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The first concerted multi-model intercomparison of halogenated very short-lived substances (VSLS) has been performed, within the framework of the ongoing Atmospheric Tracer Transport Model Intercomparison Project (TransCom). Eleven global models or model variants participated (nine chemical transport models and two chemistry–climate models) by simulating the major natural bromine VSLS, bromoform (CHBr3) and dibromomethane (CH2Br2), over a 20-year period (1993–2012). Except for three model simulations, all others were driven offline by (or nudged to) reanalysed meteorology. The overarching goal of TransCom-VSLS was to provide a reconciled model estimate of the stratospheric source gas injection (SGI) of bromine from these gases, to constrain the current measurement-derived range, and to investigate inter-model differences due to emissions and transport processes. Models ran with standardised idealised chemistry, to isolate differences due to transport, and we investigated the sensitivity of results to a range of VSLS emission inventories. Models were tested in their ability to reproduce the observed seasonal and spatial distribution of VSLS at the surface, using measurements from NOAA's long-term global monitoring network, and in the tropical troposphere, using recent aircraft measurements – including high-altitude observations from the NASA Global Hawk platform.
The models generally capture the observed seasonal cycle of surface CHBr3 and CH2Br2 well, with a strong model–measurement correlation (r ≥ 0.7) at most sites. In a given model, the absolute model–measurement agreement at the surface is highly sensitive to the choice of emissions. Large inter-model differences are apparent when using the same emission inventory, highlighting the challenges faced in evaluating such inventories at the global scale. Across the ensemble, most consistency is found within the tropics where most of the models (8 out of 11) achieve best agreement to surface CHBr3 observations using the lowest of the three CHBr3 emission inventories tested (similarly, 8 out of 11 models for CH2Br2). In general, the models reproduce observations of CHBr3 and CH2Br2 obtained in the tropical tropopause layer (TTL) at various locations throughout the Pacific well. Zonal variability in VSLS loading in the TTL is generally consistent among models, with CHBr3 (and to a lesser extent CH2Br2) most elevated over the tropical western Pacific during boreal winter. The models also indicate the Asian monsoon during boreal summer to be an important pathway for VSLS reaching the stratosphere, though the strength of this signal varies considerably among models.
We derive an ensemble climatological mean estimate of the stratospheric bromine SGI from CHBr3 and CH2Br2 of 2.0 (1.2–2.5) ppt, ∼ 57 % larger than the best estimate from the most recent World Meteorological Organization (WMO) Ozone Assessment Report. We find no evidence for a long-term, transport-driven trend in the stratospheric SGI of bromine over the simulation period. The transport-driven interannual variability in the annual mean bromine SGI is of the order of ±5 %, with SGI exhibiting a strong positive correlation with the El Niño–Southern Oscillation (ENSO) in the eastern Pacific. Overall, our results do not show systematic differences between models specific to the choice of reanalysis meteorology, rather clear differences are seen related to differences in the implementation of transport processes in the models.
The first concerted multi-model intercomparison of halogenated very short-lived substances (VSLS) has been performed, within the framework of the ongoing Atmospheric Tracer Transport Model Intercomparison Project (TransCom). Eleven global models or model variants participated, simulating the major natural bromine VSLS, bromoform (CHBr3) and dibromomethane (CH2Br2), over a 20-year period (1993-2012). The overarching goal of TransCom-VSLS was to provide a reconciled model estimate of the stratospheric source gas injection (SGI) of bromine from these gases, to constrain the current measurement-derived range, and to investigate inter-model differences
due to emissions and transport processes. Models ran with standardised idealised chemistry, to isolate differences due to transport, and we investigated the sensitivity of results to a range of VSLS emission inventories. Models were tested in their ability to reproduce the observed seasonal and spatial distribution of VSLS at the surface, using measurements from NOAA’s long-term global monitoring network, and in the tropical troposphere, using recent aircraft measurements - including high altitude observations from the NASA Global Hawk platform.
The models generally capture the seasonal cycle of surface CHBr3 and CH2Br2 well, with a strong model measurement correlation (r ≥0.7) and a low sensitivity to the choice of emission inventory, at most sites. In a given model, the absolute model-measurement agreement is highly sensitive to the choice of emissions and inter-model differences are also apparent, even when using the same inventory, highlighting the challenges faced in evaluating such inventories at the global scale. Across the ensemble, most consistency is found within the tropics where most of the models (8 out of 11) achieve optimal agreement to surface CHBr3 observations using the lowest of the three CHBr3 emission inventories tested (similarly, 8 out of 11 models for CH2Br2). In general, the models are able to reproduce well observations of CHBr3 and CH2Br2 obtained in the tropical tropopause layer (TTL) at various locations throughout the Pacific. Zonal variability in VSLS loading in the TTL is generally consistent among models, with CHBr3 (and to a lesser extent CH2Br2) most elevated over the tropical West Pacific during boreal winter. The models also indicate the Asian Monsoon during boreal summer to be an important pathway for VSLS reaching the stratosphere, though the strength of this signal varies considerably among models.
We derive an ensemble climatological mean estimate of the stratospheric bromine SGI from CHBr3 and CH2Br2 of 2.0 (1.2-2.5) ppt, ∼57% larger than the best estimate from the most re- cent World Meteorological Organization (WMO) Ozone Assessment Report. We find no evidence for a long-term, transport-driven trend in the stratospheric SGI of bromine over the simulation period. However, transport-driven inter-annual variability in the annual mean bromine SGI is of the order of a ±5%, with SGI exhibiting a strong positive correlation with ENSO in the East Pacific
The detailed biophysical mechanisms through which transcranial magnetic stimulation (TMS) activates cortical circuits are still not fully understood. Here we present a multi-scale computational model to describe and explain the activation of different cell types in motor cortex due to transcranial magnetic stimulation. Our model determines precise electric fields based on an individual head model derived from magnetic resonance imaging and calculates how these electric fields activate morphologically detailed models of different neuron types. We predict detailed neural activation patterns for different coil orientations consistent with experimental findings. Beyond this, our model allows us to predict activation thresholds for individual neurons and precise initiation sites of individual action potentials on the neurons’ complex morphologies. Specifically, our model predicts that cortical layer 3 pyramidal neurons are generally easier to stimulate than layer 5 pyramidal neurons, thereby explaining the lower stimulation thresholds observed for I-waves compared to D-waves. It also predicts differences in the regions of activated cortical layer 5 and layer 3 pyramidal cells depending on coil orientation. Finally, it predicts that under standard stimulation conditions, action potentials are mostly generated at the axon initial segment of corctial pyramidal cells, with a much less important activation site being the part of a layer 5 pyramidal cell axon where it crosses the boundary between grey matter and white matter. In conclusion, our computational model offers a detailed account of the mechanisms through which TMS activates different cortical cell types, paving the way for more targeted application of TMS based on individual brain morphology in clinical and basic research settings.
The application of the EU Commission’s Rule of Law Framework in the current Polish case is a step in the right direction. It seems a good instance to develop the Framework as an EU mechanism to protect European constitutional values in a European legal space which is rife with constitutional crises, but short of instruments to address them. Its pertinence appears even more clearly in comparison to the Council’s (in)activity under its own rule-of-law mechanism, hastily put forward after the Commission’s Framework. The activation of the Framework has shown its potential to mobilize European public opinion and orient public discourses to the current condition of EU values
The fractional release factor (FRF) gives information on the amount of a halocarbon that is released at some point in the stratosphere from its source form to the inorganic form, which can harm the ozone layer through catalytic reactions. The quantity is of major importance because it directly affects the calculation of the Ozone Depletion Potential (ODP). To apply FRF in this context, steady-state values are needed, thus representing a molecular property for a given atmospheric situation. In particular, these values should be independent of the tropospheric trends of the respective halogenated trace gases.
We analyzed the temporal evolution of FRF from ECHAM/MESSy Atmospheric Chemistry (EMAC) model simulations for several halocarbons and nitrous oxide between 1965–2011 on different mean age levels and found that the current formulation of FRF yields highly time-dependent values. We show that this is caused by the way that the tropospheric trend is handled in the current calculation method of FRF.
Taking into account chemical loss in the calculation of stratospheric mixing ratios reduces the time-dependence in correlations of different tracers. Therefore we implemented a loss term in the formulation of FRF and applied the parameterization of a "mean arrival time" to our data set.
We find that the time-dependence in FRF can almost be compensated by applying a new trend correction in the calculation of FRF. We suggest that this new method should be used to calculate time-independent FRF, which can then be used e.g. for the calculation of ODP
This paper presents a comprehensive extension of pricing two-dimensional derivatives depending on two barrier constraints. We assume randomness on the covariance matrix as a way of generalizing. We analyse common barrier derivatives, enabling us to study parameter uncertainty and the risk related to the estimation procedure (estimation risk). In particular, we use the distribution of empirical parameters from IBM and EURO STOXX50. The evidence suggests that estimation risk should not be neglected in the context of multidimensional barrier derivatives, as it could cause price differences of up to 70%.
The ubiquitin-binding zinc finger (UBZ) is a type of zinc-coordinating β-β-α fold domain found mainly in proteins involved in DNA repair and transcriptional regulation. Here, we report the crystal structure of the UBZ domain of Y-family DNA polymerase (pol) η and the crystal structure of the complex between the UBZ domain of Werner helicase-interacting protein 1 (WRNIP1) and ubiquitin, crystallized using the GFP fusion technique. In contrast to the pol η UBZ, which has been proposed to bind ubiquitin via its C-terminal α-helix, ubiquitin binds to a novel surface of WRNIP1 UBZ composed of the first β-strand and the C-terminal α-helix. In addition, we report the structure of the tandem UBZ domains of Tax1-binding protein 1 (TAX1BP1) and show that the second UBZ of TAX1BP1 binds ubiquitin, presumably in a manner similar to that of WRNIP1 UBZ. We propose that UBZ domains can be divided into at least two different types in terms of the ubiquitin-binding surfaces: the pol η type and the WRNIP1 type.
Using an advanced version of the hadron resonance gas model we have found several remarkable irregularities at chemical freeze-out. The most prominent of them are two sets of highly correlated quasi-plateaus in the collision energy dependence of the entropy per baryon, total pion number per baryon, and thermal pion number per baryon which we found at center of mass energies 3.6-4.9 GeV and 7.6-10 GeV. The low energy set of quasi-plateaus was predicted a long time ago. On the basis of the generalized shockadiabat model we demonstrate that the low energy correlated quasi-plateaus give evidence for the anomalous thermodynamic properties of the mixed phase at its boundary to the quark-gluon plasma. The question is whether the high energy correlated quasi-plateaus are also related to some kind of mixed phase. In order to answer this question we employ the results of a systematic meta-analysis of the quality of data description of 10 existing event generators of nucleus-nucleus collisions in the range of center of mass collision energies from 3.1 GeV to 17.3 GeV. These generators are divided into two groups: the first group includes the generators which account for the quark-gluon plasma formation during nuclear collisions, while the second group includes the generators which do not assume the quark-gluon plasma formation in such collisions. Comparing the quality of data description of more than a hundred of different data sets of strange hadrons by these two groups of generators, we find two regions of the equal quality of data description which are located at the center of mass collision energies 4.3-4.9 GeV and 10.-13.5 GeV. These two regions of equal quality of data description we interpret as regions of the hadron-quark-gluon mixed phase formation. Such a conclusion is strongly supported by the irregularities in the collision energy dependence of the experimental ratios of the Lambda hyperon number per proton and positive kaon number per Lambda hyperon. Although at the moment it is unclear, whether these regions belong to the same mixed phase or not, there are arguments that the most probable collision energy range to probe the QCD phase diagram (tri)critical endpoint is 12-14 GeV.
Purpose: The PELICAN trial evaluates for the first time efficacy and safety of pegylated liposomal doxorubicin (PLD) versus capecitabine as first-line treatment of metastatic breast cancer (MBC).
Methods: This randomized, phase III, open-label, multicenter trial enrolled first-line MBC patients who were ineligible for endocrine or trastuzumab therapy. Cumulative adjuvant anthracyclines of 360 mg/m2 doxorubicin or equivalent were allowed. Left ventricular ejection fraction of >50 % was required. Patients received PLD 50 mg/m2 every 28 days or capecitabine 1250 mg/m2 twice daily for 14 days every 21 days. The primary endpoint was time-to-disease progression (TTP).
Results: 210 patients were randomized (n = 105, PLD and n = 105, capecitabine). Adjuvant anthracyclines were given to 37 % (PLD) and 36 % (capecitabine) of patients. No significant difference was observed in TTP [HR = 1.21 (95 % confidence interval, 0.838–1.750)]. Median TTP was 6.0 months for both PLD and capecitabine. Comparing patients with or without prior anthracyclines, no significant difference in TTP was observed in the PLD arm (log-rank P = 0.64). For PLD versus capecitabine, respectively, overall survival (median, 23.3 months vs. 26.8 months) and time-to-treatment failure (median, 4.6 months vs. 3.7 months) were not statistically significantly different. Compared to PLD, patients on capecitabine experienced more serious adverse events (P = 0.015) and more cardiac events among patients who had prior anthracycline exposure (18 vs. 8 %; P = 0.31).
Conclusion: Both PLD and capecitabine are effective first-line agents for MBC.
The article addresses the question of who reports the dialogue in fictional texts featuring an unreliable narrator. Since no human being can remember and reproduce lengthy conversations accurately, some narrative theorists attribute direct speech representation to the author instead of the character narrator. This means that the speech of other characters may be reported reliably even if the narrator is totally unreliable. The narrator’s version of the events may then be contradicted by others, which allows the reader to perceive his biases. However, Kazuo Ishiguro’s An Artist of the Floating World illustrates the fact that direct speech reports, too, can be distorted by the narrator’s subjectivity, especially his emotions. In Ishiguro’s novel, the narrator’s grief and depression lead him to misremember and invent past conversations. Following Meir Sternberg, the article argues that the reliability of speech reporting in unreliable narration must be determined on a case-by-case basis. The text must signal that the narrator’s speech reporting is unreliable. In the absence of a signal, the reader is supposed to disregard any deviations from verbatim reproduction and to accept the transgression of the limits of human memory.