Impact of MET targeting on tumor-associated angiogenesis and growth of MET mutations-driven models of liver cancer

Deregulated expression of the MET receptor tyrosine kinase has been reported in up to 50% of patients with hepatocellular carcinoma, the most abundant form of liver cancers, and is associated with decreased survival. Consequently, MET is considered as a molecular target in this malignancy, whose progression is highly dependent on extensive angiogenesis. Here we studied the impact of MET small molecule inhibitors on angiogenesis-associated parameters and growth of xenograft liver models consisting of cells expressing MET-mutated variants M1268T and Y1248H, which exhibit constitutive kinase activity. We demonstrate that MET mutations expression is associated with significantly increased production of vascular endothelial growth factor, which is blocked by MET targeting only in cells expressing the M1268T inhibitor-sensitive but not in the Y1248H inhibitor-resistant variant. Decrease in vascular endothelial growth factor production is also associated with reduction of tyrosine phopshorylation of the vascular endothelial growth factor receptor 2 expressed on primary liver sinusoidal endothelial cells and with inhibition of vessel formation. Furthermore, MET inhibition demonstrated an efficient anti-tumor activity and considerable reduction in microvessel density only against the M1268T-derived intrahepatic tumors. Collectively, our data support the role of targeting MET-associated angiogenesis as a major biological determinant for liver tumor growth control.

Quantifying differences in land use emission estimates implied by definition discrepancies

The quantification of CO2 emissions from anthropogenic land use and land use change (eLUC) is essential to understand the drivers of the atmospheric CO2 increase and to inform climate change mitigation policy. Reported values in synthesis reports are commonly derived from different approaches (observation-driven bookkeeping and process-modelling) but recent work has emphasized that inconsistencies between methods may imply substantial differences in eLUC estimates. However, a consistent quantification is lacking and no concise modelling protocol for the separation of primary and secondary components of eLUC has been established. Here, we review differences of eLUC quantification methods and apply an Earth System Model (ESM) of Intermediate Complexity to quantify them. We find that the magnitude of effects due to merely conceptual differences between ESM and offline vegetation model-based quantifications is ~ 20 % for today. Under a future business-as-usual scenario, differences tend to increase further due to slowing land conversion rates and an increasing impact of altered environmental conditions on land-atmosphere fluxes. We establish how coupled Earth System Models may be applied to separate secondary component fluxes of eLUC arising from the replacement of potential C sinks/sources and the land use feedback and show that secondary fluxes derived from offline vegetation models are conceptually and quantitatively not identical to either, nor their sum. Therefore, we argue that synthesis studies should resort to the "least common denominator" of different methods, following the bookkeeping approach where only primary land use emissions are quantified under the assumption of constant environmental boundary conditions.

A climatology of the diurnal variations of stratospheric and mesospheric ozone over Bern, Switzerland

The ground-based radiometer GROMOS, stationed in Bern (47.95° N, 7.44° E), Switzerland, has a unique dataset: it obtains ozone profiles from November 1994 to present with a time resolution of 30 min and equal quality during night- and daytime. Here, we derive a monthly climatology of the daily ozone cycle from 17 yr of GROMOS observation. We present the diurnal ozone variation of the stratosphere and mesosphere. Characterizing the diurnal cycle of stratospheric ozone is important for correct trend estimates of the ozone layer derived from satellite observations. The diurnal ozone cycle from GROMOS is compared to two models: The Whole Atmosphere Community Climate Model (WACCM) and the Hamburg Model of Neutral and Ionized Atmosphere (HAMMONIA). Aura Microwave Limb Sounder (Aura/MLS) ozone data, from night- and daytime overpasses over Bern, have also been included in the comparison. Generally, observation and models show good qualitative agreement: in the lower mesosphere, daytime ozone is for both GROMOS and models around 25% less than nighttime ozone (reference is 22:30–01:30). In the stratosphere, ozone reaches its maximum in the afternoon showing values several percent larger than the midnight value. It is important that diurnal ozone variations of this order are taken into account when merging different data sets for the derivation of long-term ozone trends in the stratosphere. Further, GROMOS and models indicate a seasonal behavior of daily ozone variations in the stratosphere with a larger afternoon maximum during daytime in summer than in winter. At 0.35 hPa, observations from GROMOS and Aura/MLS show a seasonal pattern in diurnal ozone variations with larger relative amplitudes during daytime in winter (−25 ± 5%) than in summer (−18 ± 4%) (compared to mean values around midnight). For the first time, a time series of the diurnal variations in ozone is presented: 17 yr of GROMOS data show strong interannual variations in the diurnal ozone cycle for both the stratosphere and the mesosphere. There are some indications that strong temperature tides can suppress the diurnal variation of stratospheric ozone via the anticorrelation of temperature and ozone. That means the spatio-temporal variability of solar thermal tides seems to affect the diurnal cycle of stratospheric ozone.

A climatology of the diurnal variations of stratospheric and mesospheric ozone over Bern, Switzerland

The ground-based radiometer GROMOS, stationed in Bern (47.95° N, 7.44° E), Switzerland, has a unique dataset: it obtains ozone profiles from November 1994 to present with a time resolution of 30 min and equal quality during night- and daytime. Here, we derive a monthly climatology of the daily ozone cycle from 17 yr of GROMOS observation. We present the diurnal ozone variation of the stratosphere and mesosphere. Characterizing the diurnal cycle of stratospheric ozone is important for correct trend estimates of the ozone layer derived from satellite observations. The diurnal ozone cycle from GROMOS is compared to two models: The Whole Atmosphere Community Climate Model (WACCM) and the Hamburg Model of Neutral and Ionized Atmosphere (HAMMONIA). Aura Microwave Limb Sounder (Aura/MLS) ozone data, from night- and daytime overpasses over Bern, have also been included in the comparison. Generally, observation and models show good qualitative agreement: in the lower mesosphere, daytime ozone is for both GROMOS and models around 25% less than nighttime ozone (reference is 22:30–01:30). In the stratosphere, ozone reaches its maximum in the afternoon showing values several percent larger than the midnight value. It is important that diurnal ozone variations of this order are taken into account when merging different data sets for the derivation of long-term ozone trends in the stratosphere. Further, GROMOS and models indicate a seasonal behavior of daily ozone variations in the stratosphere with a larger afternoon maximum during daytime in summer than in winter. At 0.35 hPa, observations from GROMOS and Aura/MLS show a seasonal pattern in diurnal ozone variations with larger relative amplitudes during daytime in winter (−25 ± 5%) than in summer (−18 ± 4%) (compared to mean values around midnight). For the first time, a time series of the diurnal variations in ozone is presented: 17 yr of GROMOS data show strong interannual variations in the diurnal ozone cycle for both the stratosphere and the mesosphere. There are some indications that strong temperature tides can suppress the diurnal variation of stratospheric ozone via the anticorrelation of temperature and ozone. That means the spatio-temporal variability of solar thermal tides seems to affect the diurnal cycle of stratospheric ozone.

Quasi-Self-Dual Exponential Lévy Processes

The important application of semistatic hedging in financial markets naturally leads to the notion of quasi--self-dual processes. The focus of our study is to give new characterizations of quasi--self-duality. We analyze quasi--self-dual Lévy driven markets which do not admit arbitrage opportunities and derive a set of equivalent conditions for the stochastic logarithm of quasi--self-dual martingale models. Since for nonvanishing order parameter two martingale properties have to be satisfied simultaneously, there is a nontrivial relation between the order and shift parameter representing carrying costs in financial applications. This leads to an equation containing an integral term which has to be inverted in applications. We first discuss several important properties of this equation and, for some well-known Lévy-driven models, we derive a family of closed-form inversion formulae.

Multi-Model Data Fusion to Improve an Early Warning System for Hypo-/Hyperglycemic Events

Correct predictions of future blood glucose levels in individuals with Type 1 Diabetes (T1D) can be used to provide early warning of upcoming hypo-/hyperglycemic events and thus to improve the patient's safety. To increase prediction accuracy and efficiency, various approaches have been proposed which combine multiple predictors to produce superior results compared to single predictors. Three methods for model fusion are presented and comparatively assessed. Data from 23 T1D subjects under sensor-augmented pump (SAP) therapy were used in two adaptive data-driven models (an autoregressive model with output correction - cARX, and a recurrent neural network - RNN). Data fusion techniques based on i) Dempster-Shafer Evidential Theory (DST), ii) Genetic Algorithms (GA), and iii) Genetic Programming (GP) were used to merge the complimentary performances of the prediction models. The fused output is used in a warning algorithm to issue alarms of upcoming hypo-/hyperglycemic events. The fusion schemes showed improved performance with lower root mean square errors, lower time lags, and higher correlation. In the warning algorithm, median daily false alarms (DFA) of 0.25%, and 100% correct alarms (CA) were obtained for both event types. The detection times (DT) before occurrence of events were 13.0 and 12.1 min respectively for hypo-/hyperglycemic events. Compared to the cARX and RNN models, and a linear fusion of the two, the proposed fusion schemes represents a significant improvement.

GSR deposition along the bullet path in contact shots to composite models

In contact shots, all the materials emerging from the muzzle (combustion gases, soot, powder grains, and metals from the primer) will be driven into the depth of the entrance wound and the following sections of the bullet track. The so-called "pocket" ("powder cavity") under the skin containing soot and gunpowder particles is regarded as a significant indicator of a contact entrance wound since one would expect that the quantity of GSR deposited along the bullet's path rapidly declines towards the exit hole. Nevertheless, experience has shown that soot, powder particles, and carboxyhemoglobin may be found not only in the initial part of the wound channel, but also far away from the entrance and even at the exit. In order to investigate the propagation of GSRs under standardized conditions, contact test shots were fired against composite models of pig skin and 25-cm-long gelatin blocks using 9-mm Luger pistol cartridges with two different primers (Sinoxid® and Sintox®). Subsequently, 1-cm-thick layers of the gelatin blocks were examined as to their primer element contents (lead, barium, and antimony as discharge residues of Sinoxid® as well as zinc and titanium from Sintox®) by means of X-ray fluorescence spectroscopy. As expected, the highest element concentrations were found in the initial parts of the bullet tracks, but also the distal sections contained detectable amounts of the respective primer elements. The same was true for amorphous soot and unburned/partly burned powder particles, which could be demonstrated even at the exit site. With the help of a high-speed motion camera it was shown that for a short time the temporary cavitation extends from the entrance to the exit thus facilitating the unlimited spread of discharge residues along the whole bullet path.

Pulsatile shear and Gja5 modulate arterial identity and remodeling events during flow-driven arteriogenesis

In the developing chicken embryo yolk sac vasculature, the expression of arterial identity genes requires arterial hemodynamic conditions. We hypothesize that arterial flow must provide a unique signal that is relevant for supporting arterial identity gene expression and is absent in veins. We analyzed factors related to flow, pressure and oxygenation in the chicken embryo vitelline vasculature in vivo. The best discrimination between arteries and veins was obtained by calculating the maximal pulsatile increase in shear rate relative to the time-averaged shear rate in the same vessel: the relative pulse slope index (RPSI). RPSI was significantly higher in arteries than veins. Arterial endothelial cells exposed to pulsatile shear in vitro augmented arterial marker expression as compared with exposure to constant shear. The expression of Gja5 correlated with arterial flow patterns: the redistribution of arterial flow provoked by vitelline artery ligation resulted in flow-driven collateral arterial network formation and was associated with increased expression of Gja5. In situ hybridization in normal and ligation embryos confirmed that Gja5 expression is confined to arteries and regulated by flow. In mice, Gja5 (connexin 40) was also expressed in arteries. In the adult, increased flow drives arteriogenesis and the formation of collateral arterial networks in peripheral occlusive diseases. Genetic ablation of Gja5 function in mice resulted in reduced arteriogenesis in two occlusion models. We conclude that pulsatile shear patterns may be central for supporting arterial identity, and that arterial Gja5 expression plays a functional role in flow-driven arteriogenesis.