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

Inflammatory bowel disease, colorectal cancer and type 2 diabetes mellitus: the links

Abstract The co-occurrence of the three disease entities, inflammatory bowel disease (IBD), colorectal cancer (CRC), type 2diabetes mellitus (T2DM) along with inflammation and dismicrobism has been frequently reported. Some authors have even suggested that dysbiosis could be the link through a molecular crosstalk of multiple inflammatory loops including TGFβ, NFKB, TNFα and ROS among others. This review focuses on the inflammatory process along with the role of microbiota in the pathophysiology of the three diseases. The etiology of IBD is multifactorial, and like CRC and T2DM, it is associated with a widespread and sustained GI inflammation and dismicrobism, whereby an array of proinflammatory mediators and other related biomolecules are up-regulated, both locally and systematically. Such a persistent or an inadequately resolved chronic inflammation may be a causative agent, in the presence other factors, leading to several pathologies such as IBD, CRC and T2DM. TGFβ plays a crucial role in pancreatic β cell malfunctioning as glucotoxicity stimulates its signaling cascade through smad 3, IL-6 and epithelial to mesenchymal transition. Such a cascade could lead to macrophages and other cells recruitment, inflammation, then IBD and CRC. NFkB is also another key regulator in the crosstalk among the pathways leading to the three disease entities. It plays a major role in linking inflammation to cancer development through its ability to up regulate several inflammatory and tumor promoting cytokines like: IL-6, IL-1 α and TNF α, as well as genes like BCL2 and BCLXL. It activates JAK/STAT signaling network via STAT3 transcription factors and promotes epithelial to mesenchymal transition. It also increases the risk for T2DM in obese people. In brief, NFKB is a matchmaker between inflammation, IBD, cancer and diabetes. In addition, TNFα plays a pivotal role in systemic inflammation. It is increased in the mucosa of IBD patients and has a central role in its pathogenesis. It also activates other signaling pathways like NFKB and MAPK leading to CRC. It is also overexpressed in the adipose tissues of obese patients thus linking it to T2DM, chronic inflammation and consequently CRC.On the other hand, increasing evidence suggests that dysbiosis plays a role in initiating, maintaining and determining the severity of IBD. Actually, among its functions, it modulates genotoxic metabolites which are able to induce CRC, a fact proven to be sustained by stool transfer from patients with CRC. Probiotics, however, may actively prevent CRC as well as IBD and results in a significant decrease in fasting glycemia in T2DM patients. In conclusion, IBD, CRC and T2DM are commonly occurring interrelated clinical problems

Solution Structure, Dynamics, and New Antifungal Aspects of the Cysteine-Rich Miniprotein PAFC

The genome of Penicillium chrysogenum Q176 contains a gene coding for the 88-amino-acid (aa)-long glycine- and cysteine-rich P. chrysogenum antifungal protein C (PAFC). After maturation, the secreted antifungal miniprotein (MP) comprises 64 aa and shares 80% aa identity with the bubble protein (BP) from Penicillium brevicompactum, which has a published X-ray structure. Our team expressed isotope (15N, 13C)-labeled, recombinant PAFC in high yields, which allowed us to determine the solution structure and molecular dynamics by nuclear magnetic resonance (NMR) experiments. The primary structure of PAFC is dominated by 14 glycines, and therefore, whether the four disulfide bonds can stabilize the fold is challenging. Indeed, unlike the few published solution structures of other antifungal MPs from filamentous ascomycetes, the NMR data indicate that PAFC has shorter secondary structure elements and lacks the typical β-barrel structure, though it has a positively charged cavity and a hydrophobic core around the disulfide bonds. Some parts within the two putative γ-core motifs exhibited enhanced dynamics according to a new disorder index presentation of 15N-NMR relaxation data. Furthermore, we also provided a more detailed insight into the antifungal spectrum of PAFC, with specific emphasis on fungal plant pathogens. Our results suggest that PAFC could be an effective candidate for the development of new antifungal strategies in agriculture

Septins and Bacterial Infection

Septins, a unique cytoskeletal component associated with cellular membranes, are increasingly recognized as having important roles in host defense against bacterial infection. A role for septins during invasion of Listeria monocytogenes into host cells was first proposed in 2002. Since then, work has shown that septins assemble in response to a wide variety of invasive bacterial pathogens, and septin assemblies can have different roles during the bacterial infection process. Here we review the interplay between septins and bacterial pathogens, highlighting septins as a structural determinant of host defense. We also discuss how investigation of septin assembly in response to bacterial infection can yield insight into basic cellular processes including phagocytosis, autophagy, and mitochondrial dynamics