No abstract

A variety of studies indicated that inorganic arsenic and its methylated metabolites have paradoxical effects, namely, carcinogenic and anticancer effects. Epidemiological studies have shown that long term exposure to arsenic can increase the risk of cancers of lung, skin or bladder in man, which is probably associated with the arsenic metabolism. In fact, the enzymatic conversion of inorganic arsenic by Arsenic (+3 oxidation state) methyltransferase (AS3MT) to mono-and dimethylated arsenic species has long been considered as a major route for detoxification.However, several studies have also indicated that biomethylation of inorganic arsenic, particularly the production of trivalent methylated metabolites, is a process that activates arsenic as a toxin and a carcinogen. On the other hand, arsenic trioxide (As 2 O 3 ) has recently been recognized as one of the most effective drugs for the treatment of APL. However, elaboration of the cytotoxic mechanisms of arsenic and its methylated metabolites in eradicating cancer is sorely lacking. To provide a deeper understanding of the toxicity and carcinogenicity along with them use of arsenic in chemotherapy, caution is required considering the poor understanding of its various mechanisms of exerting toxicity. Thereby, in this review, we have focused on arsenic metabolic pathway, the roles of the methylated arsenic metabolites in toxicity and in the therapeutic efficacy for the treatments of solid tumors, APL and/or non-APL malignancies.

Software debugging is tedious and time consuming. To reduce the manual effort needed for debugging, researchers have proposed a considerable number of techniques to automate the process of fault localization; in particular, techniques based on information retrieval (IR) have drawn increased attention in recent years. Although reportedly effective, these techniques have some potential limitations that may affect their performance. First, their effectiveness is likely to depend heavily on the quality of the bug reports; unfortunately, high-quality bug reports that contain rich information are not always available. Second, these techniques have not been evaluated through studies that involve actual developers, which is less than ideal, as purely analytical evaluations can hardly show the actual usefulness of debugging techniques. The goal of this work is to evaluate the usefulness of IR-based techniques in real-world scenarios. Our investigation shows that bug reports do not always contain rich information, and that low-quality bug reports can considerably affect the effectiveness of these techniques. Our research also shows, through a user study, that high-quality bug reports benefit developers just as much as they benefit IR-based techniques. In fact, the information provided by IR-based techniques when operating on high-quality reports is only helpful to developers in a limited number of cases. And even in these cases, such information only helps developers get to the faulty file quickly, but does not help them in their most time consuming task: understanding and fixing the bug within that file.

Bisphenol A (BPA) can interact with nuclear receptors and affect the normal function of nuclear receptors in very low doses, which causes BPA to be one of the most controversial endocrine disruptors. However, the detailed molecular mechanism about how BPA interferes the normal function of nuclear receptors is still undiscovered. Herein, molecular dynamics simulations were performed to explore the detailed interaction mechanism between BPA with three typical nuclear receptors, including hERα, hERRγ and hPPARγ. The simulation results and calculated binding free energies indicate that BPA can bind to these three nuclear receptors. The binding affinities of BPA were slightly lower than that of E2 to these three receptors. The simulation results proved that the binding process was mainly driven by direct hydrogen bond and hydrophobic interactions. In addition, structural analysis suggested that BPA could interact with these nuclear receptors by mimicking the action of natural hormone and keeping the nuclear receptors in active conformations. The present work provided the structural evidence to recognize BPA as an endocrine disruptor and would be important guidance for seeking safer substitutions of BPA.