Analysis of Bmp-signaling during muscle regeneration

Die Fähigkeit der Skelettmuskulatur zu Regenerieren ist auf das Vorhandensein von Stammzellen, den sogenannten Satellitenzellen, zurückzuführen. Diese befinden sich unter der Basallamina, die jede einzelne Muskelfaser umgibt. Diese Zellen können durch externe Stimuli wie Training oder Verletzung aktiviert werden. Nach der Aktivierung kommt es zum Eintritt in den Zellzyklus. Die Satellitenzellen proliferieren und bilden eine Vielzahl von Myoblasten, die während der Differenzierung mit beschädigten Muskelfasern fusionieren oder selbst neuen Muskelfasern bilden. Diese Prozesse werden von einer Vielzahl von Wachstumsfaktoren gesteuert. In dieser Arbeit wurde die Rolle des Bmp-Signalweges während der Muskelregeneration untersucht. Die detaillierte Analyse zeigte, dass ex vivo kultivierte Satellitenzellen bereits während der Aktivierung auf Bmp-Signale reagieren können. Zusätzlich konnte eine Stimulation der Satellitenzellen mit Bmps die Expression des Transkriptionsfaktors Pax7 während dieser Phase aufrechterhalten. Des Weiteren stellte sich heraus, dass Bmp-Signale die Satellitenzellen in einem aktiv proliferierenden Zustand halten. Im Gegensatz dazu verursachte die Inhibition der Bmp-Signale den Austritt der Myoblasten aus dem Zellzyklus, wodurch es zu einer verstärkten Differenzierung und der damit verbundenen Bildung von Myotuben kommt. Interessanterweise konnte die endogene Expression des Bmp-Inhibitors Chordin im Verlauf der Differenzierung in ex vivo Kulturen festgestellt werden. Diese Beobachtungen ließen vermuten, dass Bmp-Signale eine frühzeitige Differenzierung von Satellitenzellen verhindern, während die Inhibition der Bmp-Signale für den Übergang von der Proliferation in die Differenzierung benötigt wird. Um diese Funktion des Bmp-Signalweges während der Regeneration in vivo zu bestätigen, wurden die regenerierenden Muskeln von Mäusen untersucht, die ein standardisiertes Muskeltrauma erfahren hatten. Auch während der in vivo Regeneration konnte in der frühen Phase der Regeneration der aktivierte Bmp-Signalweg in den Satellitenzellen der regenerierenden Muskulatur nachgewiesen werden. In der späten Phase hingegen, in der die Myogenin Expression bereits abnahm, waren die intrazellulären Mediatoren des Bmp-Signalwegs kaum detektierbar. Die Analyse der Genexpression zeigte außerdem, dass in dieser späten Phase der Muskelregeneration der Bmp-Inhibitor Chordin deutlich höher exprimiert war als in den frühen Stadien der Regeneration. Basierend auf diesen Ergebnissen ergibt sich ein Modell, in dem der aktivierte Bmp-Signalweg während der frühen Phase der Regeneration die Proliferation der Myoblasten stimuliert und eine frühzeitige Differenzierung verhindert. Die intrinsische, zeitlich koordinierte Inhibition der Bmp-Signale während der späten Regeneration ermöglicht dann den Austritt der Myoblasten aus dem Zellzyklus und die Differenzierung in Muskelfasern.The capacity of muscle to grow or to regenerate after damage is provided by adult stem cells- so called satellite cells, which are located under the basement lamina of each myofiber. Upon activation satellite cells enter the cell cycle, proliferate and differentiate into myoblasts, which fuse to injured myofibers or form new fibers. These processes are tightly controlled by many growth factors. In this study we investigated the role of Bmp-signaling during satellite cell differentiation. Detailed analysis revealed that satellite cells respond to Bmp signals during early stages of the activation process. Furthermore, Bmp-signaling seems to support Pax7 expression at early activation stages. Bmp signaling enhances the proliferation rate thereby preventing cell cycle exit of activated satellite cells In contrast inhibition of Bmp-signaling promotes cell cycle exit leading to a reduced number of myonuclei and enhanced myotube formation. Interestingly, the Bmp inhibitor Chordin is upregulated during the differentiation process. To test if inhibition of Bmp-signaling supports the transition from proliferation to differentiation in vivo we analyzed muscle regeneration in a standardized injury mouse model. Similar to the ex vivo experiment we found Bmp-signaling activated in satellite cells at early stages of differentiation. At later stages, when Myogenin expression decreases in the trauma muscle and the intracellular mediators of Bmp-signals were hardly detectable we found Chordin expression upregulated. Based on these data we propose a role for endogenous Bmp signals in expanding the pool of proliferating satellite cells and preventing premature terminal differentiation. A temporally coordinated, intrinsic inhibition of Bmp signals by Chordin will subsequently regulate the pace of the differentiation process

BMP signaling balances proliferation and differentiation of muscle satellite cell descendants

<p>Abstract</p> <p>Background</p> <p>The capacity of muscle to grow or to regenerate after damage is provided by adult stem cells, so called satellite cells, which are located under the basement lamina of each myofiber. Upon activation satellite cells enter the cell cycle, proliferate and differentiate into myoblasts, which fuse to injured myofibers or form new fibers. These processes are tightly controlled by many growth factors.</p> <p>Results</p> <p>Here we investigate the role of bone morphogenetic proteins (BMPs) during satellite cell differentiation. Unlike the myogenic C2C12 cell line, primary satellite cells do not differentiate into osteoblasts upon BMP signaling. Instead BMP signaling inhibits myogenic differentiation of primary satellite cells <it>ex vivo</it>. In contrast, inhibition of BMP signaling results in cell cycle exit, followed by enhanced myoblast differentiation and myotube formation. Using an <it>in vivo </it>trauma model we demonstrate that satellite cells respond to BMP signals during the regeneration process. Interestingly, we found the BMP inhibitor <it>Chordin </it>upregulated in primary satellite cell cultures and in regenerating muscles. In both systems <it>Chordin </it>expression follows that of Myogenin, a marker for cells committed to differentiation.</p> <p>Conclusion</p> <p>Our data indicate that BMP signaling plays a critical role in balancing proliferation and differentiation of activated satellite cells and their descendants. Initially, BMP signals maintain satellite cells descendants in a proliferating state thereby expanding cell numbers. After cells are committed to differentiate they upregulate the expression of the BMP inhibitor <it>Chordin </it>thereby supporting terminal differentiation and myotube formation in a negative feedback mechanism.</p

Covid-19 triage in the emergency department 2.0: how analytics and AI transform a human-made algorithm for the prediction of clinical pathways

The Covid-19 pandemic has pushed many hospitals to their capacity limits. Therefore, a triage of patients has been discussed controversially primarily through an ethical perspective. The term triage contains many aspects such as urgency of treatment, severity of the disease and pre-existing conditions, access to critical care, or the classification of patients regarding subsequent clinical pathways starting from the emergency department. The determination of the pathways is important not only for patient care, but also for capacity planning in hospitals. We examine the performance of a human-made triage algorithm for clinical pathways which is considered a guideline for emergency departments in Germany based on a large multicenter dataset with over 4,000 European Covid-19 patients from the LEOSS registry. We find an accuracy of 28 percent and approximately 15 percent sensitivity for the ward class. The results serve as a benchmark for our extensions including an additional category of palliative care as a new label, analytics, AI, XAI, and interactive techniques. We find significant potential of analytics and AI in Covid-19 triage regarding accuracy, sensitivity, and other performance metrics whilst our interactive human-AI algorithm shows superior performance with approximately 73 percent accuracy and up to 76 percent sensitivity. The results are independent of the data preparation process regarding the imputation of missing values or grouping of comorbidities. In addition, we find that the consideration of an additional label palliative care does not improve the results

Lamination of the cerebral cortex is disturbed in Gli3 mutant mice

AbstractThe layered organization of the cerebral cortex develops in an inside-out pattern, a process which is controlled by the secreted protein reelin. Here we report on cortical lamination in the Gli3 hypomorphic mouse mutant XtJ/Pdn which lacks the cortical hem, a major source of reelin+ Cajal Retzius cells in the cerebral cortex. Unlike other previously described mouse mutants with hem defects, cortical lamination is disturbed in XtJ/Pdn animals. Surprisingly, these layering defects occur in the presence of reelin+ cells which are probably derived from an expanded Dbx1+ progenitor pool in the mutant. However, while these reelin+ neurons and also Calretinin+ cells are initially evenly distributed over the cortical surface they form clusters later during development suggesting a novel role for Gli3 in maintaining the proper arrangement of these cells in the marginal zone. Moreover, the radial glial network is disturbed in the regions of these clusters. In addition, the differentiation of subplate cells is affected which serve as a framework for developing a properly laminated cortex

Effect of Tip Injection on an Axial Compressor using Airflow Recirculation - Numerical Investigations

International audienceIn this paper the results of a numerical analysis concerning the impact of a passive flow control technique on a 1.5-stage axial compressor are presented. In order to examine the effects occurring due to the application of discrete tip blowing in the rotor domain, unsteady flow simulations are conducted. In low speed axial compressors the rotor blade tip area is critical concerning the effect of flow separation because of low momentum fluid in the endwall boundary layer and the rotor tip leakage vortex. These flow effects cause a loss in efficiency and are furthermore responsible for a cutback in the compressor working range. As a potential method to increase the working range the impact of recirculation ducts in the rotor casing is investigated in this study. Due to the static pressure gradient over the rotor passage fluid flows through the recirculation ducts, reenergizing the boundary layer at the leading edge of the rotor tip. Their design and positioning take the limited available space in aeroengines into account. This survey focuses on the impact of the tip blowing jet on the rotor performance, in particular the interaction of the recirculated mass flow and the tip leakage vortex will be discussed

Effect of Tip Injection on an Axial Compressor using Airflow Recirculation - Numerical Investigations

International audienceIn this paper the results of a numerical analysis concerning the impact of a passive flow control technique on a 1.5-stage axial compressor are presented. In order to examine the effects occurring due to the application of discrete tip blowing in the rotor domain, unsteady flow simulations are conducted. In low speed axial compressors the rotor blade tip area is critical concerning the effect of flow separation because of low momentum fluid in the endwall boundary layer and the rotor tip leakage vortex. These flow effects cause a loss in efficiency and are furthermore responsible for a cutback in the compressor working range. As a potential method to increase the working range the impact of recirculation ducts in the rotor casing is investigated in this study. Due to the static pressure gradient over the rotor passage fluid flows through the recirculation ducts, reenergizing the boundary layer at the leading edge of the rotor tip. Their design and positioning take the limited available space in aeroengines into account. This survey focuses on the impact of the tip blowing jet on the rotor performance, in particular the interaction of the recirculated mass flow and the tip leakage vortex will be discussed

Baseline of Physiological Body Temperature and Hematological Parameters in Captive Rousettus aegyptiacus and Eidolon helvum Fruit Bats

The discovery of bats as reservoir hosts for a number of highly pathogenic zoonotic agents has led to an increasing interest of infectious disease research in experimental studies with bats. Therefore, we established breeding colonies of Rousettus aegyptiacus and Eidolon helvum fruit bats, which both have been identified as reservoir hosts for relevant zoonotic disease agents, such as Marburg virus and Lagos bat virus. Since 2013, individuals of both species have been recruited to the Friedrich-Loeffler-Institut (FLI) from zoological gardens in Europe, to where these species had been introduced from the wild several decades ago. The aviaries have been designed according to national recommendations published by the Federal Ministry of Agriculture. Under these conditions, both species have been reproducing for years. To better understand the physiology of these animals, and to generate baseline knowledge for infection experiments, we monitored the body core temperatures of R. aegyptiacus bats in the aviaries, and found a circadian variation between 34 degrees C and 41.5 degrees C. We also determined the hematological parameters of both species, and detected specific differences between both bat species. For values of clinical chemistry, no correlation to age or sex was observed. However, species-specific differences were detected since ALT, BUN and CREA were found to be significantly higher in R. aegyptiacus and GLU and TP were significantly higher in E. helvum bats. A higher hematocrit, hemoglobin and red blood cell level was observed in subadult R. aegyptiacus, with hemoglobin and red blood cells also being significantly increased compared to E. helvum. Lymphocytes were found to be the dominant white blood cells in both species and are higher in female E. helvum. Neutrophil granulocytes were significantly higher in E. helvum bats. This underlines the necessity to define baseline profiles for each bat species prior to their use in experimental challenge

Transient acute right coronary artery deformation during transcatheter interventional tricuspid repair with the Cardioband tricuspid system

Background: The Cardioband tricuspid valve reconstruction system is a size-adjustable tricuspid reconstruction device for interventional treatment of tricuspid regurgitation (TR). Contraction of the device after successful implantation can be associated with an acute deformation of the right coronary artery (RCA). Aims: The aim of this study was to provide data on the persistence and clinical significance of acute RCA deformation following Cardioband implant procedures. Methods: Data from all patients with intraprocedural RCA deformation during Cardioband implantation were collected from four centres between October 2018 and January 2020. Control angiographies were performed in all of these patients before discharge. Results: RCA deformation occurred in 14 out of 51 patients. Follow-up coronary angiography showed a complete resolution of deformation in all cases while patients remained clinically asymptomatic and had an uneventful post-interventional course. Intraprocedural coronary stent implantation was performed in two of the earlier cases according to the personal assessment of the implanters. Conclusions: RCA deformation is relatively frequent following interventional tricuspid annuloplasty but appears to be completely reversible in the absence of flow impairment or vascular damage. Based on our early experience watchful waiting is the most appropriate strategy to avoid unnecessary coronary interventions

Transcatheter Treatment of Secondary Tricuspid Regurgitation With Direct Annuloplasty Results From a Multicenter Real-World Experience

Background: Treatment options for secondary tricuspid regurgitation (TR) remain limited. Early real-world data of a new percutaneous direct annuloplasty system for tricuspid repair were examined. Methods: The first 60 patients treated with the Cardioband tricuspid valve repair system at 4 centers were included in this retrospective study. The primary efficacy end point was technical success with reduction of TR >= 2 grades at discharge. Combined primary safety end point was major adverse events (death, myocardial infarction, cardiothoracic surgery, and stroke) at 30 days. Results: Median patient age was 76 years (73-82), median EuroScore II was 3.9% (2.2-8.1), heart failure with preserved ejection fraction was present in 78%, and 81.7% were in the New York Heart Association class III/IV. Massive or torrential TR was found in 51.7%, and severe TR in 48.3%. The primary efficacy end point was achieved in 45%, while 60.3% of patients had less-than-severe TR at discharge. Vena contracta was reduced by 47% from 12.9 +/- 4.8 to 7.0 +/- 3.4 mm (P<0.001). Overall, the majority of patients (81.7%) improved at least by 1 New York Heart Association class. At follow-up 81.3% of patients presented in the New York Heart Association class I or II. The primary safety end point occurred in 4 patients with 2 in-hospital deaths, both not device related. Right coronary artery complications (vessel perforation or stent implantation) occurred in 9 patients (15%). Procedural time decreased from 298 to 185 minutes (P<0.001) with efficacy remaining stable (P=0.817) when comparing procedure numbers 11 or more to the earliest 5 procedures per center. Conclusions: This first real-world experience suggests that transcatheter treatment of advanced secondary TR using direct annuloplasty is feasible and reasonably safe early in the learning curve, with significant symptomatic benefit. Further studies are warranted to provide data on long-term outcome and patient prognosis