Protein Design Strategies for the Structural-Functional Studies of G Protein-Coupled Receptors.

G protein-coupled receptors (GPCRs) are an important family of membrane proteins responsible for many physiological functions in human body. High resolution GPCR structures are required to understand their molecular mechanisms and perform rational drug design, as GPCRs play a crucial role in a variety of diseases. That is difficult to obtain for the wild-type proteins because of their low stability. In this review, we discuss how this problem can be solved by using protein design strategies developed to obtain homogeneous stabilized GPCR samples for crystallization and cryoelectron microscopy.

Natural-focal diseases: mapping experience in Russia.

BACKGROUND: Natural-focal diseases constitute a serious hazard for human health. Agents and vectors of such diseases belong to natural landscapes. The aim of this study is to identify the diversity and geography of natural-focal diseases in Russia and to develop cartographic approaches for their mapping, including mathematical-cartographical modeling. Russian medico-geographical mapping of natural-focal diseases is highly developed regionally and locally but extremely limited at the national level. To solve this problem, a scientific team of the Faculty of Geography at Lomonosov Moscow State University has developed and implemented a project of a medico-geographical Atlas of Russia "Natural-Focal Diseases". METHODS: The mapping is based on medical statistics data. The Atlas contains a series of maps on disease incidence, long-term dynamics of disease morbidity, etc. In addition, other materials available to the authors were used: mapping of the natural environment, field data, archival materials, analyzed satellite images, etc. The maps are processed using ArcGIS (ESRI) software application. Different methods of rendering of mapped phenomena are used (geographical ranges, diagrams, choropleth maps etc.). RESULTS: A series of analytical, integrated, and synthetic maps shows disease incidence in the population at both the national and regional levels for the last 15 years. Maps of the mean annual morbidity of certain infections and maps of morbidity dynamics and nosological profiles allow for a detailed analysis of the situation for each of 83 administrative units of the Russian Federation. The degree of epidemic hazard in Russia by natural-focal diseases is reflected in a synthetic medico-geographical map that shows the degree of epidemic risks due to such diseases in Russia and allows one to estimate the risk of disease manifestation in a given region. CONCLUSIONS: This is the first attempt at aggregation and public presentation of diverse and multifaceted information about natural-focal diseases in Russia. Taken in entirety, the maps that have been prepared for the Atlas will enable researchers to evaluate the stability of epidemic manifestation of individual diseases and the susceptibility of a given territory to disease transmission. The results can be used for sanitary monitoring and disease prevention.

IL-1 receptor antagonist as an aerosol in inflammation.

The feasibility of efficient aerosol delivery of the human IL-1 receptor antagonist (IL-1Ra) for reduction of acute lung inflammation was demonstrated in a mouse model study. The therapeutic efficacy of dry powder formulations PM(2), PM(10) of IL-1Ra was studied at nonforced inhalation in an aerosol chamber using the DPI "Spinhaler". Micronized powder formulations for insufflation were produced by air-jet milling. The anti-inflammatory effect of IL-Ra preparation was assessed by differential cell counts and biochemical composition of bronchoalveolar lavage (BAL). Reactive oxygen species (ROS), metabolic parameters of BAL (pH, redox potential, total protein, and lactate), and morphological lung changes were investigated by methods of luminol-dependent chemoluminescence, electrochemistry, microscopy, optical, and NMR spectroscopy. Inhalation of IL-1Ra aerosol ensured the systemic absorption of IL-1Ra in the circulatory system and reduced the acute inflammatory response to intranasal lipopolysaccharide challenge. The inhaled anti-inflammatory dosage in aerosol administration appeared to be comparable with i.p. injection. The mechanism of positive action of pulmonary aerosol delivery of Il-Ra includes normalization of the oxidative activity of bronchoalveolar cells, prevention of neutrophil recruitment to the bronchoalveolar tract, and improving of cell respiration. The results were used to develop mathematical models of the anti-inflammatory effects of IL-Ra as functions of the doses and dispersion grades of IL-Ra preparations. Aerosol application of IL-Ra may be an apparent way for prophylactic treating of respiratory inflammation caused by bacterial antigens.