651 research outputs found
Fault-Tolerance by Graceful Degradation for Car Platoons
The key advantage of autonomous car platoons are their short inter-vehicle distances that increase traffic flow and reduce fuel consumption. However, this is challenging for operational and functional safety. If a failure occurs, the affected vehicles cannot suddenly stop driving but instead should continue their operation with reduced performance until a safe state can be reached or, in the case of temporal failures, full functionality can be guaranteed again. To achieve this degradation, platoon members have to be able to compensate sensor and communication failures and have to adjust their inter-vehicle distances to ensure safety. In this work, we describe a systematic design of degradation cascades for sensor and communication failures in autonomous car platoons using the example of an autonomous model car. We describe our systematic design method, the resulting degradation modes, and formulate contracts for each degradation level. We model and test our resulting degradation controller in Simulink/Stateflow
Biological characterization, mechanistic investigation and structureâactivity relationships of chemically stable TLR2 antagonists
Tollâlike receptors (TLRs) build the first barrier in the innate immune response and therefore represent promising targets for the modulation of inflammatory processes. Recently, the pyrogallolâcontaining TLR2 antagonists CUâCPT22 and MMGâ11 were reported; however, their 1,2,3âtriphenol motif renders them highly susceptible to oxidation and excludes them from use in extended experiments under aerobic conditions. Therefore, we have developed a set of novel TLR2 antagonists (1 â9 ) based on the systematic variation of substructures, linker elements, and the hydrogenâbonding pattern of the pyrogallol precursors by using chemically robust building blocks. The novel series of chemically stable and synthetically accessible TLR2 antagonists (1 â9 ) was pharmacologically characterized, and the potential binding modes of the active compounds were evaluated structurally. Our results provide new insights into structureâactivity relationships and allow rationalization of structural binding characteristics. Moreover, they support the hypothesis that this class of TLR ligands bind solely to TLR2 and do not directly interact with TLR1 or TLR6 of the functional heterodimer. The most active compound from this series (6 ), is chemically stable, nontoxic, TLR2âselective, and shows a similar activity with regard to the pyrogallol starting points, thus indicating the variability of the hydrogen bonding pattern
A Synthesis of the Procedural and Declarative Styles of Interactive Theorem Proving
We propose a synthesis of the two proof styles of interactive theorem
proving: the procedural style (where proofs are scripts of commands, like in
Coq) and the declarative style (where proofs are texts in a controlled natural
language, like in Isabelle/Isar). Our approach combines the advantages of the
declarative style - the possibility to write formal proofs like normal
mathematical text - and the procedural style - strong automation and help with
shaping the proofs, including determining the statements of intermediate steps.
Our approach is new, and differs significantly from the ways in which the
procedural and declarative proof styles have been combined before in the
Isabelle, Ssreflect and Matita systems. Our approach is generic and can be
implemented on top of any procedural interactive theorem prover, regardless of
its architecture and logical foundations. To show the viability of our proposed
approach, we fully implemented it as a proof interface called miz3, on top of
the HOL Light interactive theorem prover. The declarative language that this
interface uses is a slight variant of the language of the Mizar system, and can
be used for any interactive theorem prover regardless of its logical
foundations. The miz3 interface allows easy access to the full set of tactics
and formal libraries of HOL Light, and as such has "industrial strength". Our
approach gives a way to automatically convert any procedural proof to a
declarative counterpart, where the converted proof is similar in size to the
original. As all declarative systems have essentially the same proof language,
this gives a straightforward way to port proofs between interactive theorem
provers
The selective PI3Kα inhibitor BYL719 as a novel therapeutic option for neuroendocrine tumors: Results from multiple cell line models
BACKGROUND/AIMS The therapeutic options for metastatic neuroendocrine tumors (NETs) are limited. As PI3K signaling is often activated in NETs, we have assessed the effects of selective PI3Kp110\textgreeka inhibition by the novel agent BYL719 on cell viability, colony formation, apoptosis, cell cycle, signaling pathways, differentiation and secretion in pancreatic (BON-1, QGP-1) and pulmonary (H727) NET cell lines. METHODS Cell viability was investigated by WST-1 assay, colony formation by clonogenic assay, apoptosis by caspase3/7 assay, the cell cycle by FACS, cell signaling by Western blot analysis, expression of chromogranin A and somatostatin receptors 1/2/5 by RT-qPCR, and chromogranin A secretion by ELISA. RESULTS BYL719 dose-dependently decreased cell viability and colony formation with the highest sensitivity in BON-1, followed by H727, and lowest sensitivity in QGP-1 cells. BYL719 induced apoptosis and G0/G1 cell cycle arrest associated with increased p27 expression. Western blots showed inhibition of PI3K downstream targets to a varying degree in the different cell lines, but IGF1R activation. The most sensitive BON-1 cells displayed a significant, and H727 cells a non-significant, GSK3 inhibition after BYL719 treatment, but these effects do not appear to be mediated through the IGF1R. In contrast, the most resistant QGP-1 cells showed no GSK3 inhibition, but a modest activation, which would partially counteract the other anti-proliferative effects. Accordingly, BYL719 enhanced neuroendocrine differentiation with the strongest effect in BON-1, followed by H727 cells indicated by induction of chromogranin A and somatostatin receptor 1/2 mRNA-synthesis, but not in QGP-1 cells. In BON-1 and QGP-1 cells, the BYL719/everolimus combination was synergistic through simultaneous AKT/mTORC1 inhibition, and significantly increased somatostatin receptor 2 transcription compared to each drug separately. CONCLUSION Our results suggest that the agent BYL719 could be a novel therapeutic approach to the treatment of NETs that may sensitize NET cells to somatostatin analogs, and that if there is resistance to its action this may be overcome by combination with everolimus
Dual Function of the NK Cell Receptor 2B4 (CD244) in the Regulation of HCV-Specific CD8+ T Cells
The outcome of viral infections is dependent on the function of CD8+ T cells
which are tightly regulated by costimulatory molecules. The NK cell receptor 2B4
(CD244) is a transmembrane protein belonging to the Ig superfamily which can
also be expressed by CD8+ T cells. The aim of this study was to analyze the
role of 2B4 as an additional costimulatory receptor regulating CD8+ T cell
function and in particular to investigate its implication for exhaustion of
hepatitis C virus (HCV)-specific CD8+ T cells during persistent infection.
We demonstrate that (i) 2B4 is expressed on virus-specific CD8+ T cells
during acute and chronic hepatitis C, (ii) that 2B4 cross-linking can lead to
both inhibition and activation of HCV-specific CD8+ T cell function,
depending on expression levels of 2B4 and the intracellular adaptor molecule SAP
and (iii) that 2B4 stimulation may counteract enhanced proliferation of
HCV-specific CD8+ T cells induced by PD1 blockade. We suggest that 2B4 is
another important molecule within the network of costimulatory/inhibitory
receptors regulating CD8+ T cell function in acute and chronic hepatitis C
and that 2B4 expression levels could also be a marker of CD8+ T cell
dysfunction. Understanding in more detail how 2B4 exerts its differential
effects could have implications for the development of novel immunotherapies of
HCV infection aiming to achieve immune control
New fossils of Australopithecus sediba reveal a nearly complete lower back
Abstract: Adaptations of the lower back to bipedalism are frequently discussed but infrequently demonstrated in early fossil hominins. Newly discovered lumbar vertebrae contribute to a near-complete lower back of Malapa Hominin 2 (MH2), offering additional insights into posture and locomotion in Australopithecus sediba. We show that MH2 demonstrates a lower back consistent with human-like lumbar lordosis and other adaptations to bipedalism, including an increase in the width of intervertebral articular facets from the upper to lower lumbar column (âpyramidal configurationâ). This contrasts with recent work on lordosis in fossil hominins, where MH2 was argued to demonstrate no appreciable lordosis (âhypolordosisâ) similar to Neandertals. Our three-dimensional geometric morphometric (3D GM) analyses show that MH2âs nearly complete middle lumbar vertebra is human-like in shape but bears large, cranially-directed transverse processes, implying powerful trunk musculature. We interpret this combination of features to indicate that A. sediba used its lower back in both human-like bipedalism and ape-like arboreal positional behaviors, as previously suggested based on multiple lines of evidence from other parts of the skeleton and reconstructed paleobiology of A. sediba
Analog circuit simulation using range arithmetics
Abstract â The impact of parameter variations in integrated analog circuits is usually analyzed by Monte Carlo methods with a high number of simulation runs. Few approaches based on interval arithmetic were not successful due to tremendous overapproximations. In this paper, we describe an innovative approach com-puting transient and DC simulations of nonlinear ana-log circuits with symbolic range representations that keeps correlation information, and hence has a very limited overapproximation. The methods are based on affine and quadratic arithmetic. Ranges are rep-resented by unique symbols so that linear correlation information is preserved. We demonstrate feasibility of the methods by simulation results using complex analog circuits. I
Structural anomaly in the high-entropy alloy ZrNbTiTaHf
We present a high-resolution scanning transmission electron microscopy study on the microstructure of a non-equiatomic high-entropy alloy with the composition of Zr12.7 Nb30.8 Ti17.7 Ta30.8 Hf8.0 (at.%). We identify a novel inter-grain phase (IGP) that compositionally and structurally differs from the surrounding body-centred cubic host. In particular, we find that the IGP has a composition of Zr52.8 Nb6.9 Ti4.6 Ta20.6 Hf15.1 (at.%) and that it solidifies in a face-centred cubic crystal lattice structure. The occurrence of the latter is unexpected and remarkable since all possible binary phase diagrams of the involved elements only show body-centred cubic and hexagonal close-packed crystal structures. Therefore, to validate our experimental findings we have conducted parameter-free ab-initio calculations based on density-functional theory and the coherent-potential approximation. The simulations support our experimental findings showing that for the composition of the IGP, the face-centred cubic crystal structure is indeed the most stable one
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