Effekte und Mechanismen nach Inhibition des 26S Proteasoms in humanen dendritischen Zellen und T-Zellen

Das Proteasom stellt die zentrale proteolytische Maschinerie des hoch konservierten Ubiquitin-Proteasom-Systems (UPS) dar. Dieses System ist für die Regulation und Aufrechterhaltung von wesentlichen zellulären Prozessen, wie z.B. Differenzierung, Proliferation, Zellzyklus, Gentranskription und Apoptose erforderlich. In dieser Arbeit sollte untersucht werden, inwiefern die spezifischen Proteasom-Inhibitoren Bortezomib, Lactacystin und Epoxomycin essentielle Immunfunktionen von aus Monozyten-generierten humanen DCs und von durch allogene DCs aktivierte humane CD4+ T-Zellen supprimieren. Darüber hinaus sollten die Mechanismen der Apoptose-Induktion in aktivierten CD4+ T-Zellen durch den Proteasom-Inhibitor Bortezomib aufgeklärt werden. In der vorliegenden Arbeit konnte gezeigt werden, dass die Inhibition der proteolytischen Aktivität des 26S Proteasom in humanen unreifen DC (iDC) und reifen DC (mDC) die Expression wichtiger Zelloberflächenrezeptoren von DCs supprimiert, Apoptose induziert und die Maturation von DCs inhibiert. Weiterhin konnte gezeigt werden, dass eine Proteasom-Inhibition die Makropinozytose und Rezeptor-vermittelte Endozytose von Antigenen einschränkt und die Synthese von Interleukin (IL)-12p70 und IL-12p40 hemmt. Als funktionelle Konsequenz, zeigten mDCs, welche eine Proteasom-Inhibition überlebten, eine deutlich supprimierte Kapazität allogene CD4+ und CD8+ T-Zellen und autologe CD4+T-Zellen zu stimulieren. Ferner konnte diese Arbeit demonstrieren, dass eine Proteasom-Inhibition in aktivierten CD4+ T-Zellen Apoptose induziert. Aktivierte CD4+ T-Zellen, die die Proteasom-Inhibition überlebten, zeigten eine Inhibition der Proliferation durch die Induktion eines Zellzyklus-Arrests in der G1-Phase. Dieses ging einher mit der Akkumulation von Proteinen, welche bekanntermaßen die Transition des Zellzyklus von der G1- in die S-Phase steuern. Des Weiteren konnte demonstriert werden, dass aktivierte CD4+ T-Zellen nach Proteasom-Inhibition eine verringerte Expression von mit einer Aktivierung assoziierten Zelloberflächenrezeptoren sowie eine verringerte Produktion von inflammatorischen Zytokinen aufweisen. Darüber hinaus konnte in der vorliegenden Arbeit gezeigt werden, dass eine Proteasom-Inhibition die Aktivierung und nukleäre Translokation von NFATc2 und die proteasomale Degradation des Inhibitor of kappaB-alpha- (IkappaBalpha-) Protein in aktivierten CD4+ T-Zellen inhibiert. Die Proteasom-Inhibition aktivierte den mitochondrialen Apoptoseweg in aktivierten CD4+ T-Zellen. Dieses erfolgte über eine Störung des Gleichgewichts zwischen pro- und anti-apoptotischen Proteinen an der äußeren mitochondrialen Membran. Die rasche Freisetzung der intramitochondrialen pro-apoptotischen Proteine Smac/DIABLO und HtrA2 antagonisierte die IAP-vermittelte Inhibition der moderat proteolytisch-aktiven Caspasen und eine rasche Zunahme der Caspase-3-Aktivität vor einer Caspase-9-Aktivitäts-Steigerung konnte demonstriert werden. Daraus kann geschlossen werden, dass Caspase-3 im Verlauf einer Proteasom-Inhibition in aktivierten CD4+ T-Zellen den intrinsischen Apoptoseweg initiiert. Caspase-9 fungiert dagegen nur als Apoptose-Verstärker. Insgesamt demonstriert die vorliegende Arbeit, dass die proteasomale Aktivität für essentielle Funktionen von humanen DCs und aktivierten humanen CD4+ T-Zellen benötigt wird und ein molekulares Ziel für eine Suppression von dysregulierten und unerwünschten Immunantworten definiert werden kann

Adaptive modification and flexibility of the proteasome system in response to proteasome inhibition

AbstractThe highly conserved ubiquitin–proteasome system is the principal machinery for extralysosomal protein degradation in eukaryotic cells. The 26S proteasome, a large multicatalytic multisubunit protease that processes cell proteins by limited and controlled proteolysis, constitutes the central proteolytic component of the ubiquitin–proteasome system. By processing cell proteins essential for development, differentiation, proliferation, cell cycling, apoptosis, gene transcription, signal transduction, senescence, and inflammatory and stress response, the 26S proteasome plays a key role in the regulation and maintenance of basic cellular processes. Various synthetic and biologic inhibitors with different inhibitory profiles towards the proteolytic activities of the 26S proteasome have been identified recently. Such proteasome inhibitors induce apoptosis and cell cycle arrest preferentially in neoplastic cells. Based on these findings proteasome inhibitors became useful in cancer therapy. However, under the pressure of continuous proteasome inhibition, eukaryotic cells can develop complex adaptive mechanisms to subvert the lethal attack of proteasome inhibitors. Such mechanisms include the adaptive modification of the proteasome system with increased expression, enhanced proteolytic activity and altered subcomplex assembly and subunit composition of proteasomes as well as the expression of a giant oligomeric protease complex, tripeptidyl peptidase II, which partially compensates for impaired proteasome function. Here we review the adaptive mechanisms developed by eukaryotic cells in response to proteasome inhibition. These mechanisms reveal enormous flexibility of the proteasome system and may have implications in cancer biology and therapy

Revealing the nano-structures of low-dimensional germanium on Ag(1 1 0) using XPS and XPD

In this work, we present a structural investigation of sub-monolayer films of germanium on Ag(1 1 0) by means of photoelectron spectroscopy (XPS) and diffraction (XPD), as well as low-energy electron diffraction (LEED). Since the rising progress in the synthesis of various kinds of nanoribbons, also germanium nanoribbons (Ge-NR) have been synthesized on Ag(1 1 0), recently. Here, we focus on their structural evolution and found the formation of two different phases of germanium at coverages of 0.5ML and 0.7ML, differing fundamentally from predicted nanoribbon structures. By means of LEED measurements, we obtained evidence for germanium superstructures which are not aligned along the [1¯¯¯10]-direction, as expected for nanoribbon growth. Using synchrotron-based high-resolution XPS and XPD experiments of the Ge 3d and Ag 3d core-levels, we resolved the local chemical and atomic order of the germanium films. Thus, the strong internal bonding of the buckled germanium film and a weak Van-der-Waals interaction between silver and germanium were discovered. Moreover, XPD-simulations delivered a detailed model of the structural arrangement of the preliminary nanoribbon phase, which also provided an approach to identify the origin of the two chemically shifted components in the Ge 3d signal by applying a component-wise decomposition of the XPD data

Tracing the structural evolution of quasi-freestanding germanene on Ag(111)

In the last decade, research on 2D materials has expanded massively due to the popularity of graphene. Although the chemical engineering of two-dimensional elemental materials as well as heterostructures has been extensively pursued, the fundamental understanding of the synthesis of 2D materials is not yet complete. Structural parameters, such as buckling or the interface structure of a 2D material to the substrate directly affect its electronic characteristics. In order to proceed the understanding of the element-specific growth and the associated ability of tuning material properties of two-dimensional materials, we performed a study on the structural evolution of the promising 2D material germanene on Ag(111). This study provides a survey of germanium formations at different layer thicknesses right up to the arising of quasi-freestanding germanene. Using powerful surface analysis tools like low-energy electron diffraction, x-ray photoelectron spectroscopy, and x-ray photoelectron diffraction with synchrotron radiation, we will reveal the internal and interfacial structure of all discovered germanium phases. Moreover, we will present models of the atomic and chemical structure of a Ag2Ge surface alloy and the quasi-freestanding germanene with special focus on the structural parameters and electronic interaction at the interface

Exposure to Inhalable, Respirable, and Ultrafine Particles in Welding Fume

This investigation aims to explore determinants of exposure to particle size-specific welding fume. Area sampling of ultrafine particles (UFP) was performed at 33 worksites in parallel with the collection of respirable particles. Personal sampling of respirable and inhalable particles was carried out in the breathing zone of 241 welders. Median mass concentrations were 2.48 mg m−3 for inhalable and 1.29 mg m−3 for respirable particles when excluding 26 users of powered air-purifying respirators (PAPRs). Mass concentrations were highest when flux-cored arc welding (FCAW) with gas was applied (median of inhalable particles: 11.6 mg m−3). Measurements of particles were frequently below the limit of detection (LOD), especially inside PAPRs or during tungsten inert gas welding (TIG). However, TIG generated a high number of small particles, including UFP. We imputed measurements <LOD from the regression equation with manganese to estimate determinants of the exposure to welding fume. Concentrations were mainly predicted by the welding process and were significantly higher when local exhaust ventilation (LEV) was inefficient or when welding was performed in confined spaces. Substitution of high-emission techniques like FCAW, efficient LEV, and using PAPRs where applicable can reduce exposure to welding fume. However, harmonizing the different exposure metrics for UFP (as particle counts) and for the respirable or inhalable fraction of the welding fume (expressed as their mass) remains challenging

Height and body-mass index trajectories of school-aged children and adolescents from 1985 to 2019 in 200 countries and territories: a pooled analysis of 2181 population-based studies with 65 million participants

Summary Background Comparable global data on health and nutrition of school-aged children and adolescents are scarce. We aimed to estimate age trajectories and time trends in mean height and mean body-mass index (BMI), which measures weight gain beyond what is expected from height gain, for school-aged children and adolescents. Methods For this pooled analysis, we used a database of cardiometabolic risk factors collated by the Non-Communicable Disease Risk Factor Collaboration. We applied a Bayesian hierarchical model to estimate trends from 1985 to 2019 in mean height and mean BMI in 1-year age groups for ages 5–19 years. The model allowed for non-linear changes over time in mean height and mean BMI and for non-linear changes with age of children and adolescents, including periods of rapid growth during adolescence. Findings We pooled data from 2181 population-based studies, with measurements of height and weight in 65 million participants in 200 countries and territories. In 2019, we estimated a difference of 20 cm or higher in mean height of 19-year-old adolescents between countries with the tallest populations (the Netherlands, Montenegro, Estonia, and Bosnia and Herzegovina for boys; and the Netherlands, Montenegro, Denmark, and Iceland for girls) and those with the shortest populations (Timor-Leste, Laos, Solomon Islands, and Papua New Guinea for boys; and Guatemala, Bangladesh, Nepal, and Timor-Leste for girls). In the same year, the difference between the highest mean BMI (in Pacific island countries, Kuwait, Bahrain, The Bahamas, Chile, the USA, and New Zealand for both boys and girls and in South Africa for girls) and lowest mean BMI (in India, Bangladesh, Timor-Leste, Ethiopia, and Chad for boys and girls; and in Japan and Romania for girls) was approximately 9–10 kg/m2. In some countries, children aged 5 years started with healthier height or BMI than the global median and, in some cases, as healthy as the best performing countries, but they became progressively less healthy compared with their comparators as they grew older by not growing as tall (eg, boys in Austria and Barbados, and girls in Belgium and Puerto Rico) or gaining too much weight for their height (eg, girls and boys in Kuwait, Bahrain, Fiji, Jamaica, and Mexico; and girls in South Africa and New Zealand). In other countries, growing children overtook the height of their comparators (eg, Latvia, Czech Republic, Morocco, and Iran) or curbed their weight gain (eg, Italy, France, and Croatia) in late childhood and adolescence. When changes in both height and BMI were considered, girls in South Korea, Vietnam, Saudi Arabia, Turkey, and some central Asian countries (eg, Armenia and Azerbaijan), and boys in central and western Europe (eg, Portugal, Denmark, Poland, and Montenegro) had the healthiest changes in anthropometric status over the past 3·5 decades because, compared with children and adolescents in other countries, they had a much larger gain in height than they did in BMI. The unhealthiest changes—gaining too little height, too much weight for their height compared with children in other countries, or both—occurred in many countries in sub-Saharan Africa, New Zealand, and the USA for boys and girls; in Malaysia and some Pacific island nations for boys; and in Mexico for girls. Interpretation The height and BMI trajectories over age and time of school-aged children and adolescents are highly variable across countries, which indicates heterogeneous nutritional quality and lifelong health advantages and risks

Rising rural body-mass index is the main driver of the global obesity epidemic in adults

Body-mass index (BMI) has increased steadily in most countries in parallel with a rise in the proportion of the population who live in cities(.)(1,2) This has led to a widely reported view that urbanization is one of the most important drivers of the global rise in obesity(3-6). Here we use 2,009 population-based studies, with measurements of height and weight in more than 112 million adults, to report national, regional and global trends in mean BMI segregated by place of residence (a rural or urban area) from 1985 to 2017. We show that, contrary to the dominant paradigm, more than 55% of the global rise in mean BMI from 1985 to 2017-and more than 80% in some low- and middle-income regions-was due to increases in BMI in rural areas. This large contribution stems from the fact that, with the exception of women in sub-Saharan Africa, BMI is increasing at the same rate or faster in rural areas than in cities in low- and middle-income regions. These trends have in turn resulted in a closing-and in some countries reversal-of the gap in BMI between urban and rural areas in low- and middle-income countries, especially for women. In high-income and industrialized countries, we noted a persistently higher rural BMI, especially for women. There is an urgent need for an integrated approach to rural nutrition that enhances financial and physical access to healthy foods, to avoid replacing the rural undernutrition disadvantage in poor countries with a more general malnutrition disadvantage that entails excessive consumption of low-quality calories.Peer reviewe

Worldwide trends in hypertension prevalence and progress in treatment and control from 1990 to 2019: a pooled analysis of 1201 population-representative studies with 104 million participants.

BACKGROUND: Hypertension can be detected at the primary health-care level and low-cost treatments can effectively control hypertension. We aimed to measure the prevalence of hypertension and progress in its detection, treatment, and control from 1990 to 2019 for 200 countries and territories. METHODS: We used data from 1990 to 2019 on people aged 30-79 years from population-representative studies with measurement of blood pressure and data on blood pressure treatment. We defined hypertension as having systolic blood pressure 140 mm Hg or greater, diastolic blood pressure 90 mm Hg or greater, or taking medication for hypertension. We applied a Bayesian hierarchical model to estimate the prevalence of hypertension and the proportion of people with hypertension who had a previous diagnosis (detection), who were taking medication for hypertension (treatment), and whose hypertension was controlled to below 140/90 mm Hg (control). The model allowed for trends over time to be non-linear and to vary by age. FINDINGS: The number of people aged 30-79 years with hypertension doubled from 1990 to 2019, from 331 (95% credible interval 306-359) million women and 317 (292-344) million men in 1990 to 626 (584-668) million women and 652 (604-698) million men in 2019, despite stable global age-standardised prevalence. In 2019, age-standardised hypertension prevalence was lowest in Canada and Peru for both men and women; in Taiwan, South Korea, Japan, and some countries in western Europe including Switzerland, Spain, and the UK for women; and in several low-income and middle-income countries such as Eritrea, Bangladesh, Ethiopia, and Solomon Islands for men. Hypertension prevalence surpassed 50% for women in two countries and men in nine countries, in central and eastern Europe, central Asia, Oceania, and Latin America. Globally, 59% (55-62) of women and 49% (46-52) of men with hypertension reported a previous diagnosis of hypertension in 2019, and 47% (43-51) of women and 38% (35-41) of men were treated. Control rates among people with hypertension in 2019 were 23% (20-27) for women and 18% (16-21) for men. In 2019, treatment and control rates were highest in South Korea, Canada, and Iceland (treatment >70%; control >50%), followed by the USA, Costa Rica, Germany, Portugal, and Taiwan. Treatment rates were less than 25% for women and less than 20% for men in Nepal, Indonesia, and some countries in sub-Saharan Africa and Oceania. Control rates were below 10% for women and men in these countries and for men in some countries in north Africa, central and south Asia, and eastern Europe. Treatment and control rates have improved in most countries since 1990, but we found little change in most countries in sub-Saharan Africa and Oceania. Improvements were largest in high-income countries, central Europe, and some upper-middle-income and recently high-income countries including Costa Rica, Taiwan, Kazakhstan, South Africa, Brazil, Chile, Turkey, and Iran. INTERPRETATION: Improvements in the detection, treatment, and control of hypertension have varied substantially across countries, with some middle-income countries now outperforming most high-income nations. The dual approach of reducing hypertension prevalence through primary prevention and enhancing its treatment and control is achievable not only in high-income countries but also in low-income and middle-income settings. FUNDING: WHO

Worldwide trends in hypertension prevalence and progress in treatment and control from 1990 to 2019: a pooled analysis of 1201 population-representative studies with 104 million participants

Background Hypertension can be detected at the primary health-care level and low-cost treatments can effectively control hypertension. We aimed to measure the prevalence of hypertension and progress in its detection, treatment, and control from 1990 to 2019 for 200 countries and territories. Methods We used data from 1990 to 2019 on people aged 30-79 years from population-representative studies with measurement of blood pressure and data on blood pressure treatment. We defined hypertension as having systolic blood pressure 140 mm Hg or greater, diastolic blood pressure 90 mm Hg or greater, or taking medication for hypertension. We applied a Bayesian hierarchical model to estimate the prevalence of hypertension and the proportion of people with hypertension who had a previous diagnosis (detection), who were taking medication for hypertension (treatment), and whose hypertension was controlled to below 140/90 mm Hg (control). The model allowed for trends over time to be non-linear and to vary by age. Findings The number of people aged 30-79 years with hypertension doubled from 1990 to 2019, from 331 (95% credible interval 306-359) million women and 317 (292-344) million men in 1990 to 626 (584-668) million women and 652 (604-698) million men in 2019, despite stable global age-standardised prevalence. In 2019, age-standardised hypertension prevalence was lowest in Canada and Peru for both men and women; in Taiwan, South Korea, Japan, and some countries in western Europe including Switzerland, Spain, and the UK for women; and in several low-income and middle-income countries such as Eritrea, Bangladesh, Ethiopia, and Solomon Islands for men. Hypertension prevalence surpassed 50% for women in two countries and men in nine countries, in central and eastern Europe, central Asia, Oceania, and Latin America. Globally, 59% (55-62) of women and 49% (46-52) of men with hypertension reported a previous diagnosis of hypertension in 2019, and 47% (43-51) of women and 38% (35-41) of men were treated. Control rates among people with hypertension in 2019 were 23% (20-27) for women and 18% (16-21) for men. In 2019, treatment and control rates were highest in South Korea, Canada, and Iceland (treatment >70%; control >50%), followed by the USA, Costa Rica, Germany, Portugal, and Taiwan. Treatment rates were less than 25% for women and less than 20% for men in Nepal, Indonesia, and some countries in sub-Saharan Africa and Oceania. Control rates were below 10% for women and men in these countries and for men in some countries in north Africa, central and south Asia, and eastern Europe. Treatment and control rates have improved in most countries since 1990, but we found little change in most countries in sub-Saharan Africa and Oceania. Improvements were largest in high-income countries, central Europe, and some upper-middle-income and recently high-income countries including Costa Rica, Taiwan, Kazakhstan, South Africa, Brazil, Chile, Turkey, and Iran. Interpretation Improvements in the detection, treatment, and control of hypertension have varied substantially across countries, with some middle-income countries now outperforming most high-income nations. The dual approach of reducing hypertension prevalence through primary prevention and enhancing its treatment and control is achievable not only in high-income countries but also in low-income and middle-income settings. Copyright (C) 2021 World Health Organization; licensee Elsevier

Worldwide trends in hypertension prevalence and progress in treatment and control from 1990 to 2019: a pooled analysis of 1201 population-representative studies with 104 million participants

Background Hypertension can be detected at the primary health-care level and low-cost treatments can effectively control hypertension. We aimed to measure the prevalence of hypertension and progress in its detection, treatment, and control from 1990 to 2019 for 200 countries and territories. Methods We used data from 1990 to 2019 on people aged 30–79 years from population-representative studies with measurement of blood pressure and data on blood pressure treatment. We defined hypertension as having systolic blood pressure 140 mm Hg or greater, diastolic blood pressure 90 mm Hg or greater, or taking medication for hypertension. We applied a Bayesian hierarchical model to estimate the prevalence of hypertension and the proportion of people with hypertension who had a previous diagnosis (detection), who were taking medication for hypertension (treatment), and whose hypertension was controlled to below 140/90 mm Hg (control). The model allowed for trends over time to be non-linear and to vary by age. Findings The number of people aged 30–79 years with hypertension doubled from 1990 to 2019, from 331 (95% credible interval 306–359) million women and 317 (292–344) million men in 1990 to 626 (584–668) million women and 652 (604–698) million men in 2019, despite stable global age-standardised prevalence. In 2019, age-standardised hypertension prevalence was lowest in Canada and Peru for both men and women; in Taiwan, South Korea, Japan, and some countries in western Europe including Switzerland, Spain, and the UK for women; and in several low-income and middle-income countries such as Eritrea, Bangladesh, Ethiopia, and Solomon Islands for men. Hypertension prevalence surpassed 50% for women in two countries and men in nine countries, in central and eastern Europe, central Asia, Oceania, and Latin America. Globally, 59% (55–62) of women and 49% (46–52) of men with hypertension reported a previous diagnosis of hypertension in 2019, and 47% (43–51) of women and 38% (35–41) of men were treated. Control rates among people with hypertension in 2019 were 23% (20–27) for women and 18% (16–21) for men. In 2019, treatment and control rates were highest in South Korea, Canada, and Iceland (treatment >70%; control >50%), followed by the USA, Costa Rica, Germany, Portugal, and Taiwan. Treatment rates were less than 25% for women and less than 20% for men in Nepal, Indonesia, and some countries in sub-Saharan Africa and Oceania. Control rates were below 10% for women and men in these countries and for men in some countries in north Africa, central and south Asia, and eastern Europe. Treatment and control rates have improved in most countries since 1990, but we found little change in most countries in sub-Saharan Africa and Oceania. Improvements were largest in high-income countries, central Europe, and some upper-middle-income and recently high-income countries including Costa Rica, Taiwan, Kazakhstan, South Africa, Brazil, Chile, Turkey, and Iran. Interpretation Improvements in the detection, treatment, and control of hypertension have varied substantially across countries, with some middle-income countries now outperforming most high-income nations. The dual approach of reducing hypertension prevalence through primary prevention and enhancing its treatment and control is achievable not only in high-income countries but also in low-income and middle-income settings