A high-affinity conformation of Hsp90 confers tumour selectivity on Hsp90 inhibitors

Heat shock protein 90 (Hsp90) is a molecular chaperone that plays a key role in the conformational maturation of oncogenic signalling proteins, including HER-2/ErbB2, Akt, Raf-1, Bcr-Abl and mutated p53. Hsp90 inhibitors bind to Hsp90, and induce the proteasomal degradation of Hsp90 client proteins. Although Hsp90 is highly expressed in most cells, Hsp90 inhibitors selectively kill cancer cells compared to normal cells, and the Hsp90 inhibitor 17-allylaminogeldanamycin (17-AAG) is currently in phase I clinical trials. However, the molecular basis of the tumour selectivity of Hsp90 inhibitors is unknown. Here we report that Hsp90 derived from tumour cells has a 100-fold higher binding affinity for 17-AAG than does Hsp90 from normal cells. Tumour Hsp90 is present entirely in multi-chaperone complexes with high ATPase activity, whereas Hsp90 from normal tissues is in a latent, uncomplexed state. In vitro reconstitution of chaperone complexes with Hsp90 resulted in increased binding affinity to 17-AAG, and increased ATPase activity. These results suggest that tumour cells contain Hsp90 complexes in an activated, high-affinity conformation that facilitates malignant progression, and that may represent a unique target for cancer therapeutics.     

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.     

Constrained Multilevel Latent Class Models for the Analysis of Three-Way Three-Mode Binary Data

Probabilistic feature models (PFMs) can be used to explain binary rater judgements about the associations between two types of elements (e.g., objects and attributes) on the basis of binary latent features. In particular, to explain observed object-attribute associations PFMs assume that respondents classify both objects and attributes with respect to a, usually small, number of binary latent features, and that the observed object-attribute association is derived as a specific mapping of these classifications. Standard PFMs assume that the object-attribute association probability is the same according to all respondents, and that all observations are statistically independent. As both assumptions may be unrealistic, a multilevel latent class extension of PFMs is proposed which allows objects and/or attribute parameters to be different across latent rater classes, and which allows to model dependencies between associations with a common object (attribute) by assuming that the link between features and objects (attributes) is fixed across judgements. Formal relationships with existing multilevel latent class models for binary three-way data are described. As an illustration, the models are used to study rater differences in product perception and to investigate individual differences in the situational determinants of anger-related behavior.     

Peripheral neuropathy associated with inhalation of methyl-n-butyl ketone

Résumé Dix-sept rats sont exposés pendant 6 semaines 5 jours par semaine, 8 h par jour, à une atmosphère contenant soit du méthyl-n-butyl kétone seul soit un mélange de MnBK et de méthyl-éthyl kétone. Tous les rats présentèrent une faiblesse musculaire généralisée après l'inhalation qui dura de quelques h à 24 h avec récupération motrice totale. En dépit de cette apparence normale, l'examen histologique révéla une hypertrophie, un ballonement en grains de chapelet, et une dégénérescence des axones, associée à une démyélination secondaire, habituellement située dans la région des nodes de Ranvier. La toxicité du MnBK est prouvée, celle du MEK est encore à l'étude.     

Photosynthesis by isolated chloroplasts ofSorghum vulgare

Summary The ambiguous location of photosynthetic carboxylases of mesophyll and bundle sheath chloroplasts of sorghum was investigated after successful homogeneous preparation. The phosphoenol pyruvate carboxylase was found as a particulate enzyme in the mesophyll cell chloroplasts and ribulose 1,5-biphosphate carboxylase in the stroma of the bundle sheath cell chloroplasts. Extensive characterization was carried out on these 2 enzymes for better understanding of the enzyme action.     

Imaging the Indian subcontinent beneath the Himalaya

The rocks of the Indian subcontinent are last seen south of the Ganges before they plunge beneath the Himalaya and the Tibetan plateau. They are next glimpsed in seismic reflection profiles deep beneath southern Tibet, yet the surface seen there has been modified by processes within the Himalaya that have consumed parts of the upper Indian crust and converted them into Himalayan rocks. The geometry of the partly dismantled Indian plate as it passes through the Himalayan process zone has hitherto eluded imaging. Here we report seismic images both of the decollement at the base of the Himalaya and of the Moho (the boundary between crust and mantle) at the base of the Indian crust. A significant finding is that strong seismic anisotropy develops above the decollement in response to shear processes that are taken up as slip in great earthquakes at shallower depths. North of the Himalaya, the lower Indian crust is characterized by a high-velocity region consistent with the formation of eclogite, a high-density material whose presence affects the dynamics of the Tibetan plateau.