The activation of mixed lineage kinase-like (MLKL) by receptor-interacting protein kinase-3 (RIPK3) results in plasma membrane (PM) disruption and a form of regulated necrosis, called necroptosis. ...Here, we show that, during necroptosis, MLKL-dependent calcium (Ca2+) influx and phosphatidylserine (PS) exposure on the outer leaflet of the plasma membrane preceded loss of PM integrity. Activation of MLKL results in the generation of broken, PM “bubbles” with exposed PS that are released from the surface of the otherwise intact cell. The ESCRT-III machinery is required for formation of these bubbles and acts to sustain survival of the cell when MLKL activation is limited or reversed. Under conditions of necroptotic cell death, ESCRT-III controls the duration of plasma membrane integrity. As a consequence of the action of ESCRT-III, cells undergoing necroptosis can express chemokines and other regulatory molecules and promote antigenic cross-priming of CD8+ T cells.
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•Phosphatidylserine is exposed prior to loss of cell integrity during necroptosis•ESCRT-III facilitates the shedding of MLKL-damaged plasma membrane from intact cells•ESCRT-III supports cell survival and functions downstream of active MLKL•ESCRT-III allows necroptotic cells to signal surrounding cells
Cells undergoing necroptosis are not always headed towards death; ESCRT-III helps preserve the plasma membrane in these cells, contributing to survival.
Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) constitutes life-threatening autoimmune diseases affecting every organ, including the kidneys, where they cause necrotizing ...crescentic glomerulonephritis. ANCA activates neutrophils and activated neutrophils damage the endothelium, leading to vascular inflammation and necrosis. Better understanding of neutrophil-mediated AAV disease mechanisms may reveal novel treatment strategies. Here we report that ANCA induces neutrophil extracellular traps (NETs) via receptor-interacting protein kinase (RIPK) 1/3- and mixed-lineage kinase domain-like (MLKL)-dependent necroptosis. NETs from ANCA-stimulated neutrophils caused endothelial cell (EC) damage in vitro. This effect was prevented by (i) pharmacologic inhibition of RIPK1 or (ii) enzymatic NET degradation. The alternative complement pathway (AP) was recently implicated in AAV, and C5a inhibition is currently being tested in clinical studies. We observed that NETs provided a scaffold for AP activation that in turn contributed to EC damage. We further established the in vivo relevance of NETs and the requirement of RIPK1/3/MLKL-dependent necroptosis, specifically in the bone marrow-derived compartment, for disease induction using murine AAV models and in human kidney biopsies. In summary, we identified a mechanistic link between ANCA-induced neutrophil activation, necroptosis, NETs, the AP, and endothelial damage. RIPK1 inhibitors are currently being evaluated in clinical trials and exhibit a novel therapeutic strategy in AAV.
Das soziale Entschädigungsrecht ist auf viele und oft wenig bekannte Einzelgesetze verteilt. Es bewegt nur einen sehr kleinen Teil des Sozialbudgets. Schon deshalb ist es kein Lieblingskind von ...Journalisten, Politikern und Wissenschaftlern. Licht fällt auf es nur am Rand, wenn Flutkatastrophen und Straßenkrawalle kurzzeitig für Aufsehen sorgen.Tatsächlich aber wirft das soziale Entschädigungsrecht ganz grundlegende Fragen einer staatlichen Verantwortungsübernahme auf, die im Zusammenhang mit dem privaten und öffentlich-rechtlichen Haftungsrecht stehen. Was unterscheidet es vom gemeinhin eigenständig behandelten Staatshaftungsrecht? Wieso übernimmt der Staat die Aufgabe, für einen Schadensausgleich zu sorgen? Warum wird bis heute auf Katastrophen und Krawalle nur mit Einzelgesetzen ad hoc reagiert?Die Beantwortung erfolgt in drei Schritten: erstens durch eine Bestandsaufnahme, die Randbereiche und internationale Vorgaben auch in historischer und vergleichender Perspektive einbezieht; zweitens durch eine Systematisierung, die normative Grundvorstellungen über die Verpflichtung zum Schadensausgleich aufnimmt; und drittens durch Überlegungen, wie bestehende Entschädigungstatbestände zu ordnen, neue anzuerkennen und alle diese im Wege einer Kodifikation zusammenzufassen sind.
Acute kidney injury (AKI) is morphologically characterized by a synchronized plasma membrane rupture of cells in a specific section of a nephron, referred to as acute tubular necrosis (ATN). Whereas ...the involvement of necroptosis is well characterized, genetic evidence supporting the contribution of ferroptosis is lacking. Here, we demonstrate that the loss of ferroptosis suppressor protein 1 (Fsp1) or the targeted manipulation of the active center of the selenoprotein glutathione peroxidase 4 (Gpx4
) sensitize kidneys to tubular ferroptosis, resulting in a unique morphological pattern of tubular necrosis. Given the unmet medical need to clinically inhibit AKI, we generated a combined small molecule inhibitor (Nec-1f) that simultaneously targets receptor interacting protein kinase 1 (RIPK1) and ferroptosis in cell lines, in freshly isolated primary kidney tubules and in mouse models of cardiac transplantation and of AKI and improved survival in models of ischemia-reperfusion injury. Based on genetic and pharmacological evidence, we conclude that GPX4 dysfunction hypersensitizes mice to ATN during AKI. Additionally, we introduce Nec-1f, a solid inhibitor of RIPK1 and weak inhibitor of ferroptosis.
Nationaler, unionaler und menschenrechtlicher Grundrechtsschutz haben zwar ihre eigenen Funktionen, sind aber nicht voneinander abgegrenzt, sondern mit‐ einander vernetzt. Das führt zu einem ...europäischen Grundrechtepluralismus, der praktisch immer wichtiger wird, wie sich am Beispiel der Grundrechte der Arbeit belegen lässt: Ihr Schutz führt derzeit zu aufsehenerregenden Fällen, die in allen drei Grundrechtsordnungen die jeweils zuständigen Gerichte beschäftigen und Konfliktlinien offenlegen. Die Konflikte lassen sich nicht allein auf der Grundlage nationaler Kollisionsregeln lösen, wenn ein international vereinbarter Schutz ernst genommen werden soll. Vielmehr sind alle Akteure gehalten, die geltenden Grundrechtsordnungen zu respektieren. Das setzt auch die Bereitschaft voraus, vergleichend voneinander zu lernen.
Social insurance thrives, among other things, on the involvement of employers. This cooperation has remained important to the present day. In fact, in some Western European countries, employers are ...duty bound more than before, for example in cases of work accidents or continued payments of wages in the event of sickness. In the USSR, “employers“ were in a different position from the outset: their companies were state-owned and therefore, administrative state duties in the field of social security could be delegated to them at any time. The purpose of these conference proceedings is to investigate how the role of the Russian employer in the social security system has changed compared to the situation during the USSR era. Which legal liability is ascribed to employers today? Does the enforcement of employees’ entitlements to social benefits depend on the fulfilment of employers’ obligations in the fields of social insurance and occupational safety law? The answer to these questions contributes fundamentally to the understanding of Russian social security law. An analysis of the main aspects of the topic is given from a Russian point of view and subsequently summarised and expanded upon from a German point of view.
Evidence suggests an increasing demand for culturally and linguistically responsive disease prevention programs and health interventions. It is important to understand how individuals seek health ...information to address the potential needs of the health care system.
Latent classes of health information-seeking behaviors in a linguistically mixed region of Italy were explored through a population-based telephone survey of ten health information sources. Data were collected in August and September 2014 from 504 adults in South Tyrol, Italy (primary language German, 68%; Italian, 28%), and analyzed using latent class analysis and latent class multinomial logistic regression models.
Three classes of health information-seeking behaviors emerged: "multidimensional" (23.3%), "interpersonal" (38.6%) and "technical/online" (38.1%). Compared to the "technical/online" class, "interpersonal" class members were older, had lower education than high school, and were less likely to be of Italian ethnicity. "Multidimensional" class members were more likely to be female, older, and of German ethnicity than those in the "technical/online" class.
Linguistic ethnicity explains membership in classes on health information-seeking behavior. Policymakers and healthcare providers should consider the health information-seeking behaviors of population subgroups to promote health and medical care in linguistic minority groups.
O Tribunal Constitucional Federal depreende da Lei Fundamental um direito de defesa contra a ameaça de destruição dos fundamentos de nossa ordem calcada na liberdade. Isso constitui o cerne de sua ...decisão sobre a proteção do clima. Pergunta-se se, com isso, indivíduos também recebem um poder jurídico para controlar o futuro do Estado Social. A conformação deste último depende, com efeito, não só da definição do objetivo do Estado (Art. 20.º, 1 da Lei Fundamental LF), mas também de diretrizes dos direitos fundamentais. Estas, porém, assentam-se, por sua vez, em uma jurisprudência – modificada em seu conjunto – sobre funções dos direitos fundamentais e a separação dos poderes que, por sua vez, preparou o caminho para a decisão sobre a proteção climática.
Background Belief in complementary and alternative medicine practices is related to reduced preparedness for vaccination. This study aimed to assess home remedy awareness and use in South Tyrol, ...where vaccination rates in the coronavirus pandemic were lowest in Italy and differed between German- and Italian-speaking inhabitants. Methods A population-based survey was conducted in 2014 and analyzed using descriptive statistics, multiple logistic regression, and latent class analysis. Results Of the representative sample of 504 survey respondents, 357 (70.8%) participants (43.0% male; primary language German, 76.5%) reported to use home remedies. Most commonly reported home remedies were teas (48.2%), plants (21.0%), and compresses (19.5%). Participants from rural regions were less likely (odds ratio 0.35, 95% confidence interval 0.19-0.67), while female (2.62, 1.69-4.10) and German-speaking participants (5.52, 2.91-9.88) were more likely to use home remedies. Latent classes of home remedies were "alcoholic home remedies" (21.4%) and "non-alcohol-containing home remedies" (78.6%). Compared to the "non-alcohol-containing home remedies" class, members of the "alcoholic home remedies" class were more likely to live in an urban region, to be male and German speakers. Conclusion In addition to residence and sex, language group membership associates with awareness and use of home remedies. Home remedies likely contribute to socio-cultural differences between the language groups in the Italian Alps. If the observed associations explain the lower vaccination rates in South Tyrol among German speakers requires further study. Keywords: Language group, Vaccine hesitancy, Complementary and alternative medicine, Latent class analysis
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