Preliminary in silico investigation of cox 2 selective inhibitors

We report herein an attempt to generate QSAR models for a large number of structurally diverse compounds (1078 compounds) whose affinities for cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) were experimentally determined. Initially, individual QSAR models for COX-1 (M1) and COX-2 (M2) for biological activity were developed. A selectivity QSAR model, M3 was then developed using as dependent variable Y the differences in pIC50 values between COX-1 and COX-2. The statistical results for all three models showed a satisfactory to good statistical parameters where the values for squared correlation coefficient (coefficient of determination) for the training set are: M1: 0.872, M2: 0.797 respectively M3: 0.739. The predicted values of affinity in the case of all three models selected M1, M2 and respectively M3, are very good 84.88%, 91.12%, 79.59% which lead to very small diffrences between observed and predicted biological activity/selectivity (less than 0.5 logarithimic units)

Preliminary study of the blood brain barrier penetration of some organic compounds and drugs

Partial Least Squares (PLS) regression of blood–brain permeation data (logBB) including 348 diverse organic compounds and drugs was built using 903 Dragon descriptors. The prediction performance of the obtained PLS model is acceptable: the squared correlation coefficient (cumulative sum of squares of all the Y's explained by all extracted components) R 2 Y(CUM) = 0.822, the crossvalidated correlation coefficient (cumulative fraction of the total variation of the Y's that can be predicted by all the extracted components) Q 2 Y(CUM) = 0.640, the number of independent variables, X=487, for a dataset of 342 compounds (six compounds was outliers). The Y-randomization test demonstrated the absence of chance correlation which is confirmed by the lower values of regression line intercepts for R2 X(CUM) (0.307) and Q2 (CUM) (-0.320). The descriptors such as polar surface area (N,O and N,O,S,P polar contributions), octanol-water partition coefficient (Ghose-Crippen and Moriguchi), hydrophilic factor, complementary information content index and the number of H-bond donor atoms showed the largest Variables Importance in the Projection (VIP) values and can influence the logBB. The values of logBB predicted by our model display lower differences against experimental values of 342 compounds than logBB values predicted by QikProp

Preliminary investigation of common GSK3, PPARγ AND DPP IV chemical space

Cross-target biochemical experiments demonstrated that some molecules display an ample spectrum of biological activities which are therapeutically effective. In this regard we investigated the chemical space of the following targets GSK3, DPP IV and PPAR gamma since the DPP IV inhibitors, and PPAR gamma agonists are used to treat diabetes miellitus of type 2. Nevertheless, GSK-3 inhibitors have shown therapeutic potential for insulin resistant type-2 diabetes, the drug market does not register yet an inhibitor of GSK-2 for therapeutical use. The ChEMBL homo sapiens assay data for GSK-3, DPP IV and PPAR gamma were assembled into are database including 7599 compounds. GSK-3 assay comprise 2497 compounds, from which 1889 are unique divided into 428 chemotypes. DPP IV register 3482 compounds and 3026 were unique sharing 510 chemotypes. PPAR gamma incldes 1620 agonists from which 1333 are unique partitioned into 264 chemotypes. The chemical space of GSK3, DPP IV and PPAR gamma share 12 chemotypes, GSK3 and DPP IV share 30 chemotypes, DPP IV and PPAR gamma share 13 chemotypes, whereas GSK3 and PPAR gamma share 17 chemotypes. The 12 chemotypes active on all three proteins were superposed to develop a common pharmacophore which will be further used to identify novel chemotyes with potential biological activity

Water-yield relations of maize (Zea mays L) in temperate climatic conditions

A field study was carried out from 2001 to 2007 in order to determine the water-yield relationship of maize in the Vojvodina region, a northern part of the Serbia Republic. The yield response factor (K-y) was calculated to express the response of maize to water stress both for the growing season and specific growth stages. To assess the effectiveness of irrigation on maize yield, an irrigation water use efficiency (I-WUE) and evapotranspiration water use efficiency (ETWUE) were determined. The study indicated that in the climatic conditions of Vojvodina maize is most sensitive to water stress in the flowering and pollination stage (K-y = 0.52), but less sensitive in the stages of vegetative gowth (K-y = 0.37), grain filling and maturity (K-y = 0.41). Values of yield response factor in the growing period (K-y = 0.54) indicated that maize is moderately sensitive to soil water stress in the temperate climatic conditions of Vojvodina. The I-WUE and ETWUE were in intervals of 0.47 to 3.00 kg m(-3) and 0.67 to 2.34 kg m(-3) respectively, mostly depending on the extent of favorable conditions of the season for maize production and irrigation water applied. The parameters K-y, I-WUE and ETWUE could be used by maize growers as a guide in the study region in terms of optimum utilization of irrigation water for the planning, design and operation of irrigation projects and for improving the production technology of the crop

Sample Preparation and Warping Accuracy for Correlative Multimodal Imaging in the Mouse Olfactory Bulb Using 2-Photon, Synchrotron X-Ray and Volume Electron Microscopy

Integrating physiology with structural insights of the same neuronal circuit provides a unique approach to understanding how the mammalian brain computes information. However, combining the techniques that provide both streams of data represents an experimental challenge. When studying glomerular column circuits in the mouse olfactory bulb, this approach involves e.g., recording the neuronal activity with in vivo 2-photon (2P) calcium imaging, retrieving the circuit structure with synchrotron X-ray computed tomography with propagation-based phase contrast (SXRT) and/or serial block-face scanning electron microscopy (SBEM) and correlating these datasets. Sample preparation and dataset correlation are two key bottlenecks in this correlative workflow. Here, we first quantify the occurrence of different artefacts when staining tissue slices with heavy metals to generate X-ray or electron contrast. We report improvements in the staining procedure, ultimately achieving perfect staining in ∼67% of the 0.6 mm thick olfactory bulb slices that were previously imaged in vivo with 2P. Secondly, we characterise the accuracy of the spatial correlation between functional and structural datasets. We demonstrate that direct, single-cell precise correlation between in vivo 2P and SXRT tissue volumes is possible and as reliable as correlating between 2P and SBEM. Altogether, these results pave the way for experiments that require retrieving physiology, circuit structure and synaptic signatures in targeted regions. These correlative function-structure studies will bring a more complete understanding of mammalian olfactory processing across spatial scales and time

REACTION OF SUNFLOWER GENOTYPES TO THERMAL STRESS CONDITIONS IN THE SANDY SOILS AREA OF SOUTHERN OLTENIA

The researches carried out during 2016-2017 at RDCSPS Dabuleni aimed at the behavior of biological sunflower material, created at NARDI Fundulea, under conditions of thermal water stress from the sandy soils in southern Oltenia. The results obtained at 109 sunflower genotypes underline the favorability of Romania's southern area for sunflower culture. It showed significantly distinct positive correlation between the rate of  photosynthesis in the plant, and photosynthetic active radiation (r = 0.282 **) as well as between foliar sweating rate and leaf surface temperature (0.412 **). The production was differentiated according to the genotype and the climatic conditions of the agricultural year, ranging from 2299-5180 kg / ha, with an average of 4307 kg / ha

Combined use of x-ray fluorescence microscopy, phase contrast imaging for high resolution quantitative iron mapping in inflamed cells

X-ray fluorescence microscopy (XRFM) is a powerful technique to detect and localize elements in cells. To derive information useful for biology and medicine, it is essential not only to localize, but also to map quantitatively the element concentration. Here we applied quantitative XRFM to iron in phagocytic cells. Iron, a primary component of living cells, can become toxic when present in excess. In human fluids, free iron is maintained at 10-18 M concentration thanks to iron binding proteins as lactoferrin (Lf). The iron homeostasis, involving the physiological ratio of iron between tissues/secretions and blood, is strictly regulated by ferroportin, the sole protein able to export iron from cells to blood. Inflammatory processes induced by lipopolysaccharide (LPS) or bacterial pathoge inhibit ferroportin synthesis in epithelial and phagocytic cells thus hindering iron export, increasing intracellular iron and bacterial multiplication. In this respect, Lf is emerging as an important regulator of both iron and inflammatory homeostasis. Here we studied phagocytic cells inflamed by bacterial LPS and untreated or treated with milk derived bovine Lf. Quantitative mapping of iron concentration and mass fraction at high spatial resolution is obtained combining X-ray fluorescence microscopy, atomic force microscopy and synchrotron phase contrast imaging

Unveiling the impact of the effective particles distribution on strengthening mechanisms: A multiscale characterization of Mg+Y2O3 nanocomposites

International audienceMost models used to account for the hardening of nanocomposites only consider a global volume fraction of particles which is a simplified indicator that overlooks the particles size and spatial distribution. The current study aims at quantifying the effect of the real experimental particles spatial and size distribution on the strengthening of a magnesium based nanocomposites reinforced with Y 2 O 3 particles processed by Friction Stir Processing (FSP). X-ray tomographic 3-D images allowed to identify the best FSP parameters for the optimum nanocomposite. A detailed analysis indicates that the observed hardening is mainly due to Orowan strengthening and the generation of geometrically necessary dislocations (GND) due to thermal expansion coefficients (CTE) mismatch between magnesium and Y 2 O 3 particles. A multiscale characterization coupling 3D X-ray laboratory, synchrotron nanoholotomography and transmission electron microscopy (TEM) has been used to investigate particles size and spatial distribution over four orders of magnitude in length scales. Two dedicated micromechanical models for the two strengthening mechanisms are applied on the experimental particle fields taking into account the real particles size and spatial distribution, and compared to classical models based on average data. This required to develop a micromechanical model for CTE mismatch hardening contribution. This analysis reveals that the contribution from CTE mismatch is decreased by a factor two when taking into account the real distribution of particles instead of an average volume fraction

Registration of phase contrast images in propagation-based X-ray phase tomography

International audienceX-ray phase tomography aims at reconstructing the 3D electron density distribution of an object. It offers enhanced sensitivity compared to attenuation-based X-ray absorption tomography. In propagation-based methods, phase contrast is achieved by letting the beam propagate after interaction with the object. The phase shift is then retrieved at each projection angle, and subsequently used in tomographic reconstruction to obtain the refractive index decrement distribution, which is proportional to the electron density. Accurate phase retrieval is achieved by combining images at different propagation distances. For reconstructions of good quality, the phase-contrast images recorded at different distances need to be accurately aligned. In this work, we characterise the artefacts related to misalignment of the phase-contrast images, and investigate the use of different registration algorithms for aligning in-line phase-contrast images. The characterisation of artefacts is done by a simulation study and comparison with experimental data. Loss in resolution due to vibrations is found to be comparable to attenuation-based computed tomography. Further, it is shown that registration of phase-contrast images is nontrivial due to the difference in contrast between the different images, and the often periodical artefacts present in the phase-contrast images if multilayer X-ray optics are used. To address this, we compared two registration algorithms for aligning phase-contrast images acquired by magnified X-ray nanotomography: one based on cross-correlation and one based on mutual information. We found that the mutual information-based registration algorithm was more robust than a correlation-based method