Subtypes of medulloblastoma have distinct developmental origins

Medulloblastoma encompasses a collection of clinically and molecularly diverse tumour subtypes that together comprise the most common malignant childhood brain tumour. These tumours are thought to arise within the cerebellum, with approximately 25% originating from granule neuron precursor cells (GNPCs) after aberrant activation of the Sonic Hedgehog pathway (hereafter, SHH subtype). The pathological processes that drive heterogeneity among the other medulloblastoma subtypes are not known, hindering the development of much needed new therapies. Here we provide evidence that a discrete subtype of medulloblastoma that contains activating mutations in the WNT pathway effector CTNNB1 (hereafter, WNT subtype) arises outside the cerebellum from cells of the dorsal brainstem. We found that genes marking human WNT-subtype medulloblastomas are more frequently expressed in the lower rhombic lip (LRL) and embryonic dorsal brainstem than in the upper rhombic lip (URL) and developing cerebellum. Magnetic resonance imaging (MRI) and intra-operative reports showed that human WNT-subtype tumours infiltrate the dorsal brainstem, whereas SHH-subtype tumours are located within the cerebellar hemispheres. Activating mutations in Ctnnb1 had little impact on progenitor cell populations in the cerebellum, but caused the abnormal accumulation of cells on the embryonic dorsal brainstem which included aberrantly proliferating Zic1(+) precursor cells. These lesions persisted in all mutant adult mice; moreover, in 15% of cases in which Tp53 was concurrently deleted, they progressed to form medulloblastomas that recapitulated the anatomy and gene expression profiles of human WNT-subtype medulloblastoma. We provide the first evidence, to our knowledge, that subtypes of medulloblastoma have distinct cellular origins. Our data provide an explanation for the marked molecular and clinical differences between SHH- and WNT-subtype medulloblastomas and have profound implications for future research and treatment of this important childhood cancer.     

AlGaN/GaN heterostructure field transistor for label-free detection of DNA hybridization

This paper demonstrates electrical detection of single strand deoxyribonucleic acid (ssDNA) conjugation by AlGaN/GaN hetero-structure field effect transistor (HFET) biological sensors. The probe ssDNA molecules are modified by thiol groups. The immobilization of probe molecules is achieved by S-Au bonding on a thin layer of gold film in the sensing area. The immobilization and hybridization process are firstly implemented on Si surfaces and checked by fluorescent and atomic force microscopy (AFM) imaging. The hybridization process is monitored on AlGaN/GaN HFETs. Time-dependent current change is observed when a matched ssDNA solution is applied, while no response is observed for a mismatched ssDNA sequence. The DNA hybridization process is dominated by the conjugation between matched ssDNA sequences in the first few tens of seconds. After that, the hybridization process is dominated by mass transfer processes and saturation of the immobilized probe ssDNA molecules.     

Modified binary particle swarm optimization

This paper presents a modified binary particle swarm optimization （BPSO） which adopts concepts of the genotype-phenotype representation and the mutation operator of genetic algorithms. Its main feature is that the BPSO can be treated as a continuous PSO. The proposed BPSO algorithm is tested on various benchmark functions, and its performance is compared with that of the original BPSO. Experimental results show that the modified BPSO outperforms the original BPSO algorithm.     

An e?ective evolutionary algorithm for the multiple container packing problem

This paper focuses on a new optimization problem, which is called “The Multiple Container Packing Problem (MCPP)” and proposes a new evolutionary approach for it. The proposed evolutionary approach uses “Adaptive Link Adjustment Evolutionary Algorithm (ALA-EA)” as a basic framework and it incorporates a heuristic local improvement approach into ALA-EA. The first step of the local search algorithm is to raise empty space through the exchange among the packed items and then to improve the fitness value through packing unpacked items into the raised empty space. The second step is to exchange the packed items and the unpacked items one another toward improving the fitness value. The proposed algorithm is compared to the previous evolutionary approaches at the benchmark instances (with the same container capacity) and the modified benchmark instances (with different container capacity) and that the algorithm is proved to be superior to the previous evolutionary approaches in the solution quality.     

Functional genomics in the rice blast fungus to unravel the fungal pathogenicity

A rapidly growing number of successful genome sequencing projects in plant pathogenic fungi greatly increase the demands for tools and methodologies to study fungal pathogenicity at genomic scale. Magnaporthe oryzae is an economically important plant pathogenic fungus whose genome is fully sequenced. Recently we have reported the development and application of functional genomics platform technologies in M. oryzae. This model approach would have many practical ramifications in design and implementation of upcoming functional genomics studies of filamentous fungi aimed at understanding fungal pathogenicity.     

Prolyl 4-hydroxylation regulates Argonaute 2 stability

Human Argonaute (Ago) proteins are essential components of the RNA-induced silencing complexes (RISCs). Argonaute 2 (Ago2) has a P-element-induced wimpy testis (PIWI) domain, which folds like RNase H and is responsible for target RNA cleavage in RNA interference. Proteins such as Dicer, TRBP, MOV10, RHA, RCK/p54 and KIAA1093 associate with Ago proteins and participate in small RNA processing, RISC loading and localization of Ago proteins in the cytoplasmic messenger RNA processing bodies. However, mechanisms that regulate RNA interference remain obscure. Here we report physical interactions between Ago2 and the alpha-(P4H-alpha(I)) and beta-(P4H-beta) subunits of the type I collagen prolyl-4-hydroxylase (C-P4H(I)). Mass spectrometric analysis identified hydroxylation of the endogenous Ago2 at proline 700. In vitro, both Ago2 and Ago4 seem to be more efficiently hydroxylated than Ago1 and Ago3 by recombinant human C-P4H(I). Importantly, human cells depleted of P4H-alpha(I) or P4H-beta by short hairpin RNA and P4H-alpha(I) null mouse embryonic fibroblast cells showed reduced stability of Ago2 and impaired short interfering RNA programmed RISC activity. Furthermore, mutation of proline 700 to alanine also resulted in destabilization of Ago2, thus linking Ago2 P700 and hydroxylation at this residue to its stability regulation. These findings identify hydroxylation as a post-translational modification important for Ago2 stability and effective RNA interference.     

Reactive oxygen species are crucial for hydroxychavicol toxicity toward KB epithelial cells

Betel quid (BQ) chewing shows a strong correlation to the incidence of oral submucous fibrosis (OSF), leukoplakia and oral cancer. BQ contains mainly areca nut, lime, Piper betle leaf (PBL) and the inflorescence of P. betle (IPB). Hydroxychavicol (4-allyl-catechol, HC), as a major phenolic compound in PBL and IPB, is shown to induce oxidative stress, glutathione (GSH) depletion and cell cycle deregulation. Using bivariate BrdU/PI flow cytometry, KB cells in DNA synthesis (S phase) are shown to be sensitive to the toxic effect of HC and show cell cycle arrest and apoptosis following exposure to 0.1 and 0.3 mM HC. HC-induced apoptosis and cell cycle arrest are associated with mitochondrial membrane potential (m) depolarization as revealed by a decrease in rhodamine fluorescence. N-acetyl-L-cysteine (1 mM), superoxide dismutase (100 U/ml) and catalase (1000 U/ml) were effective in prevention of HC-induced GSH depletion (as indicated by chloromethylfluorescein fluorescence), reactive oxygen species (ROS) production (by dichlorofluorescein fluorescence), cell cycle arrest and apoptosis. However, dimethylthiourea (2 mM), neocuproine (1 mM), 1,10-phenanthroline (200 M) and desferrioxamine (0.5 mM) showed little effect on HC-induced cell changes. HC elevated the cellular and mitochondrial GSH levels at moderate concentrations (0.05–0.1 mM), whereas at a concentration of 0.3 mM, inhibitory effects were noted. These results indicate that HC consumption may be associated with BQ-chewing-related oral mucosal diseases via GSH depletion, ROS production, mitochondrial dysfunction, cell cycle disturbance and the induction of apoptosis. These events are related to the production of superoxide radicals and hydrogen peroxide.Received 9 July 2003; received after revision 28 September 2003; accepted 24 October 2003     

He-Ar isotopic system of fluid inclusions in pyrite from the molybdenum deposits in south margin of North China Block and its trace to metallogenetic and geodynamic background

The helium and argon isotopic compositions of the ore-forming fluids from the molybdenum deposits such as Jinduicheng, Donggou, Shijiawan, and Sandaozhuang, which are located in the East Qinling molybdenum belt in south margin of North China Block （SMCNB）, are reported in this paper. The origin and the evolution of the ore-forming fluids and their coupled-relationships with the intra-continental collision and orogenic process of Qinling Orogen in Mesozoic-Cenozoic have been discussed. The 3He/4He and 40Ar/36Ar values （3He/4He=1.38-3.64 Ra, and 40Ar/36Ar=295.68-346.39, respectively） of the fluid inclusions in pyrite from the molybdenum deposits in East Qinling suggest that, the ore-forming fluid system is mixed by two end members. One is the high temperature deep-derived fluid congenetic with the porphyries generated by crust-mantle mixing, and the other is the low-temperature meteoric water which is rich in crustal radiogenic He with the component of atmospheric Ar. From the Pb isotopic composition, and ore-bearing potential of the porphyry and the regional stratum, we can conclude that the ore-forming materials of the deposits in the East Qinling molybdenum belt are derived from the deep source by the mixing of lower crust and upper mantle. Therefore, the formation of the molybdenum deposits in SMNCB can be related to the crust-mantle interaction, which is accompanied by the intra-continental orogenic and extension process in the post-collision period of Qinling Orogen. The granitic porphyries which are related to Mo mineralization are not simple crust-remelting type granites or S type granites, but belong to syntexis-type or mantle-derived granites, hence their formation has a profound and regional geodynamic background.