Novel mutations target distinct subgroups of medulloblastoma

Medulloblastoma is a malignant childhood brain tumour comprising four discrete subgroups. Here, to identify mutations that drive medulloblastoma, we sequenced the entire genomes of 37 tumours and matched normal blood. One-hundred and thirty-six genes harbouring somatic mutations in this discovery set were sequenced in an additional 56 medulloblastomas. Recurrent mutations were detected in 41 genes not yet implicated in medulloblastoma; several target distinct components of the epigenetic machinery in different disease subgroups, such as regulators of H3K27 and H3K4 trimethylation in subgroups 3 and 4 (for example, KDM6A and ZMYM3), and CTNNB1-associated chromatin re-modellers in WNT-subgroup tumours (for example, SMARCA4 and CREBBP). Modelling of mutations in mouse lower rhombic lip progenitors that generate WNT-subgroup tumours identified genes that maintain this cell lineage (DDX3X), as well as mutated genes that initiate (CDH1) or cooperate (PIK3CA) in tumorigenesis. These data provide important new insights into the pathogenesis of medulloblastoma subgroups and highlight targets for therapeutic development.     

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.     

Non-adaptive origins of interactome complexity

The boundaries between prokaryotes, unicellular eukaryotes and multicellular eukaryotes are accompanied by orders-of-magnitude reductions in effective population size, with concurrent amplifications of the effects of random genetic drift and mutation. The resultant decline in the efficiency of selection seems to be sufficient to influence a wide range of attributes at the genomic level in a non-adaptive manner. A key remaining question concerns the extent to which variation in the power of random genetic drift is capable of influencing phylogenetic diversity at the subcellular and cellular levels. Should this be the case, population size would have to be considered as a potential determinant of the mechanistic pathways underlying long-term phenotypic evolution. Here we demonstrate a phylogenetically broad inverse relation between the power of drift and the structural integrity of protein subunits. This leads to the hypothesis that the accumulation of mildly deleterious mutations in populations of small size induces secondary selection for protein-protein interactions that stabilize key gene functions. By this means, the complex protein architectures and interactions essential to the genesis of phenotypic diversity may initially emerge by non-adaptive mechanisms.     

The origins of insect metamorphosis.

Insect metamorphosis is a fascinating and highly successful biological adaptation, but there is much uncertainty as to how it evolved. Ancestral insect species did not undergo metamorphosis and there are still some existing species that lack metamorphosis or undergo only partial metamorphosis. Based on endocrine studies and morphological comparisons of the development of insect species with and without metamorphosis, a novel hypothesis for the evolution of metamorphosis is proposed. Changes in the endocrinology of development are central to this hypothesis. The three stages of the ancestral insect species-pronymph, nymph and adult-are proposed to be equivalent to the larva, pupa and adult stages of insects with complete metamorphosis. This proposal has general implications for insect developmental biology.     

胃蛋白酶原亚群与胃部疾病相关性研究

为测定胃蛋白酶原亚群(pepsinogenI PGI,pepsinogenⅡPGⅡ)在健康体检者及胃部疾病患者的血清含量,探讨血清中PG亚群检测对萎缩性胃炎和胃癌早期诊断的临床意义,利用放射免疫法(radioimmunoassay RIA)检测35例健康体检者、18例胃溃疡、30例萎缩性胃炎和30例胃癌患者血清中PGⅠ、PGⅡ及PGⅠ/PGⅡ比值的变化,比较正常组与各疾病组的胃蛋白酶原含量。结果:(1)与正常组相比,胃溃疡组PGⅠ、PGⅡ升高,以PGⅡ增高明显,而PGⅠ/PGⅡ比值降低;萎缩性胃炎和胃癌组PGⅠ水平均呈下降趋势,而PGⅡ水平变化不明显,PGⅠ/PGⅡ比值下降。(2)与溃疡组相比,萎缩性胃炎和胃癌组PGⅠ、PGⅡ及PGⅠ/PGⅡ比值均明显降低。(3)与萎缩性胃炎组相比,胃癌组PGⅠ、PGⅡ及PGⅠ/PGⅡ比值虽略低于萎缩性胃炎,但差异无统计学意义。(4)当PGⅠ≤80 ng/mL和PGⅠ/PGⅡ≤6时,检出萎缩性胃炎的特异度和灵敏度分别为94.3%和53.3%。说明血清PGⅠ和PGⅠ/PGⅡ比值的降低,是萎缩性胃炎及胃癌人群筛查和辅助诊断的一项血清学指标。血清PGI≤80 ng/mL且PGⅠ/PGⅡ≤6时检测萎缩性胃炎具有较好的特异度和灵敏度。测定血清PG亚群的方法简单易行,适于初筛萎缩性胃炎及胃癌人群及胃镜检查禁忌者。     

Evolutionary origins of vertebrate appendicular muscle

The evolution of terrestrial tetrapod species heralded a transition in locomotor strategies. While most fish species use the undulating contractions of the axial musculature to generate propulsive force, tetrapods also rely on the appendicular muscles of the limbs to generate movement. Despite the fossil record generating an understanding of the way in which the appendicular skeleton has evolved to provide the scaffold for tetrapod limb musculature, there is, by contrast, almost no information as to how this musculature arose. Here we examine fin muscle formation within two extant classes of fish. We find that in the teleost, zebrafish, fin muscles arise from migratory mesenchymal precursor cells that possess molecular and morphogenetic identity with the limb muscle precursors of tetrapod species. Chondrichthyan dogfish embryos, however, use the primitive mechanism of direct epithelial somitic extensions to derive the muscles of the fin. We conclude that the genetic mechanism controlling formation of tetrapod limb muscles evolved before the Sarcopterygian radiation.     

CP破坏的物理根源

本文介绍了几个重要的CP破坏模型,讨论了它们的成功之处和所存在的问题,结合CP破坏研究的现状,提出几点展望。     

RNA evolution and the origins of life

The evolution of RNA is likely to have played an important role in the very early history of life on Earth but it is doubtful that life began with RNA. Consideration of what came before RNA must take into account relevant information from geochemistry, prebiotic chemistry and nucleic acid biochemistry.     

The origins and the future of microfluidics

The manipulation of fluids in channels with dimensions of tens of micrometres--microfluidics--has emerged as a distinct new field. Microfluidics has the potential to influence subject areas from chemical synthesis and biological analysis to optics and information technology. But the field is still at an early stage of development. Even as the basic science and technological demonstrations develop, other problems must be addressed: choosing and focusing on initial applications, and developing strategies to complete the cycle of development, including commercialization. The solutions to these problems will require imagination and ingenuity.