The Role of TRP Proteins in Mast Cells

Transient receptor potential (TRP) proteins form cation channels that are regulated through strikingly diverse mechanisms including multiple cell surface receptors, changes in temperature, in pH and osmolarity, in cytosolic free Ca2+ concentration ([Ca2+]i), and by phosphoinositides which makes them polymodal sensors for fine tuning of many cellular and systemic processes in the body. The 28 TRP proteins identified in mammals are classified into six subfamilies: TRPC, TRPV, TRPM, TRPA, TRPML, and TRPP. When activated, they contribute to cell depolarization and Ca2+ entry. In mast cells, the increase of [Ca2+]i is fundamental for their biological activity, and several entry pathways for Ca2+ and other cations were described including Ca2+ release activated Ca2+ (CRAC) channels. Like in other non-excitable cells, TRP channels could directly contribute to Ca2+ influx via the plasma membrane as constituents of Ca2+ conducting channel complexes or indirectly by shifting the membrane potential and regulation of the driving force for Ca2+ entry through independent Ca2+ entry channels. Here, we summarize the current knowledge about the expression of individual Trp genes with the majority of the 28 members being yet identified in different mast cell models, and we highlight mechanisms how they can regulate mast cell functions. Since specific agonists or blockers are still lacking for most members of the TRP family, studies to unravel their function and activation mode still rely on experiments using genetic approaches and transgenic animals. RNAi approaches suggest a functional role for TRPC1, TRPC5, and TRPM7 in mast cell derived cell lines or primary mast cells, and studies using Trp gene knock-out mice reveal a critical role for TRPM4 in mast cell activation and for mast cell mediated cutaneous anaphylaxis, whereas a direct role of cold- and menthol-activated TRPM8 channels seems to be unlikely for the development of cold urticaria at least in mice

Developing a Taxonomy for Digital Platforms – A Conceptual Approach

Disruptive companies like Google, Apple, Facebook, and Amazon transform economic and business activity. Faced with their growing economic importance, digital platforms are increasingly adopting essential functions in business and daily life. Discussions of platforms are extended by decisive aspects accompanying this development. Established economic, social, and organization theory show limitations in understanding and describing digital platforms. Researchers need a sophisticated conceptualization of the complex manifold perspectives to fully understand the dynamics of digital platforms and lead the development of platforms in the proper direction. To enable comparability of research results and uniform theory building, this study analyzes existing literature and conceptually develops a comprehensive taxonomy for digital platforms based on multi-faceted approaches. Our taxonomy consists of technological, economic, and socio-cultural perspectives with sixteen dimensions and corresponding characteristics analyzed in detail, which helps scholars classify and articulate the full range of digital platform specifications

RNA-seq analysis reveals TRPC genes to impact an unexpected number of metabolic and regulatory pathways

The seven-member transient receptor potential canonical genes (TRPC1-7) encode cation channels linked to several human diseases. There is little understanding of the participation of each TRPC in each pathology, considering functional redundancy. Also, most of the inhibitors available are not specifc. Thus, we developed mice that lack all of the TRPCs and performed a transcriptome analysis in eight tissues. The aim of this research was to address the impact of the absence of all TRPC channels on gene expression. We obtained a total of 4305 diferentially expressed genes (DEGs) in at least one tissue where spleen showed the highest number of DEGs (1371). Just 21 genes were modifed in all the tissues. Performing a pathway enrichment analysis, we found that many important signaling pathways were modifed in more than one tissue, including PI3K (phosphatidylinositol 3-kinase/protein kinase-B) signaling pathway, cytokine-cytokine receptor interaction, extracellular matrix (ECM)-receptor interaction and circadian rhythms. We describe for the frst time the changes at the transcriptome level due to the lack of all TRPC proteins in a mouse model and provide a starting point to understand the function of TRPC channels and their possible roles in pathologies.Fil: Formoso, Karina. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; ArgentinaFil: Susperreguy, Sebastian. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; ArgentinaFil: Freichel, Marc. Universität Heidelberg; AlemaniaFil: Birnbaumer, Lutz. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentin

A Platform Business Model for Collaborative Additive Manufacturing

Modern manufacturing is caught in a trade-off between maximizing efficiency and staying flexible in dynamic markets. Inter-organizational sharing of manufacturing capacities on a digital marketplace could contribute to gain flexibility, reduce cost and capital employed as well as provide further business opportunities. Although current research has already prepared the ground for its technical conceptualization, research on such a marketplace’s implementation in a business model is scarce. However, since an efficient matching of supply and demand requires a sufficient number of platform users, attracting corporate customers with a suitable business model is crucial. The present research aims to address this problem by developing and evaluating a business model for a marketplace provider, illustrated for the case of additive manufacturing

Requirements and a Meta Model for Exchanging Additive Manufacturing Capacities

In an environment shaped by digital transformation and globalization, manufacturers face increasing market dynamics, cost pressure, and more sophisticated customer requirements. As this demands flexibility and adaptability, enterprises rely on new solutions for collaboration. A marketplace for production capacities supports companies in reducing order risks and improving responsiveness to changing market conditions. We seek to define requirements for a marketplace that is capable of matching products with production processes. With an initial focus on additive manufacturing, we aim to build a blueprint for similar application scenarios in other industrial contexts. Therefore, we employ a qualitative research based on expert interviews. Our results suggest that a marketplace for production capacities must address various requirements, which can be grouped under the categories of technologies, machines, and products. We further build a conceptual meta model that sets the groundwork for the matching and thus facilitates the implementation of the marketplace in practice

Challenges of supply chain visibility in distribution logistics – a literature review

Purpose: Complex supply chains characterise today\u27s economic life, which is determined by uncertainties and risks. Managing those successfully requires the development of resilient and flexible structures and processes based on information transparency, which enables better decision-making, especially in times of global crises. In this context, supply chain visibility (SCV) is defined as the stakeholders\u27 capability to have access to accurate and timely information about the flow of goods. Although the importance of SCV has been discussed in scientific literature and practice, challenges still inhibit improved SCV, particularly in distribution logistics. These have been scarcely investigated. The purpose of this study is to identify the challenges of SCV in distribution logistics and to provide implications to address them. Methodology: A qualitative content analysis (QCA) spanning 26 scientific articles was used. Results: We found evidence of challenges inhibiting SCV in distribution logistics within the three aggregated dimensions of inappropriate processes & technologies and information systems, lack of communication & trust, and insufficient monitoring & decision-making metrics. The findings show that trust can be seen as both a challenge and a prerequisite. Despite the possibilities of digitalisation, there exist trade-offs between manual processes and new technology implementation. Decision-making can be based on individual experiences, and monitoring can be difficult due to undefined metrics. Conclusion: Practitioners may use the findings to better identify and address the challenges of SCV in distribution logistics. Further studies could extend the findings through empirical studies, which would allow practitioners to assess their level of SCV and derive initial solutions

Klonierung und Charakterisierung neuer Guaninnukleotid-Austauschfaktoren für die GTPase Rho

Die Aktivierung kleiner GTPasen der Rho-Familie ist eine Antwort vieler Zellen auf die Stimulation membranständiger Rezeptoren und spielt bei zahlreichen zellulären Prozessen wie der Reorganisation des Aktin-Cytoskeletts und der Stimulation der Gentranskription eine bedeutende Rolle. Der Aktivitätszustand der Rho-Proteine wird vermutlich vor allem durch die Interaktion mit entsprechenden Guaninnukleotid-Austauschfaktoren der Dbl-Familie (Rho-GEFs) positiv reguliert. Die bis heute bekannten Rho-GEFs bilden eine Familie von homologen Proteinen und zeigen zumindest hinsichtlich zweier Strukturmerkmale einen einheitlichen Aufbau, wenn sie auch ganz unterschiedliche Expressionsmuster und Spezifitäten für die verschiedenen Rho-GTPasen aufweisen. So besitzen alle bislang identifizierten Rho-GEFs ein Tandem aus katalytischer "Dbl homology" (DH)-Domäne und C-terminal benachbarter "Pleckstrin homology" (PH)-Domäne. Mit p114-Rho-GEF (114 kDa), Mono (64 kDa) und KIAA0337 (164 kDa) gelang die Identifizierung und Charakterisierung dreier neuer, für Rho(A) spezifischer Rho-GEFs, wobei KIAA0337 aufgrund der fehlenden PH-Domäne möglicherweise den ersten Vertreter einer neuen Untergruppe der Dbl-Familie darstellt. Die cDNA von Mono wurde durch Homologie-Klonierungen aus einer humanen, embryonalen Gehirn-cDNA-Bibliothek isoliert, während die cDNAs von p114-Rho-GEF und KIAA0337 vom japanischen Kazusa-DNA-Forschungsinstitut zur Verfügung gestellt wurden. Northern Blot-Analysen der Expression von Mono und KIAA0337 in verschiedenen humanen Geweben zeigten, daß beide recht gewebespezifisch exprimiert werden, und zwar Mono recht spezifisch im Gehirn und KIAA0337 als erstes Rho-GEF recht dominant im Herzen. Dagegen wird p114-Rho-GEF ubiquitär exprimiert. Die Guaninnukleotid-Austauschaktivität und die Spezifität gegenüber der GTPase RhoA wurden durch folgende in vitro-Untersuchungen belegt: Die aufgereinigten Proteine von p114-Rho-GEF, Mono und KIAA0337 katalysierten deutlich den GDP/GTP-Austausch an RhoA, hatten jedoch keinen Einfluß auf Rac1 oder Cdc42, und alle drei GEFs interagierten spezifisch mit RhoA. In Übereinstimmung mit diesen Ergebnissen führte die Überexpression von p114-Rho-GEF ebenso wie die Expression von Mono zur Ausbildung von Aktin-Streßfasern in J82-Zellen, wie sie für aktiviertes RhoA typisch ist, und stimulierte spezifisch über RhoA die SRF-vermittelte Gentranskription in HEK 293-Zellen. Dagegen führte die Überexpression von KIAA0337 nur zu einer sehr schwachen Ausbildung von Aktin-Streßfasern und zeigte keinen Effekt auf die SRF-vermittelte Gentranskription. Untersuchungen der Regulation der GEF-Aktivität der drei Rho-GEFs durch Messung der SRF-vermittelten Gentranskription zeigten, daß im Falle von Mono möglicherweise der C-Terminus als regulatorische Domäne der GEF-Aktivität durch G-Protein-gekoppelte Rezeptoren fungiert, vermutlich über Galpahq vermittelt. Auch p114-Rho-GEF scheint an der Aktivierung von Rho durch G-Protein-gekoppelte Rezeptoren beteiligt zu sein. Es gelang jedoch nicht, eine klare Zuordnung zu den an der Stimulation beteiligten G-Protein-Untereinheiten zu treffen. Die Aktivität von KIAA0337 unterliegt dagegen wahrscheinlich nicht der Regulation durch membranständige Rezeptoren und nachgeschaltete G-Proteine sondern einem intramolekularen Hemmechanismus durch eine Interaktion von N- und C-Terminus