Clonal selection drives genetic divergence of metastatic medulloblastoma

Medulloblastoma, the most common malignant paediatric brain tumour, arises in the cerebellum and disseminates through the cerebrospinal fluid in the leptomeningeal space to coat the brain and spinal cord. Dissemination, a marker of poor prognosis, is found in up to 40% of children at diagnosis and in most children at the time of recurrence. Affected children therefore are treated with radiation to the entire developing brain and spinal cord, followed by high-dose chemotherapy, with the ensuing deleterious effects on the developing nervous system. The mechanisms of dissemination through the cerebrospinal fluid are poorly studied, and medulloblastoma metastases have been assumed to be biologically similar to the primary tumour. Here we show that in both mouse and human medulloblastoma, the metastases from an individual are extremely similar to each other but are divergent from the matched primary tumour. Clonal genetic events in the metastases can be demonstrated in a restricted subclone of the primary tumour, suggesting that only rare cells within the primary tumour have the ability to metastasize. Failure to account for the bicompartmental nature of metastatic medulloblastoma could be a major barrier to the development of effective targeted therapies.     

The complete family of genes encoding G proteins of Caenorhabditis elegans

Caenorhabditis elegans is the first animal whose genomic sequence has been determined. One of the new possibilities in post-sequence genetics is the analysis of complete gene families at once. We studied the family of heterotrimeric G proteins. C. elegans has 20 Galpha, 2 Gbeta and 2 Ggamma genes. There is 1 homologue of each of the 4 mammalian classes of Galpha genes, G(i)/G(o)alpha, G(s)alpha , G(q)alpha and G12alpha, and there are 16 new alpha genes. Although the conserved Galpha subunits are expressed in many neurons and muscle cells, GFP fusions indicate that 14 new Galpha genes are expressed almost exclusively in a small subset of the chemosensory neurons of C. elegans. We generated loss-of-function alleles using target-selected gene inactivation. None of the amphid-expressed genes are essential for viability, and only four show any detectable phenotype (chemotaxis defects), suggesting extensive functional redundancy. On the basis of functional analysis, the 20 genes encoding Galpha proteins can be divided into two groups: those that encode subunits affecting muscle activity (homologues of G(i)/G(o)alpha, G(s)alpha and G(q)), and those (14 new genes) that encode proteins most likely involved in perception.     

Uptake of L-glutamate and L-aspartate in neurones and glial cells of cultured human and rat spinal cord.

Autoradiographic investigations on the uptake of L-glutamate and L-aspartate have shown that the amino acids were taken up by neurones as well as by glial cells of cultured human and rat spinal cord. The activity of glutamate and aspartate varied considerably between individual neurones, whereas glial cells showed a more even distribution of the labelled amino acids. Our results suggest that both neurones and glial cells are involved in the uptake of amino acid transmitters.     

Phaeomelanic pigments from a human melanoma

Summary The pigments in melanomas from 2 patients were studied with regard to solubility and chemical composition. Melanoma pigment from a patient with red-blonde hair was alkali-soluble and contained 9 or 10% sulfur and was thus of phaeomelanic type. Melanoma pigment from a patient with red-brown hair was insoluble in 0.2N NaOH. Its sulfur content was 6%. This pigment was eumelanic with regard to solubility characteristics but the sulfur content was higher than previously observed for eumelanin.Supported by grants from the Swedish Cancer Society (No. 626-B75-04XA), the Swedish Medical Research Council (No. B76-04X-00056-12), and the Walter, Ellen, and Lennart Hesselman Foundation for Scientific Research. ProfessorProta was a visiting scientist of the Swedish Cancer Society (No. 626-B75-04U).     

Spectrin assembly in avian erythroid development is determined by competing reactions of subunit homo- and hetero-oligomerization

Erythroid differentiation entails the biogenesis of a membrane skeleton, a network of proteins underlying and interacting with the plasma membrane, whose major constituent is the heterodimeric protein spectrin, composed of two structurally similar but distinct subunits, alpha (relative molecular mass (Mr) 240,000) and beta (Mr 220,000), which interact side-on with each other to form a long rod-like molecule. Interaction of this network with the membrane is mediated by the binding of the beta subunit to ankyrin, which in turn binds to the cytoplasmic domain of the transmembrane anion transporter (also referred to as band 3). Purified alpha and beta subunits of spectrin from the membrane of mature red blood cells will spontaneously heterodimerize, suggesting that assembly of the spectrin-actin skeleton is a simple self-assembly process, but in vivo studies with developing chicken embryo erythroid cells have indicated that assembly in vivo is more complex. We now present evidence that newly synthesized spectrin subunits in vivo or in vitro rapidly adopt one of two competing conformations, a heterodimer or a homo-oligomer. These competing reactions seem to determine the overall extent of spectrin assembled during erythroid development by determining which conformation will assemble onto the membrane-skeleton (the heterodimer) and which conformations are targeted for degradation (the homo-oligomers).     

二氧化碳气体水合物生成特性的实验研究

在小型高压水合物反应装置上研究了二氧化碳水合物的生成特性.实验结果表明,静态系统下,二氧化碳气体在纯水体系中的生成速率非常缓慢,只在气-液界面处有一薄层浆状水合物生成.通过添加适当的表面活性剂可以有效改善气-水体系的传质阻力,增加气-水接触面,显著提高水合物的生成速率.     

基于函数链神经网络的管道煤气流量计量系统

在管道煤气计量系统测量中引入管道煤气相对湿度修正,并采用湿度传感器转换相对湿度信号,利用函数链神经网络对管道煤气工况温度下所对应的水蒸汽饱和压力进行拟合,得到基于函数链神经网络的管道煤气流量计量模型和在线计量系统,从而大大简化管道煤气流量计量软件,在流量计设计范围内实现管道煤气流量实时在线计量.实际应用结果表明,该计量系统测量管道煤气流量误差小于0.7%.     

Subcellular patterns of calcium release determined by G protein-specific residues of muscarinic receptors.

Calcium release from intracellular stores is a point of convergence for a variety of receptors involved in cell signaling. Consequently, the mechanism(s) by which cells differentiate between individual receptor signals is central to transmembrane communication. There are significant differences in timing and magnitude of Ca2+ release stimulated by the m2 and m3 muscarinic acetylcholine receptors. The m2 receptors couple to a pertussis toxin-sensitive G protein to activate phosphatidyl inositol hydrolysis weakly and to stimulate small, delayed and oscillatory chloride currents. In contrast, m3 receptors potently activate phosphatidyl inositol hydrolysis and stimulate large, rapid and transient chloride currents by a pertussis toxin-insensitive G protein pathway. Using confocal microscopy, we now show that the m2- and m3-coupled Ca2+ release pathways can also be spatially distinguished. At submaximal acetylcholine concentrations, both receptors stimulated pulses of Ca2+ release from discrete foci in random, periodic and frequently bursting patterns of activity. But maximal stimulation of m2 receptors increased the number of focal release sites, whereas m3 receptors invariably evoked a Ca2+ wave propagating rapidly just beneath the plasma membrane surface. Analysis of pertussis toxin sensitivity and hybrid m2-m3 muscarinic acetylcholine receptors confirmed that these Ca2+ release patterns represent distinct cell signalling pathways.