Untersuchungen zur limitierten Proteolyse transmembraner Chemokine durch Disintegrin-ähnliche Metalloproteinasen

CX3CL1 (fractalkine) and CXCL16 are the only known chemokines so far which are expressed as membrane-bound molecules. Interestingly, their ectodomain can be cleaved off the cell-surface by the proteolytic activity of certain proteases, a process referred to as shedding. The identification of the proteases involved as well as a more detailed understanding of the function of the membrane-bound and soluble forms of CX3CL1 and CXCL16 was the objective of the study. It could be shown that both chemokines are upregulated by proinflammatory cytokines and shed by at least two members of the ADAM-family of disintegrin-like metalloproteinases, which are ADAM10 and ADAM17 (TACE). This finding was consistently supported by using selective ADAM-inhibitors and by comparing the shedding behaviour of CX3CL1 and CXCL16 in ADAM10-positive and -deficient cells. Static adhesion assays confirmed the involvement of CX3CL1 in leukocyte recruitment and pointed towards a role of CX3CL1-shedding for leukocyte diapedesis. Finally, for the first time, the presence of CXCL16 and its receptor CXCR6 in human brain was demonstrated, indicating a possible role for this chemokine in inflammatory processes of the brain

Computational modelling elucidates the mechanism of ciliary regulation in health and disease

<p>Abstract</p> <p>Background</p> <p>Ciliary dysfunction leads to a number of human pathologies, including primary ciliary dyskinesia, nephronophthisis, situs inversus pathology or infertility. The mechanism of cilia beating regulation is complex and despite extensive experimental characterization remains poorly understood. We develop a detailed systems model for calcium, membrane potential and cyclic nucleotide-dependent ciliary motility regulation.</p> <p>Results</p> <p>The model describes the intimate relationship between calcium and potassium ionic concentrations inside and outside of cilia with membrane voltage and, for the first time, describes a novel type of ciliary excitability which plays the major role in ciliary movement regulation. Our model describes a mechanism that allows ciliary excitation to be robust over a wide physiological range of extracellular ionic concentrations. The model predicts the existence of several dynamic modes of ciliary regulation, such as the generation of intraciliary Ca²⁺spike with amplitude proportional to the degree of membrane depolarization, the ability to maintain stable oscillations, monostable multivibrator regimes, all of which are initiated by variability in ionic concentrations that translate into altered membrane voltage.</p> <p>Conclusions</p> <p>Computational investigation of the model offers several new insights into the underlying molecular mechanisms of ciliary pathologies. According to our analysis, the reported dynamic regulatory modes can be a physiological reaction to alterations in the extracellular environment. However, modification of the dynamic modes, as a result of genetic mutations or environmental conditions, can cause a life threatening pathology.</p

Роботизированные пожарные системы для защиты объектов с массовым пребыванием людей

В статье показано значение автоматизированных систем пожаротушения на базе пожарных роботов для защиты объектов с массовым пребыванием людей, рассмотрена их функциональная схема, проанализированы их достоинства, представлена нормативно-правовая база применения пожарных роботов

Modelling the Material Resistance of Wood—Part 3: Relative Resistance in above- and in-Ground Situations—Results of a Global Survey

Durability-based designs with timber require reliable information about the wood properties and how they affect its performance under variable exposure conditions. This study aimed at utilizing a material resistance model (Part 2 of this publication) based on a dose–response approach for predicting the relative decay rates in above-ground situations. Laboratory and field test data were, for the first time, surveyed globally and used to determine material-specific resistance dose values, which were correlated to decay rates. In addition, laboratory indicators were used to adapt the material resistance model to in-ground exposure. The relationship between decay rates in- and above-ground, the predictive power of laboratory indicators to predict such decay rates, and a method for implementing both in a service life prediction tool, were established based on 195 hardwoods, 29 softwoods, 19 modified timbers, and 41 preservative-treated timbers

Modeling the material resistance of wood—part 2:Validation and optimization of the meyer-veltrup model

Service life planning with timber requires reliable models for quantifying the effects of exposure-related parameters and the material-inherent resistance of wood against biotic agents. The Meyer-Veltrup model was the first attempt to account for inherent protective properties and the wetting ability of wood to quantify resistance of wood in a quantitative manner. Based on test data on brown, white, and soft rot as well as moisture dynamics, the decay rates of different untreated wood species were predicted relative to the reference species of Norway spruce (Picea abies). The present study aimed to validate and optimize the resistance model for a wider range of wood species including very durable species, thermally and chemically modified wood, and preservative treated wood. The general model structure was shown to also be suitable for highly durable materials, but previously defined maximum thresholds had to be adjusted (i.e., maximum values of factors accounting for wetting ability and inherent protective properties) to 18 instead of 5 compared to Norway spruce. As expected, both the enlarged span in durability and the use of numerous and partly very divergent data sources (i.e., test methods, test locations, and types of data presentation) led to a decrease in the predictive power of the model compared to the original. In addition to the need to enlarge the database quantity and improve its quality, in particular for treated wood, it might be advantageous to use separate models for untreated and treated wood as long as the effect of additional impact variables (e.g., treatment quality) can be accounted for. Nevertheless, the adapted Meyer-Veltrup model will serve as an instrument to quantify material resistance for a wide range of wood-based materials as an input for comprehensive service life prediction software

A Systems Model for Immune Cell Interactions Unravels the Mechanism of Inflammation in Human Skin

Inflammation is characterized by altered cytokine levels produced by cell populations in a highly interdependent manner. To elucidate the mechanism of an inflammatory reaction, we have developed a mathematical model for immune cell interactions via the specific, dose-dependent cytokine production rates of cell populations. The model describes the criteria required for normal and pathological immune system responses and suggests that alterations in the cytokine production rates can lead to various stable levels which manifest themselves in different disease phenotypes. The model predicts that pairs of interacting immune cell populations can maintain homeostatic and elevated extracellular cytokine concentration levels, enabling them to operate as an immune system switch. The concept described here is developed in the context of psoriasis, an immune-mediated disease, but it can also offer mechanistic insights into other inflammatory pathologies as it explains how interactions between immune cell populations can lead to disease phenotypes

The TYK2-P1104A Autoimmune Protective Variant Limits Coordinate Signals Required to Generate Specialized T Cell Subsets

TYK2 is a JAK family member that functions downstream of multiple cytokine receptors. Genome wide association studies have linked a SNP (rs34536443) within TYK2 encoding a Proline to Alanine substitution at amino acid 1104, to protection from multiple autoimmune diseases including systemic lupus erythematosus (SLE) and multiple sclerosis (MS). The protective role of this SNP in autoimmune pathogenesis, however, remains incompletely understood. Here we found that T follicular helper (Tfh) cells, switched memory B cells, and IFNAR signaling were decreased in healthy individuals that expressed the protective variant TYK2A1104 (TYK2P). To study this variant in vivo, we developed a knock-in murine model of this allele. Murine Tyk2P expressing T cells homozygous for the protective allele, but not cells heterozygous for this change, manifest decreased IL-12 receptor signaling, important for Tfh lineage commitment. Further, homozygous Tyk2P T cells exhibited diminished in vitro Th1 skewing. Surprisingly, despite these signaling changes, in vivo formation of Tfh and GC B cells was unaffected in two models of T cell dependent immune responses and in two alternative SLE models. TYK2 is also activated downstream of IL-23 receptor engagement. Here, we found that Tyk2P expressing T cells had reduced IL-23 dependent signaling as well as a diminished ability to skew toward Th17 in vitro. Consistent with these findings, homozygous, but not heterozygous, Tyk2P mice were fully protected in a murine model of MS. Homozygous Tyk2P mice had fewer infiltrating CD4+ T cells within the CNS. Most strikingly, homozygous mice had a decreased proportion of IL-17+/IFNγ+, double positive, pathogenic CD4+ T cells in both the draining lymph nodes (LN) and CNS. Thus, in an autoimmune model, such as EAE, impacted by both altered Th1 and Th17 signaling, the Tyk2P allele can effectively shield animals from disease. Taken together, our findings suggest that TYK2P diminishes IL-12, IL-23, and IFN I signaling and that its protective effect is most likely manifest in the setting of autoimmune triggers that concurrently dysregulate at least two of these important signaling cascades