Copy number variation and selection during reprogramming to pluripotency

The mechanisms underlying the low efficiency of reprogramming somatic cells into induced pluripotent stem (iPS) cells are poorly understood. There is a clear need to study whether the reprogramming process itself compromises genomic integrity and, through this, the efficiency of iPS cell establishment. Using a high-resolution single nucleotide polymorphism array, we compared copy number variations (CNVs) of different passages of human iPS cells with their fibroblast cell origins and with human embryonic stem (ES) cells. Here we show that significantly more CNVs are present in early-passage human iPS cells than intermediate passage human iPS cells, fibroblasts or human ES cells. Most CNVs are formed de novo and generate genetic mosaicism in early-passage human iPS cells. Most of these novel CNVs rendered the affected cells at a selective disadvantage. Remarkably, expansion of human iPS cells in culture selects rapidly against mutated cells, driving the lines towards a genetic state resembling human ES cells.     

Subtractive proteomic mapping of the endothelial surface in lung and solid tumours for tissue-specific therapy

The molecular complexity of tissues and the inaccessibility of most cells within a tissue limit the discovery of key targets for tissue-specific delivery of therapeutic and imaging agents in vivo. Here, we describe a hypothesis-driven, systems biology approach to identifying a small subset of proteins induced at the tissue-blood interface that are inherently accessible to antibodies injected intravenously. We use subcellular fractionation, subtractive proteomics and bioinformatics to identify endothelial cell surface proteins exhibiting restricted tissue distribution and apparent tissue modulation. Expression profiling and gamma-scintigraphic imaging with antibodies establishes two of these proteins, aminopeptidase-P and annexin A1, as selective in vivo targets for antibodies in lungs and solid tumours, respectively. Radio-immunotherapy to annexin A1 destroys tumours and increases animal survival. This analytical strategy can map tissue- and disease-specific expression of endothelial cell surface proteins to uncover novel accessible targets useful for imaging and therapy.     

Lysosomal mutations increase susceptibility to anaesthetics

The anaesthetic responses of homozygous mutant mice were compared with those of their normal heterozygous littermates. The two recessive mutations studied were beige (bg) and reduced pigmentation (rp). Homozygosity for either significantly increased the sleeping time of both sexes after treatment with pentobarbital, tribromoethanol or the steroid anaesthetic alphaxalone.     

Use of three specific radioimmunoassays in measuring neurohypophysial hormone content and plasma concentrations of vasopressin, oxytocin and DDAVP in rats after prolonged infusion of DDAVP

Specific radioimmunoassays (RIA) were employed for measuring plasma and neurohypophysial concentrations of oxytocin (OT) and vasopressin (AVP) after administration of 1-deamino-8-D-Arg-vasopressin (DDAVP). DDAVP concentrations were measured by a newly-developed specific RIA. Through the use of minipumps, DDAVP was infused i.p. over a period of 3 days in normally hydrated rats. Despite decreased urine production and increased urine osmolality no changes could be observed in neurohypophysial and plasma hormone concentrations.     

含铜结构钢的氢致开裂

本文通过Ｂａｔｔｅｌｌｅ焊道下开裂试验、ＵＴ氢敏感性试验和插销试验对４种含Ｃｕ结构钢的氢致开裂敏感性作出评价。测得的氢致开裂敏感性顺序为：ＨＳＬＡ－８０Ｍ＞ＨＳＬＡ－８Ｏ－２＞ＨＳＬＡ－８Ｏ－１＞ＤＱ－８０，即随着碳当量降低，氢致开裂敏感性也随之降低。与相同强度级别的传统淬火—回火钢相比，含Ｃｕ结构钢具有较好的防止氢致开裂的性能，可以在室温（ＤＱ－８０）或较低的预热温度下（其它三种钢）进行焊接。根据插销试验的实测数据对下临界应力（ＬＣＳ）的６种计算公式进行验证，发现所有公式的计算值普遍偏低。这是由于存在于含Ｃｕ结构钢粗晶热影响区的奥氏体“袋”具有扩散氢“贮室”及裂纹扩展“屏障”的作用，因而在相同的Ｐ＿ｃｍ情况下，含Ｃｕ结构钢比传统钢种具有更高的ＬＣＳ值。     

The first cleavage of the mouse zygote predicts the blastocyst axis

One of the unanswered questions in mammalian development is how the embryonic-abembryonic axis of the blastocyst is first established. It is possible that the first cleavage division contributes to this process, because in most mouse embryos the progeny of one two-cell blastomere primarily populate the embryonic part of the blastocyst and the progeny of its sister populate the abembryonic part. However, it is not known whether the embryonic-abembryonic axis is set up by the first cleavage itself, by polarity in the oocyte that then sets the first cleavage plane with respect to the animal pole, or indeed whether it can be divorced entirely from the first cleavage and established in relation to the animal pole. Here we test the importance of the orientation of the first cleavage by imposing an elongated shape on the zygote so that the division no longer passes close to the animal pole, marked by the second polar body. Non-invasive lineage tracing shows that even when the first cleavage occurs along the short axis imposed by this experimental treatment, the progeny of the resulting two-cell blastomeres tend to populate the respective embryonic and abembryonic parts of the blastocyst. Thus, the first cleavage contributes to breaking the symmetry of the embryo, generating blastomeres with different developmental characteristics.     

低合金结构钢焊接热影响区最大硬度估算

通过钢材的碳当量（ＣＥ）和焊接热影响区的冷却速度（通常取８００～５００℃的冷却时间ｔ８／５来代替）预测ＨＡＺ的最大硬度（Ｈｍａｘ）为分析材料焊接性的便捷途径。现有文献已经提供了不少ＣＥ、ｔ８／５以及Ｈｍａｘ的公式或图解方法。由于这些公式或方法都是针对一定的材料并且是在一定的试验方法和焊接条件下建立，因而在应用上存在着局限性。本文根据对９种低合金结构钢的试验结果，说明在不同ＣＥ范围内，Ｈｍａｘ与ｔ＿８／５有着不同的关系，并根据测得的数据对ｔ＿８／５的３种图解方法和２种计算公式以及Ｈｍａｘ的７种计算公式进行验证。结果表明，Ｕｗｅｒ和Ｄｅｇｅｎｋｏｌｂｅ提出的ｔ＿８／５计算公式和百合冈信孝－３Ｈｍａｘ计算公式具有较高的精确性和实用价值。     

Recurrent gross mutations of the PTEN tumor suppressor gene in breast cancers with deficient DSB repair

Basal-like breast cancer (BBC) is a subtype of breast cancer with poor prognosis. Inherited mutations of BRCA1, a cancer susceptibility gene involved in double-strand DNA break (DSB) repair, lead to breast cancers that are nearly always of the BBC subtype; however, the precise molecular lesions and oncogenic consequences of BRCA1 dysfunction are poorly understood. Here we show that heterozygous inactivation of the tumor suppressor gene Pten leads to the formation of basal-like mammary tumors in mice, and that loss of PTEN expression is significantly associated with the BBC subtype in human sporadic and BRCA1-associated hereditary breast cancers. In addition, we identify frequent gross PTEN mutations, involving intragenic chromosome breaks, inversions, deletions and micro copy number aberrations, specifically in BRCA1-deficient tumors. These data provide an example of a specific and recurrent oncogenic consequence of BRCA1-dependent dysfunction in DNA repair and provide insight into the pathogenesis of BBC with therapeutic implications. These findings also argue that obtaining an accurate census of genes mutated in cancer will require a systematic examination for gross gene rearrangements, particularly in tumors with deficient DSB repair.     

On the location of cholinesterase in fishes

Zusammenfassung Es wird eine sehr hohe Acetylcholinesteraseaktivität im Schwanzmuskel von Guppy und Goldfish gefunden. Die Aktivität ist in Endomysium und Septa lokalisiert.     

The loss of ions from Venus through the plasma wake

Venus, unlike Earth, is an extremely dry planet although both began with similar masses, distances from the Sun, and presumably water inventories. The high deuterium-to-hydrogen ratio in the venusian atmosphere relative to Earth's also indicates that the atmosphere has undergone significantly different evolution over the age of the Solar System. Present-day thermal escape is low for all atmospheric species. However, hydrogen can escape by means of collisions with hot atoms from ionospheric photochemistry, and although the bulk of O and O2 are gravitationally bound, heavy ions have been observed to escape through interaction with the solar wind. Nevertheless, their relative rates of escape, spatial distribution, and composition could not be determined from these previous measurements. Here we report Venus Express measurements showing that the dominant escaping ions are O+, He+ and H+. The escaping ions leave Venus through the plasma sheet (a central portion of the plasma wake) and in a boundary layer of the induced magnetosphere. The escape rate ratios are Q(H+)/Q(O+) = 1.9; Q(He+)/Q(O+) = 0.07. The first of these implies that the escape of H+ and O+, together with the estimated escape of neutral hydrogen and oxygen, currently takes place near the stoichometric ratio corresponding to water.