USP36 promotes tumorigenesis and tamoxifen resistance in breast cancer by deubiquitinating and stabilizing ERα.

BACKGROUND: Breast cancer is the most prevalent cancer in women globally. Over-activated estrogen receptor (ER) α signaling is considered the main factor in luminal breast cancers, which can be effectively managed with selective estrogen receptor modulators (SERMs) like tamoxifen. However, approximately 30-40% of ER + breast cancer cases are recurrent after tamoxifen therapy. This implies that the treatment of breast cancer is still hindered by resistance to tamoxifen. Recent studies have suggested that post-translational modifications of ERα play a significant role in endocrine resistance. The stability of both ERα protein and its transcriptome is regulated by a balance between E3 ubiquitin ligases and deubiquitinases. According to the current knowledge, approximately 100 deubiquitinases are encoded in the human genome, but it remains unclear which deubiquitinases play a critical role in estrogen signaling and endocrine resistance. Thus, decoding the key deubiquitinases that significantly impact estrogen signaling, including the control of ERα expression and stability, is critical for the improvement of breast cancer therapeutics. METHODS: We used several ER positive breast cancer cell lines, DUB siRNA library screening, xenograft models, endocrine-resistant (ERα-Y537S) model and performed immunoblotting, real time PCR, RNA sequencing, immunofluorescence, and luciferase activity assay to investigate the function of USP36 in breast cancer progression and tamoxifen resistance. RESULTS: In this study, we identify Ubiquitin-specific peptidase 36 (USP36) as a key deubiquitinase involved in ERα signaling and the advancement of breast cancer by deubiquitinases siRNA library screening. In vitro and in vivo studies showed that USP36, but not its catalytically inactive mutant (C131A), could promote breast cancer progression through ERα signaling. Conversely, silencing USP36 inhibited tumorigenesis. In models resistant to endocrine therapy, silencing USP36 destabilized the resistant form of ERα (Y537S) and restored sensitivity to tamoxifen. Molecular studies indicated that USP36 inhibited K48-linked polyubiquitination of ERα and enhanced the ERα transcriptome. It is interesting to note that our results suggest USP36 as a novel biomarker for treatment of breast cancer. CONCLUSION: Our study revealed the possibility that inhibiting USP36 combined with tamoxifen could provide a potential therapy for breast cancer.

A robust optimal control by grey wolf optimizer for underwater vehicle-manipulator system.

Underwater vehicle-manipulator system (UVMS) is a commonly used underwater operating equipment. Its control scheme has been the focus of control researchers, as it operates in the presence of lumped disturbances, including modelling uncertainties and water disturbances. To address the nonlinear control problem of the UVMS, we propose a robust optimal control approach optimized using grey wolf optimizer (GWO). In this scheme, the nonlinear dynamic model of UVMS is deduced to a linear state-space model in the case of the lumped disturbances. Then, the GWO algorithm is used to optimize the Riccati equation parameters of the H∞ controller in order to achieve the H∞ performance criterion, such as stability and disturbance rejection. The optimization is performed by evaluating the performance of the closed-loop UVMS in real-time comparison with the popular artificial intelligent algorithms, such as as ant colony algorithm (ACO), genetic algorithm (GA), and particle swarm optimization (PSO), using feedback control from the physical hardware-in-the-loop UVMS platform. This scheme can result in improved H∞ control system performance, and it is able to ensure that UVMS has strong robustness to these lumped disturbances. Last, the validity of the proposed scheme can be established, and its performance in overcoming modeling uncertainties and external disturbances can be observed and analyzed by performing the hardware-in-the-loop experiments.

Comparing avian species richness estimates from structured and semi-structured citizen science data.

Citizen science, including structured and semi-structured forms, has become a powerful tool to collect biodiversity data. However, semi-structured citizen science data have been criticized for higher variability in quality, including less information to adjust for imperfect detection and uneven duration that bias the estimates of species richness. Species richness estimators may quantify bias in estimates. Here, we test the effectiveness of Chao1 estimator in eBird (semi-structured) by comparing it to averaged species richness in Breeding Bird Survey Taiwan, BBS (structured) and quantifying bias. We then fit a power function to compare bias while controlling for differences in count duration. The Chao1 estimator increased the species richness estimates of eBird data from 56 to 69% of the average observed BBS and from 47 to 59% of the average estimated BBS. Effects of incomplete short duration samples and variability in detectability skills of observers can lead to biased estimates. Using the Chao1 estimator improved estimates of species richness from semi-structured and structured data, but the strong effect of singleton species on bias, especially in short duration counts, should be evaluated in advance to reduce the uncertainty of estimation processes.

Cu∥-loaded polydopamine coatings with in situ nitric oxide generation function for improved hemocompatibility.

NO is the earliest discovered gas signal molecule which is produced by normal healthy endothelial cells, and it has many functions, such as maintaining cardiovascular homeostasis, regulating vasodilation, inhibiting intimal hyperplasia and preventing atherosclerosis in the blood system. Insufficient NO release is often observed in the pathological environment, for instance atherosclerosis. It was discovered that NO could be released from the human endogenous NO donor by many compounds, and these methods can be used for the treatment of certain diseases in the blood system. In this work, a series of copper-loaded polydopamine (PDA) coatings were produced through self-polymerization time for 24, 48 and 72 h. The chemical composition and structure, coating thickness and hydrophilicity of the different copper-loaded PDA coatings surfaces were characterized by phenol hydroxyl quantitative, X-ray photoelectron spectroscopy, ellipsometry atomic force microscopy and water contact angles. The results indicate that the thickness and the surface phenolic hydroxyl density of the PDA coatings increased with the polymerization time.This copper-loaded coating has glutathione peroxidase-like activity, and it has the capability of catalyzing NO releasing from GSNO. The surface of the coating showed desirable hemocompatibility, the adhesion and activation of platelets were inhibited on the copper-loaded coatings. At the same time, the formation of the thrombosis was also suppressed. These copper-loaded PDA coatings could provide a promising platform for the development of blood contact materials.

Endothelial mimetic multifunctional surfaces fabricated via polydopamine mediated copper immobilization.

Nitric oxide (NO), which is continuously released from the normal healthy endodermis cell layer of the vascular system, plays a crucial role in the stability and health maintenance of blood vessels. It is one of the most important gaseous signaling molecules and regulates cardiovascular homeostasis, inhibits blood clotting and intimal hyperplasia, and prevents atherosclerosis. Insufficient NO production is often observed in atherosclerosis lesions. In this work, a NO-generating bioactive coating built by a polydopamine film (PDA) and a copper ion was fabricated. The coating (Cu/PDA) had glutathione peroxidase (GPx)-like activity and was able to catalyze NO release from S-nitrosothiols (RSNOs) due to the catalytic activity of the copper ion. It was also capable of catalyzing RSNO decomposition and NO production. The copper ion was embedded in the PDA coating to ensure the effectiveness of long-term NO-catalytic activity. The surface exhibited a favorable suppression of vascular smooth muscle cell (VSMC) proliferation and also efficiently reduced thrombosis formation. Additionally, the NO catalytic surface had a positive influence on endothelial cell (EC) growth behavior. The in vivo study verified that the modified surface promoted healthy endothelium formation and suppressed intimal hyperplasia, which is conducive to re-endothelialization and for reducing restenosis of vascular stents. This work provides a potential strategy for the development of novel cardiovascular implants.