Alterations of the CARD15/NOD2 gene and the impact on management and treatment of Crohn's disease patients

The recent identification of the CARD15/NOD2 gene as a susceptibility locus for Crohn's disease represents an important step towards the delineation of the immuno-pathogenesis of inflammatory bowel disease. CARD15 functions as an intracellular receptor for bacterial components and thus represents an important link between inflammatory bowel disease and innate immunity. Three major CARD15/NOD2 gene mutations have been associated with Crohn's disease in Caucasians in several independent studies. Together, they explain about 20% of the genetic susceptibility for Crohn's disease. Genotype-phenotype analyses demonstrated an association of these mutations with ileum-specific disease, an increased incidence of the fibrostenotic phenotype and an earlier age of disease onset. Beside these associations, no other relationship between the CARD15/NOD2 genotype and disease behavior or response to treatment has been detailed so far. Thus, the clinical impact of knowing the patient's genotype is limited at this time. Screening for CARD15 mutations in order to identify high-risk individuals or to introduce an individualized disease management is therefore currently not recommended. Copyright (C) 2003 S. Karger AG, Basel

Regulation of 92-kD gelatinase release in HL-60 leukemia cells

Matrix metalloproteinase 9 (MMP-9), also known as 92-kD type IV collagenase/gelatinase, is believed to play a critical role in tumor invasion and metastasis. Here, we report that MMP-9 was constitutively released from the human promyelocytic cell line HL-60 as determined by zymographic analysis. Tumor necrosis factor-alpha (TNF-alpha) enhanced the enzyme release threefold to fourfold and the protein kinase C (PKC) activator and differentiation inducer 12-O-tetradecanoylphorbol-13- acetate (TPA) eightfold to ninefold. Gelatinase induction by TNF-alpha and TPA was inhibited by actinomycin D or cycloheximide, indicating that de novo protein synthesis was required. Neutralizing monoclonal antibodies to TNF-alpha (anti-TNF-alpha) decreased the basal MMP-9 release of these cells. In addition, these antibodies also significantly interfered with the TPA-induced enzyme release. Agents that inhibit TNF-alpha expression in HL-60 cells, such as pentoxifylline and dexamethasone, completely abrogated both the constitutive and TPA-evoked MMP-9 release. Diethyldithiocarbamate, which is known to stimulate TNF-alpha production in HL-60 cells, exerted a positive effect on MMP-9 release in untreated cells but was inhibitory in TPA-treated HL-60 cells. The PKC inhibitor staurosporine at low concentrations (100 ng/mL) caused a significant augmentation of MMP-9 release in untreated cultures that was blocked by the addition of anti-TNF-alpha. High concentrations (2 mumol/L) of staurosporine completely abolished the extracellular enzyme activity both in untreated and TPA-stimulated cells. These results suggest, that TNF- alpha is required for basal and PKC-mediated MMP-9 release in HL-60 leukemia cells. Thus, MMP-9 secretion may be regulated by TNF-alpha not only in a paracrine but also in an autocrine fashion. This may potentiate the matrix degradative capacity of immature leukemic cells in the processes of bone marrow egress and the evasion of these cells into peripheral tissue

Einselection without pointer states

We consider small subsystems of large, closed quantum systems that evolve according to the von Neumann equation. Without approximations and without making any special assumptions on the form of the interaction we prove that, for almost all initial states and almost all times, the off-diagonal elements of the density matrix of the subsystem in the eigenbasis of its local Hamiltonian must be small, whenever the energy difference of the corresponding eigenstates is larger than the interaction energy. This proves that decoherence with respect to the local energy eigenbasis is a natural property of weakly interacting quantum systems.Comment: published in Phys. Rev. E, 4 pages, no figures, revised introduction and conclusions, references revised and new references added, editorial change

Using parallel computation to improve Independent Metropolis--Hastings based estimation

In this paper, we consider the implications of the fact that parallel raw-power can be exploited by a generic Metropolis--Hastings algorithm if the proposed values are independent. In particular, we present improvements to the independent Metropolis--Hastings algorithm that significantly decrease the variance of any estimator derived from the MCMC output, for a null computing cost since those improvements are based on a fixed number of target density evaluations. Furthermore, the techniques developed in this paper do not jeopardize the Markovian convergence properties of the algorithm, since they are based on the Rao--Blackwell principles of Gelfand and Smith (1990), already exploited in Casella and Robert (1996), Atchade and Perron (2005) and Douc and Robert (2010). We illustrate those improvements both on a toy normal example and on a classical probit regression model, but stress the fact that they are applicable in any case where the independent Metropolis-Hastings is applicable.Comment: 19 pages, 8 figures, to appear in Journal of Computational and Graphical Statistic

Anti-Saccharomyces cerevisiae antibodies in patients with inflammatory bowel disease and their first-degree relatives: Potential clinical value

Anti-Saccharomyces cerevisiae antibodies (ASCA) have been described as specific markers in Crohn's disease and their healthy first-degree relatives. 171 patients with Crohn's disease, their 105 first-degree relatives, 145 patients with ulcerative colitis and 101 first-degree relatives of patients with ulcerative colitis, 50 patients with infectious enterocolitis and 100 healthy controls were tested for ASCA employing the ELISA technique. When compared with the healthy controls (p < 0.0001) and patients with infectious enterocolitis (p < 0.0001) the prevalence of ASCA was significantly increased in patients with Crohn's disease and their first-degree relatives (p < 0.01). Further significant differences concerning the frequency of ASCA within the different groups of our study population were not observed. In particular, ASCA were not found in increased prevalence in infectious enterocolitis. These observations are compatible with a role of ASCA as a marker of genetic predisposition to Crohn's disease. Copyright (C) 2002 S. Karger AG, Basel

COOPERATION IN LARGE NETWORKS: AN EXPERIMENTAL

We present a new design of a simple public goods experiment with a large number of players, where up to 80 people in a computer lab have the possibility to connect with others in the room to induce more cooperators to contribute to the public good and overcome the social dilemma. This experimental design explores the possibility of social networks to be used and institutional devices to create the same behavioral responses we observe with small groups (e.g. commitments, social norms, reciprocity, trust, shame, guilt) that seem to induce cooperativebehavior in the private provision of public goods. The results of our experiment suggest that the structure of the network affects not only the players´ ability to communicate, but their willingness to do so as well. Finally, we find that the local connectivity structure of the network has an important role as determinant of the willingness of the players to engage in a more costly type of collective action, namely the endogenous creation of new links to individuals previously out of reach.Social capital, social networks, collective action, cooperation, VCM,experiments, public goods provision

Mindful Eating: Trait and State Mindfulness Predict Healthier Eating Behavior

Obesity and excess weight are significant societal problems. Mindfulness may encourage healthier weight and eating habits. Across four studies, we found a positive relation between mindfulness and healthier eating. Trait mindfulness was associated with less impulsive eating, reduced calorie consumption, and healthier snack choices. In addition, we found a causal effect of mindfulness on healthier eating. An experimental manipulation of state mindfulness led participants to consume fewer calories in a spontaneous eating task. We also found preliminary evidence that mindfulness affects eating behavior by encouraging attitudinal preferences for healthier foods. Taken together, these results provide strong evidence that mindfulness encourages healthier eating, even in the absence of specific instruction in mindful eating. These results suggest that generic mindfulness-based strategies could have ancillary benefits for encouraging healthier eating behavior

Generating Focussed Molecule Libraries for Drug Discovery with Recurrent Neural Networks

In de novo drug design, computational strategies are used to generate novel molecules with good affinity to the desired biological target. In this work, we show that recurrent neural networks can be trained as generative models for molecular structures, similar to statistical language models in natural language processing. We demonstrate that the properties of the generated molecules correlate very well with the properties of the molecules used to train the model. In order to enrich libraries with molecules active towards a given biological target, we propose to fine-tune the model with small sets of molecules, which are known to be active against that target. Against Staphylococcus aureus, the model reproduced 14% of 6051 hold-out test molecules that medicinal chemists designed, whereas against Plasmodium falciparum (Malaria) it reproduced 28% of 1240 test molecules. When coupled with a scoring function, our model can perform the complete de novo drug design cycle to generate large sets of novel molecules for drug discovery.Comment: 17 pages, 17 figure