The conceptual schema of Ethereum

There is an abundant literature on Ethereum, but as far as we know what is missing is its explicit conceptual schema. We present here the conceptual schema of Ethereum in UML. The schema should be useful to those that want to understand Ethereum. We also show that the schema is necessary for developing the schema of Ethereum–based DApps. We present a few population constraints, and show that they suffice for the specification at the conceptual level of what is understood by immutability of a blockchain. We also show that the well–known reification construct and an initial constraint suffice to specify at the conceptual level that the Ethereum blockchain stores the full state history.Peer ReviewedPreprin

All-oral combination of oral vinorelbine and capecitabine as first-line chemotherapy in HER2-negative metastatic breast cancer: an International Phase II Trial

BACKGROUND: This multicentre, international phase II trial evaluated the efficacy and safety profile of a first-line combination of oral vinorelbine plus capecitabine for women with metastatic breast cancer (MBC). METHODS: Patients with measurable, HER2-negative disease received, as a first line in metastatic setting, 3-weekly cycles of oral vinorelbine 80 mg m(-2) (after a first cycle at 60) on day 1 and day 8, plus capecitabine 1000 mg m(-2) (750 if >or=65 years of age) twice daily, on days 1-14. Treatment was continued until progression or unacceptable toxicity. RESULTS: A total of 55 patients were enrolled and 54 were treated (median age: 58.5 years). Most (78%) had visceral involvement and 63% had received earlier (neo)adjuvant chemotherapy. The objective response rate (RECIST) in 49 evaluable patients was 51% (95% confidence interval (CI), 36-66), including complete response in 4%. The clinical benefit rate (response or stable disease for >or=6 months) was 63% (95% CI, 48-77). The median duration of response was 7.2 months (95% CI, 6.4-10.2). After a median follow-up of 41 months, median progression-free survival was 8.4 months (95% CI, 5.8-9.7) and median overall survival was 29.2 months (95% CI, 18.2-40.1). Treatment-related adverse events were manageable, the main grade 3-4 toxicity was neutropaenia (49%); two patients experienced febrile neutropaenia and three patients had a neutropaenic infection (including one septic death). A particularly low rate of alopaecia was observed. CONCLUSION: These results show that the all-oral combination of oral vinorelbine and capecitabine is an effective and well-tolerated first-line regimen for MB

Increased light, moderate, and severe clear-air turbulence in response to climate change

Anthropogenic climate change is expected to strengthen the vertical wind shears at aircraft cruising altitudes within the atmospheric jet streams. Such a strengthening would increase the prevalence of shear instabilities, which generate clear-air turbulence. Climate modelling studies have indicated that the amount of moderate-or-greater clear-air turbulence on transatlantic flight routes in winter will increase significantly in future as the climate changes. However, the individual responses of light, moderate, and severe clear-air turbulence have not previously been studied, despite their importance for aircraft operations. Here we use climate model simulations to analyse the transatlantic wintertime clear-air turbulence response to climate change in five aviation-relevant turbulence strength categories. We find that the probability distributions for an ensemble of 21 clear-air turbulence diagnostics generally gain probability in their right-hand tails when the atmospheric carbon dioxide concentration is doubled. By converting the diagnostics into equivalent eddy dissipation rates, we find that the ensemble-average airspace volume containing light clear-air turbulence increases by 59% (with an intra-ensemble range of 43–68%), light-to-moderate by 75% (39–96%), moderate by 94% (37–118%), moderate-to-severe by 127% (30–170%), and severe by 149% (36–188%). These results suggest that the prevalence of transatlantic wintertime clear-air turbulence will increase significantly in all aviation-relevant strength categories as the climate changes

Single-cell sequencing of human midbrain reveals glial activation and a Parkinson-specific neuronal state

Idiopathic Parkinson's disease is characterized by a progressive loss of dopaminergic neurons, but the exact disease etiology remains largely unknown. To date, Parkinson's disease research has mainly focused on nigral dopaminergic neurons, although recent studies suggest disease-related changes also in non-neuronal cells and in midbrain regions beyond the substantia nigra. While there is some evidence for glial involvement in Parkinson's disease, the molecular mechanisms remain poorly understood. The aim of this study was to characterize the contribution of all cell types of the midbrain to Parkinson's disease pathology by single-nuclei RNA sequencing and to assess the cell type-specific risk for Parkinson's disease employing the latest genome-wide association study. We profiled >41 000 single-nuclei transcriptomes of postmortem midbrain from six idiopathic Parkinson's disease patients and five age-/sex-matched controls. To validate our findings in a spatial context, we utilized immunolabeling of the same tissues. Moreover, we analyzed Parkinson's disease-associated risk enrichment in genes with cell type-specific expression patterns. We discovered a neuronal cell cluster characterized by CADPS2 overexpression and low TH levels, which was exclusively present in IPD midbrains. Validation analyses in laser-microdissected neurons suggest that this cluster represents dysfunctional dopaminergic neurons. With regard to glial cells, we observed an increase in nigral microglia in Parkinson's disease patients. Moreover, nigral idiopathic Parkinson's disease microglia were more amoeboid, indicating an activated state. We also discovered a reduction in idiopathic Parkinson's disease oligodendrocyte numbers with the remaining cells being characterized by a stress-induced upregulation of S100B. Parkinson's disease risk variants were associated with glia- and neuron-specific gene expression patterns in idiopathic Parkinson's disease cases. Furthermore, astrocytes and microglia presented idiopathic Parkinson's disease-specific cell proliferation and dysregulation of genes related to unfolded protein response and cytokine signaling. While reactive patient astrocytes showed CD44 overexpression, idiopathic Parkinson's disease-microglia revealed a pro-inflammatory trajectory characterized by elevated levels of IL1B, GPNMB, and HSP90AA1. Taken together, we generated the first single-nuclei RNA sequencing dataset from the idiopathic Parkinson's disease midbrain, which highlights a disease-specific neuronal cell cluster as well as 'pan-glial' activation as a central mechanism in the pathology of the movement disorder. This finding warrants further research into inflammatory signaling and immunomodulatory treatments in Parkinson's disease

Aviation turbulence: dynamics, forecasting, and response to climate change

Atmospheric turbulence is a major hazard in the aviation industry and can cause injuries to passengers and crew. Understanding the physical and dynamical generation mechanisms of turbulence aids with the development of new forecasting algorithms and, therefore, reduces the impact that it has on the aviation industry. The scope of this paper is to review the dynamics of aviation turbulence, its response to climate change, and current forecasting methods at the cruising altitude of aircraft. Aviation-affecting turbulence comes from three main sources: vertical wind shear instabilities, convection, and mountain waves. Understanding these features helps researchers to develop better turbulence diagnostics. Recent research suggests that turbulence will increase in frequency and strength with climate change, and therefore, turbulence forecasting may become more important in the future. The current methods of forecasting are unable to predict every turbulence event, and research is ongoing to find the best solution to this problem by combining turbulence predictors and using ensemble forecasts to increase skill. The skill of operational turbulence forecasts has increased steadily over recent decades, mirroring improvements in our understanding. However, more work is needed—ideally in collaboration with the aviation industry—to improve observations and increase forecast skill, to help maintain and enhance aviation safety standards in the future

Mitochondrial DNA heteroplasmy distinguishes disease manifestation in PINK1/PRKN-linked Parkinson’s disease

Biallelic mutations in PINK1/PRKN cause recessive Parkinson’s disease. Given the established role of PINK1/Parkin in regulating mitochondrial dynamics, we explored mitochondrial DNA (mtDNA) integrity and inflammation as disease modifiers in carriers of mutations in these genes. MtDNA integrity was investigated in a large collection of biallelic (n = 84) and monoallelic (n = 170) carriers of PINK1/PRKN mutations, idiopathic Parkinson’s disease patients (n = 67) and controls (n = 90). In addition, we studied global gene expression and serum cytokine levels in a subset. Affected and unaffected PINK1/PRKN monoallelic mutation carriers can be distinguished by heteroplasmic mtDNA variant load (AUC = 0.83, CI:0.74-0.93). Biallelic PINK1/PRKN mutation carriers harbor more heteroplasmic mtDNA variants in blood (p = 0.0006, Z = 3.63) compared to monoallelic mutation carriers. This enrichment was confirmed in iPSC-derived (controls, n = 3; biallelic PRKN mutation carriers, n = 4) and postmortem (control, n = 1; biallelic PRKN mutation carrier, n = 1) midbrain neurons. Lastly, the heteroplasmic mtDNA variant load correlated with IL6 levels in PINK1/PRKN mutation carriers (r = 0.57, p = 0.0074). PINK1/PRKN mutations predispose individuals to mtDNA variant accumulation in a dose- and disease-dependent manner

Generic Data Manipulation in a Mixed Global/Local Conceptual Model

Modern content management systems allow end-user schema creation, which can result in schema heterogeneity within a system. Building functionality to create and modify data must keep pace with this heterogeneity, but the cost of constant development is high. In this paper, we present a novel approach that extends our previous integration system that uses domain structures—global schema fragments—and local type and integration operators by introducing new local record operators and global insert and update operators. We present two widgets that use the new operators: (i) a generic clone widget that allows users to selectively clone records shown in a global widget while creating new local records; (ii) a generic clone exploration widget that allows users to browse the CloneOf relationships and reason about how different cloned records and structures have evolved. We demonstrate our system with a running example of the clone and exploration widgets in a robotics educational repository