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Systemic autoinflammatory diseases (SAIDs) are a group of inflammatory disorders caused by dysregulation in the innate immune system that leads to enhanced immune responses. The clinical diagnosis of SAIDs can be difficult since individually these are rare diseases with considerable phenotypic overlap. Most SAIDs have a strong genetic background, but environmental and epigenetic influences can modulate the clinical phenotype. Molecular diagnosis has become essential for confirmation of clinical diagnosis. To date there are over 30 genes and a variety of modes of inheritance that have been associated with monogenic SAIDs. Mutations in the same gene can lead to very distinct phenotypes and can have different inheritance patterns. In addition, somatic mutations have been reported in several of these conditions. New genetic testing methods and databases are being developed to facilitate the molecular diagnosis of SAIDs, which is of major importance for treatment, prognosis and genetic counselling. The aim of this review is to summarize the latest advances in genetic testing for SAIDs and discuss potential obstacles that might arise during the molecular diagnosis of SAIDs.
The pyrin inflammasome has evolved as an innate immune sensor to detect bacterial toxin-induced Rho guanosine triphosphatase (Rho GTPase)-inactivation, a process that is similar to the "guard" mechanism in plants. Rho GTPases act as molecular switches to regulate a variety of signal transduction pathways including cytoskeletal organization. Pathogens can modulate Rho GTPase activity to suppress host immune responses such as phagocytosis. Pyrin is encoded by MEFV, the gene that is mutated in patients with familial Mediterranean fever (FMF). FMF is the prototypic autoinflammatory disease characterized by recurring short episodes of systemic inflammation and is a common disorder in many populations in the Mediterranean basin. Pyrin specifically senses modifications in the activity of the small GTPase RhoA, which binds to many effector proteins including the serine/threonine-protein kinases PKN1 and PKN2 and actin-binding proteins. RhoA activation leads to PKN-mediated phosphorylation-dependent pyrin inhibition. Conversely, pathogen virulence factors downregulate RhoA activity in a variety of ways, and these changes are detected by the pyrin inflammasome irrespective of the type of modifications. MEFV pathogenic variants favor the active state of pyrin and elicit proinflammatory cytokine release and pyroptosis. They can be inherited either as a dominant or recessive trait depending on the variant's location and effect on the protein function. Mutations in the C-terminal B30.2 domain are usually considered recessive, although heterozygotes may manifest a biochemical or even a clinical phenotype. These variants are hypomorphic in regard to their effect on intramolecular interactions, but ultimately accentuate pyrin activity. Heterozygous mutations in other domains of pyrin affect residues critical for inhibition or protein oligomerization, and lead to constitutively active inflammasome. In healthy carriers of FMF mutations who have the subclinical inflammatory phenotype, the increased activity of pyrin might have been protective against endemic infections over human history. This finding is supported by the observation of high carrier frequencies of FMF-mutations in multiple populations. The pyrin inflammasome also plays a role in mediating inflammation in other autoinflammatory diseases linked to dysregulation in the actin polymerization pathway. Therefore, the assembly of the pyrin inflammasome is initiated in response to fluctuations in cytoplasmic homeostasis and perturbations in cytoskeletal dynamics.
Towards self-explaining social robots. Verbal explanation strategies for a needs-based architecture
(2019)
In order to establish long-term relationships with users, social companion robots and their behaviors need to be comprehensible. Purely reactive behavior such as answering questions or following commands can be readily interpreted by users. However, the robot's proactive behaviors, included in order to increase liveliness and improve the user experience, often raise a need for explanation. In this paper, we provide a concept to produce accessible “why-explanations” for the goal-directed behavior an autonomous, lively robot might produce. To this end we present an architecture that provides reasons for behaviors in terms of comprehensible needs and strategies of the robot, and we propose a model for generating different kinds of explanations.
Plant sap-feeding insects are widespread, having evolved to occupy diverse environmental niches despite exclusive feeding on an impoverished diet lacking in essential amino acids and vitamins. Success depends exquisitely on their symbiotic relationships with microbial symbionts housed within specialized eukaryotic bacteriocyte cells. Each bacteriocyte is packed with symbionts that are individually surrounded by a host-derived symbiosomal membrane representing the absolute host-symbiont interface. The symbiosomal membrane must be a dynamic and selectively permeable structure to enable bidirectional and differential movement of essential nutrients, metabolites, and biosynthetic intermediates, vital for growth and survival of host and symbiont. However, despite this crucial role, the molecular basis of membrane transport across the symbiosomal membrane remains unresolved in all bacteriocyte-containing insects. A transport protein was immuno-localized to the symbiosomal membrane separating the pea aphid Acyrthosiphon pisum from its intracellular symbiont Buchnera aphidicola. The transporter, A. pisum nonessential amino acid transporter 1, or ApNEAAT1 (gene: ACYPI008971), was characterized functionally following heterologous expression in Xenopus oocytes, and mediates both inward and outward transport of small dipolar amino acids (serine, proline, cysteine, alanine, glycine). Electroneutral ApNEAAT1 transport is driven by amino acid concentration gradients and is not coupled to transmembrane ion gradients. Previous metabolite profiling of hemolymph and bacteriocyte, alongside metabolic pathway analysis in host and symbiont, enable prediction of a physiological role for ApNEAAT1 in bidirectional host-symbiont amino acid transfer, supplying both host and symbiont with indispensable nutrients and biosynthetic precursors to facilitate metabolic complementarity.
The limited sodium availability of freshwater and terrestrial environments was a major physiological challenge during vertebrate evolution. The epithelial sodium channel (ENaC) is present in the apical membrane of sodium-absorbing vertebrate epithelia and evolved as part of a machinery for efficient sodium conservation. ENaC belongs to the degenerin/ENaC protein family and is the only member that opens without an external stimulus. We hypothesized that ENaC evolved from a proton-activated sodium channel present in ionocytes of freshwater vertebrates and therefore investigated whether such ancestral traits are present in ENaC isoforms of the aquatic pipid frog Xenopus laevis. Using whole-cell and single-channel electrophysiology of Xenopus oocytes expressing ENaC isoforms assembled from alpha beta gamma- or delta beta gamma-subunit combinations, we demonstrate that Xenopus delta beta gamma-ENaC is profoundly activated by extracellular acidification within biologically relevant ranges (pH 8.0-6.0). This effect was not observed in Xenopus alpha beta gamma-ENaC or human ENaC orthologs. We show that protons interfere with allosteric ENaC inhibition by extracellular sodium ions, thereby increasing the probability of channel opening. Using homology modeling of ENaC structure and site-directed mutagenesis, we identified a cleft region within the extracellular loop of the delta-subunit that contains several acidic amino acid residues that confer proton-sensitivity and enable allosteric inhibition by extracellular sodium ions. We propose that Xenopus delta beta gamma-ENaC can serve as a model for investigating ENaC transformation from a proton-activated toward a constitutively-active ion channel. Such transformation might have occurred during the evolution of tetrapod vertebrates to enable bulk sodium absorption during the water-to-land transition.
For protection from inhaled pathogens many strategies have evolved in the airways such as mucociliary clearance and cough. We have previously shown that protective respiratory reflexes to locally released bacterial bitter taste substances are most probably initiated by tracheal brush cells (BC). Our single-cell RNA-seq analysis of murine BC revealed high expression levels of cholinergic and bitter taste signaling transcripts (Tas2r108, Gnat3, Trpm5). We directly demonstrate the secretion of acetylcholine (ACh) from BC upon stimulation with the Tas2R agonist denatonium. Inhibition of the taste transduction cascade abolished the increase in [Ca2+](i) in BC and subsequent ACh-release. ACh-release is regulated in an autocrine manner. While the muscarinic ACh-receptors M3R and M1R are activating, M2R is inhibitory. Paracrine effects of ACh released in response to denatonium included increased [Ca2+](i) in ciliated cells. Stimulation by denatonium or with Pseudomonas quinolone signaling molecules led to an increase in mucociliary clearance in explanted tracheae that was Trpm5- and M3R-mediated. We show that ACh-release from BC via the bitter taste cascade leads to immediate paracrine protective responses that can be boosted in an autocrine manner. This mechanism represents the initial step for the activation of innate immune responses against pathogens in the airways.
This article examines similarities and differences in the attitudes and social representations of destination managers towards implementing sustainable tourism between the mountain regions of the Alps and the Dinarides. Bearing in mind the transnational impacts (i.e., environmental, economic and social) of the tourism industry the research methodology adopted an international perspective by sending a questionnaire to tourism organizations in fourteen different countries in the Alps and the Dinarides. The research is interdisciplinary in nature, because it integrates knowledge from sustainability and management science with tourism geography and social psychology. The findings confirm that social representations of sustainable tourism differ significantly in the two mountain regions.
The media is considered to be the fourth pillar in a democratic country. It acts as an effective control mechanism to check the other branches of the government. But this is only consequential when the media functions in an independent and transparent fashion with trained and neutral professionals who are aware of the accountability and consequences of their work. All these factors together would further the country as a democratic institution. Traditionally, it was legacy media responsible for a one-to-many communication process. Their goal was to provide information to the citizens. But this changed with development in technology and the use of social media in daily life. The internet brought with it new media formats which are easily accessible but also unstructured. These lowered barriers of entry in the media enabled citizens to become active participants in the communication process. As a result, these citizens developed a different relationship with the already existing media wherein they were not only the receivers to information but also co-producers. Real-time information allows users to communicate with each other and in turn widely generate public opinion on internet platforms. A many-to-many communication style emerged. While on the one hand, this type of discourse could be an opportunity for citizens to exercise their fundamental freedom of speech and expression, it is on the other hand, proving to have a detrimental effect in two parts: Lack of neutrality, polarized views and pre-existing misconceptions on the part of citizens as well as algorithms and formation of echo-chambers on the part of technology. Some questions arise in this scenario about the capability of citizen journalists, the duties they should adhere to along with the enjoyment of their rights and freedoms, the risks involved in an unchecked method of communication and the effect of citizen journalism in the democratic process.
Background & Objective: Due to the policy goals for sustainable energy production, renewable energy plants such as photovoltaics are increasingly in use. The energy production from solar radiation depends strongly on atmospheric conditions. As the weather mostly changes, electrical power generation fluctuates, making technical planning and control of power grids to a complex problem. Due to used materials (semiconductors e.g. silicon, gallium arsenide, cadmium telluride) the photovoltaic cells are spectrally selective. It means that only radiation of certain wavelengths converts into electrical energy. A material property called spectral response characterizes a certain degree of conversion of solar radiation into the electric current for each wavelength of solar light.
We present a systematization of usable security principles, guidelines and patterns to facilitate the transfer of existing knowledge to researchers and practitioners. Based on a literature review, we extracted 23 principles, 11 guidelines and 47 patterns for usable security and identified their interconnection. The results indicate that current research tends to focus on only a subset of important principles. The fact that some principles are not yet addressed by any design patterns suggests that further work on refining these patterns is needed. We developed an online repository, which stores the harmonized principles, guidelines and patterns. The tool enables users to search for relevant guidance and explore it in an interactive and programmatic manner. We argue that both the insights presented in this article and the web-based repository will be highly valuable for students to get a good overview, practitioners to implement usable security and researchers to identify areas of future research.