Selective activation of p53-mediated tumour suppression in high-grade tumours

Non-small cell lung carcinoma (NSCLC) is the leading cause of cancer-related death worldwide, with an overall 5-year survival rate of only 10-15%. Deregulation of the Ras pathway is a frequent hallmark of NSCLC, often through mutations that directly activate Kras. p53 is also frequently inactivated in NSCLC and, because oncogenic Ras can be a potent trigger of p53 (ref. 3), it seems likely that oncogenic Ras signalling has a major and persistent role in driving the selection against p53. Hence, pharmacological restoration of p53 is an appealing therapeutic strategy for treating this disease. Here we model the probable therapeutic impact of p53 restoration in a spontaneously evolving mouse model of NSCLC initiated by sporadic oncogenic activation of endogenous Kras. Surprisingly, p53 restoration failed to induce significant regression of established tumours, although it did result in a significant decrease in the relative proportion of high-grade tumours. This is due to selective activation of p53 only in the more aggressive tumour cells within each tumour. Such selective activation of p53 correlates with marked upregulation in Ras signal intensity and induction of the oncogenic signalling sensor p19(ARF)( )(ref. 6). Our data indicate that p53-mediated tumour suppression is triggered only when oncogenic Ras signal flux exceeds a critical threshold. Importantly, the failure of low-level oncogenic Kras to engage p53 reveals inherent limits in the capacity of p53 to restrain early tumour evolution and in the efficacy of therapeutic p53 restoration to eradicate cancers.     

The endothelial-cell-derived secreted factor Egfl7 regulates vascular tube formation

Vascular development is a complex but orderly process that is tightly regulated. A number of secreted factors produced by surrounding cells regulate endothelial cell (EC) differentiation, proliferation, migration and coalescence into cord-like structures. Vascular cords then undergo tubulogenesis to form vessels with a central lumen. But little is known about how tubulogenesis is regulated in vivo. Here we report the identification and characterization of a new EC-derived secreted factor, EGF-like domain 7 (Egfl7). Egfl7 is expressed at high levels in the vasculature associated with tissue proliferation, and is downregulated in most of the mature vessels in normal adult tissues. Loss of Egfl7 function in zebrafish embryos specifically blocks vascular tubulogenesis. We uncover a dynamic process during which gradual separation and proper spatial arrangement of the angioblasts allow subsequent assembly of vascular tubes. This process fails to take place in Egfl7 knockdown embryos, leading to the failure of vascular tube formation. Our study defines a regulator that controls a specific and important step in vasculogenesis.     

Susceptibility to leprosy is associated with PARK2 and PACRG

Leprosy is caused by Mycobacterium leprae and affects about 700,000 individuals each year. It has long been thought that leprosy has a strong genetic component, and recently we mapped a leprosy susceptibility locus to chromosome 6 region q25-q26 (ref. 3). Here we investigate this region further by using a systematic association scan of the chromosomal interval most likely to harbour this leprosy susceptibility locus. In 197 Vietnamese families we found a significant association between leprosy and 17 markers located in a block of approx. 80 kilobases overlapping the 5' regulatory region shared by the Parkinson's disease gene PARK2 and the co-regulated gene PACRG. Possession of as few as two of the 17 risk alleles was highly predictive of leprosy. This was confirmed in a sample of 975 unrelated leprosy cases and controls from Brazil in whom the same alleles were strongly associated with leprosy. Variants in the regulatory region shared by PARK2 and PACRG therefore act as common risk factors for leprosy.     

Design for Mass Customisation in Higher Education: a Systems-Thinking Approach

The point of this research is to investigate the impact of systems-thinking principles (Seddon 2003) on operationalising the ‘mass customisation’ capability of student services in higher education institutions. The research empirically contributes to student-service mass customisation in higher education through the findings of a case study conducted at the admission and academic registry service department of one of the UK’s leading universities. A qualitative methodology was employed with the use of semi-structured interviews, focus group, observations, and documentation supplements. It was found that the principles of systems-thinking are positively related to enhancement of mass customisation capability through the realisation of three different levels of service mass customisation determinants. These three levels are: employee level (i.e. micro determinants); operational level (i.e. meso determinants); and functional level (i.e. macro determinants). A conceptual model was developed to explain the relationships among these three organisational levels, supported by empirical evidences. The value of this paper is the introduction of a conceptual model that could operationalise ‘mass customisation’ in universities by integrating human resources, operational and functional dimensions in a systematic design to deliver customised services for students as individuals.     

The Dynamics and Control of the Fractional Forms of Some Rational Chaotic Maps

This paper proposes three fractional discrete chaotic systems based on the Rulkov, Chang,and Zeraoulia–Sprott rational maps. The dynamics of the proposed maps are investigated by means of phase plots and bifurcations diagrams. Adaptive stabilization schemes are proposed for each of the three maps and the convergence of the states is established by using the Lyapunov method. Furthermore, a combination synchronization scheme is proposed whereby a combination of the fractional Rulkov and Chang maps is synchronized to the fractional Zeraoulia-Sprott map. Numerical results are used to confirm the findings of the paper.     

平行机上单位加工时间加权总完工时间排序问题的反问题

在给定工序下,排序问题的反问题研究目标是对于预先给定的加工任务,要求确定加工时间或者工件权重的最小调整值,使得给定的工件排序最优。本文研究了平行机上单位加工时间的加权总完工时间排序问题的反问题,即对于给定的加工工序,在不同范数下,通过最小限度调整工件的权值,实现给定加工工序最优,同时满足调整权值后,目标函数值不超过原来的值。     

Towards specific NADPH oxidase inhibition by small synthetic peptides

Reactive oxygen species (ROS) production by the phagocyte NADPH oxidase is essential for host defenses against pathogens. ROS are very reactive with biological molecules such as lipids, proteins and DNA, potentially resulting in cell dysfunction and tissue insult. Excessive NADPH oxidase activation and ROS overproduction are believed to participate in disorders such as joint, lung, vascular and intestinal inflammation. NADPH oxidase is a complex enzyme composed of six proteins: gp91phox (renamed NOX2), p22phox, p47phox, p67phox, p40phox and Rac1/2. Inhibitors of this enzyme could be beneficial, by limiting ROS production and inappropriate inflammation. A few small non-peptide inhibitors of NADPH oxidase are currently used to inhibit ROS production, but they lack specificity as they inhibit NADPH oxidase homologues or other unrelated enzymes. Peptide inhibitors that target a specific sequence of NADPH oxidase components could be more specific than small molecules. Here we review peptide-based inhibitors, with particular focus on a molecule derived from gp91phox/NOX2 and p47phox, and discuss their possible use as specific phagocyte NADPH oxidase inhibitors.     

A three-parameter fault-detection software reliability model with the uncertainty of operating environments

As requirements for system quality have increased, the need for high system reliability is also increasing. Software systems are extremely important, in terms of enhanced reliability and stability, for providing high quality services to customers. However, because of the complexity of software systems, software development can be time-consuming and expensive. Many statistical models have been developed in the past years to estimate software reliability. In this paper, we propose a new three-parameter fault-detection software reliability model with the uncertainty of operating environments. The explicit mean value function solution for the proposed model is presented. Examples are presented to illustrate the goodness-of-fit of the proposed model and several existing non-homogeneous Poisson process (NHPP) models based on three sets of failure data collected from software applications. The results show that the proposed model fits significantly better than other existing NHPP models based on three criteria such as mean squared error (MSE), predictive ratio risk (PRR), and predictive power (PP).     

Inhibition of biological methylations by t,t-farnesylacetone, a constituant of the androgenic gland of the male crab, Carcinus maenas]

t, t-farnesylacetone 1 and hexahydrofarnesylacetone 2 have been previously identified in extracts from the androgenic gland of the male Crab Carcinus maenas. These compounds inhibit in vitro the methylation of E. coli B tRNA and of Calf thymus histones with S-adenosylmethionine methyl-14C as methyl donor and methylases from Crab testis. Rat liver or a 1-adenine methylase from a Mouse plasmocytoma (1 is approximately 200 times more active than 2).     

Epistasis between mouse Klra and major histocompatibility complex class I loci is associated with a new mechanism of natural killer cell-mediated innate resistance to cytomegalovirus infection

Experimental infection with mouse cytomegalovirus (MCMV) has been used to elucidate the intricate host-pathogen mechanisms that determine innate resistance to infection. Linkage analyses in F(2) progeny from MCMV-resistant MA/My (H2 (k)) and MCMV-susceptible BALB/c (H2 (d)) and BALB.K (H2 (k)) mouse strains indicated that only the combination of alleles encoded by a gene in the Klra (also called Ly49) cluster on chromosome 6, and one in the major histocompatibility complex (H2) on chromosome 17, is associated with virus resistance. We found that natural killer cell-activating receptor Ly49P specifically recognized MCMV-infected cells, dependent on the presence of the H2 (k) haplotype. This binding was blocked using antibodies to H-2D(k) but not antibodies to H-2K(k). These results are suggestive of a new natural killer cell mechanism implicated in MCMV resistance, which depends on the functional interaction of the Ly49P receptor and the major histocompatibility complex class I molecule H-2D(k) on MCMV-infected cells.