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Summary: Olaparib is a pioneering PARP inhibitor (PARPi) approved for treating castration-resistant prostate cancer (CRPC) tumors harboring DNA repair defects, but clinical resistance has been documented. To study acquired resistance, we developed Olaparib-resistant (OlapR) cell lines through chronic Olaparib treatment of LNCaP and C4-2B cell lines. Here, we found that IGFBP3 is highly expressed in acquired (OlapR) and intrinsic (Rv1) models of Olaparib resistance. We show that IGFBP3 expression promotes Olaparib resistance by enhancing DNA repair capacity through activation of EGFR and DNA-PKcs. IGFBP3 depletion enhances efficacy of Olaparib by promoting DNA damage accumulation and subsequently, cell death in resistant models. Mechanistically, we show that silencing IGFBP3 or EGFR expression reduces cell viability and resensitizes OlapR cells to Olaparib treatment. Inhibition of EGFR by Gefitinib suppressed growth of OlapR cells and improved Olaparib sensitivity, thereby phenocopying IGFBP3 inhibition. Collectively, our results highlight IGFBP3 and EGFR as critical mediators of Olaparib resistance.

Building-integrated flexible resources can offer economical availability to accommodate high-penetrated renewable energy sources (RESs), which can be potentially coordinated to achieve cost-effective supply. This paper proposes a resilience-oriented planning model of urban distribution system source–network–load–storage in the context of high-penetrated building-integrated resources. In this model, source–network–load–storage resources are cost-optimally planned, including the lines, soft open point (SOP), building-integrated photovoltaics (BIPVs), building-integrated wind turbine (BIWT), building-integrated energy storage system (ESS), etc. To enhance fault recovery capability during extreme faults, fault scenarios are incorporated into the distribution system operation via coupled multiple recovery stages. The resilience-oriented planning is a thorny problem due to its source–network–load–storage couplings, normal-fault couplings, etc. The original resilience-oriented planning is reformulated as a mixed-integer linear programming (MILP) problem, which can then be solved with a two-stage method and evaluated via a multi-dimensional evaluation metrics. The proposed planning methodology is benchmarked over a Portugal 54-node urban distribution system to verify the superiority and effectiveness on the system economy and resilience levels. Case studies show that the proposed methodology can exploit the optimal synergies of different source–network–load–storage components and enhance system dispatchability.

Abstract Introduction We aim to introduce a method using confocal scanning laser ophthalmoscopy (cSLO) images for measuring retinal vascular geometry, including vessel branch angle (BA), vessel diameter, vessel tortuosity, and fractal dimension (D f), and to elucidate the relationship between hypertension and these metrics. Methods A total of 119 participants (119 eyes) were enrolled, among which 72 were normotensive and 47 were hypertensive. Infrared cSLO images were extracted from the circular scan around the optics disc using a commercial cSLO + optical coherence tomography instrument. Preprocessed cSLO images were further analyzed using the appropriate tool/macro/plugin of ImageJ. Results Intraclass correlation coefficients of selected methods used for conducting the cSLO-based geometric analyses were all higher than 0.80. Arterial/arteriolar BA, arteriolar vessel diameter, and total D f in normotensive subjects were 85.80 ± 7.79°, 116.80 ± 12.58 μm, and 1.430 ± 0.037, respectively, significantly higher than those of hypertensive subjects (82.13 ± 10.83°, 108.2 ± 11.12 μm, and 1.361 ± 0.044, all P 0.05). Conclusion Proposed cSLO-based methods for assessing various vascular geometric parameters were highly repeatable and reproducible. Arterial/arteriolar BA, arteriolar vessel diameter, and total D f were retinal vascular parameters significantly correlated with hypertension in a negative manner.

Abstract Background To ascertain the agreement of corneal aberrations obtained from the Pentacam and the KR-1W in myopic populations and to investigate the influence of the level of myopia as well as the laterality on the agreement. Methods In this observational study, a rotating Scheimpflug camera (Pentacam AXL) and a Hartmann-Shack wavefront analyzer with Placido-disc topographer (KR-1W) were used to measure the aberrations of myopes in the anterior corneal surface by one experienced operator. All examinations were computed across a 6 mm diameter. Six subgroups were generated according to the degree of myopia (mild, moderate, and severe myopia) and the laterality of eyes (right and left eyes). Results The study included 245 eyes of 170 participants. For certain anterior corneal aberrations, statistically significant differences existed between the Pentacam and the KR-1W (all P 0.1 μm) for aberrations closely correlated with visual quality, including Z(3, ± 3), Z(3, ± 1), and Z(4,0), and almost all aberrations, indicating poor agreement. Conclusions In clinical practice, the Pentacam based on Scheimpflug technology and the KR-1W based on Placido Disc System are not interchangeable in measuring anterior corneal aberration for myopes regardless of myopia degree and the laterality, suggesting that a consistent instrument should be selected for surgical design as well as follow-up.

In the transactional processes within a multi-building microgrid system, it is imperative to safeguard stakeholders’ interests and ensure stable, economically efficient operation. Therefore, this paper proposes an integrated interactive control of distribution systems with multi-building microgrids based on game theory. Initially, an interactive framework encompassing superior power grids, distribution network operators, and multi-building microgrids is proposed. This framework establishes a master–slave game model between distribution network operators and multi-building microgrids. Additionally, it introduces the concept of Soft Open Points between building microgrids to enhance system operational safety while also reducing economic costs for distribution network operators. Subsequently, to maintain solution accuracy and optimality, it employs linearization and cone relaxation methods to transform the original model into a mixed-integer second-order cone programming model. Furthermore, it enhances an iterative search method and the price mechanism based on supply and demand ratios. The revised price mechanism serves to boost the participation of building microgrid users in energy regulation, while the iterative search method effectively resolves the equilibrium point of interest among all game participants. Finally, a simulation analysis is conducted on an IEEE-33 test system, and the effectiveness of the proposed strategy is verified by comparing three schemes.

Ning et al. report expression of a neural lineage gene signature in enzalutamide-resistant prostate cancer cells and datasets from patients with neuroendocrine prostate cancer. One of these genes, ARHGEF2, is associated with poor overall and disease-free survival in patients with castration-resistant disease and supports cell viability in vitro.

Abstract Background Benzo [a] pyrene (BaP), a potent carcinogen, has been proved that it has toxicological effects via activation the aryl hydrocarbon receptor (AhR) pathway. AhR can participate in regulating lipogenesis and lipolysis. This topic will verify whether BaP regulates lipid metabolism via AhR. Methods (1) C57BL/6 mice were gavaged with BaP for 12 weeks to detect serum lipids, glucose tolerance, and insulin resistance. Morphological changes in white adipose tissue (WAT) were detected by Hematoxylin and Eosin staining. The mRNA expression levels of adipogenesis-related factors included recombinant human CCAAT/enhancer binding protein alpha (C/EBPα), peroxisome proliferator-activated receptor gamma (PPARγ), and fatty acid binding protein 4 (FABP4) and inflammatory factors included nuclear factor kappa-B (NF-κB), monocyte chemotactic protein-1 (MCP-1), and tumor necrosis factor alpha (TNF-α) were detected using PCR. (2) Neutral lipid content changes in differentiated 3 T3-L1 adipocytes treated with BaP with and w/o AhR inhibitor were detected by Oil red staining. The protein expression levels of adipogenesis- and decomposition-related factors included PPARγ coactivator-1 alpha (PGC-1α), and peroxisome proliferation-activated receptor alpha (PPARα) were detected using western blotting. The mRNA expression levels of inflammatory factors were detected using PCR. Results (1) BaP inhibited body weight gain, decreased lipid content, increased lipid levels, and decreased glucose tolerance and insulin tolerance in mice; (2) BaP reduced the expressions of C/EBPα, PPARγ, FABP4, PGC-1α, and PPARα and increased the expressions of NF-κB, MCP-1, and TNF-α by activating AhR. Conclusion BaP inhibit fat synthesis and oxidation while inducing inflammation by activating AhR, leading to WAT dysfunction and causing metabolic complications.

Purpose. To evaluate refractive outcomes, intraocular lens (IOL) power calculation, and IOL position following a novel conjunctiva-sparing transscleral fixation technique. Methods. Forty-one eyes of 40 patients managed with a flapless transscleral-sutured technique were included. Preoperative and postoperative refractive errors (spherical equivalents, SE) were compared. IOL position was assessed on the Scheimpflug images. IOL power was calculated by SRK/T, Holladay 1, and Hoffer Q formulas. Results. The mean age was 57.39 ± 14.83 years (range: 26 to 79 years), and the mean follow-up was 7.46 ± 6.42 months (range: 1 to 24 months). Surgical indications were aphakia (n = 14), subluxated lenses (n = 3), and IOL dislocation (n = 24). The SE was 4.50 ± 6.38 diopter (D) (range: −3.75 to 13.75 D) preoperatively and −1.68 ± 1.57 D (range: −5.50 to 1.13 D) postoperatively (P

Demand–response (DR) can provide the economic flexibility required to adapt a high proportion of renewable energy in the context of a smart grid. This paper proposes a transactive DR framework to enable the multi-time-scale proactive participation of demand-side flexible multi-energy resources. In this framework, the distribution system operator distributes the real-time DR request and the high renewable penetrated multi-energy prosumer aggregators provide the ancillary services based on their adjustable potential. To facilitate such multi-time-scale prosumer–operator interactions, a flexibility potential evaluation method is developed for the quantification and pricing of prosumer flexibility. The positive and negative flexibility potential of the demand-side prosumer aggregators are defined as deviations from the optimal pre-dispatch operation, which are further quantified using the aspects of flexible time and power. Based on the introduction of a flexibility pricing mechanism to identify the economically optimal ancillary service requirements, each prosumer aggregator performs an optimal real-time DR scheduling. Case studies over several DR schemes are performed to confirm the effectiveness and superiority of the proposed method on the economy and flexibility of the system.

Study region: Qingjiang cascade reservoir, China. Study focus: Reservoirs regulate the natural streamflow to utilize water resources comprehensively. How to mine the existing massive reservoir operation data to describe human operation behaviors is a challenge. To address this issue, a data-driven method, Long short-term memory (LSTM), was used to simulate the reservoir outflow by inputting historical information. The physics-guided LSTM model, shortly named PG-LSTM, was formulated by using synthetic flood samples and physical constraints of water balance, boundary, and monotonicity. New hydrological insights: (1) PG-LSTM can reproduce historical outflow with seasonal variations, or predict outflow without lags, (2) knowledge of reservoir operations can guide LSTM with the reduction of negative flow occurrence and the accurate identification of operation behaviors under extreme hydrological conditions, (3) specifically, compared with conventional LSTM, gradient boosting regression tree and conventional reservoir operation, PG-LSTM can improve the Nash-Sutcliffe efficiency of cascade reservoir during the test period from 0.50, 0.20, and 0.17 to 0.54 in the reproduction scenario, and from 0.84, 0.26, and 0.17 to 0.85 in the prediction scenario with five-fold cross-validation method. The PG-LSTM is helpful to describe human operation behaviors of reservoirs.

This paper proposes a denoising method of vibration signal based on improved multiresolution singular value decomposition (IMRSVD) and effective component selection. A new construction method of trajectory matrix is used, which can enhance the oscillating component of the original signal. Next, based on the improved trajectory matrix, singular value decomposition (SVD), which plays the role of pre-decomposition, is used to obtain multiple one-dimensional components, and the further decomposition of that is achieved by multiresolution singular value decomposition (MRSVD). Finally, the effective components selection of a series of decomposed signal components is achieved based on the proposed feature evaluation index (FEI). The denoising experiments are carried out using the simulation signal and the vibration signal of planetary gear, respectively. The experimental results show that the proposed method performs better than the traditional SVD denoising method, and the weak fault feature in the vibration signal can be extracted successfully. In addition, the comparison between periodic modulation intensity (PMI) and FEI displays that the proposed method has better robustness and accuracy than the interference components with similar frequency. Thus, the proposed method is an effective weak fault feature extraction and denoising tool of vibration signals for fault diagnosis.

With the evolution of cataract surgery from visual rehabilitation to refractive surgery, aspheric intraocular lenses (IOLs) are being increasingly used in the field of ophthalmology. This increased use can be attributed to negative or zero spherical aberrations with unique optical designs, which counteract some of the positive spherical aberrations of the cornea. These alterations reduce the total spherical aberration of human eyes and improve the visual acuity in patients with cataract postoperatively. At present, various types of aspheric IOLs are used worldwide. Although the implantation of aspheric IOL is beneficial to the patients who need correction of spherical aberrations, much controversy is still associated with ocular residual spherical aberrations that facilitate the best visual quality for patients postoperatively. In order to provide reference for future clinical work and scientific research, this report reviews the relationship between the ocular residual spherical aberration of human eyes and visual quality.

Castration-resistant prostate cancer remains as an incurable disease. Exploiting DNA damage repair defects via inhibition of poly (ADP-ribose) polymerase (PARP) is becoming an attractive therapeutic option. The TOPARP-A clinical trial demonstrated that the PARP inhibitor olaparib may be an effective strategy for treating prostate cancer. However, several unanswered questions regarding the use of olaparib remain: 1) How do we best stratify patients for olaparib treatment? 2) Where do we place olaparib in the treatment sequence paradigm? 3) Is there cross-resistance between olaparib and currently used therapies? Here, we tested putative cross-resistance between current therapies and olaparib in treatment-resistant castration-resistant prostate cancer models. Docetaxel-resistant cells exhibited robust resistance to olaparib which could be attributed to blunted PARP trapping in response to olaparib treatment. Upregulated ABCB1 mediates cross-resistance between taxanes and olaparib, which can be overcome through decreasing ABCB1 expression or inhibiting ABCB1 using elacridar or enzalutamide. We also show that combining olaparib with enzalutamide is more effective in olaparib-sensitive cells than either single agent. Our results demonstrate that cross-resistance between olaparib and other therapies could blunt response to treatment and highlight the need to develop strategies to maximize olaparib efficacy.

In the context of global warming, vegetation activity in northeastern East Asia (40–45°N, 105–130°E) (NEA) shows a significant growth trend on a multidecadal scale, but how vegetation changes on a decadal scale is unclear. In this study, we find a significant trend of vegetation greening in northeastern East Asia during 1982–1998 and a slowdown in the greening trend during 1998–2014. Trend analysis of the extreme climate indices reveals that the trends of precipitation-related extreme climate indices are similar to those of vegetation change, and further correlation analysis reveals that precipitation-related extreme climate indices have a strong positive correlation with the NDVI. The results indicate that the vegetation in northeastern East Asia is more sensitive to precipitation changes, especially extreme precipitation, compared with the temperature and related extreme indices. Furthermore, the analysis of large-scale atmospheric circulation changes suggests a role of Northwest Pacific subtropical high (NPSH) in the trend changes of precipitation-related extreme indices. The strengthening of NPSH before 1998 enhances the moisture transport to the NEA, providing abundant water vapor favorable for extreme precipitation events, while after 1998, the NPSH trend is much weakened, corresponding to a decrease in the moisture transport trend.

The AR-V7 isoform is associated with anti-androgen drug resistance in prostate cancer. Here, the authors show that AR-V7 protein stability is regulated by HSP70/STUB1 complex-mediated proteostasis which confers drug resistance in late stage prostate cancer. Inhibition of HSP70 re-sensitizes resistant cells to enzalutamide therapy.

Wireless community networks (WCNs) are emerging as an alternative to provide wireless offloading before the deployment of 5G network. However, it is not clear about its development prospects, e.g., how to understand the WCN technology affects the adoption of users, and the competition in a communication market coexisting different wireless technologies, i.e., LTE in unlicensed spectrum. To this end, we envision three distinct development stages of WCN: evolution, regulation, and competition. Specially, we first study the evolution of self-organizing WCN in which the WCN services expands as WCN participants increases. We propose a dynamic model and show the existence of unique equilibrium point at which the fraction of subscribers does not change. Next, we turn to investigate the impact of regulation on a commercial WCN by introducing an operator. The users in commercial WCN can be divided into two parts: insiders and outsiders, according to whether contributing connectivity into the community. We discuss the economic interactions with regard to insiders, outsiders, and the operator, and derive the equilibrium adoption of various users and the optimal price of the WCN operator. We then investigate a competitive duopoly market that coexists a WCN provider (WCNP) and an LTE-U provider (LP). We model the economic relationships among the users, WCNP and LP as a tripartite game, in which the two providers choose their market shares independently. We derive a sufficient condition that guarantees the existence of equilibrium in the market competition game.

Objective Osteopontin (OPN) plays an important role in chronic airway remodeling and bronchial hyperresponsiveness. The association between OPN protein expression and asthma has been investigated extensively, but the results of these studies are inconsistent. The aim of this meta-analysis was to determine the relationship between OPN protein expression and asthma. Methods A systematic search was performed to identify published studies regarding the association between OPN protein expression and asthma. Studies with quantitative data were analyzed, and standardized mean differences were determined with 95% confidence intervals. Results Nine studies were included in this analysis, involving 706 patients with asthma and 332 healthy controls. The pooled data from these studies demonstrated that OPN protein expression was significantly higher in patients with asthma than in controls. There was no significant difference in OPN protein between allergic asthma and nonallergic asthma. Moreover, there was no obvious relationship between OPN protein expression and the severity of asthma. Conclusion The results of this meta-analysis suggested that OPN protein expression is significantly upregulated in patients with asthma, but that it does not correlate with the type or severity of asthma.

Desalination has been considered as an essential way to solve water stress all over the world. Most of previous studies focused on its environmental impacts, energy consumption and desalination technologies rather than human health. However, the safety of desalinated water remains unclear. This study was undertaken to investigate the knowledge, attitude and practice (KAP) of the residents in an island county in eastern China to desalinated water. Seventeen people working in medical and water industries were recruited, and focus group discussion and in-depth interview were conducted among them. Our results showed that the majority of people interviewed knew the definition and local supply pattern of desalinated water, while some of them showed some concern about the safety and nutrition of desalinated water. Current drinking water standard has no specific item for desalination, so we strongly suggest issuing a standard for desalinated water.

Target tracking is a typical and important application of wireless sensor networks (WSNs). In consideration of the network scalability and energy efficiency for target tracking in large-scale WSNs, it has been employed as an effective solution by organizing the WSNs into clusters. However, tracking a moving target in cluster-based WSNs suffers a boundary problem when the target moves across or along the boundaries of clusters, as the static cluster membership prevents sensors in different clusters from sharing information. In this paper, we propose a novel mobility management protocol, called hybrid cluster-based target tracking (HCTT), which integrates on-demand dynamic clustering into a cluster-based WSN for target tracking. By constructing on-demand dynamic clusters at boundary regions, nodes from different static clusters that detect the target can temporarily share information, and the tracking task can be handed over smoothly from one static cluster to another. As the target moves, static clusters and on-demand dynamic clusters alternately manage the target tracking task. Simulation results show that the proposed protocol performs better in tracking the moving target when compared with other typical target tracking protocols.

Wakeup scheduling has been widely used in wireless sensor networks (WSNs), for it can reduce the energy wastage caused by the idle listening state. In a traditional wakeup scheduling, sensor nodes start up numerous times in a period, thus consuming extra energy due to state transitions (e.g., from the sleep state to the active state). In this paper, we address a novel interference-free wakeup scheduling problem called compact wakeup scheduling, in which a node needs to wake up only once to communicate bidirectionally with all its neighbors. However, not all communication graphs have valid compact wakeup schedulings, and it is NP-complete to decide whether a valid compact wakeup scheduling exists for an arbitrary graph. In particular, tree and grid topologies, which are commonly used in WSNs, have valid compact wakeup schedulings. We propose polynomial-time algorithms using the optimum number of time slots in a period for trees and grid graphs. Simulations further validate our theoretical results.

Prostate cancer (PCa) is characterized by deregulated expression of several tumor suppressor or oncogenic miRNAs. The objective of this study was the identification and characterization of miR-let-7c as a potential tumor suppressor in PCa.Levels of expression of miR-let-7c were examined in human PCa cell lines and tissues using qRT-PCR and in situ hybridization. Let-7c was overexpressed or suppressed to assess the effects on the growth of human PCa cell lines. Lentiviral-mediated re-expression of let-7c was utilized to assess the effects on human PCa xenografts.We identified miR-let-7c as a potential tumor suppressor in PCa. Expression of let-7c is downregulated in castration-resistant prostate cancer (CRPC) cells. Overexpression of let-7c decreased while downregulation of let-7c increased cell proliferation, clonogenicity and anchorage-independent growth of PCa cells in vitro. Suppression of let-7c expression enhanced the ability of androgen-sensitive PCa cells to grow in androgen-deprived conditions in vitro. Reconstitution of Let-7c by lentiviral-mediated intratumoral delivery significantly reduced tumor burden in xenografts of human PCa cells. Furthermore, let-7c expression is downregulated in clinical PCa specimens compared to their matched benign tissues, while the expression of Lin28, a master regulator of let-7 miRNA processing, is upregulated in clinical PCa specimens.These results demonstrate that microRNA let-7c is downregulated in PCa and functions as a tumor suppressor, and is a potential therapeutic target for PCa.

Wormhole attacks can negatively affect the localization in wireless sensor networks. A typical wormhole attack can be launched by two colluding attackers, one of which sniffs packets at one point in the network and tunnels them through a wired or wireless link to another point, and the other relays them within its vicinity. In this paper, we investigate the impact of the wormhole attack on the localization and propose a novel distance-consistency-based secure localization scheme against wormhole attacks, which includes three phases of wormhole attack detection, valid locators identification and self-localization. The theoretical model is further formulated to analyze the proposed secure localization scheme. The simulation results validate the theoretical results and also demonstrate the effectiveness of our proposed scheme.