Hypoxia Inducible Factor (HIF)-1 Coordinates Induction of Toll-Like Receptors TLR2 and TLR6 during Hypoxia

During acute infection and inflammation, dramatic shifts in tissue metabolism are typical, thereby resulting in profound tissue hypoxia. Therefore, we pursued the hypothesis, that tissue hypoxia may influence innate immune responses by transcriptional modulation of Toll-like receptor (TLRs) expression and function.We gained first insight from transcriptional profiling of murine dendritic cells exposed to hypoxia (2% oxygen for 24 h). While transcript levels of other TLRs remained unchanged, we found a robust induction of TLR2 (2.36+/-0.7-fold; P<0.05) and TLR6 (3.46+/-1.56-fold; P<0.05). Additional studies in different cells types and cell-lines including human dendritic cells, monocytic cells (MM6), endothelia (HMEC-1) or intestinal epithelia (Caco-2) confirmed TLR2 and TLR6 induction of transcript, protein and function during hypoxia. Furthermore, analysis of the putative TLR2 and TLR6 promoters revealed previously unrecognized binding sites for HIF-1, which were shown by chromatin immunoprecipitation to bind the pivotal hypoxia-regulating transcription factor HIF-1alpha. Studies using loss and gain of function of HIF-1 confirmed a critical role of HIF-1alpha in coordinating TLR2 and TLR6 induction. Moreover, studies of murine hypoxia (8% oxygen over 6 h) showed TLR2 and TLR 6 induction in mucosal organs in vivo. In contrast, hypoxia induction of TLR2 and TLR6 was abolished in conditional HIF-1alpha mutant mice.Taking together, these studies reveal coordinated induction of TLR2 and TLR6 during hypoxia and suggest tissue hypoxia in transcriptional adaptation of innate immune responses during acute infection or inflammation

Digitalisierung im Unterricht. Individuelle Förderplanung durch die App SPLINT

Die Digitalisierung gilt in unserer heutigen Gesellschaft im Bildungsbereich als Chance des Lehrens und Lernens. Sie findet zunehmend verstärkt Einzug in den Schulalltag und bietet großes Potenzial, die Unterrichtsgestaltung zu vereinfachen sowie die individuelle Förderplanung zu optimieren. Mit der Web App SPLINT, welche im Jahr 2020 vom Sonderpädagogen Friedo Scharf entwickelt wurde, werden diese Vorstellungen in einer App vereint. Die SPLINT-App wurde aus der Praxis entwickelt und hält sowohl Beobachtungs- als auch Formulierungshilfen für Pädagog:innen aller Schulformen bereit. Innerhalb kürzester Zeit können individuelle Förderpläne erstellt und zusammen mit den Kolleg:innen bearbeitet werden. Mit Hilfe einer Fragebogenerhebung bei einer Stichprobe von 1000 Lehrer:innen an 150 Schulen in Deutschland wurden von Februar bis Juni 2021 erste Erfahrungen hinsichtlich der Effektivität und der Praxistauglichkeit der App erhoben und ausgewertet. Die Ergebnisse machen deutlich, dass die Arbeit mit der App von den Befragten als gewinnbringend für den schulischen Alltag eingeschätzt wird. Insbesondere werden den Bereichen Kollaboration, Ressourcen und dem Netzwerkeffekt eine besonders hohe Relevanz zugeschrieben. Weiterhin hat sich gezeigt, dass sich durch die Anwendung der App die Förderplanung in den Kollegien deutlich verbessert hat. Die in SPLINT vorhandenen Beobachtungsbögen ermöglichen es, strukturierte Beobachtungen aller Beteiligten einzubeziehen, die als Basis der Förderplanung dienen. (DIPF/Orig.

Projektreport : Schulkommunikation im digitalen Wandel : Entwicklung eines Führungsinstruments für Schulleitungen für die Kommunikation von Schulen mit Erziehungsberechtigten

https://www.zhaw.ch/schulkommunikation https://blog.zhaw.ch/languagematters/2021/04/27/schulkommunikation-digital

Different Response of Ptch Mutant and Ptch Wildtype Rhabdomyosarcoma Toward SMO and PI3K Inhibitors

Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma with poor prognosis. RMS frequently show Hedgehog (HH) pathway activity, which is predominantly seen in the embryonal subtype (ERMS). They also show activation of Phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) signaling. Here we compared the therapeutic effectiveness and the impact on HH target gene expression of Smoothened (SMO) antagonists with those of the PI3K inhibitor pictilisib in ERMS with and without mutations in the HH receptor Patched1 (PTCH). Our data demonstrate that growth of ERMS showing canonical Hh signaling activity due to Ptch germline mutations is efficiently reduced by SMO antagonists. This goes along with strong downregulation of the Hh target Gli1. Likewise Ptch mutant tumors are highly responsive toward the PI3K inhibitor pictilisib, which involves modulation of AKT and caspase activity. Pictilisib also modulates Hh target gene expression, which, however, is rather not correlated with its antitumoral effects. In contrast, sporadic ERMS, which usually express HH target genes without having PTCH mutation, apparently lack canonical HH signaling activity. Thus, stimulation by Sonic HE (SHH) or SAG (Smoothened agonist) or inhibition by SMO antagonists do not modulate HH target gene expression. In addition, SMO antagonists do not provoke efficient anticancer effects and rather exert off-target effects. In contrast, pictilisib and other PI3K/AKT/mTOR inhibitors potently inhibit cellular growth. They also efficiently inhibit HH target gene expression. However, of whether this is correlated with their antitumoral effects it is not clear. Together, these data suggest that PI3K inhibitors are a good and reliable therapeutic option for all ERMS, whereas SMO inhibitors might only be beneficial for ERMS driven by PTCH mutations

Man against machine reloaded : performance of a market-approved convolutional neural network in classifying a broad spectrum of skin lesions in comparison with 96 dermatologists working under less artificial conditions

Copyright © 2019 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.Background: Convolutional neural networks (CNNs) efficiently differentiate skin lesions by image analysis. Studies comparing a market-approved CNN in a broad range of diagnoses to dermatologists working under less artificial conditions are lacking. Materials and methods: One hundred cases of pigmented/non-pigmented skin cancers and benign lesions were used for a two-level reader study in 96 dermatologists (level I: dermoscopy only; level II: clinical close-up images, dermoscopy, and textual information). Additionally, dermoscopic images were classified by a CNN approved for the European market as a medical device (Moleanalyzer Pro, FotoFinder Systems, Bad Birnbach, Germany). Primary endpoints were the sensitivity and specificity of the CNN's dichotomous classification in comparison with the dermatologists’ management decisions. Secondary endpoints included the dermatologists’ diagnostic decisions, their performance according to their level of experience, and the CNN's area under the curve (AUC) of receiver operating characteristics (ROC). Results: The CNN revealed a sensitivity, specificity, and ROC AUC with corresponding 95% confidence intervals (CI) of 95.0% (95% CI 83.5% to 98.6%), 76.7% (95% CI 64.6% to 85.6%), and 0.918 (95% CI 0.866–0.970), respectively. In level I, the dermatologists’ management decisions showed a mean sensitivity and specificity of 89.0% (95% CI 87.4% to 90.6%) and 80.7% (95% CI 78.8% to 82.6%). With level II information, the sensitivity significantly improved to 94.1% (95% CI 93.1% to 95.1%; P < 0.001), while the specificity remained unchanged at 80.4% (95% CI 78.4% to 82.4%; P = 0.97). When fixing the CNN's specificity at the mean specificity of the dermatologists’ management decision in level II (80.4%), the CNN's sensitivity was almost equal to that of human raters, at 95% (95% CI 83.5% to 98.6%) versus 94.1% (95% CI 93.1% to 95.1%); P = 0.1. In contrast, dermatologists were outperformed by the CNN in their level I management decisions and level I and II diagnostic decisions. More experienced dermatologists frequently surpassed the CNN's performance. Conclusions: Under less artificial conditions and in a broader spectrum of diagnoses, the CNN and most dermatologists performed on the same level. Dermatologists are trained to integrate information from a range of sources rendering comparative studies that are solely based on one single case image inadequate.publishersversionPeer reviewe

A meta-analysis of the investment-uncertainty relationship

In this article we use meta-analysis to investigate the investment-uncertainty relationship. We focus on the direction and statistical significance of empirical estimates. Specifically, we estimate an ordered probit model and transform the estimated coefficients into marginal effects to reflect the changes in the probability of finding a significantly negative estimate, an insignificant estimate, or a significantly positive estimate. Exploratory data analysis shows that there is little empirical evidence for a positive relationship. The regression results suggest that the source of uncertainty, the level of data aggregation, the underlying model specification, and differences between short- and long-run effects are important sources of variation in study outcomes. These findings are, by and large, robust to the introduction of a trend variable to capture publication trends in the literature. The probability of finding a significantly negative relationship is higher in more recently published studies. JEL Classification: D21, D80, E22 1

COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P &lt; 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men

"… das war fast Glück!" Interview mit Franz Schuh

Was kann das sein, die Utopie des Wiener Gemeindebaus? Franz Schuh, Schriftsteller und Essayist, beantwortet diese Frage mit der Beschreibung alltäglicher Erfahrungen der Menschen, denen der Gemeindebau ein Dach über dem Kopf gibt. Utopie kann eine neue Heizung sein, die Jahre der Kälte und Mühsal beendet, und sie kann eine Form des Zusammenlebens sein, in der etwa die Kinderbetreuung gemeinsam organisiert wird. Franz Schuh, geboren 1947, ist im Gemeindebau aufgewachsen. Seine Erinnerungen an die Kindheit sind Teil seines 2008 bei Zsolnay erschienen Buches Memoiren. Ein Interview gegen mich selbst. Im Gespräch, das Julia Rosenberger und Florian Bettel im März 2012 mit dem Autor geführt haben, bezieht Franz Schuh seine Ausführungen auf den Gemeindebau seiner Kindheit. Den Versuch von Wiener Wohnen beispielsweise, ein „problemloses und angenehmes“ Zusammenleben über Regeln herzustellen, kommentiert Franz Schuh damit, dass das Leben früher „nicht dramatisiert durch Verbote und Regeln“ gewesen sei, vielmehr habe die Arbeit, die als Absicherung gegen die omnipräsente Armut galt, dominiert. Das Utopische des Gemeindebaus in den 1950er-Jahren vermutet Schuh also nicht im ideologischen Kampf des Proletariats, sondern in der Sehnsucht nach Sicherheit in einer von Instabilität und Armut geprägten kapitalistischen Gesellschaft

Strategisches Kommunikationsmanagement von Kliniken in der digitalen Transformation

Wie für alle Organisationen bedeutet Digitalisierung auch für die öffentlichen Krankenhäuser in der Schweiz nicht nur, neue Technologien einzuführen, sondern auch ihre organisationalen Strukturen zu verändern. Gleichzeitig verlangt dies, die Führungs- und Unternehmenskultur anzupassen, um intern und extern Verständnis für die digitale Transformation zu schaffen. Somit hängt das Gelingen dieser großen Veränderungsprozesse auch vom strategischen Kommunikationsmanagement ab. Explorativ wurden fünf Expert*inneninterviews mit Kommunikationsverantwortlichen durchgeführt. Mit dem Framework der Rolle von Corporate Communications in der digitalen Transformation als Grundlage wurden die Funktionen und Aufgaben des strategischen Kommunikationsmanagements der Krankenhäuser auf der Mikro-, Meso- und Makroebene betrachtet. Die Ergebnisse zeigen, dass die Kommunikation zwar die Funktion auf der Mikroebene übernimmt, die digitale Kommunikation und Transformation der Krankenhäuser zu ermöglichen, dass diese Digitalisierung der Kommunikation aber zugleich die ökonomische Orientierung des strategischen Kommunikationsmanagements verstärkt. Dies verhindert ein Stück weit das Mitgestalten der digitalen Transformation der Krankenhäuser und das Schaffen von Akzeptanz für diesen Prozess durch die strategische Kommunikation