The stress kinase MKK7 couples oncogenic stress to p53 stability and tumor suppression

Most preneoplastic lesions are quiescent and do not progress to form overt tumors. It has been proposed that oncogenic stress activates the DNA damage response and the key tumor suppressor p53, which prohibits tumor growth. However, the molecular pathways by which cells sense a premalignant state in vivo are largely unknown. Here we report that tissue-specific inactivation of the stress signaling kinase MKK7 in KRas(G12D)-driven lung carcinomas and NeuT-driven mammary tumors markedly accelerates tumor onset and reduces overall survival. Mechanistically, MKK7 acts through the kinases JNK1 and JNK2, and this signaling pathway directly couples oncogenic and genotoxic stress to the stability of p53, which is required for cell cycle arrest and suppression of epithelial cancers. These results show that MKK7 functions as a major tumor suppressor in lung and mammary cancer in mouse and identify MKK7 as a vital molecular sensor to set a cellular anti-cancer barrier.     

Observations of kinetic Alfvén waves by THEMIS near a substorm onset

Low frequency electromagnetic fluctuations in the vicinity of a magnetospheric substorm onset were investigated using simultaneous observations by THEMIS multiple probes in the near-Earth plasma sheet in the magnetotail.The observations indicate that in the vicinity of a substorm onset,kinetic Alfvén waves can be excited in the high-βplasma sheet(β=2μ0nT/B 2 ,the ratio of plasma thermal pressure to magnetic pressure)within the near-Earth magnetotail.The kinetic Alfvén wave has a small spatial scale in the high-βplasma.The parallel electric field accompanying kinetic Alfvén waves accelerates the charged particles along the magnetic field.The kinetic Alfvén waves play an important role in the substorm trigger process,and possibly in the formation of a substorm current wedge.     

Fras1 deficiency results in cryptophthalmos,renal agenesis and blebbed phenotype in mice

Loss of tight association between epidermis and dermis underlies several blistering disorders and is frequently caused by impaired function of extracellular matrix (ECM) proteins. Here we describe a new protein in mouse, Fras1, that is specifically detected in a linear fashion underlying the epidermis and the basal surface of other epithelia in embryos. Loss of Fras1 function results in the formation of subepidermal hemorrhagic blisters as well as unilateral or bilateral renal agenesis during mouse embryogenesis. Postnatally, homozygous Fras1 mutants have fusion of the eyelids and digits and unilateral renal agenesis or dysplasia. The defects observed in Fras1-/- mice phenocopy those of the existing bl (blebbed) mouse mutants, which have been considered a model for the human genetic disorder Fraser syndrome. We show that bl/bl homozygous embryos are devoid of Fras1 protein, consistent with the finding that Fras1 is mutated in these mice. In sum, our data suggest that perturbations in the composition of the extracellular space underlying epithelia could account for the onset of the blebbed phenotype in mouse and Fraser syndrome manifestation in human.     

Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints

Recent studies have indicated the existence of tumorigenesis barriers that slow or inhibit the progression of preneoplastic lesions to neoplasia. One such barrier involves DNA replication stress, which leads to activation of the DNA damage checkpoint and thereby to apoptosis or cell cycle arrest, whereas a second barrier is mediated by oncogene-induced senescence. The relationship between these two barriers, if any, has not been elucidated. Here we show that oncogene-induced senescence is associated with signs of DNA replication stress, including prematurely terminated DNA replication forks and DNA double-strand breaks. Inhibiting the DNA double-strand break response kinase ataxia telangiectasia mutated (ATM) suppressed the induction of senescence and in a mouse model led to increased tumour size and invasiveness. Analysis of human precancerous lesions further indicated that DNA damage and senescence markers cosegregate closely. Thus, senescence in human preneoplastic lesions is a manifestation of oncogene-induced DNA replication stress and, together with apoptosis, provides a barrier to malignant progression.     

Specific structural features of LnZrOx (Ln: La, Sm) mixed oxides prepared by different methods

LnZrOx(Ln: La, Sm) mixed oxides of Ln: Zr = 1 were prepared by different methods(complex polymerized method, sorption of cations on starch from aqueous salt solution and conventional co-precipitation with additional redispersion of precipitate by ultra sound) and calcined at 700–1300 °C. Their specific structural features and changes were studied and discussed. Various characterization methods were used such as X-ray diffraction,Electron microscopy, Fourier-transform infrared and Raman spectroscopy, UV–Vis spectroscopy, X-Ray absorption fine structure and X-ray photoelectron spectroscopy.The formation of pyrochlore structure occurred at 1100–1300 °C from fluorite-like pseudocubic phase ZrO_2 regardless the method of preparation. This phase had a block-like structure consisting of ZrO_2 nanocrystals stabilized by Ln cations and residual anions such as hydroxyls and carbonates. The desorption of such anions with heating already started at 900 °C and lead to local changes of Zr cations coordination to octahedral and to the formation of pyrochlore nanodomains inclusions within fluorite-like phase. The increased cation mobility and further elimination of anions caused by further heating was accompanied by the formation of bulk pyrochlore phase at 1100–1300 °C. Even after calcination at 1300 °C the local microheterogeneity as well as defects were identified at domains boundaries or sintered microstructure. These specific features of the formed pyrochlores depend on the method of preparation.     

SERVICE ATTRIBUTE-PROCESS MATRIX： A TOOL FOR DESIGNING AND MANAGING SERVICES

The growing importance of the service economy during the last 40 years has raised the need for new tools for designing and managing services. As a result, several authors have developed service classification systems, in order to better understand the nature of service operations and provide methods and tools to improve service efficiency and quality. This paper exploits the work resulting from service classification systems and identifies the principal attributes to be considered in service management. The tool introduced for this purpose is the Service Attribute-Process Matrix （SAPM）, which uses selected results from existing service classification schemes to investigate the importance of the significant service attributes to major processes of the service life cycle.     

Are common fragile sites merely structural domains or highly organized “functional” units susceptible to oncogenic stress?

Common fragile sites (CFSs) are regions of the genome with a predisposition to DNA double-strand breaks in response to intrinsic (oncogenic) or extrinsic replication stress. CFS breakage is a common feature in carcinogenesis from its earliest stages. Given that a number of oncogenes and tumor suppressors are located within CFSs, a question that emerges is whether fragility in these regions is only a structural “passive” incident or an event with a profound biological effect. Furthermore, there is sparse evidence that other elements, like non-coding RNAs, are positioned with them. By analyzing data from various libraries, like miRbase and ENCODE, we show a prevalence of various cancer-related genes, miRNAs, and regulatory binding sites, such as CTCF within CFSs. We propose that CFSs are not only susceptible structural domains, but highly organized “functional” entities that when targeted, severe repercussion for cell homeostasis occurs.     

Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions

DNA damage checkpoint genes, such as p53, are frequently mutated in human cancer, but the selective pressure for their inactivation remains elusive. We analysed a panel of human lung hyperplasias, all of which retained wild-type p53 genes and had no signs of gross chromosomal instability, and found signs of a DNA damage response, including histone H2AX and Chk2 phosphorylation, p53 accumulation, focal staining of p53 binding protein 1 (53BP1) and apoptosis. Progression to carcinoma was associated with p53 or 53BP1 inactivation and decreased apoptosis. A DNA damage response was also observed in dysplastic nevi and in human skin xenografts, in which hyperplasia was induced by overexpression of growth factors. Both lung and experimentally-induced skin hyperplasias showed allelic imbalance at loci that are prone to DNA double-strand break formation when DNA replication is compromised (common fragile sites). We propose that, from its earliest stages, cancer development is associated with DNA replication stress, which leads to DNA double-strand breaks, genomic instability and selective pressure for p53 mutations.     

Braking of high-speed flows in the magnetotail:THEMIS joint observations

The motion and deceleration processes of plasma sheet high-speed flows have great significance to magnetospheric particle acceleration,magnetic field perturbation,magnetic flux transport,triggering of substorm,and the current system formation in the magnetotail.From February to April 2009,two satellites of the Time History of Events and Macroscale Interactions during Substorms mission,THA and THE,were often separated largely in Z direction,but had small X and Y separations.Such special configuration allows simultaneous observations of highspeed flows at the center and boundary of the plasma sheet.Based on selected case study and statistical analysis,it is found that for about 89%of the events we selected,the probe further away from the neutral sheet observed the high-speed flow earlier than the one close to the center,and the flow is mainly field aligned.And for about 95%events the probe further away from the neutral sheet observed higher X component of the plasma flow.With the hypothesis that parallel flow keeps the same speed during its earthward propagation while central plasma sheet stream uniformly or suddenly brakes on its way to the earth,we deduced the position where the deceleration begins to be between 13 Re and 17 Re downtail,where thenear-earth reconnection is supposed to occur.In addition,our statistical results show that dipolarization fronts observed in the central plasma sheet are more prominent than those observed in the plasma sheet boundary layer ahead of the high-speed flow.     

Tyrosine kinase receptor RET is a key regulator of Peyer's patch organogenesis

Normal organogenesis requires co-ordinate development and interaction of multiple cell types, and is seemingly governed by tissue specific factors. Lymphoid organogenesis during embryonic life is dependent on molecules the temporal expression of which is tightly regulated. During this process, haematopoietic 'inducer' cells interact with stromal 'organizer' cells, giving rise to the lymphoid organ primordia. Here we show that the haematopoietic cells in the gut exhibit a random pattern of motility before aggregation into the primordia of Peyer's patches, a major component of the gut-associated lymphoid tissue. We further show that a CD45+CD4-CD3-Il7Ralpha-c-Kit+CD11c+ haematopoietic population expressing lymphotoxin has an important role in the formation of Peyer's patches. A subset of these cells expresses the receptor tyrosine kinase RET, which is essential for mammalian enteric nervous system formation. We demonstrate that RET signalling is also crucial for Peyer's patch formation. Functional genetic analysis revealed that Gfra3-deficiency results in impairment of Peyer's patch development, suggesting that the signalling axis RET/GFRalpha3/ARTN is involved in this process. To support this hypothesis, we show that the RET ligand ARTN is a strong attractant of gut haematopoietic cells, inducing the formation of ectopic Peyer's patch-like structures. Our work strongly suggests that the RET signalling pathway, by regulating the development of both the nervous and lymphoid system in the gut, has a key role in the molecular mechanisms that orchestrate intestine organogenesis.