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familial and ~10 % of sporadic schwannomatosis patients [4, 10, 12]. recently, another schwannomatosis-predisposing gene within the 22q candidate region has been identified. piotrowski et al. [9] reported germline loss-of-function mutations in LZTR1 in 80 % of familial and sporadic schwannomatosis cases with combined chr22 loss and somatic NF2 mutation (MIM #615670). LZTr1 functions as an adaptor of the cullin 3-containing e3 ubiquitin ligase complex and has recently been implicated in glioblastoma multiforme development [3], indicating a broader role in tumorigenesis. We therefore sought to further explore the prevalence of LZTR1 mutations in a cohort of 23 sporadic schwannomatosis patients. eight tumor-blood DNA pairs from de novo schwannomatosis patients were subjected to whole exome schwannomatosis (MIM #162091) is characterized by the development of multiple schwannomas without vestibular nerve involvement (which is a characteristic of neurofibromatosis type 2—NF2—MIM #101000). About 10 % of patients have a family history of the disease, with the remaining 90 % presumed to be sporadic [7]. Germline mutations of NF2 are not observed [8], although schwannomas frequently harbor somatic NF2 mutations and often display chromosome 22 loss [6]. rare cases with somatic mosaicism for NF2 alterations have also been described [5]. Germline mutations in SMARCB1 (INI1), located proximal to NF2 on chromosome 22, are found in ~30–60 % of

Glioblastomas are highly aggressive brain tumours and are characterised by substantial cellular heterogeneity within a single tumour. A sub-population of glioblastoma stem-like cells (GSCs) that shares properties with neural precursor cells has been described, exhibiting resistance to therapy and therefore being considered responsible for the high recurrence rate in glioblastoma. To elucidate the underlying cellular processes we investigated the role of phosphatases in the GSC phenotype, using an in vitro phosphatome-wide RNA interference screen. We identified a set of genes, the knockdown of which induces a significant decrease in the glioma stem cell marker CD133, indicating a role in the glioblastoma stem-like phenotype. Among these genes, the ecto-nucleotidase ENPP1 (ectonucleotide pyrophosphatase/phosphodiesterase 1) was found to be highly expressed in GSCs compared with normal brain and neural stem cells. Knockdown of ENPP1 in cultured GSCs resulted in an overall downregulation of stem cell-associated genes, induction of differentiation into astrocytic cell lineage, impairment of sphere formation, in addition to increased cell death, accumulation of cells in G1/G0 cell cycle phase and sensitisation to chemotherapeutic treatment. Genome-wide gene expression analysis and nucleoside and nucleotide profiling revealed that knockdown of ENPP1 affects purine and pyrimidine metabolism, suggesting a link between ENPP1 expression and a balanced nucleoside–nucleotide pool in GSCs. The phenotypic changes in E-NPP1-deficient GSCs are assumed to be a consequence of decreased transcriptional function of E2F1. Together, these results reveal that E-NPP1, by acting upstream of E2F1, is indispensable for the maintenance of GSCs in vitro and hence required to keep GSCs in an undifferentiated, proliferative state.

Here we show that glioblastoma express high levels of branched-chain amino acid transaminase 1 (BCAT1), the enzyme that initiates the catabolism of branched-chain amino acids (BCAAs). Expression of BCAT1 was exclusive to tumors carrying wild-type isocitrate dehydrogenase 1 (IDH1) and IDH2 genes and was highly correlated with methylation patterns in the BCAT1 promoter region. BCAT1 expression was dependent on the concentration of α-ketoglutarate substrate in glioma cell lines and could be suppressed by ectopic overexpression of mutant IDH1 in immortalized human astrocytes, providing a link between IDH1 function and BCAT1 expression. Suppression of BCAT1 in glioma cell lines blocked the excretion of glutamate and led to reduced proliferation and invasiveness in vitro, as well as significant decreases in tumor growth in a glioblastoma xenograft model. These findings suggest a central role for BCAT1 in glioma pathogenesis, making BCAT1 and BCAA metabolism attractive targets for the development of targeted therapeutic approaches to treat patients with glioblastoma.

Although much has been learned about hereditary mechanisms since Gregor Mendel’s famous experiments, gene concepts have always remained vague, notwithstanding their central role in biology. During over hundred years of genetic research, gene concepts have often and dynamically changed to accommodate novel experimental findings, without ever providing a generally accepted definition of the ‘gene.’ Yet, the distinction between ‘regulatory genes’ and ‘structural genes’ has remained a common theme in modern gene concepts since the definition of the operon-model. This distinction is now challenged by recent findings which suggest that, at least in eukaryotes, structural genes may in many situations have a regulatory function that is independent of the function of the gene product (protein or non-coding RNA molecule). This brief paper discusses these new findings and some possible implications for the notion of the ‘regulatory gene.’

The workload management task of the DataGrid project was mandated to define and implement a suitable architecture for distributed scheduling and resource management in a Grid environment. The result was the design and implementation of a Grid Workload Management System, a super-scheduler with the distinguishing property of being able to take data access requirements into account when scheduling jobs to the available Grid resources. Many novel issues in various fields were faced such as resource management, resource reservation and co-allocation, Grid accounting. In this paper, the architecture and the functionality provided by the DataGrid Workload Management System are presented.

Common approaches to pathway analysis treat pathways merely as lists of genes disregarding their topological structures, that is, ignoring the genes' interactions on which a pathway's cellular function depends. In contrast, PathWave has been developed for the analysis of high-throughput gene expression data that explicitly takes the topology of networks into account to identify both global dysregulation of and localized (switch-like) regulatory shifts within metabolic and signaling pathways. For this purpose, it applies adjusted wavelet transforms on optimized 2D grid representations of curated pathway maps. Here, we present the new version of PathWave with several substantial improvements including a new method for optimally mapping pathway networks unto compact 2D lattice grids, a more flexible and user-friendly interface, and pre-arranged 2D grid representations. These pathway representations are assembled for several species now comprising H. sapiens, M. musculus, D. melanogaster, D. rerio, C. elegans, and E. coli. We show that PathWave is more sensitive than common approaches and apply it to RNA-seq expression data, identifying crucial metabolic pathways in lung adenocarcinoma, as well as microarray expression data, identifying pathways involved in longevity of Drosophila. PathWave is a generic method for pathway analysis complementing established tools like GSEA, and the update comprises efficient new features. In contrast to the tested commonly applied approaches which do not take network topology into account, PathWave enables identifying pathways that are either known be involved in or very likely associated with such diverse conditions as human lung cancer or aging of D. melanogaster. The PathWave R package is freely available at http://www.ichip.de/software/pathwave.html .

The crystallization kinetics of as-deposited amorphous Ge2Sb2Te5 thin films has been measured by in situ time resolved reflectivity. X-ray diffraction and Raman scattering analyses of partially transformed samples allowed to correlate the evolution of the transition to the structural modification in the long and short range configuration. The experimental results evidenced that during the early stages of crystallization there is a reduction of Ge-Te tetrahedral bonds, characteristics of the Ge coordination in amorphous Ge2Sb2Te5 films.

The paper reports on the amorphization kinetics of chalcogenides ternary alloy induced by Ar or Sb ion irradiation. The reflectivity data, obtained “in situ” during irradiation, allow a description of the amorphization process in terms of a threshold fluence. The results demonstrate that amorphization is caused by the elastic collisions of the projectiles with target nuclei. The influence of the ion mass and energy, of the target temperature in the amorphization is also reported.