Ailanthone targets p23 to overcome MDV3100 resistance in castration-resistant prostate cancer

Androgen receptor (AR) antagonist MDV3100 is the first therapeutic approach in treating castration-resistant prostate cancer (CRPC), but tumours frequently become drug resistant via multiple mechanisms including AR amplification and mutation. Here we identify the small molecule Ailanthone (AIL) as a potent inhibitor of both full-length AR (AR-FL) and constitutively active truncated AR splice variants (AR-Vs). AIL binds to the co-chaperone protein p23 and prevents AR's interaction with HSP90, thus resulting in the disruption of the AR-chaperone complex followed by ubiquitin/proteasome-mediated degradation of AR as well as other p23 clients including AKT and Cdk4, and downregulates AR and its target genes in PCa cell lines and orthotopic animal tumours. In addition, AIL blocks tumour growth and metastasis of CRPC. Finally, AIL possesses favourable drug-like properties such as good bioavailability, high solubility, lack of CYP inhibition and low hepatotoxicity. In general, AIL is a potential candidate for the treatment of CRPC

Desalination by forward osmosis: Identifying performance limiting parameters through module-scale modeling

In this study, we analyze the effects of membrane properties, namely water permeability, solute permeability, and structural parameter, on the overall performance of an FO membrane module to extract water from simulated seawater (0.6 M NaCl). By considering the thermodynamic limit of operation, we demonstrate that the maximum achievable water recovery is practically independent of membrane properties, and higher maximum water recovery is achievable with counter-current compared to co-current mode. Analysis of the module-scale model indicates that reducing the support layer structural parameter offers substantial reductions in the membrane area required to achieve a specified water recovery. For example, a 25% reduction of the structural parameter of a state-of-the-art thin-film composite (TFC) membrane (from 400 to 300 μm) yields a sizable 20% reduction in membrane area. In contrast, quintupling the water permeability coefficient (from 2.0 to 10.0 L m−2 h−1 bar−1) of a modern TFC membrane generates only a modest 10% saving in membrane area. In addition, because of the permeability-selectivity trade-off that governs current polymeric membranes, doubling the water permeability coefficient would cause crippling ~7-fold increases in forward and reverse solute permeation. This quantitative study models the potential performance of a module-scale FO desalination process and firmly highlights the need to prioritize the reduction of support layer mass transport resistances over water permeability increases in membrane development

Ergodic behaviour of extreme values

Let {Xn, n ≥ 1} be independent identically distributed random variables with a common non-degenerate distribution function F. For each n ≥ 1, denote Mn = max{X1, . . . , Xn}. Under certain conditions on F, there exist constants an > 0 and bn ∈ ℝ

Do Perceived Risk, Perception of Self-Efficacy, and Openness to Technology Matter for Solar PV Adoption? An Application of the Extended Theory of Planned Behavior

Solar PV (photovoltaic) technology has gained considerable attention worldwide, as it can help reduce the adverse effects of CO2 emissions. Though the government of Pakistan is adopting solar PV technology due to its environmental friendliness nature, studies focusing on consumer’s acceptance of solar PV are limited in the country. This research aims to close this knowledge gap by looking into the various considerations that may influence consumers’ willingness to adopt (WTA) solar PV for household purposes. The study further contributes by expanding the conceptual framework of the theory of planned behavior by including three novel factors (perceived risk, perception of self-efficacy, and openness to technology). The analysis is based on questionnaire data collected from 683 households in Pakistan’s provincial capitals, including Lahore, Peshawar, Quetta, Gilgit, and Karachi. The proposed hypotheses are investigated using the state-of-the-art structural equation modeling approach. The empirical results reveal that social norms, perception of self-efficacy, and belief about solar PV benefits positively influence consumers’ WTA solar PV. On the contrary, the perceived risk and solar PV cost have negative effects. Notably, the openness to technology has an insignificant effect. This study can help government officials and policymakers explore cost-effective, risk-free technologies to lessen the environmental burden and make the country more sustainable. Based on research results, study limitations, as well as prospective research directions, are also addressed