Periportal steatosis in mice affects distinct parameters of pericentral drug metabolism

Little is known about the impact of morphological disorders in distinct zones on metabolic zonation. It was described recently that periportal fibrosis did affect the expression of CYP proteins, a set of pericentrally located drug-metabolizing enzymes. Here, we investigated whether periportal steatosis might have a similar effect. Periportal steatosis was induced in C57BL6/J mice by feeding a high-fat diet with low methionine/choline content for either two or four weeks. Steatosis severity was quantified using image analysis. Triglycerides and CYP activity were quantified in photometric or fluorometric assay. The distribution of CYP3A4, CYP1A2, CYP2D6, and CYP2E1 was visualized by immunohistochemistry. Pharmacokinetic parameters of test drugs were determined after injecting a drug cocktail (caffeine, codeine, and midazolam). The dietary model resulted in moderate to severe mixed steatosis confined to periportal and midzonal areas. Periportal steatosis did not affect the zonal distribution of CYP expression but the activity of selected CYPs was associated with steatosis severity. Caffeine elimination was accelerated by microvesicular steatosis, whereas midazolam elimination was delayed in macrovesicular steatosis. In summary, periportal steatosis affected parameters of pericentrally located drug metabolism. This observation calls for further investigations of the highly complex interrelationship between steatosis and drug metabolism and underlying signaling mechanisms

Vasor: Accurate prediction of variant effects for amino acid substitutions in multidrug resistance protein 3

The phosphatidylcholine floppase multidrug resistance protein 3 (MDR3) is an essential hepatobiliary transport protein. MDR3 dysfunction is associated with various liver diseases, ranging from severe progressive familial intrahepatic cholestasis to transient forms of intrahepatic cholestasis of pregnancy and familial gallstone disease. Single amino acid substitutions are often found as causative of dysfunction, but identifying the substitution effect in in vitro studies is time and cost intensive. We developed variant assessor of MDR3 (Vasor), a machine learning‐based model to classify novel MDR3 missense variants into the categories benign or pathogenic. Vasor was trained on the largest data set to date that is specific for benign and pathogenic variants of MDR3 and uses general predictors, namely Evolutionary Models of Variant Effects (EVE), EVmutation, PolyPhen‐2, I‐Mutant2.0, MUpro, MAESTRO, and PON‐P2 along with other variant properties, such as half‐sphere exposure and posttranslational modification site, as input. Vasor consistently outperformed the integrated general predictors and the external prediction tool MutPred2, leading to the current best prediction performance for MDR3 single‐site missense variants (on an external test set: F1‐score, 0.90; Matthew's correlation coefficient, 0.80). Furthermore, Vasor predictions cover the entire sequence space of MDR3. Vasor is accessible as a webserver at https://cpclab.uni‐duesseldorf.de/mdr3_predictor/ for users to rapidly obtain prediction results and a visualization of the substitution site within the MDR3 structure. The MDR3‐specific prediction tool Vasor can provide reliable predictions of single‐site amino acid substitutions, giving users a fast way to initially assess whether a variant is benign or pathogenic

A physical and regulatory map of host-influenza interactions reveals pathways in H1N1 infection

available in PMC 2010 June 28.During the course of a viral infection, viral proteins interact with an array of host proteins and pathways. Here, we present a systematic strategy to elucidate the dynamic interactions between H1N1 influenza and its human host. A combination of yeast two-hybrid analysis and genome-wide expression profiling implicated hundreds of human factors in mediating viral-host interactions. These factors were then examined functionally through depletion analyses in primary lung cells. The resulting data point to potential roles for some unanticipated host and viral proteins in viral infection and the host response, including a network of RNA-binding proteins, components of WNT signaling, and viral polymerase subunits. This multilayered approach provides a comprehensive and unbiased physical and regulatory model of influenza-host interactions and demonstrates a general strategy for uncovering complex host-pathogen relationships.National Institutes of Health (U.S.) (grant U01 AI074575)National Institutes of Health (U.S.) (grant U54 AI057159)National Institutes of Health (U.S.) (NIH New Innovator Award)Ford Foundation (Predoctoral Fellowship)Ellison Medical FoundationNational Institutes of Health (U.S.) (NIH grant R01 HG001715)National Institutes of Health (U.S.) (grant P50 HG004233)National Institutes of Health (U.S.) (PIONEER award)Howard Hughes Medical InstituteBurroughs Wellcome Fund (Career Award at the Scientific Interface)Alfred P. Sloan Foundatio

30 years of upper air soundings on board of R/V POLARSTERN

The research vessel and supply icebreaker POLARSTERN is the flagship of the Alfred-Wegener- Institut in Bremerhaven (Germany) and one of the infrastructural pillars of German Antarctic research. Since its commissioning in 1982, POLARSTERN has conducted 30 campaigns to Antarctica (157 legs, mostly austral summer), and 29 to the Arctic (94 legs, northern summer). Usually, POLARSTERN is more than 300 days per year in operation and crosses the Atlantic Ocean in a meridional section twice a year. The first radiosonde on POLARSTERN was released on the 29 December 1982, 2 days after POLARSTERN started on its maiden voyage to the Antarctic. And these daily soundings have continued up to the present. Due to the fact that POLARSTERN has reliably and regularly been providing upper air observations from data sparse regions (oceans and polar regions), the radiosonde data are of special value for researchers and weather forecast services alike. In the course of 30 years (29 December 1982 to 25 November 2012) a total of 12 378 radiosonde balloons were started on POLARSTERN. All radiosonde data can now be found at König-Langlo (2015, doi:10.1594/PANGAEA.810000). Each data set contains the directly measured parameters air temperature, relative humidity and air pressure, and the derived altitude, wind direction and wind speed. 432 data sets additionally contain ozone measurements. Although more sophisticated techniques (meteorological satellites, aircraft observation, remote-sensing sys- tems, etc.) have nowadays become increasingly important, the high vertical resolution and quality of radiosonde data remains paramount for weather forecasts and modelling approaches

The World Radiation Monitoring Center (WRMC)of the Baseline Surface Radiation Network (BSRN)

The WRMC is the central archive of the BSRN. It was established in1992 at ETH Zurich. The objective of the archive is to provide the best possible quality for short- and long-wave surface radiation fluxes. These readings are taken from a small number of selected stations, in contrasting climatic zones, together with collocated surface and upper air meteorological data and other supporting observations. Originally, the archive was used only from climate scientists. Meanwhile, the WRMC also gets used more and more in the framework of solar energy research. The typical average interval for radiation data is one minute. The parameters offered: global, diffuse, direct, long-wave down, reflex, long-wave up, UV radiation, synoptic observations, upper air soundings, total ozone, ceilometer data, and radiation measurements from towers. More than 8700 months (~ 725 years) of high quality radiation data submitted from 59 stations since 1992 are archived. BSRN data are available for non commercial users for bona fide research purposes at no cost. For details see: http://bsrn.awi.de/data/conditions-of-data-release.html. All data can be retrieved interactively by any registered user from a ftp-server and the Publishing Network PANGAEA (http://www.pangaea.de/search?q=BSRN)

Kontrastive Analyse chinesischer und deutscher SMS-Kommunikation – ein interaktionaler und gattungstheoretischer Ansatz

Ziel der vorliegenden Untersuchung ist also eine kontrastive Analyse, die u.a. den folgenden Fragen nachgeht: Inwiefern geben die medialen Voraussetzungen bei der Verschriftlichung von chinesischen und deutschen SMS-Nachrichten sprachliche Strukturen vor? Welche Besonderheiten können sich durch die Unterschiedlichkeit des Schriftsystems ergeben? Inwiefern kann man bei sprachlichen Merkmalen deutscher und chinesischer Kurznachrichten von einer Zuordnung zum Pol der konzeptionellen Mündlichkeit nach Koch/Oesterreicher sprechen? Dialogische Ansätze bei der Erforschung von SMS-Nachrichten gehen zudem verstärkt davon aus, dass analysiert werden muss, welche interaktionalen Aufgaben durch bestimmte, routinisierte sprachliche Muster gelöst werden sollen. Das Konzept der kommunikativen Gattungen kann hierbei zeigen, dass sich innerhalb der Kommunikationsform SMS verschiedene Gattungen herausgebildet haben, die den jeweiligen kommunikativen Bedürfnissen der SchreiberInnen und den von ihnen zu bewältigenden kommunikativen Aufgaben entsprechen

Physiologically based pharmacokinetic (PBPK) model of talinolol

<p>This repository provides the talinolol physiologically based pharmacokinetic (PBPK) model.</p> <p>If you have any questions or problems please <a href="https://github.com/matthiaskoenig/talinolol-model/issues">open an issue</a></p> <h2>Funding</h2><p>Matthias König was supported by the Federal Ministry of Education and Research (BMBF, Germany) within LiSyM by grant number 031L0054 and ATLAS by grant number 031L0304B and by the German Research Foundation (DFG) within the Research Unit Program FOR 5151 QuaLiPerF (Quantifying Liver Perfusion-Function Relationship in Complex Resection - A Systems Medicine Approach) by grant number 436883643 and by grant number 465194077 (Priority Programme SPP 2311, Subproject SimLivA). This work was supported by the BMBF-funded de.NBI Cloud within the German Network for Bioinformatics Infrastructure (de.NBI) (031A537B, 031A533A, 031A538A, 031A533B, 031A535A, 031A537C, 031A534A, 031A532B).</p&gt

The Baseline Surface Radiation Network and its World Radiation Monitoring Centre at the Alfred Wegener Institute

The Earth’s radiation budget is essential for driving the general circulation of the atmosphere and ocean, and for building the main conditions for the Earth's climate system. To detect changes in the Earth’s surface radiation field the Baseline Surface Radiation Network (BSRN) and its central archive - the World Radiation Monitoring Center (WRMC) - was created in 1992. BSRN is a project of the Radiation Panel (now the Data and Assessment Panel) from the Global Energy and Water Cycle Experiment (GEWEX) under the umbrella of the World Climate Research Programme (WCRP). It is the global baseline network for surface radiation for the Global Climate Observing System (GCOS), contributing to the Global Atmospheric Watch (GAW), and forming a cooperative network with the Network for the Detection of Atmospheric Composition Change (NDACC). The data are of primary importance in supporting the validation and confirmation of satellite and computer model estimates. At a relatively small number of stations (currently 58) in contrasting climatic zones, solar and atmospheric radiation is measured with instruments of the highest available accuracy and with high temporal resolution (mainly 1 minute). A total of about 7000 station-month datasets were available in the WRMC in mid 2013. All data are interactively accessible to external users for bona fide research purposes at no cost. This report provides information for scientists interested in high quality surface radiation data as well as for scientists running a BSRN station. It offers information about the available data, the data access and describes tools to visualize the data and to check their quality

A comparison of ERA interim reanalysis data with meteorological observations from the central Arctic

Both, the analysis of polar climate change on the basis of observations and the validation of weather and climate prediction in polar regions are challenging since only few observations are available. In the inner arctic regions in-situ observations are available only from buoys, ship cruises and aircraft campaigns with large temporal differences and spatial separations. In the present contribution we compare near-surface meteorological observations and rawinsonde soundings from Arctic cruises with the German icebreaker RV Polarstern during August 1996, 2001, and 2007 with each other and with ERA-Interim reanalyses. Although the used observations are usually applied in the reanalysis, they differ considerably from ERA data. ERA overestimates the relative humidity and temperature in the atmospheric boundary layer and the base height of the capping inversion. Warm biases of ERA near-surface temperatures amount up to 2K. The melting point of snow is the most frequent near-surface temperature in ERA, while the observed value is the sea water freezing temperature. While this points to general drawbacks in the models, it shows also that the quantification of trends based on reanalyses is problematic especially when only one reanalysis is considered