Mutations in SEC63 cause autosomal dominant polycystic liver disease

Mutations in PRKCSH, encoding the beta-subunit of glucosidase II, an N-linked glycan-processing enzyme in the endoplasmic reticulum (ER), cause autosomal dominant polycystic liver disease. We found that mutations in SEC63, encoding a component of the protein translocation machinery in the ER, also cause this disease. These findings are suggestive of a role for cotranslational protein-processing pathways in maintaining epithelial luminal structure and implicate noncilial ER proteins in human polycystic disease.     

Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma

Glioblastoma multiforme (GBM) is a lethal brain tumour in adults and children. However, DNA copy number and gene expression signatures indicate differences between adult and paediatric cases. To explore the genetic events underlying this distinction, we sequenced the exomes of 48 paediatric GBM samples. Somatic mutations in the H3.3-ATRX-DAXX chromatin remodelling pathway were identified in 44% of tumours (21/48). Recurrent mutations in H3F3A, which encodes the replication-independent histone 3 variant H3.3, were observed in 31% of tumours, and led to amino acid substitutions at two critical positions within the histone tail (K27M, G34R/G34V) involved in key regulatory post-translational modifications. Mutations in ATRX (α-thalassaemia/mental retardation syndrome X-linked) and DAXX (death-domain associated protein), encoding two subunits of a chromatin remodelling complex required for H3.3 incorporation at pericentric heterochromatin and telomeres, were identified in 31% of samples overall, and in 100% of tumours harbouring a G34R or G34V H3.3 mutation. Somatic TP53 mutations were identified in 54% of all cases, and in 86% of samples with H3F3A and/or ATRX mutations. Screening of a large cohort of gliomas of various grades and histologies (n = 784) showed H3F3A mutations to be specific to GBM and highly prevalent in children and young adults. Furthermore, the presence of H3F3A/ATRX-DAXX/TP53 mutations was strongly associated with alternative lengthening of telomeres and specific gene expression profiles. This is, to our knowledge, the first report to highlight recurrent mutations in a regulatory histone in humans, and our data suggest that defects of the chromatin architecture underlie paediatric and young adult GBM pathogenesis.     

An immunohistochemical and ultrastructural comparison of the effects of 2-bromo-α-ergocryptine on intrasellar and transplanted rat pituitaries

Summary Following 2 weeks of administration of 2-bromo--ergocryptine, a marked decrease was observed in prolactin immunoreactivity of the grafted pituitaries, whereas no reduction was noted in the intrasellar pituitaries. No evidence of crinophagy was revealed by electron microscopy in prolactin cells of 2-bromo--ergocryptine-treated rats.Acknowledgments. This work was supported in part by the Medical Research Council of Canada (grant MA-6349). The excellent technical assistance of Mrs Cynthia Edwards and secretarial help of Mrs Wanda Wlodarski are gratefully acknowledged.     

An immunohistochemical and ultrastructural comparison of the effects of 2-bromo-alpha-ergocryptine on intrasellar and transplanted rat pituitaries.

Following 2 weeks of administration of 2-bromo-alpha-ergocryptine, a marked decrease was observed in prolactin immunoreactivity of the grafted pituitaries, whereas no reduction was noted in the intrasellar pituitaries. No evidence of crinophagy was revealed by electron microscopy in prolactin cells of 2-bromo-alpha-ergocryptine-treated rats.     

Self-association of 5'-GMP: nucelation by potassium ions]

23Na and 39K nuclear magnetic resonance are used to follow the self-assocation of 5'-GMP in aqueous solutions. For a 0,1 M concentration in 5'-GMP, large aggregates are formed only in presence of the potassium ion, at greater than 0.2 M concentrations. They do not appear with the other alkali metal cations. A plausible explantation is inclusion of the cation in the central cavity of 5'-GMP tetramers, with a marked selectivity in favor of potassium.     

Correlation of mechanical properties in bulk metallic glasses with ~（27）Al NMR characteristics

We report 27Al NMR and magnetic susceptibility measurements of Zr and ZrHf-based bulk metallic glasses (BMGs). 27Al NMR Knight shift shows that there exists a clear correlation between the local electronic properties at Al sites and mechanical properties. In addition,magnetic susceptibility measurements also provide clues on the influence of the electronic states,especially the strong influence of d-orbital characteristics on the mechanical properties of toughness and hardness.     

Syndecan-4 promotes cytokinesis in a phosphorylation-dependent manner

During mitosis, cells detach, and the cell–matrix interactions become restricted. At the completion of cytokinesis, the two daughter cells are still connected transiently by an intercellular bridge (ICB), which is subjected to abscission, as the terminal step of cytokinesis. Cell adhesion to the matrix is mediated by syndecan-4 (SDC4) transmembrane heparan sulfate proteoglycan. Our present work demonstrated that SDC4 promotes cytokinesis in a phosphorylation-dependent manner in MCF-7 breast adenocarcinoma cells. The serine179-phosphorylation and the ectodomain shedding of SDC4 changed periodically in a cell cycle-dependent way reaching the maximum at G2/M phases. On the contrary, the phospho-resistant Ser179Ala mutant abrogated the shedding. The phosphorylated full-length and shed remnants enriched along the mitotic spindles, and subsequently in the ICBs, however, proper membrane insertion was necessary for midbody localization. Expression of phosphomimicking Ser179Glu SDC4 resulted in incomplete abscission, whereas expression of the phospho-resistant SDC4 led to giant, multinucleated cells.     

tRNA splicing endonuclease mutations cause pontocerebellar hypoplasia

Pontocerebellar hypoplasias (PCH) represent a group of neurodegenerative autosomal recessive disorders with prenatal onset, atrophy or hypoplasia of the cerebellum, hypoplasia of the ventral pons, microcephaly, variable neocortical atrophy and severe mental and motor impairments. In two subtypes, PCH2 and PCH4, we identified mutations in three of the four different subunits of the tRNA-splicing endonuclease complex. Our findings point to RNA processing as a new basic cellular impairment in neurological disorders.