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This paper summarizes key elements of the German Federal Constitutional Court’s decision on the European Central Bank’s Public Sector Asset Purchase Programme. It briefly explains how it is possible for the German Court to disagree with the ruling of the Court of Justice of the European Union. Finally, it makes suggestions concerning a practical way forward for the Governing Council of the ECB in light of these developments.
Diamond formation in the Earth has been extensively discussed in recent years on the basis of geochemical analysis of natural materials, high-pressure experimental studies, or theoretical aspects. Here, we demonstrate experimentally for the first time, the spontaneous crystallization of diamond from CH4-rich fluids at pressure, temperature and redox conditions approximating those of the deeper parts of the cratonic lithospheric mantle (5-7 GPa) without using diamond seed crystals or carbides. In these experiments the fluid phase is nearly pure methane, even though the oxygen fugacity was significantly above metal saturation. We propose several previously unidentified mechanisms that may promote diamond formation under such conditions and which may also have implications for the origin of sublithospheric diamonds. These include the hydroxylation of silicate minerals like olivine and pyroxene, H2 incorporation into these phases and the "etching" of graphite by H2 and CH4 and reprecipitation as diamond. This study also serves as a demonstration of our new high-pressure experimental technique for obtaining reduced fluids, which is not only relevant for diamond synthesis, but also for investigating the metasomatic origins of diamond in the upper mantle, which has further implications for the deep carbon cycle.
Hintergrund: Die chronische metabolischen Azidose (cmA) ist eine häufige Komplikation bei chronischer Niereninsuffizienz, deren Behandlung bei niereninsuffizienten Patienten mit Diabetes mellitus die Insulinresistenz verbessern kann. Um die aktuelle Therapiesituation der cmA im diabetologischen Umfeld abzubilden und mehr über die Zusammenarbeit von Diabetologen und Nephrologen zu erfahren, wurden diabetologisch tätige Haus- und Fachärzte zur cmA befragt.
Methoden An 5863 Ärzten mit diabetologischer Zusatzqualifikation wurde postalisch ein Fragebogen versandt. Alle 97 erhaltenen Antwortbögen wurden deskriptiv ausgewertet.
Ergebnisse Die meisten Teilnehmer sind Internisten mit diabetologischer Zusatzqualifikation (46 %) und behandeln im Median 50 (10; 112) Patienten mit Typ-1-Diabetes bzw. 210 (100; 450) Patienten mit Typ-2-Diabetes pro Quartal. Eine cmA wurde von 12 % der Teilnehmer in den letzten 12 Monaten bei median 4 (2; 6) Patienten mit Typ-1-Diabetes und 10 (3; 30) Patienten mit Typ-2-Diabetes beobachtet. Die cmA wird überwiegend durch Bestimmung des Serum-Bikarbonats (27; 28 %) und des Base Excess (19; 20 %) diagnostiziert. 38 (39 %) der Teilnehmer erhalten regelmäßig von Nephrologen die Empfehlung zur Behandlung der cmA. Sie wird von knapp 1 Drittel als relevant (29 %) und gut umsetzbar (27 %) betrachtet. Zur Behandlung der cmA wird vor allem orales Bikarbonat empfohlen (Bikarbonat: 39 %, Zitrat: 5 %, sonst: keine Angabe). Maßnahmen, die die Mehrheit der Diabetologen in der Verantwortung der Nephrologen sehen, sind ergänzende Diagnostik (87; 90 %) einschließlich Blutgasanalyse (59 %) sowie die Behandlung der cmA (62 %) und renalen Anämie (53 %). 34 % der Diabetologen gaben an, bisher noch keine cmA-Fälle in der Praxis behandelt zu haben. Die meisten Diabetologen überlassen die Behandlung und Überwachung der cmA dem Nephrologen (38 %). Dabei wird die Zusammenarbeit mit den Nephrologen als zufriedenstellend (81 %) bewertet. 38 % der Befragten haben in der täglichen Praxis beobachtet, dass die Einstellung der cmA auch die Insulinresistenz positiv beeinflusst. Eine CME-Fortbildung in der Diabetologie speziell zur cmA würden 76 (78 %) begrüßen.
Diskussion Bei der Behandlung der cmA wird die Kooperation zwischen Diabetologen und Nephrologen generell gut bewertet, wobei die Diagnose, Behandlung und Überwachung einer cmA in der Verantwortung des Nephrologen gesehen werden. Da die Behandlung der cmA die Insulinresistenz verringern kann, sollte der Stellenwert der cmA-Therapie im diabetologischen Umfeld nicht unterschätzt werden. Um die cmA-Behandlung bei diabetischer Nephropathie zu optimieren, wären CME-Fortbildungen zur cmA geeignet. Zudem könnten Schulungen im Rahmen einer interdisziplinären Kooperation mit Diätberatern die Umsetzbarkeit diätetischer Interventionen zur Behandlung der cmA verbessern.
Background & Aims: Spontaneous portosystemic shunts (SPSS) frequently develop in liver cirrhosis. Recent data suggested that the presence of a single large SPSS is associated with complications, especially overt hepatic encephalopathy (oHE). However, the presence of >1 SPSS is common. This study evaluates the impact of total cross-sectional SPSS area (TSA) on outcomes in patients with liver cirrhosis.
Methods: In this retrospective international multicentric study, CT scans of 908 cirrhotic patients with SPSS were evaluated for TSA. Clinical and laboratory data were recorded. Each detected SPSS radius was measured and TSA calculated. One-year survival was the primary endpoint and acute decompensation (oHE, variceal bleeding, ascites) was the secondary endpoint.
Results: A total of 301 patients (169 male) were included in the training cohort. Thirty percent of all patients presented with >1 SPSS. A TSA cut-off of 83 mm2 was used to classify patients with small or large TSA (S-/L-TSA). Patients with L-TSA presented with higher model for end-stage liver disease score (11 vs. 14) and more commonly had a history of oHE (12% vs. 21%, p <0.05). During follow-up, patients with L-TSA experienced more oHE episodes (33% vs. 47%, p <0.05) and had lower 1-year survival than those with S-TSA (84% vs. 69%, p <0.001). Multivariate analysis identified L-TSA (hazard ratio 1.66; 95% CI 1.02–2.70, p <0.05) as an independent predictor of mortality. An independent multicentric validation cohort of 607 patients confirmed that patients with L-TSA had lower 1-year survival (77% vs. 64%, p <0.001) and more oHE development (35% vs. 49%, p <0.001) than those with S-TSA.
Conclusion: This study suggests that TSA >83 mm2 increases the risk for oHE and mortality in patients with cirrhosis. Our results support the clinical use of TSA/SPSS for risk stratification and decision-making in the management of patients with cirrhosis.
Lay summary: The prevalence of spontaneous portosystemic shunts (SPSS) is higher in patients with more advanced chronic liver disease. The presence of more than 1 SPSS is common in advanced chronic liver disease and is associated with the development of hepatic encephalopathy. This study shows that total cross-sectional SPSS area (rather than diameter of the single largest SPSS) predicts survival in patients with advanced chronic liver disease. Our results support the clinical use of total cross-sectional SPSS area for risk stratification and decision-making in the management of SPSS.
Cryptocurrencies have received growing attention from individuals, the media, and regulators. However, little is known about the investors whom these financial instruments attract. Using administrative data, we describe the investment behavior of individuals who invest in cryptocurrencies with structured retail products. We find that cryptocurrency investors are active traders, prone to investment biases, and hold risky portfolios. In line with attention effects and anticipatory utility, we find that the average cryptocurrency investor substantially increases log-in and trading activity after his or her first cryptocurrency purchase. Our results document which investors are more likely to adopt new financial products and help inform regulators about investors' vulnerability to cryptocurrency investments.
The transition from local to global patterns governs the differentiation of mouse blastocysts
(2020)
During mammalian blastocyst development, inner cell mass (ICM) cells differentiate into epiblast (Epi) or primitive endoderm (PrE). These two fates are characterized by the expression of the transcription factors NANOG and GATA6, respectively. Here, we investigate the spatio-temporal distribution of NANOG and GATA6 expressing cells in the ICM of the mouse blastocysts with quantitative three-dimensional single cell-based neighbourhood analyses. We define the cell neighbourhood by local features, which include the expression levels of both fate markers expressed in each cell and its neighbours, and the number of neighbouring cells. We further include the position of a cell relative to the centre of the ICM as a global positional feature. Our analyses reveal a local three-dimensional pattern that is already present in early blastocysts: 1) Cells expressing the highest NANOG levels are surrounded by approximately nine neighbours, while 2) cells expressing GATA6 cluster according to their GATA6 levels. This local pattern evolves into a global pattern in the ICM that starts to emerge in mid blastocysts. We show that FGF/MAPK signalling is involved in the three-dimensional distribution of the cells and, using a mutant background, we further show that the GATA6 neighbourhood is regulated by NANOG. Our quantitative study suggests that the three-dimensional cell neighbourhood plays a role in Epi and PrE precursor specification. Our results highlight the importance of analysing the three-dimensional cell neighbourhood while investigating cell fate decisions during early mouse embryonic development.
How is semantic information stored in the human mind and brain? Some philosophers and cognitive scientists argue for vectorial representations of concepts, where the meaning of a word is represented as its position in a high-dimensional neural state space. At the intersection of natural language processing and artificial intelligence, a class of very successful distributional word vector models has developed that can account for classic EEG findings of language, that is, the ease versus difficulty of integrating a word with its sentence context. However, models of semantics have to account not only for context-based word processing, but should also describe how word meaning is represented. Here, we investigate whether distributional vector representations of word meaning can model brain activity induced by words presented without context. Using EEG activity (event-related brain potentials) collected while participants in two experiments (English and German) read isolated words, we encoded and decoded word vectors taken from the family of prediction-based Word2vec algorithms. We found that, first, the position of a word in vector space allows the prediction of the pattern of corresponding neural activity over time, in particular during a time window of 300 to 500 ms after word onset. Second, distributional models perform better than a human-created taxonomic baseline model (WordNet), and this holds for several distinct vector-based models. Third, multiple latent semantic dimensions of word meaning can be decoded from brain activity. Combined, these results suggest that empiricist, prediction-based vectorial representations of meaning are a viable candidate for the representational architecture of human semantic knowledge.
Background: Naturalistic developmental behavioural interventions (NDBI) have been shown to improve autism-specific symptoms in young children with Autism Spectrum Disorder (ASD). NDBI approaches, such as the ASD-specific Frankfurt Early Intervention Programme for ASD (A-FFIP), are based on ASD-specific developmental and learning aspects. A-FFIP is a low-intensity intervention which can easily be implemented in the local health care/social welfare system. The aim of the present study is to establish 1-year efficacy of the manualised early intervention programme A-FFIP in toddlers and preschool children with ASD. It is hypothesised that A-FFIP will result in improved ASD-specific symptoms compared to early intervention as usual (EIAU). Child- and family-specific secondary outcomes, as well as moderators and mediators of outcome, will be explored.
Methods/design: A prospective, multi-centre, parallel-group, randomised controlled, phase-III trial comparing A-FFIP versus EIAU. A total of 134 children (A-FFIP: 67, EIAU: 67) aged 24–66 months at baseline assessment meeting the criteria for ASD (DSM-5) will be included. The primary outcome is the absolute change of the total score of the Brief Observation of Social Communication Change (BOSCC-AT) between baseline (T2) and 1-year follow-up (T6). The treatment effect will be tested, adjusted for relevant covariates applying a mixed model for repeated measures. Secondary outcomes are BOSCC social communication and repetitive-behaviour scores, single ASD symptoms, language, cognition, psychopathology, parental well-being and family quality of life. Predictors, moderators and mediating mechanisms will be explored.
Discussion: If efficacy of the manualised A-FFIP early intervention is established, the current study has the potential to change clinical practice strongly towards the implementation of a low-intensity, evidence-based, natural early intervention in ASD. Early intervention in ASD requires specialist training, which subsequently needs to be developed or included into current training curricula.
Trial registration: German Registry for Clinical Trials (Deutscher Register Klinischer Studien, DRKS); ID: 00016330. Retrospectively registered on 4 January 2019. URL: https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00016330.
Background: Depression is a widespread disorder with severe impacts for individuals and society, especially in its chronic form. Current treatment approaches for persistent depression have focused primarily on reducing negative affect and have paid little attention to promoting positive affect. Previous studies have shown that metta meditation increases positive affect in chronically depressed patients. Results from previous trials provide evidence for the efficacy of a stand-alone metta meditation group treatment in combination with mindfulness-based approaches. Further research is needed to better understand the implementation of meditation practice into everyday life. Therefore, mindfulness and metta meditation in a group setting are combined with individual cognitive behavioral therapy (CBT) into a new, low-intensity, cost-effective treatment (“MeCBT”) for chronic depression. Methods/design: In this single-center, randomized, observer-blinded, parallel-group clinical trial we will test the efficacy of MeCBT in reducing depression compared to a wait-list control condition. Forty-eight participants in a balanced design will be allocated randomly to a treatment group or a wait-list control group. Metta-based group meditation will be offered in eight weekly sessions and one additional half-day retreat. Subsequent individual CBT will be conducted in eight fortnightly sessions. Outcome measures will be assessed at four time points: before intervention (T0); after group meditation (T1); after individual CBT (T2); and, in the treated group only, at 6-month follow-up (T3). Changes in depressive symptoms (clinician rating), assessed with the Quick Inventory of Depressive Symptoms (QIDS-C) are the primary outcome. We expect a significant decline of depressive symptoms at T2 compared to the wait-list control group. Secondary outcome measures include self-rated depression, mindfulness, benevolence, rumination, emotion regulation, social connectedness, social functioning, as well as behavioral and cognitive avoidance. We will explore changes at T1 and T2 in all these secondary outcome variables. Discussion: To our knowledge this is the first study to combine a group program focusing on Metta meditation with stateof-the art individual CBT specifically tailored to chronic depression. Implications for further refinement and examination of the treatment program are discussed. Trial registration: ISRCTN, ISRCTN97264476. Registered 29 March 2018 (applied on 14 December 2017)—retrospectively registered.
High-quality single crystals of the unconventional superconductor NdFeAsO1 − xFx were grown. We developed a new optimized flux technique to overcome the difficulties in single-crystal growth and the sample quality limitations of NdFeAsO1 − xFx. The normal state of the F-doped samples exhibits simple metallic behavior upon cooling down from room temperature, followed by a sharp superconducting transition. The values of residual resistivity ratio (RRR) is 3.2, 6.4, and 10.3 for x = 0.1, 0.15, and 0.2, respectively. Both the large RRR and the narrow superconducting transition signpost the high quality of the crystals. We have examined the in- and out-of-plane lower critical fields, and the field at which vortices penetrate the sample of NdFeAsO1 − xFx (x = 0.1). The anisotropy ratio [γHc1 (0)] increased slightly with increasing temperature from 0.8 Tc to Tc. The temperature dependence of the first vortex penetration field was obtained under the static magnetic field, H, parallel to the c- and ab- axis, and pronounced changes in the Hc1(T) curvature were observed, which are attributed to the multi-band superconductivity.
Ferroptosis, a newly discovered form of cell death mediated by reactive oxygen species (ROS) and lipid peroxidation, has recently been shown to have an impact on various cancer types; however, so far there are only few studies about its role in hepatocellular carcinoma (HCC). The delicate equilibrium of ROS in cancer cells has found to be crucial for cell survival, thus increased levels may trigger ferroptosis in HCC.In our study, we investigated the effect of different ROS modulators and ferroptosis inducers on a human HCC cell line and a human hepatoblastoma cell line. We identified a novel synergistic cell death induction by the combination of Auranofin and buthionine sulfoxime (BSO) or by Erastin and BSO at subtoxic concentrations. We found a caspase-independent, redox-regulated cell death, which could be rescued by different inhibitors of ferroptosis. Both cotreatments stimulated lipid peroxidation. All these findings indicated ferroptotic cell death. Both cotreatments affected the canonical ferroptosis pathway through GPX4 downregulation. We also found an accumulation of Nrf2 and HO-1, indicating an additional effect on the non-canonical pathway. Our results implicate that targeting these two main ferroptotic pathways simultaneously can overcome chemotherapy resistance in HCC.
The production of light (anti-)(hyper-)nuclei in heavy-ion collisions at the LHC is considered in the framework of the Saha equation, making use of the analogy between the evolution of the early universe after the Big Bang and that of “Little Bangs” created in the lab. Assuming that disintegration and regeneration reactions involving light nuclei proceed in relative chemical equilibrium after the chemical freeze-out of hadrons, their abundances are determined through the famous cosmological Saha equation of primordial nucleosynthesis and show no exponential dependence on the temperature typical for the thermal model. A quantitative analysis, performed using the hadron resonance gas model in partial chemical equilibrium, shows agreement with experimental data of the ALICE collaboration on d, 3He, HΛ3, and 4He yields for a very broad range of temperatures at T≲155 MeV. The presented picture is supported by the observed suppression of resonance yields in central Pb–Pb collisions at the LHC. Keywords: Light (anti-)(hyper-)nuclei production, Saha equation, Partial chemical equilibrium.
Children with reading and/or spelling disorders have increased rates of behavioral and emotional problems and combinations of these. Some studies also find increased rates of attention-deficit/hyperactivity disorder (ADHD), conduct disorder, anxiety disorder, and depression. However, the comorbidities of, e.g., arithmetic disorders with ADHD, anxiety disorder, and depression have been addressed only rarely. The current study explored the probability of children with specific learning disorders (SLD) in reading, spelling, and/or arithmetic to also have anxiety disorder, depression, ADHD, and/or conduct disorder. The sample consisted of 3,014 German children from grades 3 and 4 (mean age 9;9 years) who completed tests assessing reading, spelling as well as arithmetic achievement and intelligence via a web-based application. Psychopathology was assessed using questionnaires filled in by the parents. In children with a SLD we found high rates of anxiety disorder (21%), depression (28%), ADHD (28%), and conduct disorder (22%). Children with SLD in multiple learning domains had a higher risk for psychopathology and had a broader spectrum of psychopathology than children with an isolated SLD. The results highlight the importance of screening for and diagnosing psychiatric comorbidities in children with SLD.
Polyacrylamide gel electrophoresis (PAGE) and immunoblotting (Western blotting) are the most common methods in life science. In conjunction with these methods, the polyhistidine-tag has proven to be a superb fusion tag for protein purification as well as specific protein detection by immunoblotting, which led to a vast amount of commercially available antibodies. Nevertheless, antibody batch-to-batch variations and nonspecific binding complicate the laborious procedure. The interaction principle applied for His-tagged protein purification by metal-affinity chromatography using N-nitrilotriacetic acid (NTA) was employed to develop small high-affinity lock-and-key molecules coupled to a fluorophore. These multivalent NTA probes allow specific detection of His-tagged proteins by fluorescence. Here, we report on HisQuick-PAGE as a fast and versatile immunoblot alternative, using such high-affinity fluorescent super-chelator probes. The procedure allows direct, fast, and ultra-sensitive in-gel detection and analysis of soluble proteins as well as intact membrane protein complexes and macromolecular ribonucleoprotein particles.