Explore the vast range of titles available.

Topical application of imiquimod (IMQ) on the skin of mice induces inflammation with common features found in psoriatic skin. Recently, it was postulated that IL-17 has an important role both in psoriasis and in the IMQ model. To further investigate the impact of IL-17RA signaling in psoriasis, we generated IL-17 receptor A (IL-17RA)–deficient mice (IL-17RAdel) and challenged these mice with IMQ. Interestingly, the disease was only partially reduced and delayed but not abolished when compared with controls. In the absence of IL-17RA, we found persisting signs of inflammation such as neutrophil and macrophage infiltration within the skin. Surprisingly, already in the naive state, the skin of IL-17RAdel mice contained significantly elevated numbers of Th17- and IL-17-producing γδ T cells, assuming that IL-17RA signaling regulates the population size of Th17 and γδ T cells. Upon IMQ treatment of IL-17RAdel mice, these cells secreted elevated amounts of tumor necrosis factor-α, IL-6, and IL-22, accompanied by increased levels of the chemokine CXCL2, suggesting an alternative pathway of neutrophil and macrophage skin infiltration. Hence, our findings have major implications in the potential long-term treatment of psoriasis by IL-17-targeting drugs.

Background: Psoriasis is hallmarked by vascular dysfunction, arterial hypertension, and an increased risk for cardiovascular diseases. We have shown recently that skin-driven interleukin (IL)-17A expression promotes psoriasis-like disease in mice, and this is associated with vascular inflammation, vascular dysfunction, and hypertension. As an intensive risk-factor reduction is recommended for psoriasis patients, we aimed to elucidate the impact of the angiotensin II receptor type 1 (AT1) antagonist telmisartan in a mouse model of severe psoriasis-like skin disease. Methods and Results: Elevated blood pressure measured by tail-cuff plethysmography in mice with keratinocyte-specific IL-17A overexpression (K14-IL-17Aind/+ mice) was significantly reduced in response to telmisartan. Importantly, vascular dysfunction, as assessed by isometric tension studies of isolated aortic rings, vascular inflammation measured by flow cytometry analysis of CD45+CD11b+ immune cells, as well as the increased peripheral oxidative stress levels assessed by L-012-enhanced chemiluminescence were not attenuated by telmisartan treatment of K14-IL-17Aind/+ mice, nor was the persisting skin inflammation. Conclusion: We provide first evidence for an effective antihypertensive treatment in experimental psoriasis by AT1 blockade, but without any impact on vascular inflammation and dysfunction in our mouse model of severe psoriasis-like skin disease. This suggests that vascular function and inflammation in psoriasis might not be attenuated as long as skin inflammation persists.

Aims. The neutrophil recruiting cytokine Interleukin-17A (IL-17A) is a key component in vascular dysfunction and arterial hypertension. Moreover, IL-17A has a central role for the vascular infiltration of myeloid cells into the arterial wall in Angiotensin II-induced vascular inflammation. The intention of our study was to analyze the impact of T cell-derived IL-17A on hypertension, vascular function, and inflammation. Methods and Results. Chronic IL-17A overexpression in T cells (CD4-IL-17Aind/+ mice) resulted in elevated reactive oxygen species in the peripheral blood and a significant vascular dysfunction compared to control mice. The vascular dysfunction seen in the CD4-IL-17Aind/+ mice was only accompanied by a modest and nonsignificant accumulation of inflammatory cells within the vessel wall. Therefore, infiltrating myeloid cells did not serve as an explanation of the vascular dysfunction seen in a chronic IL-17A-driven mouse model. In addition to vascular dysfunction, CD4-IL-17Aind/+ mice displayed vascular fibrosis with highly proliferative fibroblasts. This fibroblast proliferation was induced by exposure to IL-17A as confirmed by in vitro experiments with primary murine fibroblastic cells. We also found that the ⋅NO/cGMP pathway was downregulated in the vasculature of the CD4-IL-17Aind/+ mice, while levels of protein tyrosine kinase 2 (PYK2), an oxidative stress-triggered process associated with T cell activation, were upregulated in the perivascular fat tissue (PVAT). Conclusions. Our data demonstrate that T cell-derived IL-17A elicits vascular dysfunction by mediating proliferation of fibroblasts and subsequent vascular fibrosis associated with PYK2 upregulation.

The lack of a generally accepted animal model for human psoriasis has hindered progress with respect to understanding the pathogenesis of the disease. Here we present a model in which transgenic IL-17A expression is targeted to the skin in mice, achievable after crossing our IL-17Aind allele to the K14-Cre strain. K14-IL-17Aind/+ mice invariably develop an overt skin inflammation bearing many hallmark characteristics of human psoriasis including dermal infiltration of effector T cells, formation of neutrophil microabscesses, and hyperkeratosis. IL-17A expression in the skin results in upregulated granulopoiesis and migration of IL-6R-expressing neutrophils into the skin. Neutralization of IL-6 signaling efficiently reduces the observed pathogenesis in skin of IL-17A-overexpressing mice, with marked reductions in epidermal neutrophil abscess formation and epidermal thickening. Thus, IL-6 functions downstream of IL-17A to exacerbate neutrophil microabscess development in psoriasiform lesions.

Cardiovascular risk factors may act by modulating the composition and function of the adventitia. Here we examine how age affects perivascular adipose tissue (PVAT) and its paracrine activities during neointima formation. Aortic tissue and PVAT or primary aortic smooth muscle cells from male C57BL/6JRj mice aged 52 weeks (“middle-aged”) were compared to tissue or cells from mice aged 16 weeks (“adult”). Vascular injury was induced at the carotid artery using 10% ferric chloride. Carotid arteries from the middle-aged mice exhibited smooth muscle de-differentiation and elevated senescence marker expression, and vascular injury further aggravated media and adventitia thickening. Perivascular transplantation of PVAT had no effect on these parameters, but age-independently reduced neointima formation and lumen stenosis. Quantitative PCR analysis revealed a blunted increase in senescence-associated proinflammatory changes in perivascular tissue compared to visceral adipose tissue and higher expression of mediators attenuating neointima formation. Elevated levels of protein inhibitor of activated STAT1 (PIAS1) and lower expression of STAT1- or NFκB-regulated genes involved in adipocyte differentiation, inflammation, and apoptosis/senescence were present in mouse PVAT, whereas PIAS1 was reduced in the PVAT of patients with atherosclerotic vessel disease. Our findings suggest that age affects adipose tissue and its paracrine vascular activities in a depot-specific manner. PIAS1 may mediate the age-independent vasculoprotective effects of perivascular fat.

Die vorliegende Studie betrachtet mittels Critical Incidents, wie Lehrkräfte sprachbezogenes Lernen im mehrsprachigen Klassenzimmer wahrnehmen, gestalten und entsprechende Potenziale nutzen. In den Critical Incidents schließen Lehrkräfte häufig von den Sprachkenntnissen, einer Stagnation oder Progression, auf individuelle Anstrengungsbereitschaft, allgemeines Leistungsvermögen und Verhalten von Schüler*innen. Zudem betrachten sie den Umgang mit Sprache(n) als davon abhängig, ob an der Schule Ressourcen für Förderung verfügbar sind. Diese Zuschreibungen werden mit Blick auf die Bildungspotenziale mehrsprachiger Schüler*innen und Implikationen für Schule und Lehrende diskutiert.

NKp46 + innate lymphoid cells (ILC) modulate tissue homeostasis and anti-microbial immune responses. ILC development and function are regulated by cytokines such as Interleukin (IL)−7 and IL-15. However, the ILC-intrinsic pathways translating cytokine signals into developmental programs are largely unknown. Here we show that the anti-apoptotic molecule cellular FLICE-like inhibitory protein (c-FLIP) is crucial for the generation of IL-7/IL-15-dependent NKp46 + ILC1, including conventional natural killer (cNK) cells, and ILC3. Cytokine-induced phosphorylation of signal transducer and activator of transcription 5 (STAT5) precedes up-regulation of c-FLIP, which protects developing NKp46 + ILC from TNF-induced apoptosis. NKp46 + ILC-specific inactivation of c-FLIP leads to the loss of all IL-7/IL-15-dependent NKp46 + ILC, thereby inducing early-onset chronic colitis and subsequently microbial dysbiosis; meanwhile, the depletion of cNK, but not NKp46 + ILC1/3, aggravates experimental colitis. In summary, our data demonstrate a non-redundant function of c-FLIP for the generation of NKp46 + ILC, which protect T/B lymphocyte-sufficient mice from intestinal inflammation. Innate lymphoid cells (ILC) are important immune cells for maintaining the gut homeostasis. Here the authors show that c-FLIP, an anti-apoptotic molecule, is important for the development of NKP46 + ILC1, including conventional natural killer (cNK) cells, and ILC3, with cNK being more critical for ameliorating intestinal inflammation.

Genetically encoded voltage indicators (GEVIs) based on microbial rhodopsins utilize the voltage-sensitive fluorescence of all-trans retinal (ATR), while in electrochromic FRET (eFRET) sensors, donor fluorescence drops when the rhodopsin acts as depolarization-sensitive acceptor. In recent years, such tools have become widely used in mammalian cells but are less commonly used in invertebrate systems, mostly due to low fluorescence yields. We systematically assessed Arch(D95N), Archon, QuasAr, and the eFRET sensors MacQ-mCitrine and QuasAr-mOrange, in the nematode Caenorhabditis elegans. ATR-bearing rhodopsins reported on voltage changes in body wall muscles (BWMs), in the pharynx, the feeding organ [where Arch(D95N) showed approximately 128% ΔF/F increase per 100 mV], and in neurons, integrating circuit activity. ATR fluorescence is very dim, yet, using the retinal analog dimethylaminoretinal, it was boosted 250-fold. eFRET sensors provided sensitivities of 45 to 78% ΔF/F per 100 mV, induced by BWM action potentials, and in pharyngeal muscle, measured in simultaneous optical and sharp electrode recordings, MacQ-mCitrine showed approximately 20% ΔF/F per 100 mV. All sensors reported differences in muscle depolarization induced by a voltage-gated Ca2+-channel mutant. Optogenetically evoked de- or hyperpolarization of motor neurons increased or eliminated action potential activity and caused a rise or drop in BWM sensor fluorescence. Finally, we analyzed voltage dynamics across the entire pharynx, showing uniform depolarization but compartmentalized repolarization of anterior and posterior parts. Our work establishes alloptical, noninvasive electrophysiology in live, intact C. elegans.

Context Converting monocultures to mixed-species stands is thought to be a promising approach to increase forest productivity and resilience, while additionally providing other ecosystem goods and services (EGS). However, the importance of tree species composition and structure remains unclear, particularly beyond the stand scale due to the difficulty of conducting comprehensive, long-term experiments. Objectives To compare the ability of different tree species mixtures to provide various EGS at the landscape scale. Methods We used a dynamic forest landscape model to simulate all possible combinations of dominant tree species for two landscapes; a high-elevation alpine region (Dischma valley, Switzerland) and a lowland valley (Mt. Feldberg, Germany). We evaluated multiple EGS, including protection from gravitational hazards, aboveground biomass, and habitat quality, and examined trade-offs and synergies between them. Results Mixed-species forests were usually better in providing multiple EGS, although monocultures were often best for single EGS. The simulation results also demonstrated how changing environmental conditions along an elevational gradient had a strong impact on the structure of different species combinations and therefore on the provisioning of EGS. Conclusion Tree species diversity alone is not a good predictor of multifunctionality. Mixtures should be selected based on local environmental conditions, complementary functional traits, and the ability to provide the EGS of interest. Although our work focused on current climatic conditions, we discuss how the modelling framework could be employed to consider the impacts of climate change and disturbances to improve our understanding of how mixed-species stands could be used to cope with these challenges.

Children are exposed to ionizing radiation through radiographs during their development for various reasons. At present, there are no officially valid reference values for dental X-rays in children and adolescents for dental X-ray diagnostics. This study retrospectively examined 9680 extraoral dental radiographs in pediatric patients between 2002 and 2020. The aim was to analyze the radiation doses in pediatric patients, which indications were used, and whether there were specific age and gender differences. The evaluation showed that radiation doses were considered low, with dose area products of 2.2 cGy × cm2 for a lateral cephalogram, 14 cGy × cm2 for an orthopantomogram (OPG), and 45 cGy × cm2 for cone beam computer tomography (CBCT). This corresponds to an effective dose of 1.5 μSv for a lateral cephalogram, 7 μSv for an OPG, and 33.8 μSv for CBCT. Of the 9680 images, 78% were orthopantomograms, and only 0.4% were CBCT images. OPG has become more important over the years, as reflected in the indication. Approximately one-third of all extraoral exposures are orthodontic indications. Overall, the indications were similar for both genders. According to the dental indications, boys were X-rayed slightly more frequently than girls (54.5–45.5%). A future publication of dose guide values and corresponding guidelines is of high priority.