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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.
Contemporary software is inherently distributed. The principles guiding the design of such software have been mainly manifested by the service-oriented architecture (SOA) concept. In a SOA, applications are orchestrated by software services generally operated by distinct entities. Due to the latter fact, service security has been of importance in such systems ever since. A dominant protocol for implementing SOA-based systems is SOAP, which comes with a well-elaborated security framework. As an alternative to SOAP, the architectural style representational state transfer (REST) is gaining traction as a simple, lightweight and flexible guideline for designing distributed service systems that scale at large. This paper starts by introducing the basic constraints representing REST. Based on these foundations, the focus is afterwards drawn on the security needs of REST-based service systems. The limitations of transport-oriented protection means are emphasized and the demand for specific message-oriented safeguards is assessed. The paper then reviews the current activities in respect to REST-security and finds that the available schemes are mostly HTTP-centered and very heterogeneous. More importantly, all of the analyzed schemes contain vulnerabilities. The paper contributes a methodology on how to establish REST-security as a general security framework for protecting REST-based service systems of any kind by consistent and comprehensive protection means. First adoptions of the introduced approach are presented in relation to REST message authentication with instantiations for REST-ful HTTP (web/cloud services) and REST-ful constraint application protocol (CoAP) (internet of things (IoT) services).
Energy Profiles of the Ring Puckering of Cyclopentane, Methylcyclopentane and Ethylcyclopentane
(2019)
Beyond HCI and CSCW: Challenges and Useful Practices Towards a Human-Centred Vision of AI and IA
(2019)
Incoming solar radiation is an important driver of our climate and weather. Several studies (see for instance Frank et al. 2018) have revealed discrepancies between ground-based irradiance measurements and the predictions of regional weather models. In the realm of electricity generation, accurate forecasts of solar photovoltaic (PV)energy yield are becoming indispensable for cost-effective grid operation: in Germany there are 1.6 million PVsystems installed, with a nominal power of 46 GW (Bundesverband Solarwirtschaft 2019). The proliferation of PV systems provides a unique opportunity to characterise global irradiance with unprecedented spatiotemporalresolution, which in turn will allow for highly resolved PV power forecasts.
Renewable energies play an increasingly important role for energy production in Europe. Unlike coal or gas powerplants, solar energy production is highly variable in space and time. This is due to the strong variability of cloudsand their influence on the surface solar irradiance. Especially in regions with large contribution from photovoltaicpower production, the intermittent energy feed-in to the power grid can be a risk for grid stability. Therefore goodforecasts of temporal and spatial variability of surface irradiance are necessary to be able to properly regulate thepower supply.
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.
Emotion and gender recognition from facial features are important properties of human empathy. Robots should also have these capabilities. For this purpose we have designed special convolutional modules that allow a model to recognize emotions and gender with a considerable lower number of parameters, enabling real-time evaluation on a constrained platform. We report accuracies of 96% in the IMDB gender dataset and 66% in the FER-2013 emotion dataset, while requiring a computation time of less than 0.008 seconds on a Core i7 CPU. All our code, demos and pre-trained architectures have been released under an open-source license in our repository at https://github.com/oarriaga/face classification.
Risk-based authentication (RBA) is an adaptive security measure to strengthen password-based authentication. RBA monitors additional implicit features during password entry such as device or geolocation information, and requests additional authentication factors if a certain risk level is detected. RBA is recommended by the NIST digital identity guidelines, is used by several large online services, and offers protection against security risks such as password database leaks, credential stuffing, insecure passwords and large-scale guessing attacks. Despite its relevance, the procedures used by RBA-instrumented online services are currently not disclosed. Consequently, there is little scientific research about RBA, slowing down progress and deeper understanding, making it harder for end users to understand the security provided by the services they use and trust, and hindering the widespread adoption of RBA.
In this paper, with a series of studies on eight popular online services, we (i) analyze which features and combinations/classifiers are used and are useful in practical instances, (ii) develop a framework and a methodology to measure RBA in the wild, and (iii) survey and discuss the differences in the user interface for RBA. Following this, our work provides a first deeper understanding of practical RBA deployments and helps fostering further research in this direction.
The need for innovation around the control functions of inverters is great. PV inverters were initially expected to be passive followers of the grid and to disconnect as soon as abnormal conditions happened. Since future power systems will be dominated by generation and storage resources interfaced through inverters these converters must move from following to forming and sustaining the grid. As “digital natives” PV inverters can also play an important role in the digitalisation of distribution networks. In this short review we identified a large potential to make the PV inverter the smart local hub in a distributed energy system. At the micro level, costs and coordination can be improved with bidirectional inverters between the AC grid and PV production, stationary storage, car chargers and DC loads. At the macro level the distributed nature of PV generation means that the same devices will support both to the local distribution network and to the global stability of the grid. Much success has been obtained in the former. The later remains a challenge, in particular in terms of scaling. Yet there is some urgency in researching and demonstrating such solutions. And while digitalisation offers promise in all control aspects it also raises significant cybersecurity concerns.
This work introduces a semi-Lagrangian lattice Boltzmann (SLLBM) solver for compressible flows (with or without discontinuities). It makes use of a cell-wise representation of the simulation domain and utilizes interpolation polynomials up to fourth order to conduct the streaming step. The SLLBM solver allows for an independent time step size due to the absence of a time integrator and for the use of unusual velocity sets, like a D2Q25, which is constructed by the roots of the fifth-order Hermite polynomial. The properties of the proposed model are shown in diverse example simulations of a Sod shock tube, a two-dimensional Riemann problem and a shock-vortex interaction. It is shown that the cell-based interpolation and the use of Gauss-Lobatto-Chebyshev support points allow for spatially high-order solutions and minimize the mass loss caused by the interpolation. Transformed grids in the shock-vortex interaction show the general applicability to non-uniform grids.