Hypermutability of mouse chromosome 2 during the development of x-ray-induced murine myeloid leukemia

In an effort to identify the precise role of a deletion at regions D-E of mouse chromosome 2 [del2(D-E)] during the development of radiation-induced myeloid leukemia, we conducted a serial sacrifice study in which metaphase chromosomes were examined by the G-banding technique. Such metaphase cells were collected from x-irradiated mice during the period of transformation of some of the normal hematopoietic cells to the fully developed leukemic phenotype. A group of 250 CBA/Ca male mice (10-12 weeks old) were exposed to a single dose of 2 Gy of 250-kilovolt-peak x-rays; 42 age-matched male mice served as controls. Groups of randomly selected mice were sacrificed at 20 hr, 1 week, and then at intervals of 3 months up to 24 months after x-irradiation. Slides for cytogenetic, hematological, and histological examination were prepared for each animal at each sacrifice time. An expansion of cells with lesions on one copy of chromosome 2 was evident in 20-25% of treated mice at each sacrifice time. The majority of such lesions were translocations at 2F or 2H, strongly suggesting hypermutability of these sites on mouse chromosome 2. No lesions were found in control mice. The finding leads to the possibility that genomic lesions close to 2D and 2E are aberrants associated with radiation leukemogenesis, whereas a single clone of cells with a del2(D-E) may lead directly to overt leukemia. The data also indicate that leukemic transformation arises from the cumulative effects of multiple genetic events on chromosome 2, reinforcing the thesis that multiple steps of mutation occur in the pathogenesis of cancer.     

Porous poly(2-hydroxyethyl acrylate) hydrogels prepared by radical polymerisation with methanol as diluent

Dynamic-mechanical and water sorption properties of porous and non-porous hydrogels have been studied as a function of their porosity and crosslinking density. Porous hydrogels with different crosslinking densities were prepared by co-polymerisation of 2-hydroxyethyl acrylate and ethyleneglycol dimethacrylate in solution in methanol. Pores were formed due to the segregation of the solvent from the polymer network during the polymerisation process. The porosity of the samples was observed by scanning electron microscopy. The pores collapse during the drying process after polymerisation but they reopen when the xerogel is immersed in liquid water. Bulk polymer networks with varying crosslinking densities were also synthesised and used as a reference in the analysis of the porous hydrogels. Water sorption from the gas phase and from the liquid phase was studied by means of equilibrium sorption isotherms and immersion experiments, respectively. Dynamic-mechanical spectroscopy conducted on the xerogels shows that the elastic modulus in the rubber-like state highly depends on the amount of solvent used in the polymerisation what is attributed to the presence of discontinuity surfaces in the xerogel although the pores are closed.     

Molecular dynamics simulations of the docking of substituted N5- deazapterins to dihydrofolate reductase

Orientations of the deazapterin ring and the conformational preferences of groups appended to the deazapterin ring in a set of 8-substituted deazapterin cations docked into the dihydrofolate reductase (DHFR) binding site have been investigated using a methodology based on the simulated annealing technique within molecular dynamics (MD) simulations. Of five possible binding pockets for the 8-substituents, identified from a preliminary manual docking study, one has been definitively eliminated after an analysis of MD trajectories, while another remains uncertain. Using a new method based on standard thermodynamic cycles and a linear approximation of polar and non-polar free energy contributions from MD averages, binding affinities of the different ligands in each binding site have been correlated with experimental dissociation constants. The study has provided insights into structure-activity relationships for use in the design of modified inhibitors of DHFR.      

Synthesis,Structural Analysis,and Biological Evaluation of Thioxoquinazoline Derivatives as Phosphodiesterase 7 Inhibitors

PDE7 inhibitors regulate pro‐inflammatory and immune T‐cell functions, and are a potentially novel class of drugs particularly useful for treatment of a wide variety of immune and inflammatory disorders. Structural optimization of thioxoquinazoline derivatives led to new compounds with very interesting profiles as PDE7 or PDE7/PDE4 dual inhibitors, which may be further developed as new drugs for inflammatory and neurological diseases.

     

Crack growth in microalloyed pipeline steels for sour gas transport

Different cracking modes in a sour gas environment were observed. These modes were mainly related to the microstructure obtained during the manufacturing process of two API X52 microalloyed steels. A banded ferrite/pearlite microstructure was found to be susceptible to hydrogen effects, whereas an acicular ferrite with a grain boundary bainite/bainite microstructure was found to be more susceptible to dissolution in crack-tip regions.