Legitimation durch Verfassunggebung

PublishedTrotz der Arbeiten des EU-Verfassungskonvents zweifeln viele an der Möglichkeit europäischer Verfassunggebung, weil die EU kein Staat ist und es kein einheitliches EU-Volk gibt. Tobias Herbst untersucht, wie Hoheitsgewalt durch Verfassunggebung legitimiert werden kann. Dabei kritisiert er die simplifizierende »urheberorientierte« Vorstellung, dass legitime Verfassunggebung auf ein einheitliches, souveränes Staatsvolk zurückgehen müsse. Unter Rückgriff auf die Verfassungstheorien der Amerikanischen und der Französischen Revolution und auf die Theorie des Gesellschaftsvertrages entwirft Herbst ein Prinzipienmodell der Verfassunggebung mit drei zum Teil gegenläufigen Legitimitätsprinzipien: Freiheitssicherung, kollektive Autonomie und dauerhafte Konsensfähigkeit. Aus diesem Modell lassen sich Aussagen über die Legitimität staatlicher und supranationaler Verfassungen gewinnen. Europäische Verfassunggebung ist demnach jedenfalls möglich und setzt kein einheitliches, souveränes EU-Volk voraus. Das Buch erhellt den staatsphilosophischen Hintergrund der gegenwärtigen Diskussion über eine Europäische Verfassung und spricht damit Juristen, Politikwissenschaftler und interessierte Laien an

Revisiting Empirical Solar Energetic Particle Scaling Relations I. Solar flares

Aims The possible influence of solar superflares on the near-Earth space radiation environment are assessed through the investigation of scaling laws between the peak proton flux and fluence of Solar Energetic Particle (SEP) events with the solar flare soft X-ray peak photon flux. Methods We compiled a catalog of 65 well-connected (W20-90) SEP events during the last three solar cycles covering a period of $\sim$34 years (1984-2020) that were associated with flares of class $\geq$C6.0 and investigated the statistical relations between the recorded peak proton fluxes ($I_{P}$) and the fluences ($F_{P}$) at a set of integral energies from E $>$10; $>$30; $>$60; to $>$100 MeV versus the associated solar flare peak soft X-ray flux in the 1$-$8 A band ($F_{SXR}$). Based on the inferred relations, we calculate the integrated energy dependence of the peak proton flux ($I_{P}$) and fluence ($F_{P}$) of the SEP events, assuming that they follow an inverse power-law with respect to energy. Finally, we make use of simple physical assumptions, combining our derived scaling laws, and estimate the upper limits for $I_{P}$ and $F_{P}$ focusing on the flare associated with the strongest GLE yet directly observed (GLE 05 on 23 February 1956), and that inferred for the cosmogenic radionuclide based SEP event of AD774/775. Results We show that $I_{P}$ and $F_{P}$ scale with the solar flare SXR flux as $\propto$~$F_{SXR}^{5/6}$. For the AD774/775 event (with a re-scaled upper limit $F_{SXR}$ = X600) these scaling laws yield values of $F_{P}$ at E$>$200 MeV of $\sim$10$^{10}$ cm$^{-2}$ and $\sim$1.5 $\times$ 10$^{9}$ cm$^{-2}$ at E$>$430 MeV that are consistent with values inferred from the measurements of $^{14}$C and $^{10}$Be

Functional analysis of structural variants in single cells using Strand-seq

Somatic structural variants (SVs) are widespread in cancer, but their impact on disease evolution is understudied due to a lack of methods to directly characterize their functional consequences. We present a computational method, scNOVA, which uses Strand-seq to perform haplotype-aware integration of SV discovery and molecular phenotyping in single cells by using nucleosome occupancy to infer gene expression as a readout. Application to leukemias and cell lines identifies local effects of copy-balanced rearrangements on gene deregulation, and consequences of SVs on aberrant signaling pathways in subclones. We discovered distinct SV subclones with dysregulated Wnt signaling in a chronic lymphocytic leukemia patient. We further uncovered the consequences of subclonal chromothripsis in T cell acute lymphoblastic leukemia, which revealed c-Myb activation, enrichment of a primitive cell state and informed successful targeting of the subclone in cell culture, using a Notch inhibitor. By directly linking SVs to their functional effects, scNOVA enables systematic single-cell multiomic studies of structural variation in heterogeneous cell populations

Comparing the value of mono- vs coculture for high-throughput compound screening in hematological malignancies

Large-scale compound screens are a powerful model system for understanding variability of treatment response and discovering druggable tumor vulnerabilities of hematological malignancies. However, as mostly performed in a monoculture of tumor cells, these assays disregard modulatory effects of the in vivo microenvironment. It is an open question whether and to what extent coculture with bone marrow stromal cells could improve the biological relevance of drug testing assays over monoculture. Here, we established a high-throughput platform to measure ex vivo sensitivity of 108 primary blood cancer samples to 50 drugs in monoculture and coculture with bone marrow stromal cells. Stromal coculture conferred resistance to 52% of compounds in chronic lymphocytic leukemia (CLL) and 36% of compounds in acute myeloid leukemia (AML), including chemotherapeutics, B-cell receptor inhibitors, proteasome inhibitors, and Bromodomain and extraterminal domain inhibitors. Only the JAK inhibitors ruxolitinib and tofacitinib exhibited increased efficacy in AML and CLL stromal coculture. We further confirmed the importance of JAK-STAT signaling for stroma-mediated resistance by showing that stromal cells induce phosphorylation of STAT3 in CLL cells. We genetically characterized the 108 cancer samples and found that drug-gene associations strongly correlated between monoculture and coculture. However, effect sizes were lower in coculture, with more drug-gene associations detected in monoculture than in coculture. Our results justify a 2-step strategy for drug perturbation testing, with large-scale screening performed in monoculture, followed by focused evaluation of potential stroma-mediated resistances in coculture

Dietary spermidine for lowering high blood pressure

Loss of cardiac macroautophagy/autophagy impairs heart function, and evidence accumulates that an increased autophagic flux may protect against cardiovascular disease. We therefore tested the protective capacity of the natural autophagy inducer spermidine in animal models of aging and hypertension, which both represent major risk factors for the development of cardiovascular disease. Dietary spermidine elicits cardioprotective effects in aged mice through enhancing cardiac autophagy and mitophagy. In salt-sensitive rats, spermidine supplementation also delays the development of hypertensive heart disease, coinciding with reduced arterial blood pressure. The high blood pressure-lowering effect likely results from improved global arginine bioavailability and protection from hypertension-associated renal damage. The polyamine spermidine is naturally present in human diets, though to a varying amount depending on food type and preparation. In humans, high dietary spermidine intake correlates with reduced blood pressure and decreased risk of cardiovascular disease and related death. Altogether, spermidine represents a cardio- and vascular- protective autophagy inducer that can be readily integrated in common diets

Fine-Tuning Cardiac Insulin-Like Growth Factor 1 Receptor Signaling to Promote Health and Longevity

Background: The insulin-like growth factor 1 (IGF1) pathway is a key regulator of cellular metabolism and aging. Although its inhibition promotes longevity across species, the effect of attenuated IGF1 signaling on cardiac aging remains controversial. Methods: We performed a lifelong study to assess cardiac health and lifespan in 2 cardiomyocyte-specific transgenic mouse models with enhanced versus reduced IGF1 receptor (IGF1R) signaling. Male mice with human IGF1R overexpression or dominant negative phosphoinositide 3-kinase mutation were examined at different life stages by echocardiography, invasive hemodynamics, and treadmill coupled to indirect calorimetry. In vitro assays included cardiac histology, mitochondrial respiration, ATP synthesis, autophagic flux, and targeted metabolome profiling, and immunoblots of key IGF1R downstream targets in mouse and human explanted failing and nonfailing hearts, as well. Results: Young mice with increased IGF1R signaling exhibited superior cardiac function that progressively declined with aging in an accelerated fashion compared with wild-type animals, resulting in heart failure and a reduced lifespan. In contrast, mice with low cardiac IGF1R signaling exhibited inferior cardiac function early in life, but superior cardiac performance during aging, and increased maximum lifespan, as well. Mechanistically, the late-life detrimental effects of IGF1R activation correlated with suppressed autophagic flux and impaired oxidative phosphorylation in the heart. Low IGF1R activity consistently improved myocardial bioenergetics and function of the aging heart in an autophagy-dependent manner. In humans, failing hearts, but not those with compensated hypertrophy, displayed exaggerated IGF1R expression and signaling activity. Conclusions: Our findings indicate that the relationship between IGF1R signaling and cardiac health is not linear, but rather biphasic. Hence, pharmacological inhibitors of the IGF1 pathway, albeit unsuitable for young individuals, might be worth considering in older adults

Effectiveness and cost-effectiveness of four different strategies for SARS-CoV-2 surveillance in the general population (CoV-Surv Study): study protocol for a two-factorial randomized controlled multi-arm trial with cluster sampling

Background: To achieve higher effectiveness in population-based SARS-CoV-2 surveillance and to reliably predict the course of an outbreak, screening, and monitoring of infected individuals without major symptoms (about 40% of the population) will be necessary. While current testing capacities are also used to identify such asymptomatic cases, this rather passive approach is not suitable in generating reliable population-based estimates of the prevalence of asymptomatic carriers to allow any dependable predictions on the course of the pandemic. Methods: This trial implements a two-factorial, randomized, controlled, multi-arm, prospective, interventional, single-blinded design with cluster sampling and four study arms, each representing a different SARS-CoV-2 testing and surveillance strategy based on individuals' self-collection of saliva samples which are then sent to and analyzed by a laboratory. The targeted sample size for the trial is 10,000 saliva samples equally allocated to the four study arms (2500 participants per arm). Strategies differ with respect to tested population groups (individuals vs. all household members) and testing approach (without vs. with pre-screening survey). The trial is complemented by an economic evaluation and qualitative assessment of user experiences. Primary outcomes include costs per completely screened person, costs per positive case, positive detection rate, and precision of positive detection rate. Discussion: Systems for active surveillance of the general population will gain more importance in the context of pandemics and related disease prevention efforts. The pandemic parameters derived from such active surveillance with routine population monitoring therefore not only enable a prospective assessment of the short-term course of a pandemic, but also a more targeted and thus more effective use of local and short-term countermeasures. Trial registration: ClinicalTrials.gov DRKS00023271. Registered November 30, 2020, with the German Clinical Trials Register (Deutsches Register Klinischer Studien

Drug-microenvironment perturbations reveal resistance mechanisms and prognostic subgroups in CLL

The tumour microenvironment and genetic alterations collectively influence drug efficacy in cancer, but current evidence is limited and systematic analyses are lacking. Using chronic lymphocytic leukaemia (CLL) as a model disease, we investigated the influence of 17 microenvironmental stimuli on 12 drugs in 192 genetically characterised patient samples. Based on microenvironmental response, we identified four subgroups with distinct clinical outcomes beyond known prognostic markers. Response to multiple microenvironmental stimuli was amplified in trisomy 12 samples. Trisomy 12 was associated with a distinct epigenetic signature. Bromodomain inhibition reversed this epigenetic profile and could be used to target microenvironmental signalling in trisomy 12 CLL. We quantified the impact of microenvironmental stimuli on drug response and their dependence on genetic alterations, identifying interleukin 4 (IL4) and Toll-like receptor (TLR) stimulation as the strongest actuators of drug resistance. IL4 and TLR signalling activity was increased in CLL-infiltrated lymph nodes compared with healthy samples. High IL4 activity correlated with faster disease progression. The publicly available dataset can facilitate the investigation of cell-extrinsic mechanisms of drug resistance and disease progression

Major flaws in conflict prevention policies towards Africa : the conceptual deficits of international actors’ approaches and how to overcome them

Current thinking on African conflicts suffers from misinterpretations oversimplification, lack of focus, lack of conceptual clarity, state-centrism and lack of vision). The paper analyses a variety of the dominant explanations of major international actors and donors, showing how these frequently do not distinguish with sufficient clarity between the ‘root causes’ of a conflict, its aggravating factors and its triggers. Specifically, a correct assessment of conflict prolonging (or sustaining) factors is of vital importance in Africa’s lingering confrontations. Broader approaches (e.g. “structural stability”) offer a better analytical framework than familiar one-dimensional explanations. Moreover, for explaining and dealing with violent conflicts a shift of attention from the nation-state towards the local and sub-regional level is needed.Aktuelle Analysen afrikanischer Gewaltkonflikte sind häufig voller Fehlinterpretationen (Mangel an Differenzierung, Genauigkeit und konzeptioneller Klarheit, Staatszentriertheit, fehlende mittelfristige Zielvorstellungen). Breitere Ansätze (z. B. das Modell der Strukturellen Stabilität) könnten die Grundlage für bessere Analyseraster und Politiken sein als eindimensionale Erklärungen. häufig differenzieren Erklärungsansätze nicht mit ausreichender Klarheit zwischen Ursachen, verschärfenden und auslösenden Faktoren. Insbesondere die richtige Einordnung konfliktverlängernder Faktoren ist in den jahrzehntelangen gewaltsamen Auseinandersetzungen in Afrika von zentraler Bedeutung. Das Diskussionspapier stellt die große Variationsbreite dominanter Erklärungsmuster der wichtigsten internationalen Geber und Akteure gegenüber und fordert einen Perspektivenwechsel zum Einbezug der lokalen und der subregionalen Ebene für die Erklärung und Bearbeitung gewaltsamer Konflikte

Scoping carbon dioxide removal options for Germany–What is their potential contribution to Net-Zero CO2_{2}?

In its latest assessment report the IPCC stresses the need for carbon dioxide removal (CDR) to counterbalance residual emissions to achieve net zero carbon dioxide or greenhouse gas emissions. There are currently a wide variety of CDR measures available. Their potential and feasibility, however, depends on context specific conditions, as among others biophysical site characteristics, or availability of infrastructure and resources. In our study, we selected 13 CDR concepts which we present in the form of exemplary CDR units described in dedicated fact sheets. They cover technical CO2 removal (two concepts of direct air carbon capture), hybrid solutions (six bioenergy with carbon capture technologies) and five options for natural sink enhancement. Our estimates for their CO2 removal potentials in 2050 range from 0.06 to 30 million tons of CO2, depending on the option. Ten of the 13 CDR concepts provide technical removal potentials higher than 1 million tons of CO2 per year. To better understand the potential contribution of analyzed CDR options to reaching net-zero CO2 emissions, we compare our results with the current CO2 emissions and potential residual CO2 emissions in 2050 in Germany. To complement the necessary information on technology-based and hybrid options, we also provide an overview on possible solutions for CO2 storage for Germany. Taking biophysical conditions and infrastructure into account, northern Germany seems a preferable area for deployment of many concepts. However, for their successful implementation further socio-economic analysis, clear regulations, and policy incentives are necessary