Self-healing concepts involving fine-grained redundancy for electronic systems

The start of the digital revolution came through the metal-oxide-semiconductor field-effect transistor (MOSFET) in 1959 followed by massive integration onto a silicon die by means of constant down scaling of individual components. Digital systems for certain applications require fault-tolerance against faults caused by temporary or permanent influence. The most widely used technique is triple module redundancy (TMR) in conjunction with a majority voter, which is regarded as a passive fault mitigation strategy. Design by functional resilience has been applied to circuit structures for increased fault-tolerance and towards self-diagnostic triggered self-healing. The focus of this thesis is therefore to develop new design strategies for fault detection and mitigation within transistor, gate and cell design levels. The research described in this thesis makes three contributions. The first contribution is based on adding fine-grained transistor level redundancy to logic gates in order to accomplish stuck-at fault-tolerance. The objective is to realise maximum fault-masking for a logic gate with minimal added redundant transistors. In the case of non-maskable stuck-at faults, the gate structure generates an intrinsic indication signal that is suitable for autonomous self-healing functions. As a result, logic circuitry utilising this design is now able to differentiate between gate faults and faults occurring in inter-gate connections. This distinction between fault-types can then be used for triggering selective self-healing responses. The second contribution is a logic matrix element which applies the three core redundancy concepts of spatial- temporal- and data-redundancy. This logic structure is composed of quad-modular redundant structures and is capable of selective fault-masking and localisation depending of fault-type at the cell level, which is referred to as a spatiotemporal quadded logic cell (QLC) structure. This QLC structure has the capability of cellular self-healing. Through the combination of fault-tolerant and masking logic features the QLC is designed with a fault-behaviour that is equal to existing quadded logic designs using only 33.3% of the equivalent transistor resources. The inherent self-diagnosing feature of QLC is capable of identifying individual faulty cells and can trigger self-healing features. The final contribution is focused on the conversion of finite state machines (FSM) into memory to achieve better state transition timing, minimal memory utilisation and fault protection compared to common FSM designs. A novel implementation based on content-addressable type memory (CAM) is used to achieve this. The FSM is further enhanced by creating the design out of logic gates of the first contribution by achieving stuck-at fault resilience. Applying cross-data parity checking, the FSM becomes equipped with single bit fault detection and correction

Zeitökonomie in der Qualitativen Sozialforschung - Möglichkeiten und Grenzen

"Hohe Fallzahlen gelten in der empirischen Sozialforschung nach wie vor als Garant allgemeingültiger Aussagen. Im Hinblick auf zeitökonomische Überlegungen erfolgt die Datenerhebung bei umfangreichen Stichproben vorwiegend mittels quantitativer Erhebungsinstrumente, die eine ebensolche Datenaufbereitung und -auswertung nach sich ziehen. Dem Einsatz qualitativer Erhebungs- und Auswertungsverfahren kommt in diesem Zusammenhang nur ein geringer Stellenwert zu. Die Einzelfallbezogenheit der qualitativen Sozialforschung sowie ein erheblicher Zeitaufwand und -intensität sind Argumente, die gegen den Einsatz qualitativer Methoden angeführt werden. Die Vorteile eines offenen Zugangs zum Forschungsgegenstand und die soziale Interaktion zwischen ForscherIn und Beforschten kommen bei dieser Argumentationsweise zu kurz. Für einen Forschungsbereich wie dem der Gerontopsychologie stellt sich die berechtigte Frage nach der geeigneten Forschungsmethodik, um von beeinträchtigten alten Menschen verwertbare Informationen zu erzielen. Wahl und Richter (1994) betonen, dass der Einsatz quantitativer Messinstrumente den alten Menschen inhaltlich und skalentechnisch überfordern können. Aus diesem Grund ist ein alternatives methodisches Vorgehen, wie es u. a. von Rowles und Reinharz (1988) oder Gubrium und Sankar (1994) propagiert wird, unerlässlich für eine gegenstandsangemessene Forschung. Eine Kombination bzw. Integration von qualitativen und quantitativen Forschungselementen wird erst ansatzweise diskutiert (Mayring & Jenull-Schiefer, 2005). Ziel der Studie „Aktivitäten in Senioren- und Pflegeheimen“ (Miklautz, 2004) war es, über einen qualitativen Zugang Aktivitätsmöglichkeiten und -gewohnheiten von institutionalisierten alten Menschen zu erheben. Der vorliegende Beitrag widmet sich jedoch weniger den inhaltlichen Ergebnissen der Studie, sondern reflektiert den Einsatz qualitativ orientierter Forschungsstrategien, die unter der Perspektive der Gegenstandsangemessenheit sowie der Zeitökonomie zum Einsatz gekommen sind. Deshalb wurde bei der Auswahl von Verfahren darauf geachtet, dass diese den jeweiligen Kompetenzen der alten Menschen begegnen konnten sowie eine Auswertung analog den Richtlinien der qualitativen Inhaltsanalyse erlaubten. Darüber hinaus war für die Studie interessant, inwieweit sich qualitative Sozialforschung zeitökonomisch betreiben lässt." (Autorenreferat

BRD9 is a druggable component of interferon-stimulated gene expression and antiviral activity

Interferon (IFN) induction of IFN-stimulated genes (ISGs) creates a formidable protective antiviral state. However, loss of appropriate control mechanisms can result in constitutive pathogenic ISG upregulation. Here, we used genome-scale loss-of-function screening to establish genes critical for IFN-induced transcription, identifying all expected members of the JAK-STAT signaling pathway and a previously unappreciated epigenetic reader, bromodomain-containing protein 9 (BRD9), the defining subunit of non-canonical BAF (ncBAF) chromatin-remodeling complexes. Genetic knockout or small-molecule-mediated degradation of BRD9 limits IFN-induced expression of a subset of ISGs in multiple cell types and prevents IFN from exerting full antiviral activity against several RNA and DNA viruses, including influenza virus, human immunodeficiency virus (HIV1), and herpes simplex virus (HSV1). Mechanistically, BRD9 acts at the level of transcription, and its IFN-triggered proximal association with the ISG transcriptional activator, STAT2, suggests a functional localization at selected ISG promoters. Furthermore, BRD9 relies on its intact acetyl-binding bromodomain and unique ncBAF scaffolding interaction with GLTSCR1/1L to promote IFN action. Given its druggability, BRD9 is an attractive target for dampening ISG expression under certain autoinflammatory conditions

Oncogenic role of miR-155 in anaplastic large cell lymphoma lacking the t(2;5) translocation.

Anaplastic large cell lymphoma (ALCL) is a rare, aggressive, non-Hodgkin's lymphoma that is characterized by CD30 expression and disease onset in young patients. About half of ALCL patients bear the t(2;5)(p23;q35) translocation, which results in the formation of the nucleophosmin-anaplastic lymphoma tyrosine kinase (NPM-ALK) fusion protein (ALCL ALK(+)). However, little is known about the molecular features and tumour drivers in ALK-negative ALCL (ALCL ALK(-)), which is characterized by a worse prognosis. We found that ALCL ALK(-), in contrast to ALCL ALK(+), lymphomas display high miR-155 expression. Consistent with this, we observed an inverse correlation between miR-155 promoter methylation and miR-155 expression in ALCL. However, no direct effect of the ALK kinase on miR-155 levels was observed. Ago2 immunoprecipitation revealed miR-155 as the most abundant miRNA, and enrichment of target mRNAs C/EBPβ and SOCS1. To investigate its function, we over-expressed miR-155 in ALCL ALK(+) cell lines and demonstrated reduced levels of C/EBPβ and SOCS1. In murine engraftment models of ALCL ALK(-), we showed that anti-miR-155 mimics are able to reduce tumour growth. This goes hand-in-hand with increased levels of cleaved caspase-3 and high SOCS1 in these tumours, which leads to suppression of STAT3 signalling. Moreover, miR-155 induces IL-22 expression and suppresses the C/EBPβ target IL-8. These data suggest that miR-155 can act as a tumour driver in ALCL ALK(-) and blocking miR-155 could be therapeutically relevant. Original miRNA array data are to be found in the supplementary material (Table S1).This work was supported by the SCRI-LIMCR GmbH, the “Jubiläumsfond der Österreichischen Nationalbank” (grant-no. 14856 to O.M.), R.G. was supported by grant SFB P021 from the Austrian Science Funds (FWF), L.K. was supported by grant FWF, P26011, R.M. was supported by FWF grants SFB F28 and SFB F47. S.D.T. is a Senior Lecturer supported with funding from Leukemia and Lymphoma Research.This is the final version of the article. It first appeared from Wiley via http://dx.doi.org/10.1002/path.453

Identification of regulatory variants associated with genetic susceptibility to meningococcal disease.

Non-coding genetic variants play an important role in driving susceptibility to complex diseases but their characterization remains challenging. Here, we employed a novel approach to interrogate the genetic risk of such polymorphisms in a more systematic way by targeting specific regulatory regions relevant for the phenotype studied. We applied this method to meningococcal disease susceptibility, using the DNA binding pattern of RELA - a NF-kB subunit, master regulator of the response to infection - under bacterial stimuli in nasopharyngeal epithelial cells. We designed a custom panel to cover these RELA binding sites and used it for targeted sequencing in cases and controls. Variant calling and association analysis were performed followed by validation of candidate polymorphisms by genotyping in three independent cohorts. We identified two new polymorphisms, rs4823231 and rs11913168, showing signs of association with meningococcal disease susceptibility. In addition, using our genomic data as well as publicly available resources, we found evidences for these SNPs to have potential regulatory effects on ATXN10 and LIF genes respectively. The variants and related candidate genes are relevant for infectious diseases and may have important contribution for meningococcal disease pathology. Finally, we described a novel genetic association approach that could be applied to other phenotypes

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

Creating a Self-configuring Finite State Machine out of Memory Look-up Tables

A finite state machine (FSM) is one of the most used digital logic applications in today's electrical systems. An FSM can be implemented in electrical systems based on programmable logic devices (PLD) or combinatorial logic platforms. Both platforms for a FSM contain advantages and restrictions for the hardware and software design. In regards of coding, FSM can be coded in alternatives styles and programming languages. In this paper we introduce the concept of a self-configuring FSM based on coding data as memory look-up tables. The resulting FSM is then able to self-configure the combinatorial logic of this FSM required to perform the compulsory state sequence. The primary benefit of using memory based look-up table (LUT) FSM is that well established data error correction methods can be applied to protect the FSM behavior, even in the event of single error events (SEE). A high level hardware design of this FSM will be presented in comparison to a PLD FSM implementation

Demonstration of a Self-recovering ALU Using a Convergent Cellular Automata

This paper presents work in progress towards the demonstration of a self-restoring arithmetic logic unit (ALU) based on convergent cellular automata (CCA). The need for fault tolerance and self-recovery strategies for electronic circuits is discussed, with particular focus on well-known redundancy and reconfiguration approaches. Our CCA fault tolerant strategy is demonstrated via MATLAB simulation using fault injection. The combined roles of the CCA as coordination layer and restoration agent are discussed. Work in progress towards a hardware demonstration using VHDL description and FPGA hardware is also described

Fault Tolerant Quadded Logic Cell Structure with Built-in Adaptive Time Redundancy

This paper describes research carried out using a quadded logic cell (QLC) structure with the purpose of creating a fault tolerant strategy for stuck-at faults. In order to create the tolerant built-in behaviour, the basic logic elements must have resilience against transistor level stuck-at failures. To achieve this, we add fine-grained redundancy to the transistor structure of the individual logic gates. In our research NAND gates which are been used throughout the QLC design. Simulation data shows that the chosen enhanced NAND gate structure can cope with single random stuck-at fault and if not indicates it through a distinct current indication. The QLC design contains four individual logic units which can be configured to perform four different types of two input logic functions. The QLC contains an interconnection structure that links three logic units to form a logic structure with four inputs and one output. This fixed internal structure revolves clockwise in four steps in a “round-robin” time redundancy scheme to create a set number of results. Through a majority voting a combined overall output result gets generated. Individual comparison of each clock cycle result against the voted result reveals the cycle and logic unit combination in which the faulty result has been generated. In this case alteration of the individual logic unit configuration has been used to generate another set of results for pattern mapping to identify the single logic unit within the QLC. After identification a self-initiated logic unit replacement with a spare unit happens. An additional detection method based on power rail grading of the individual logic units is devised to enable built-in classification of the stuck-at fault occurring within the unit and subsequently to trigger self-repair. These features are intended to be self-coordinated without requiring outside influence, making this resulting design capable of autonomous self-healing under specific failure conditions