Multiversioning hardware transactional memory for fail-operational multithreaded applications

Modern safety-critical embedded applications like autonomous driving need to be fail-operational, while high performance and low power consumption are demanded simultaneously. The prevalent fault tolerance mechanisms suffer from disadvantages: Some (e.g. triple modular redundancy) require a substantial amount of duplication, resulting in high hardware costs and power consumption. Others, like lockstep, require supplementary checkpointing mechanisms to recover from errors. Further approaches (e.g. software-based process-level redundancy) cannot handle the indeterminism caused by multithreaded execution. This paper presents a novel approach for fail-operational systems using hardware transactional memory for embedded systems. The hardware transactional memory is extended to support multiple versions, enabling redundant atomic operations and recovery in case of an error. In our FPGA-based evaluation, we executed the PARSEC benchmark suite with fault tolerance on 12 cores. The evaluation shows that multiversioning can successfully recover from all transient errors with an overhead comparable to fault tolerance mechanisms without recovery

P3-[2-(4-hydroxyphenyl)-2-oxo]ethyl ATP for the Rapid Activation of the Na+,K+-ATPase

This is the published version, also available here: http://dx.doi.org/10.1016/S0006-3495(00)76387-9.P3-[2-(4-hydroxyphenyl)-2-oxo]ethyl ATP (pHP-caged ATP) has been investigated for its application as a phototrigger for the rapid activation of electrogenic ion pumps. The yield of ATP after irradiation with a XeCl excimer laser (λ = 308 nm) was determined at pH 6.0–7.5. For comparison, the photolytic yields of P3-[1-(2-nitrophenyl)]ethyl ATP (NPE-caged ATP) and P3-[1,2-diphenyl-2-oxo]ethyl ATP (desyl-caged ATP) were also measured. It was shown that at λ = 308 nm pHP-caged ATP is superior to the other caged ATP derivatives investigated in terms of yield of ATP after irradiation. Using time-resolved single-wavelength IR spectroscopy, we determined a lower limit of 106 s−1 for the rate constant of release of ATP from pHP-caged ATP at pH 7.0. Like NPE-caged ATP, pHP-caged ATP and desyl-caged ATP bind to the Na+,K+-ATPase and act as competitive inhibitors of ATPase function. Using pHP-caged ATP, we investigated the charge translocation kinetics of the Na+,K+-ATPase at pH 6.2–7.4. The kinetic parameters obtained from the electrical measurements are compared to those obtained with a technique that does not require caged ATP, namely parallel stopped-flow experiments using the voltage-sensitive dye RH421. It is shown that the two techniques yield identical results, provided the inhibitory properties of the caged compound are taken into account. Our results demonstrate that under physiological (pH 7.0) and slightly basic (pH 7.5) or acidic (pH 6.0) conditions, pHP-caged ATP is a rapid, effective, and biocompatible phototrigger for ATP-driven biological systems

Human neutrophil clearance of bacterial pathogens triggers anti-microbial gamma delta T cell responses in early infection

Human blood Vc9/Vd2 T cells, monocytes and neutrophils share a responsiveness toward inflammatory chemokines and are rapidly recruited to sites of infection. Studying their interaction in vitro and relating these findings to in vivo observations in patients may therefore provide crucial insight into inflammatory events. Our present data demonstrate that Vc9/Vd2 T cells provide potent survival signals resulting in neutrophil activation and the release of the neutrophil chemoattractant CXCL8 (IL-8). In turn, Vc9/Vd2 T cells readily respond to neutrophils harboring phagocytosed bacteria, as evidenced by expression of CD69, interferon (IFN)-c and tumor necrosis factor (TNF)-a. This response is dependent on the ability of these bacteria to produce the microbial metabolite (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMB-PP), requires cell-cell contact of Vc9/Vd2 T cells with accessory monocytes through lymphocyte function-associated antigen-1 (LFA-1), and results in a TNF-a dependent proliferation of Vc9/Vd2 T cells. The antibiotic fosmidomycin, which targets the HMB-PP biosynthesis pathway, not only has a direct antibacterial effect on most HMB-PP producing bacteria but also possesses rapid anti-inflammatory properties by inhibiting cd T cell responses in vitro. Patients with acute peritoneal-dialysis (PD)-associated bacterial peritonitis – characterized by an excessive influx of neutrophils and monocytes into the peritoneal cavity – show a selective activation of local Vc9/Vd2 T cells by HMB-PP producing but not by HMB-PP deficient bacterial pathogens. The cd T celldriven perpetuation of inflammatory responses during acute peritonitis is associated with elevated peritoneal levels of cd T cells and TNF-a and detrimental clinical outcomes in infections caused by HMB-PP positive microorganisms. Taken together, our findings indicate a direct link between invading pathogens, neutrophils, monocytes and microbe-responsive cd T cells in early infection and suggest novel diagnostic and therapeutic approaches.Martin S. Davey, Chan-Yu Lin, Gareth W. Roberts, Sinéad Heuston, Amanda C. Brown, James A. Chess, Mark A. Toleman, Cormac G.M. Gahan, Colin Hill, Tanya Parish, John D. Williams, Simon J. Davies, David W. Johnson, Nicholas Topley, Bernhard Moser and Matthias Eber

Nitro drugs for the treatment of trypanosomatid diseases:past, present, and future prospects

There is an urgent need for new, safer, and effective treatments for the diseases caused by the protozoan parasites Trypanosoma brucei, Trypanosoma cruzi, and Leishmania spp. In the search for more effective drugs to treat these ‘neglected diseases’ researchers have chosen to reassess the therapeutic value of nitroaromatic compounds. Previously avoided in drug discovery programs owing to potential toxicity issues, a nitro drug is now being used successfully as part of a combination therapy for human African trypanosomiasis. We describe here the rehabilitation of nitro drugs for the treatment of trypanosomatid diseases and discuss the future prospects for this compound class

Palladium- and base-free synthesis of conjugated ynones by cross-coupling reactions of alkynylboronates with acid chlorides mediated by CuCl

Alkynylboronates can be employed as a practical and versatile precursor for a variety of pi-conjugated organic compounds. In the presence of Cu(I) salt, cross-coupling reactions of acid chlorides with alkynylboronates giving rise to the corresponding conjugated ynones takes place readily in aprotic polar solvents such as DMI under neutral conditions

Restricting Glycolysis Preserves T Cell Effector Functions and Augments Checkpoint Therapy

Tumor-derived lactic acid inhibits T and natural killer (NK) cell function and, thereby, tumor immunosurveillance. Here, we report that melanoma patients with high expression of glycolysis-related genes show a worse progression free survival upon anti-PD1 treatment. The non-steroidal anti-inflammatory drug (NSAID) diclofenac lowers lactate secretion of tumor cells and improves anti-PD1-induced T cell killing in vitro. Surprisingly, diclofenac, but not other NSAIDs, turns out to be a potent inhibitor of the lactate transporters monocarboxylate transporter 1 and 4 and diminishes lactate efflux. Notably, T cell activation, viability, and effector functions are preserved under diclofenac treatment and in a low glucose environment in vitro. Diclofenac, but not aspirin, delays tumor growth and improves the efficacy of checkpoint therapy in vivo. Moreover, genetic suppression of glycolysis in tumor cells strongly improves checkpoint therapy. These findings support the rationale for targeting glycolysis in patients with high glycolytic tumors together with checkpoint inhibitors in clinical trials

Loosely-coupled fail-operational execution on embedded heterogeneous multi-cores

Modern safety-critical embedded applications like autonomous driving need to be fail-operational, since failure can endanger human lives. At the same time, high performance and low power consumption are demanded. A common way to achieve this is the use of heterogeneous multi-cores. However, prevalent fault tolerance mechanisms do not benefit from the heterogeneity and suffer from further disadvantages: Some (e.g. dual modular lockstep) require supplementary checkpointing mechanisms to recover from errors. Others (e.g. triple modular redundancy) require a substantial amount of duplication, resulting in high hardware costs and high power consumption. Further approaches (e.g. software-based process-level redundancy) cannot handle the indeterminism introduced by multi-threaded execution. To overcome these issues, this thesis presents a novel approach to fault tolerance utilizing hardware transactional memory. Each thread is automatically split into transactions, which execute redundantly on two cores. These transactions can complete at different times due to loose coupling. The trailing cores are accelerated by forwarding information from the leading cores, which makes the approach well suited for heterogeneous systems. Recovery utilizes the preexisting rollback capability of the transactional memory, which reduces the overhead in terms of chip area and performance. The transactional memory is extended to support multiple versions of each memory word, which are used to guarantee identical outcomes in the presence of different execution schedules on leading and trailing cores. These versions also enable the simultaneous rollback of multiple cores to a consistent state if an error occurs. Use of the transactional memory for synchronization is still possible, which enables the execution of shared memory multi-threaded applications. The single-threaded variant was evaluated in a simulator and the multi-threaded variant was evaluated on an FPGA. The single-threaded evaluation demonstrates that the approach runs faster than a lockstep configuration of energy-efficient cores, while consuming less energy than a lockstep configuration of fast cores. The multi-threaded approach exhibits an error detection latency that is low enough for most embedded systems and its fault injection analysis shows that it can successfully correct all errors.Moderne sicherheitskritische Anwendungsbereiche für eingebettete Systeme wie autonomes Fahren benötigen Fehlertoleranz, da ein Ausfall Menschenleben gefährden kann. Gleichzeitig wird eine hohe Rechenleistung bei geringem Stromverbrauch gefordert. Ein übliches Verfahren, um dies zu erreichen, ist der Einsatz von heterogenen Multicores. Gängige Fehlertoleranzmechanismen profitieren jedoch nicht von der Heterogenität und leiden unter weiteren Nachteilen: Einige (z. B. Dual Modular Lockstep) benötigen zusätzliches Checkpointing, um Fehler zu beheben. Andere (z. B. Triple Modular Redundancy) haben einen hohen Ressourcenbedarf, was zu hohen Hardwarekosten und einem hohen Stromverbrauch führt. Weitere Ansätze (z. B. softwarebasierte Redundanz auf Prozessebene) können nicht mit dem Indeterminismus umgehen, der durch parallele Ausführung entsteht. Zur Lösung dieser Probleme stellt diese Dissertation einen neuartigen Ansatz zur fehlertoleranten Ausführung mit Hardware-Transaktionsspeicher vor. Jeder Thread wird automatisch in Transaktionen aufgeteilt, die redundant auf zwei Kernen ausgeführt werden. Diese Transaktionen können aufgrund ihrer losen Kopplung zu unterschiedlichen Zeiten abgeschlossen werden. Die nachlaufenden Kerne werden durch die Weiterleitung von Informationen der vorauslaufenden Kerne beschleunigt, wodurch sich der Ansatz gut für heterogene Systeme eignet. Die bereits vorhandene Rückrollfähigkeit des Transaktionsspeichers wird zur Fehlerbeseitigung benutzt, wodurch der Overhead an Chipfläche und Leistung verringert wird. Der Transaktionsspeicher wird erweitert, um für jedes Speicherwort mehrere Versionen bereitzustellen, welche verwendet werden, um identische Ergebnisse bei unterschiedlicher Ausführungsreihenfolge auf vorauslaufenden und nachfolgenden Kernen zu garantieren. Diese Versionen erlauben auch das gleichzeitige Zurücksetzen mehrerer Kerne in einen konsistenten Zustand, wenn ein Fehler auftritt. Eine Nutzung des Transaktionsspeichers zur Synchronisation ist weiterhin möglich, was die Ausführung von parallelen Anwendungen mit gemeinsam genutztem Speicher ermöglicht. Der Ansatz für sequenzielle Anwendungen wurde in einem Simulator und der Ansatz für parallele Anwendungen auf einem FPGA evaluiert. Die Auswertung im Simulator zeigt, dass der Ansatz schneller als eine Lockstep-Konfiguration aus energieeffizienten Kernen läuft und dabei weniger Energie verbraucht als eine Lockstep-Konfiguration aus schnellen Kernen. Die FPGA-Implementierung weist eine Fehlererkennungslatenz auf, die gering genug für die meisten eingebetteten Systeme ist, und die Fehlerinjektionsanalyse zeigt, dass alle Fehler erfolgreich korrigiert werden können

Computerbasierte Messwerterfassung fuer die cyclovoltammetrische Untersuchung von Organometallverbindungen und technischen Elektrodenmaterialien

Available from TIB Hannover: DW 2610 / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEDEGerman

Auf dem Weg zu einer digitalen Edition der Notizen von Max Frisch

Tobias Amslinger liefert einen Werkstattbericht aus dem Max Frisch Archiv (ETH Zürich), das etwa 130 kleine Notizhefte aus den Jahren 1943 bis 1952 verwahrt. Im Rahmen einer digitalen Edition wird das umfangreiche werkgenetische, biographische und zeitgeschichtliche Quellenmaterial einerseits systematisch erschlossen, andererseits kann es als integraler Bestandteil von Frischs Werk angesehen werden. Ein neuer Werkkomplex tut sich auf: „Schreiben als Entwurf“. Toward a digital edition of Max Frisch’s notes: The Max Frisch Archiv (ETH Zurich) contains approximately 130 small notebooks that Max Frisch used between 1943 and 1952. In the context of a digital edition, this extensive work genetic, biographical and historical source material is made accessible in a systematic manner one the one hand, on the other hand, we may regard it as an integral part of Frisch’s oeuvre. A new work complex appears: “writing as draft”, as Tobias Amslinger illustrates in his work in progress report