Combined logical and data-driven models for linking signalling pathways to cellular response

Background Signalling pathways are the cornerstone on understanding cell function and predicting cell behavior. Recently, logical models of canonical pathways have been optimised with high-throughput phosphoproteomic data to construct cell-type specific pathways. However, less is known on how signalling pathways can be linked to a cellular response such as cell growth, death, cytokine secretion, or transcriptional activity. Results In this work, we measure the signalling activity (phosphorylation levels) and phenotypic behavior (cytokine secretion) of normal and cancer hepatocytes treated with a combination of cytokines and inhibitors. Using the two datasets, we construct "extended" pathways that integrate intracellular activity with cellular responses using a hybrid logical/data-driven computational approach. Boolean logic is used whenever a priori knowledge is accessible (i.e., construction of canonical pathways), whereas a data-driven approach is used for linking cellular behavior to signalling activity via non-canonical edges. The extended pathway is subsequently optimised to fit signalling and behavioural data using an Integer Linear Programming formulation. As a result, we are able to construct maps of primary and transformed hepatocytes downstream of 7 receptors that are capable of explaining the secretion of 22 cytokines. Conclusions We developed a method for constructing extended pathways that start at the receptor level and via a complex intracellular signalling pathway identify those mechanisms that drive cellular behaviour. Our results constitute a proof-of-principle for construction of "extended pathways" that are capable of linking pathway activity to diverse responses such as growth, death, differentiation, gene expression, or cytokine secretion.Marie Curie International Reintegration Grants (MIRG-14-CT-2007-046531)Vertex Pharmaceuticals IncorporatedBundesministerium für Wissenschaft und Forschung (HepatoSys)Massachusetts Institute of Technology (Rockwell International Career Development Professorship)Bundesministerium für Wissenschaft und Forschung (HepatoSys 0313081D

Translational systems pharmacology‐based predictive assessment of drug‐induced cardiomyopathy

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/142916/1/psp412272.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/142916/2/psp412272_am.pd

Translational Systems Pharmacology-Based Predictive Assessment of Drug-Induced Cardiomyopathy

Drug-induced cardiomyopathy contributes to drug attrition. We compared two pipelines of predictive modeling: (1) applying elastic net (EN) to differentially expressed genes (DEGs) of drugs; (2) applying integer linear programming (ILP) to construct each drug’s signaling pathway starting from its targets to downstream proteins, to transcription factors, and to its DEGs in human cardiomyocytes, and then subjecting the genes/proteins in the drugs’ signaling networks to EN regression. We classified 31 drugs with availability of DEGs into 13 toxic and 18 nontoxic drugs based on a clinical cardiomyopathy incidence cutoff of 0.1%. The ILP-augmented modeling increased prediction accuracy from 79% to 88% (sensitivity: 88%; specificity: 89%) under leave-one-out cross validation. The ILP-constructed signaling networks of drugs were better predictors than DEGs. Per literature, the microRNAs that reportedly regulate expression of our six top predictors are of diagnostic value for natural heart failure or doxorubicin-induced cardiomyopathy. This translational predictive modeling might uncover potential biomarkers

The impact of temperature changes on summer time ozone and its precursors in the Eastern Mediterranean

Changes in temperature due to variability in meteorology and climate change are expected to significantly impact atmospheric composition. The Mediterranean is a climate sensitive region and includes megacities like Istanbul and large urban agglomerations such as Athens. The effect of temperature changes on gaseous air pollutant levels and the atmospheric processes that are controlling them in the Eastern Mediterranean are here investigated. The WRF/CMAQ mesoscale modeling system is used, coupled with the MEGAN model for the processing of biogenic volatile organic compound emissions. A set of temperature perturbations (spanning from 1 to 5 K) is applied on a base case simulation corresponding to July 2004. The results indicate that the Eastern Mediterranean basin acts as a reservoir of pollutants and their precursor emissions from large urban agglomerations. During summer, chemistry is a major sink at these urban areas near the surface, and a minor contributor at downwind areas. On average, the atmospheric processes are more effective within the first 1000 m above ground. Temperature increases lead to increases in biogenic emissions by 9±3% K<sup>−1</sup>. Ozone mixing ratios increase almost linearly with the increases in ambient temperatures by 1±0.1 ppb O<sub>3</sub> K<sup>−1</sup> for all studied urban and receptor stations except for Istanbul, where a 0.4±0.1 ppb O<sub>3</sub> K<sup>−1</sup> increase is calculated, which is about half of the domain-averaged increase of 0.9±0.1 ppb O<sub>3</sub> K<sup>−1</sup>. The computed changes in atmospheric processes are also linearly related with temperature changes

Decadal regional air quality simulations over Europe in present climate: near surface ozone sensitivity to external meteorological forcing

Abstract. Regional climate-air quality decadal simulations over Europe were carried out with the RegCM3/CAMx modeling system for the time slice 1991–2000, in order to study the impact of different meteorological forcing on surface ozone. The RegCM3 regional climate model was firstly constrained by the ERA40 reanalysis dataset which is considered as an experiment with perfect meteorological boundary conditions and then it was constrained by the global circulation model ECHAM5. A number of meteorological parameters were examined including the 500 mb geopotential height, solar radiation, temperature, cloud liquid water path, planetary boundary layer height and surface wind. The different RegCM meteorological forcing resulted in changes of near surface ozone over Europe ranging between ± 4 ppb for winter and summer. The area showing the greatest sensitivity in O3 during winter is central and southern Europe while in summer central north continental Europe. The different meteorological forcing impacts on the atmospheric circulation, which in turn affects cloudiness and solar radiation, temperature, wind patterns and the meteorology depended biogenic emissions. For comparison reasons, the impact of chemical boundary conditions on surface ozone was additionally examined with a series of sensitivity studies, indicating that surface ozone changes are comparable to those caused by the different meteorological forcing. These findings suggest that, when it comes to regional climate-air quality simulations, the selection of external meteorological forcing can be as important as the selection of adequate chemical lateral boundary conditions

Investigating the quality of modeled aerosol profiles based on combined lidar and sunphotometer data

In this study we present an evaluation of the Comprehensive Air Quality Model with extensions (CAMx) for Thessaloniki using radiometric and lidar data. The aerosol mass concentration profiles of CAMx are compared against the PM2.5 and PM2. 5−10 concentration profiles retrieved by the Lidar-Radiometer Inversion Code (LIRIC). The CAMx model and the LIRIC algorithm results were compared in terms of mean mass concentration profiles, center of mass and integrated mass concentration in the boundary layer and the free troposphere. The mean mass concentration comparison resulted in profiles within the same order of magnitude and similar vertical structure for the PM2. 5 particles. The mean centers of mass values are also close, with a mean bias of 0.57 km. On the opposite side, there are larger differences for the PM2. 5−10 mode, both in the boundary layer and in the free troposphere. In order to grasp the reasons behind the discrepancies, we investigate the effect of aerosol sources that are not properly included in the model's emission inventory and in the boundary conditions such as the wildfires and the desert dust component. The identification of the cases that are affected by wildfires is performed using wind backward trajectories from the Hybrid Single Particle Lagrangian Integrated Trajectory (HYSPLIT) model in conjunction with satellite fire pixel data from MODerate-resolution Imaging Spectroradiometer (MODIS) Terra and Aqua global monthly fire location product MCD14ML. By removing those cases the correlation coefficient improves from 0.69 to 0.87 for the PM2. 5 integrated mass in the boundary layer and from 0.72 to 0.89 in the free troposphere. The PM2.5 center of mass fractional bias also decreases to 0.38 km. Concerning the analysis of the desert dust component, the simulations from the Dust Regional Atmospheric Model (BSC-DREAM8b) were deployed. When only the Saharan dust cases are taken into account, BSC-DREAM8b generally outperforms CAMx when compared with LIRIC, achieving a correlation of 0.91 and a mean bias of −29.1 % for the integrated mass in the free troposphere and a correlation of 0.57 for the center of mass. CAMx, on the other hand, underestimates the integrated mass in the free troposphere. Consequently, the accuracy of CAMx is limited concerning the transported Saharan dust cases. We conclude that the performance of CAMx appears to be best for the PM2.5 particles, both in the boundary layer and in the free troposphere. Sources of particles not properly taken into account by the model are confirmed to negatively affect its performance, especially for the PM2. 5−10 particles.The authors would like to acknowledge the EU projects MACC-III (Monitoring Atmospheric Composition and Climate – III, grant agreement no. 633080) and MACC-II project (Monitoring Atmospheric Composition and Climate – Interim Implementation, grant agreement no. 283576). The simulated results presented in this research paper have been produced using the EGI and HellasGrid infrastructures. The ACTRIS-2 project from the European Union’s Horizon 2020 research and innovation programme under grant agreement no. 654109 is gratefully acknowledged. The authors would also like to acknowledge the support provided by the Scientific Computing Center at Aristotle University of Thessaloniki throughout the progress of the work on air quality forecasting. BSC-DREAM8b simulations were performed on the Mare Nostrum supercomputer hosted by Barcelona Supercomputing Center-Centro Nacional de Supercomputacion (BSC-CNS). S. Basart wants to acknowledge the CICYT project (CGL2013-46736). Elina Giannakaki acknowledges the support of the Academy of Finland (project no. 270108).Peer ReviewedPostprint (published version

An Assessment of the Efficiency of Dust Regional Modelling to Predict Saharan Dust Transport Episodes

Aerosol levels at Mediterranean Basin are significantly affected by desert dust that is eroded in North Africa and is transported northwards. This study aims to assess the performance of the Dust REgional Atmospheric Model (BSC-DREAM8b) in the prediction of dust outbreaks near the surface in Eastern Mediterranean. For this purpose, model PM10 predictions covering a 7-year period and PM10 observations at five surface monitoring sites in Greece are used. A quantitative criterion is set to select the significant dust outbreaks defined as those when the predicted PM10 surface concentration exceeds 12 μg/m3. The analysis reveals that significant dust transport is usually observed for 1–3 consecutive days. Dust outbreak seasons are spring and summer, while some events are also forecasted in autumn. The seasonal variability of dust transport events is different at Finokalia, where the majority of events are observed in spring and winter. Dust contributes by 19–25% to the near surface observed PM10 levels, which can be increased to more than 50 μg/m3 during dust outbreaks, inducing violations of the air quality standards. Dust regional modeling can be regarded as a useful tool for air quality managers when assessing compliance with air quality limit values

Anesthésie générale du chien. De l'usage intrapéritonéal du Nembutal

(1) Pour provoquer une anesthésie générale par voie intrapéritonéale par le Nembutal la dose considérée comme dose optima est celle de 35 mg/kg. poids vif, soit 1 cm3 d’une solution à 3,5 % par kilogramme. Cette dose provoque une anesthésie chirurgicale profonde dans 87 % environ des cas (expérimentation portant sur 29 chiens) et est assez éloignée des doses toxiques (M.L.D. 10 = 62 mg/kg poids vif). (2) Par suite de l’absorption lente du Nembutal par le péritoine on assiste à une période d’excitation — qui est absente dans l’administration intraveineuse — mais celle-là est relativement courte, environ 20 mn. 50 s. ± 42 s. sur une expérimentation de 20 chiens et peu agitée passant parfois presque inaperçue. (3) Dans l’injection intrapéritonéale, les apnées, qui sont assez souvent à craindre avec les barbituriques, ne s’observent jamais, ceci par suite de l’absorption lente de l’anesthésique par le péritoine. (4) L’anesthésie chirurgicale profonde survient environ 10 minutes après l’injection (10 mn. 33 s. ± 2 mn. 3 s.) et dure en moyenne 3 h. 45 mn. (3 h. 47 mn. ± 1 h. 42 mn, sur une expérimentation de 25 chiens). Comme anesthsie chirurgicale profonde est considérée la période pendant laquelle le réflexe podal disparaît. Le réflexe cornéen a été trouvé comme aboli dans les plus extrêmes degrés de l’anesthésie chirurgicale profonde. (5) La durée de la période d’animation (d’après une expérimentation portant sur 25 chiens) s’est trouvée d’une durée égale à 5 heures environ (3 h. 11 mn. jusqu’à l’élévation de l’animal et 1 h. 48 mn. jusqu’à son rétablissement complet). (6) Les actions pharmacologiques les plus importantes signalées au cours de l’expérimentation sont les suivantes : — Chute de la température. Depuis une température initiale de 39 °, 2 C une chute a été observée de 35 °, 4 C, pour une température ambiante de 16° C. — Augmentation du nombre des pulsations dans une proportion de 107 : 150. — Diminution du rythme respiratoire dans une proportion de 29 : 17 (expérimentation portant sur 20 chiens). (7) L’anesthésie générale du chien pour intervention de longue durée par injection intrapéritonéale de Nembutal constitue donc une méthode précieuse et sans danger. Selon ce procédé, tous les avantages de l’anesthésie au Nembutal administré par voie intraveineuse sont obtenus, alors que aucun des inconvénients ne sont rencontrés : lenteur de l’opération et dangers présentés par les chiens méchants ou dangereux.Aspiotis N., Papadopoulos O., Melas D., Stoilis E., Elezoglou B. Anesthésie générale du chien. De l'usage intrapéritonéal du Nembutal. In: Bulletin de l'Académie Vétérinaire de France tome 111 n°4, 1958. pp. 173-181

Effects on surface atmospheric photo-oxidants over Greece during the total solar eclipse event of 29 March 2006

International audienceThis study investigates the effects of the total solar eclipse of 29 March 2006 on surface air-quality levels over Greece based on observations at a number of sites in conjunction with chemical box modelling and 3-D air-quality modelling. Emphasis is given on surface ozone and other photooxidants at four Greek sites Kastelorizo, Finokalia (Crete), Pallini (Athens) and Thessaloniki, which are located at gradually increasing distances from the path of the eclipse totality and are characterized by different air pollution levels. The eclipse offered the opportunity to test our understanding of air pollution build-up and the response of the gas-phase chemistry of photo-oxidants during a photolytical perturbation using both a photochemical box model and a regional air-quality offline model based on the modeling system WRF/CAMx. At the relatively unpolluted sites of Kastelorizo and Finokalia no clear impact of the solar eclipse on surface O3, NO2 and NO concentrations can be deduced from the observations and model simulations as the calculated changes in net ozone production rates between eclipse and non eclipse conditions are rather small compared to the ozone variability and hence the solar eclipse effects on ozone can be easily masked by transport. At the polluted sites of Thessaloniki and Pallini, the solar eclipse effects on O3, NO2 and NO concentrations are clearly revealed from both the measurements and 3-D air-quality modeling with the net effect being a decrease in O3 and NO and an increase in NO2 as NO2 formed from the reaction of O3 with NO while at the same time NO2 is not efficiently photolysed. It is evident from the 3-D air quality modeling over Greece that the maximum effects of the eclipse on O3, NO2 and NO are reflected at the large urban agglomerations of Athens, and Thessaloniki where the maximum of the emissions occur

Towards Canonical Quantum Gravity for G1 Geometries in 2+1 Dimensions with a Lambda--Term

The canonical analysis and subsequent quantization of the (2+1)-dimensional action of pure gravity plus a cosmological constant term is considered, under the assumption of the existence of one spacelike Killing vector field. The proper imposition of the quantum analogues of the two linear (momentum) constraints reduces an initial collection of state vectors, consisting of all smooth functionals of the components (and/or their derivatives) of the spatial metric, to particular scalar smooth functionals. The demand that the midi-superspace metric (inferred from the kinetic part of the quadratic (Hamiltonian) constraint) must define on the space of these states an induced metric whose components are given in terms of the same states, which is made possible through an appropriate re-normalization assumption, severely reduces the possible state vectors to three unique (up to general coordinate transformations) smooth scalar functionals. The quantum analogue of the Hamiltonian constraint produces a Wheeler-DeWitt equation based on this reduced manifold of states, which is completely integrated.Comment: Latex 2e source file, 25 pages, no figures, final version (accepted in CQG