The Roles of APC and Axin Derived from Experimental and Theoretical Analysis of the Wnt Pathway

Wnt signaling plays an important role in both oncogenesis and development. Activation of the Wnt pathway results in stabilization of the transcriptional coactivator β-catenin. Recent studies have demonstrated that axin, which coordinates β-catenin degradation, is itself degraded. Although the key molecules required for transducing a Wnt signal have been identified, a quantitative understanding of this pathway has been lacking. We have developed a mathematical model for the canonical Wnt pathway that describes the interactions among the core components: Wnt, Frizzled, Dishevelled, GSK3β, APC, axin, β-catenin, and TCF. Using a system of differential equations, the model incorporates the kinetics of protein–protein interactions, protein synthesis/degradation, and phosphorylation/dephosphorylation. We initially defined a reference state of kinetic, thermodynamic, and flux data from experiments using Xenopus extracts. Predictions based on the analysis of the reference state were used iteratively to develop a more refined model from which we analyzed the effects of prolonged and transient Wnt stimulation on β-catenin and axin turnover. We predict several unusual features of the Wnt pathway, some of which we tested experimentally. An insight from our model, which we confirmed experimentally, is that the two scaffold proteins axin and APC promote the formation of degradation complexes in very different ways. We can also explain the importance of axin degradation in amplifying and sharpening the Wnt signal, and we show that the dependence of axin degradation on APC is an essential part of an unappreciated regulatory loop that prevents the accumulation of β-catenin at decreased APC concentrations. By applying control analysis to our mathematical model, we demonstrate the modular design, sensitivity, and robustness of the Wnt pathway and derive an explicit expression for tumor suppression and oncogenicity

Characteristics of clinical-pharmacological recommendations in psychiatry.

OBJECTIVE Psychiatric patients in general, and elderly psychiatric patients in particular, are at risk of adverse drug reactions due to comorbidities and inappropriate polypharmacy. Interdisciplinary and clinical-pharmacologist-led medication reviews may contribute to medication safety in the field of psychiatry. In this study, we reported the frequency and characteristics of clinical-pharmacological recommendations in psychiatry, with a particular focus on geriatric psychiatry. METHOD A clinical pharmacologist, in collaboration with the attending psychiatrists and a consulting neurologist, conducted interdisciplinary medication reviews in a general psychiatric ward with a geropsychiatric focus at a university hospital over a 25-week period. All clinical and pharmacological recommendations were recorded and evaluated. RESULTS A total of 316 recommendations were made during 374 medication reviews. Indications/contraindications of drugs were the most frequently discussed topics (59/316; 18.7 %), followed by dose reductions (37/316; 11.7 %), and temporary or permanent discontinuation of medications (36/316; 11.4 %). The most frequent recommendations for dose reduction involvedbenzodiazepines (9/37; 24.3 %). An unclear or absent indication was the most common reason for recommending temporary or permanent discontinuation of the medication (6/36; 16.7 %). CONCLUSION Interdisciplinary clinical pharmacologist-led medication reviews represented a valuable contribution to medication management in psychiatric patients, particularly the elderly ones

Distributed System Contract Monitoring

The use of behavioural contracts, to specify, regulate and verify systems, is particularly relevant to runtime monitoring of distributed systems. System distribution poses major challenges to contract monitoring, from monitoring-induced information leaks to computation load balancing, communication overheads and fault-tolerance. We present mDPi, a location-aware process calculus, for reasoning about monitoring of distributed systems. We define a family of Labelled Transition Systems for this calculus, which allow formal reasoning about different monitoring strategies at different levels of abstractions. We also illustrate the expressivity of the calculus by showing how contracts in a simple contract language can be synthesised into different mDPi monitors.Comment: In Proceedings FLACOS 2011, arXiv:1109.239

Algorithm exploitation: humans are keen to exploit benevolent AI

We cooperate with other people despite the risk of being exploited or hurt. If future artificial intelligence (AI) systems are benevolent and cooperative toward us, what will we do in return? Here we show that our cooperative dispositions are weaker when we interact with AI. In nine experiments, humans interacted with either another human or an AI agent in four classic social dilemma economic games and a newly designed game of Reciprocity that we introduce here. Contrary to the hypothesis that people mistrust algorithms, participants trusted their AI partners to be as cooperative as humans. However, they did not return AI's benevolence as much and exploited the AI more than humans. These findings warn that future self-driving cars or co-working robots, whose success depends on humans' returning their cooperativeness, run the risk of being exploited. This vulnerability calls not just for smarter machines but also better human-centered policies

Натечные карбонатные новообразования набережной реки Туры: особенности строения и процессы формирования

International audienc

Building Information Modeling (BIM) für Bahn-Bauwerke: Von Datenakquisition bis Virtueller Realität

Die Digitalisierung im Bauwesen steht unter der großen Überschrift Building Information Modeling (BIM). Ziel ist es, Software-Unterstützung für den gesamten Lebenszyklus eines Bauwerks zu schaffen, beginnend bei der Planung über die Bauausführung bis hin zu Bewirtschaftung und Rückbau. Im Ergebnis sollen alle Prozesse effektiver und effizienter gestaltet werden, um die Produktivität der Bauwirtschaft signifikant zu erhöhen. Hierbei sind die verschiedenen Software-Lösungen so ausgelegt, dass ein übergreifendes virtuelles Gesamtmodell entsteht, welches die Gebäudefunktion zum Planungszeitpunkt simuliert und zu optimieren erlaubt, die interdisziplinäre Zusammenarbeit fördert und die Kommunikation zwischen allen Beteiligten erleichtert. Die vielleicht wichtigste und am deutlichsten sichtbare Rolle spielt dabei, neben der Standardisierung der Datenformate, die Umstellung von 2D- auf 3D-Geometriemodelle. In dieser Arbeit wird beschrieben, welche Herausforderungen und Chancen bezüglich BIM für die Planung von Bahn-Bauwerken bestehen. Der spezifische Fokus liegt auf der Anwendung von 3D-CAD- und 3D-Laserscan-Modellen der zu erstellenden Anlagen

Temperature and feeding induce tissue level changes in autotrophic and heterotrophic nutrient allocation in the coral symbiosis – A NanoSIMS study

Corals access inorganic seawater nutrients through their autotrophic endosymbiotic dinoflagellates, but also capture planktonic prey through heterotrophic feeding. Correlating NanoSIMS and TEM imaging, we visualized and quantified the subcellular fate of autotrophic and heterotrophic C and N in the coral Stylophora pistillata using stable isotopes. Six scenarios were compared after 6 h: autotrophic pulse (13C-bicarbonate, 15N-nitrate) in either unfed or regularly fed corals, and heterotrophic pulse (13C-, 15N-labelled brine shrimps) in regularly fed corals; each at ambient and elevated temperature. Host assimilation of photosynthates was similar under fed and unfed conditions, but symbionts assimilated 10% more C in fed corals. Photoautotrophic C was primarily channelled into host lipid bodies, whereas heterotrophic C and N were generally co-allocated to the tissue. Food-derived label was detected in some subcellular structures associated with the remobilisation of host lipid stores. While heterotrophic input generally exceeded autotrophic input, it was more negatively affected by elevated temperature. The reduced input from both modes of nutrition at elevated temperature was accompanied by a shift in the partitioning of C and N, benefiting epidermis and symbionts. This study provides a unique view into the nutrient partitioning in corals and highlights the tight connection of nutrient fluxes in symbiotic partners

Влияние исходного состава углеродных пресс - композиций на внутреннюю и внешнюю поверхность получаемых из них таблеток

Исследование влияния наличия в исходных для прессования углеродных смесях связующих веществ, их свойств и количества, на размеры внутренней и внешней поверхности получающихся из них таблеток.Investigation of the effect of the presence of binders in the initial compression mixtures of carbon mixtures, their properties and quantities, on the dimensions of the inner and outer surfaces of the tablets obtained from them

Extending the Knowledge Driven Approach for Scalable Autonomy Teleoperation of a Robotic Avatar

Crewed missions to celestial bodies such as Moon and Mars are in the focus of an increasing number of space agencies. Precautions to ensure a safe landing of the crew on the extraterrestrial surface, as well as reliable infrastructure on the remote location, for bringing the crew back home are key considerations for mission planning. The European Space Agency (ESA) identified in its Terrae Novae 2030+ roadmap, that robots are needed as precursors and scouts to ensure the success of such missions. An important role these robots will play, is the support of the astronaut crew in orbit to carry out scientific work, and ultimately ensuring nominal operation of the support infrastructure for astronauts on the surface. The METERON SUPVIS Justin ISS experiments demonstrated that supervised autonomy robot command can be used for executing inspection, maintenance and installation tasks using a robotic co-worker on the planetary surface. The knowledge driven approach utilized in the experiments only reached its limits when situations arise that were not anticipated by the mission design. In deep space scenarios, the astronauts must be able to overcome these limitations. An approach towards more direct command of a robot was demonstrated in the METERON ANALOG-1 ISS experiment. In this technical demonstration, an astronaut used haptic telepresence to command a robotic avatar on the surface to execute sampling tasks. In this work, we propose a system that combines supervised autonomy and telepresence by extending the knowledge driven approach. The knowledge management is based on organizing the prior knowledge of the robot in an object-centered context. Action Templates are used to define the knowledge on the handling of the objects on a symbolic and geometric level. This robot-agnostic system can be used for supervisory command of any robotic coworker. By integrating the robot itself as an object into the object-centered domain, robot-specific skills and (tele-)operation modes can be injected into the existing knowledge management system by formulating respective Action Templates. In order to efficiently use advanced teleoperation modes, such as haptic telepresence, a variety of input devices are integrated into the proposed system. This work shows how the integration of these devices is realized in a way that is agnostic to the input devices and operation modes. The proposed system is evaluated in the Surface Avatar ISS experiment. This work shows how the system is integrated into a Robot Command Terminal featuring a 3-Degree-of-Freedom Joystick and a 7-Degree-of-Freedom haptic input device in the Columbus module of the ISS. In the preliminary experiment sessions of Surface Avatar, two astronauts on orbit took command of the humanoid service robot Rollin' Justin in Germany. This work presents and discusses the results of these ISS-to-ground sessions and derives requirements for extending the scalable autonomy system for the use with a heterogeneous robotic team

Treating axial spondyloarthritis and peripheral spondyloarthritis, especially psoriatic arthritis, to target: 2017 update of recommendations by an international task force

Therapeutic targets have been defined for axial and peripheral spondyloarthritis (SpA) in 2012, but the evidence for these recommendations was only of indirect nature. These recommendations were re-evaluated in light of new insights. Based on the results of a systematic literature review and expert opinion, a task force of rheumatologists, dermatologists, patients and a health professional developed an update of the 2012 recommendations. These underwent intensive discussions, on site voting and subsequent anonymous electronic voting on levels of agreement with each item. A set of 5 overarching principles and 11 recommendations were developed and voted on. Some items were present in the previous recommendations, while others were significantly changed or newly formulated. The 2017 task force arrived at a single set of recommendations for axial and peripheral SpA, including psoriatic arthritis (PsA). The most exhaustive discussions related to whether PsA should be assessed using unidimensional composite scores for its different domains or multidimensional scores that comprise multiple domains. This question was not resolved and constitutes an important research agenda. There was broad agreement, now better supported by data than in 2012, that remission/inactive disease and, alternatively, low/minimal disease activity are the principal targets for the treatment of PsA. As instruments to assess the patients on the path to the target, the Ankylosing Spondylitis Disease Activity Score (ASDAS) for axial SpA and the Disease Activity index for PSoriatic Arthritis (DAPSA) and Minimal Disease Activity (MDA) for PsA were recommended, although not supported by all. Shared decision-making between the clinician and the patient was seen as pivotal to the process. The task force defined the treatment target for SpA as remission or low disease activity and developed a large research agenda to further advance the field