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BACKGROUND: Within the last years the investigation of cellulosic materials got into the focus of biomaterial research due to biocompatibility, sustainability, ubiquitous deposits and the potential of simple modification. Thereby this material is an ideal candidate to tailor material properties as charge, swelling, hydrophilicity and elasticity to clinical demands. OBJECTIVE: In this study a cellulose-based material was functionalized using plasma and gas (O2, N2, silane). METHODS: The effect of material modification on two cell lines using different animal species was investigated using indirect and direct cytotoxicity analysis. The following parameters were investigated: number of adherent cells, cell viability, metabolic activity, cell membrane integrity and morphology. RESULTS: Pristine and functionalized material eluates did not harm L929 cells and could be classified as non-cytotoxic according to DIN-EN-ISO 10993. A direct seeding of CHO-cells onto material surfaces showed a similar result. None of the conducted modifications had a negative effect on CHO-cells. Interestingly, parameters investigated during the study were positively influenced after material functionalization. In special, the treatment of cellulose with silane improved cell viability, metabolic activity, cellular adherence and cell membrane integrity significantly. CONCLUSIONS: Within this study the potential of cellulose-based material functionalization with tailorable effects on different cell lines was proven. This indicates that all investigated medical grade sponge materials are promising polymers for applications in clinical routine.

Because of imperfect discrimination against ribonucleoside triphosphates by the replicative DNA polymerases, large numbers of ribonucleotides are incorporated into the eukaryotic nuclear genome during S-phase. Ribonucleotides, by far the most common DNA lesion in replicating cells, destabilize the DNA, and an evolutionarily conserved DNA repair machinery, ribonucleotide excision repair (RER), ensures ribonucleotide removal. Whereas complete lack of RER is embryonically lethal, partial loss-of-function mutations in the genes encoding subunits of RNase H2, the enzyme essential for initiation of RER, cause the SLE-related type I interferonopathy Aicardi-Goutières syndrome. Here, we demonstrate that selective inactivation of RER in mouse epidermis results in spontaneous DNA damage and epidermal hyperproliferation associated with loss of hair follicle stem cells and hair follicle function. The animals developed keratinocyte intraepithelial neoplasia and invasive squamous cell carcinoma with complete penetrance, despite potent type I interferon production and skin inflammation. These results suggest that compromises to RER-mediated genome maintenance might represent an important tumor-promoting principle in human cancer. Significance: Selective inactivation of ribonucleotide excision repair by loss of RNase H2 in the murine epidermis results in spontaneous DNA damage, type I interferon response, skin inflammation, and development of squamous cell carcinoma. Cancer Res; 78(20); 5917–26. ©2018 AACR.

Neutrophil recruitment and plasma exudation are key elements in the immune response to injury or infection. Activated neutrophils stimulate opening of the endothelial barrier; however, the underlying mechanisms have remained largely unknown. In this study, we identified a pivotal role of the proinflammatory kallikrein-kinin system and consequent formation of bradykinin in neutrophil-evoked vascular leak. In mouse and hamster models of acute inflammation, inhibitors of bradykinin generation, and signaling markedly reduced plasma exudation in response to chemoattractant activation of neutrophils. The neutrophil-driven leak was likewise suppressed in mice deficient in either the bradykinin B2 receptor or factor XII (initiator of the kallikrein-kinin system). In human endothelial cell monolayers, material secreted from activated neutrophils induced cytoskeletal rearrangement, leading to paracellular gap formation in a bradykinin-dependent manner. As a mechanistic basis, we found that a neutrophil-derived heparin-binding protein (HBP/azurocidin) displaced the bradykinin precursor high-molecular-weight kininogen from endothelial cells, thereby enabling proteolytic processing of kininogen into bradykinin by neutrophil and plasma proteases. These data provide novel insight into the signaling pathway by which neutrophils open up the endothelial barrier and identify the kallikrein-kinin system as a target for therapeutic interventions in acute inflammatory reactions.-Kenne, E., Rasmuson, J., Renne, T., Vieira, M. L., Muller-Esterl, W., Herwald, H., Lindbom, L. Neutrophils engage the kallikrein-kinin system to open up the endothelial barrier in acute inflammation.

Inflammatory bowel diseases (IBDs) cause significant morbidity and mortality. Aberrant NF-κB signalling is strongly associated with these conditions, and several established drugs influence the NF-κB signalling network to exert their effect. This study aimed to identify drugs that alter NF-κB signalling and could be repositioned for use in IBD. The SysmedIBD Consortium established a novel drug-repurposing pipeline based on a combination of in silico drug discovery and biological assays targeted at demonstrating an impact on NF-κB signalling, and a murine model of IBD. The drug discovery algorithm identified several drugs already established in IBD, including corticosteroids. The highest-ranked drug was the macrolide antibiotic clarithromycin, which has previously been reported to have anti-inflammatory effects in aseptic conditions. The effects of clarithromycin effects were validated in several experiments: it influenced NF-κB-mediated transcription in murine peritoneal macrophages and intestinal enteroids; it suppressed NF-κB protein shuttling in murine reporter enteroids; it suppressed NF-κB (p65) DNA binding in the small intestine of mice exposed to lipopolysaccharide; and it reduced the severity of dextran sulphate sodium-induced colitis in C57BL/6 mice. Clarithromycin also suppressed NF-κB (p65) nuclear translocation in human intestinal enteroids. These findings demonstrate that in silico drug repositioning algorithms can viably be allied to laboratory validation assays in the context of IBD, and that further clinical assessment of clarithromycin in the management of IBD is required. This article has an associated First Person interview with the joint first authors of the paper., Summary: Using state-of-the-art in silico drug discovery and real-time live-cell imaging techniques, we identify clarithromycin as a drug with potential for repositioning for inflammatory bowel disease.

How B cells contribute to protective immunity against parasitic nematodes remains unclear, with their importance as accessory cells under-explored. By using anti-CD20 monoclonal antibody (mAb) (Genentech-clone 5D2) to deplete B cells in two genetically distinct strains of mouse, C57BL/6 and BALB/c, this study reveals that, on the C57BL/6 genetic background, B cells are important for the expulsion of Trichuris muris (T. muris) by acting as accessory cells, supporting Th2 immune responses. C57BL/6 mice receiving anti-CD20 treatment prior to and during T. muris infection, or anti-CD20 treatment that commenced two weeks post infection (p.i.), were susceptible to high dose T. muris infection. In complete contrast, BALB/c mice were still able to expel T. muris in the absence of B cells. Th2 type cytokines produced by mesenteric lymph nodes (MLN) cells from C57BL/6 mice receiving α-CD20 mAb treatment were significantly lower than produced by cells from isotype control treated mice. Interestingly, although the production of IFN-γ in the MLN of C57BL/6 mice receiving α-CD20 mAb treatment was not affected, the expression of IFN-γ and IFN-γ induced genes at the effector site, the gut, were significantly increased compared to isotype control treated mice, reflecting the overall change in Th1/Th2 balance in favour of Th1. To explore whether the important role played by the B cell in the protective immune response of C57BL/6 mice was in enabling strong Th2 responses in the context of mixed Th1/Th2 settings, IFN-γ was blocked using anti-IFN-γ mAb post B cell depletion. Neutralization of IFN-γ restored the resistance against T. muris infection in the absence of B cells. Thus, our data suggest an important role of B cells in supporting Th2 type immune responses in mixed IFN-γ-rich Th1/Th2 settings.

In the last decades, fluorescence microscopy has evolved into a powerful tool for modern cell biology and immunology. However, while modern fluorescence microscopes allow to study processes at subcellular level, the informative content of the recorded images is frequently constrained by the limited dynamic range of the camera mounted to the optical system. In addition, the quality of acquired images is generally affected by the typically low-light conditions that lead to comparatively high levels of noise in the data. Addressing these issues, we introduce a variational method for high dynamic range (HDR) imaging in the context of fluorescence microscopy that explicitly accounts for the Poisson statistics of the unavoidable signal-dependent photon shot noise and complements HDR image reconstruction with edge-preserving denoising. Since the proposed model contains a weight function to confine the influence of under- and overexposed pixels on the result, we briefly discuss the choice of this function. We evaluate our approach by showing HDR results for real fluorescence microscopy exposure sequences acquired with the recently developed MACSimaTM System for fully automated cyclic immunofluorescence imaging. These results are obtained using a first-order primal-dual implementation. On top of this, we also provide the corresponding saddle-point and dual formulations of the problem.

We recently showed that interleukin (IL)-6–type cytokine signaling in adipocytes induces free fatty acid release from visceral adipocytes, thereby promoting obesity-induced hepatic insulin resistance and steatosis. In addition, IL-6–type cytokines may increase the release of leptin from adipocytes and by those means induce glucagon-like peptide 1 (GLP-1) secretion. We thus hypothesized that IL-6–type cytokine signaling in adipocytes may regulate insulin secretion. To this end, mice with adipocyte-specific knockout of gp130, the signal transducer protein of IL-6, were fed a high-fat diet for 12 weeks. Compared with control littermates, knockout mice showed impaired glucose tolerance and circulating leptin, GLP-1, and insulin levels were reduced. In line, leptin release from isolated adipocytes was reduced, and intestinal proprotein convertase subtilisin/kexin type 1 (Pcsk1) expression, the gene encoding PC1/3, which controls GLP-1 production, was decreased in knockout mice. Importantly, treatment with the GLP-1 receptor antagonist exendin 9–39 abolished the observed difference in glucose tolerance between control and knockout mice. Ex vivo, supernatant collected from isolated adipocytes of gp130 knockout mice blunted Pcsk1 expression and GLP-1 release from GLUTag cells. In contrast, glucose- and GLP-1–stimulated insulin secretion was not affected in islets of knockout mice. In conclusion, adipocyte-specific IL-6 signaling induces intestinal GLP-1 release to enhance insulin secretion, thereby counteracting insulin resistance in obesity.

Zusammenfassung Hintergrund Hemithyreoidektomie ist eine häufige Behandlung einseitiger Schilddrüsenknoten. Postoperative Hypothyreose ist eine häufig unterschätzte Komplikation. Wir untersuchten Inzidenz, Zeitpunkt, Symptomatik sowie mögliche Risikofaktoren der postoperativen Hypothyreose. Material und Methoden 127 Patienten nach Hemithyreoidektomie wurden mit retrospektiver Datenanalyse sowie strukturierter Befragung der nachbetreuenden Hausärzte und Endokrinologen untersucht. Patienten wurden mit dem postoperativen TSH als hypothyreot (> 4.0 mU/L) oder euthyreot (0.4–4.0 mU/L) klassifiziert. Schilddrüsenhormone wurden nach 4–6 Wochen, 6 Monaten und 1 Jahr gemessen. Ergebnisse 55 Patienten (43 %) entwickelten eine postoperative Hypothyreose und 72 (57%) blieben euthyreot. Die Hypothyreose zeigte sich innerhalb der ersten 2 Monaten bei 39 Patienten (71 %), zwischen 2–6 Monaten bei 13 Patienten (24 %) sowie nach 6–12 Monaten bei 3 Patienten (5 %). 33 Patienten (60 %) waren zum Zeitpunkt der Diagnose asymptomatisch. Nur 16 Patienten (29 %) hatten Symptome. Der präoperative TSH Wert war signifikant höher in der Gruppe der hypothyreoten Patienten (1.64), verglichen mit der euthyreoten Gruppe (1.13, P = 0.0017). Die anderen Variablen wie Alter, Geschlecht und präoperativen Werte von T3, T4, Calcium und PTH zeigten keinen signifikanten Unterschied. Schlussfolgerung Die postoperative Hypothyreose ist eine häufige Komplikation nach Hemithyreoidektomie, welche nicht verpasst werden sollte. Präoperativ erhöhter TSH Wert ist ein Risikofaktor für die postoperative Hypothyreose. Alle Patienten nach Hemithyreoidektomie sollten postoperative TSH Kontrollen nach 4–6 Wochen, 6 Monaten und 12 Monaten haben.

Der Zugversuch ist ein wichtiges Prufverfahren fur die Qualitatssicherung von Kunststoffdichtungsbahnen, die in der Geotechnik (Deponiebau, Tunnelbau usw.) verwendet werden. Fur die Vergleichbarkeit und Beurteilung der Ergebnisse ist ein standardisiertes Verfahren erforderlich. Da sich Kunststoffe durch ihr ausgepragtes viskoelastisches Verformungsverhalten von anderen Baumaterialien unterscheiden, werden die ermittelten Kennwerte sowie deren Bedeutung und Verwendbarkeit fur die Praxis diskutiert. Die Einsatzmoglichkeiten und -grenzen von Extensometern werden erlautert. Am Beispiel des Zugversuchs werden zudem die Schwierigkeiten bei der Normungsarbeit aufgezeigt: Angefangen vom Einfluss unterschiedlicher Normungsorganisationen und -komitees sowie der Hersteller auf den Entstehungsprozess der Normen bis hin zu Ubersetzungsfehlern. Dabei zeigt sich, dass es durchaus sinnvoll sein kann, fur bestimmte Arten von Produkten, wie z. B. PEHD-Dichtungsbahnen, eine eigene Norm zu erarbeiten.

Bradykinin (or kinin) receptors (nomenclature as agreed by the NC-IUPHAR subcommittee on Bradykinin (kinin) Receptors [76]) are activated by the endogenous peptides bradykinin (BK), [des-Arg9]bradykinin, Lys-BK (kallidin), [des-Arg10]kallidin, [Phospho-Ser6]-Bradykinin, T-kinin (Ile-Ser-BK), [Hyp3]bradykinin and Lys-[Hyp3]-bradykinin. Variation in pharmacology and activity of B1 and B2 receptor antagonists at species orthologs has been documented. icatibant (Hoe140, Firazir) is approved in North America and Europe for the treatment of acute attacks of hereditary angioedema.

This retrospective report focuses on the diagnosis of the Paxillus syndrome, based on two fatal cases of haemolysis following the consumption of Paxillus involutus. These mushrooms are still consumed regularly, despite earlier reports of life-threatening autoimmune haemolytic anaemia. Such cases are nevertheless rare, and thus far no toxin could be identified that causes this unusual form of mushroom poisoning. All these factors contribute to the difficulty in diagnosing the Paxillus syndrome. The following aspects support the diagnosis in the two cases presented here: Both patients consumed the mushroom oftentimes before, yet allegedly without ill effects. Symptoms occurred 2−3 h after the last consumption, exacerbating into circulatory collapse, multiorgan failure, and death. Disseminated intravascular coagulation was identified as cause of death by autopsy of patient 1. Patient 2 died of multiorgan failure, mainly hepatic. Our mycological analyses could identify the consumed mushroom in both cases as Paxillus involutus. Furthermore, we could exclude anticoagulants and several other drugs as trigger for the haemolysis by post-mortem toxicological analysis. However, findings in each of the two cases may have led to the haemolysis, independent of the consumption of Paxillus involutus. Patient 1 carried the anti-erythrocytic antibody, auto-anti-e. Patient 2 contracted chronic hepatitis C years prior to the current incident. Considering the rarity of the Paxillus syndrome, our findings suggest that these patients were particularly susceptible for haemolysis after consuming this mushroom over a prolonged period. Occurrence of the Paxillus syndrome may thus be restricted to regular consumers of Paxillus involutus mushrooms with an existing predisposition for haemolysis.

Apart from dedicated oligodendroglial progenitor cells, adult neural stem cells (aNSCs) can also give rise to new oligodendrocytes in the adult central nervous system (CNS). This process mainly confers myelinating glial cell replacement in pathological situations and can hence contribute to glial heterogeneity. Our previous studies demonstrated that the p57kip2 gene encodes an intrinsic regulator of glial fate acquisition and we here investigated to what degree its modulation can affect stem cell‐dependent oligodendrogenesis in different CNS environments. We therefore transplanted p57kip2 knockdown aNSCs into white and gray matter (WM and GM) regions of the mouse brain, into uninjured spinal cords as well as in the vicinity of spinal cord injuries and evaluated integration and differentiation in vivo. Our experiments revealed that under healthy conditions intrinsic suppression of p57kip2 as well as WM localization promote differentiation toward myelinating oligodendrocytes at the expense of astrocyte generation. Moreover, p57kip2 knockdown conferred a strong benefit on cell survival augmenting net oligodendrocyte generation. In the vicinity of hemisectioned spinal cords, the gene knockdown led to a similar induction of oligodendroglial features; however, newly generated oligodendrocytes appeared to suffer more from the hostile environment. This study contributes to our understanding of mechanisms of adult oligodendrogenesis and glial heterogeneity and further reveals critical factors when considering aNSC mediated cell replacement in injury and disease.

The knee is the largest and most complex joint of the musculoskeletal system. Compared to the other joints of the lower limb, the knee has the least inherent stability, secondary to the minimal congruence between the distal cam-shaped femur and the relatively flat, proximal tibia.

This study investigates the role of B cells in immunity toTrichuris muris(T. muris) infection in two genetically distinct strains of mouse, using anti-CD20 monoclonal antibody (mAb) (Genentech-clone 5D2) to deplete B cells. Data is presented for the mouse strains: C57BL/6 and BALB/c, which mount mixed Th1/Th2, and highly polarised Th2 immune responses toT. muris, respectively. C57BL/6 mice receiving anti-CD20 treatment prior to and during, or anti-CD20 treatment that commenced two weeks post infection (p.i.), were susceptible toT. muris. Parasite-specific IgG1 antibodies were absent and Th2 type cytokines produced by mesenteric lymph nodes cells from mice receiving α-CD20 mAb treatment were significantly lower than produced by cells from isotype control treated mice. T follicular helper cells were also significantly reduced. Importantly, and in complete contrast, BALB/c mice were still able to expelT.murisin the absence of B cells, revealing that the essential role played by B cells in protective immunity was dependent on genetic background. To explore whether the important role played by the B cell in the protective immune response of C57BL/6 mice was in enabling strong Th2 responses in the presence of IFN-γ, IFN-γ was blocked using anti-IFN-γ mAb post B cell depletion. Depleting IFN-γ, in the absence of B cells restored worm expulsion in the absence of parasite-specific IgG1/IgG2c and partially rescued theT. murisspecific IL-13 response. Thus, our data suggest an important, antibody independent role for B cells in supporting Th2 type immune responses in mixed IFN-γ-rich Th1/Th2 immune response settings.Author summaryHow B cells contribute to protective immunity against parasitic nematodes remains unclear, with their importance as accessory cells under-explored. This study reveals that, on some genetic backgrounds, B cells are important for the expulsion ofT. murisby acting as accessory cells, supporting Th2 immune responses.

Summary MyD88, an adaptor molecule downstream of innate pathways, plays a significant tumor-promoting role in sporadic intestinal carcinogenesis of the Apcmin/+ model, which carries a mutation in the Apc gene. Here, we show that deletion of MyD88 in intestinal mesenchymal cells (IMCs) significantly reduces tumorigenesis in this model. This phenotype is associated with decreased epithelial cell proliferation, altered inflammatory and tumorigenic immune cell infiltration, and modified gene expression similar to complete MyD88 knockout mice. Genetic deletion of TLR4, but not interleukin-1 receptor (IL-1R), in IMCs led to altered molecular profiles and reduction of intestinal tumors similar to the MyD88 deficiency. Ex vivo analysis in IMCs indicated that these effects could be mediated through downstream signals involving growth factors and inflammatory and extracellular matrix (ECM)-regulating genes, also found in human cancer-associated fibroblasts (CAFs). Our results provide direct evidence that during tumorigenesis, IMCs and CAFs are activated by innate TLR4/MyD88-mediated signals and promote carcinogenesis in the intestine., Graphical Abstract, Highlights • Deletion of MyD88 or TLR4 in IMCs and/or CAFs leads to reduced intestinal tumorigenesis • The phenotype of the IMC-specific MyD88 mice is similar to the complete knockouts • MyD88−/− IMCs show a reduced pro-tumorigenic and/or inflammatory gene expression profile • Human CAFs show upregulation of a similar MyD88-specific gene expression signature, Koliaraki et al. show that MyD88 in mesenchymal cells is responsible for its tumor-promoting role in the Apcmin/+ model. They further show that this is a TLR4-mediated mechanism that leads to the production of pro-tumorigenic molecules, also identified in human CAFs.

In the agriculture sector, combining physically based soil water balance and simulation models with GIS (Geographic Information System) tools is of a considerable interest to manage the available water amount. Indeed, this combination can enhance water supply management, optimize agricultural catchments management and study impact of management intervention from small scale (plot) to a larger one, such as irrigated district and/or region. This work presents the case of Sidi Saad Dam System (central Tunisia). The main objectives were (1) to create a specific GIS data base for the four irrigated districts of the area (Sidi Mansour, Sidi Saad, Fjij and Touila) based on the characteristics of cultivated crops, soil types and used irrigation systems; (2) to assess spatial and temporal variation of soil water budget terms from plot and farm levels to irrigated district and regional scales; (3) to map results for different time steps. The achievement of these objectives was made possible using the WEAP-MABIA Model. Thus, daily Penman–Monteith reference evapotranspiration (ETo), effective precipitation (PE), crop water requirement (CWR), actual crop evapotranspiration (ETa) and irrigation water requirement (IWR) were estimated for the four irrigated districts using spatially distributed parameters on climate, crop, soil characteristics, irrigation system and basic irrigation management practice during the cropping season 2014/2015. The delivered information is maps of the Sidi Saad Dam System with its four irrigated districts and their related farms and plots; representing the current land use, the water consumption at farm level; the crop water requirement (CWR) and the irrigation water requirement (IWR) at a daily, weekly, monthly and yearly steps. Also and thanks to WEAP (Water Evaluation And Planning system) tool functionalities, these results can be displayed on Google Earth and shared between all water irrigation managers.

The chapter analyzes the contours of Cold War liberalism more broadly. Three central elements, which mutually supported each other, are identified: first, philosophical positions that can best be summed up with the concepts value pluralism and anti-determinism. Second, a set of distinct political principles, in particular a defense of negative liberty as the genuinely liberal conception of freedom and, in addition, liberal constitutionalism (which was not at all the same as an outright endorsement of electoral democracy, or a concern with electoral democracy as intrinsically valuable). Third, there was an insistence on a decent measure of social provision (or, put more directly: a sort of social democracy). Berlin’s political thought exhibits all these features to some degree and is analyzed accordingly.

The introduction discusses the complex ways in which Isaiah Berlin’s intellectual legacy has been contested. There is basic uncertainty as to where to place him on the political spectrum; and there are questions about the depth of his political thought, as well as his conduct as an intellectual during the Cold War. I argue that Berlin’s ideas and stance cannot simply be copied in the context of what some observers take to be a new Cold War, but that they merit renewed attention and do indeed hold important lessons for the present. The introduction also briefly summarizes the three chapters of the volume.

The outcome of intracellular parasitic infection can be determined by the immunoregulatory activities of natural regulatory CD4+ Foxp3+ T (Treg) cells and the anti-inflammatory cytokine IL-10. These mechanisms protect tissue but can also suppress antiparasitic CD4+ T cell responses. The specific contribution of these regulatory pathways during human parasitic diseases remains unclear. In this study, we investigated the roles of Treg cells and IL-10 during experimental visceral leishmaniasis caused by Leishmania donovani infection of C57BL/6 mice. We report only a limited contribution of Treg cells in suppressing antiparasitic immunity, but important roles in delaying the development of splenic pathology and restricting leukocyte expansion. We next employed a range of cell-specific, IL-10– and IL-10R–deficient mice and found these Treg cell functions were independent of IL-10. Instead, conventional CD4+ T cells and dendritic cells were the most important cellular sources of IL-10, and the absence of IL-10 in either cell population resulted in greater control of parasite growth but also caused accelerated breakdown in splenic microarchitecture. We also found that T cells, dendritic cells, and other myeloid cells were the main IL-10–responding cells because in the absence of IL-10R expression by these cell populations, there was greater expansion of parasite-specific CD4+ T cell responses associated with improved control of parasite growth. Again, however, there was also an accelerated breakdown in splenic microarchitecture in these animals. Together, these findings identify distinct, cell-specific, immunoregulatory networks established during experimental visceral leishmaniasis that could be manipulated for clinical advantage.

Interleukin‐1 (IL‐1) is implicated in numerous pathologies, including multiple sclerosis and its animal model experimental autoimmune encephalomyelitis (EAE). However, the exact mechanism by which IL‐1 is involved in the generation of pathogenic T cells and in disease development remains largely unknown. We found that following EAE induction, pertussis toxin administration leads to IL‐1 receptor type 1 (IL‐1R1)‐dependent IL‐1β expression by myeloid cells in the draining lymph nodes. This myeloid‐derived IL‐1β did not vitally contribute to the generation and plasticity of Th17 cells, but rather promoted the expansion of a GM‐CSF + Th17 cell subset, thereby enhancing its encephalitogenic potential. Lack of expansion of GM‐CSF‐producing Th17 cells led to ameliorated disease in mice deficient for IL‐1R1 specifically in T cells. Importantly, pathogenicity of IL‐1R1‐deficient T cells was fully restored by IL‐23 polarization and expansion in vitro . Therefore, our data demonstrate that IL‐1 functions as a mitogenic mediator of encephalitogenic Th17 cells rather than qualitative inducer of their generation.

MARKUS STEPHANI BEGLEITET DAS DEUTSCHE PROFIRADSPORTTEAM BORA-ARGON 18 ZU DEN GROSSTEN RADRENNEN DER WELT – Direkt nach der Etappenankunft muss es schnell gehen. Fahrer verpflegen, die Behandlungsbank vorbereiten, massieren. Sportler fur Sportler, bis spat in den Abend. Drei Wochen lang, jeden Tag. Als Physiotherapeut begleitet der 32-Jahrige das im oberbayerischen Raubling beheimatete Profiradsportteam Bora-Argon 18 zu den wichtigsten Radrennen auf der ganzen Welt – auch bei der diesjahrigen Tour de France war Stephani im Einsatz. „Von fruh bis spat ist immer etwas zu tun.“

This article assesses recent normative theorizing on militant democracy—the idea that, to protect themselves, democracies might under some circumstances have to restrict the rights of those set on undermining or outright destroying democracy. Particular attention is paid to new justifications of militant democracy that seek to avoid the danger of militant democracy itself damaging democracy, as well as to the question of who the agent deciding on implementing militant democracy ought to be. Three new challenges for thinking about militant democracy are identified: certain forms of religious belief and practice, new varieties of authoritarianism that include elections and some limited freedoms, and the question of whether international and supranational institutions can play a role in protecting democracies.

Zusammenfassung: Asymptomatische Schilddrüsenknoten treten sehr häufig auf und werden zunehmend als sogenannte Inzidentalome im Rahmen von radiologischen Halsuntersuchungen entdeckt. Ist ein Schilddrüsenknoten dokumentiert stellt sich die Frage wie der Befund nun weiter abgeklärt werden soll. Das Ziel ist es die sehr seltenen bösartigen Befunde mit auch insgesamt sehr geringer Mortalität zu erkennen und einer adäquaten Therapie zu zuführen. Die Funktionsdiagnostik mittels Bestimmung des Thyroidea stimulierende Hormons (TSH) gehört dabei zu jeder Abklärung von Schilddrüsenknoten. Ist das Hormon supprimiert, wird zur Suche eines heissen Knotens eine Szintigraphie durchgeführt. Der Ultraschall ist die Bildgebung der Wahl für die Schilddrüse und liefert Informationen bezüglich Grösse, Anzahl und Aufbau der Knoten. Je nach vorhandenen sonomorphologischen Kriterien und anderen möglichen Risikofaktoren wird zur weiteren Abklärung eine Feinnadelpunktion des auffälligen Knotens durchgeführt. Anhand des zytologischen Resultates soll dann das weitere therapeutische Procedere bestimmt werden.

The EU will not become something like a traditional nation-state anytime soon, and no supranational public sphere is likely to ever replace national public spheres.

IFN-γ is an enigmatic cytokine that shows direct anti-viral effects, confers upregulation of MHC-II and other components relevant for antigen presentation, and that adjusts the composition and balance of complex cytokine responses. It is produced during immune responses by innate as well as adaptive immune cells and can critically affect the course and outcome of infectious diseases, autoimmunity, and cancer. To selectively analyze the function of innate immune cell-derived IFN-γ, we generated conditional IFN-γOFF mice, in which endogenous IFN-γ expression is disrupted by a loxP flanked gene trap cassette inserted into the first intron of the IFN-γ gene. IFN-γOFF mice were intercrossed with Ncr1-Cre or CD4-Cre mice that express Cre mainly in NK cells (IFN-γNcr1-ON mice) or T cells (IFN-γCD4-ON mice), respectively. Rosa26RFP reporter mice intercrossed with Ncr1-Cre mice showed selective RFP expression in more than 80% of the NK cells, while upon intercrossing with CD4-Cre mice abundant RFP expression was detected in T cells, but also to a minor extent in other immune cell subsets. Previous studies showed that IFN-γ expression is needed to promote survival of vaccinia virus (VACV) infection. Interestingly, during VACV infection of wild type and IFN-γCD4-ON mice two waves of serum IFN-γ were induced that peaked on day 1 and day 3/4 after infection. Similarly, VACV infected IFN-γNcr1-ON mice mounted two waves of IFN-γ responses, of which the first one was moderately and the second one profoundly reduced when compared with WT mice. Furthermore, IFN-γNcr1-ON as well as IFN-γCD4-ON mice survived VACV infection, whereas IFN-γOFF mice did not. As expected, ex vivo analysis of splenocytes derived from VACV infected IFN-γNcr1-ON mice showed IFN-γ expression in NK cells, but not T cells, whereas IFN-γOFF mice showed IFN-γ expression neither in NK cells nor T cells. VACV infected IFN-γNcr1-ON mice mounted normal cytokine responses, restored neutrophil accumulation, and showed normal myeloid cell distribution in blood and spleen. Additionally, in these mice normal MHC-II expression was detected on peripheral macrophages, whereas IFN-γOFF mice did not show MHC-II expression on such cells. In conclusion, upon VACV infection Ncr1 positive cells including NK cells mount two waves of early IFN-γ responses that are sufficient to promote the induction of protective anti-viral immunity., Author summary Viral infections induce interferon (IFN) responses that constitute a first line of defense. Type II IFN (IFN-γ) is required for protection against lethal vaccinia virus (VACV) infection. To address the cellular origin of protective IFN-γ responses during VACV infection, we generated IFN-γOFF mice, in which the endogenous IFN-γ gene function can be reconstituted in a Cre-dependent manner. IFN-γOFF mice were intercrossed with Ncr1-Cre mice that express Cre selectively in Ncr1+ innate cell subsests such as NK cells. Surprisingly, VACV infected IFN-γNcr1-ON mice mounted two waves of IFN-γ responses. Reconstitution of innate IFN-γ was sufficient to restore cytokine responses that supported normal myeloid cell distribution and survival upon VACV infection. In conclusion, IFN-γ derived from Ncr1+ innate immune cells is sufficient to elicit fully effective immune responses upon VACV infection. Our new mouse model is suitable to further address the role of Ncr1+ cell-derived IFN-γ also in other models of infection, as well as of autoimmunity and cancer.