Promoter-bound METTL3 maintains myeloid leukaemia by m6A-dependent translation control.

N6-methyladenosine (m6A) is an abundant internal RNA modification in both coding and non-coding RNAs that is catalysed by the METTL3-METTL14 methyltransferase complex. However, the specific role of these enzymes in cancer is still largely unknown. Here we define a pathway that is specific for METTL3 and is implicated in the maintenance of a leukaemic state. We identify METTL3 as an essential gene for growth of acute myeloid leukaemia cells in two distinct genetic screens. Downregulation of METTL3 results in cell cycle arrest, differentiation of leukaemic cells and failure to establish leukaemia in immunodeficient mice. We show that METTL3, independently of METTL14, associates with chromatin and localizes to the transcriptional start sites of active genes. The vast majority of these genes have the CAATT-box binding protein CEBPZ present at the transcriptional start site, and this is required for recruitment of METTL3 to chromatin. Promoter-bound METTL3 induces m6A modification within the coding region of the associated mRNA transcript, and enhances its translation by relieving ribosome stalling. We show that genes regulated by METTL3 in this way are necessary for acute myeloid leukaemia. Together, these data define METTL3 as a regulator of a chromatin-based pathway that is necessary for maintenance of the leukaemic state and identify this enzyme as a potential therapeutic target for acute myeloid leukaemia

Molecular Characterization of the Ro/SS-A Autoantigens

AbstractMolecular techniques have recently revealed that there are several immunologically distinct Ro/SS-A antigens. Three genes encoding putative Ro/SS-A protein antigens with calculated masses of 46, 52, and 60 kD have been isolated. The encoded amino acid sequence of each is quite dissimilar. The 46-kD antigen is calreticulin (CR), a highly conserved calcium-binding protein that resides predominately in the endoplasmic reticulum where it may be involved in protein assembly. Although CR has recently been confirmed to be a new human rheumatic disease-associated autoantigen, its relationship to the other components of the Ro/SS-A ribonucleoprotein has become somewhat controversial owing predominately to the fact that recombinant forms of calreticulin have not displayed the same pattern of autoantibody reactivity possesse by the native form of this protein.The 52-kD antigen most likely resides in the nucleus and may be involved in the regulation of gene expression. The cellular location and function of the 60-kD antigen is uncertain but studies indicate that it is a RNA-binding protein.The 46- and 60-kD antigens share homology with foreign polypeptides, suggesting that an immune response initially directed against a foreign protein may give rise to the autoimmune response directed at cross-reacting self proteins

Recent experiments on Alfven eigenmodes in MAST

The developments of advanced tokamak scenarios as well as the employment of a new neutral beam injection (NBI) source with higher power and beam energy up to approximate to 65 keV have significantly broadened the frequency range and the variety of Alfven eigenmodes (AEs) excited by the super-Alfvenic NBI on the spherical tokamak MAST. During recent experiments on MAST, several distinct classes of beam-driven AEs have been identified, with different modes being most unstable in different MAST scenarios. In MAST discharges with elevated monotonic q(r)-profiles and NBI power >= 3MW, chirping modes starting in the frequency range <= 150 kHz decreased in frequency down to approximate to 20 kHz as q( 0) decreased and then smoothly transformed to long-living modes with a weakly-varying frequency and a n = 1 kink-mode structure. The bolometer data suggest that the long-living modes can be responsible for fast ion losses on MAST, while the charge-exchange data show that a coupling between these modes and other low-frequency modes can cause a collapse of toroidal plasma rotation with a subsequent disruption. In MAST discharges with reversed magnetic shear, Alfven cascade eigenmodes in the frequency range 40-180 kHz were observed at a moderate NBI power <= 2MW allowing an additional assessment of q(r)-profile evolution in time. A robust reproducible scenario was found on MAST, in which the instability of high-frequency modes in the range 0.4-3.8MHz and typically with negative toroidal mode numbers was dominating the spectrum of beam-driven AEs. Since the highest frequency of such modes is close to the on-axis ion cyclotron frequency and the polarization study of these modes show a significant parallel perturbed magnetic field, these modes are identified as compressional Alfven eigenmodes. For investigating the AE spectrum in plasmas with high beta, an active AE antenna has been installed on MAST. First measurements of stable AE modes in MAST have been performed successfully and are described here

Ring-like pore structures of SecA: Implication for bacterial protein-conducting channels

SecA, an essential component of the general protein secretion pathway of bacteria, is present in Escherichia coli as soluble and membrane-integral forms. Here we show by electron microscopy that SecA assumes two characteristic forms in the presence of phospholipid monolayers: dumbbell-shaped elongated structures and ring-like pore structures. The ring-like pore structures with diameters of 8 nm and holes of 2 nm are found only in the presence of anionic phospholipids. These ring-like pore structures with larger 3- to 6-nm holes (without staining) were also observed by atomic force microscopic examination. They do not form in solution or in the presence of uncharged phosphatidylcholine. These ring-like phospholipid-induced pore-structures may form the core of bacterial protein-conducting channels through bacterial membranes