A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera

Myeloproliferative disorders are clonal haematopoietic stem cell malignancies characterized by independency or hypersensitivity of haematopoietic progenitors to numerous cytokines. The molecular basis of most myeloproliferative disorders is unknown. On the basis of the model of chronic myeloid leukaemia, it is expected that a constitutive tyrosine kinase activity could be at the origin of these diseases. Polycythaemia vera is an acquired myeloproliferative disorder, characterized by the presence of polycythaemia diversely associated with thrombocytosis, leukocytosis and splenomegaly. Polycythaemia vera progenitors are hypersensitive to erythropoietin and other cytokines. Here, we describe a clonal and recurrent mutation in the JH2 pseudo-kinase domain of the Janus kinase 2 (JAK2) gene in most (> 80%) polycythaemia vera patients. The mutation, a valine-to-phenylalanine substitution at amino acid position 617, leads to constitutive tyrosine phosphorylation activity that promotes cytokine hypersensitivity and induces erythrocytosis in a mouse model. As this mutation is also found in other myeloproliferative disorders, this unique mutation will permit a new molecular classification of these disorders and novel therapeutical approaches.     

Geomagnetic dipole strength and reversal rate over the past two million years

Independent records of relative magnetic palaeointensity from sediment cores in different areas of the world can be stacked together to extract the evolution of the geomagnetic dipole moment and thus provide information regarding the processes governing the geodynamo. So far, this procedure has been limited to the past 800,000 years (800 kyr; ref. 3), which does not include any geomagnetic reversals. Here we present a composite curve that shows the evolution of the dipole moment during the past two million years. This reconstruction is in good agreement with the absolute dipole moments derived from volcanic lavas, which were used for calibration. We show that, at least during this period, the time-averaged field was higher during periods without reversals but the amplitude of the short-term oscillations remained the same. As a consequence, few intervals of very low intensity, and thus fewer instabilities, are expected during periods with a strong average dipole moment, whereas more excursions and reversals are expected during periods of weak field intensity. We also observe that the axial dipole begins to decay 60-80 kyr before reversals, but rebuilds itself in the opposite direction in only a few thousand years.     

血管成形术和Stent放置术放射治疗后动脉损伤的治疗

用于评价经皮穿刺血管成形术和Ｓｔｅｎｔ在放疗后所致动脉疾病的治疗,及靶血管内Ｓｔｅｎｔ的长期支撑开放作用。资料和方法：１４例患者,因为放疗所致１８处动脉性病变,而给予血管成形术治疗。１３个Ｓｔｅｎｔ放置于８个患者,分别治疗血管闭塞３例,内膜撕裂１例,动脉瘤１例,残存狭窄２例,多发狭窄１例,球囊成形术后再发狭窄１例。所有病例均用ＣＴ扫描和／或多普勒超声检查,观察Ｓｔｅｎｔ及其靶血管内和Ｓｔｅｎｔ内的血流情况。结果：血管成形术成功治疗１４例病人,８例患者在动脉病变处放置Ｓｔｅｎｔ。１１例动脉病基本消失,追踪２年（８月～５年）,临床症状完全解除,３例临床症改善。１１例患者接受了１或２次血管成形术。１例患者重复承受了４次血管成形术,并放置３个Ｓｔｅｎｔ,２个Ｓｔｅｎｔ放在两髂总动脉和腹主动脉,１个Ｓｔｅｎｔ放在腹腔动脉。另１位重复４次血管成形术的患者,在肠系膜上动脉放了２个Ｓｔｅｎｔ。最后１例,因为血管成形术后内膜撕裂和血管闭塞,而放置了１个Ｓｔｅｎｔ,经５年随防,其动脉病变为临床治愈。结论：单一的血管成形术或者多技术综合运用,可有效治疗放疗所致的动脉性病变,应考虑其为动脉损伤性病变的首选治疗     

Exploiting non-canonical translation to identify new targets for T cell-based cancer immunotherapy

Cryptic MHC I-associated peptides (MAPs) are produced via two mechanisms: translation of protein-coding genes in non-canonical reading frames and translation of allegedly non-coding sequences. In general, cryptic MAPs are coded by relatively short open reading frames whose translation can be regulated at the level of initiation, elongation or termination. In contrast to conventional MAPs, the processing of cryptic MAPs is frequently proteasome independent. The existence of cryptic MAPs derived from allegedly non-coding regions enlarges the scope of CD8 T cell immunosurveillance from a mere ~2% to as much as ~75% of the human genome. Considering that 99% of cancer-specific mutations are located in those allegedly non-coding regions, cryptic MAPs could furthermore represent a particularly rich source of tumor-specific antigens. However, extensive proteogenomic analyses will be required to determine the breath as well as the temporal and spatial plasticity of the cryptic MAP repertoire in normal and neoplastic cells.     

The fungal glutathione S-transferase system. Evidence of new classes in the wood-degrading basidiomycete Phanerochaete chrysosporium

The recent release of several basidiomycete genome sequences allows an improvement of the classification of fungal glutathione S-transferases (GSTs). GSTs are well-known detoxification enzymes which can catalyze the conjugation of glutathione to non-polar compounds that contain an electrophilic carbon, nitrogen, or sulfur atom. Following this mechanism, they are able to metabolize drugs, pesticides, and many other xenobiotics and peroxides. A genomic and phylogenetic analysis of GST classes in various sequenced fungi—zygomycetes, ascomycetes, and basidiomycetes—revealed some particularities in GST distribution, in comparison with previous analyses with ascomycetes only. By focusing essentially on the wood-degrading basidiomycete Phanerochaete chrysosporium, this analysis highlighted a new fungal GST class named GTE, which is related to bacterial etherases, and two new subclasses of the omega class GSTs. Moreover, our phylogenetic analysis suggests a relationship between the saprophytic behavior of some fungi and the number and distribution of some GST isoforms within specific classes.     

“Controlled” and “Living” Cationic Polymerizations:Another Way Towards Well Defined Polymer Architectures and Materials

1 Results No doubt that one of the major breakthroughs in polymer chemistry was the discovery and the progressive implementation of the “living“ and “controlled“ polymerizations.These now widely used techniques allow not only to control with an extreme precision the molar masses and their distributions but also to synthesise easily a broad variety of architectures from block and graft copolymers,miktoarms stars,to polymer brushes,hyperbranched polymers,dendrimers,etc....They opened an immense domain of ...     

No signature of clear CO2 ice from the 'cryptic' regions in Mars' south seasonal polar cap

The seasonal polar ice caps of Mars are composed mainly of CO2 ice. A region of low (< 30%) albedo has been observed within the south seasonal cap during early to mid-spring. The low temperature of this 'cryptic region' has been attributed to a clear slab of nearly pure CO2 ice, with the low albedo resulting from absorption by the underlying surface. Here we report near-infrared imaging spectroscopy of the south seasonal cap. The deep and broad CO2 absorption bands that are expected in the near-infrared with a thick transparent slab of CO2 ice are not observed. Models of the observed spectra indicate that the low albedo results from extensive dust contamination close to the surface of a CO2 ice layer, which could be linked to atmospheric circulation patterns. The strength of the CO2 absorption increases after mid-spring, so part of the dust is either carried away or buried more deeply in the ice layer during the CO2 ice sublimation process.