Frequent pathway mutations of splicing machinery in myelodysplasia

Myelodysplastic syndromes and related disorders (myelodysplasia) are a heterogeneous group of myeloid neoplasms showing deregulated blood cell production with evidence of myeloid dysplasia and a predisposition to acute myeloid leukaemia, whose pathogenesis is only incompletely understood. Here we report whole-exome sequencing of 29 myelodysplasia specimens, which unexpectedly revealed novel pathway mutations involving multiple components of the RNA splicing machinery, including U2AF35, ZRSR2, SRSF2 and SF3B1. In a large series analysis, these splicing pathway mutations were frequent (～45 to ～85%) in, and highly specific to, myeloid neoplasms showing features of myelodysplasia. Conspicuously, most of the mutations, which occurred in a mutually exclusive manner, affected genes involved in the 3'-splice site recognition during pre-mRNA processing, inducing abnormal RNA splicing and compromised haematopoiesis. Our results provide the first evidence indicating that genetic alterations of the major splicing components could be involved in human pathogenesis, also implicating a novel therapeutic possibility for myelodysplasia.     

Enzyme-Mediated Hydrolysis of Poly（ethylene glycol）-Supported Carbonates

Enzymatic kinetic resolution of racemic alcohols or esters is known as a useful method for the preparation of optically active secondary alcohols. However, the work-up including the separation of the mixture of the remaining substrate and the resulting compound spend a lot of time and waste much amount of solvents. On the other hand, organic synthesis based on polymer supports has made rapid progress. Although the methodology is potentially useful for the easy separation of compounds obtained by the enzymatic reaction, there have been relatively few reports on enzymatic resolutions of using a polymer so far. We have noticed that using a watersoluble polymer could be suitable for enzymatic transformation. Here, we report the first example of an enzyme-mediated enantioseleetive hydrolysis of poly（ethylene glycol）（PEG）-supported substrates with a carbonate moiety to afford optically active compounds, and the method enables us to achieve the easy separation of the products. See Scheme 1.     

Enzyme-Mediated Hydrolysis of Poly(ethylene glycol)-Supported Carbonates

1Introduction Enzymatic kinetic resolution of racemic alcohols or esters is known as a useful method for the preparation of optically active secondary alcohols. However, the work-up including the separation of the mixture of the remaining substrate and the resulting compound spend a lot of time and waste much amount of solvents. On the other hand, organic synthesis based on polymer supports has made rapid progress. Although the methodology is potentially useful for the easy separation of compounds obtained by the enzymatic reaction, there have been relatively few reports on enzymatic resolutions of using a polymer so far. We have noticed that using a watersoluble polymer could be suitable for enzymatic transformation. Here, we report the first example of an enzyme-mediated enantioselective hydrolysis of poly(ethylene glycol)(PEG)-supported substrates with a carbonate moiety to afford optically active compounds, and the method enables us to achieve the easy separation of the products[1]. See Scheme 1.     

An increase in Sendai virus-induced cell fusion of erythrocytes infected withPlasmodium chabaudi

Summary The extent of cell fusion induced by Sendai virus was examined in erythrocytes infected withPlasmodium chabaudi. An increase in cell fusion of erythrocytes with Ehrlich tumor cells and of erythrocytes with erythrocytes was observed wit the infected erythrocytes. However, agglutination by the virus was not changed between erythrocytes of normal and malarial mice. These results indicate that the increase in cell fusion occurred in the process of membrane fusion, suggesting that some membrane property ofPlasmodium-parasitized erythrocytes is changed in terms of Sendai virus-induced cell fusion.We thank Drs George L. Gerton, T. Matsuyama and M. Niwa for their comments on this work and Mr I. Kimata for preparing photographs.     

Induction of IgG1 and IgE responses to protein-conjugated and unconjugated beta-lactam antibiotics in the mouse--efficacy of Freund's complete adjuvant

One or two injections two weeks apart of protein-conjugated penicillin G, cephalothin or cefmetazole emulsified with Freund's complete adjuvant were quite effective in producing anti-antibiotic antibodies of the IgE as well as of the IgG1 class in mice. Long-lasting and boostable production of both antibody classes was also obtained against unconjugated cephalothin or cefmetazole, though the positivity depended on the mouse strain.     

Molecular dynamics simulation of the ice nucleation and growth process leading to water freezing

Upon cooling, water freezes to ice. This familiar phase transition occurs widely in nature, yet unlike the freezing of simple liquids, it has never been successfully simulated on a computer. The difficulty lies with the fact that hydrogen bonding between individual water molecules yields a disordered three-dimensional hydrogen-bond network whose rugged and complex global potential energy surface permits a large number of possible network configurations. As a result, it is very challenging to reproduce the freezing of 'real' water into a solid with a unique crystalline structure. For systems with a limited number of possible disordered hydrogen-bond network structures, such as confined water, it is relatively easy to locate a pathway from a liquid state to a crystalline structure. For pure and spatially unconfined water, however, molecular dynamics simulations of freezing are severely hampered by the large number of possible network configurations that exist. Here we present a molecular dynamics trajectory that captures the molecular processes involved in the freezing of pure water. We find that ice nucleation occurs once a sufficient number of relatively long-lived hydrogen bonds develop spontaneously at the same location to form a fairly compact initial nucleus. The initial nucleus then slowly changes shape and size until it reaches a stage that allows rapid expansion, resulting in crystallization of the entire system.