CHFR: a key checkpoint component implicated in a wide range of cancers

CHFR (Checkpoint with Forkhead-associated and RING finger domains) has been implicated in a checkpoint regulating entry into mitosis. However, the details underlying its roles and regulation are unclear due to conflicting lines of evidence supporting different notions of its functions. We provide here an overview of how CHFR is thought to contribute towards regulating mitotic entry and present possible explanations for contradictory observations published on the functions and regulation of CHFR. Furthermore, we survey key data showing correlations between promoter hypermethylation or down-regulation of CHFR and cancers, with a view on the likely reasons why different extents of correlations have been reported. Lastly, we explore the possibilities of exploiting CHFR promoter hypermethylation status in diagnostics and therapeutics for cancer patients. With keen interest currently focused on the association between hypermethylation of CHFR and cancers, details of how CHFR functions require further study to reveal how its absence might possibly contribute to tumorigenesis.     

Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways

Through genome-wide association meta-analyses of up to 133,010 individuals of European ancestry without diabetes, including individuals newly genotyped using the Metabochip, we have increased the number of confirmed loci influencing glycemic traits to 53, of which 33 also increase type 2 diabetes risk (q < 0.05). Loci influencing fasting insulin concentration showed association with lipid levels and fat distribution, suggesting impact on insulin resistance. Gene-based analyses identified further biologically plausible loci, suggesting that additional loci beyond those reaching genome-wide significance are likely to represent real associations. This conclusion is supported by an excess of directionally consistent and nominally significant signals between discovery and follow-up studies. Functional analysis of these newly discovered loci will further improve our understanding of glycemic control.     

Ambivalent effect of protein binding on computed distributions of metal ions complexed by ligands in blood plasma.

Although the absolute concentrations of metal complexes in blood plasma are controlled by protein binding, the percentage distribution of transition metal ions amongst low molecular weight ligands is not. Thus, computer simulations which omit protein equilibria can nevertheless afford reliable information about such metals in the biofluid.     

磁控溅射用于细微颗粒涂镀功能薄膜的新技术

磁控溅射是一项成熟的技术,可用在各种基体上沉积高质量金属及陶瓷涂层。然而,此项技术一般并不适于涂镀微粒粒度为nm或μm到100μm的细微粒涂层。本文详述了一种可涂镀微粒粒径在上述范围的均匀功能薄膜的技术。在磁场下面安放的一个碗状容器内放有微粒子,容器可以振动可使粒子均匀地振出碗边沉落到真空腔,薄膜沉积工艺为反应或非反应脉冲磁控溅射。Ti,Ti O2,Sn及Sn O2从单磁场源沉积,而Bi/W的氧化物从双磁场源沉积。用SEM,TEM和EDX,以及其它与应用相关的技术表征所沉积的微粒,以表明此项技术的潜在功能。     

Systemic risk in banking ecosystems

In the run-up to the recent financial crisis, an increasingly elaborate set of financial instruments emerged, intended to optimize returns to individual institutions with seemingly minimal risk. Essentially no attention was given to their possible effects on the stability of the system as a whole. Drawing analogies with the dynamics of ecological food webs and with networks within which infectious diseases spread, we explore the interplay between complexity and stability in deliberately simplified models of financial networks. We suggest some policy lessons that can be drawn from such models, with the explicit aim of minimizing systemic risk.     

RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E)

Activated RAS promotes dimerization of members of the RAF kinase family. ATP-competitive RAF inhibitors activate ERK signalling by transactivating RAF dimers. In melanomas with mutant BRAF(V600E), levels of RAS activation are low and these drugs bind to BRAF(V600E) monomers and inhibit their activity. This tumour-specific inhibition of ERK signalling results in a broad therapeutic index and RAF inhibitors have remarkable clinical activity in patients with melanomas that harbour mutant BRAF(V600E). However, resistance invariably develops. Here, we identify a new resistance mechanism. We find that a subset of cells resistant to vemurafenib (PLX4032, RG7204) express a 61-kDa variant form of BRAF(V600E), p61BRAF(V600E), which lacks exons 4-8, a region that encompasses the RAS-binding domain. p61BRAF(V600E) shows enhanced dimerization in cells with low levels of RAS activation, as compared to full-length BRAF(V600E). In cells in which p61BRAF(V600E) is expressed endogenously or ectopically, ERK signalling is resistant to the RAF inhibitor. Moreover, a mutation that abolishes the dimerization of p61BRAF(V600E) restores its sensitivity to vemurafenib. Finally, we identified BRAF(V600E) splicing variants lacking the RAS-binding domain in the tumours of six of nineteen patients with acquired resistance to vemurafenib. These data support the model that inhibition of ERK signalling by RAF inhibitors is dependent on levels of RAS-GTP too low to support RAF dimerization and identify a novel mechanism of acquired resistance in patients: expression of splicing isoforms of BRAF(V600E) that dimerize in a RAS-independent manner.     

春潮

春天来了,万物复苏,三家平时不动声色的超级豪华轿车制造商不约而同地有了行动。一时间,宾利出了四门车大陆 Flying Spur(Continental Flying Spur),劳斯莱斯加长了幻影(Phantom),迈巴赫(Maybach)为3月开幕的日内瓦车展带来了新开发的迈巴赫57特别版