Counter Machines and Distributed Automata: A Story about Exchanging Space and Time

We prove the equivalence of two classes of counter machines and one class of distributed automata. Our counter machines operate on finite words, which they read from left to right while incrementing or decrementing a fixed number of counters. The two classes differ in the extra features they offer: one allows to copy counter values, whereas the other allows to compute copyless sums of counters. Our distributed automata, on the other hand, operate on directed path graphs that represent words. All nodes of a path synchronously execute the same finite-state machine, whose state diagram must be acyclic except for self-loops, and each node receives as input the state of its direct predecessor. These devices form a subclass of linear-time one-way cellular automata.Comment: 15 pages (+ 13 pages of appendices), 5 figures; To appear in the proceedings of AUTOMATA 2018

Pretubulysin derived probes as novel tools for monitoring the microtubule network via activity-based protein profiling and fluorescence microscopy

Microtubules (mt) are highly dynamic polymers composed of alpha- and beta-tubulin monomers that are present in all dividing and non-dividing cells. A broad variety of natural products exists that are known to interfere with the microtubule network, by either stabilizing or de-stabilizing these rope-like polymers. Among those tubulysins represent a new and potent class of cytostatic tetrapeptides originating from myxobacteria. Early studies suggested that tubulysins interact with the eukaryotic cytoskeleton by inhibition of tubulin polymerization with EC50 values in the picomolar range. Recently, pretubulysins have been described to retain the high tubulindegradation activity of their more complex tubulysin relatives and represent an easier synthetic target with an efficient synthesis already in place. Although tubulin has been suggested as the dedicated target of tubulysin a comprehensive molecular target analysis of pretubulysin in the context of the whole proteome has not been carried out so far. Here we utilize synthetic chemistry to develop two pretubulysin photoaffinity probes which were applied in cellular activity-based protein profiling and imaging studies in order to unravel and visualize dedicated targets. Our results clearly show a remarkable selectivity of pretubulysin for beta-tubulin which we independently confirmed by a mass-spectrometry based proteomic profiling platform as well as by tubulin antibody based co-staining on intact cells

A Bit-String Model for Biological Aging

We present a simple model for biological aging. We studied it through computer simulations and we have found this model to reflect some features of real populations.Comment: LaTeX file, 4 PS figures include

A novel technique for selective NF-kappa B inhibition in Kupffer cells: contrary effects in fulminant hepatitis and ischaemia-reperfusion.

Background and aims: The transcription factor nuclear factor kappa B (NF-kB) has risen as a promising target for anti-inflammatory therapeutics. In the liver, however, NFkB inhibition mediates both damaging and protective effects. The outcome is deemed to depend on the liver cell type addressed. Recent gene knock-out studies focused on the role of NF-kB in hepatocytes, whereas the role of NF-kB in Kupffer cells has not yet been investigated in vivo. Here we present a novel approach, which may be suitable for clinical application, to selectively target NF-kB in Kupffer cells and analyse the effects in experimental models of liver injury. Methods: NF-kB inhibiting decoy oligodeoxynucleotides were loaded upon gelatin nanoparticles (D-NPs) and their in vivo distribution was determined by confocal microscopy. Liver damage, NF-kB activity, cytokine levels and apoptotic protein expression were evaluated after lipopolysaccharide (LPS), D-galactosamine (GalN)/LPS, or concanavalin A (ConA) challenge and partial warm ischaemia and subsequent reperfusion, respectively. Results: D-NPs were selectively taken up by Kupffer cells and inhibited NF-kB activation. Inhibition of NF-kB in Kupffer cells improved survival and reduced liver injury after GalN/LPS as well as after ConA challenge. While anti-apoptotic protein expression in liver tissue was not reduced, pro-apoptotic players such as cJun N-terminal kinase (JNK) were inhibited. In contrast, selective inhibition of NF-kB augmented reperfusion injury. Conclusions: NF-kB inhibiting decoy oligodeoxynucleotide- loaded gelatin nanoparticles is a novel tool to selectively inhibit NF-kB activation in Kupffer cells in vivo. Thus, liver injury can be reduced in experimental fulminant hepatitis, but increased at ischaemia–reperfusion

Inhibitor of Apoptosis Proteins as Novel Targets in Inflammatory Processes

Objective: Inhibitor of apoptosis proteins (IAPs), such as X-linked or cellular IAP 1/2 (XIAP, cIAP1/2), are important regulators of apoptosis. IAP antagonists are currently under clinical investigation as anticancer agents. Interestingly, IAPs participate in the inflammation-associated TNF receptor signaling complex and regulate NFκB signaling. This raises the question about the role of IAPs in inflammation. Here, we investigated the anti-inflammatory potential of IAP inhibitors and the role of IAPs in inflammatory processes of endothelial cells. Methods and Results: In mice, the small molecule IAP antagonist A-4.10099.1 (ABT) suppressed antigen-induced arthritis, leukocyte infiltration in concanavalin A-evoked liver injury, and leukocyte transmigration in the TNFα-activated cremaster muscle. In vitro, we observed an attenuation of leukocyte– endothelial cell interaction by downregulation of the intercellular adhesion molecule-1. ABT did not impair NFκB signaling but decreased the TNFα-induced activation of the TGF-β–activated kinase 1, p38, and c-Jun N-terminal kinase. These effects are based on the proteasomal degradation of cIAP1/2 accompanied by an altered ratio of the levels of membrane-localized TNF receptor-associated factors 2 and 5. Conclusion: Our results reveal IAP antagonism as a profound anti-inflammatory principle in vivo and highlight IAPs as important regulators of inflammatory processes in endothelial cells

Atrial Natriuretic Peptide Protects against Histamine-Induced Endothelial Barrier Dysfunction in Vivo

Endothelial barrier dysfunction is a hallmark of many severe pathologies, including sepsis or atherosclerosis. The cardiovascular hormone atrial natriuretic peptide (ANP) has increasingly been suggested to counteract endothelial leakage. Surprisingly, the precise in vivo relevance of these observations has never been evaluated. Thus, we aimed to clarify this issue and, moreover, to identify the permeability-controlling subcellular systems that are targeted by ANP. Histamine was used as important pro-inflammatory, permeability-increasing stimulus. Measurements of fluorescein isothiocyanate (FITC)-dextran extravasation from venules of the mouse cremaster muscle and rat hematocrit values were performed to judge changes of endothelial permeability in vivo. It is noteworthy that ANP strongly reduced the histamine-evoked endothelial barrier dysfunction in vivo. In vitro, ANP blocked the breakdown of transendothelial electrical resistance (TEER) induced by histamine. Moreover, as judged by immunocytochemistry and Western blot analysis, ANP inhibited changes of vascular endothelial (VE)-cadherin, β-catenin, and p120ctn morphology; VE-cadherin and myosin light chain 2 (MLC2) phosphorylation; and F-actin stress fiber formation. These changes seem to be predominantly mediated by the natriuretic peptide receptor (NPR)-A, but not by NPR-C. In summary, we revealed ANP as a potent endothelial barrier protecting agent in vivo and identified adherens junctions and the contractile apparatus as subcellular systems targeted by ANP. Thus, our study highlights ANP as an interesting pharmacological compound opening new therapeutic options for preventing endothelial leakage

General Practitioners' preferences and use of educational media: a German perspective

<p>Abstract</p> <p>Background</p> <p>Several studies suggest that General Practitioners (GPs) prefer "traditional" media such as journals or quality circles when they are seeking out different options to meet their continuing medical education (CME) requirements. A survey was designed in order to gain a better understanding of German General Practitioners' preferences for different forms of educational media that will meet their CME needs.</p> <p>Methods</p> <p>Four hundred and forty nine (N = 449) German physicians were contacted to take part in this study on the occasion of one of their quality circle meetings. The participating physicians received a standardized 26-item-questionnaire that surveyed their preferences for different forms of educational media. A factor analysis was performed in order to determine whether the observed variables can be explained largely or entirely in terms of the underlying patterns.</p> <p>Results</p> <p>Two hundred and sixty-four physicians with an average age of 51.1 years participated (28.5% female, 71.5% male). We found that GPs favor learning environments such as: <it>journals</it>, <it>colleagues</it>, and <it>quality circles</it>. New media like the <it>internet </it>was used less often for their learning activities, even though the usage of the internet in general was quite high. The most important requirements for media in medical education as perceived by the participants were its <it>relevancy for daily practice </it>and <it>dependability</it>.</p> <p>Conclusion</p> <p>Despite a growing use of the Internet it seems that German GPs favor "classical/traditional" settings for their learning activities. These results should be taken into consideration when planning CME or CPD programs or other learning activities.</p> <p>Trial registration</p> <p>Current Controlled Trials ISRCTN36550981.</p

Flavopiridol Protects Against Inflammation by Attenuating Leukocyte-Endothelial Interaction via Inhibition of Cyclin-Dependent Kinase 9

Objective: The cyclin-dependent kinase (CDK) inhibitor flavopiridol is currently being tested in clinical trials as anticancer drug. Beyond its cell death–inducing action, we hypothesized that flavopiridol affects inflammatory processes. Therefore, we elucidated the action of flavopiridol on leukocyte–endothelial cell interaction and endothelial activation in vivo and in vitro and studied the underlying molecular mechanisms. Methods and Results: Flavopiridol suppressed concanavalin A–induced hepatitis and neutrophil infiltration into liver tissue. Flavopiridol also inhibited tumor necrosis factor-α–induced leukocyte– endothelial cell interaction in the mouse cremaster muscle. Endothelial cells were found to be the major target of flavopiridol, which blocked the expression of endothelial cell adhesion molecules (intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin), as well as NF-κB-dependent transcription. Flavopiridol did not affect inhibitor of κB (IκB) kinase, the degradation and phosphorylation of IκBα, nuclear translocation of p65, or nuclear factor-κB (NF-κB) DNA-binding activity. By performing a cellular kinome array and a kinase activity panel, we found LIM domain kinase-1 (LIMK1), casein kinase 2, c-Jun N-terminal kinase (JNK), protein kinase Cθ (PKCθ), CDK4, CDK6, CDK8, and CDK9 to be influenced by flavopiridol. Using specific inhibitors, as well as RNA interference (RNAi), we revealed that only CDK9 is responsible for the action of flavopiridol. Conclusion: Our study highlights flavopiridol as a promising antiinflammatory compound and inhibition of CDK9 as a novel approach for the treatment of inflammation-associated diseases

Ictal SPECT in Sturge-Weber syndrome

We report on a patient with right-sided Sturge-Weber syndrome (SWS), in whom earlier functional hemispherectomy failed. Subtraction of ictal and interictal single-photon-emission-computed-tomography (SPECT) superimposed on individual MRI showed a right fronto-orbital hyperperfusion, with a left-sided EEG seizure pattern. Ictal SPECT supported our assumption that right frontal originated seizure pattern propagated to left hemisphere via the remaining right frontal bridge. Right orbito-frontal resection and disconnection from corpus callosum resulted in seizure freedom