Development and validation of tools for the implementation of european air quality policy in Germany (Project VALIUM)

International audienceIn the framework of the German Atmospheric Research Program AFO-2000 a system of consistent coupled numerical models has been developed. The purpose of the model system is to serve as a tool for the execution of European urban air quality regulations. A consortium with the acronym VALIUM was formed, which consisted of German research institutes, environmental consultancies and an environmental agency. A substantial part of the VALIUM program was devoted to the generation of a set of high quality data for the validation of the numerical model system. The validation data are based on a combination of field studies, tracer experiments and corresponding wind tunnel experiments. The field experiments were carried out inside and around a street canyon in a city district of Hanover/Germany. After a brief introduction to the VALIUM project a summary of the main results will be given

The microscale obstacle-resolving meteorological model MITRAS v2.0: model theory

This paper describes the developing theory and underlying processes of the microscale obstacle-resolving model MITRAS version 2. MITRAS calculates wind, temperature, humidity, and precipitation fields, as well as transport within the obstacle layer using Reynolds averaging. It explicitly resolves obstacles, including buildings and overhanging obstacles, to consider their aerodynamic and thermodynamic effects. Buildings are represented by impermeable grid cells at the building positions so that the wind speed vanishes in these grid cells. Wall functions are used to calculate appropriate turbulent fluxes. Most exchange processes at the obstacle surfaces are considered in MITRAS, including turbulent and radiative processes, in order to obtain an accurate surface temperature. MITRAS is also able to simulate the effect of wind turbines. They are parameterized using the actuator-disk concept to account for the reduction in wind speed. The turbulence generation in the wake of a wind turbine is parameterized by adding an additional part to the turbulence mechanical production term in the turbulent kinetic energy equation. Effects of trees are considered explicitly, including the wind speed reduction, turbulence production, and dissipation due to drag forces from plant foliage elements, as well as the radiation absorption and shading. The paper provides not only documentation of the model dynamics and numerical framework but also a solid foundation for future microscale model extensions.</p

An inter-comparison exercise of mesoscale flow models applied to an ideal case simulation

An exercise is described aiming at the comparison of the results of seven mesoscale models used for the simulation of an ideal circulation case. The exercise foresees the simulation of the flow over an ideal sea–land interface including ideal topography in order to verify model deviations on a controlled case. All models involved use the same initial and boundary conditions, circulation and temperature forcings as well as grid resolution in the horizontal and simulate the circulation over a 24-h period of time. The model differences at start are reduced to the minimum by the case specification and consist mainly of the parameterisation and numerical formulation of the fundamental equations of the atmospheric flow. The exercise reveals that despite the reduction of the differences in the case configuration, the differences in model results are still remarkable. An ad hoc investigation using one model of the original seven identifies the treatment of the boundary conditions, the parameterisation of the horizontal diffusion and of the surface heat flux as the main cause for the model deviations. The analysis of ideal cases represents a revealing and interesting exercise to be performed after the validation of models against analytical solution but prior to the application to real cases

Catalytic cleavage of HEAT and subsequent covalent binding of the tetralone moiety by the SARS-CoV-2 main protease

Here we present the crystal structure of SARS-CoV-2 main protease (Mpro) covalently bound to 2-methyl-1-tetralone. This complex was obtained by co-crystallization of Mpro with HEAT (2-(((4-hydroxyphenethyl)amino)methyl)-3,4-dihydronaphthalen-1(2H)-one) in the framework of a large X-ray crystallographic screening project of Mpro against a drug repurposing library, consisting of 5632 approved drugs or compounds in clinical phase trials. Further investigations showed that HEAT is cleaved by Mpro in an E1cB-like reaction mechanism into 2-methylene-1-tetralone and tyramine. The catalytic Cys145 subsequently binds covalently in a Michael addition to the methylene carbon atom of 2-methylene-1-tetralone. According to this postulated model HEAT is acting in a pro-drug-like fashion. It is metabolized by Mpro, followed by covalent binding of one metabolite to the active site. The structure of the covalent adduct elucidated in this study opens up a new path for developing non-peptidic inhibitors

Azithromycin-chloroquine and the intermittent preventive treatment of malaria in pregnancy

In the high malaria-transmission settings of sub-Saharan Africa, malaria in pregnancy is an important cause of maternal, perinatal and neonatal morbidity. Intermittent preventive treatment of malaria in pregnancy (IPTp) with sulphadoxine-pyrimethamine (SP) reduces the incidence of low birth-weight, pre-term delivery, intrauterine growth-retardation and maternal anaemia. However, the public health benefits of IPTp are declining due to SP resistance. The combination of azithromycin and chloroquine is a potential alternative to SP for IPTp. This review summarizes key in vitro and in vivo evidence of azithromycin and chloroquine activity against Plasmodium falciparum and Plasmodium vivax, as well as the anticipated secondary benefits that may result from their combined use in IPTp, including the cure and prevention of many sexually transmitted diseases. Drug costs and the necessity for external financing are discussed along with a range of issues related to drug resistance and surveillance. Several scientific and programmatic questions of interest to policymakers and programme managers are also presented that would need to be addressed before azithromycin-chloroquine could be adopted for use in IPTp

X ray screening identifies active site and allosteric inhibitors of SARS CoV 2 main protease

The coronavirus disease COVID 19 caused by SARS CoV 2 is creating tremendous human suffering. To date, no effective drug is available to directly treat the disease. In a search for a drug against COVID 19, we have performed a high throughput x ray crystallographic screen of two repurposing drug libraries against the SARS CoV 2 main protease Mpro , which is essential for viral replication. In contrast to commonly applied x ray fragment screening experiments with molecules of low complexity, our screen tested already approved drugs and drugs in clinical trials. From the three dimensional protein structures, we identified 37 compounds that bind to Mpro. In subsequent cell based viral reduction assays, one peptidomimetic and six nonpeptidic compounds showed antiviral activity at nontoxic concentrations. We identified two allosteric binding sites representing attractive targets for drug development against SARS CoV