Humane invariante natürliche Killer-T-Zellen unterdrücken die Alloreaktivität von T-Zellen und kontrollieren das Tumorwachstum in vitro

Nach aktuellen Hochrechnungen erkranken weltweit pro Jahr ca. 350 000 Menschen an einer Leukämie (Miranda-Filho et al., 2018). Oftmals stellt für diese Patienten eine allogene SZT die letzte und einzige kurative Therapieoption dar. Durch die allogene SZT konnten seit ihrer ersten Anwendung im Jahr 1968 tausende Leben gerettet werden, aber trotz zahlreicher Optimierungen bleibt die Entstehung einer GvHD noch immer eine der Hauptkomplikationen die zu einer beträchtlichen Morbidität und Mortalität führt. Aktuelle angewandte immunsuppressive Therapien zur Behandlung einer GvHD sind zwar wirkungsvoll, gehen aber mit einer Reduktion des GvL-Effekts einher, was in erhöhten Rezidivraten resultiert, weshalb noch immer mit Nachdruck nach neuen Strategien zur GvHD-Prävention gesucht wird. Ein hoffnungsvoller neuer Ansatz zur Prävention einer GvHD ist die Entwicklung einer Zytotherapie auf Basis von iNKT-Zellen. Neueste Studien zeigen, dass Patienten, die eine hohe Anzahl an iNKT-Zellen mit dem Transplantat gespendet bekommen, signifikant seltener eine GvHD entwickeln (Rubio et al., 2012; Malard et al., 2016). Zudem konnte in präklinischen Mausmodellen demonstriert werden, dass der adoptive Transfer von iNKT-Zellen verlässlich vor einer letalen GvHD schützt, ohne dass dabei der zur Tumorkontrolle nötige GvL-Effekt dabei verloren geht (Schneidawind et al., 2014; Schneidawind et al., 2015). Im Rahmen dieser Arbeit konnte gezeigt werden, dass auch humane expandierte iNKT-Zellen sowohl die Aktivierung als auch die Proliferation alloreaktiver T-Zellen in vitro, durch die Eliminierung von allogenen Mo-DCs, unterdrücken können. Die Eliminierung allogener Mo-DCs vermitteln iNKT-Zellen über die Freisetzung der Apoptose-induzierenden Moleküle Perforin und Granzym, infolge einer direkten CD1d-TCR-abhängigen Interaktion. Neben der Unterdrückung alloreaktiver T-Zellen waren expandierte iNKT-Zellen außerdem in der Lage, Tumorzellen in vitro direkt zu lysieren. Aufgrund der Tatsache, dass expandierte iNKT-Zellen durch die Unterdrückung alloreaktiver T-Zellen und über die direkte Lyse von Tumorzellen sowohl das Potenzial zur GvHD-Prävention als auch zu Tumorkontrolle besitzen, scheint der adoptive Transfer von iNKT-Zellen eine sinnvolle Optimierung der allogenen SZT zu sein

Inequality and Income Dynamics in Germany

We provide a comprehensive analysis of income inequality and income dynamics for Germany over the last two decades. Combining personal income tax and social security data allows us – for the first time – to offer a complete picture of the distribution of annual earnings in Germany. We find that cross-sectional inequality rose until 2009 for men and women. After the Great Recession inequality continued to rise at a slower rate for men and fell slightly for women due to compression at the lower tail. We further document substantial gender differences in average earnings and inequality over the life-cycle. While for men earnings rise and inequality falls as they grow older, many women reduce working hours when starting a family such that average earnings fall and inequality increases. Men’s earnings changes are on average smaller than women’s but are substantially more affected by the business cycle. During the Great Recession, men’s earnings losses become magnified and gains are attenuated. Apart from recession years, earnings changes are significantly right-skewed reflecting the good overall state of the German labor market and increasing labor supply. In the second part of the paper, we study the distribution of total income including incomes of self-employed, business owners, and landlords. We find that total inequality increased significantly more than earnings inequality. Regarding income dynamics, entrepreneurs’ income changes are more dispersed, less skewed, less leptokurtic and less dependent on average past income than workers’ income changes. Finally, we find that top income earners have become less likely to fall out of the top 1 and 0.1 percent

Behavioural endophenotypes in mice lacking the auxiliary GABAB receptor subunit KCTD16

Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the brain and is implicated in the pathophysiology of a number of neuropsychiatric disorders. The GABAB receptors are G-protein coupled receptors consisting of principle subunits and auxiliary potassium channel tetramerization domain (KCTD) subunits. The KCTD subunits 8, 12, 12b and 16 are cytosolic proteins that determine the kinetics of the GABAB receptor response. Previously, we demonstrated that Kctd12 null mutant mice (Kctd12(-/-)) exhibit increased auditory fear learning and that Kctd12(+/-) mice show altered circadian activity, as well as increased intrinsic excitability in hippocampal pyramidal neurons. KCTD16 has been demonstrated to influence neuronal excitability by regulating GABAB receptor-mediated gating of postsynaptic ion channels. In the present study we investigated for behavioural endophenotypes in Kctd16(-/-) and Kctd16(+/-) mice. Compared with wild-type (WT) littermates, auditory and contextual fear conditioning were normal in both Kctd16(-/-) and Kctd16(+/-) mice. When fear memory was tested on the following day, Kctd16(-/-) mice exhibited less extinction of auditory fear memory relative to WT and Kctd16(+/-) mice, as well as more contextual fear memory relative to WT and, in particular, Kctd16(+/-) mice. Relative to WT, both Kctd16(+/-) and Kctd16(-/-) mice exhibited normal circadian activity. This study adds to the evidence that auxillary KCTD subunits of GABAB receptors contribute to the regulation of behaviours that could constitute endophenotypes for hyper-reactivity to aversive stimuli in neuropsychiatric disorders

Relationship between a Self-Reported History of Depression and Persistent Elevation in C-Reactive Protein after Myocardial Infarction.

BACKGROUND Elevated levels of C-reactive protein (CRP) are associated with both an increased risk of cardiovascular disease (CVD) and depression. We aimed to test the hypothesis that a self-report history of depression is associated with a smaller decrease in CRP levels from hospital admission to 3-month follow-up in patients with acute myocardial infarction (MI). METHODS We assessed 183 patients (median age 59 years; 84% men) with verified MI for a self-report history of lifetime depression and plasma CRP levels within 48 h of an acute coronary intervention and again for CRP levels at three months. CRP values were categorized according to their potential to predict CVD risk at hospital admission (acute inflammatory response: 0 to <5 mg/L, 5 to <10 mg/L, 10 to <20 mg/L, and ≥20 mg/L) and at 3 months (low-grade inflammation: 0 to <1 mg/L, 1 to <3 mg/L, and ≥3 mg/L). Additionally, in a subsample of 84 patients showing admission CRP levels below 20 mg/L, changes in continuous CRP values over time were also analyzed. RESULTS After adjustment for a range of potentially important covariates, depression history showed a significant association with a smaller decrease in both CRP risk categories (r = 0.261, p < 0.001) and log CRP levels (r = 0.340, p = 0.005) over time. CONCLUSIONS Self-reported history of depression may be associated with persistently elevated systemic inflammation three months after MI. This finding warrants studies to test whether lowering of inflammation in patients with an acute MI and a history of depression may improve prognosis

Relationship between a Self-Reported History of Depression and Persistent Elevation in C-Reactive Protein after Myocardial Infarction

Background: Elevated levels of C-reactive protein (CRP) are associated with both an increased risk of cardiovascular disease (CVD) and depression. We aimed to test the hypothesis that a self-report history of depression is associated with a smaller decrease in CRP levels from hospital admission to 3-month follow-up in patients with acute myocardial infarction (MI). Methods: We assessed 183 patients (median age 59 years; 84% men) with verified MI for a self-report history of lifetime depression and plasma CRP levels within 48 h of an acute coronary intervention and again for CRP levels at three months. CRP values were categorized according to their potential to predict CVD risk at hospital admission (acute inflammatory response: 0 to <5 mg/L, 5 to <10 mg/L, 10 to <20 mg/L, and ≥20 mg/L) and at 3 months (low-grade inflammation: 0 to <1 mg/L, 1 to <3 mg/L, and ≥3 mg/L). Additionally, in a subsample of 84 patients showing admission CRP levels below 20 mg/L, changes in continuous CRP values over time were also analyzed. Results: After adjustment for a range of potentially important covariates, depression history showed a significant association with a smaller decrease in both CRP risk categories (r = 0.261, p < 0.001) and log CRP levels (r = 0.340, p = 0.005) over time. Conclusions: Self-reported history of depression may be associated with persistently elevated systemic inflammation three months after MI. This finding warrants studies to test whether lowering of inflammation in patients with an acute MI and a history of depression may improve prognosis

Leaf Mass per Area of Wetland Vegetation under Water Stress Analyzed with Imaging Spectroscopy

Plant and community traits of wetland vegetation show a high intra-specific plasticity, originating from the high variability of environmental conditions. Remote sensing approaches promise to be able to retrieve some of these traits and their plasticity from the spectral reflectance signal of the canopy. In the present study, we evaluate a remote-sensing based approach for an analysis of spatial patterns of leaf mass per area (LMA), a key trait for ecosystem functioning and good negative correlate of potential growth rate. The test was conducted in Las Tablas de Daimiel, a National Park in Central Spain. This wetland was affected by a long-term drought, which introduced pronounced trait plasticity as part of the adaptation mechanisms of the vegetation to reduced water availability as well as a decrease in photosynthetic activity. Imaging spectroscopy (HyMap) data of the wetland were acquired in 2009 at peak drought intensity. At the same time, a field campaign was conducted. We applied an inversion of the PROSAIL model on these data to map the LMA distribution across the wetland. PROSAIL is a radiative transfer model that simulates the physical principles of light absorption and scattering in a vegetation canopy. The inversion enables the retrieval of trait information from the spectral signal. Furthermore, we assessed trends in photosynthetic activity and changing species composition across the wetland by analyzing time series of the normalized difference vegetation index (NDVI) as determined from various multispectral sensors. The mapped LMA values were analyzed within and between stands of different species and communities along a gradient of changing photosynthetic activity and species composition. LMA values retrieved for stands of species with high photosynthetic activity at peak drought intensity closely met values reported in trait data bases. The observed intra-specific LMA variability is in line with the expected plasticity of this trait along a moisture gradient that is reflected in a change in photosynthetic activity and species composition. We thus conclude that remote sensing approaches provide sufficient detail to trace the LMA-response of wetland vegetation to long-term drought stress

Inequality and income dynamics in Germany

We provide a comprehensive analysis of income inequality and income dynamics for Germany over the last two decades. Combining personal income tax and social security data allows us – for the first time – to offer a complete picture of the distribution of annual earnings in Germany. We find that cross-sectional inequality rose until 2009 for men and women. After the Great Recession inequality continued to rise at a slower rate for men and fell slightly for women due to compression at the lower tail. We further document substantial gender differences in average earnings and inequality over the life-cycle. While for men earnings rise and inequality falls as they grow older, many women reduce working hours when starting a family such that average earnings fall and inequality increases. Men’s earnings changes are on average smaller than women’s but are substantially more affected by the business cycle. During the Great Recession, men’s earnings losses become magnified and gains are attenuated. Apart from recession years, earnings changes are significantly right-skewed reflecting the good overall state of the German labor market and increasing labor supply. In the second part of the paper, we study the distribution of total income including incomes of self-employed, business owners, and landlords. We find that total inequality increased significantly more than earnings inequality. Regarding income dynamics, entrepreneurs’ income changes are more dispersed, less skewed, less leptokurtic and less dependent on average past income than workers’ income changes. Finally, we find that top income earners have become less likely to fall out of the top 1 and 0.1 percent.Accepted manuscrip