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Dank intensiver Forschung konnte Stickstoffmonoxid (NO) innerhalb der letzten Jahrzehnte als ein gasförmiges Signalmolekül (second messenger) identifiziert werden, das innerhalb der Zelle verschiedene Signalkaskaden beeinflusst. Dabei spielt sowohl der Syntheseort als auch die synthetisierte NO-Menge eine entscheidende Rolle für die Spezifität des über NO vermittelten Signals. Dies spiegelt sich unter Anderem in den zahlreichen regulatorischen Mechanismen, denen die NO-Synthasen unterliegen, wider. In jüngster Vergangenheit konnte gezeigt werden, dass nicht nur der Aktivitätsstatus der NO-Synthasen, sondern ebenfalls deren subzelluläre Lokalisation durch solche Mechanismen entscheidend beeinflusst werden. Von besonderer Bedeutung scheinen dabei mit den NO-Synthasen interagierende Proteine zu sein. So resultiert beispielsweise eine Überexpression von NOSIP – einem eNOS interagierenden Protein – in CHO-NOS-Zellen in einer Umverteilung von eNOS von der Plasmamembran hin zu intrazellulären Kompartimenten. Diese Umverteilung führt zu einem signifikanten Aktivitätsverlust der eNOS. Die physiologische Relevanz dieser Interaktion wird sowohl durch den Interaktionsnachweis der endogenen Proteine in Endothelzellen als auch durch eine weitreichende Co-Expression in Gastro-Intestinaltrakt, Leber und Bauchspeicheldrüse der Ratte gestützt.
Eine nähere Charakterisierung dieser Interaktion war bisher jedoch noch nicht erfolgt. Auch blieben die biochemischen Eigenschaften von endogenem NOSIP bisher unerforscht. Daher war es Ziel dieser Arbeit, endogenes NOSIP näher zu charakterisieren und dadurch die Voraussetzungen für eine physiologische Interaktion zwischen NOSIP und eNOS aufzuklären. Dabei konnte festgestellt werden, dass es sich bei NOSIP um ein überwiegend nukleär lokalisiertes Protein handelt. Diese nukleäre Lokalisation wird über ein zweiteiliges Kernlokalisationssignal (NLS = nuclear localisation signal) vermittelt. Sukzessive Mutation dieses Signals resultiert in einer zytoplasmatischen Akkumulation von NOSIP. Ferner ist das NLS nach Fusion an heterologe Proteine in der Lage, deren Lokalisation in Richtung Zellkern zu verschieben. In Heterokaryon-Assays konnte gezeigt werden, dass NOSIP zusätzlich aus dem Kern exportiert wird und daher ein zwischen Kern und Zytoplasma wanderndes Protein ist. Dieses „trafficking“ wird über ein dynamisches Gleichgewicht aus Kernimport und Kernexport reguliert. Der Kernexport von NOSIP wird durch einen ungewöhnlichen - nicht durch Leptomycin B inhibierbaren - Mechanismus bewerkstelligt. Entsprechend findet sich innerhalb der NOSIP-Sequenz kein typisches, leucinreiches Exportsignal, durch welches gewöhnlich Kernexport über Bindung an Crm1 (chromosome region maintenance 1) vermittelt wird. Das dynamische Gleichgewicht zwischen Kernimport und Kernexport, verschiebt sich in Abhängigkeit vom Zellzyklus in der G2-Phase in Richtung Export, was in einer zytoplasmatischen Akkumulation von NOSIP resultiert. Beeinflusst wird das dynamische Gleichgewicht dabei möglicherweise von einer Interaktion zwischen NOSIP und der Zellzyklus-regulatorischen Kinase CDK1 (cyclin dependent kinase 1).
In Bezug auf eNOS ist diese zytoplasmatische Lokalisation von NOSIP von entscheidender Bedeutung, wie in vergleichenden Transfektionsexperimenten mit zytoplasmatischen NOSIP-Mutanten in CHO-NOS-Zellen gezeigt werden konnte. Danach vermittelt ausschließlich Transfektion dieser Mutanten eine Translokation von eNOS an das Aktin-Zytoskelett, während natives, primär nukleär lokalisiertes NOSIP keinen Einfluss auf die eNOS-Lokalisation hat. Analog dazu resultiert die zytoplasmatische Akkumulation von endogenem NOSIP in der G2-Phase des Zellzyklus ebenfalls in einer Translokation von eNOS an das Aktin-Zytoskelett, welche eine signifikante Aktivitätsminderung der NO-Synthase zur Folge hat. Diese zellzyklusspezifischen, eNOS-regulativen Effekte erfolgen in Abhängigkeit von endogenem zytoplasmatischem NOSIP, wie mittels RNA-Interferenzexperimente belegt werden konnte. Danach können sowohl die Umverteilung von eNOS als auch die daraus resultierende Aktivitätsminderung durch eine Expressionsunterdrückung von NOSIP vollständig inhibiert werden.
Die innerhalb dieser Arbeit erhobenen Daten stellen den ersten Bericht über eine Zellzyklusabhängige Regulation einer NOS-Isoform dar. Diese negative Regulation wird durch eine Umverteilung von eNOS an ein inaktives Kompartiment erreicht, welche wiederum über eine zellzyklusabhängige Lokalisationsänderung von NOSIP bewerkstelligt wird. In der Literatur finden sich zahlreiche Berichte über die Auswirkungen von exogen verabreichtem NO auf Zellzyklus-gesteuerte Ereignisse, wie Apoptose oder Proliferation. In diesem Zusammenhang zeigen die hier erhobenen Daten, dass die endogene NO-Menge tatsächlich zellzyklusspezifisch reguliert wird. Diese Regulation könnte möglicherweise ein Teil eines endogenen, NO-abhängigen Mechanismus darstellen, der die Apoptose und/oder die Proliferation beeinflusst.
This paper empirically examines differences in how 50-year-olds imagine their future. It draws on answers to an open-ended survey question in a large British cohort study—the National Child Development Study. Over 6,700 written responses about respondents’ imagined future are examined using text mining methods. Results from a relative frequency analysis and a topic model reveal differences according to gender, occupational class, and educational qualification. The cohort members’ written texts reflect different lifestyles. Men are more likely to mention sport, like golf and football, whereas women are more prone to use words related to family and friends. Respondents with a degree are more likely to write about cultural activities, such as museum or theater visits. Overall, the findings reveal gendered and socially stratified patterns in individual future perceptions, contextualized in relation to leisure, health, and family.
Background: Efficacy of treatment after failure of check point inhibitors (ICI) therapy remains ill-defined in metastatic renal cell carcinoma (mRCC).
Objective: To evaluate the safety and effectiveness of cabozantinib after failure of ICI-based therapies.
Design, setting and participants: Patients with mRCC who concluded cabozantinib treatment directly after an ICI-based therapy were eligible. Data was collected retrospectively from participating sites in Germany.
Interventions: Cabozantinib was administered as a standard of care.
Outcome measurements and statistical analysis
Adverse events (AE) were reported according to CTCAE v5.0. Objective response rate according to RECIST 1.1 and Progression Free Survival (PFS) were collected from medical records. Descriptive statistics and Kaplan-Meyer-plots were utilized.
Results and limitations: About 56 eligible patients (71.4% male) with median age of 66 years and clear cell histology in 66.1% (n = 37) were analyzed. 87.5% (n = 49) had ≥ 2 previous lines. IMDC risk was intermediate or poor in 17 patients (30.4%) and missing in 66.1%. 20 patients (35.7%) started with 60 mg. 55.4% (n = 31) required dose reductions, 26.8% (n = 15) treatment delays and 1.8% (n = 1) treatment discontinuation. Partial response was reported in 10.7% (n = 6), stable and progressive disease were reported in 19.6% (n = 11) and in 12.5% (n = 7). 32 patients were not evaluable (57.1%). Median treatment duration was 6.1 months. Treatment related AE were reported in 76.8% (n = 43) and 19.6% (n = 11) had grade 3-5. Fatigue (26.8%), diarrhea (26.8%) and hand-foot-syndrome (25.0%) were the 3 most frequent AEs of any grade and causality. SAE were reported in 21.4% (n = 12), 2 were fatal. Major limitation was the retrospective data capture in our study.
Conclusions: Cabozantinib followed directly after ICI-based therapy was safe and feasible. No new safety signals were reported. A lower starting dose was frequently utilized in this real-world cohort, which was associated with a favorable tolerability profile. Our data supports the use of cabozantinib after ICI treatment.
Was soll es bedeuten, dass etwas geschichtlich ist und nicht nur vergangen? Diese nur scheinbar harmlose Frage führt in ein Labyrinth verschiedener Antworten. Hier tut sich eine oft behauptete und ebenso oft bestrittene Beziehung von Geschichtlichkeit und Unsterblichkeit als Leitlinie auf. Im 18. und 19. Jahrhundert entsteht auf eher zufällige Weise eine Ideenkonstellation, in der die Unsterblichkeit der menschlichen Gattung und der einzelnen menschlichen Seele gegeneinander ausgespielt, kombiniert oder auch gemeinsam abgewiesen werden. Erschließbar durch Lektüren geschichtsphilosophischer Beiträge von Leibniz, Nietzsche, Benjamin und anderen, scheint sich für das 20. Jahrhundert zunächst abzuzeichnen, dass die Verschränkung von (Un-)Sterblichkeitsbehauptungen verschwunden ist. Doch tatsächlich hat sie sich vor allem verwandelt und verlagert. Insbesondere zeigt sich im modernen Verständnis von Normen als in die Unsterblichkeit überführten Werten ein unterschwelliger Fortbestand der älteren Konstellation. Die Studie erarbeitet eine neuartige Konzeption von Historizität, Historisierung und deren Zusammenhängen in kulturellen Erscheinungen wie der Totenfürsorge, des Humanitarismus und der Lebensrettung. Damit lassen sich zeitgenössische Welt- und Krisendeutungen bis hin zu derjenigen des Anthropozäns neu erklären.
The CP-even fractions (F+) of the decays D0→π+π−π0 and D0→K+K−π0 are measured with a quantum-correlated ψ(3770)→DD¯ data sample collected by the BESIII experiment corresponding to an integrated luminosity of 7.93 fb−1. The results are Fπ+π−π0+=0.9406±0.0036±0.0021 and FK+K−π0+=0.631±0.014±0.011, where the first uncertainties are statistical and the second systematic. These measurements are consistent with the previous determinations, and the uncertainties for Fπ+π−π0+ and FK+K−π0+ are reduced by factors of 3.9 and 2.6, respectively. The reported results provide important inputs for the precise measurement of the angle γ of the Cabibbo-Kobayashi-Maskawa matrix and indirect CP violation in charm mixing.
Charge-dependent two- and three-particle correlations measured in Xe-Xe collisions at sNN−−−√=5.44 TeV are presented. Results are obtained for charged particles in the pseudorapidity range |η|<0.8 and transverse momentum interval 0.2≤pT<5.0 GeV/c for different collision centralities. The three-particle correlator γαβ≡⟨cos(φα+φβ−2Ψ2)⟩, calculated for different combinations of charge sign α and β, is expected to be sensitive to the presence of the Chiral Magnetic Effect (CME). Its magnitude is similar to the one observed in Pb-Pb collisions in contrast to a smaller CME signal in Xe-Xe collisions than in Pb-Pb collisions predicted by Monte Carlo (MC) calculations including a magnetic field induced by the spectator protons. These observations point to a large non-CME contribution to the correlator. Furthermore, the charge dependence of γαβ can be described by a blast wave model calculation that incorporates background effects and by the Anomalous Viscous Fluid Dynamics model with values of the CME signal consistent with zero. The Xe-Xe and Pb-Pb results are combined with the expected CME signal dependence on the system size from the MC calculations including a magnetic field to obtain the fraction of CME contribution in γαβ, fCME. The CME fraction is compatible with zero for the 30% most central events in both systems and then becomes positive; averaging over the 0-70% centrality interval yields an upper limit of 2% (3%) and 25% (32%) at 95% (99.7%) confidence level for the CME signal contribution to γαβ in Xe-Xe and Pb-Pb collisions, respectively.
In high-energy heavy-ion collisions, the correlations between the emitted particles can be used as a probe to gain insight into the charge creation mechanisms. In this article, we report the first results of such studies using the electric charge balance function in the relative pseudorapidity \Delta\eta and azimuthal angle \Delta\phi in Pb-Pb collisions at sqrt{s_{NN}} = 2.76 TeV with the ALICE detector at the Large Hadron Collider. The width of the balance function decreases with growing centrality (i.e. for more central collisions) in both projections. This centrality dependence is not reproduced by HIJING, while AMPT, a model which incorporates strings and parton rescattering, exhibits qualitative agreement with the measured correlations in \Delta\phi but fails to describe the correlations in \Delta\eta. A thermal blast wave model incorporating local charge conservation and tuned to describe the p_T spectra and v_2 measurements reported by ALICE, is used to fit the centrality dependence of the width of the balance function and to extract the average separation of balancing charges at freeze-out. The comparison of our results with measurements at lower energies reveals an ordering with sqrt{s_{NN}}: the balance functions become narrower with increasing energy for all centralities. This is consistent with the effect of larger radial flow at the LHC energies but also with the late stage creation scenario of balancing charges. However, the relative decrease of the balance function widths in \Delta\eta and \Delta\phi with centrality from the highest SPS to the LHC energy exhibits only small differences. This observation cannot be interpreted solely within the framework where the majority of the charge is produced at a later stage in the evolution of the heavy-ion collision.
In high--energy heavy--ion collisions, the correlations between the emitted particles can be used as a probe to gain insight into the charge creation mechanisms. In this Letter, we report the first results of such studies using the electric charge balance function in the relative pseudorapidity (Δη) and azimuthal angle (Δφ) in Pb--Pb collisions at sNN−−−−√=2.76 TeV with the ALICE detector at the Large Hadron Collider. The width of the balance function decreases with growing centrality (i.e. for more central collisions) in both projections. This centrality dependence is not reproduced by HIJING, while AMPT, a model which incorporates strings and parton rescattering, exhibits qualitative agreement with the measured correlations in Δφ but fails to describe the correlations in Δη. A thermal blast--wave model incorporating local charge conservation and tuned to describe the pmT spectra and v2 measurements reported by ALICE, is used to fit the centrality dependence of the width of the balance function and to extract the average separation of balancing charges at freeze--out. The comparison of our results with measurements at lower energies reveals an ordering with sNN−−−−√:the balance functions become narrower with increasing energy for all centralities. This is consistent with the effect of larger radial flow at the LHC energies but also with the late stage creation scenario of balancing charges. However, the relative decrease of the balance function widths in Δη and \dphi with centrality from the highest SPS to the LHC energy exhibits only small differences. This observation cannot be interpreted solely within the framework where the majority of the charge is produced at a later stage in the evolution of the heavy--ion collision.
In high-energy heavy-ion collisions, the correlations between the emitted particles can be used as a probe to gain insight into the charge creation mechanisms. In this Letter, we report the first results of such studies using the electric charge balance function in the relative pseudorapidity (Δη) and azimuthal angle (Δφ) in Pb--Pb collisions at sNN−−−√=2.76 TeV with the ALICE detector at the Large Hadron Collider. The width of the balance function decreases with growing centrality (i.e. for more central collisions) in both projections. This centrality dependence is not reproduced by HIJING, while AMPT, a model which incorporates strings and parton rescattering, exhibits qualitative agreement with the measured correlations in Δφ but fails to describe the correlations in Δη. A thermal blast-wave model incorporating local charge conservation and tuned to describe the pT spectra and v2 measurements reported by ALICE, is used to fit the centrality dependence of the width of the balance function and to extract the average separation of balancing charges at freeze-out. The comparison of our results with measurements at lower energies reveals an ordering with sNN−−−√: the balance functions become narrower with increasing energy for all centralities. This is consistent with the effect of larger radial flow at the LHC energies but also with the late stage creation scenario of balancing charges. However, the relative decrease of the balance function widths in Δη and Δφ with centrality from the highest SPS to the LHC energy exhibits only small differences. This observation cannot be interpreted solely within the framework where the majority of the charge is produced at a later stage in the evolution of the heavy--ion collision.
In high--energy heavy--ion collisions, the correlations between the emitted particles can be used as a probe to gain insight into the charge creation mechanisms. In this Letter, we report the first results of such studies using the electric charge balance function in the relative pseudorapidity (Δη) and azimuthal angle (Δφ) in Pb--Pb collisions at sNN−−−−√=2.76 TeV with the ALICE detector at the Large Hadron Collider. The width of the balance function decreases with growing centrality (i.e. for more central collisions) in both projections. This centrality dependence is not reproduced by HIJING, while AMPT, a model which incorporates strings and parton rescattering, exhibits qualitative agreement with the measured correlations in Δφ but fails to describe the correlations in Δη. A thermal blast--wave model incorporating local charge conservation and tuned to describe the pmT spectra and v2 measurements reported by ALICE, is used to fit the centrality dependence of the width of the balance function and to extract the average separation of balancing charges at freeze--out. The comparison of our results with measurements at lower energies reveals an ordering with sNN−−−−√:the balance functions become narrower with increasing energy for all centralities. This is consistent with the effect of larger radial flow at the LHC energies but also with the late stage creation scenario of balancing charges. However, the relative decrease of the balance function widths in Δη and \dphi with centrality from the highest SPS to the LHC energy exhibits only small differences. This observation cannot be interpreted solely within the framework where the majority of the charge is produced at a later stage in the evolution of the heavy--ion collision.