Germline KRAS mutations cause Noonan syndrome

Noonan syndrome (MIM 163950) is characterized by short stature, facial dysmorphism and cardiac defects. Heterozygous mutations in PTPN11, which encodes SHP-2, cause approximately 50% of cases of Noonan syndrome. The SHP-2 phosphatase relays signals from activated receptor complexes to downstream effectors, including Ras. We discovered de novo germline KRAS mutations that introduce V14I, T58I or D153V amino acid substitutions in five individuals with Noonan syndrome and a P34R alteration in a individual with cardio-facio-cutaneous syndrome (MIM 115150), which has overlapping features with Noonan syndrome. Recombinant V14I and T58I K-Ras proteins show defective intrinsic GTP hydrolysis and impaired responsiveness to GTPase activating proteins, render primary hematopoietic progenitors hypersensitive to growth factors and deregulate signal transduction in a cell lineage-specific manner. These studies establish germline KRAS mutations as a cause of human disease and infer that the constellation of developmental abnormalities seen in Noonan syndrome spectrum is, in large part, due to hyperactive Ras.     

Photosystem II core phosphorylation and photosynthetic acclimation require two different protein kinases

Illumination changes elicit modifications of thylakoid proteins and reorganization of the photosynthetic machinery. This involves, in the short term, phosphorylation of photosystem II (PSII) and light-harvesting (LHCII) proteins. PSII phosphorylation is thought to be relevant for PSII turnover, whereas LHCII phosphorylation is associated with the relocation of LHCII and the redistribution of excitation energy (state transitions) between photosystems. In the long term, imbalances in energy distribution between photosystems are counteracted by adjusting photosystem stoichiometry. In the green alga Chlamydomonas and the plant Arabidopsis, state transitions require the orthologous protein kinases STT7 and STN7, respectively. Here we show that in Arabidopsis a second protein kinase, STN8, is required for the quantitative phosphorylation of PSII core proteins. However, PSII activity under high-intensity light is affected only slightly in stn8 mutants, and D1 turnover is indistinguishable from the wild type, implying that reversible protein phosphorylation is not essential for PSII repair. Acclimation to changes in light quality is defective in stn7 but not in stn8 mutants, indicating that short-term and long-term photosynthetic adaptations are coupled. Therefore the phosphorylation of LHCII, or of an unknown substrate of STN7, is also crucial for the control of photosynthetic gene expression.     

Effects of antithymic reticuloepithelial cells serum on the levels of circulating thymic factor and on the sensitivity to azathioprine of spleen spontaneous rosette-forming cells

Summary Swiss mice treated with an antithymic reticuloepithelial cells serum (ATRES) showed a drastic and prolonged depression of the serum thymic factor. A similar but less pronounced effect was also observed following the administration of the antithymocyte (ATS) and the antilymphocyte (ALS) sera. Conversely, the azathioprine sensitivity of spleen spontaneous rosette-forming cells was highly modified by the ATRES but not by the ATS or the ALS. The probable mechanisms of such effects are discussed.     

Whole-genome analysis informs breast cancer response to aromatase inhibition

To correlate the variable clinical features of oestrogen-receptor-positive breast cancer with somatic alterations, we studied pretreatment tumour biopsies accrued from patients in two studies of neoadjuvant aromatase inhibitor therapy by massively parallel sequencing and analysis. Eighteen significantly mutated genes were identified, including five genes (RUNX1, CBFB, MYH9, MLL3 and SF3B1) previously linked to haematopoietic disorders. Mutant MAP3K1 was associated with luminal A status, low-grade histology and low proliferation rates, whereas mutant TP53 was associated with the opposite pattern. Moreover, mutant GATA3 correlated with suppression of proliferation upon aromatase inhibitor treatment. Pathway analysis demonstrated that mutations in MAP2K4, a MAP3K1 substrate, produced similar perturbations as MAP3K1 loss. Distinct phenotypes in oestrogen-receptor-positive breast cancer are associated with specific patterns of somatic mutations that map into cellular pathways linked to tumour biology, but most recurrent mutations are relatively infrequent. Prospective clinical trials based on these findings will require comprehensive genome sequencing.     

Determination of electron orbital magnetic moments in carbon nanotubes

The remarkable transport properties of carbon nanotubes (CNTs) are determined by their unusual electronic structure. The electronic states of a carbon nanotube form one-dimensional electron and hole sub-bands, which, in general, are separated by an energy gap. States near the energy gap are predicted to have an orbital magnetic moment, mu(orb), that is much larger than the Bohr magneton (the magnetic moment of an electron due to its spin). This large moment is due to the motion of electrons around the circumference of the nanotube, and is thought to play a role in the magnetic susceptibility of CNTs and the magnetoresistance observed in large multiwalled CNTs. But the coupling between magnetic field and the electronic states of individual nanotubes remains to be quantified experimentally. Here we report electrical measurements of relatively small diameter (2-5 nm) individual CNTs in the presence of an axial magnetic field. We observe field-induced energy shifts of electronic states and the associated changes in sub-band structure, which enable us to confirm quantitatively the predicted values for mu(orb).     

Soviet psychiatric abuse: allegations met by red tape

Responding to accusations by human rights groups concerning the confinement of dissidents in mental hospitals, the Soviet All-Union Society of Psychiatrists (AUSP) has supplied the World Psychiatric Association (WPA) with data on two alleged cases of abuse and promised information on four more. Some member societies are suspicious that the move is simply a delaying tactic to forestall possible ouster of the AUSP from the WPA. Some members are also concerned that the WPA executive council's "overscrupulous" stance on confidentiality has hindered investigation of complaints of psychiatric abuse.