Predicting the Impact of Deleterious Mutations in the Protein Kinase Domain of FGFR2 in the Context of Function, Structure, and Pathogenesis—a Bioinformatics Approach

Fibroblast growth factor receptor 2 (FGFR2) controls a wide range of biological functions by regulating the cellular proliferation, survival, migration and differentiation. A growing body of preclinical data demonstrated that deregulation of the FGFR signalling through genetic modification was observed in various types of cancers. However, the extent to which genetic modifications interfere with gene regulation and their involvement in cancer susceptibility remains largely unknown. In this work, we performed in silico profiling of harmful non-synonymous single nucleotide polymorphisms (SNPs) in the protein kinase domain of FGFR2. Tolerance index, position-specific independent count score, change in free energy score (ΔΔG), Eris and FoldX indicated that seven mutations were found to be deleterious and may alter the protein function and structure. Furthermore, based on physico-chemical properties, two mutations K659N and R747H were found to be most deleterious in protein kinase domain and taken for further structural analysis. Docking study showed a complete loss of binding affinity followed by interference in hydrogen bonding and surrounding residues due to K659N and R747H mutations. In order to elucidate the mechanism behind the impact of mutation that can generate a ripple effect throughout the protein structure and ultimately affect the function, in-depth molecular dynamics simulation and principal component analysis were performed. The obtained results indicate that K659N and R747H mutations have a distinct effect on the dynamic behaviour of FGFR2 protein. Our strategy may be helpful for understanding SNP effects on proteins with function and their role in human genetic diseases and for the development of novel pharmacological strategies.     

Synthesis of bi- and tervalent ligands of galectins,derivatives of β-lactosylamine,with the amino group in the terminal position of the spacer

A method for the synthesis of glycoclusters by N-alkylation of N-glycyl-β-lactosylamine with N-chloroacetyl derivatives of β-lactosylamine and N,N’-iminodiacetyldilactosylamine has been developed. The glycoclusters obtained with two and three lactosylamine residues with the amino group in the spacer were found to be suitable for further conjugation with carboxy-containing physiologically active compounds. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 647–651, March, 2008.     

Breaking of Symmetry of Solitons in the Ion-Radicals of α,ω-Disubstituted Polyenes

Quantum-chemical calculations in the AM1 approximation were made for the optimized geometry and also the electron and spin density distributions in the ion-radicals of ,-substituted polyenes [R—(CH=CH) _n —R]^±·. It was found that a soliton (of hole or electron type) with half-integral spin forms waves for the and components of the electron density, in contrast to the wave for the charges in the ions of polymethine dyes with a closed electron shell, containing a zero-spin soliton. The introduction of terminal groups of medium electron-donating power [—NH₂,—C(CN)₂] leads to the breaking of symmetry of the soliton at n2, whereas in unsubstituted polyenes the symmetrical geometry and symmetrical distribution of the electron and spin density are retained irrespective of the length of the conjugation chain.     

A peroxidase-based method for the determination of dopamine, adrenaline, and α-methyldopa in the presence of thyroid hormones in pharmaceutical forms

The analytical properties of two commercial plant peroxidases isolated from horseradish roots and soybean hulls in the catalysis of the transformation of some catecholamines were demonstrated in the absence and presence of thyroid hormones (l-thyroxine and 3,3′,5′-iodothyronine). For the first time the reactions of dopamine, adrenaline, and α-methyldopa oxidation with H₂O₂ catalysed by horseradish peroxidase with the addition of l-thyroxine as the amplification agent were studied and proposed as the indicator reactions for the simple and rapid enzymatic determination of the indicated catecholamines in their concentration ranges 0.5-300, 4-300, and 100-400 μM, respectively. The catalytic activity of the enzyme (characterized by the reaction rate) was controlled spectrophotometrically. The optimum conditions for the indicator reactions were thoroughly characterized. The mechanism of the stimulatory effect of l-thyroxine on the oxidation of the catecholamines was discussed. The developed enzymatic procedures were successfully applied for the determination of dopamine, adrenaline, and α-methyldopa in some pharmaceutical forms.     

Anode oxidation of copper in alkali media in the presence of glycine, α-alanine,and asparagine acid

The effect of glycine, α-alanine, and asparagine acid on the kinetics of anode processes occurring for copper in alkali electrolytes is studied. The experiments are performed in a background solution of 1 × 10⁻² M NaOH (pH 12). The concentrations of glycine and α-alanine are varied in the range of 1 × 10⁻⁶-1 × 10⁻¹ M, and the concentration of asparagine acid is varied in the range of 1 × 10⁻⁵-1 × 10⁻³ M. All amino acids used in this work have been found to stimulate anode oxidation of passivated copper, initiating local activation (LA) of the metal. Depending on the nature of amino acids, this effect occurs in various concentration ranges: for glycine and α-alanine, it takes place at c= 5 × 10⁻³-2 × 10⁻² M, while for asparagine acid, at c = 1 × 10⁻⁵−1 × 10⁻³ M. In addition to this general regularity, several individual peculiarities have been revealed: in the systems containing a monobasic amino acid additive, local activation occurs at E = 0.10–0.20 V, while in the presence of a dibasic amino acid, the local activation is observed at two potentials, E _LA¹ = 0.20–0.30 V and = E _LA² = 0.80–0.90 V, separated by the repassivation region.     

Combination of the Claisen-Schmidt reaction,the Michael addition,and the Hantzsch reaction in the synthesis of 2,6′-bis-aryl-3,4′-bipyridines

Russian Chemical Bulletin - Pyridine-3-carbaldehyde reacted with 1-(aryl)ethan-1-ones to give 1,5-diaryl-3-(pyridin-3-yl)pentane-1,5-diones, which were further converted to...     

Trace elements in the water cycle of the Šalek valley,Slovenia, using INAA

Three watersheds were studied by sampling bulk precipitation deposition, seepage water at 50 cm soil depth and spring water. As the main analytical method for determination of trace elements and heavy metals in water samples, thek ₀-based method of INAA was used. The results showed an increased content and concentration range of trace elements in precipitation, soil water and spring water in the vicinity of the otanj Thermal Power Plant. We demonstrated that thek ₀-based method of INAA as a multielement nondestructive technique is a highly suitable approach to determining some toxic trace elements in environmental studies of the water cycle.     

Selective reduction of α,β-unsaturated esters in the presence of olefins

Several α,β-unsaturated esters containing also isolated olefins or other functionalities subject to saturation were selectively reduced to the corresponding saturated esters by magnesium in methanol.     

Fossil Sm-Nd Isotopic Dating of the Precambrian-Cambrian Boundary in the Meishucun Section, Jinning, Yunnan, China

It was for the first time that the fossil Sm-Nd isochron method was used to date the Precambrian-Cambrian boundary. The samples were collected from the Zhongyicun Member in the Meishucun section of Jinning County,Yunnan Province, southern China. The date of 562.8±7.9Ma B.P. was obtained from four hyolithid fossil samples; another date of 562.1±5.7Ma B.P. was provided by four hyolithid fossil samples and two collophanite samples. These figures suggest that the Precambrian-Cambrian boundary reference point A, which is slightly below the Zhongyicun Member, might be about 570Ma old, and the reference point B, which is near the top of the Zhongyicun Member, could be approximately 560Ma in age. This result contributed valuable reference to precise calibration of the base of the Cambrian System in the global geological time scale.     

What is the Nature of the First‐Formed Intermediates in the Electrophilic Halogenation of Alkenes,Alkynes, and Allenes?

The pi complexes first formed as essential intermediates from alkenes, alkynes, and allenes with bromine have been investigated in different solvents by UV-spectroscopy in combination with stopped-flow techniques allowing the determination of the equilibrium constants, K(f). Using alkenes with sterically protected double bonds, such as di-tert-butylstilbene and tetraneopentylethylene, the reaction stops at the stage of the 1:1 and 1:2 pi complex of the alkene with bromine as persistent species in 1,2-dichlorethane as solvent. Calculations by state-of-art ab initio and DFT methods reproduces the experimentally determined thermodynamic values quite well, and reveal the preferred structures and nature of both complexes for ethene, ethyne, and allene. Consideration of the entropy term reveals that complexes are stabilized in solution owing to reduction of the entropy loss by restricted translations and rotation. According to calculations these species are Mulliken-outer-type complexes with no or little charge transfer from bromine to the double or triple bond, respectively. The 1:2 complex has a close structural relationship to the bromonium- or bromirenium ion, which is the subsequent intermediate on the reaction coordinate. Steric influences show a strong effect on the K(f) value, which can be explained by the polarizibility of the parent system. Addition-elimination often occurs. In bromination of adamantylidenadamantane and its derivatives the reaction stops at the stage of the bromonium ion. The effect of various polar groups situated in equatorial homoallyl positions on the stability of corresponding pi complex and bromonium ion has been studied in this series.     

Photooxidation of carbonyl sulfide in the presence of the typical oxides in atmospheric aerosol

Carbonyl sulfide (COS) is one of the most abun-dant sulfur containing gases in the troposphere andlower stratosphere[1,2]. It is relatively inert in the tro-posphere and can be transported into the stratosphere,where it dissociates under the solar ultravi…     

Manifestation of the Even–Odd Effect in the Spectral Properties of Solvated Electron and in the Probability of Positronium Formation in Alcohols

A change in the energy E _max of the solvated electron, which corresponds to the maximum intensity of its optical absorption spectrum in the homologous series of alcohols seems to be alternating in character. The effect is retained upon elevation of pressure up to 2 kbar but disappears in alcohols frozen at 77 K. Probably, the effect also holds for amines. The alternating character of variation is also observed for the intensity Y ₁ of the narrow components of the angular spectrum of -photons generated upon positron annihilation in alcohols and normal alkanes. The nature of alternation of E _max is associated with the mutual elimination of electric fields induced by the dipole moments of two neighboring CH₂ groups in each solvent molecule, including also the molecules forming the solvation shell of an excess electron. That fact that the E _max value correlates to Y ₁ led to the conclusion that Y ₁, rather than the intensity I ₃ of the long-lived component of the annihilation time spectrum generally used for the purpose, more adequately characterizes the positronium formation probability.     

Thermal diffusion in Lennard–Jones fluids in the frame of the law of the corresponding states

This work is related to the definition of a reduced thermal diffusion coefficient thanks to numerical microscale molecular dynamics simulations. This cross transport process, also called Soret effect, couples mass flux and thermal gradient and is still largely misunderstood. For this study, we have applied a boundary driven non-equilibrium molecular dynamics algorithm on Lennard–Jones spheres mixtures. Simulations have been performed at a constant reduced supercritical state, using a van der Waals’ one fluid approximation in order to fulfil the law of the corresponding states. In binary mixtures, we have studied the molecular parameters and the molar fraction influences on thermal diffusion separately and then combined. It is shown that, on pressure and on thermal conductivity, the corresponding states law is fulfilled for a wide range of molecular parameters ratios. In this frame, we have then constructed simple correlations which relate thermal diffusion factor to the mixture parameters. Combining the relations obtained, a reduced thermal diffusion factor taking into account all the various contributions has been defined. Finally, it is shown that this relation enables us to estimate thermal diffusion in various binary and ternary mixtures of Lennard–Jones spheres representing alkanes with a maximum deviation of 15%.     

Crosslinking reaction in the cationic polymerization of 1, 3-pentadiene

The cationic polymerization of 1,3-pentadiene (PD) initiated by AlCl_3 in n-hexane was carried out. Effects of arenes, alkyl halides and ethers on the gel formation resulting from crosslinking reaction were investigated. The erosslinking was reduced by various arenes through a chain transfer mechanism. Alkyl halides such as tert-butyl chloride and allyl chloride could complex with AlCl_3 to generate an initiating system giving rise to a gel-free polymerization, while benzyl chloride reduced the formation of gel by chain transfer. Ethers exerted two effects on the polymerization system: giving a complex initiating system with AlCl_3 to produce a relatively high molecular weight polymer, or reducing crosslinking by lowering activity of carbocations.     

Do theories of the glass transition, in which the structural relaxation time does not define the dispersion of the structural relaxation, need revision?

Upon decreasing temperature or increasing pressure, a noncrystallizing liquid will vitrify; that is, the structural relaxation time, taualpha, becomes so long that the system cannot attain an equilibrium configuration in the available time. Theories, including the well-known free volume and configurational entropy models, explain the glass transition by invoking a single quantity that governs the structural relaxation time. The dispersion of the structural relaxation (i.e., the structural relaxation function) is either not addressed or is derived as a parallel consequence (or afterthought) and thus is independent of taualpha. In these models the time dependence of the relaxation bears no fundamental relationship to the value of taualpha or other dynamic properties. Such approaches appear to be incompatible with a general experimental fact recently discovered in glass-formers: for a given material at a fixed value of taualpha, the dispersion is constant, independent of thermodynamic conditions (T and P); that is, the shape of the alpha-relaxation function depends only on the relaxation time. If derived independently of taualpha, it is an unlikely result that the dispersion of the structural relaxation would be uniquely defined by taualpha.     

Anomalies in the Change of Volumetric Parameters of the Diels–Alder Reaction in Solution

In this article negative values of the activation volume in retro-Diels–Alder reactions are interpreted in terms of the different possibilities of penetration of the solvent molecules into the sterically branched structures of the adduct and activated complex. Empty spaces, inaccessible to penetration of solvent molecules, lead to increases of the molar volume of the screened adducts in solution and, consequently, to a less negative value of the Diels–Alder reaction volume. The values of partial molar volumes of anthracene, maleic anhydride and the adducts cyclopentadiene–maleic anhydride, anthracene–maleic anhydride and anthracene–tetracyanoethylene, in several solvents, were calculated from the solution density data.     

Congresses,Conferences, Symposia,Meetings, and Seminars in the Field of Chemical Sciences Held in 1995–1996

Information

Congresses, Conferences, Symposia, Meetings, and Seminars in the Field of Chemical Sciences Held in 1995–1996     

Congresses,Conferences, Symposia,Meetings, and Seminars in the Field of Chemical Sciences Held in 1995–1996

Information

Congresses, Conferences, Symposia, Meetings, and Seminars in the Field of Chemical Sciences Held in 1995–1996