Specific mosaic KRAS mutations affecting codon 146 cause oculoectodermal syndrome and encephalocraniocutaneous lipomatosis.

Oculoectodermal syndrome (OES) and encephalocraniocutaneous lipomatosis (ECCL) are rare disorders that share many common features, such as epibulbar dermoids, aplasia cutis congenita, pigmentary changes following Blaschko lines, bony tumor-like lesions, and others. About 20 cases with OES and more than 50 patients with ECCL have been reported. Both diseases were proposed to represent mosaic disorders, but only very recently whole-genome sequencing has led to the identification of somatic KRAS mutations, p.Leu19Phe and p.Gly13Asp, in affected tissue from two individuals with OES. Here we report the results of molecular genetic studies in three patients with OES and one with ECCL. In all four cases, Sanger sequencing of the KRAS gene in DNA from lesional tissue detected mutations affecting codon 146 (p.Ala146Val, p.Ala146Thr) at variable levels of mosaicism. Our findings thus corroborate the evidence of OES being a mosaic RASopathy and confirm the common etiology of OES and ECCL. KRAS codon 146 mutations, as well as the previously reported OES-associated alterations, are known oncogenic KRAS mutations with distinct functional consequences. Considering the phenotype and genotype spectrum of mosaic RASopathies, these findings suggest that the wide phenotypic variability does not only depend on the tissue distribution but also on the specific genotype.

Loss-of-function mutations within the IL-2 inducible kinase ITK in patients with EBV-associated lymphoproliferative diseases.

The purpose of this study was the appraisal of the clinical and functional consequences of germline mutations within the gene for the IL-2 inducible T-cell kinase, ITK. Among patients with Epstein-Barr virus-driven lymphoproliferative disorders (EBV-LPD), negative for mutations in SH2D1A and XIAP (n=46), we identified two patients with R29H or D500T,F501L,M503X mutations, respectively. Human wild-type (wt) ITK, but none of the mutants, was able to rescue defective calcium flux in murine Itk(-/-) T cells. Pulse-chase experiments showed that ITK mutations lead to varying reductions of protein half-life from 25 to 69% as compared with wt ITK (107 min). The pleckstrin homology domain of wt ITK binds most prominently to phosphatidylinositol monophosphates (PI(3)P, PI(4)P, PI(5)P) and to lesser extend to its double or triple phosphorylated derivates (PIP2, PIP3), interactions which were dramatically reduced in the patient with the ITK(R29H) mutant. ITK mutations are distributed over the entire protein and include missense, nonsense and indel mutations, reminiscent of the situation in its sister kinase in B cells, Bruton's tyrosine kinase.

Preparation of silicon nanoparticular nanocomposite with thin interparticular tin matrix.

Technology of a composite material of silicon nano-particles (99.999 w% for semiconductors) arranged densely in a metal tin matrix (99.7 w%) is presented in the present paper. The main motivation for the technology development is an endeavor to prepare a nano-composite material in which semiconductor particles are crowded densely by applying high pressure in a metal matrix. In the above arrangement, a coexistence of very narrow mesh nanostructure of a tin matrix with dispersed nanoparicles of silicon is involved. With the high level of volume density of nanoparticles, the surface interface between metal and semiconductor attains an extraordinarily large size. Thanks to this fact, a significant enhancement of the volume rate of the transitional Shottky's zone between metal tin and semiconductive silicon has been reached. Based on preliminary measurements, the abovementioned structure is characterized by an active influence on material behavior in the area of temperature dependence of resistivity which cannot be explained by mere superposition of parallel currents in two independent components: silicon and tin.

Receptor-ligand interaction and molecular modelling.

A number of computational methods for the description of the ligand-receptor interaction that were developed in the past decade are reviewed in this paper. The central two sections introduce the methods that are already established as useful tools for the qualitative and quantitative description of ligand-receptor complexes, either when the detailed atomic structure of the receptor is known or not. The following section gives two examples of the application of the described methodology on two limiting cases.

Kinetics of subcellular distribution of compounds in simple biosystems and its use in QSAR.

An explicit expression describing the kinetics of distribution and, in some cases, biological activity in drugs and other anthropogenic chemicals in a four-compartment system consisting of a catenary chain of alternating aqueous and lipoid phases is derived. Substitution of the transport rate parameters by their appropriate relations to the reference partition coefficient converts the kinetic equations into the quantitative structure-time-activity relationship (QSTAR) or its fixed-time equivalent, QSAR. The resulting expression describes satisfactorily the published data on antibacterial activity of n-alkyl amines as a function of their hydrophobicity. The hydrophobicity-activity profile consists of two or three smoothly connected linear parts. The model can be used in drug design, pharmacokinetics, and toxicology for description of the distribution of compounds in simple biosystems and in environmental sciences to predict the fate and effects of anthropogenic chemicals in ecological systems.