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PDF file - 267K, Fig. s1. HMECs induce the PCa cells invasion in vitro. Fig. s2. ECs down-regulated AR signaling in PCa cells. Fig. s3. Cytokines/chemokines level changes in ECs upon PCa cells co-culture. Fig. s4. EMT markers expressions changes in PCa cells upon ECs co-culture.

Although the potential roles of endothelial cells in the microvascules of prostate cancer during angiogenesis have been documented, their direct impacts on the prostate cancer metastasis remain unclear. We found that the CD31-positive and CD34-positive endothelial cells are increased in prostate cancer compared with the normal tissues and that these endothelial cells were decreased upon castration, gradually recovered with time, and increased after prostate cancer progressed into the castration-resistant stage, suggesting a potential linkage of these endothelial cells with androgen deprivation therapy. The in vitro invasion assays showed that the coculture of endothelial cells with prostate cancer cells significantly enhanced the invasion ability of the prostate cancer cells. Mechanism dissection found that coculture of prostate cancer cells with endothelial cells led to increased interleukin (IL)-6 secretion from endothelial cells, which may result in downregulation of androgen receptor (AR) signaling in prostate cancer cells and then the activation of TGF-β/matrix metalloproteinase-9 (MMP-9) signaling. The consequences of the IL-6→AR→TGFβ→MMP-9 signaling pathway might then trigger the increased invasion of prostate cancer cells. Blocking the IL-6→AR→TGFβ→MMP-9 signaling pathway either by IL-6 antibody, AR-siRNA, or TGF-β1 inhibitor all interrupted the ability of endothelial cells to influence prostate cancer invasion. These results, for the first time, revealed the important roles of endothelial cells within the prostate cancer microenvironment to promote the prostate cancer metastasis and provide new potential targets of IL-6→AR→TGFβ→MMP-9 signals to battle the prostate cancer metastasis. Mol Cancer Ther; 12(6); 1026–37. ©2013 AACR.

The sluggish electron transfer at the interface of microorganisms and an electrode is a bottleneck of increasing the output power density of microbial fuel cells (MFCs). Mo-doped carbon nanofibers (Mo-CNFs) prepared with electrostatic spinning and high-temperature carbonization are used as an anode in MFCs here. Results clearly indicate that Mo2C nanoparticles uniformly anchored on carbon nanowire, and Mo-doped anodes could accelerate the electron transfer rate. The Mo-CNF ΙΙ anode delivered a maximal power density of 1287.38 mW m−2, which was twice that of the unmodified CNFs anode. This fantastic improvement mechanism is attributed to the fact that Mo doped on a unique nanofiber surface could enhance microbial colonization, electrocatalytic activity, and large reaction surface areas, which not only enable direct electron transfer, but also promote flavin-like mediated indirect electron transfer. This work provides new insights into the application of electrospinning technology in MFCs and the preparation of anode materials on a large scale.

Multi-layered NiO nanowires linked with a nitrogen-doped carbon backbone grown directly on flexible carbon cloth (NiO/NCBN/CC) was successfully fabricated with a facile synthetic strategy. The NiO/NCBN/CC was further used as a binding-free electrode for flexible energy storage devices, showing a boosted performance including a high capacitance of 1039.4 F g−1 at 1 A g−1 and an 83.4% capacitance retention ratio. More importantly, after 1500 cycles, the capacitance retention can achieve 72.5% at a current density of 20 A g−1. The excellent electrochemical properties of the as-prepared NiO/NCBN/CC are not only attributed to the multi-layered structure that can help to tender unimpeded channels and accommodate the electrolyte ions around the electrode interface during the charge–discharge process, but is also due to the link between the NiO and N-doped carbon backbone and the nitrogen doping on the carbon substrate, which results in extra defects on the surface that could boost the interfacial electron transfer rate of the electrode.

FOXA1, as a pioneering transcription factor, has been shown to drive prostate cancer progression. Previous studies showed that FOXA1 expression in prostate cancer was positively associated with cancer angiolymphatic invasion and metastasis. However, the mechanism underlying the correlation between FOXA1 and prostate cancer angiolymphatic invasion and metastasis remains largely unclear. Herein, we set out to investigate the role of FOXA1 in the interactions between prostate cancer cells and endothelial cells. Endothelial cells' phenotypes were assessed through CCK‐8 assay, Transwell migration assay, and tube formation assay. The angiogenic factors acting on endothelial cells mediated by FOXA1were characterized by RNA-seq, qPCR array, angiogenesis cytokines array, and ELISA assay. The impact of FOXA1 on tumor angiogenesis was examined in a xenograft model in nude mice. The effect of FOXA1 on prostate cancer angiogenesis was validated on a primary prostate cancer tissue microarray. FOXA1 expression in prostate cancer cells promoted endothelial cell proliferation, migration, and tube formation in vitro. Mechanistically, FOXA1 increased pro-angiogenic factors production, including EGF, Endothelin-1, and Endoglin. Moreover, in vivo study showed that FOXA1 facilitated tumor angiogenesis. Furthermore, clinical samples investigation indicated that FOXA1 enhanced prostate cancer angiogenesis. Overall, these findings illustrated a tumor angiogenesis-promoting role of FOXA1 in prostate cancer.

Intratumoral hypoxia is associated with castration-resistant prostate cancer (CRPC), a lethal disease. FOXA1 is an epithelial transcription factor that is down-regulated in CRPC. We have previously reported that FOXA1 loss induces epithelial-mesenchymal transition (EMT) and cell motility through elevated TGFβ signaling. However, whether FOXA1 directly regulates hypoxia pathways of CRPC tumors has not been previously studied. Here we report that FOXA1 down-regulation induces hypoxia transcriptional programs, and FOXA1 level is negatively correlated with hypoxia markers in clinical prostate cancer (PCa) samples. Mechanistically, FOXA1 directly binds to an intragenic enhancer of HIF1A to inhibit its expression, and HIF1A, in turn, is critical in mediating FOXA1 loss-induced hypoxia gene expression. Further, we identify CCL2, a chemokine ligand that modulates tumor microenvironment and promotes cancer progression, as a crucial target of the FOXA1-HIF1A axis. We found that FOXA1 loss leads to immunosuppressive macrophage infiltration and increased cell invasion, dependent on HIF1A expression. Critically, therapeutic targeting of HIF1A-CCL2 using pharmacological inhibitors abolishes FOXA1 loss-induced macrophage infiltration and PCa cell invasion. In summary, our study reveals an essential role of FOXA1 in controlling the hypoxic tumor microenvironment and establishes the HIF1A-CCL2 axis as one mechanism of FOXA1 loss-induced CRPC progression.

Metastasis is one of the most significant independent risk factors that can negatively affect prostate cancer (PCa) patients. However, the exact mechanisms have not been fully elucidated. To illust...

To improve the diagnostic efficiency of prostate cancer (PCa) and reduce unnecessary biopsies, we defined and analyzed the diagnostic efficiency of peripheral zone prostate-specific antigen (PSA) density (PZ-PSAD). Patients who underwent systematic 12-core prostate biopsies in Shanghai General Hospital (Shanghai, China) between January 2012 and January 2018 were retrospectively identified (n = 529). Another group of patients with benign prostatic hyperplasia (n = 100) were randomly preselected to obtain the PSA density of the non-PCa cohort (N-PSAD). Prostate volumes and transition zone volumes were measured using multiparameter magnetic resonance imaging (mpMRI) and were combined with PSA and N-PSAD to obtain the PZ-PSAD from a specific algorithm. Receiver operating characteristic (ROC) curve analysis was used to assess the PCa detection efficiency in patients stratified by PSA level, and the area under the ROC curve (AUC) of PZ-PSAD was higher than that of PSA, PSA density (PSAD), and transition zone PSA density (TZ-PSAD). PZ-PSAD could amend the diagnosis for more than half of the patients with inaccurate transrectal ultrasonography (TRUS) and mpMRI results. When TRUS and mpMRI findings were ambiguous to predict PCa (PIRADS score ≤3), PZ-PSAD could increase the positive rate of biopsy from 21.7% to 54.7%, and help 63.8% (150/235) of patients avoid unnecessary prostate biopsy. In patients whose PSA was 4.0-10.0 ng ml-1, 10.1-20.0 ng ml-1, and >20.0 ng ml-1, the ideal PZ-PSAD cut-off value for predicting clinically significant PCa was 0.019 ng ml-2, 0.297 ng ml-2, and 1.180 ng ml-2, respectively (sensitivity >90%). Compared with PSA, PSAD, and TZ-PSAD, the efficiency of PZ-PSAD for predicting PCa is the highest, leading to fewer missed diagnoses and unnecessary biopsies.

Deposition of hyperphosphorylated and aggregated tau protein in the central nervous system is characteristic of Alzheimer disease and other tauopathies. Tau is subject to O-linked N-acetylglucosamine (O-GlcNAc) modification, and O-GlcNAcylation of tau has been shown to influence tau phosphorylation and aggregation. Inhibition of O-GlcNAcase (OGA), the enzyme that removes O-GlcNAc moieties, is a novel strategy to attenuate the formation of pathologic tau. Here we described the in vitro and in vivo pharmacological properties of a novel and selective OGA inhibitor, MK-8719. In vitro, this compound is a potent inhibitor of the human OGA enzyme with comparable activity against the corresponding enzymes from mouse, rat, and dog. In vivo, oral administration of MK-8719 elevates brain and peripheral blood mononuclear cell O-GlcNAc levels in a dose-dependent manner. In addition, positron emission tomography imaging studies demonstrate robust target engagement of MK-8719 in the brains of rats and rTg4510 mice. In the rTg4510 mouse model of human tauopathy, MK-8719 significantly increases brain O-GlcNAc levels and reduces pathologic tau. The reduction in tau pathology in rTg4510 mice is accompanied by attenuation of brain atrophy, including reduction of forebrain volume loss as revealed by volumetric magnetic resonance imaging analysis. These findings suggest that OGA inhibition may reduce tau pathology in tauopathies. However, since hundreds of O-GlcNAcylated proteins may be influenced by OGA inhibition, it will be critical to understand the physiologic and toxicological consequences of chronic O-GlcNAc elevation in vivo. SIGNIFICANCE STATEMENT: MK-8719 is a novel, selective, and potent O-linked N-acetylglucosamine (O-GlcNAc)-ase (OGA) inhibitor that inhibits OGA enzyme activity across multiple species with comparable in vitro potency. In vivo, MK-8719 elevates brain O-GlcNAc levels, reduces pathological tau, and ameliorates brain atrophy in the rTg4510 mouse model of tauopathy. These findings indicate that OGA inhibition may be a promising therapeutic strategy for the treatment of Alzheimer disease and other tauopathies.

In recent years, impedance-based methods have been widely used to analyze the stability of grid-connected converters. However, the impedance models in three-phase AC systems are 2 × 2 matrices and a strict stability analysis is based on the generalized Nyquist criterion, which involves eigenvalue computation. Hence many methods only study the diagonal elements of the impedance matrices, but the neglect of the non-diagonal elements may bring hidden dangers to the stability of the system. This letter proposes a stability criterion for grid-connected converters based on impedance models and Gershgorin's theorem. The effect of the non-diagonal elements is considered and the criterion is a strictly sufficient condition of stability, which is conservative but can guarantee the stability of the system.

Treatments for cognitive deficits associated with central nervous system (CNS) disorders such as Alzheimer disease and schizophrenia remain significant unmet medical needs that incur substantial pressure on the health care system. The α7 nicotinic acetylcholine receptor (nAChR) has garnered substantial attention as a target for cognitive deficits based on receptor localization, robust preclinical effects, genetics implicating its involvement in cognitive disorders, and encouraging, albeit mixed, clinical data with α7 nAChR orthosteric agonists. Importantly, previous orthosteric agonists at this receptor suffered from off-target activity, receptor desensitization, and an inverted U-shaped dose-effect curve in preclinical assays that limit their clinical utility. To overcome the challenges with orthosteric agonists, we have identified a novel selective α7 positive allosteric modulator (PAM), BNC375. This compound is selective over related receptors and potentiates acetylcholine-evoked α7 currents with only marginal effect on the receptor desensitization kinetics. In addition, BNC375 enhances long-term potentiation of electrically evoked synaptic responses in rat hippocampal slices and in vivo. Systemic administration of BNC375 reverses scopolamine-induced cognitive deficits in rat novel object recognition and rhesus monkey object retrieval detour (ORD) task over a wide range of exposures, showing no evidence of an inverted U-shaped dose-effect curve. The compound also improves performance in the ORD task in aged African green monkeys. Moreover, ex vivo 13C-NMR analysis indicates that BNC375 treatment can enhance neurotransmitter release in rat medial prefrontal cortex. These findings suggest that α7 nAChR PAMs have multiple advantages over orthosteric α7 nAChR agonists for the treatment of cognitive dysfunction associated with CNS diseases. SIGNIFICANCE STATEMENT: BNC375 is a novel and selective α7 nicotinic acetylcholine receptor (nAChR) positive allosteric modulator (PAM) that potentiates acetylcholine-evoked α7 currents in in vitro assays with little to no effect on the desensitization kinetics. In vivo, BNC375 demonstrated robust procognitive effects in multiple preclinical models across a wide exposure range. These results suggest that α7 nAChR PAMs have therapeutic potential in central nervous system diseases with cognitive impairments.

In recent years, sub-synchronous oscillations have occurred frequently. Torsional interactions may cause oscillations in turbo-generator rotor shafts and thus huge losses. Conventional studies focus on the damping of system oscillation modes, but little on the damping of components, which could aid in finding out the source of a poorly damped or undamped oscillation. This study aims at a quantitative evaluation method of the damping characteristics of each component in torsional interaction. The transient energy flow method successfully applied in component damping evaluation and source location of low-frequency and ultra-low-frequency oscillations is further developed for that of sub-synchronous oscillation. The transient energy flow method evaluates the damping of a component by its dissipation rate of transient energy. A method of computing the transient energy flow in sub-synchronous oscillation is proposed. It is found that the rate of energy flow is relevant to the difference between the super-synchronous and sub-synchronous powers. The relation between the transient energy dissipation and the damping of a component is validated by both mathematical deduction and simulation results. The transient energy flow method can evaluate component damping and therefore locate oscillation sources effectively in sub-synchronous oscillation.

Energy management and suitable sizing are regarded as major concerns at the time of designing integrated energy systems. Finding an efficient framework that combines sustainable design, reliable operation and lifetime cost at minimal level is essential for society, customers and investors. In this regard, a novel multi-objective optimization model for the design of integrated energy system with electric, thermal and cooling subsystem is established to simultaneously minimize the economic, technical and environmental objectives. It aims to obtain the optimal sizing of each component such as photovoltaic panels, wind turbine, battery energy storage system, combined cooling, heating and power generation system, heat storage tank, gas boiler and electric chiller considering system performance in economics, system autonomy and carbon emissions. A hybrid energy system in residential area is taken as a case study to demonstrate the application of the proposed method, the Pareto front of the multi-objective problem is obtained via NSGA-II method, and four design plans on the Pareto front selected by Topsis method are analyzed and discussed. Such analysis show that the optimum solution could effectively reduce both the economic and environmental impacts of the integrated energy system as well as improve the system autonomy towards main grid. And the comparison about the results illustrated the reliability of the optimization model in this paper. This study demonstrates the high capability of the proposed design optimization in supporting economic design, improving autonomic operation and reducing the carbon emissions, meanwhile meeting multiple loads.

This paper presents a two-stage optimization method for a coupled capacity planning and operation problem, cast within the economical operation of Regional Integrated Energy System. The first stage optimization of the proposed model represents a regional integrated energy system planner whose purpose is to minimize its energy and environmental cost, while the second stage is an operation problem whose primary role is to achieve the optimal operation scheme of the system. The regional integrated energy system planner pursues best interests by co-optimizing the capacity configuration and power output of individual energy supply module, while the regional integrated energy system maximizes the installed capacity of renewable energy sources and minimizes the environmental costs. To illustrate the advantage of the proposed method, the NSGA-II algorithm and the mixed integer linear programming method are implemented to solve the model based on simulation. Besides, application of the optimization method proposed to the energy infrastructure of a regional integrated energy system in China is discussed, and the results obtained through simulation are compared to the bi-level optimization objectives. The results show that the proposed method is economical and effective in practical application.

As an important ecosystem service, water supply is closely related to human well-being. Maintaining the balance of water supply and demand is essential in the sustainable development of a regional economy and society. Taking western Jilin, where the difference between water supply and demand is increasingly prominent, as the research object, from the perspective of land consolidation and precipitation changes, this paper analyzes the temporal and spatial changes of water resources supply and demand at the regional and county scales in western Jilin from 2000 to 2018 by the InVEST model and the water resource demand model. The results show that water production in western Jilin did not change significantly before and after land consolidation. The change in planting structure made water demand increase from 3.03 billion m3 to 4.96 billion m3, which reversed the relationship between supply and demand. The impact of precipitation changes on water production is extremely significant. The annual production of water in wet years is 8.05 billion m3, and the annual water production in dry years is 1.08 billion m3. The amount of precipitation can directly change the relationship between the supply and demand of local water resources. The evolution of the water resources supply and demand pattern in western Jilin is the result of the combined effect of land consolidation and precipitation changes. Precipitation mainly affects supply, while land consolidation mainly affects demand.

Background: Until recently, most enucleation techniques of the prostate were performed with the application of morcellator. We introduce a modified enucleation technique of thulium laser with non-morcellator approach, which is about incising and vaporizing remaining prostate tissue instead of a morcellator.Methods: A retrospective evaluation of 223 patients undergoing ThuLEP from January 2014 to December 2015 was performed in our institution. One hundred five of the patients used morcellator while the other 118 used non-morcellator approach. All patients were assessed with the International Prostate Symptom Score (IPSS), quality of life (Qol), ultrasonography, serum prostate-specific antigen (PSA), maximal urine flow rate (Qmax), and postvoid residual urine volume (PVR). We reassessed these parameters at 1-, 3-, 6-, and 12-months after operation. Operative time, perioperative, and postoperative complications were also recorded.Results: Significant improvement was noted in the IPSS, QoL, Qmax, and PVR in both groups at the 12-month follow-up, and assessment showed no differences in these parameters between the two groups. Comparisons of the total operation time and enucleation time demonstrated no significant differences between the two groups. Our non-morcellator approach needed more time to incise and vaporize the enucleated tissue compared to morcellation when the prostate volume was about 40–80 ml (p < 0.05), while it showed a significant lower rate of superficial bladder injury than using morcellator (p < 0.05). There were no significant differences in other complications between the two groups (p > 0.05).Conclusions: Our modified technique is a safe and effective procedure for the treatment of BPH avoiding the potential complications caused by morcellator.

Metastasis is one of the most significant independent risk factors that can negatively affect prostate cancer (PCa) patients. However, the exact mechanisms have not been fully elucidated. To illustrate the mechanisms underlying PCa metastasis, we conducted a series of integrated bioinformatics analyses. The essential genes involved in PCa metastasis were obtained by analyzing differentially expressed genes (DEGs) between metastatic PCa and localized PCa. Gene Ontology and KEGG pathway enrichment analysis were performed for functional annotation. Protein-protein interaction networks were constructed for hub gene selection. Three transcription factor genes (FOS, CENPA, and FOXM1) were identified by integrating the hub genes with human transcription factors from The Human Transcription Factors database. Moreover, expression validation and prognostic analysis of the three transcription factor genes were carried out on GEO, TCGA, GEPIA, and the Human Protein Atlas, respectively. Further verification showed that expression variation of the three transcription factor genes existed between metastatic PCa and localized PCa as well as between localized PCa and normal prostate. In addition, different expressions of the three transcription factor genes were associated with the prognosis of localized PCa. In summary, the three transcription factor genes can serve as potential prognostic biomarkers as well as therapeutic targets for PCa.

The α7 nicotinic acetylcholine receptor (nAChR) is a promising target for the treatment of cognitive deficits associated with psychiatric and neurological disorders, including schizophrenia and Alzheimer's disease (AD). Several α7 nAChR agonists and positive allosteric modulators (PAMs) have demonstrated procognitive effects in preclinical models and early clinical trials. However, despite intense research efforts in the pharmaceutical industry and academia, none of the α7 nAChR ligands has been approved for clinical use. This chapter will focus on the α7 nAChR ligands that have advanced to clinical studies and explore the reasons why these agents have not met with unequivocal clinical success.

Deposition of hyperphosphorylated and aggregated tau protein in the central nervous system is characteristic of Alzheimer disease and other tauopathies. Tau is subject to

Integrating electric heater (EH) and heat storage (HS) into power systems is a feasible solution to reduce wind power curtailment. However, most researches consider the capacities optimization without their distribution. Based on a practical power grid with eight buses, utilizing the DC power flow model together with the capacity and operation constraints of EH, HS and other power units gives the mathematic model of the integrated energy system. On this basis, applying the economic benefit as the optimization objective gives the optimal capacities and distribution of EH and HS to satisfy certain proportion of heat load. Besides, the concept of “generalized energy storage” is put forward to provide an explanation of the regulating ability of power generation and consumption of a region. The results show that the economic benefit in the optimal case with the optimal distribution of EH and HS is 44.65% higher compared to the case that maintains the same power transmitted after installing EH and HS, and 1.76% higher than that in the case that allocates the electric heaters equally. Besides, the influence of the coal price is nearly twice of the HS price, and 4 times of the EH price on economic benefit.

To compare the safety and efficacy of thulium laser enucleation of the prostate (ThuLEP) versus thulium laser resection of the prostate (TmLRP) in small prostates (≤ 30 g) and to test the validity of ThuLEP for bladder neck contracture (BNC). A total of 115 patients with benign prostatic hyperplasia (BPH) (prostate size ≤ 30 g) were randomly assigned to ThuLEP (n = 56) or TmLRP (n = 59). All patients were evaluated preoperatively and at 1, 3, 6, and 12 months after surgery. Baseline characteristics of the patients, perioperative data, postoperative outcomes and complications were assessed. Comparisons of the baseline and perioperative data demonstrated no significant differences between the ThuLEP and TmLRP groups. Significant improvement was noted in the International Prostate Symptom Score, quality of life, maximal urinary flow rate (Qmax) and post-void residual volume (PVR) in both groups at the 12-month follow-up, and assessment showed no differences in these parameters between the two groups. The TmLRP group showed a significantly higher rate (13.6%) of BNC than the ThuLEP group (1.8%; P = 0.045). There were no significant differences in other complications between the two groups (P > 0.05). ThuLEP and TmLRP are both safe and efficient procedures for the treatment of patients with small prostate volume, while ThuLEP can significantly reduce the risk of BNC in patients with a small prostate because the procedure enucleates adenomas without thermal damage to the bladder neck.

Due to the nature of fluctuation and intermittence, integration of renewable energy sources (RESs) requests more flexibility of power systems. However, the “heat-led” operation mode limits the adjustability of combined heat and power (CHP) plants, and reduce the accommodation of RESs. This paper studies an integrated thermal and power system and introduces a phase-change heat storage (HS) facility into the CHP plant to improve the adjustability, where the heat released from the extraction steam is not consistent to the heat load at each moment. Furthermore, the heat transfer processes in the HS facility are modelled as a thermal resistance network, which provides the feasibility for analyzing the integrated system in a unified model. On this basis, the operation plan of the integrated system is optimized by the linear programming (LP) method to minimize the wind energy loss. The results show that: 1) HS facility installation increases the flexibility of power system, and reduces the wind energy loss from 18.7% to 11.2%. 2) Heat transfer processes should be carefully taken into account for precisely setting the power generations of each plant. 3) The phase-change temperatures of HS materials should be between 90 °C and 100 °C for the maximum wind power accommodation.