Activation of RhoA and ROCK Are Essential for Detachment of Migrating Leukocytesh

Detachment of the rear of the cell from its substratum is an important aspect of locomotion. The signaling routes involved in this adhesive release are largely unknown. One of the few candidate proteins to play a role is RhoA, because activation of RhoA in many cell types leads to contraction, a mechanism probably involved in detachment. To study the role of RhoA in detachment regulation, we analyzed several subsets of expert migratory leukocytes by video microscopy. In contrast to fast-migrating neutrophils, eosinophils do not detach the rear of the cell unless stimulated with serum. When measuring the amount of active RhoA, with the use of a GSTRhotekin pulldown assay, we found that serum is an excellent activator of RhoA in granulocytes. Inhibition of RhoA or one of Rhos target proteins, the kinase ROCK, in neutrophils leads to the phenotype seen in eosinophils: the rear of the cell is firmly attached to the substratum, whereas the cell body is highly motile. ROCK-inhibition leads to impaired migration of granulocytes in filters, on glass, and through endothelial monolayers. Also, the ROCK signaling pathway is involved in changes of integrin-mediated adhesion. Eosinophil transduction by a tat-fusion construct containing active RhoA resulted in detachment stimulation in the presence of chemoattractant. From these results we conclude that activation of the RhoA-ROCK pathway is essential for detachment of migratory leukocytes

Measure-valued differentiation for stationary Markov chains

http://staff.feweb.vu.nl/bheidergot

On RAF Sets and Autocatalytic Cycles in Random Reaction Networks

The emergence of autocatalytic sets of molecules seems to have played an important role in the origin of life context. Although the possibility to reproduce this emergence in laboratory has received considerable attention, this is still far from being achieved. In order to unravel some key properties enabling the emergence of structures potentially able to sustain their own existence and growth, in this work we investigate the probability to observe them in ensembles of random catalytic reaction networks characterized by different structural properties. From the point of view of network topology, an autocatalytic set have been defined either in term of strongly connected components (SCCs) or as reflexively autocatalytic and food-generated sets (RAFs). We observe that the average level of catalysis differently affects the probability to observe a SCC or a RAF, highlighting the existence of a region where the former can be observed, whereas the latter cannot. This parameter also affects the composition of the RAF, which can be further characterized into linear structures, autocatalysis or SCCs. Interestingly, we show that the different network topology (uniform as opposed to power-law catalysis systems) does not have a significantly divergent impact on SCCs and RAFs appearance, whereas the proportion between cleavages and condensations seems instead to play a role. A major factor that limits the probability of RAF appearance and that may explain some of the difficulties encountered in laboratory seems to be the presence of molecules which can accumulate without being substrate or catalyst of any reaction.Comment: pp 113-12

Continuation rates of alpha-blockers mono-therapy in adult men, prescribed by urologists or general practitioners:A pharmacy-based study

PURPOSE: α-Blockers are commonly used for the treatment of male lower urinary tract symptoms (LUTS). The Dutch GP guideline on male LUTS contains an advice to discontinue treatment after 3-6 months of successful treatment. The guideline for urologists does not support this advice. It is unclear if these differences lead to other patterns of (dis)continuation of α-blockers. We aim to study continuation rates of α-blockers, prescribed by a urologist or a general practitioner (GP), and to predict discontinuation after 1 year. METHODS: We conducted a retrospective inception cohort study on prescription patterns of α-blockers among Dutch men between 2006 and 2014, using the IADB.nl pharmacy prescription database from the University of Groningen. We selected men aged 30 years or older with a first α-blocker prescription between 2006 and 2013, and analysed continuation of prescriptions. RESULTS: The database included 12,191 individual patients with at least one α-blocker prescriptions from a urologist (44.5%) or a GP (55.5%). The median treatment period for patients who started in the GPs office was 210 days, compared to 150 days for patients with a prescription from a urologist. Of all patients, 60.3% (GP prescriptions) and 66.1% (urologists' prescriptions) had discontinued treatment (Chi-square p < 0.001). Discontinuation rates were age dependent with higher rates in the youngest age groups. CONCLUSION: In this study, the discontinuation rate 1 year after the initiation of treatment was high. Although Dutch GP's and urologist's guidelines differ with respect to a discontinuation advice, we could not find clinically relevant difference in (temporary) discontinuation rates

Environmental Conflicts: The Case of Acid Rain in Europe

The acid rain problem is transboundary in nature: sulfur emissions in one country may lead to deposition of sulfur in a receptor country. A policy conflict may arise in estimating the damage at some receptor due to the various pollutant sources. This paper first reviews the international policy context that led to the development of the Regional Acidification Informational and Simulation (RAINS) model. The model computes sulfur emissions, transport and deposition which is then transferred into soil and lake acidity. The model is an interactive tool designed to assist policy makers in evaluating the effect of the control measures related to sulfur emissions. A mathematical description of the model is provided followed by a set of objective functions to be introduced within the RAINS model. The current interactive usage of RAINS will be extended with the possibility for the decision maker to progressively define objectives and set constraints in order to obtain an optimal policy

The Footprint Sorting Problem

Phylogenetic footprints are short pieces of noncoding DNA sequence in the vicinity of a gene that are conserved between evolutionary distant species. A seemingly simple problem is to sort footprints in their order along the genomes. It is complicated by the fact that not all footprints are collinear:  they may cross each other. The problem thus becomes the identification of the crossing footprints, the sorting of the remaining collinear cliques, and finally the insertion of the noncollinear ones at “reasonable” positions. We show that solving the footprint sorting problem requires the solution of the “Minimum Weight Vertex Feedback Set Problem”, which is known to be NP-complete and APX-hard. Nevertheless good approximations can be obtained for data sets of interest. The remaining steps of the sorting process are straightforward:  computation of the transitive closure of an acyclic graph, linear extension of the resulting partial order, and finally sorting w.r.t. the linear extension. Alternatively, the footprint sorting problem can be rephrased as a combinatorial optimization problem for which approximate solutions can be obtained by means of general purpose heuristics. Footprint sortings obtained with different methods can be compared using a version of multiple sequence alignment that allows the identification of unambiguously ordered sublists. As an application we show that the rat has a slighly increased insertion/deletion rate in comparison to the mouse genome

Phase transition and landscape statistics of the number partitioning problem

The phase transition in the number partitioning problem (NPP), i.e., the transition from a region in the space of control parameters in which almost all instances have many solutions to a region in which almost all instances have no solution, is investigated by examining the energy landscape of this classic optimization problem. This is achieved by coding the information about the minimum energy paths connecting pairs of minima into a tree structure, termed a barrier tree, the leaves and internal nodes of which represent, respectively, the minima and the lowest energy saddles connecting those minima. Here we apply several measures of shape (balance and symmetry) as well as of branch lengths (barrier heights) to the barrier trees that result from the landscape of the NPP, aiming at identifying traces of the easy/hard transition. We find that it is not possible to tell the easy regime from the hard one by visual inspection of the trees or by measuring the barrier heights. Only the {\it difficulty} measure, given by the maximum value of the ratio between the barrier height and the energy surplus of local minima, succeeded in detecting traces of the phase transition in the tree. In adddition, we show that the barrier trees associated with the NPP are very similar to random trees, contrasting dramatically with trees associated with the $p$ spin-glass and random energy models. We also examine critically a recent conjecture on the equivalence between the NPP and a truncated random energy model

Acidification in Europe : A Simulation Model for Evaluating Control Strategies

RAINS (Regional Acidification Information and Simulation) is an integrated model of acidification in Europe designed as a tool for evaluating control strategies. It is currently sulfur-based, but is being expanded to include nitrogen species. Emphasis of the model is on the transboundary aspects of the acidification problem. Model computations are performed on a personal computer. Linked submodels are available for SO2 emissions, cost of control strategies, atmospheric transport of sulfur, forest soil and groundwater acidity, lake acidification, and the direct impact of SO2 on forests. The model can be used for scenario analysis, where the user prescribes a control strategy and then examines the cost and environmental consequences of this strategy, or for optimization analysis, in which the user sets cost and deposition goals, and identifies an "optimal" sulfur-reduction strategy. Preliminary use of the model has pointed to 1. the importance of examining long-term environmental consequences of control strategies, and 2. the cost advantages of a cooperative European sulfur-reduction program