Synthesis of truncated androgen receptor (AR) splice variants has emerged as an important mechanism of prostate cancer (PCa) resistance to AR-targeted therapy and progression to a lethal ...castration-resistant phenotype. However, the precise role of these factors at this stage of the disease is not clear due to loss of multiple COOH-terminal AR protein domains, including the canonical nuclear localization signal (NLS) in the AR hinge region. Despite loss of this NLS, we show that diverse truncated AR variant species have a basal level of nuclear localization sufficient for ligand-independent transcriptional activity. Whereas full-length AR requires Hsp90 and importin-β for active nuclear translocation, basal nuclear localization of truncated AR variants is independent of these classical signals. For a subset of truncated AR variants, this basal level of nuclear import can be augmented by unique COOH-terminal sequences that reconstitute classical AR NLS activity. However, this property is separable from ligand-independent transcriptional activity. Therefore, the AR splice variant core consisting of the AR NH2-terminal domain and DNA binding domain is sufficient for nuclear localization and androgen-independent transcriptional activation of endogenous AR target genes. Indeed, we show that truncated AR variants with nuclear as well as nuclear/cytoplasmic localization patterns can drive androgen-independent growth of PCa cells. Together, our data demonstrate that diverse truncated AR species with varying efficiencies of nuclear localization can contribute to castration-resistant PCa pathology by driving persistent ligand-independent AR transcriptional activity.
Truncated AR splice variants support castration-resistant prostate cancer.
The AR NTD/DBD core is sufficient for AR variants to access the nucleus, activate AR target genes, and support androgen-independent prostate cancer cell growth.
Diverse truncated AR variants are constitutively active transcription factors.
These novel biochemical properties could lead to the development of new prostate cancer therapies.
•Exposure to PFASs was inversely associated with the risk of type 2 diabetes.•Serum PFOA was positively associated with fasting plasma glucose in controls.•PFNA, PFUnDA, PFOS and 6:2 Cl-PFESA may ...disturb lipid metabolism in human.
Associations between per- and polyfluoroalkyl substances (PFASs) and the incidence of type 2 diabetes are controversial in epidemiological studies. In addition, limited data are available for assessing the health effects of novel PFAS alternatives. Our study evaluated the effects of PFAS exposure on type 2 diabetes by estimating the associations of PFASs in human serum with the risk of type 2 diabetes and levels of glycemic biomarkers and lipid fractions. The case-control study consisted of 304 participants from Shandong Province, East China, half of which were diagnosed with type 2 diabetes. Logistic regression showed that most PFASs were inversely associated with the risk of type 2 diabetes after adjusting for age, sex, and body mass index. However, concentrations of perfluorooctanoic acid (PFOA) in the control group were positively associated with fasting plasma glucose levels (β = 0.04, 95% confidence interval (CI): 0.0003, 0.08), which may promote the development of type 2 diabetes. Furthermore, each log-unit increase in the concentrations of perfluorononanoic acid (PFNA), perfluoroundecanoic acid (PFUnDA), and 6:2 chlorinated polyfluoroalkyl ether sulfonic acid (Cl-PFESA) were associated with a total cholesterol increase (i.e., 17.49% (95% CI: 0.93%, 34.90%), 17.49% (95% CI: 4.71%, 31.83%), and 17.49% (95% CI: 4.71%, 31.83%), respectively). Positive associations were also observed between PFNA, PFUnDA, perfluorooctane sulfonate (PFOS), and 6:2 Cl-PFESA and low-density lipoprotein cholesterol. However, no associations between PFASs and hemoglobin A1c, triglycerides, or high-density lipoprotein cholesterol reached statistical significance, nor associations between PFAS mixtures and outcomes of interest. In conclusion, the significant correlations between serum PFASs and glycemic biomarkers and lipid fractions indicated that PFAS exposure may be a potential diabetogenic factor. To the best of our knowledge, this is the first study to assess the associations between novel Cl-PFESAs and type 2 diabetes, although the inverse associations observed require clarification in future studies.
Persistent androgen receptor (AR) transcriptional activity underlies resistance to AR-targeted therapy and progression to lethal castration-resistant prostate cancer (CRPC). Recent success in ...retargeting persistent AR activity with next generation androgen/AR axis inhibitors such as enzalutamide (MDV3100) has validated AR as a master regulator during all stages of disease progression. However, resistance to next generation AR inhibitors limits therapeutic efficacy for many patients. One emerging mechanism of CRPC progression is AR gene rearrangement, promoting synthesis of constitutively active truncated AR splice variants (AR-V) that lack the AR ligand-binding domain. In this study, we show that cells with AR gene rearrangements expressing both full-length and AR-Vs are androgen independent and enzalutamide resistant. However, selective knock-down of AR-V expression inhibited androgen-independent growth and restored responsiveness to androgens and antiandrogens. In heterogeneous cell populations, AR gene rearrangements marked individual AR-V-dependent cells that were resistant to enzalutamide. Gene expression profiling following knock-down of full-length AR or AR-Vs showed that AR-Vs drive resistance to AR-targeted therapy by functioning as constitutive and independent effectors of the androgen/AR transcriptional program. Further, mitotic genes deemed previously to be unique AR-V targets were found to be biphasic targets associated with a proliferative level of signaling output from either AR-Vs or androgen-stimulated AR. Overall, these studies highlight AR-Vs as key mediators of persistent AR signaling and resistance to the current arsenal of conventional and next generation AR-directed therapies, advancing the concept of AR-Vs as therapeutic targets in advanced disease.
Enterprises’ green technology innovation is critical to achieving the “win-win” of enterprise competitiveness and environmental protection. The impact of environmental regulation on green technology ...innovation by enterprises has been widely considered, but the conclusion has not yet been determined, and needs to be studied in detail. To this end, we studied the impact of pollution charge policy on different types of green technology innovation by industrial enterprises in China. We found that (1) the impact of pollution charges on most types of green technology innovation by enterprises has increased significantly over time; (2) the pollution charge policy has a certain inhibition effect on the end-of-pipe technology innovation, but can promote the process improvement of reducing industrial wastewater emissions; (3) there is a U-shaped relationship between the pollution charges and some green technological innovation (e.g., emission intensity of SO2, industrial wastewater emission intensity, and industrial wastewater removal intensity), which is dynamically adjusted over time; and (4) the larger the enterprise’s solid assets, the faster the asset depreciation will inhibit the enterprise from adopting the green process innovation strategy.
The levels of eight organophosphate esters (OPEs) were analyzed in air and soil samples collected at Ny-Ålesund and London Island, Svalbard during the Chinese Scientific Research Expedition to the ...Arctic during 2014–2015. The concentrations of total OPEs (∑OPEs) ranged from 357 pg/m3 to 852 pg/m3 in the air and from 1.33 ng/g to 17.5 ng/g dry weight (dw) in the soils. Non-Cl OPEs accounted for 56 ± 13% and 62 ± 16% of ∑OPEs for the air and soil, respectively. Tris(2-chloroethyl) phosphate (TCEP) was the dominant compound in the air, with an average concentration of 180 ± 122 pg/m3. Triphenyl phosphate, tri(1-chloro-2-propyl) phosphate, and TCEP were the most abundant OPEs in the soils, with mean values of 1.77, 2.13, and 1.02 ng/g dw, respectively. Compared with the levels of polybrominated diphenyl ethers found in Arctic regions in previous studies, OPEs showed significantly higher concentrations, thereby indicating the large production and wide usage of OPEs globally. In addition, the fugacity fraction results indicated that net deposition from air to soil was dominated in the area. Overall, the occurrence and distribution of OPEs in the air and soils in the Arctic region indicated that OPEs can undergo long-range atmospheric transport and accumulate in remote regions.
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•The concentrations of OPEs in soils were higher than those of PBDEs in Arctic.•Net deposition of OPEs from air to soil was dominated in the area.•OPEs can undergo long-range atmospheric transport and accumulate in Arctic.
OPEs can undergo long-range atmospheric transport and accumulate in remote regions.
A nanocluster Ni–WC/C electrocatalyst is prepared through a sequential impregnation method and is used for the urea electrooxidation in alkaline conditions. The micro-morphology, lattice parameter, ...composition and surface states of Ni–WC/C particles are determined by scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray diffraction (XRD), energy dispersive X-ray (EDX) and X-ray photoelectron spectrometry (XPS) analysis. The electrooxidation activity and stability of the Ni–WC/C catalyst are also investigated by cyclic voltammograms and chronoamperograms. Characterization results indicate that the Ni nanoclusters are uniformly distributed on the WC/C framework, and the Ni–WC/C catalyst shows high electrocatalytic activity and stability for urea electrooxidation. The maximum current density at the Ni–WC/C electrode is almost 700 mA cm−2 mg−1 which is one order of magnitude higher than that at the Ni/C electrode, and the steady current density at the Ni–WC/C electrode is also markedly improved. Furthermore, the ESA values and XPS spectra indicate that the enhanced performance of the Ni–WC/C catalyst could be attributed to the structure effect and electron effect between nickel and tungsten carbide.
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•The Ni–WC/C catalysts were prepared successfully by a simple impregnation method.•The nickel particles were grown on the WC/C framework in clusters with nanoscale.•Tungsten carbide promotes nickel to more active sites for urea electrooxidation.•Ni–WC/C nanoclusters show superior catalytic activity for urea electrooxidation.
•Engineering investigation about asymmetry instability in kilometre-deep roadways.•Elaborate relationship between in-situ rock and the rock-like material.•Correlation analysis of the load-bearing ...feature and the roadway structural stability.•Control effect of the multi-echelon support on the structural instability of roadway.
This paper investigated the effect of a multi-echelon support on the asymmetry structural instability of different lithologykilometre-deep roadways. An engineering background investigation was carried out to determine asymmetry instability in different lithology kilometre-deep roadways using acoustic emission signals of in situ rock and 3D in situ ground stress. The mechanical coupling-bearing structure and multi-echelon support method of the surrounding rock were proposed based on the analysis of the secondary stress distribution and strength degradation of the surrounding rock. A numerical simulation and scale-model experiments were conducted to analyse the asymmetry structural failure mechanism and the effect of a multi-echelon support. The results indicated that the high ground stress created a serious impact on the stability of the coupling-bearing strata, an increase in horizontal ground stress created obvious extensions of the weak bearing stratum and the transfer of the main and key bearing strata. The larger asymmetric deformation phenomena of surrounding rock was often accompanied by wedge-shaped roof caving, serious floor heave and spalling, which indicated the decline of the bearing capacity of the surrounding rock. The redesigned multi-echelon support was shown to reduce the scope of a weak bearing stratum and limit the transfer of the main and key bearing strata, preventing the roadway asymmetry structural instability to a certain degree and relieving plastic flow in the surrounding rock.
We report the synthesis of nitrogen-doped hierarchical meso/microporous carbon using renewable biomass bamboo fungus as precursor via two-step pyrolysis processes. It is found that the developed ...porous carbon (NHPC-800) features honeycomb-like cellular framework with well-developed porosity, huge specific surface area (1708 m
g
), appropriate nitrogen-doping level (3.2 at.%) and high mesopore percentage (25.5%), which are responsible for its remarkable supercapacitive performances. Electrochemical tests suggest that the NHPC-800 electrode offers the largest specific capacitance of 228 F g
, asplendid rate capability and stable electrochemical behaviors in a traditional three-electrode system. Additionally, asymmetric supercapacitor device is built based on this product as well. An individual as-assembled supercapacitor of NHPC-800//NHPC-800 delivers the maximum energy density of 4.3 Wh kg
; retains the majority of capacitanceat large current densities; and shows terrific cycling durability with negligible capacitance drop after long-term charge/discharge for beyond 10,000 cycles even at a high current density of 10 A g
. These excellent supercapacitive properties of NHPC-800 in both three- and two-electrode setups outperform those of lots of biomass-derived porous carbons and thus make it a perspective candidate for producing cost-effective and high-performance supercapacitors.
Molecularly targeted therapies for advanced prostate cancer include castration modalities that suppress ligand-dependent transcriptional activity of the androgen receptor (AR). However, persistent AR ...signalling undermines therapeutic efficacy and promotes progression to lethal castration-resistant prostate cancer (CRPC), even when patients are treated with potent second-generation AR-targeted therapies abiraterone and enzalutamide. Here we define diverse AR genomic structural rearrangements (AR-GSRs) as a class of molecular alterations occurring in one third of CRPC-stage tumours. AR-GSRs occur in the context of copy-neutral and amplified AR and display heterogeneity in breakpoint location, rearrangement class and sub-clonal enrichment in tumours within and between patients. Despite this heterogeneity, one common outcome in tumours with high sub-clonal enrichment of AR-GSRs is outlier expression of diverse AR variant species lacking the ligand-binding domain and possessing ligand-independent transcriptional activity. Collectively, these findings reveal AR-GSRs as important drivers of persistent AR signalling in CRPC.
Severe gas disasters in deep mining areas are increasing, and traditional protective coal seam mining is facing significant challenges. This paper proposes an innovative technology using soft rock as ...the protective seam in the absence of an appropriate coal seam. Based on the geological engineering conditions of the new horizontal first mining area of Luling Coal Mine in Huaibei, China, the impacts of different mining parameters of the soft-rock protective seam on the pressure-relief effect of the protected coal seam were analyzed through numerical simulation. The unit stress of the protected coal seam, which was less than half of the primary rock stress, was used as the mining stress pressure-relief index. The optimized interlayer space was found to be 59 m for the first soft-rock working face, with a 2 m mining thickness and 105 m face length. The physicochemical characteristics of the orebody were analyzed, and a device selection framework for the soft-rock protective seam was developed. Optimal equipment for the working face was selected, including the fully-mechanized hydraulic support and coal cutter. A production technology that combined fully-mechanized and blasting-assisted soft-rock mining was developed. Engineering practices demonstrated that normal circulation operation can be achieved on the working face of the soft-rock protective seam, with an average advancement rate of 1.64 m/d. The maximum residual gas pressure and content, which were measured at the cut hole position of the protected coal seams (Nos. 8 and 9), decreased to 0.35 MPa and 4.87 m3/t, respectively. The results suggested that soft-rock protective seam mining can produce a significant gas-control effect.
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