Dual hepatocyte-targeting fluorescent probe with high sensitivity to tumorous pH: Precise detection of hepatocellular carcinoma cells

A new dual hepatocyte-targeting fluorescent probe HPL-1, which can precisely distinguish tumorous pH from physiological pH, was developed. The OFF-ON switch of HPL-1 can be triggered via pH-induced structural change of the lactam group of the rhodamine moiety from closed-ring to open-ring. Our results showed that the phosphate group of HPL-1 is beneficial to its accumulation in liver cells, and combination of the phosphate and galactose units could synergistically increase the hepatocyte-targeting capacity. HPL-1 could selectively distinguish hepatoma cells from other tissue cells, and precisely distinguish cancerous liver cells from normal liver cells. Compared with other reported probes, HPL-1 not only enable a simple and convenient detection method, but also has good hepatocyte-targeting capacity and precise recognition capacity of tumors under weak acid micro-environment, which opens new avenues for precise diagnosis and treatment of hepatocellular carcinoma

Three novel components of the human exosome

Contains fulltext : 186951.pdf (publisher's version ) (Open Access)The yeast exosome is a complex of 3' --> 5' exoribonucleases. Sequence analysis identified putative human homologues for exosome components, although several were found only as expressed sequence tags. Here we report the cloning of full-length cDNAs, which encode putative human homologues of the Rrp40p, Rrp41p, and Rrp46p components of the exosome. Recombinant proteins were expressed and used to raise rabbit antisera. In Western blotting experiments, these decorated HeLa cell proteins of the predicted sizes. All three human proteins were enriched in the HeLa cells nucleus and nucleolus, but were also clearly detected in the cytoplasm. Size exclusion chromatography revealed that hRrp40p, hRrp41p, and hRrp46p were present in a large complex. This cofractionated with the human homologues of other exosome components, hRrp4p and PM/Scl-100. Anti-PM/Scl-positive patient sera coimmunoprecipitated hRrp40p, hRrp41p, and hRrp46p demonstrating their physical association. The immunoprecipitated complex exhibited 3' --> 5' exoribonuclease activity in vitro. hRrp41p was expressed in yeast and shown to suppress the lethality of genetic depletion of yeast Rrp41p. We conclude that hRrp40p, hRrp41p, and hRrp46p represent novel components of the human exosome complex

CFO role and CFO compensation: an empirical analysis of their implications

Given concerns over CFO pay, especially incentives, and considering the tension between a CFO’s fiduciary responsibility and being a key member of the firm’s executive team, we examine the determinants and effects of CFO compensation amount, incentive intensity, and proximity to CEO compensation in a sample of European companies (FTE 500, 2005-2009). First, we focus on the CFO role as a determinant of CFO compensation. Like prior work, we proxy for CFO roles by using hand-collected public data on education and past professional experience, but we supplement these proxies with proprietary data to more directly capture the firm-specific nature of the CFO job in term of its similarity with that of the CEO. We thus argue how CFOs can have varied roles characterized by different levels of financial expertise and CEO-likeness, and document that it is this latter aspect that is associated with CFO compensation. Second, we study the effects of CFO compensation design on outcomes in the CFO’s realm related to financial reporting. We find that CFO financial expertise is positively associated with financial reporting quality, while a CFO’s pay long-term incentive intensity and a CFO’s incentive compensation proximity with the CEO are negatively associated with financial reporting quality. Overall, then, our results suggest that CFOs get rewarded for their CEO-likeness, and particularly for their being similar to the CEO in terms of tasks and decision making authority. But it is their financial expertise that is positively related to financial reporting quality. At the same time, using compensation that is more incentive intensive and more similar to that of the CEO appears to be potentially detrimental to the quality of financial reporting. These results are relevant for boards involved in selecting highly expert CFOs, and their compensation committees charged with defining subsequently effective incentive compensation plans for those CFOs

A Comprehensive Predictive Corrosion Model incorporating varying Environmental Gas Pollutants applied to Wider Steel Applications

A comprehensive model has been developed to predict uniform corrosion rate of structural steel under the effect of low pH conditions for example acid rain. Acid rain is mainly caused by emissions of sulfur dioxide (SO2) which reacts with the water droplets in atmosphere to produce acidic solution which is the primary cause of corrosion of steel structures such as bridges, and weathering of stone buildings and statues. A five-stage division was applied to mathematically describe the model as: (i) the growth rate of air-suspended water droplets (i.e. moisture) depending on the condensation/evaporation rate, (ii) the absorption of gas phase SO2 in the droplets forming bisulfite HSO_3^- ions, (iii) the coalescence of these SO2 absorbed water droplets under the effects of wind speed and gravity, (iv) the deposition rate of SO2 absorbed droplets on steel substrate depending on the inclination and azimuth angles of steel surfaces and, (v) the corrosion rate of steel due to the deposition of these SO2 absorbed droplets. The incorporation of all the above stages develops a comprehensive corrosion prediction model which not only includes the electrochemical parameters but also large number of physical, environmental and material parameters. Experiment was performed to analyse the corrosion rate of steel samples by exposing them to moist SO2 corrosion test. A comparative analysis between the model predictions and experimental results was performed to verify the reliability of model. The predictive trends of corrosion rate of steel were also generated for different values of temperature, relative humidity, and SO2 mole percentage

The human exosome: an autoantigenic complex of exoribonucleases in myositis and scleroderma

The anti-PM/Scl autoantibodies are known to characterize a subset of autoimmune patients with myositis, scleroderma (Scl), and the PM/Scl overlap syndrome. The major autoantigens that are recognized by anti-PM/Scl autoantibodies are designated PM/Scl-100 and PM/Scl-75. These autoantigens have been reported to associate into a large complex consisting of 11 to 16 proteins and to play a role in ribosome synthesis. Recently, it was discovered that the PM/Scl complex is the human counterpart of the yeast (Saccharomyces cerevisiae) exosome, which is an RNA-processing complex consisting of 11 3' → 5' exoribonucleases. To date, 10 human exosome components have been identified, although only some of these were studied in more detail. In this review, we discuss some recent advances in the characterization of the PM/Scl complex

Culling-Induced Changes in Badger (Meles meles) Behaviour, Social Organisation and the Epidemiology of Bovine Tuberculosis

In the UK, attempts since the 1970s to control the incidence of bovine tuberculosis (bTB) in cattle by culling a wildlife host, the European badger (Meles meles), have produced equivocal results. Culling-induced social perturbation of badger populations may lead to unexpected outcomes. We test predictions from the ‘perturbation hypothesis’, determining the impact of culling operations on badger populations, movement of surviving individuals and the influence on the epidemiology of bTB in badgers using data dervied from two study areas within the UK Government's Randomised Badger Culling Trial (RBCT). Culling operations did not remove all individuals from setts, with between 34–43% of badgers removed from targeted social groups. After culling, bTB prevalence increased in badger social groups neighbouring removals, particularly amongst cubs. Seventy individual adult badgers were fitted with radio-collars, yielding 8,311 locational fixes from both sites between November 2001 and December 2003. Home range areas of animals surviving within removed groups increased by 43.5% in response to culling. Overlap between summer ranges of individuals from Neighbouring social groups in the treatment population increased by 73.3% in response to culling. The movement rate of individuals between social groups was low, but increased after culling, in Removed and Neighbouring social groups. Increased bTB prevalence in Neighbouring groups was associated with badger movements both into and out of these groups, although none of the moving individuals themselves tested positive for bTB. Significant increases in both the frequency of individual badger movements between groups and the emergence of bTB were observed in response to culling. However, no direct evidence was found to link the two phenomena. We hypothesise that the social disruption caused by culling may not only increase direct contact and thus disease transmission between surviving badgers, but may also increase social stress within the surviving population, causing immunosuppression and enhancing the expression of disease

Gene therapy for monogenic liver diseases: clinical successes, current challenges and future prospects

Over the last decade, pioneering liver-directed gene therapy trials for haemophilia B have achieved sustained clinical improvement after a single systemic injection of adeno-associated virus (AAV) derived vectors encoding the human factor IX cDNA. These trials demonstrate the potential of AAV technology to provide long-lasting clinical benefit in the treatment of monogenic liver disorders. Indeed, with more than ten ongoing or planned clinical trials for haemophilia A and B and dozens of trials planned for other inherited genetic/metabolic liver diseases, clinical translation is expanding rapidly. Gene therapy is likely to become an option for routine care of a subset of severe inherited genetic/metabolic liver diseases in the relatively near term. In this review, we aim to summarise the milestones in the development of gene therapy, present the different vector tools and their clinical applications for liver-directed gene therapy. AAV-derived vectors are emerging as the leading candidates for clinical translation of gene delivery to the liver. Therefore, we focus on clinical applications of AAV vectors in providing the most recent update on clinical outcomes of completed and ongoing gene therapy trials and comment on the current challenges that the field is facing for large-scale clinical translation. There is clearly an urgent need for more efficient therapies in many severe monogenic liver disorders, which will require careful risk-benefit analysis for each indication, especially in paediatrics