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.     

少油断路器机械特性智能测试仪研究

对少油断路器机械特性智能测试仪的硬件组成原理、智能化方法进行了深入探讨.并在软件设计中论述了模糊故障诊断原理及此技术在智能化装置中的应用.     

Loss of Cul1 results in early embryonic lethality and dysregulation of cyclin E.

The sequential timing of cell-cycle transitions is primarily governed by the availability and activity of key cell-cycle proteins. Recent studies in yeast have identified a class of ubiquitin ligases (E3 enzymes) called SCF complexes, which regulate the abundance of proteins that promote and inhibit cell-cycle progression at the G1-S phase transition. SCF complexes consist of three invariable components, Skp1, Cul-1 (Cdc53 in yeast) and Rbx1, and a variable F-box protein that recruits a specific cellular protein to the ubquitin pathway for degradation. To study the role of Cul-1 in mammalian development and cell-cycle regulation, we generated mice deficient for Cul1 and analysed null embryos and heterozygous cell lines. We show that Cul1 is required for early mouse development and that Cul1 mutants fail to regulate the abundance of the G1 cyclin, cyclin E (encoded by Ccne), during embryogenesis.     

THE DEVELOPMENT OF A MANIKIN TO SIMULATE THE THERMAL PHYSIOLOGY OF PREMATURE INFANTS

This paper describes a manikin (also known as mannequin) to simulate the thermal physiology of premature infants and experiments performed on it.The performance of the manikin is shown to compare well with that a selection of premature infants in terms of their rate of heat loss.     

Effect of natural iron fertilization on carbon sequestration in the Southern Ocean

The availability of iron limits primary productivity and the associated uptake of carbon over large areas of the ocean. Iron thus plays an important role in the carbon cycle, and changes in its supply to the surface ocean may have had a significant effect on atmospheric carbon dioxide concentrations over glacial-interglacial cycles. To date, the role of iron in carbon cycling has largely been assessed using short-term iron-addition experiments. It is difficult, however, to reliably assess the magnitude of carbon export to the ocean interior using such methods, and the short observational periods preclude extrapolation of the results to longer timescales. Here we report observations of a phytoplankton bloom induced by natural iron fertilization--an approach that offers the opportunity to overcome some of the limitations of short-term experiments. We found that a large phytoplankton bloom over the Kerguelen plateau in the Southern Ocean was sustained by the supply of iron and major nutrients to surface waters from iron-rich deep water below. The efficiency of fertilization, defined as the ratio of the carbon export to the amount of iron supplied, was at least ten times higher than previous estimates from short-term blooms induced by iron-addition experiments. This result sheds new light on the effect of long-term fertilization by iron and macronutrients on carbon sequestration, suggesting that changes in iron supply from below--as invoked in some palaeoclimatic and future climate change scenarios--may have a more significant effect on atmospheric carbon dioxide concentrations than previously thought.     

Interation of quasi-rational mapping

The more general ease of interation of quasi-rational mappings, including their Julia sets and quasi normal sets, is studied and some results corresponding to complex dynamics are obtained.     

Investigation in Longitudinal Compression of Wool Based Suiting Fabrics

This paper describes an investigation in the fabric longi-tudinal compressibility of thirty-one suiting and trouse-ring materials using a newly developed device attached to the advanced Instron extensometer Model4466.The at-tachment was designed mainly to ensure a correct align-meat of fabric plane at the start of compression.Usingthe newly developed testing method,fabric longitudinalcompression curve was obtained and the results of longi-tudinal compressibility measured by two different com-pression load ranges(from 0 to 0.5 N/m width and 0 to1 N/m width)were examined.In addition,their rela-tionships with the fabric low-stress mechanical proper-ties measured by the KES-F system were investigatedusing statistical analysis.The results clearly indicatedthat significant differences existed when substituting fab-ric longitudinal compressibility with fabric extensibilitymeasured using the KES-F system under a low-load.Significant infiuence of yarn rotational movement in fab-ric on the longitudinal compressibi     

Experimental Investigation of Yarn Twist Blockage

In twisting a yarn running over a guide surface, the twist inserted into the part in front of the guide is impeded to transmit freely to the part behind the contact zone. A new device has been set up for investigating twist blockage and yarn torque - twist simultaneously. Measurements of twist blockage in relationship to different parameters have been carried out by using a monofilament yarn and a multifilament yarn. The factors under consideration include the wrap angle, yarn tension and input twist.