Endogenous, or therapeutically induced, type I interferon responses differentially modulate Th1/Th17-mediated autoimmunity in the CNS

Different viruses trigger pattern recognition receptor systems, such as Toll-like receptors or cytosolic RIG-I like helicases (RLH), and thus induce early type I interferon (IFN-I) responses. Such responses may confer protection until adaptive immunity is activated to an extent that the pathogen can be eradicated. Interestingly, the same innate immune mechanisms that are relevant for early pathogen defense have a role in ameliorating experimental autoimmune encephalomyelitis (EAE), a rodent model of human multiple sclerosis. We and others found that mice devoid of a component of the IFN-I receptor (Ifnar1−/−) showed significantly enhanced autoimmune disease of the central nervous system (CNS). A detailed analysis revealed that in wild-type mice IFN-I triggering of myeloid cells was instrumental in reducing brain damage. A more recent study indicated that similar to Ifnar1−/− mice, RLH-signaling-deficient mice showed enhanced autoimmune disease of the CNS as well. Moreover, when peripherally treated with synthetic RLH ligands wild-type animals with EAE disease showed reduced clinical scores. Under such conditions, IFN-I receptor triggering of dendritic cells had a crucial role. The therapeutic effect of treatment with RLH ligands was associated with negative regulation of Th1 and Th17 T-cell responses within the CNS. These experiments are consistent with the hypothesis that spatiotemporal conditions of, and cell types involved in, disease-ameliorating IFN-I responses differ significantly, depending on whether they were endogenously induced in the context of EAE pathogenesis within the CNS or upon therapeutic RLH triggering in the periphery. It is attractive to speculate that RLH triggering represents a new strategy to treat multiple sclerosis by stimulating endogenous immunoregulatory IFN-I responses

NFC-BASED ELECTRONIC DATA CAPTURE SYSTEMS - THE CASE OF A QUALITY OF LIFE QUESTIONNAIRE

In this paper, we present a Near Field Communication (NFC)-based electronic data capture prototype for patient self-reported rating scales. Such scales are valuable feedback for medical treatment and care processes. As traditional paper-based questionnaires are time- and cost-consuming and may be affected by low patient compliance, our prototype allows patient monitoring and electronic data acquisition directly from the patient\u27s home. It enables real time representation and analysis of patient data and thus allows direct medical intervention by physicians. In developing the prototype, we followed a design science approach, developed design goals for the special case of patients suffering from impaired motor skills, and tested the prototype in a field study over the course of twelve weeks. We chose NFC, as the interaction paradigm is intuitive and quickly learned, without prior knowledge being necessary. Our results indicate that NFC is almost as simple as to fill out a paper-based questionnaire. During the study patients used the prototype autonomously and with minimal errors. Further, NFC technology was perceived as very intuitive and the information quality of each patient\u27s health status could be improved. Based on the findings we derive recommendations for future research and applications of NFC based electronic data capture systems

Identification of CNS Injury-Related microRNAs as Novel Toll-Like Receptor 7/8 Signaling Activators by Small RNA Sequencing

Toll-like receptors (TLRs) belong to pattern recognition receptors, which respond to danger signals such as pathogen-associated molecular patterns or damage-associated molecular patterns. Upon TLR activation in microglia, the major immune cells in the brain, distinct signaling cascades trigger the production of inflammatory molecules, being a critical feature in neuroinflammation and neurodegenerative processes. Recently, individual microRNAs (miRNAs) were shown to act as endogenous TLR ligands. Here, we conducted systematic screening for miRNAs as potential TLR7/8 ligands by small RNA sequencing of apoptotic neurons and their corresponding supernatants. Several miRNA species were identified in both supernatants and injured neurons, and 83.3% of the media-enriched miRNAs activated murine and/or human TLR7/8 expressed in HEK293-derived TLR reporter cells. Among the detected extracellular miRNAs, distinct miRNAs such as miR-340-3p and miR-132-5p induced cytokine and chemokine release from microglia and triggered neurotoxicity in vitro. Taken together, our systematic study establishes miRNAs released from injured neurons as new TLR7/8 activators, which contribute to inflammatory and neurodegenerative responses in the central nervous system (CNS)

Tuning of the Gap in a Laughlin-Bychkov-Rashba Incompressible Liquid

We report on our investigation of the influence of Bychkov-Rashba spin-orbit interaction (SOI) on the incompressible Laughlin state. We find that experimentally obtainable values of the spin-orbit coupling strength can induce as much as a 25% increase in the quasiparticle-quasihole gap Eg at low magnetic fields in InAs, thereby increasing the stability of the liquid state. The SOI-modulated enhancement of Eg is also significant for filling factors 1/5 and 1/7, where the FQH state is usually weak. This raises the intriguing possibility of tuning, via the SO coupling strength, the liquid to solid transition to much lower densities.Comment: 4 pages, 3 figure

Current concepts and controversies in prion immunopathology

Scrapie in sheep and new variant Creutzfeldt-Jakob disease in humans are typically initiated by extracerebral exposure to prions. Both exhibit early prion accumulation in sites of the peripheral lymphoreticular system, such as splenic or lymph nodal germinal centers. In germinal centers, follicular dendritic cells (FDCs), whose development and maintenance depend on lymphotoxin and tumor necrosis factor signaling, are believed to be the main cell type for efficient prion replication in the periphery. Here, we discuss the molecular requirements for prion replication competence in stromal and lymphoid compartments of lymphoid organs. In addition, we examine the preconditions of transepithelial passage of prions in the mucosal-associated lymphoid system. Our results suggest that under specific conditions, efficient prion replication in mesenteric and inguinal lymph nodes is possible in the absence of mature FDCs. M cells are a plausible candidate for the mucosal portal of prion infectio

NG2 expressed by macrophages and oligodendrocyte precursor cells is dispensable in experimental autoimmune encephalomyelitis

Increased expression of the chondroitin proteoglycan NG2 is a prominent feature in central nervous system injury with unknown cellular source and biological relevance. Here, we describe the first detailed analysis of experimental autoimmune encephalomyelitis in NG2 knockout mice and NG2 knockout bone marrow chimeras. We show that both macrophages and oligodendrocyte progenitor cells express and secrete NG2 in response to transforming growth factor-β. A subpopulation of macrophages expresses NG2 within leucocyte infiltrates in the central nervous system, but only oligodendrocyte progenitor cells contribute to NG2 accumulation. Notably, NG2 plays no role in experimental autoimmune encephalomyelitis initiation, progression or recuperation. In concurrence, the immune response is unaltered in NG2-deficient mice as are the extent of central nervous system damage and degree of remyelinatio

Induction of inhibitory central nervous system-derived and stimulatory blood-derived dendritic cells suggests a dual role for granulocyte-macrophage colony-stimulating factor in central nervous system inflammation

The mononuclear phagocyte system, particularly dendritic cells, plays several pivotal roles in the development of multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis. Here, we demonstrate that functionally distinct dendritic cell subpopulations are present in the central nervous system during experimental autoimmune encephalomyelitis. At peak experimental autoimmune encephalomyelitis, the majority of dendritic cells consisted of a CD11b+F4/80+ inflammatory dendritic cell subtype. Both granulocyte-macrophage colony-stimulating factor and chemokine (C-C motif) ligand 2 were previously suggested to recruit ‘inflammatory' monocyte-derived dendritic cells to the central nervous system during experimental autoimmune encephalomyelitis. We show that intra-cerebral production of granulocyte-macrophage colony-stimulating factor leading to chemokine (C-C motif) ligand 2 induction and attraction of chemokine (C-C motif) receptor 2-positive precursors suffices to recruit dendritic cell populations identical to those observed in experimental autoimmune encephalomyelitis into the central nervous system of healthy mice. This does not occur with fms-like tyrosine kinase-3-ligand treatment. Both during experimental autoimmune encephalomyelitis and upon intra-cerebral granulocyte-macrophage colony-stimulating factor production, all myeloid dendritic cells, lymphoid dendritic cells and periphery-derived inflammatory dendritic cells stimulated T cell proliferation, whereas inflammatory dendritic cells that differentiated from central nervous system precursors inhibited T cell activation and pro-inflammatory cytokine production. Despite the capacity of granulocyte-macrophage colony-stimulating factor to induce central nervous system-derived inhibitory inflammatory dendritic cells, the administration of granulocyte-macrophage colony-stimulating factor into mice with experimental autoimmune encephalomyelitis resulted in exacerbated disease. Granulocyte-macrophage colony-stimulating factor thus has a dual role in the central nervous system: it directs both central nervous system-derived dendritic cells towards an inhibitory phenotype and recruits peripheral dendritic cells exhibiting pro-inflammatory function

Immune system and peripheral nerves in propagation of prions to CNS

Prions are not only unique in the way they replicate. Also the sequence of events triggered by peripheral prion infection, generically termed ‘peripheral pathogenesis', sets prions aside from all other known pathogens. Whereas most bacteria, parasites, and viruses trigger innate and adaptive immune responses, the mammalian immune system appears to be remarkably oblivious to prions. Transmissible spongiform encephalopathies (TSEs) do not go along with inflammatory infiltrates, and antibodies to the prion protein are not typically raised during the course of the disease. On the other hand, there is conspicuous involvement of lymphoid organs, which accumulate sizeable concentrations of the infectious agent early during disease. Moreover, various states of immune deficiency can abolish peripheral pathogenesis and prevent ‘take' of infection when prions are administered to peripheral sites. Here, we critically re-visit the current evidence for an involvement of the immune system in prion diseases, and will attempt to trace the elaborate mechanisms by which prions, upon entry into the body from peripheral sites, reach the brai

Methodical Implementation Of Digital Data Consistency In Assembly Lines Of A Learning Factory

The possibility of acquiring data in production and manufacturing processes is almost limitless. But especially small and medium-sized enterprises (SMEs) lack the knowledge to successfully integrate digital tools and use real-time production data for critical decision-making. Numerous initiatives already exist to inform and support SMEs in Germany, funded at various levels by municipal, federal, and state entities. These initiatives offer expertise in digitalisation and provide diverse activities to support SMEs across different industrial sectors. To make abstract concepts such as artificial intelligence (AI) or digitalisation more tangible, demonstrations and practical best practice showcases demonstrate methodological approaches for facilitating independent implementation initiatives within SMEs. However, most of these activities primarily showcase rudimentary and isolated technological implementations, with limited integration into the complex environment of a manufacturing company. This paper focuses on a holistic methodical brownfield implementation of a demonstrator for digital data consistency in an assembly line of a learning factory by applying an extended methodology for implementing demonstrators and its validation by industrial participants. It stresses the complexity of production data acquisition in a practical environment and illustrates a best-practice showcase. Key performance indicators are visualized by acquiring, storing, and cross-linking data points. The demonstrator is implemented and evaluated by SMEs' representatives, to show promising potential for sustainable knowledge transfer into the SMEs

Transfer Learning Approaches In The Domain Of Radial-Axial Ring Rolling For Machine Learning Applications

Due to increased data accessibility, data-centric approaches, such as machine learning, are getting more represented in the forming industry to improve resource efficiency and to optimise processes. Prior research shows, that a classification of the roundness of shaped rings, using machine learning algorithms, is applicable to radial-axial ring rolling. The accuracy of these predictions nowadays is still limited by the amount and quality of the data. Therefore, this paper will focus on how to make the best use of the limited amount of data, using transfer learning approaches. Since acquiring data for homogenised databases is time, energy and resource consuming, logged data gathered by the industry is often used in research. This paper takes both, industrial data from thyssenkrupp rothe erde Germany GmbH and a smaller dataset of an inhouse research plant, into account. Additionally, a synthetic dataset, created by generative adversarial networks, is considered. To accomplish an improvement of machine learning predictions using accessible data, three transfer learning approaches are investigated in order to extend existing models: (I) transferring from a radial-axial ring rolling mill to a different mill containing less available data with a ratio of 20:1, (II) learning from unlabelled data using an autoencoder and (III) training on synthetic data. The obtained improvements are further evaluated. Based on these results, future possible investigations are elaborated, in particular the consideration of transfer learning from the less complex cold ring rolling process