The dipeptide Phe-Phe amide attenuates signs of hyperalgesia, allodynia and nociception in diabetic mice using a mechanism involving the sigma receptor system

<p>Abstract</p> <p>Background</p> <p>Previous studies have demonstrated that intrathecal administration of the substance P amino-terminal metabolite substance P_1-7(SP_1-7) and its C-terminal amidated congener induced antihyperalgesic effects in diabetic mice. In this study, we studied a small synthetic dipeptide related to SP_1-7and endomorphin-2, i.e. Phe-Phe amide, using the tail-flick test and von Frey filament test in diabetic and non-diabetic mice.</p> <p>Results</p> <p>Intrathecal treatment with the dipeptide increased the tail-flick latency in both diabetic and non-diabetic mice. This effect of Phe-Phe amide was significantly greater in diabetic mice than non-diabetic mice. The Phe-Phe amide-induced antinociceptive effect in both diabetic and non-diabetic mice was reversed by the σ₁receptor agonist (+)-pentazocine. Moreover, Phe-Phe amide attenuated mechanical allodynia in diabetic mice, which was reversible by (+)-pentazocine. The expression of spinal σ1 receptor mRNA and protein did not differ between diabetic mice and non-diabetic mice. On the other hand, the expression of phosphorylated extracellular signal-regulated protein kinase 1 (ERK1) and ERK2 proteins was enhanced in diabetic mice. (+)-Pentazocine caused phosphorylation of ERK1 and ERK2 proteins in non-diabetic mice, but not in diabetic mice.</p> <p>Conclusions</p> <p>These results suggest that the spinal σ₁receptor system might contribute to diabetic mechanical allodynia and thermal hyperalgesia, which could be potently attenuated by Phe-Phe amide.</p

Cytoskeletal protein kinases: titin and its relations in mechanosensing

Titin, the giant elastic ruler protein of striated muscle sarcomeres, contains a catalytic kinase domain related to a family of intrasterically regulated protein kinases. The most extensively studied member of this branch of the human kinome is the Ca2+–calmodulin (CaM)-regulated myosin light-chain kinases (MLCK). However, not all kinases of the MLCK branch are functional MLCKs, and about half lack a CaM binding site in their C-terminal autoinhibitory tail (AI). A unifying feature is their association with the cytoskeleton, mostly via actin and myosin filaments. Titin kinase, similar to its invertebrate analogue twitchin kinase and likely other “MLCKs”, is not Ca2+–calmodulin-activated. Recently, local protein unfolding of the C-terminal AI has emerged as a common mechanism in the activation of CaM kinases. Single-molecule data suggested that opening of the TK active site could also be achieved by mechanical unfolding of the AI. Mechanical modulation of catalytic activity might thus allow cytoskeletal signalling proteins to act as mechanosensors, creating feedback mechanisms between cytoskeletal tension and tension generation or cellular remodelling. Similar to other MLCK-like kinases like DRAK2 and DAPK1, TK is linked to protein turnover regulation via the autophagy/lysosomal system, suggesting the MLCK-like kinases have common functions beyond contraction regulation

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

BLUE GOVERNANCE: INTERNATIONAL ENVIRONMENTAL COOPERATION IN THE ARCTIC REGION Arctic environmental management and the constitution of regimes concerning rules, norms and governance

It has for a long time been called ‘the earth’s last frontier’ and its harsh environment has discouraged heavy investments in the region, up until now when all attention is directed towards the white dot on the map, the Arctic. By melting ices and permafrost, the natural resources of the Arctic have been made visible and actors are now preparing to exploit its assets. Without any explicit regime-structure, the Arctic is facing a scenario in which national territorial selfclaims will incuse the agenda as well as aspects of ‘creeping sovereignty’. The aim of this dissertation is to explain the Arctic national strategies concerning the eight Arctic states and how the strategies have evolved since the United Nations Conference on Sustainable Development in 2012. To analyse different forms of transnational cooperation, I draw on the theories of governance and regime theory, as well as developing the concept of ‘Blue Governance’. The empirical study investigates the establishment of regimes in the Arctic, concerning aspects of rules, norms and governance. Using a qualitative approach and the method of content analysis, data is based on Arctic national strategies and documents. The results show that there has been a development towards more ‘green’ or ‘blue’ geopolitics but also that national self-interests regarding resource exploitation seem to affect current Arctic environmental cooperation. The results also indicate that Arctic regimes now are more influenced by environmental norms and rules than earlier. Still, the absence of common Arctic regulations or guidelines constantly risk disturbing the Arctic legal order

Swimming Pool on top of High-Rise Buildings : A comparison of different structural designs and positions of swimming pools

This thesis is about determining the risks of positioning swimming pools on top of high-rise buildings.Pursuing this determination, computational simulations of constructed structural models in a finiteelement model software called RFEM have been analyzed. In further pursuit of wanted results comingfrom the computational software, the models have acquired relevant theory regarding both swimmingpools and high-rise buildings respectively to obtain realistic approximations of equivalent results if themodels were real life structures. Thence analytical observations and measures of each structural modelcontaining different positions of the swimming pools are generated, in several degrees, differentpossibilities of risks of failure are possible. Results have been compared out of design of swimmingpools and high-rise buildings in an initial stage of background and thereafter set as input values for themodeling where following perspectives have been analyzed:• Structural deformations,• Internal forces,• Utilization ratios, and• Mode shapes.Further analysis of social-, economic-, and environmental sustainability have been deliberated. Thus,in conclusion of this thesis, swimming pools positioned on top of the structure core or at center of theplan section tend to harm the stability of the structure likewise if the positioning of the swimming poolare cantilevered completely over the edge of the rooftop. More suitable design would either bepositioning the swimming pool attached to the core of the structure meanwhile cantilevered over theedge or integrated entirely along the edge.The results showed that some of the overhanging swimming pools pass the requirements of theEurocode. This will result in the columns experiencing a utilization which exceed its capacity. Thecolumn utilization was shown to behave differently depending on where the swimming pool was placedon the top floor. Furthermore, it was also a difference between the structures studied as dimensions ofthe members required either more or less depending on the form the structure had. The reaction of theswimming pool could be observed to behave as a stiff part of the structures with the deformation mostlybeing located at the slabs. The internal forces developed in the members due to the swimming poolaffected the columns at the bottom floors the most. The thesis finally shows how much is needed forthe worst case of each structure to pass the requirements. This resulted in different dimensions for themembers where the smaller structure (structure model 1) needed bigger dimensions and the largerstructure (structure model 2) needed smaller dimensions compared to the originally based dimensions.The social, economic, and environmental impact of the structures showed that the larger structureswould release more carbon dioxide than the smaller structures. The social aspect was treated moreregarding the safety and the experience of the user of the facility of swimming pool. The reinforcementvaried the most between the structures with the concrete being mostly the same for the two differentstructures made, in which an impact was made for both the economic and the environmental. Here itwas shown that in order to pass the requirements of the Eurocodes the impact on the climate needed tobe considerable different

Evaluation the Supply Chain of Plymovent AB

This Master Thesis is a part of PlymoVent’s business to customer plot, with the aim to investigate how the consumers receive the services that PlymoVent provides. With regard to PlymoVent's business strategy and reference theory, the demands of how to receive and monitor a supply chain for a better customer satisfaction where targeted. The findings refer to poor customer satisfaction due to obscure procedures in problem resolution and discrepancy handling, and vague transportation accuracy

Utmaningar som uppstår vid en RPA-implementering inom tillverkningsindustrin?

Verksamheter i dagens samhälle måste utvecklas i snabb takt och i samband med digitaliseringen uppstår nya tekniker som kan hjälpa till att effektivisera, förbättra och förenkla arbetet inom verksamheter. En av dessa tekniker är Robotic Process Automation (RPA) som handlar om att automatisera enkla och monotona verksamhetsprocesser med tydliga regler. Implementeringen av RPA innebär både utmaningar och möjligheter som måste hanteras för en lyckad implementering. I nuläget existerar det en begränsad information kring hur RPA implementeras in i tillverkningsindustrin och i vilka processer som lämpar sig för automatisering i detta område. Tidigare forskning som identifierats har undersökt utmaningar vid implementering av RPA, samt hur utmaningarna bör ses från leverantörens perspektiv. Vår studie handlar om vilka organisatoriska utmaningar det finns före och under en RPA-implementering inom tillverkningsindustrin. I syfte att undersöka hur RPA tillämpas i tillverkningsindustrin har frågeställningen tagits fram: Vilka organisatoriska utmaningar finns det före och under en RPA-implementering inom tillverkningsindustrin? För att besvara studiens frågeställning har en kvalitativ ansats använts. Med hjälp av semistrukturerade intervjuer har ett empiriskt datamaterial samlats in, dessa har sedan kategoriserats utifrån identifierade teman som framkom ur litteraturen. Det analyserade resultatet har legat till grund för studiens slutsats gällande att identifiera utmaningarna. Viktiga slutsatser visade sig vara att anpassa utvärderingsmetod med fokus mot valda områden i tillverkningsmoment, tydliga förankringsprocesser, ägandeskap av processer, och utbildning som matchar förändrade arbetsuppgifterToday, organizations must develop quickly and together with digitalization new technology can help organizations improve, become more effective, and simplify their work. One of these technologies is Robotic Process Automation (RPA), which automates simple and monotonous business processes with clear rules. The implementation of RPA carries challenges and opportunities that must be handled for a successful implementation. There is currently limited information regarding how RPA is implemented in the manufacturing industry and in which processes are suited for automation. Previous research has studied the challenges faced when implementing RPA and how they should be viewed from a supplier’s perspective. This study's purpose is to identify and explore organizational challenges before and under an RPA implementation within manufacturing industries. To investigate the topic, the following question is posed; Which organizational challenges can be identified before and during an RPA implementation within manufacturing industries? In order to answer the question, a qualitative method has been used through the use of semi-structured interviews that collected empirical data material. Using a thematic analysis based on identified themes found in the literature, the study can conclude, among other things, that securing a higher quality of automation is not only developed for cost efficiency but as well as using an adapted evaluation method with a focus on selected areas in manufacturing stage

Utmaningar som uppstår vid en RPA-implementering inom tillverkningsindustrin?

Verksamheter i dagens samhälle måste utvecklas i snabb takt och i samband med digitaliseringen uppstår nya tekniker som kan hjälpa till att effektivisera, förbättra och förenkla arbetet inom verksamheter. En av dessa tekniker är Robotic Process Automation (RPA) som handlar om att automatisera enkla och monotona verksamhetsprocesser med tydliga regler. Implementeringen av RPA innebär både utmaningar och möjligheter som måste hanteras för en lyckad implementering. I nuläget existerar det en begränsad information kring hur RPA implementeras in i tillverkningsindustrin och i vilka processer som lämpar sig för automatisering i detta område. Tidigare forskning som identifierats har undersökt utmaningar vid implementering av RPA, samt hur utmaningarna bör ses från leverantörens perspektiv. Vår studie handlar om vilka organisatoriska utmaningar det finns före och under en RPA-implementering inom tillverkningsindustrin. I syfte att undersöka hur RPA tillämpas i tillverkningsindustrin har frågeställningen tagits fram: Vilka organisatoriska utmaningar finns det före och under en RPA-implementering inom tillverkningsindustrin? För att besvara studiens frågeställning har en kvalitativ ansats använts. Med hjälp av semistrukturerade intervjuer har ett empiriskt datamaterial samlats in, dessa har sedan kategoriserats utifrån identifierade teman som framkom ur litteraturen. Det analyserade resultatet har legat till grund för studiens slutsats gällande att identifiera utmaningarna. Viktiga slutsatser visade sig vara att anpassa utvärderingsmetod med fokus mot valda områden i tillverkningsmoment, tydliga förankringsprocesser, ägandeskap av processer, och utbildning som matchar förändrade arbetsuppgifterToday, organizations must develop quickly and together with digitalization new technology can help organizations improve, become more effective, and simplify their work. One of these technologies is Robotic Process Automation (RPA), which automates simple and monotonous business processes with clear rules. The implementation of RPA carries challenges and opportunities that must be handled for a successful implementation. There is currently limited information regarding how RPA is implemented in the manufacturing industry and in which processes are suited for automation. Previous research has studied the challenges faced when implementing RPA and how they should be viewed from a supplier’s perspective. This study's purpose is to identify and explore organizational challenges before and under an RPA implementation within manufacturing industries. To investigate the topic, the following question is posed; Which organizational challenges can be identified before and during an RPA implementation within manufacturing industries? In order to answer the question, a qualitative method has been used through the use of semi-structured interviews that collected empirical data material. Using a thematic analysis based on identified themes found in the literature, the study can conclude, among other things, that securing a higher quality of automation is not only developed for cost efficiency but as well as using an adapted evaluation method with a focus on selected areas in manufacturing stage