49 research outputs found

    Learning from failure

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    We study decentralized learning in organizations. Decentralization is captured through a symmetry constraint on agents’ strategies. Among such attainable strategies, we solve for optimal and equilibrium strategies. We model the organization as a repeated game with imperfectly observable actions. A fixed but unknown subset of action profiles are successes and all other action profiles are failures. The game is played until either there is a success or the time horizon is reached. For any time horizon, including infinity, we demonstrate existence of optimal attainable strategies and show that they are Nash equilibria. For some time horizons, we can solve explicitly for the optimal attainable strategies and show uniqueness. The solution connects the learning behavior of agents to the fundamentals that characterize the organization: Agents in the organization respond more slowly to failure as the future becomes more important, the size of the organization increases and the probability of success decreases.Game theory

    De aquarel; verkennende studie ten behoeve van het waterbeleid van het ministerie van LNV

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    Dit rapport is een verantwoording van een verkennende studie naar de mogelijkheden en consequenties van verschillende opties voor het waterbeleid in het landelijk gebied, rekening houdend met ontwikkelingen in landgebruik en gevolgen van klimaatverandering tot 2030. Voor drie scenario's is een verschillende ontwikkeling in beeld gebracht en zijn de gevolgen voor economie, werkgelegenheid en leefbaarheid beschreven

    Multifunctional Magnetic-fluorescent Nanocomposites for Biomedical Applications

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    Nanotechnology is a fast-growing area, involving the fabrication and use of nano-sized materials and devices. Various nanocomposite materials play a number of important roles in modern science and technology. Magnetic and fluorescent inorganic nanoparticles are of particular importance due to their broad range of potential applications. It is expected that the combination of magnetic and fluorescent properties in one nanocomposite would enable the engineering of unique multifunctional nanoscale devices, which could be manipulated using external magnetic fields. The aim of this review is to present an overview of bimodal “two-in-one” magnetic-fluorescent nanocomposite materials which combine both magnetic and fluorescent properties in one entity, in particular those with potential applications in biotechnology and nanomedicine. There is a great necessity for the development of these multifunctional nanocomposites, but there are some difficulties and challenges to overcome in their fabrication such as quenching of the fluorescent entity by the magnetic core. Fluorescent-magnetic nanocomposites include a variety of materials including silica-based, dye-functionalised magnetic nanoparticles and quantum dots-magnetic nanoparticle composites. The classification and main synthesis strategies, along with approaches for the fabrication of fluorescent-magnetic nanocomposites, are considered. The current and potential biomedical uses, including biological imaging, cell tracking, magnetic bioseparation, nanomedicine and bio- and chemo-sensoring, of magnetic-fluorescent nanocomposites are also discussed

    Prediction of outcome and endovascular treatment benefit validation and update of the MR PREDICTS decision tool

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    BACKGROUND AND PURPOSE: Benefit of early endovascular treatment (EVT) for ischemic stroke varies considerably among patients. The MR PREDICTS decision tool, derived from MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands), predicts outcome and treatment benefit based on baseline characteristics. Our aim was to externally validate and update MR PREDICTS with data from international trials and daily clinical practice.METHODS: We used individual patient data from 6 randomized controlled trials within the HERMES (Highly Effective Reperfusion Evaluated in Multiple Endovascular Stroke Trials) collaboration to validate the original model. Then, we updated the model and performed a second validation with data from the observational MR CLEAN Registry. Primary outcome was functional independence (defined as modified Rankin Scale score 0-2) 3 months after stroke. Treatment benefit was defined as the difference between the probability of functional independence with and without EVT. Discriminative performance was evaluated using a concordance (C) statistic.RESULTS: We included 1242 patients from HERMES (633 assigned to EVT, 609 assigned to control) and 3156 patients from the MR CLEAN Registry (all of whom underwent EVT within 6.5 hours). The C-statistic for functional independence was 0.74 (95% CI, 0.72-0.77) in HERMES and, after model updating, 0.80 (0.78-0.82) in the Registry. Median predicted treatment benefit of routinely treated patients (Registry) was 10.3% (interquartile range, 5.8%-14.4%). Patients with low (<1%) predicted treatment benefit (n=135/3156 [4.3%]) had low rates of functional independence, irrespective of reperfusion status, suggesting potential absence of treatment benefit. The updated model was made available online for clinicians and researchers at .CONCLUSIONS: Because of the substantial treatment effect and small potential harm of EVT, most patients arriving within 6 hours at an endovascular-capable center should be treated regardless of their clinical characteristics. MR PREDICTS can be used to support clinical judgement when there is uncertainty about the treatment indication, when resources are limited, or before a patient is to be transferred to an endovascular-capable center.Analysis and support of clinical decision makingDevelopment and application of statistical models for medical scientific researc

    Functional and genetic analysis of the Ccr4-Not complex in Yeast

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    Transcription is a complex process that is regulated at multiple levels. This involves a wide variety of multi-subunit protein-complexes including the basal (or general) transcription factors and RNA polymerase II. One of the major obstacles for the transcription machinery is chromatin, which consists of DNA wrapped around an octamer composed of the histone core particle (two molecules of H2A, H2B, H3 and H4) and the linker histone H1. One of the complexes involved in regulation of transcription is the nine-subunit Ccr4-Not complex. Initially, components of this complex were identified as negative regulators of the non-consensus TATA box driven transcription of the HIS3 gene. In addition, some data also suggest an additional positive role in transcription. Recently, Ccr4p and Caf1p were identified as the major cytoplasmic deadenylases in yeast, indicating that his complex functions in both transcription and mRNA turnover. In addition, human CNOT4 displays RING-finger mediated UbcH5B-dependent ubiquitylation activity. To address the physiological cones-quences of the ubiquitylation activity of Not4p, we used Saccharomyces cerevisiae (bakers' yeast) as a model organism. First, site-directed mutagenesis of the RING-finger of yeast Not4p identified residues required for interaction with Ubc4p and Ubc5p, the yeast orthologs of UbcH5B. Subsequent in vitro assays with purified Ccr4-Not complexes showed Not4p mediated E3 ligase activity, which was dependent on the interaction with Ubc4p. Next, we performed synthetic genetic array (SGA) analyses using not4Δ and not4L35A alleles. This indicates involvement of the RING-finger of Not4p in transcription, ubiquitylation and DNA damage responses. In addition, we found overlapping phenotypes for deletions of UBC4 and mutants encoding single amino acid substitutions of the RING-finger of Not4p. Together, the results presented in chapter 2 show that Not4p functions as an E3 ligase by modulating Ubc4p/Ubc5p mediated stress responses in vivo. Furthermore, genetic experiments have indicated a role for the Ccr4-Not complex in the response to hydroxyurea (HU)-induced replication stress and ionizing radiation. This response includes transcriptional induction of the four genes constituting the ribonucleotide reductase (RNR) enzymatic complex, RNR1-4, and degradation of its inhibitor, Sml1p. In chapter 3, we investigated the mechanism of the HU sensitivity conferred by mutation of CCR4-NOT genes. We found that the ubiquitin protein ligase activity of Not4p does not play a role in HU-induced Sml1p degradation. We showed, however, that the HU sensitivity of ccr4-not mutant strains correlated very well with a defect in accumulation of RNR2, RNR3 and RNR4 mRNA after HU or MMS treatment. Chromatin immuno-precipitation experiments showed that TBP, RNA polymerase II and Set1p recruitment to the activated RNR3 locus was defective in cells lacking NOT4. Moreover, RNR3 promoter activity was not induced by HU treatment of these cells. Together, these experiments show that induction of RNR gene transcription is defective in ccr4-not mutant strains, providing an explanation for their sensitivity to HU and implicating the Ccr4-Not complex in positive regulation of transcription. Chapter 4 elaborates on this positive role as we found that Ccr4-Not components display genetic interactions with BUR1 and BUR2. These genes were previously shown to be involved in transcription elongation. We found that the genes encoding the Not-proteins are essential for efficient regulation of H3K4me3, but not H3K4me1/2, H3K36me2 or H3K79me2/3 levels. In addition, we show that NOT4 is important for ubiquitylation of histone H2B via recruitment of the PAF complex without affecting Bur1/2 recruitment, providing evidence that the Ccr4-Not complex facilitates H3K4 tri-methylation by functioning downstream of the Bur1/2 kinase. Finally, the proteomic and electron microscopy (EM) study of the Ccr4-Not complex described in chapter 5 provides insight in possible regulation of its functions. Multiple phosphorylation sites on Not4p, Not1p and Caf1p were identified. The functional consequences of these modifications are the subject of current work. Overall, the work presented here contributes to our understanding of the function of the Ccr4-Not complex and act as a basis for future experiments to further explore the exact function(s) of this complex in regulation of mRNA deadenylation and transcription

    Adaptation trajectories during adhesion and spreading affect future cell states

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    Contains fulltext : 177911.pdf (publisher's version ) (Open Access)11 p

    The interplay of chromatin and transcription factors during cell fate transitions in development and reprogramming

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    Contains fulltext : 214239.pdf (publisher's version ) (Open Access
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