Inactivation of the p53 pathway in retinoblastoma

Most human tumours have genetic mutations in their Rb and p53 pathways, but retinoblastoma is thought to be an exception. Studies suggest that retinoblastomas, which initiate with mutations in the gene retinoblastoma 1 (RB1), bypass the p53 pathway because they arise from intrinsically death-resistant cells during retinal development. In contrast to this prevailing theory, here we show that the tumour surveillance pathway mediated by Arf, MDM2, MDMX and p53 is activated after loss of RB1 during retinogenesis. RB1-deficient retinoblasts undergo p53-mediated apoptosis and exit the cell cycle. Subsequently, amplification of the MDMX gene and increased expression of MDMX protein are strongly selected for during tumour progression as a mechanism to suppress the p53 response in RB1-deficient retinal cells. Our data provide evidence that the p53 pathway is inactivated in retinoblastoma and that this cancer does not originate from intrinsically death-resistant cells as previously thought. In addition, they support the idea that MDMX is a specific chemotherapeutic target for treating retinoblastoma.     

基于字典学习的低剂量X-ray CT图像去噪

介绍了一种基于字典学习的去噪方法,并将其应用于降低低剂量CT图像噪声水平的研究.针对体模图像和病人图像,分别选择低剂量CT图像和正常剂量CT图像作为训练样本,采用K-SVD算法,通过迭代学习构建图像字典;然后,结合正交匹配跟踪算法,实现图像稀疏表示,稀疏成分对应于图像的有用信息,其他成分对应于图像噪声;最后,依据图像的稀疏成分重建图像,达到去除噪声的目的.实验结果表明:字典的大小、稀疏表示的约束条件等参数会显著影响所提算法的去噪结果;相比低剂量CT图像,将正常剂量CT图像作为训练样本可以得到更好的去噪结果;在相同的噪声水平下,所提算法与传统图像去噪算法相比可以更好地去除图像噪声,且保留了图像的细节信息.     

Hsp90 as a capacitor of phenotypic variation

Heat-shock protein 90 (Hsp90) chaperones the maturation of many regulatory proteins and, in the fruitfly Drosophila melanogaster, buffers genetic variation in morphogenetic pathways. Levels and patterns of genetic variation differ greatly between obligatorily outbreeding species such as fruitflies and self-fertilizing species such as the plant Arabidopsis thaliana. Also, plant development is more plastic, being coupled to environmental cues. Here we report that, in Arabidopsis accessions and recombinant inbred lines, reducing Hsp90 function produces an array of morphological phenotypes, which are dependent on underlying genetic variation. The strength and breadth of Hsp90's effects on the buffering and release of genetic variation suggests it may have an impact on evolutionary processes. We also show that Hsp90 influences morphogenetic responses to environmental cues and buffers normal development from destabilizing effects of stochastic processes. Manipulating Hsp90's buffering capacity offers a tool for harnessing cryptic genetic variation and for elucidating the interplay between genotypes, environments and stochastic events in the determination of phenotype.     

Reduced airway surface pH impairs bacterial killing in the porcine cystic fibrosis lung

Cystic fibrosis (CF) is a life-shortening disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Although bacterial lung infection and the resulting inflammation cause most of the morbidity and mortality, how the loss of CFTR function first disrupts airway host defence has remained uncertain. To investigate the abnormalities that impair elimination when a bacterium lands on the pristine surface of a newborn CF airway, we interrogated the viability of individual bacteria immobilized on solid grids and placed onto the airway surface. As a model, we studied CF pigs, which spontaneously develop hallmark features of CF lung disease. At birth, their lungs lack infection and inflammation, but have a reduced ability to eradicate bacteria. Here we show that in newborn wild-type pigs, the thin layer of airway surface liquid (ASL) rapidly kills bacteria in vivo, when removed from the lung and in primary epithelial cultures. Lack of CFTR reduces bacterial killing. We found that the ASL pH was more acidic in CF pigs, and reducing pH inhibited the antimicrobial activity of ASL. Reducing ASL pH diminished bacterial killing in wild-type pigs, and, conversely, increasing ASL pH rescued killing in CF pigs. These results directly link the initial host defence defect to the loss of CFTR, an anion channel that facilitates HCO(3)(-) transport. Without CFTR, airway epithelial HCO(3)(-) secretion is defective, the ASL pH falls and inhibits antimicrobial function, and thereby impairs the killing of bacteria that enter the newborn lung. These findings suggest that increasing ASL pH might prevent the initial infection in patients with CF, and that assaying bacterial killing could report on the benefit of therapeutic interventions.     

Taxonomy Based Models for Reasoning: Making Inferences from Electronic Road Sign Information

Taxonomy Based modeling was applied to describe drivers’ mental models of variable message signs (VMS’s) displayed on expressways. Progress in road telematics has made it possible to introduce variable message signs (VMS’s). Sensors embedded in the carriageway every 500m record certain variables (speed, flow rate, etc.) that are transformed in real time into “driving times” to a given destination if road conditions do not change. VMS systems are auto-regulative Man-Machine (AMMI) systems which incorporate a model of the user: if the traffic flow is too high, then drivers should choose alternative routes. In so doing, the traffic flow should decrease. The model of the user is based on suppositions such as: people do not like to waste time, they fully understand the displayed messages, they trust the displayed values, they know of alternative routes. However, people also have a model of the way the system functions. And if they do not believe the contents of the message, they will not act as expected. We collected data through interviews with drivers using the critical incidents technique (Flanagan, 1985). Results show that the mental models that drivers have of the way the VMS system works are various but not numerous and that most of them differ from the“ideal expert” mental model. It is clear that users don’t have an adequate model of how the VMS system works and that VMS planners have a model of user behaviour that does not correspond to the behaviour of the drivers we interviewed. Finally, Taxonomy Based Modeling is discussed as a tool for mental model remediation.     

Hepatocyte nuclear factor 4alpha controls the development of a hepatic epithelium and liver morphogenesis

Although advances have been made in understanding cell differentiation, only rudimentary knowledge exists concerning how differentiated cells form tissues and organs. We studied liver organogenesis because the cell and tissue architecture of this organ is well defined. Approximately 60% of the adult liver consists of hepatocytes that are arranged as single-cell anastomosing plates extending from the portal region of the liver lobule toward the central vein. The basal surface of the hepatocytes is separated from adjacent sinusoidal endothelial cells by the space of Disse, where the exchange of substances between serum and hepatocytes takes place. The hepatocyte's apical surface forms bile canaliculi that transport bile to the hepatic ducts. Proper liver architecture is crucial for hepatic function and is commonly disrupted in disease states, including cirrhosis and hepatitis. Here we report that hepatocyte nuclear factor 4alpha (Hnf4alpha) is essential for morphological and functional differentiation of hepatocytes, accumulation of hepatic glycogen stores and generation of a hepatic epithelium. We show that Hnf4alpha is a dominant regulator of the epithelial phenotype because its ectopic expression in fibroblasts induces a mesenchymal-to-epithelial transition. Most importantly, the morphogenetic parameters controlled by Hnf4alpha in hepatocytes are essential for normal liver architecture, including the organization of the sinusoidal endothelium.     

Solitons and production of defects in flow-aligning nematic liquid crystals under simple shear flow

The production of defects in flow-aligning nematic liquid crystals under simple shear flow is analyzed by linear stability analysis based on Leslie-Ericksen theory. It is pointed out that the equation of motion of the nematic director under simple shear flow conforms to the driven over-damped sine-Gordon equation and has a soliton solution of amplitude π. It has also been shown that the stationary state with the director uniformly oriented at a Leslie angle is only a metastable state and that the potential, which governs the motion of the director, has infinite numbers of stable stationary states. Therefore, the defects, appearing as a stable solitary solution, can be nucleated from a uniformly aligned flow-aligning type of nematic liquid crystal by shear flow. On the other hand, the bands with long axis parallel to the vorticity axis, appearing as an unstable solution, can be observed as transient patterns at low shear rate and low shear strain value. The theoretical predictions are compared with previous experimental observations.