Analyzable dataflow executions with adaptive redundancy

Increasing performance requirements in the embedded systems domain have encouraged a drift from singlecore to multicore processors, and thus multicore processors are widely used in embedded systems today. Cars are an example for complex embedded systems in which the use of multicore processors is continuously increasing. A major reason for this is to consolidate different software components on one chip and thus reduce the number of electronic control units. However, the de facto standard in the automotive industry, AUTOSAR (AUTomotive Open System ARchitecture), was originally designed for singlecore processors. Although basic support for multicore processors was added, more complex architectures are currently not compatible with the software stack. Regarding the software components running on the ECUS of modern cars, requirements are diverse. On the one hand, there are safety-critical tasks, like the airbag control, anti-lock braking system, electronic stability control and emergency brake assist, and on the other hand, tasks which do not have any safety-related requirements at all, for example tasks controlling the infotainment system. Trends like autonomous driving lead to even more demanding tasks in the system since such tasks are both safety-critical and data-intensive. As embedded applications, like those in the automotive domain, become more complex, new approaches are necessary. Data-intensive tasks are usually tackled with large-scale computing frameworks. In this thesis, some major concepts of such frameworks are transferred to the high-performance embedded systems domain. For this purpose, the thesis describes a runtime environment (RTE) that is suitable for different kinds of multi- and manycore hardware architectures. The RTE follows a dataflow execution model based on directed acyclic graphs (DAGs). Graphs are divided into sections which are scheduled separately. For each section, the RTE uses a DAG scheduling heuristic to compute multiple schedules covering different redundancy configurations. This allows the RTE to dynamically change the redundancy of parts of the graph at runtime despite the use of fixed schedules. Alternatively, the RTE also provides an online scheduler. To specify suitable graphs, the RTE also provides a programming model which shares similarities with common large-scale computing frameworks, for example Apache Spark. Using this programming model, three common distributed algorithms, namely Cannon's algorithm, the Cooley-Tukey algorithm and bitonic sort, were implemented. With these three programs, the performance of the RTE was evaluated for a variety of configurations on two different hardware architectures. The results show that the proposed RTE is able to reach the performance of established parallel computation frameworks and that for suitable graphs with reasonable sectionings the negative influence on the runtime is either small or non-existent.Aufgrund steigender Anforderungen an die Leistungsfähigkeit von eingebetteten Systemen finden Mehrkernprozessoren mittlerweile auch in eingebetteten Systemen Verwendung. Autos sind ein Beispiel für eingebettete Systeme, in denen die Verbreitung von Mehrkernprozessoren kontinuierlich zunimmt. Ein Hauptgrund ist, dass es dadurch möglich wird, mehrere Applikationen, für die ursprünglich mehrere Electronic Control Units (ECUs) notwendig waren, auf ein und demselben Chip auszuführen und dadurch die Anzahl der ECUs im Gesamtsystem zu verringern. Der De-facto-Standard AUTOSAR (AUTomotive Open System ARchitecture) wurde jedoch ursprünglich nur im Hinblick auf Einkernprozessoren entworfen und, obwohl der Softwarestack um grundlegende Unterstützung für Mehrkernprozessoren erweitert wurde, sind komplexere Architekturen nicht damit kompatibel. Die Anforderungen der Softwarekomponenten von modernen Autos sind vielfältig. Einerseits gibt es hochgradig sicherheitskritische Tasks, die beispielsweise die Airbags, das Antiblockiersystem, die Fahrdynamikregelung oder den Notbremsassistenten steuern und andererseits Tasks, die keinerlei sicherheitskritische Anforderungen aufweisen, wie zum Beispiel Tasks zur Steuerung des Infotainment-Systems. Neue Trends wie autonomes Fahren führen zu weiteren anspruchsvollen Tasks, die sowohl hohe Leistungs- als auch Sicherheitsanforderungen aufweisen. Da die Komplexität eingebetteter Anwendungen, beispielsweise im Automobilbereich, stetig zunimmt, sind neue Ansätze erforderlich. Für komplexe, datenintensive Aufgaben werden in der Regel Cluster-Computing-Frameworks eingesetzt. In dieser Arbeit werden Konzepte solcher Frameworks auf den Bereich der eingebetteten Systeme übertragen. Dazu beschreibt die Arbeit eine Laufzeitumgebung (RTE) für eingebettete Mehrkernarchitekturen. Die RTE folgt einem Datenfluss-Ausführungsmodell, das auf gerichteten azyklischen Graphen basiert. Graphen können in Abschnitte eingeteilt werden, für welche separat mehrere unterschiedlich redundante Schedules mit Hilfe einer Scheduling-Heuristik berechnet werden. Dieser Ansatz erlaubt es, die Redundanz von Teilen der Anwendung zur Laufzeit zu verändern. Alternativ unterstützt die RTE auch Scheduling zur Laufzeit. Zur Erzeugung von Graphen stellt die RTE ein Programmiermodell bereit, welches sich an etablierten Frameworks, insbesondere Apache Spark, orientiert. Damit wurden drei Beispielanwendungen implementiert, die auf gängigen Algorithmen basieren. Konkret handelt es sich um Cannon's Algorithmus, den Cooley-Tukey-Algorithmus und bitonisches Sortieren. Um die Leistungsfähigkeit der RTE zu ermitteln, wurden diese drei Anwendungen mehrfach mit verschiedenen Konfigurationen auf zwei Hardware-Architekturen ausgeführt. Die Ergebnisse zeigen, dass die RTE in ihrer Leistungsfähigkeit mit etablierten Systemen vergleichbar ist und die Laufzeit bei einer sinnvollen Graphaufteilung im besten Fall nur geringfügig beeinflusst wird

Redundant dataflow applications on clustered manycore architectures

Increasing performance requirements in the embedded systems domain have encouraged a drift from singlecore to multicore processors. Cars are an example for complex embedded systems in which the use of multicores continues to grow. The requirements of software components running in modern cars are diverse. On the one hand there are safety-critical tasks like the airbag control, on the other hand tasks which do not have any safety-related requirements at all, for example those controlling the infotainment system. Trends like autonomous driving lead to tasks which are simultaneously safety-critical and computationally complex. To satisfy the requirements of modern embedded applications we developed a dataflow-based runtime environment (RTE) for clustered manycore architectures. The RTE is able to execute dataflow graphs in various redundancy configurations and with different schedulers. We implemented our RTE design on the Kalray Bostan Massively Parallel Processor Array and evaluated all possible configurations for three common computation tasks. To classify the performance of our RTE, we compared the non-redundant graph executions with OpenCL versions of the three applications. The results show that our RTE can come close or even surpass Kalray's OpenCL framework, although maximum performance was not the primary goal of our design

The fungal expel of 5-fluorocytosine derived fluoropyrimidines mitigates its antifungal activity and generates a cytotoxic environment

Invasive aspergillosis remains one of the most devastating fungal diseases and is predominantly linked to infections caused by the opportunistic human mold pathogen Aspergillus fumigatus. Major treatment regimens for the disease comprise the administration of antifungals belonging to the azole, polyene and echinocandin drug class. The prodrug 5-fluorocytosine (5FC), which is the only representative of a fourth class, the nucleobase analogs, shows unsatisfactory in vitro activities and is barely used for the treatment of aspergillosis. The main route of 5FC activation in A. fumigatus comprises its deamination into 5-fluorouracil (5FU) by FcyA, which is followed by Uprt-mediated 5FU phosphoribosylation into 5-fluorouridine monophosphate (5FUMP). In this study, we characterized and examined the role of a metabolic bypass that generates this nucleotide via 5-fluorouridine (5FUR) through uridine phosphorylase and uridine kinase activities. Resistance profiling of mutants lacking distinct pyrimidine salvage activities suggested a minor contribution of the alternative route in 5FUMP formation. We further analyzed the contribution of drug efflux in 5FC tolerance and found that A. fumigatus cells exposed to 5FC reduce intracellular fluoropyrimidine levels through their export into the environment. This release, which was particularly high in mutants lacking Uprt, generates a toxic environment for cytosine deaminase lacking mutants as well as mammalian cells. Employing the broad-spectrum fungal efflux pump inhibitor clorgyline, we demonstrate synergistic properties of this compound in combination with 5FC, 5FU as well as 5FUR.This research was funded by the Austrian Science Fund (FWF), grant P31093 to F.G. and M2867 to C.B. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.S

Genome-Wide siRNA Screen Identifies Complementary Signaling Pathways Involved in Listeria Infection and Reveals Different Actin Nucleation Mechanisms during Listeria Cell Invasion and Actin Comet Tail Formation

Listeria monocytogenes enters nonphagocytic cells by a receptor-mediated mechanism that is dependent on a clathrin-based molecular machinery and actin rearrangements. Bacterial intra- and intercellular movements are also actin dependent and rely on the actin nucleating Arp2/3 complex, which is activated by host-derived nucleation-promoting factors downstream of the cell receptor Met during entry and by the bacterial nucleation-promoting factor ActA during comet tail formation. By genome-wide small interfering RNA (siRNA) screening for host factors involved in bacterial infection, we identified diverse cellular signaling networks and protein complexes that support or limit these processes. In addition, we could precise previously described molecular pathways involved in Listeria invasion. In particular our results show that the requirements for actin nucleators during Listeria entry and actin comet tail formation are different. Knockdown of several actin nucleators, including SPIRE2, reduced bacterial invasion while not affecting the generation of comet tails. Most interestingly, we observed that in contrast to our expectations, not all of the seven subunits of the Arp2/3 complex are required for Listeria entry into cells or actin tail formation and that the subunit requirements for each of these processes differ, highlighting a previously unsuspected versatility in Arp2/3 complex composition and function. IMPORTANCE: Listeria is a bacterial pathogen that induces its internalization within the cytoplasm of human cells and has been used for decades as a major molecular tool to manipulate cells in order to explore and discover cellular functions. We have inactivated individually, for the first time in epithelial cells, all the genes of the human genome to investigate whether each gene modifies positively or negatively the Listeria infectious process. We identified novel signaling cascades that have never been associated with Listeria infection. We have also revisited the role of the molecular complex Arp2/3 involved in the polymerization of the actin cytoskeleton, which was shown previously to be required for Listeria entry and movement inside host cells, and we demonstrate that contrary to the general dogma, some subunits of the complex are dispensable for both Listeria entry and bacterial movement

Imaging InlC secretion to investigate cellular infection by the bacterial pathogen Listeria monocytogenes

Listeria monocytogenes is a Gram positive bacterial pathogen frequently used as a major model for the study of intracellular parasitism. Imaging late L. monocytogenes infection stages within the context of small-interfering RNA screens allows for the global study of cellular pathways required for bacterial infection of target host cells

Simultaneous analysis of large-scale RNAi screens for pathogen entry

Large-scale RNAi screening has become an important technology for identifying genes involved in biological processes of interest. However, the quality of large-scale RNAi screening is often deteriorated by off-targets effects. In order to find statistically significant effector genes for pathogen entry, we systematically analyzed entry pathways in human host cells for eight pathogens using image-based kinome-wide siRNA screens with siRNAs from three vendors. We propose a Parallel Mixed Model (PMM) approach that simultaneously analyzes several non-identical screens performed with the same RNAi libraries.; We show that PMM gains statistical power for hit detection due to parallel screening. PMM allows incorporating siRNA weights that can be assigned according to available information on RNAi quality. Moreover, PMM is able to estimate a sharedness score that can be used to focus follow-up efforts on generic or specific gene regulators. By fitting a PMM model to our data, we found several novel hit genes for most of the pathogens studied.; Our results show parallel RNAi screening can improve the results of individual screens. This is currently particularly interesting when large-scale parallel datasets are becoming more and more publicly available. Our comprehensive siRNA dataset provides a public, freely available resource for further statistical and biological analyses in the high-content, high-throughput siRNA screening field