ISEK⁴ – A Regional Approach to Inner City Development

Integrated planning approaches provide the toolkit for delivering holistic and interdisciplinary solutions to meet the complex challenges of the 21st century. However, established instruments such as the integrated urban development concept (ISEK, common in Germany) lack the multilevel spatial integration required to tackle these issues effectively. Designed as a pilot project for the development of a new planning instrument, ISEK⁴ addressed two spatial spheres that – despite obvious necessity – are rarely considered together in the existing planning toolkit: the inner city and the functional region. Within eight months, integrated urban development concepts for the inner cities of Bruneck (South Tyrol), Hermagor-Pressegger See (Upper Carinthia), Lienz (East Tyrol), and Spittal an der Drau (Upper Carinthia) were developed along with a regional symbiosis of the SOUTH ALPINE SPACE, demonstrating and using synergies between the inner cities as anchor points of public life in the region. The ISEK⁴ project was based on a transdisciplinary planning approach and developed together with local steering groups from the cities. During the project, knowledge and needs were collected, recorded, and spatially contextualized in different workshop settings. In the work process, a mixed methods approach comprised of qualitative (GIS accessibility analyses, heat mapping) and qualitative (visioneering, storytelling, document analysis, design thinking lab, etc.) planning and research methods was employed. The central outcome of the ISEK⁴ project was a joint regional vision of the future, in both which local potentials and characteristics as well as regional strategies for action are represented. Alongside a geographically warped future image of the region, a vision story was used to outline the key areas of joint action. The ISEK⁴ concept also contains four city-specific sections (local ISEKs) drawing upon the so-called regional guiding principles, which are combined in one joint document. The key innovation of the project was the simultaneous consideration of four municipal city centres within a regional framework. It was shown that through the symbiosis of multiple concepts, activities in the field of inner-city development can be bundeled strategically and, in many cases, also implemented together. This paper focuses on the work process, the lessons learned and the transferability of the project approach, as well as selected results. A special focus will be on the methodological aspects of the storytelling method that was employed in the design of the regional and local future visions for ISEK⁴

Sympatho-renal axis in chronic disease

Essential hypertension, insulin resistance, heart failure, congestion, diuretic resistance, and functional renal disease are all characterized by excessive central sympathetic drive. The contribution of the kidney’s somatic afferent nerves, as an underlying cause of elevated central sympathetic drive, and the consequences of excessive efferent sympathetic signals to the kidney itself, as well as other organs, identify the renal sympathetic nerves as a uniquely logical therapeutic target for diseases linked by excessive central sympathetic drive. Clinical studies of renal denervation in patients with resistant hypertension using an endovascular radiofrequency ablation methodology have exposed the sympathetic link between these conditions. Renal denervation could be expected to simultaneously affect blood pressure, insulin resistance, sleep disorders, congestion in heart failure, cardiorenal syndrome and diuretic resistance. The striking epidemiologic evidence for coexistence of these disorders suggests common causal pathways. Chronic activation of the sympathetic nervous system has been associated with components of the metabolic syndrome, such as blood pressure elevation, obesity, dyslipidemia, and impaired fasting glucose with hyperinsulinemia. Over 50% of patients with essential hypertension are hyperinsulinemic, regardless of whether they are untreated or in a stable program of treatment. Insulin resistance is related to sympathetic drive via a bidirectional mechanism. In this manuscript, we review the data that suggests that selective impairment of renal somatic afferent and sympathetic efferent nerves in patients with resistant hypertension both reduces markers of central sympathetic drive and favorably impacts diseases linked through central sympathetics—insulin resistance, heart failure, congestion, diuretic resistance, and cardiorenal disorders

The three-dimensional structure of caspase-8: an initiator enzyme in apoptosis

AbstractBackground: In the initial stages of Fas-mediated apoptosis the cysteine protease caspase-8 is recruited to the cell receptor as a zymogen (procaspase-8) and is incorporated into the death-signalling complex. Procaspase-8 is subsequently activated leading to a cascade of proteolytic events, one of them being the activation of caspase-3, and ultimately resulting in cell destruction. Variations in the substrate specificity of different caspases have been reported.Results: We report here the crystal structure of a complex of the activated human caspase-8 (proteolytic domain) with the irreversible peptidic inhibitor Z-Glu-Val-Asp-dichloromethylketone at 2.8 Å resolution. This is the first structure of a representative of the long prodomain initiator caspases and of the group III substrate specificity class. The overall protein architecture resembles the caspase-1 and caspase-3 folds, but shows distinct structural differences in regions forming the active site. In particular, differences observed in subsites S3, S4 and the loops involved in inhibitor interactions explain the preference of caspase-8 for substrates with the sequence (Leu/Val)-Glu-X-Asp.Conclusions: The structural differences could be correlated with the observed substrate specificities of caspase-1, caspase-3 and caspase-8, as determined from kinetic experiments. This information will help us to understand the role of the various caspases in the propagation of the apoptotic signal. The information gained from this investigation should be useful for the design of specific inhibitors

Agrin is a differentiation-inducing "stop signal" for motoneurons in vitro

Proteins of the synaptic basal lamina are important in directing the differentiation of motor nerve terminals. One synaptic basal lamina protein, agrin, which influences postsynaptic muscle differentiation, has been suggested to influence nerve terminals as well. To test this hypothesis, we cocultured chick ciliary ganglion neurons with agrin-expressing CHO cells. Ciliary ganglion neurons, but not sensory neurons, adhered five times as well to agrin-expressing cells as to untransfected cells. Further, ciliary ganglion neurites were growth inhibited upon contact with agrin-expressing cells. Finally, the synaptic vesicle protein synaptotagmin became concentrated at contacts between ciliary ganglion neurites and agrin-expressing cells. These activities were shared by neuronal and muscle-derived agrin isoforms, consistent with the hypothesis that muscle agrin may influence the presynaptic axon. Our results suggest that agrin influences the growth and differentiation of motoneurons in vivo

Lung microdialysis—A powerful tool for the determination of exogenous and endogenous compounds in the lower respiratory tract (mini-review)

In vivo measurement of concentrations of drugs and endogenous substances at the site of action has become a primary focus of research. In this context the minimal invasive microdialysis (MD) technique has been increasingly employed for the determination of pharmacokinetics in lung. Although lung MD is frequently employed to investigate various drugs and endogenous substances, the majority of lung MD studies were performed to determine the pharmacokinetic profile of antimicrobials that can be related to the importance of respiratory tract infections. For the lower respiratory tract various methods, such as surgical collection of whole lung tissue and bonchoalveolar lavage (BAL), are currently available for the determination of pharmacokinetics of antimicrobials. Head-to-head comparison of pharmacokinetics of antibiotics in lung revealed high differences between MD and conventional methods. MD might be regarded as a more advantageous approach because of its higher anatomical resolution and the ability to obtain dynamic time-vs-concentration profiles within one subject. However, due to ethical objections lung MD is limited to animals or patients undergoing elective thoracic surgery. From these studies it was speculated that the concentrations in healthy lung tissue may be predicted reasonably by the measurement of concentrations in skeletal muscle tissue. However, until now this was only demonstrated for β-lactam antibiotics and needs to be confirmed for other classes of antimicrobials. In conclusion, the present review shows that MD is a promising method for the determination of antimicrobials in the lung, but might also be applicable for measuring a wide range of other drugs and for the investigation of metabolism in the lower respiratory tract

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Effects of climate and atmospheric nitrogen deposition on early to mid-term stage litter decomposition across biomes

International audienceLitter decomposition is a key process for carbon and nutrient cycling in terrestrial ecosystems and is mainly controlled by environmental conditions, substrate quantity and quality as well as microbial community abundance and composition. In particular, the effects of climate and atmospheric nitrogen (N) deposition on litter decomposition and its temporal dynamics are of significant importance, since their effects might change over the course of the decomposition process. Within the TeaComposition initiative, we incubated Green and Rooibos teas at 524 sites across nine biomes. We assessed how macroclimate and atmospheric inorganic N deposition under current and predicted scenarios (RCP 2.6, RCP 8.5) might affect litter mass loss measured after 3 and 12 months. Our study shows that the early to mid-term mass loss at the global scale was affected predominantly by litter quality (explaining 73% and 62% of the total variance after 3 and 12 months, respectively) followed by climate and N deposition. The effects of climate were not litter-specific and became increasingly significant as decomposition progressed, with MAP explaining 2% and MAT 4% of the variation after 12 months of incubation. The effect of N deposition was litter-specific, and significant only for 12-month decomposition of Rooibos tea at the global scale. However, in the temperate biome where atmospheric N deposition rates are relatively high, the 12-month mass loss of Green and Rooibos teas decreased significantly with increasing N deposition, explaining 9.5% and 1.1% of the variance, respectively. The expected changes in macroclimate and N deposition at the global scale by the end of this century are estimated to increase the 12-month mass loss of easily decomposable litter by 1.1– 3.5% and of the more stable substrates by 3.8–10.6%, relative to current mass loss. In contrast, expected changes in atmospheric N deposition will decrease the mid-term mass loss of high-quality litter by 1.4–2.2% and that of low-quality litter by 0.9–1.5% in the temperate biome. Our results suggest that projected increases in N deposition may have the capacity to dampen the climate-driven increases in litter decomposition depending on the biome and decomposition stage of substrate