RNA cytosine methyltransferase Nsun3 regulates embryonic stem cell differentiation by promoting mitochondrial activity

Chemical modifications of RNA have been attracting increasing interest because of their impact on RNA fate and function. Therefore, the characterization of enzymes catalyzing such modifications is of great importance. The RNA cytosine methyltransferase NSUN3 was recently shown to generate 5-methylcytosine in the anticodon loop of mitochondrial tRNA^Met. Further oxidation of this position is required for normal mitochondrial translation and function in human somatic cells. Because embryonic stem cells (ESCs) are less dependent on oxidative phosphorylation than somatic cells, we examined the effects of catalytic inactivation of Nsun3 on self-renewal and differentiation potential of murine ESCs. We demonstrate that Nsun3-mutant cells show strongly reduced mt-tRNA^Met methylation and formylation as well as reduced mitochondrial translation and respiration. Despite the lower dependence of ESCs on mitochondrial activity, proliferation of mutant cells was reduced, while pluripotency marker gene expression was not affected. By contrast, ESC differentiation was skewed towards the meso- and endoderm lineages at the expense of neuroectoderm. Wnt3 was overexpressed in early differentiating mutant embryoid bodies and in ESCs, suggesting that impaired mitochondrial function disturbs normal differentiation programs by interfering with cellular signalling pathways. Interestingly, basal levels of reactive oxygen species (ROS) were not altered in ESCs, but Nsun3 inactivation attenuated induction of mitochondrial ROS upon stress, which may affect gene expression programs upon differentiation. Our findings not only characterize Nsun3 as an important regulator of stem cell fate but also provide a model system to study the still incompletely understood interplay of mitochondrial function with stem cell pluripotency and differentiation.     

Effect of halogenmethylenebisphosphonates on bone cells in culture and on bone resorption in vivo

Dihalogenmethylenebisphosphonates increase alkaline phosphatase activity and fatty acid oxidation in calvaria cells in culture (Cl2MBP greater than Br2MBP approximately equal to F2MBP). The monohalogen ClMBP and the non-halogenated analogues are less active on phosphatase and inactive on or inhibitory towards fatty acid oxidation. The three dihalogenbisphosphonates and ClMBP inhibit bone resorption in vivo, Cl2MBP most strongly.     

Measurement of collateral flow in experimental coronary occlusion

Zusammenfassung Es wird ein Verfahren zur autoradiographischen Darstellung der intramyocardialen Durchblutungsverteilung nach experimenteller Coronarocclusion angegeben. Im Versorgungsbereich akut verschlossener Coronararterien wird eine inhomogene Reduktion der Durchblutung beobachtet, wobei die Innenschichten regelmässig stärker als die subepicardialen Myocardanteile betroffen sind.     

Extremely fast acceleration of cosmic rays in a supernova remnant

Galactic cosmic rays (CRs) are widely believed to be accelerated by shock waves associated with the expansion of supernova ejecta into the interstellar medium. A key issue in this long-standing conjecture is a theoretical prediction that the interstellar magnetic field can be substantially amplified at the shock of a young supernova remnant (SNR) through magnetohydrodynamic waves generated by cosmic rays. Here we report a discovery of the brightening and decay of X-ray hot spots in the shell of the SNR RX J1713.7-3946 on a one-year timescale. This rapid variability shows that the X-rays are produced by ultrarelativistic electrons through a synchrotron process and that electron acceleration does indeed take place in a strongly magnetized environment, indicating amplification of the magnetic field by a factor of more than 100. The X-ray variability also implies that we have witnessed the ongoing shock-acceleration of electrons in real time. Independently, broadband X-ray spectrometric measurements of RX J1713.7-3946 indicate that electron acceleration proceeds in the most effective ('Bohm-diffusion') regime. Taken together, these two results provide a strong argument for acceleration of protons and nuclei to energies of 1 PeV (10(15) eV) and beyond in young supernova remnants.     

Effects of Gd solutes on hardness and yield strength of Mg alloys

Relative contribution of individual strengthening mechanisms to the yield strength of Mg–0–15 wt%Gd alloys were investigated.Alloys with different grain size were prepared by adding Zr and hot extrusion.Hardness and tensile/compression yield strength were tested on the alloys after solid solution treatment and extrusion.HallPetch constants were calculated with hardness and tensile/compressive data.The results showed that the hardness of Mg–Gd alloys with similar Gd content and different grain size were almost the same,which indicates that grain size had little effect on hardness.The hardness linearly increased with rising Gd content(d H_v/dc≈25 kg mm~(-2)/at%Gd).The tensile and compressive yield strengths enhanced with the increase of Gd content for all alloys in different conditions.In addition,the tensile/compressive(t/c)yield asymmetry of extruded alloys decreased with increasing Gd content.Large t/c yield asymmetry ratio(1.77)was observed for pure Mg,and with increasing Gd content this value decreased to 1.With the increasing of tensile strength,the stress intensity factor,k_y,decreased from 0.27 MPa m~(1/2)for Mg–2 wt%Gd alloy to 0.19 MPa m~(1/2) for Mg–5 wt%Gd alloy,then increased to 0.29 MPa m~(1/2) for Mg–15 wt%Gd alloy.However,k_yincreased linearly form 0.16–0.31 MPa for compression test.The influence of grain size strengthening was eliminated,and the yield strength of tension and compression both linearly increased with c~n,where c is the atom concentration of Gd,and n=1/2 or 2/3.     

Effect of halogenmethylenebisphosphonates on bone cells in culture and on bone resorption in vivo

Summary Dihalogenmethylenebisphosphonates increase alkaline phosphatase activity and fatty acid oxidation in calvaria cells in culture (Cl₂MBP>Br₂MBPF₂MBP). The monohalogen C1MBP and the non-halogenated analogues are less active on phosphatase and inactive on or inhibitory towards fatty acid oxidation. The three dihalogenbisphosphonates and C1MBP inhibit bone resorption in vivo, Cl₂MBP most strongly.Acknowledgments. We thank Miss M.-L. Aebersold, Miss J. Portenier, Mrs I. Tschudi and Mrs Ch. Marti for their skilled technical assistance. This work has been supported by the Swiss National Science Foundation (grant 3.937.82), by the Procter & Gamble Company, Cincinnati, USA, by the Istituto Gentili S.p.A., Pisa, Italy, and by the Ausbildungs- und Förderungsfonds der Arbeitsgemeinschaft für Osteosynthese (AO), Chur, Switzerland.