Ru2 and Ru encode mouse orthologs of the genes mutated in human Hermansky-Pudlak syndrome types 5 and 6

Hermansky-Pudlak syndrome (HPS) is a genetically heterogeneous disease involving abnormalities of melanosomes, platelet dense granules and lysosomes. Here we have used positional candidate and transgenic rescue approaches to identify the genes mutated in ruby-eye 2 and ruby-eye mice (ru2 and ru, respectively), two 'mimic' mouse models of HPS. We also show that these genes are orthologs of the genes mutated in individuals with HPS types 5 and 6, respectively, and that their protein products directly interact. Both genes are previously unknown and are found only in higher eukaryotes, and together represent a new class of genes that have evolved in higher organisms to govern the synthesis of highly specialized lysosome-related organelles.     

Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells

Several proteins implicated in the pathogenesis of polycystic kidney disease (PKD) localize to cilia. Furthermore, cilia are malformed in mice with PKD with mutations in TgN737Rpw (encoding polaris). It is not known, however, whether ciliary dysfunction occurs or is relevant to cyst formation in PKD. Here, we show that polycystin-1 (PC1) and polycystin-2 (PC2), proteins respectively encoded by Pkd1 and Pkd2, mouse orthologs of genes mutated in human autosomal dominant PKD, co-distribute in the primary cilia of kidney epithelium. Cells isolated from transgenic mice that lack functional PC1 formed cilia but did not increase Ca(2+) influx in response to physiological fluid flow. Blocking antibodies directed against PC2 similarly abolished the flow response in wild-type cells as did inhibitors of the ryanodine receptor, whereas inhibitors of G-proteins, phospholipase C and InsP(3) receptors had no effect. These data suggest that PC1 and PC2 contribute to fluid-flow sensation by the primary cilium in renal epithelium and that they both function in the same mechanotransduction pathway. Loss or dysfunction of PC1 or PC2 may therefore lead to PKD owing to the inability of cells to sense mechanical cues that normally regulate tissue morphogenesis.     

CUL-4 ubiquitin ligase maintains genome stability by restraining DNA-replication licensing

To maintain genome stability, DNA replication is strictly regulated to occur only once per cell cycle. In eukaryotes, the presence of 'licensing proteins' at replication origins during the G1 cell-cycle phase allows the formation of the pre-replicative complex. The removal of licensing proteins from chromatin during the S phase ensures that origins fire only once per cell cycle. Here we show that the CUL-4 ubiquitin ligase temporally restricts DNA-replication licensing in Caenorhabditis elegans. Inactivation of CUL-4 causes massive DNA re-replication, producing cells with up to 100C DNA content. The C. elegans orthologue of the replication-licensing factor Cdt1 (refs 2, 3) is required for DNA replication. C. elegans CDT-1 is present in G1-phase nuclei but disappears as cells enter S phase. In cells lacking CUL-4, CDT-1 levels fail to decrease during S phase and instead remain constant in the re-replicating cells. Removal of one genomic copy of cdt-1 suppresses the cul-4 re-replication phenotype. We propose that CUL-4 prevents aberrant re-initiation of DNA replication, at least in part, by facilitating the degradation of CDT-1.     

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…     

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.     

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.     

An autoregulatory circuit for long-range self-organization in Dictyostelium cell populations

Nutrient-deprived Dictyostelium amoebae aggregate to form a multicellular structure by chemotaxis, moving towards propagating waves of cyclic AMP that are relayed from cell to cell. Organizing centres are not formed by founder cells, but are dynamic entities consisting of cores of outwardly rotating spiral waves that self-organize in a homogeneous cell population. Spiral waves are ubiquitously observed in chemical reactions as well as in biological systems. Although feedback control of spiral waves in spatially extended chemical reactions has been demonstrated in recent years, the mechanism by which control is achieved in living systems is unknown. Here we show that mutants of the cyclic AMP/protein kinase A pathway show periodic signalling, but fail to organize coherent long-range wave territories, owing to the appearance of numerous spiral cores. A theoretical model suggests that autoregulation of cell excitability mediated by protein kinase A acts to optimize the number of signalling centres.