DAMPs and Innate Immune Training

The ability to remember a previous encounter with pathogens was long thought to be a key feature of the adaptive immune system enabling the host to mount a faster, more specific and more effective immune response upon the reencounter, reducing the severity of infectious diseases. Over the last 15 years, an increasing amount of evidence has accumulated showing that the innate immune system also has features of a memory. In contrast to the memory of adaptive immunity, innate immune memory is mediated by restructuration of the active chromatin landscape and imprinted by persisting adaptations of myelopoiesis. While originally described to occur in response to pathogen-associated molecular patterns, recent data indicate that host-derived damage-associated molecular patterns, i.e. alarmins, can also induce an innate immune memory. Potentially this is mediated by the same pattern recognition receptors and downstream signaling transduction pathways responsible for pathogen-associated innate immune training. Here, we summarize the available experimental data underlying innate immune memory in response to damage-associated molecular patterns. Further, we expound that trained immunity is a general component of innate immunity and outline several open questions for the rising field of pathogen-independent trained immunity

Tidy up - The unfolded protein response in sepsis

Pathogens, their toxic byproducts, and the subsequent immune reaction exert different forms of stress and damage to the tissue of the infected host. This stress can trigger specific transcriptional and post-transcriptional programs that have evolved to limit the pathogenesis of infectious diseases by conferring tissue damage control. If these programs fail, infectious diseases can take a severe course including organ dysfunction and damage, a phenomenon that is known as sepsis and which is associated with high mortality. One of the key adaptive mechanisms to counter infection-associated stress is the unfolded protein response (UPR), aiming to reduce endoplasmic reticulum stress and restore protein homeostasis. This is mediated via a set of diverse and complementary mechanisms, i.e. the reduction of protein translation, increase of protein folding capacity, and increase of polyubiquitination of misfolded proteins and subsequent proteasomal degradation. However, UPR is not exclusively beneficial since its enhanced or prolonged activation might lead to detrimental effects such as cell death. Thus, fine-tuning and time-restricted regulation of the UPR should diminish disease severity of infectious disease and improve the outcome of sepsis while not bearing long-term consequences. In this review, we describe the current knowledge of the UPR, its role in infectious diseases, regulation mechanisms, and further clinical implications in sepsis

Towards Logical Clocks in P2P-based MMVEs

A crucial requirement for peer-to-peer-based Massively Multiuser Virtual Environments (P2P-based MMVEs) is the accurate and reliable synchronization of actions among the users (processes). To do so, clock synchronization protocols can be used. In this paper we first analyze the usage of standard vector clocks for this purpose and show their deficits (e.g. growing large). Then we present a novel variation of vector clocks – pruned vector clocks – which overcome the deficits of standard vector clocks and are therefore suited for their usage in MMVEs. The basic idea of pruned vector clocks is to prune all entries in a vector clock, which are not relevant at some point in time. We show, that with this approach vector clocks will stay constant in size and still provide the necessarily synchronization among the processes

Cross-Talk Between Iron and Glucose Metabolism in the Establishment of Disease Tolerance

Infectious diseases are associated with disruption of host homeostasis. This can be triggered directly by pathogens or indirectly by host immune-driven resistance mechanisms. Disease tolerance is a defense strategy against infection that sustains host homeostasis, without exerting a direct negative impact on pathogens. The mechanisms governing disease tolerance encompass host metabolic responses that maintain vital homeostatic parameters within a range compatible with survival. Central to this defense strategy is the host's ability to sense and adapt to variations in nutrients, such as iron and glucose. Here we address how host responses regulating iron and glucose metabolism interact to establish disease tolerance and possibly modulate resistance to infection

Fighting Cheating in P2P-based MMVEs with Disjoint Path Routing

In a P2P-based Massively Multiuser Virtual Environment (MMVE) where nodes cannot be trusted, replicating data on multiple nodes is a possibility to increase the reliability to obtain correct data. Current structured P2P networks mostly place replicas in such a way that queries for the replicas travel along similar paths. A malicious node in the common part of all paths can nullify the security gain of replicated data. We therefore propose to combine radix-based prefix routing with a symmetric replication scheme to gain disjoint paths to each of the replicas

Identifizierung und Charakterisierung zweier für die Entwicklung essentieller Serin/Threonin-Proteinkinasen in Myxococcus xanthus

Die Fähigkeit von Myxococcus xanthus zur Bildung von Fruchtkörpern und Myxosporen ist unter anderem vom Austausch interzellulärer Signale abhängig. Das C Signal spielt hierbei eine entscheidende Rolle. Die Erkennung dieses 17 kDa großen Proteins (CsgA) ist abhängig von direktem Zell-Zell-Kontakt, weshalb ein Rezeptor in der äußeren Membran vermutet wird, über den das Signal über die Zellhülle hinweg ins Zytoplasma weitergeleitet wird, wo es die Expression zahlreicher für die Entwicklung notwendiger Gene anschaltet. Das Ziel dieser Arbeit war die Identifizierung von Proteinen, die an der Erkennung und Weiterleitung des C-Signals beteiligt sind, insbesondere des bislang unbekannten CsgA-Rezeptors. CsgA sollte zunächst als natives Protein gereinigt werden, um es für die Identifizierung seiner Interaktionspartner zu verwenden. Hierzu wurde versucht, CsgA mit N- und C-terminalen Affinitäts-Tags in M. xanthus zu produzieren. Dies gelang mit einem N-terminalen His-Tag, und mit diesem Konstrukt wurde die csgA-Mutante erfolgreich komplementiert. Es gibt Hinweise darauf, daß Ser/Thr-Proteinkinasen an der Weiterleitung des C-Signals beteiligt sein könnten. Aufgrund einer bioinformatischen Analyse wurden für ein Mutagenese-Screening mehrere Ser/Thr-Proteinkinasen ausgewählt, die in möglichen Transkriptionseinheiten mit Proteinen der inneren und äußeren Membran kodiert werden. Durch Deletionsmutagenese dieser Kandidaten konnten zwei Kinasen (MXAN4557 und MXAN6570) identifiziert werden, die essentiell für die Fruchtkörperbildung sind. Ihre Inaktivierung führte zu einem kompletten Verlust der Fähigkeit zur Aggregation und Sporulation. MXAN4557 wird mit einem TonB-abhängigen Rezeptor ko-transkribiert und liegt in Nachbarschaft zu einer Ser/Thr-spezifischen Phosphatase. Diese beiden Proteine sind jedoch nicht essentiell für die Entwicklung. Die Kinase MXAN6570 bildet eine Transkriptionseinheit mit einem Protein, welches eine FHA-Domäne trägt und ebenfalls nicht für die Entwicklung notwendig ist. Die Analyse charakteristischer Entwicklungsmarker in den Mutanten der beiden Kinasen zeigte, daß frühe Entwicklungsprozesse nicht beeinträchtigt sind und deutet darauf hin, daß beide Proteine downstream des C-Signals und vor dem Verzweigungspunkt von Aggregation und Sporulation essentiell für das Fortschreiten der Entwicklung sind

Tissue damage control in disease tolerance

The deposited article is a prost-print version.This publication hasn't any creative commons license associated.This deposit is composed by the main article, and it hasn't any supplementary materials associated.Immune-driven resistance mechanisms are the prevailing host defense strategy against infection. By contrast, disease tolerance mechanisms limit disease severity by preventing tissue damage or ameliorating tissue function without interfering with pathogen load. We propose here that tissue damage control underlies many of the protective effects of disease tolerance. We explore the mechanisms of cellular adaptation that underlie tissue damage control in response to infection as well as sterile inflammation, integrating both stress and damage responses. Finally, we discuss the potential impact of targeting these mechanisms in the treatment of disease.Fundação para a Ciência e Tecnologia grants: (PTDC/SAU-TOX/116627/2010, HMSP-ICT/0022/2010, SFRH/BPD/44256/2008); European Commission 7th Framework grant: (ERC-2011-AdG. 294709-DAMAGECONTROL); Deutsche Forschungsgemeinschaft grant: (DFG WE 4971/3-1).info:eu-repo/semantics/publishedVersio

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

An accurate and flexible analog emulation of AdEx neuron dynamics in silicon

Analog neuromorphic hardware promises fast brain emulation on the one hand and an efficient implementation of novel, brain-inspired computing paradigms on the other. Bridging this spectrum requires flexibly configurable circuits with reliable and reproducible dynamics fostered by an accurate implementation of the targeted neuron and synapse models. This manuscript presents the analog neuron circuits of the mixed-signal accelerated neuromorphic system BrainScaleS-2. They are capable of flexibly and accurately emulating the adaptive exponential leaky integrate-and-fire model equations in combination with both current- and conductance-based synapses, as demonstrated by precisely replicating a wide range of complex neuronal dynamics and firing patterns.Comment: Accepted for ICECS 202