The Ter mutation in the dead end gene causes germ cell loss and testicular germ cell tumours

In mice, the Ter mutation causes primordial germ cell (PGC) loss in all genetic backgrounds. Ter is also a potent modifier of spontaneous testicular germ cell tumour (TGCT) susceptibility in the 129 family of inbred strains, and markedly increases TGCT incidence in 129-Ter/Ter males. In 129-Ter/Ter mice, some of the remaining PGCs transform into undifferentiated pluripotent embryonal carcinoma cells, and after birth differentiate into various cells and tissues that compose TGCTs. Here, we report the positional cloning of Ter, revealing a point mutation that introduces a termination codon in the mouse orthologue (Dnd1) of the zebrafish dead end (dnd) gene. PGC deficiency is corrected both with bacterial artificial chromosomes that contain Dnd1 and with a Dnd1-encoding transgene. Dnd1 is expressed in fetal gonads during the critical period when TGCTs originate. DND1 has an RNA recognition motif and is most similar to the apobec complementation factor, a component of the cytidine to uridine RNA-editing complex. These results suggest that Ter may adversely affect essential aspects of RNA biology during PGC development. DND1 is the first protein known to have an RNA recognition motif directly implicated as a heritable cause of spontaneous tumorigenesis. TGCT development in the 129-Ter mouse strain models paediatric TGCT in humans. This work will have important implications for our understanding of the genetic control of TGCT pathogenesis and PGC biology.     

Structures of APC/C(Cdh1) with substrates identify Cdh1 and Apc10 as the D-box co-receptor

The ubiquitylation of cell-cycle regulatory proteins by the large multimeric anaphase-promoting complex (APC/C) controls sister chromatid segregation and the exit from mitosis. Selection of APC/C targets is achieved through recognition of destruction motifs, predominantly the destruction (D)-box and KEN (Lys-Glu-Asn)-box. Although this process is known to involve a co-activator protein (either Cdc20 or Cdh1) together with core APC/C subunits, the structural basis for substrate recognition and ubiquitylation is not understood. Here we investigate budding yeast APC/C using single-particle electron microscopy and determine a cryo-electron microscopy map of APC/C in complex with the Cdh1 co-activator protein (APC/C(Cdh1)) bound to a D-box peptide at ～10 ? resolution. We find that a combined catalytic and substrate-recognition module is located within the central cavity of the APC/C assembled from Cdh1, Apc10--a core APC/C subunit previously implicated in substrate recognition--and the cullin domain of Apc2. Cdh1 and Apc10, identified from difference maps, create a co-receptor for the D-box following repositioning of Cdh1 towards Apc10. Using NMR spectroscopy we demonstrate specific D-box-Apc10 interactions, consistent with a role for Apc10 in directly contributing towards D-box recognition by the APC/C(Cdh1) complex. Our results rationalize the contribution of both co-activator and core APC/C subunits to D-box recognition and provide a structural framework for understanding mechanisms of substrate recognition and catalysis by the APC/C.     

Conventionalism in Reid’s ‘geometry of visibles’

The subject of this investigation is the role of conventions in the formulation of Thomas Reid’s theory of the geometry of vision, which he calls the ‘geometry of visibles’. In particular, we will examine the work of N. Daniels and R. Angell who have alleged that, respectively, Reid’s ‘geometry of visibles’ and the geometry of the visual field are non-Euclidean. As will be demonstrated, however, the construction of any geometry of vision is subject to a choice of conventions regarding the construction and assignment of its various properties, especially metric properties, and this fact undermines the claim for a unique non-Euclidean status for the geometry of vision. Finally, a suggestion is offered for trying to reconcile Reid’s direct realist theory of perception with his geometry of visibles.While Thomas Reid is well-known as the leading exponent of the Scottish ‘common-sense’ school of philosophy, his role in the history of geometry has only recently been drawing the attention of the scholarly community. In particular, several influential works, by N. Daniels and R. B. Angell, have claimed Reid as the discoverer of non-Euclidean geometry; an achievement, moreover, that pre-dates the geometries of Lobachevsky, Bolyai, and Gauss by over a half century. Reid’s alleged discovery appears within the context of his analysis of the geometry of the visual field, which he dubs the ‘geometry of visibles’. In summarizing the importance of Reid’s philosophy in this area, Daniels is led to conclude that ‘there can remain little doubt that Reid intends the geometry of visibles to be an alternative to Euclidean geometry’;¹ while Angell, similarly inspired by Reid, draws a much stronger inference: ‘The geometry which precisely and naturally fits the actual configurations of the visual field is a non-Euclidean, two-dimensional, elliptical geometry. In substance, this thesis was advanced by Thomas Reid in 1764 ...’² The significance of these findings has not gone unnoticed in mathematical and scientific circles, moreover, for Reid’s name is beginning to appear more frequently in historical surveys of the development of geometry and the theories of space.³Implicit in the recent work on Reid’s ‘geometry of visibles’, or GOV, one can discern two closely related but distinct arguments: first, that Reid did in fact formulate a non-Euclidean geometry, and second, that the GOV is non-Euclidean. This essay will investigate mainly the latter claim, although a lengthy discussion will be accorded to the first. Overall, in contrast to the optimistic reports of a non-Euclidean GOV, it will be argued that there is a great deal of conceptual freedom in the construction of any geometry pertaining to the visual field. Rather than single out a non-Euclidean structure as the only geometry consistent with visual phenomena, an examination of Reid, Daniels, and Angell will reveal the crucial role of geometric ‘conventions’, especially of the metric sort, in the formulation of the GOV (where a ‘metric’ can be simply defined as a system for determining distances, the measures of angles, etc.). Consequently, while a non-Euclidean geometry is consistent with Reid’s GOV, it is only one of many different geometrical structures that a GOV can possess. Angell’s theory that the GOV can only be construed as non-Euclidean, is thus incorrect. After an exploration of Reid’s theory and the alleged non-Euclidean nature of the GOV, in 1 and 2 respectively, the focus will turn to the tacit role of conventionalism in Daniels’ reconstruction of Reid’s GOV argument, and in the contemporary treatment of a non-Euclidean visual geometry offered by Angell ( 3 and 4). Finally, in the conclusion, a suggestion will be offered for a possible reconstruction of Reid’s GOV that does not violate his avowed ‘direct realist’ theory of perception, since this epistemological thesis largely prompted his formulation of the GOV.     

用海水浇灌农作物

随着世界人口的增长和淡水资源的日趋珍贵,研究人员正把眼光投向大海,他们要用海水浇灌某些经挑选的植物。当前全球最紧迫的问题之一就是要找到足够的水和土地来满足全球性食品需求。据联合国粮农组织估计,在今后的30年内需要20亿公顷（约合49．42亿英亩）的新耕地─—面积相当于亚利桑那、新墨西哥、犹他、科罗拉多、爱达荷、怀俄明以及蒙大拿诸州的总和──才能满足热带和亚热带地区迅速增长的人口的食品需求、可是在这些地带的国家中可供农业拓展的土地只有9亿3千万公顷──而且其中很大一部分被森林覆盖,是应保护之地。显然,我们需…