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IL-6 plays a fundamental role in T cell differentiation and is strictly controlled by surface expression and shedding of IL-6R. IL-6 also acts on other cells that might affect T cell maturation. To study the impact of cell-autonomous and uncontrolled IL-6 signaling in T cells, we generated mice with a constitutively active IL-6R gp130 chain (Lgp130) expressed either in all T cells (Lgp130 × CD4Cre mice) or inducible in CD4+ T cells (Lgp130 × CD4CreERT2 mice). Lgp130 × CD4Cre mice accumulated activated T cells, including TH17 cells, in the lung, resulting in severe inflammation. Tamoxifen treatment of Lgp130 × CD4CreERT2 mice caused Lgp130 expression in 40–50% of CD4+ T cells, but mice developed lung disease only after several months. Lgp130+ CD4+ T cells were also enriched for TH17 cells; however, there was concomitant expansion of Lgp130− regulatory T cells, which likely restricted pathologic Lgp130+ T cells. In vitro, constitutive gp130 signaling in T cells enhanced but was not sufficient for TH17 cell differentiation. Augmented TH17 cell development of Lgp130+ T cells was also observed in Lgp130 × CD4CreERT2 mice infected with Staphylococcus aureus, but gp130 activation did not interfere with formation of TH1 cells against Listeria monocytogenes. Lgp130+ CD4+ T cells acquired a memory T cell phenotype and persisted in high numbers as a polyclonal T cell population in lymphoid and peripheral tissues, but we did not observe T cell lymphoma formation. In conclusion, cell-autonomous gp130 signaling alters T cell differentiation. Although gp130 signaling is not sufficient for TH17 cell differentiation, it still promotes accumulation of activated T cells in the lung that cause tissue inflammation.

BACKGROUND AND AIMS: Primary liver cancers include: Hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (CCA) and combined HCC-CCA tumors (cHCC-CCA). It has been suggested, but not unequivocally proven, that hepatic progenitor cells (HPCs) can contribute to hepatocarcinogenesis. We aimed to determine whether HPCs contribute to HCC, cHCC-CCA or both types of tumors.METHOD: To trace progenitor cells during hepatocarcinogenesis, we generated Mdr2-KO mice that harbor an YFP reporter gene driven by the Foxl1 promoter which is expressed specifically in progenitor cells. These mice (Mdr2-KOFoxl1-CRE;RosaYFP) develop chronic inflammation and HCCs by the age of 14-16 months, followed by cHCC-CCA tumors at the age of 18 months, as we have first observed.RESULTS: In this Mdr2-KOFoxl1-CRE;RosaYFP mouse model, liver progenitor cells are the source of cHCC-CCA tumors, but not the source of HCC. Ablating the progenitors, caused reduction of cHCC-CCA tumors but did not affect HCCs. RNA-seq revealed enrichment of the IL6 signaling pathway in cHCC-CCA tumors compared to HCC tumors. ScRNA-seq analysis revealed that IL6 is expressed from immune and parenchymal cells in senescence, and that IL6 is part of the senescence-associated secretory phenotype (SASP). Administration of anti-IL6 Ab to Mdr2-KOFoxl1-CRE;RosaYFP mice, inhibited the development of cHCC-CCA tumors. By blocking IL6 trans-signaling, cHCC-CCA tumors decreased in number and size, indicating that cHCC-CCA is dependent on IL6 trans-signaling. Furthermore, the administration of a senolytic agent inhibited IL6 and the development of cHCC-CCA tumors.CONCLUSION: Our results demonstrate that cHCC-CCA, but not HCC tumors, originate from HPCs, and that IL6, which derives in part from cells in senescence, plays an important role in this process via IL6 trans-signaling. These findings could enhance new therapeutic approaches for cHCC-CCA liver cancer.LAY SUMMARY: Combined hepatocellular carcinoma - cholangiocarcinoma is the third prevalent liver cancer. We show that the source of this tumor is the liver tissue stem cells and that, this tumor type is dependent on an inflammatory signaling of IL6 and can be inhibited by blocking IL6 signaling or using a senolytic agent.

The liver is a vital organ with multiple functions and a large regenerative capacity. Tumours of the liver are the second most frequently cause of cancer-related death and develop in chronically inflamed livers. IL-6-type cytokines are mediators of inflammation and almost all members signal via the receptor subunit gp130 and the downstream signalling molecule STAT3. We here summarize current knowledge on how gp130 signalling and STAT3 in tumour cells and cells of the tumour micro-environment drives hepatic tumorigenesis. We furthermore discuss very recent findings describing also anti-tumorigenic roles of gp130/STAT3 and important considerations for therapeutic interventions.

It is unclear whether deviations in brain and behavioral development, which may underpin elevated substance use during adolescence, are predispositions for or consequences of substance use initiation. Here, we examine behavioral and neuroimaging indices at early and mid-adolescence in drug-naive youths to identify possible predisposing factors for substance use initiation and its possible consequences.Among 304 drug-naive adolescents at baseline (age 14 years) from the IMAGEN dataset, 83 stayed drug-naive, 133 used alcohol on 1 to 9 occasions, 42 on 10 to 19 occasions, 27 on 20 to 39 occasions, and 19 on40 occasions at follow-up (age 16 years). Baseline measures included brain activation during the Monetary Incentive Delay task. Data at both baseline and follow-up included measures of trait impulsivity and delay discounting.From baseline to follow-up, impulsivity decreased in the 0 and 1- to 9-occasions groups (p .004), did not change in the 10- to 19-occasions and 20- to 29-occasions groups (p.294), and uncharacteristically increased in the40-occasions group (p = .046). Furthermore, blunted medial orbitofrontal cortex activation during reward outcome at baseline significantly predicted higher alcohol use frequency at follow-up, above and beyond behavioral and clinical variables (p = .008).These results suggest that the transition from no use to frequent drinking in early to mid-adolescence may disrupt normative developmental changes in behavioral control. In addition, blunted activity of the medial orbitofrontal cortex during reward outcome may underscore a predisposition toward the development of more severe alcohol use in adolescents. This distinction is clinically important, as it informs early intervention efforts in preventing the onset of substance use disorder in adolescents.

Digital text is quickly becoming essential to modern daily life. The article you are reading right now is born digital; unlike texts of the not-so-distant past, it may never be printed at all. Worldwide, the trend is clear: Digital text is on the way in, and print is on its way out. Year-by-year, more and more readers are turning to ebooks, internet news, and other forms of ereading, while generation by generation, print is becoming less and less relevant. 1 1 Pew research shows 50% of Americans have a dedicated ereading device, with yearly gains in ereadership [1]; industry research, too, shows a definite trend toward ereading and non-traditional publishing, with ebooks making up 50% of fiction reading in 2016 [2], while journalism is also trending online [3]. These trends are not unique to English—to meet the demands and expectations of today's readers, Tibetan texts, too, are being digitized by many organizations and institutions with a shared appreciation for the Tibetan literary heritage. They include a variety of secular publishers, monastic institutions, and Buddhist foundations, among others. But while these organizations share common goals for common texts, their work is all too frequently completely disconnected from the community at large. This situation negatively impacts what is already a minoritized and under-resourced language. While competition—from other languages, as well as other publishers in the Tibetan etext world—has been a driver of innovation in the adoption of ereading technology, we believe that a rich, shared data source is not only in everyone's best interest but also the only practical way forward when we consider the time, effort, expertise, and money that quality digitization takes. That is why we have designed OpenPecha to be a public, open platform for collaborative etext curation and annotation sharing. Its aim is providing a wide range of users with the latest version of the exact “view” of any text needed, while maintaining the integrity of the text and its annotations and simultaneously allowing for community improvements and additions. In this article, we explore the details of how the project came to be, what it is, and how it works, while also presenting a few common use cases.

Objective Irritable mood, a common and impairing symptom in psychopathology, has been proposed to underlie the developmental link between oppositional problems in youth and depression in adulthood. We examined the neural correlates of adolescent irritability in IMAGEN, a sample of 2,024 14-year-old adolescents from 5 European countries. Method The Development and Well-Being Assessment (DAWBA) was used to assess attention-deficit/hyperactivity disorder, major depressive disorder, oppositional defiant disorder, and generalized anxiety disorder. Three items from the DAWBA, selected as close matches to the Affective Reactivity Index, were used to assess irritability. Structural magnetic resonance imaging was examined using whole-brain voxel-based morphometry analysis, and functional magnetic resonance imaging was examined during a stop signal task of inhibitory control. Imaging data were included in structural equation models to examine the direct and indirect associations between irritable mood and comorbid DSM diagnoses. Results Whole-brain voxelwise analysis showed that adolescent irritable mood was associated with less gray matter volume and less neural activation underlying inhibitory control in frontal and temporal cortical areas (cluster-correction at p Conclusion This study identifies adolescent irritability as an independent construct and points to a neurobiological correlate to irritability that is an important contributing feature to many psychopathological disorders.

Worldwide, literacy is on the rise. This historically unprecedented surge—especially over the past 200 years—has changed nearly everything about the ancient technology of reading. Who reads is changing: Literacy is no longer just for elite, professional readers, but for anyone and everyone. What and why we read is changing: We do not just read difficult texts for academic, religious, legal, or record-keeping purposes; we also read easy texts to be entertained, to access information, and to communicate with each other on a daily basis. And how we read is changing: Memorization, recitation, and oral performance has given way to a rapid, silent, individual activity. Many of these democratizing changes have been made possible by technology. This has included advances in methods and materials that have made reading and writing easy, cheap, and widely available—like paper, the printing press, and the digital revolution. But perhaps the biggest reason literacy has become so widespread has been its ability to reach people in their own natural languages . More recently, this progress has been enhanced by NLP tools, like readability editors, that have helped authors, journalists, and other writing professionals make simple, clear content suitable for both beginning readers and widespread audiences. To that end, this article introduces a new readability tool, “Dakje,” alongside a specific use case, and demonstrates how it can help benefit literacy in the Tibetan languages. This NLP software works by word-splitting Tibetan text and analyzing those words using level lists that are based on frequency analysis from corpora. Users then have instant access to statistics on the readability of their word choices so they can make edits for easy-to-read text. In our test-case, Dakje helped us reduce sentence complexity by 34%, total word count by 10%, and non-level vocabulary use from 16% to 1% when compared to an original English-to-Tibetan translation.

Activating mutations in genes encoding receptor tyrosine kinases (RTKs) mediate proliferation, cell migration, and cell survival, and are therefore important drivers of oncogenesis. Numerous targeted cancer therapies are directed against activated RTKs, including small compound inhibitors, and immunotherapies. It has recently been discovered that not only certain RTK fusion proteins, but also many full-length RTKs harbouring activating mutations, notably RTKs of the class III family, are to a large extent mislocalised in intracellular membranes. Active kinases in these locations cause aberrant activation of signalling pathways. Moreover, low levels of activated RTKs at the cell surface present an obstacle for immunotherapy. We outline here why understanding of the mechanisms underlying mislocalisation will help in improving existing and developing novel therapeutic strategies.

Bordering Tibetan Languages: Making and Marking Languages in Transnational High Asia examines the complex interactions between state, ethnic, and linguistic borders in the Himalayas. These case studies from Bhutan, China, India, and Nepal show how people in the Himalayas talk borders into existence, and also how those borders speak to them and their identities. These ‘talking borders’ exist in a world where state borders are contested, and which is being irrevocably transformed by rapid social and economic change. This book offers a new perspective on this dynamic region by centring language, and in doing so, also offers new ways of thinking about how borders and language influence each other.

Background: COVID-19-associated invasive pulmonary aspergillosis (CAPA) is associated with increased mortality. Cases of CAPA caused by azole-resistant Aspergillus fumigatus strains have been reported. Objectives: To analyse the twelve-month CAPA prevalence in a German tertiary care hospital and to characterise clinical A. fumigatus isolates from two German hospitals by antifungal susceptibility testing and microsatellite genotyping. Patients/Methods. Retrospective observational study in critically ill adults from intensive care units with COVID-19 from 17 February 2020 until 16 February 2021 and collection of A. fumigatus isolates from two German centres. EUCAST broth microdilution for four azole compounds and microsatellite PCR with nine markers were performed for each collected isolate (N = 27) and additional for three non-COVID A. fumigatus isolates. Results: welve-month CAPA prevalence was 7.2% (30/414), and the rate of azole-resistant A. fumigatus isolates from patients with CAPA was 3.7% with detection of one TR34/L98H mutation. The microsatellite analysis revealed no major clustering of the isolates. Sequential isolates mainly showed the same genotype over time. Conclusions: Our findings demonstrate similar CAPA prevalence to other reports and a low azole-resistance rate. Genotyping of A. fumigatus showed polyclonal distribution except for sequential isolates. in press

‘Standard Tibetan’ – a state-building project of the Tibetan Empire – dates to the seventh-eleventh centuries CE. This medieval variety of Central Tibetan remains a cultural touchstone today. Its traditional spellings and grammars are still the reference points that defijine ‘proper’ Tibetan. However, while this standard has been maintained for writing, speech forms have continued to evolve over the last thousand years. In Himalayan settlements especially, movement, migration, and mixture have quickened the pace of language change. The result is diglossia – two horns of a dilemma, between which the borders grow ever taller. This chapter takes a closer look at these borders between traditional ‘Standard Tibetan’ and modern ‘Diaspora Tibetan’, and the dilemmas they create for education and literacy.

Multi-conjugate adaptive optics (MCAO) uses two or more deformable mirrors (DMs) at conjugate altitudes approximately matched to the atmospheric turbulence layers to increase the corrected field of view. An important unresolved problem for MCAO is determining the optimal sequence of the DMs. Theoretical considerations and numerical studies suggest that ordering the DMs from lowest to highest altitude reduces the effects of scintillation, whereas on-sky experiments report that the best performance is attained with the ground-layer DM placed last. Using analytical calculations and numerical experiments with Fresnel propagation of Kolmogorov turbulence, we demonstrate that the scintillation results from spatial frequencies higher than the spatial sampling of high-altitude DMs are able to correct. Hence, the effect of scintillation is not impacted by MCAO correction regardless of the sequence of the DMs. Using end-to-end numerical simulations, we find that the dynamic misregistration between the DMs and the wavefront sensors is minimized by placing the ground-layer DM last, leading to increased loop stability and lower wavefront errors. Contrary to conventional wisdom, we recommend that the DMs be sequenced from highest to lowest altitude.

Fish and meat production and processing will grow drastically in the coming decades. In aquacultural systems, insects are gaining interest as feed to provide a sustainable alternative to the fishmeal paradox, whose production leads to high consumption of resources and negative environmental impacts. Within the scope of this study, the production of fish feed from Hermetia illucens larvae and Lemna minor in an inline recirculating aquaponics model for urban sites was developed and optimized, which efficiently combines waste and environmental service concepts in one production system. At the same time, the value chain produces high-quality, market-accessible raw materials for the fish feed industry. All investigations were accompanied by a comparative Life Cycle Assessment (LCA) to measure and compare ecological effects to finally result in sustainable alternatives. The results achieved in this research show that fish feed based on Hermetia illucens and Lemna minor can have the potential to be ecologically competitive or more sustainable than standard feed. It should be noted that the comparison here represents the results of the project on a pilot scale. Various optimization potentials were shown, which are essential for the large-scale implementation of the breeding of both species as well as their processing up to the fish feed pellets.

International audience; Adaptive optics is challenging for smaller telescopes (0.5∼2m) due to the small isoplanatic angle, small subperatures and high correction speeds needed at visible wavelengths, requiring bright stars for guiding and thus severely limiting the sky coverage. To enable large sky coverage we can correct the turbulence which is common to the entire field we are trying to capture, which is achieved by the technique of GLAO (Ground Layer Adaptive Optics). The turbulence is measured by averaging wavefront measurements in multiple directions. The corrective element can either be a deformable lens or a small adaptive secondary mirror. The motivation to develop such a compact and robust AO system for small telescopes is twofold: On the one hand, schools and universities often have access to small telescopes as part of their education programs. Also researchers in countries with fewer resources could also benefit from well engineered and reliable adaptive optics on smaller telescopes for research and education purposes. On the other hand, amateur astronomers and enthusiasts might want improved image quality for visual observation and astrophotography.

Background Studying the neural consequences of tobacco smoking during adolescence, including those associated with early light use, may help expose the mechanisms that underlie the transition from initial use to nicotine dependence in adulthood. However, only a few studies in adolescents exist, and they include small samples. In addition, the neural mechanism, if one exists, that links nicotinic receptor genes to smoking behavior in adolescents is still unknown. Methods Structural and diffusion tensor magnetic resonance imaging data were acquired from a large sample of 14-year-old adolescents who completed an extensive battery of neuropsychological, clinical, personality, and drug-use assessments. Additional assessments were conducted at 16 years of age. Results Exposure to smoking in adolescents, even at low doses, is linked to volume changes in the ventromedial prefrontal cortex and to altered neuronal connectivity in the corpus callosum. The longitudinal analyses strongly suggest that these effects are not preexisting conditions in those who progress to smoking. There was a genetic contribution wherein the volume reduction effects were magnified in smokers who were carriers of the high-risk genotype of the alpha 5 nicotinic receptor subunit gene, rs16969968. Conclusions These findings give insight into a mechanism involving genes, brain structure, and connectivity underlying why some adolescents find nicotine especially addictive.

The European Union (EU) has introduced measures to better screen investments from third countries, in particular by enterprises and state actors of the People’s Republic of China. These measures highlight the profound change in bilateral relations which have turned from “strategic partnership” into “systemic rivalry”. Reacting to new Chinese policies of foreign trade and investment, the EU followed a revision of investment screening policies in the US. The EU has overcome deep splits among member states and established a new legal framework at the supranational level that leaves the ultimate screening and decision-making power to the national level. This paper identifies the changes in Chinese investment and investment policies and highlights key contents of the US legislation on investment control before discussing the new EU framework. It interprets the new measures as further examples of an increased reliance on state policies instead of market forces - by all partners involved.

The 4-meter Daniel K. Inouye Solar Telescope will be upgraded with multi-conjugate adaptive optics. Two high-altitude deformable mirrors shall be added, and a multi-directional wavefront sensor system and a real-time control computer cluster will replace the existing counterparts of the operational first-light, classical adaptive optics system in a few years. Herein we give a brief overview of the system. We present the current status of the project including the prototyping for the wavefront sensor system and the real-time control system.

Signaling via death receptor family members such as TNF-R1 mediates pleiotropic biological outcomes ranging from inflammation and proliferation to cell death. Pro-survival signaling is mediated via TNF-R1 complex I at the cellular plasma membrane. Cell death induction requires complex IIa/b or necrosome formation, which occurs in the cytoplasm. In many cell types, full apoptotic or necroptotic cell death induction requires the internalization of TNF-R1 and receptosome formation to properly relay the signal inside the cell. We interrogated the role of the enzyme A disintegrin and metalloprotease 17 (ADAM17)/TACE (TNF-α converting enzyme) in death receptor signaling in human hematopoietic cells, using pharmacological inhibition and genetic ablation. We show that in U937 and Jurkat cells the absence of ADAM17 does not abrogate, but rather increases TNF mediated cell death. Likewise, cell death triggered via DR3 is enhanced in U937 cells lacking ADAM17. We identified ADAM17 as the key molecule that fine-tunes death receptor signaling. A better understanding of cell fate decisions made via the receptors of the TNF-R1 superfamily may enable us, in the future, to more efficiently treat infectious and inflammatory diseases or cancer.

We performed an on-sky MCAO experiment using 4 deformable mirrors (DMs) to analyze the relevance of their sequence to the residual wavefront error. Two DMs were conjugate to 4 and 8 km. The other two DMs were placed in pupil images upstream and downstream of the 4-km and 8-km mirrors. At any time, both high altitude DMs were active but only one pupil DM was active while the other one stayed flat. Firstly, we found that the MCAO control loops using either pupil DM were stable and robust. Dynamic misregistration, which was present for the first pupil DM, was not an immediate problem for the controller. We did not notice an apparent difference when repeatedly switching between the pupil DMs during the operation. A closer analysis of the contrast in the corrected images and AO telemetry indicates an advantage when the pupil correction was applied with the DM that was downstream of the high-altitude DMs. This finding is consistent in several data recorded at different days. The difference, however, is small. A more detailed analysis is probably needed to rule out error sources potentially not considered herein to draw a final conclusion on the optimal sequence of DMs in MCAO and its practical relevance.

IL-6 signaling via its receptor (IL-6R) and co-receptor (gp130) performs multiple roles in regulating metabolic homeostasis. However, gp130 is also expressed systemically in a soluble form (sgp130), which limits soluble IL-6 receptor (sIL-6R)-mediated signaling – also called trans-signaling. Here we find that transgenic peripheral sgp130-mediated trans-signaling blockade induces mature-onset obesity, while differentially affecting age-dependent behavioral determinants of energy expenditure. In youth, trans-signaling blockade increases feeding associated with reduced leptin sensitivity but increases energy expenditure to maintain metabolic balance. In aging, reduced physical activity predisposes mice to adiposity, adipose tissue macrophage recruitment, hepatosteatosis, hyperglycemia, and insulin resistance. Mechanistically, trans-signaling blockade reduces hepatic Stat3 phosphorylation and suppresses PPARα, associated with miR-21 upregulation, while pharmacological activation of PPARα prevents obesity and hepatosteatosis, and rescues insulin sensitivity. Together these experiments reveal a role for peripheral IL-6 trans-signaling in metabolic homeostasis and provide clinical significance to elevated sgp130 levels found in some obese and diabetic patients.

Background Biallelic variants in IL6ST, encoding GP130, cause a recessive form of hyper-IgE syndrome (HIES) characterized by high IgE level, eosinophilia, defective acute phase response, susceptibility to bacterial infections, and skeletal abnormalities due to cytokine-selective loss of function in GP130, with defective IL-6 and IL-11 and variable oncostatin M (OSM) and IL-27 levels but sparing leukemia inhibitory factor (LIF) signaling. Objective Our aim was to understand the functional and structural impact of recessive HIES-associated IL6ST variants. Methods We investigated a patient with HIES by using exome, genome, and RNA sequencing. Functional assays assessed IL-6, IL-11, IL-27, OSM, LIF, CT-1, CLC, and CNTF signaling. Molecular dynamics simulations and structural modeling of GP130 cytokine receptor complexes were performed. Results We identified a patient with compound heterozygous novel missense variants in IL6ST (p.Ala517Pro and the exon-skipping null variant p.Gly484_Pro518delinsArg). The p.Ala517Pro variant resulted in a more profound IL-6– and IL-11–dominated signaling defect than did the previously identified recessive HIES IL6ST variants p.Asn404Tyr and p.Pro498Leu. Molecular dynamics simulations suggested that the p.Ala517Pro and p.Asn404Tyr variants result in increased flexibility of the extracellular membrane–proximal domains of GP130. We propose a structural model that explains the cytokine selectivity of pathogenic IL6ST variants that result in recessive HIES. The variants destabilized the conformation of the hexameric cytokine receptor complexes, whereas the trimeric LIF-GP130-LIFR complex remained stable through an additional membrane-proximal interaction. Deletion of this membrane-proximal interaction site in GP130 consequently caused additional defective LIF signaling and Stuve-Wiedemann syndrome. Conclusion Our data provide a structural basis to understand clinical phenotypes in patients with IL6ST variants.

Das Booklet ist Ergebnis eines Masterseminars zur stadtebaulichen Denkmalpflege an der Otto-Friedrich-Universitat Bamberg. Es basiert auf den ertragreichen Recherchen und Arbeiten von 16 StudentInnen im Masterstudiengang Denkmalpflege / Heritage Conservation. Hierin werden Stadtkarten als historische Quellen vorgestellt. Exemplarisch zeigen die Studierendenarbeiten, wie diese Dokumente digital uberlagert und damit im Kontext neu interpretiert werden konnen und welche Erkenntnisse man dadurch einerseits uber die Karten und ihre Entstehung und andererseits uber die Stadtentwicklung bei Kriegsende und im Wiederaufbau gewinnen kann.

The GP130 cytokine receptor subunit encoded by IL6ST is the shared receptor for ten cytokines of the IL-6 family. We describe a homozygous non-synonymous variant in IL6ST (p.R281Q) in a patient with craniosynostosis and retained deciduous teeth. We characterize the impact of the variant on cytokine signaling in vitro using transfected cell lines as well as primary patient-derived cells and support these findings using a mouse model with the corresponding genome-edited variant Il6st p.R279Q. We show that human GP130 p.R281Q is associated with selective loss of IL-11 signaling without affecting IL-6, IL-27, OSM, LIF, CT1, CLC, and CNTF signaling. In mice Il6st p.R279Q lowers litter size and causes facial synostosis and teeth abnormalities. The effect on IL-11 signaling caused by the GP130 variant shows incomplete penetrance but phenocopies aspects of IL11RA deficiency in humans and mice. Our data show that a genetic variant in a pleiotropic cytokine receptor can have remarkably selective defects.

Metastasis is the major cause of death in cancer patients. Circulating tumor cells need to migrate through the endothelial layer of blood vessels to escape the hostile circulation and establish metastases at distant organ sites. Here, we identified the membrane-bound metalloprotease ADAM17 on endothelial cells as a key driver of metastasis. We show that TNFR1-dependent tumor cell–induced endothelial cell death, tumor cell extravasation, and subsequent metastatic seeding is dependent on the activity of endothelial ADAM17. Moreover, we reveal that ADAM17-mediated TNFR1 ectodomain shedding and subsequent processing by the γ-secretase complex is required for the induction of TNF-induced necroptosis. Consequently, genetic ablation of ADAM17 in endothelial cells as well as short-term pharmacological inhibition of ADAM17 prevents long-term metastases formation in the lung. Thus, our data identified ADAM17 as a novel essential regulator of necroptosis and as a new promising target for antimetastatic and advanced-stage cancer therapies.

International audience; Objective: Cannabis consumption during adolescence has been reported as a risk factor for psychotic-like experiences (PLEs) and schizophrenia. However, brain developmental processes associated with cannabis-related PLEs are still poorly described.Method: A total of 706 adolescents from the general population who were recruited by the IMAGEN consortium had structural magnetic resonance imaging scans at both 14 and 19 years of age. We used deformation-based morphometry to map voxelwise brain changes between the two time points, using the pairwise algorithm in SPM12b. We used an a priori region-of-interest approach focusing on the hippocampus/parahippocampus to perform voxelwise linear regressions. Lifetime cannabis consumption was assessed using the European School Survey Project on Alcohol and other Drugs (ESPAD), and PLEs were assessed with the Comprehensive Assessment Psychotic-like experiences (CAPE) tool. We first tested whether hippocampus/parahippocampus development was associated with PLEs. Then we formulated and tested an a priori simple mediation model in which uncus development mediates the association between lifetime cannabis consumption and PLEs.Results: We found that PLEs were associated with reduced expansion within a specific region of the right hippocampus/parahippocampus formation, the uncus (p = .002 at the cluster level, p = .018 at the peak level). The partial simple mediation model revealed a significant total effect from lifetime cannabis consumption to PLEs (b = 0.069, 95% CI = 0.04−0.1, p =2 × 10−16), as well as a small yet significant, indirect effect of right uncus development (0.004; 95% CI = 0.0004−0.01, p = .026).Conclusion: We show here that the uncus development is involved in the cerebral basis of PLEs in a population-based sample of healthy adolescents

Background & Aims Interleukin (IL)-6 cytokine family members contribute to inflammatory and regenerative processes. Engagement of the signaling receptor subunit gp130 is common to almost all members of the family. In the liver, all major cell types respond to IL-6-type cytokines, making it difficult to delineate cell type-specific effects. We therefore generated mouse models for liver cell type-specific analysis of IL-6 signaling. Methods We produced mice with a Cre-inducible expression cassette encoding a designed pre-dimerized constitutive active gp130 variant. We bred these mice to different Cre-drivers to induce transgenic gp130 signaling in distinct liver cell types: hepatic stellate cells, cholangiocytes/liver progenitor cells or hepatocytes. We phenotyped these mice using multi-omics approaches, immunophenotyping and a bacterial infection model. Results Hepatocyte-specific gp130 activation led to the upregulation of innate immune system components, including acute-phase proteins. Consequently, we observed peripheral mobilization and recruitment of myeloid cells to the liver. Hepatic myeloid cells, including liver-resident Kupffer cells were instructed to adopt a bactericidal phenotype which ultimately conferred enhanced resistance to bacterial infection in these mice. We demonstrate that persistent hepatocyte-specific gp130 activation resulted in amyloid A amyloidosis in aged mice. In contrast, we did not observe overt effects of hepatic stellate cell- or cholangiocyte/liver progenitor cell-specific transgenic gp130 signaling. Conclusions Hepatocyte-specific gp130 activation alone is sufficient to trigger a robust innate immune response in the absence of NF-κB activation. We therefore conclude that gp130 engagement, e.g. by IL-6 trans-signaling, represents a safe-guard mechanism in innate immunity. Lay summary Members of the interleukin-6 cytokine family signal via the receptor subunit gp130 and are involved in multiple processes in the liver. However, as several liver cell types respond to interleukin-6 family cytokines, it is difficult to delineate cell type-specific effects. Using a novel mouse model, we provide evidence that hepatocyte-specific gp130 activation is sufficient to trigger a robust systemic innate immune response.