insertion of proteins into the inner membrane (Tim54p–Tim22p)

Supporting self-regulated learning

Self-regulated learning (SRL) competences are crucial for lifelong learning. Their cultivation requires the right balance between freedom and guidance during the learning processes. Current learning systems and approaches, such as personal learning environments, give overwhelming freedom, but also let weak learners alone. Other systems, such as learning management systems or adaptive systems, tend to institutionalise learners too much, which does not support the development of SRL competences. This chapter presents possibilities and approaches to support SRL by the use of technology. After discussing the theoretical background of SRL and related technologies, a formal framework is presented that describes the SRL process, related competences, and guidelines. Furthermore, a variety of methods is presented, how learners can be supported to learn in a self-regulated way

Patient-reported outcomes in metastatic castration-resistant prostate cancer

Many novel therapies are available for use in patients with metastatic castration-resistant prostate cancer (mCRPC), some of which convey substantial progression-free survival and overall survival benefits. Delaying disease progression and providing palliation of symptoms are primary therapeutic aims of treating patients with mCRPC; therefore, ensuring that the benefit-to-harm ratios are acceptable to patients, through systematic measurement of patient-reported outcomes (PROs) using validated tools, is vital. In this Perspectives, we appraised the published reports from clinical trials testing treatments of mCRPC over the past 5 years and found that PROs were either not being measured routinely, or if used, were often not reported adequately, thus hampering evaluation of the true effects of many of these treatments on patients' quality of life. Improvements are needed because data collected directly from patients, not just physician-collected safety data and adverse events, are crucial to inform clinical decision-making on treatment options

Chronic mucocutaneous candidiasis in APECED or thymoma patients correlates with autoimmunity to Th17-associated cytokines

Chronic mucocutaneous candidiasis (CMC) is frequently associated with T cell immunodeficiencies. Specifically, the proinflammatory IL-17A–producing Th17 subset is implicated in protection against fungi at epithelial surfaces. In autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED, or autoimmune polyendocrine syndrome 1), CMC is often the first sign, but the underlying immunodeficiency is a long-standing puzzle. In contrast, the subsequent endocrine features are clearly autoimmune, resulting from defects in thymic self-tolerance induction caused by mutations in the autoimmune regulator (AIRE). We report severely reduced IL-17F and IL-22 responses to both Candida albicans antigens and polyclonal stimulation in APECED patients with CMC. Surprisingly, these reductions are strongly associated with neutralizing autoantibodies to IL-17F and IL-22, whereas responses were normal and autoantibodies infrequent in APECED patients without CMC. Our multicenter survey revealed neutralizing autoantibodies against IL-17A (41%), IL-17F (75%), and/ or IL-22 (91%) in >150 APECED patients, especially those with CMC. We independently found autoantibodies against these Th17-produced cytokines in rare thymoma patients with CMC. The autoantibodies preceded the CMC in all informative cases. We conclude that IL-22 and IL-17F are key natural defenders against CMC and that the immunodeficiency underlying CMC in both patient groups has an autoimmune basis

Home on the Range: Factors Explaining Partial Migration of African Buffalo in a Tropical Environment

Partial migration (when only some individuals in a population undertake seasonal migrations) is common in many species and geographical contexts. Despite the development of modern statistical methods for analyzing partial migration, there have been no studies on what influences partial migration in tropical environments. We present research on factors affecting partial migration in African buffalo (Syncerus caffer) in northeastern Namibia. Our dataset is derived from 32 satellite tracking collars, spans 4 years and contains over 35,000 locations. We used remotely sensed data to quantify various factors that buffalo experience in the dry season when making decisions on whether and how far to migrate, including potential man-made and natural barriers, as well as spatial and temporal heterogeneity in environmental conditions. Using an information-theoretic, non-linear regression approach, our analyses showed that buffalo in this area can be divided into 4 migratory classes: migrants, non-migrants, dispersers, and a new class that we call “expanders”. Multimodel inference from least-squares regressions of wet season movements showed that environmental conditions (rainfall, fires, woodland cover, vegetation biomass), distance to the nearest barrier (river, fence, cultivated area) and social factors (age, size of herd at capture) were all important in explaining variation in migratory behaviour. The relative contributions of these variables to partial migration have not previously been assessed for ungulates in the tropics. Understanding the factors driving migratory decisions of wildlife will lead to better-informed conservation and land-use decisions in this area

A ring-like accretion structure in M87 connecting its black hole and jet

The nearby radio galaxy M87 is a prime target for studying black hole accretion and jet formation^{1,2}. Event Horizon Telescope observations of M87 in 2017, at a wavelength of 1.3 mm, revealed a ring-like structure, which was interpreted as gravitationally lensed emission around a central black hole^3. Here we report images of M87 obtained in 2018, at a wavelength of 3.5 mm, showing that the compact radio core is spatially resolved. High-resolution imaging shows a ring-like structure of 8.4_{-1.1}^{+0.5} Schwarzschild radii in diameter, approximately 50% larger than that seen at 1.3 mm. The outer edge at 3.5 mm is also larger than that at 1.3 mm. This larger and thicker ring indicates a substantial contribution from the accretion flow with absorption effects in addition to the gravitationally lensed ring-like emission. The images show that the edge-brightened jet connects to the accretion flow of the black hole. Close to the black hole, the emission profile of the jet-launching region is wider than the expected profile of a black-hole-driven jet, suggesting the possible presence of a wind associated with the accretion flow.Comment: 50 pages, 18 figures, 3 tables, author's version of the paper published in Natur

A ring-like accretion structure in M87 connecting its black hole and jet

The nearby radio galaxy M87 is a prime target for studying black hole accretion and jet formation1,2. Event Horizon Telescope observations of M87 in 2017, at a wavelength of 1.3 mm, revealed a ring-like structure, which was interpreted as gravitationally lensed emission around a central black hole3. Here we report images of M87 obtained in 2018, at a wavelength of 3.5 mm, showing that the compact radio core is spatially resolved. High-resolution imaging shows a ring-like structure of [Formula: see text] Schwarzschild radii in diameter, approximately 50% larger than that seen at 1.3 mm. The outer edge at 3.5 mm is also larger than that at 1.3 mm. This larger and thicker ring indicates a substantial contribution from the accretion flow with absorption effects, in addition\ua0to the gravitationally lensed ring-like emission. The images show that the edge-brightened jet connects to the accretion flow of the black hole. Close to the black hole, the emission profile of the jet-launching region is wider than the expected profile of a black-hole-driven jet, suggesting the possible presence of a wind associated with the accretion flow