Specific modifications to histones are essential epigenetic markers---heritable changes in gene expression that do not affect the DNA sequence. Methylation of lysine 9 in histone H3 is recognized by heterochromatin protein 1 (HP1), which directs the binding of other proteins to control chromatin structure and gene expression. Here we show that HP1 uses an induced-fit mechanism for recognition of this modification, as revealed by the structure of its chromodomain bound to a histone H3 peptide dimethylated at Nzeta of lysine 9. The binding pocket for the N-methyl groups is provided by three aromatic side chains, Tyr21, Trp42 and Phe45, which reside in two regions that become ordered on binding of the peptide. The side chain of Lys9 is almost fully extended and surrounded by residues that are conserved in many other chromodomains. The QTAR peptide sequence preceding Lys9 makes most of the additional interactions with the chromodomain, with HP1 residues Val23, Leu40, Trp42, Leu58 and Cys60 appearing to be a major determinant of specificity by binding the key buried Ala7. These findings predict which other chromodomains will bind methylated proteins and suggest a motif that they recognize.

Most cancer-related deaths are a result of metastasis, and thus the importance of this process as a target of therapy cannot be understated. By asking ‘how can we effectively treat cancer?’, we do not capture the complexity of a disease encompassing >200 different cancer types — many consisting of multiple subtypes — with considerable intratumoural heterogeneity, which can result in variable responses to a specific therapy. Moreover, we have much less information on the pathophysiological characteristics of metastases than is available for the primary tumour. Most disseminated tumour cells that arrive in distant tissues, surrounded by unfamiliar cells and a foreign microenvironment, are likely to die; however, those that survive can generate metastatic tumours with a markedly different biology from that of the primary tumour. To treat metastasis effectively, we must inhibit fundamental metastatic processes and develop specific preclinical and clinical strategies that do not rely on primary tumour responses. To address this crucial issue, Cancer Research UK and Cancer Therapeutics CRC Australia formed a Metastasis Working Group with representatives from not-for-profit, academic, government, industry and regulatory bodies in order to develop recommendations on how to tackle the challenges associated with treating (micro)metastatic disease. Herein, we describe the challenges identified as well as the proposed approaches for discovering and developing anticancer agents designed specifically to prevent or delay the metastatic outgrowth of cancer.

CHR-2797 is a novel metalloenzyme inhibitor that is converted into a pharmacologically active acid product (CHR-79888) inside cells. CHR-79888 is a potent inhibitor of a number of intracellular aminopeptidases, including leucine aminopeptidase. CHR-2797 exerts antiproliferative effects against a range of tumor cell lines in vitro and in vivo and shows selectivity for transformed over nontransformed cells.

We present an ultrafast neural network (NN) model, QLKNN, which predicts core tokamak transport heat and particle fluxes. QLKNN is a surrogate model based on a database of 300 million flux calculations of the quasilinear gyrokinetic transport model QuaLiKiz. The database covers a wide range of realistic tokamak core parameters. Physical features such as the existence of a critical gradient for the onset of turbulent transport were integrated into the neural network training methodology. We have coupled QLKNN to the tokamak modelling framework JINTRAC and rapid control-oriented tokamak transport solver RAPTOR. The coupled frameworks are demonstrated and validated through application to three JET shots covering a representative spread of H-mode operating space, predicting turbulent transport of energy and particles in the plasma core. JINTRAC-QLKNN and RAPTOR-QLKNN are able to accurately reproduce JINTRAC-QuaLiKiz T i,e and n e profiles, but 3 to 5 orders of magnitude faster. Simulations which take hours are reduced down to only a few tens of seconds. The discrepancy in the final source-driven predicted profiles between QLKNN and QuaLiKiz is on the order 1%-15%. Also the dynamic behaviour was well captured by QLKNN, with differences of only 4%-10% compared to JINTRAC-QuaLiKiz observed at mid-radius, for a study of density buildup following the L-H transition. Deployment of neural network surrogate models in multi-physics integrated tokamak modelling is a promising route towards enabling accurate and fast tokamak scenario optimization, Uncertainty Quantification, and control applications.

Background: The site of Jagged/Serrate ligand recognition by Notch is unknown.Results: Two critical residues involved in an intramolecular hydrophobic interaction across the central β-sheet of EGF12 form a ligand-binding platform.Conclusion: The ligand-binding region is adjacent to a Fringe-sensitive residue involved in modulating Notch activity.Significance: The results have implications for understanding receptor/ligand recognition, Notch regulation by O-glycosylation, and the development of paralogue-specific antibodies.

The present paper offers an overview of the potential of ion cyclotron resonance heating (ICRH) or radio frequency (RF) heating for the DEMO machine. It is found that various suitable heating schemes are available. Similar to ITER and in view of the limited bandwidth of about 10M Hz that can be achieved to ensure optimal functioning of the launcher, it is proposed to make core second harmonic tritium heating the key ion heating scheme, assisted by fundamental cyclotron heating 3 He in the early phase of the discharge; for the present design of DEMO-with a static magnetic field strength of B o = 5.855T-that places the T and 3 He layers in the core for f = 60M Hz and suggests to center the bandwidth around that main operating frequency. In line with earlier studies for hot, dense plasmas in large-size magnetic confinement machines it is shown that good single pass absorption is achieved but that the size as well as operating density and temperature of the machine cause the electrons to absorb a non-negligible fraction of the power away from the core when core ion heating is aimed at. Current drive and alternative heating options are briefly discussed and a dedicated computation is done for the traveling wave antenna, proposed for DEMO in view of its compatibility with substantial antenna-plasma distances. The various tasks that ICRH can fulfill are briefly listed. Finally, the impact of transport and the sensitivity of the obtained results to changes in the machine parameters is commented on.

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Transport analysis of MAST discharges indicates that collisions are an important loss mechanism in the core of a tight aspect ratio tokamak. In the strongly varying equilibrium fields of MAST many of the assumptions of drift kinetic and neoclassical theory (e.g. small plasma inverse aspect ratio and low ratio of toroidal Larmor radius to poloidal Larmor radius) are not met by all particle species and it becomes appropriate to use full orbit analysis to evaluate heat and particle fluxes. Collisional transport of impurity ions (C 6+ and W 20+ ) has been studied using a full orbit solver, CUEBIT, to integrate the test-particle dynamics. Electromagnetic fields in MAST plasma have been modelled using the cylindrical and toroidal two-fluid codes CUTIE and CENTORI. A detailed study of the scaling of the test-particle diffusivity with collisionality in the equilibrium field reveals deviations from the standard neoclassical theory, in both the Pfirsch-Schlüter and banana regimes, and difficulties in defining a local diffusivity at low collisionalities. The effect of electric and magnetic fluctuations is also briefly addressed. It is found that field fluctuations enhance the non-diffusive nature of transport. The full orbit analysis presented here predicts levels of transport and confinement times for the examined species broadly consistent with the experimental observations.