Long-Term Decrease in VLA-4 Expression and Functional Impairment of Dendritic Cells during Natalizumab Therapy in Patients with Multiple Sclerosis

Myeloid and plasmacytoid dendritic cells (mDCs, pDCs) are central to the initiation and the regulation of immune processes in multiple sclerosis (MS). Natalizumab (NTZ) is a humanized monoclonal antibody approved for the treatment of MS that acts by blocking expression of VLA-4 integrins on the surface of leukocytes. We determined the proportions of circulating DC subsets and analyzed expression of VLA-4 expression in 6 relapsing-remitting MS patients treated with NTZ for 1 year. VLA-4 expression levels on pDCs and mDCs decreased significantly during follow-up. In vitro coculture of peripheral blood mononuclear cells and pDCs, with different doses of NTZ in healthy controls (HC) and MS patients showed dose-dependent down-regulation of VLA-4 expression levels in both MS patients and HC, and reduced functional ability to stimulate antigen-specific T-lymphocyte responses. The biological impact of NTZ may in part be attributable to inhibition of transmigration of circulating DCs into the central nervous system, but also to functional impairment of interactions between T cells and DC

Quinpramine Ameliorates Rat Experimental Autoimmune Neuritis and Redistributes MHC Class II Molecules

Activation of inflammatory cells is central to the pathogenesis of autoimmune demyelinating diseases of the peripheral nervous system. The novel chimeric compound quinpramine—generated from imipramine and quinacrine—redistributes cholesterol rich membrane domains to intracellular compartments. We studied the immunological and clinical effects of quinpramine in myelin homogenate induced Lewis rat experimental autoimmune neuritis (EAN), a model system for acute human inflammatory neuropathies, such as the Guillain-Barré syndrome. EAN animals develop paresis of all limbs due to autoimmune inflammation of peripheral nerves. Quinpramine treatment ameliorated clinical disease severity of EAN and infiltration of macrophages into peripheral nerves. It reduced expression of MHC class II molecules on antigen presenting cells and antigen specific T cell proliferation both in vitro and in vivo. Quinpramine exerted its anti-proliferatory effect on antigen presenting cells, but not on responder T cells. Our data suggest that quinpramine represents a candidate pharmaceutical for inflammatory neuropathies

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference

Explainability of deep learning classifier decisions for optical detection of manufacturing defects in the automated fiber placement process

Automated fibre layup techniques are commonly used composite manufacturing processes in the aviation sector and require a manual visual inspection. Neural Network classification of defects has the potential to automate this visual inspection, however, the machine decision-making processes are hard to verify. Thus, we present an approach for visualising Convolutional Neural Network (CNN) based classifications of manufacturing defects and quantifying its robustness suitably. Our investigations have shown that especially Smoothed Integrated Gradients and DeepSHAP are particularly well suited for the visualisation of CNN classifications. The Smoothed Integrated Gradients technique also reveals advantages in robustness when evaluating degraded input images

Mineralogical impact on long-term patterns of soil nitrogen and phosphorus enzyme activities

During long-term ecosystem development, both soil mineralogical composition and nutrient contents change, thus possibly altering microbial nutrient cycling by constraining substrate accessibility. In addressing the mineral impact on nitrogen (N) and phosphorus (P) cycling, we determined microbial abundances, activities of N-hydrolyzing (aminopeptidases, protease, urease) and P-hydrolyzing (phosphatase) enzymes and the potential substrate availability as well as their physicochemical and mineralogical controls in whole soil profiles along the 120 kyr-old Franz Josef chronosequence (New Zealand). Pedogenic soil iron (Fe) and aluminum (Al) resided initially (<1 kyrs) in metal-humus complexes, changed to poorly crystalline Fe and Al at intermediate-aged sites (1–12 kyrs) and into dominance of clay and crystalline Fe oxides at the oldest site. Despite this, organic C (OC) and organic N (ON) stocks increased only slightly with soil age, whereas organic P (OP) stocks decreased continuously. In organic layers, enzyme activities were mainly regulated by ON and OP concentrations, whereas in mineral soils, mineral–enzyme relations were more complex and included both, direct and indirect effects. Protease, urease, and phosphatase activities were inhibited by mineral interactions, especially with poorly crystalline Fe and Al oxides, whereas aminopeptidases were less affected by mineralogical properties. On a pedon basis, most N-hydrolyzing enzyme activities per ON stocks responded negatively to increasing stocks of poorly crystalline Fe and Al minerals, but were also affected by the C:N ratio of labile organic substrates. Profile-based phosphatase activities per OP stock were highest at the oldest sites having the largest stocks of clay and crystalline Fe oxides. Overall, our study indicates that long-term mineral changes create distinct patterns of nutrient accumulation and N- and P-enzyme activities at both horizon and pedon scale, with a variable extent of the mineralogical effect for the different N-hydrolyzing enzymes