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Abstract The impact of interbasin linkage on the weather/climate and ecosystems is significantly broader and profounder than that of only appearing in an individual basin. Here, we reveal that a decadal linkage of sea surface temperature (SST) has emerged between western Australian coast and western–central tropical Pacific since 1985, associated with continuous intensification of decadal variabilities (8–16 years). The rapid SST changes in both tropical Indian Ocean and Indo-Pacific warm pool in association to greenhouse gases and volcanoes are emerging factors resulting in enhanced decadal co-variabilities between these two regions since 1985. These SST changes induce enhanced convection variability over the Maritime Continent, leading to stronger easterlies in the western–central tropical Pacific during the warm phase off western Australian coast. The above changes bring about cooling in the western–central tropical Pacific and strengthened Leeuwin Current and anomalous cyclonic wind off western Australian coast, and ultimately resulting in enhanced coupling between these two regions. Our results suggest that enhanced decadal interbasin connections can offer further understanding of decadal changes under future warmer conditions.

Electrocatalytic treatment of chemical saline wastewater showed great technical advantages due to its characteristics of simple operation, high catalytic efficiency and little secondary pollution. The review takes the classification and composition of titanium-based anodes as the starting point. Typical studies of wastewater treatment by electrocatalytic technology based on free radicals and non-free radicals were also discussed. Combined with the previous researches about electrocatalytic mechanisms in recent years, the mechanisms of titanium-based anodes were analyzed in terms of ·OH, active chlorine and others. The studies on titanium-based anodes in chemical wastewater containing different salt concentrations, such as dye wastewater, coal chemical wastewater, landfill leachate wastewater, fertilizer and pesticide production wastewater, etc., were thoroughly examined. According to the amount of electricity required for the removal of organic matter per unit, the energy consumption of titanium-based anodes for wastewater treatment by electrochemistry was described. The review would provide theoretical basis and technical support for electrocatalytic treatment of chemical saline wastewater.

Abstract Existing studies have shown changes in the impact of atmospheric teleconnections on Indian Summer Monsoon (ISM) at interannual time scales due to the changing background state. However, the exploration of potential changes at subseasonal time scales remains limited. In this study, we use a causal discovery method to find the tropical atmospheric drivers of ISM subseasonal anomalies, and quantify the causal effects of the drivers on ISM, as well as the changes in causal effects over the past 40 years. We find the impact of tropical western Pacific on ISM subseasonal anomalies has strengthened, while the ISM self‐feedback has weakened. Wavenumber‐frequency analysis shows that the Rossby wave energy over 15°N–30°N at periods of 10–20 days has increased over the past four decades, which offers a plausible explanation for the enhanced tropical atmospheric teleconnection between western Pacific and ISM at subseasonal time scales.

BackgroundAs lung squamous cell carcinoma (LUSC) patients are at increased risk of developing a second primary cancer, this complicates the patient’s condition and thus makes prognostic assessment more difficult, posing a significant prognostic challenge for clinicians. Our goal was to assess the prognosis of LUSC patients with a second primary tumor, and provide insights into appropriate therapy and monitoring strategies.MethodsData was obtained for LUSC patients from the Surveillance, Epidemiology, and End Results (SEER) database. The LUSC patients were divided into three groups (LS-SPM, OT-LUSC and LUSC-only). Univariate and stratified analyses were performed for the baseline and clinical characteristics of the participants. Multiple regression and Kaplan-Meier survival analyses were also performed, followed by a final life table analysis.ResultsIn our sample of 101,626 patients, the HR for OS in the LS-SPM group was 0.40 in univariate analysis. Kaplan-Meier survival curves showed that LS-SPM patients had considerably longer lifespans compared to the other groups. The LS-SPM patients had median and mean survival times of 64 months and 89.11 months. Unadjusted and adjusted multiple regression analyses showed that LS-SPM patients had a superior survival compared to LUSC-only and OT-LUSC groups.ConclusionLS-SPM patients have a good prognosis with aggressive therapy and immune monitoring. The present study offers novel insights into the pathophysiological causes and treatments for LS-SPM.

Abstract Modes of climate variability can affect weather extremes, posing intractable challenges to our environment. However, to what extent climate modes can modulate heatwaves in China under a warming background remains poorly understood. Here, we examine the changes in heatwave intensity in seven distinct regions: three East, two middle, and two west regions over China and systematically explore the impacts of climate modes, by analyzing observations and performing model experiments using a Bayesian dynamic linear model and an atmospheric general circulation model (AGCM). Abrupt increases in heatwave intensity are detected across China during a transition period of 1993–2000, and the intensification remains robust in northern and western China after the warming trend being removed. The combined impacts of the El Niño–Southern Oscillation (ENSO), Atlantic Multidecadal Oscillation (AMO), and Indian Ocean Dipole (IOD) explain 62.35–70.01% of the observed heatwave intensification in East I, Middle I, West I, and West II regions. Decadal changes of atmospheric circulations associated with the negative phase transition of the Interdecadal Pacific Oscillation (IPO), which is highly correlated with the decadal variability of ENSO, combined with the positive phase transition of the AMO around the mid-1990s increase surface air temperature and enhance atmospheric internal variability and climate modes’ impacts, resulting in the abrupt increase of heatwaves in the past two decades. These results highlight the importance of the concurrent phase transitions of decadal climate modes in regulating heatwaves.

Abstract The Atlantic meridional overturning circulation is an important global-scale oceanic circulation, and its changes may be responsible for past abrupt climate change events. By using two versions of a coupled climate model, here we show that the stability of this circulation depends not only on the background climate, but also on the type of primary external forcing: freshwater vs. greenhouse gases. When freshwater forcing is dominant, hysteresis of this circulation (an abrupt collapse/reactivation) becomes possible only under simulated glacial conditions with closed Bering Strait. Under present day and future conditions, both freshwater and greenhouse gas forcings could collapse this circulation, but only greenhouse gas forcing produced a bi-stable equilibrium state comparable to abrupt climate change. Our results demonstrate that the Bering Strait status (open vs. closed) may facilitate or prohibit the existence of this circulation’s hysteresis, irrespective of the background climate conditions, but is directly related to the primary forcing.

Background: Human epidermal growth factor receptor 2 (HER2) overexpression is related to anti-HER2 therapy in many tumors. RC48- antibody-drug conjugate (ADC) has shown promising efficacy in patients with HER2-positive locally advanced or metastatic urothelial carcinoma (UC). The characteristic expression and scoring systems of HER2 are nonexistent in UC. We aimed to explore HER2 status and its correlation with the efficacy of HER2-targeting ADC therapy in UC. Methods: A total of 137 and 43 patients were enrolled in cohort 1 and cohort 2, respectively, from March 2009 to December 2018. The patients in cohort 2 were enrolled in a phase II study of RC48-ADC. UC samples were tested for HER2 status using immunohistochemistry (IHC) and/or fluorescence in situ hybridization (FISH). The 2018 ASCO/CAP HER2 scoring system was adopted and modified to score HER2 expression in UC. Results: The HER2-positive (IHC 2+ or 3+) rate was 24.1% (33/137). In HER2 IHC 2+ or 3+ patients, the HER2 gene amplification rate was 31% (13/42). The objective response rates (ORRs) in RC48-ADC-treated patients with IHC 3+, IHC 2+ and FISH+, IHC 2+ and FISH- were 58.8%, 66.7% and 40%, respectively. The ORR showed a trend toward a better benefit for RC48-ADC therapy in patients with HER2 amplification than in those without amplification (61.5% vs. 44.8%, P = 0.059). The heterogeneity of HER2 expression in the primary tumor was 55.5% (15/27), and the ORR was not significantly different between patients with tumor heterogeneity and homogeneity. Conclusions: IHC testing should be performed to assess the HER2 status before the initiation of HER2-ADC therapy. There was a trend toward a better benefit for patients with HER2 amplification, and tumor heterogeneity did not influence the drug efficacy.

Abstract. Background:. LY01005 (Goserelin acetate sustained-release microsphere injection) is a modified gonadotropin-releasing hormone (GnRH) agonist injected monthly. This phase III trial study aimed to evaluated the efficacy and safety of LY01005 in Chinese patients with prostate cancer. Methods:. We conducted a randomized controlled, open-label, non-inferiority trial across 49 sites in China. This study included 290 patients with prostate cancer who received either LY01005 or goserelin implants every 28 days for three injections. The primary efficacy endpoints were the percentage of patients with testosterone suppression ≤50 ng/dL at day 29 and the cumulative probability of testosterone ≤50 ng/dL from day 29 to 85. Non-inferiority was prespecified at a margin of -10%. Secondary endpoints included significant castration (≤20 ng/dL), testosterone surge within 72 h following repeated dosing, and changes in luteinizing hormone, follicle-stimulating hormone, and prostate specific antigen levels. Results:. On day 29, in the LY01005 and goserelin implant groups, testosterone concentrations fell below medical-castration levels in 99.3% (142/143) and 100% (140/140) of patients, respectively, with a difference of -0.7% (95% confidence interval [CI], -3.9% to 2.0%) between the two groups. The cumulative probabilities of maintaining castration from days 29 to 85 were 99.3% and 97.8%, respectively, with a between-group difference of 1.5% (95% CI, -1.3% to 4.4%). Both results met the criterion for non-inferiority. Secondary endpoints were similar between groups. Both treatments were well-tolerated. LY01005 was associated with fewer injection-site reactions than the goserelin implant (0% vs. 1.4% [2/145]). Conclusion:. LY01005 is as effective as goserelin implants in reducing testosterone to castration levels, with a similar safety profile. Trial registration:. ClinicalTrials.gov, NCT04563936.

Abstract The nonstationary roles of regional forcings from alongshore wind stress and sea level pressure (SLP) in driving low‐frequency (interannual‐to‐decadal) sea level variability along the U.S. east coast for the 1959–2020 period are investigated. The role of regional forcings increases with time north of Cape Hatteras particularly during summer when their contributions to the variance of observed summertime coastal sea level anomalies increase by approximately 58%–87% from 1959–1989 to 1990–2020. The enhanced impact of regional forcings in recent decades results from an increase in the Inverted Barometer (IB) effect that act constructively with alongshore wind stress especially during summer, and to a lesser extent for the Gulf of Maine during fall. The summertime North Atlantic Oscillation (NAO) is largely responsible for the increased IB effect, owing to the stronger NAO‐associated low SLP anomalies centered around the Mid‐Atlantic Bight in recent decades compared to earlier decades.

Abstract Background Dual inhibition of PD-1/PD-L1 and TGF-β pathways is a rational therapeutic strategy for malignancies. SHR-1701 is a new bifunctional fusion protein composed of a monoclonal antibody against PD-L1 fused with the extracellular domain of TGF-β receptor II. This first-in-human trial aimed to assess SHR-1701 in pretreated advanced solid tumors and find the population who could benefit from SHR-1701. Methods This was a dose-escalation, dose-expansion, and clinical-expansion phase 1 study. Dose escalation was initiated by accelerated titration (1 mg/kg q3w; intravenous infusion) and then switched to a 3+3 scheme (3, 10, 20, and 30 mg/kg q3w and 30 mg/kg q2w), followed by dose expansion at 10, 20, and 30 mg/kg q3w and 30 mg/kg q2w. The primary endpoints of the dose-escalation and dose-expansion parts were the maximum tolerated dose and recommended phase 2 dose. In the clinical-expansion part, selected tumors were enrolled to receive SHR-1701 at the recommended dose, with a primary endpoint of confirmed objective response rate (ORR). Results In total, 171 patients were enrolled (dose-escalation: n=17; dose-expansion, n=33; clinical-expansion, n=121). In the dose-escalation part, no dose-limiting toxicity was observed, and the maximum tolerated dose was not reached. SHR-1701 showed a linear dose-exposure relationship and the highest ORR at 30 mg/kg every 3 weeks, without obviously aggravated toxicities across doses in the dose-escalation and dose-expansion parts. Combined, 30 mg/kg every 3 weeks was determined as the recommended phase 2 dose. In the clinical-expansion part, SHR-1701 showed the most favorable efficacy in the gastric cancer cohort, with an ORR of 20.0% (7/35; 95% CI, 8.4–36.9) and a 12-month overall survival rate of 54.5% (95% CI, 29.5–73.9). Grade ≥3 treatment-related adverse events occurred in 37 of 171 patients (22%), mainly including increased gamma-glutamyltransferase (4%), increased aspartate aminotransferase (3%), anemia (3%), hyponatremia (3%), and rash (2%). Generally, patients with PD-L1 CPS ≥1 or pSMAD2 histochemical score ≥235 had numerically higher ORR. Conclusions SHR-1701 showed an acceptable safety profile and encouraging antitumor activity in pretreated advanced solid tumors, especially in gastric cancer, establishing the foundation for further exploration. Trial registration ClinicalTrials.gov , NCT03710265

Increased extreme high sea level events and concurrence of marine heatwaves are observed along the Indian Ocean coast of Indonesia in the past decade due to the combined impact of anthropogenic warming and natural decadal climate variability.

A previous study demonstrated that atmospheric rivers (ARs) generate substantial air-sea fluxes in the northeast Pacific. Since the southeast Indian Ocean is one of the active regions of ARs, similar air-sea fluxes could be produced. However, the spatial pattern of sea surface temperature (SST) in the southeast Indian Ocean, especially along the west coast of Australia, is different from that in the northeast Pacific because of the poleward flowing Leeuwin Current, which may cause different air-sea fluxes. This study investigates AR-associated air-sea fluxes in the southeast Indian Ocean and their relation with SST variability. The large-scale spatial pattern of latent heat flux (evaporation) associated with ARs in the southeast Indian Ocean is similar to that in the northeast Pacific. A significant difference is however found near the coastal area where relatively warm SSTs are maintained in all seasons. While AR-induced latent heat flux is close to zero around the west coast of North America where the equatorward flowing coastal current and upwelling generate relatively cold SSTs, a significant latent heat flux induced by ARs is evident along the west coast of Australia due to the relatively warm surface waters. Temporal variations of coastal air-sea fluxes associated with landfalling ARs are investigated based on the composite analysis. While the moisture advection reduces the latent heat during landfalling, the reduction of air humidity with strong winds enhances large evaporative cooling (latent heat flux) after a few days of the landfalling. A significant SST cooling along the coast is found due to the enhanced latent heat flux.

Abstract The tropical Southeast Indian Ocean (SEIO) is a key area linking the global freshwater and heat exchanges. The Indian Ocean Dipole (IOD) fundamentally modulates the Indian Ocean circulation and thus regulates the basin‐wide freshwater balance. However, our knowledge of this effect remains limited. Using observational‐based data sets, this study suggests that extreme positive IOD events have notable signatures on the three‐dimensional freshwater content of the SEIO, leading to the vertically opposite salinity anomalies in the surface and subsurface layers. The wind changes led to the northwestward extension of the South Equatorial Current and intensified Sumatra‐Java upwelling. The changing horizontal and vertical currents jointly result in the complicated salinity anomalies. The Equatorial Undercurrent serves as the conduit for water exchange between the equator and the SEIO. This work highlights a strong coupling between the equatorial circulation and the three‐dimensional freshwater inventory of the SEIO within the framework of the IOD.

Abstract Despite the well‐recognized initial value nature of the subseasonal forecasts, the role of subsurface ocean initialization in subseasonal forecasts remains underexplored. Using observing system experiments, this study investigates the impact of ocean in situ data assimilation on the propagation of Madden–Julian Oscillation (MJO) events across the Maritime Continent in the European Centre for Medium‐Range Weather Forecasts (ECMWF) subseasonal forecast system. Two sets of twin experiments are analyzed, which only differ on the use or not of in situ ocean observations in the initial conditions. Besides using the Real‐time Multivariate MJO Index (RMMI) to evaluate the forecast performance, we also develop a new MJO tracking method based on outgoing longwave radiation anomalies (OLRa) for forecast evaluation. We find that the ocean initialization with in situ data assimilation, though having an impact on the forecasted ocean mean state, does not improve the relatively low MJO forecast skill across the Maritime Continent. Moist static energy budget analysis further suggests that a significant underestimation in the meridional moisture advection in the model forecast may hinder the potential role played by the ocean state differences associated with data assimilation. Bias of the intraseasonal meridional winds in the model is a more important factor for such underestimation than the mean state moisture biases. This finding suggests that atmospheric model biases dominate the forecast error growth, and the atmospheric circulation bias is one of the major sources of the MJO prediction error and should be a target for improving the ECMWF subseasonal forecast model.

Abstract Background Antagonizing the androgen-receptor (AR) pathway is an effective treatment strategy for patients with metastatic castration-resistant prostate cancer (CRPC). Here, we report the results of a first-in-human phase 1/2 study which assessed the safety, pharmacokinetics, and activity of SHR3680 (a novel AR antagonist) in patients with metastatic CRPC. Methods This phase 1/2 study enrolled patients with progressive metastatic CRPC who had not been previously treated with novel AR-targeted agents. In the phase 1 dose-escalation portion, patients received oral SHR3680 at a starting daily dose of 40 mg, which was subsequently escalated to 80 mg, 160 mg, 240 mg, 360 mg, and 480 mg per day. In phase 2 dose-expansion portion, patients were randomized to receive daily dose of 80 mg, 160 mg, or 240 mg of SHR3680. The primary endpoint in phase 1 was safety and tolerability and in phase 2 was the proportion of patients with a prostate-specific antigen (PSA) response (≥ 50% decrease of PSA level) at week 12. Results A total of 197 eligible patients were enrolled and received SHR3680 treatment, including 18 patients in phase 1 and 179 patients in phase 2. No dose-limiting toxicities were reported and the maximum tolerated dose was not reached. Treatment-related adverse events (TRAEs) occurred in 116 (58.9%) patients, with the most common one being proteinuria (13.7%). TRAEs of grade ≥ 3 occurred in only 23 (11.7%) patients, and no treatment-related deaths occurred. Antitumor activities were evident at all doses, including PSA response at week 12 in 134 (68.0%; 95% CI, 61.0–74.5) patients, stabilized bone disease at week 12 in 174 (88.3%; 95% CI, 87.2–95.5) patients, and responses in soft tissue lesions in 21 (34.4%, 95% CI, 22.7–47.7) of 61 patients. Conclusion SHR3680 was well tolerated and safe, with promising anti-tumor activity across all doses tested in patients with metastatic CRPC. The dose of 240 mg daily was recommended for further phase 3 study. Trial registration Clinical trials.gov NCT02691975; registered February 25, 2016.

The Atlantic Niño is an important mode of tropical Atlantic variability that influences the climate conditions in surrounding areas. Here, the authors use observational data and model simulations to show that positive phases of the Indian Ocean Dipole can trigger Atlantic Niño events.

Background Dual blockade of immune checkpoint and angiogenesis is an effective strategy for multiple cancers. Camrelizumab is a monoclonal antibody against PD-1, and famitinib is a multitargeted receptor tyrosine kinase inhibitor with antiangiogenesis and antiproliferation activities against tumor cells. We conducted an open-label, multicenter phase 2 basket study of camrelizumab and famitinib in eight cohorts of genitourinary or gynecological cancers. Here, findings in cohort of advanced or metastatic urothelial carcinoma with platinum-progressive disease (cohort 2) are presented.Methods Patients who had progressed after platinum-based chemotherapy for advanced or metastatic disease or had progressed within 12 months after completion of platinum-based (neo)adjuvant therapy were given camrelizumab (200 mg intravenously every 3 weeks) plus famitinib (20 mg orally once daily). Primary endpoint was objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1.Results Totally, 36 patients were recruited. With a median duration from enrollment to data cut-off of 11.9 months (range 6.1–28.5), ORR was 30.6% (95% CI 16.3% to 48.1%). Median duration of response (DoR) was 6.3 months (95% CI 2.1 to not reached). Median progression-free survival (PFS) was 4.1 months (95% CI 2.2 to 8.2), and median overall survival (OS) was 12.9 months (95% CI 8.8 to not reached). Patients with bladder cancer (n=18) had numerically better outcomes, with an ORR of 38.9% (95% CI 17.3% to 64.3%) and a median PFS of 8.3 months (95% CI 4.1 to not reached). Median DoR and OS in this subpopulation had not been reached with lower limit of 95% CI of 4.2 months for DoR and 11.3 months for OS, respectively. Of 36 patients, 22 (61.1%) had grade 3 or 4 treatment-related adverse events, mainly decreased platelet count and hypertension.Conclusions Camrelizumab plus famitinib showed potent antitumor activity in advanced or metastatic urothelial carcinoma patients after platinum-based chemotherapy. Patients with bladder cancer seemed to have better response to this combination.Trial registration number NCT03827837.

Objective: Accumulated evidence demonstrates that ageing is a robust risk factor of prostate cancer prognosis. Herein, we conducted a systematic analysis about ageing-relevant molecules and relevant tumor microenvironment features in prostate cancer.Methods: Transcriptome data, clinical information, and mutational data of prostate cancer patients were retrospectively collected from the Cancer Genome Atlas cohort. In accordance with the expression of specific ageing-relevant genes, prostate cancer patients were clustered with consensus clustering analyses. WGCNA was adopted for determination of subtype-associated co-expression modules and genes. Thereafter, characteristic genes were further screened with random forest algorithm and a prognostic model was conducted with multivariate cox regression analyses. Tumor microenvironment-infiltrating immune cells were estimated with ssGSEA and ESTIMATE. Activities of the cancer immunity cycle and expressions of HLA and immune checkpoint molecules were then quantified across prostate cancer cases. A serious experiment was conducted to investigate the roles of EIF2S2 in prostate tumorigenesis.Results: This study characterized three ageing-relevant subtypes (C1, C2, and C3) with diverse clinical prognosis. Subtype C1 presented the features of low mutational frequency and immune activation; C2 was characterized by stromal and immune activation; and C3 showed immune suppression. An ageing-derived gene signature was conducted, which independently and robustly predicted patients’ prognosis. Additionally, this signature was in relation to immune inactivation. Among the genes in the signature, EIF2S2 triggered proliferation, invasion, and migration of LNCaP and PC-3 cells.Conclusion: Collectively, ageing-relevant molecular subtypes and gene signature might be of great significance to determine clinical outcomes and tumor microenvironment features and immunotherapeutic responses in prostate cancer.

Objective: To establish non-inferiority of gonadotropin-releasing hormone degarelix compared with goserelin in suppressing and maintaining castrate testosterone levels from Day 28 to Day 364 in Chinese patients with prostate cancer. Methods: This is an open-label, multi-centre study in which men aged ≥18 years were randomised in a 1:1 ratio to once-a-month subcutaneous injection of either degarelix (240/80 mg) or goserelin (3.6 mg) for 12 months. The primary endpoint was difference in 1-year cumulative probability of suppressing testosterone to ≤0.5 ng/mL. Non-inferiority was to be established if the lower 95% confidence interval (CI) limit for difference in cumulative probability between the treatment arms was greater than −10%. Secondary endpoints included cumulative probability of prostate-specific-antigen-progression-free-survival (PSA-PFS). Safety was also assessed. Results: Baseline demographics and disease characteristics were similar between degarelix (n=142) and goserelin (n=141) treatment arms. The difference in cumulative probability of maintaining castrate levels from Day 28–364 was 3.6% (95% CI:−1.5%, 8.7%), demonstrating non-inferiority of degarelix. The cumulative probability of PSA-PFS at Day 364 was higher for degarelix (82.3%, 95% CI: 74.7%, 87.7%) versus goserelin (71.7%, 95% CI: 63.2%, 78.5%, p=0.038). Adverse events (AEs) were similar between treatment arms, except for more injection site reactions with degarelix versus goserelin. Four (2.8%) and nine (6.4%) patients discontinued due to AEs in degarelix and goserelin groups, respectively. Conclusion: Degarelix was non-inferior to goserelin in achieving and maintaining testosterone suppression at castrate levels during 1-year treatment. PSA-PFS was significantly higher with degarelix, suggesting improved disease control. Both treatments were well tolerated.

Clear cell renal cell carcinoma (ccRCC) was a common cancer type diagnosed with frequent metastases, harboring an unfavorable therapeutic response, and results in a poor prognosis. More promising therapeutic targets are urgently required for treating ccRCC. This study was conducted to explore the role of oxidative phosphorylation in ccRCC development and reveal its clinical potential. We first identified oxidative phosphorylation-related clusters based on consensus clustering and validated their diversity in the genome instability, environmental infiltration, and immunosuppression by Gistic, ESTIMATE, GSVA, and TIDE web tools. We also compared their prognostic and clinical feature differences and predicted the IC50 level between the clusters using pRRophetic. Subsequently, we performed weighted gene coexpression network analysis to select cluster-related genes and performed functional analysis for them. The cluster-related genes were adopted to construct a risk score and nomogram for predicting patient prognosis with predictive accuracy evaluated. Finally, we performed lentivirus to induce ccRCC cell PTPRG overexpression and conducted western blot experiments to detect the critical protein expression of oxidative phosphorylation, apoptosis, cell cycle, and epithelial-mesenchymal transition processes. Also, the cell cycle and apoptosis level were evaluated by flow cytometry. As a result, we discovered that both the C1 cluster and high-risk group predicted patient survival with high accuracy and characterized lower survival rates, lower oxidative phosphorylation levels, higher immune infiltration, and malignant clinical features. Besides, we observed that overexpression of PTPRG activated oxidative phosphorylation and inhibited apoptosis. Its overexpression also depressed the epithelial-mesenchymal transition and promoted G1/S cell cycle arrest. Comprehensively, we confirmed the anticancer role of oxidative phosphorylation in ccRCC cells and discovered its association with immune and immunosuppression. PTPRG was also identified as a potential therapeutic target due to its multiple anticancer effects. We believe this study discovered a novel mechanism of ccRCC pathological progression and will provide promising targets for therapeutic strategy development.

Membrane fouling and regeneration are the key issues for the application of membrane separation (MS) technology. Reactive electrochemical membranes (REMs) exhibited high, stable permeate flux and the function of chemical-free electrochemical regeneration. This study fabricated a micro-filtration REM characterized by a PbO2 layer (PbO2-REM) to investigate the electro-triggered anti-fouling and regeneration progress within REMs. The PbO2-REM exhibited a three-dimensional porous structure with a few branch-like micro-pores. The PbO2-REM could alleviate Humic acid (HA) and Bisphenol A (BPA) fouling through electrochemical degradation combined with bubble migration, which achieved the best anti-fouling performance at current density of 4 mA cm−2 with 99.2% BPA removal. Regeneration in the electro-backwash (e-BW) mode was found as eight times that in the forward wash and full flux recovery was achieved at a current density of 3 mA cm−2. EIS and simulation study also confirmed complete regeneration by e-BW, which was ascribed to the air–water wash formed by bubble migration and flow. Repeated regeneration tests showed that PbO2-REM was stable for more than five cycles, indicating its high durability for practical uses. Mechanism analysis assisted by finite element simulation illustrated that the high catalytic PbO2 layer plays an important role in antifouling and regeneration.

BackgroundActivity-dependent neuroprotective protein (ADNP), which is involved in embryonic development and neurogenesis, has been proven to be upregulated in some human tumors. However, its role in bladder cancer (BC) has never been studied.ObjectiveWe aimed to investigate the mechanisms by which ADNP promotes the progression of BC.MethodsADNP expressions in BC cell lines and paired BC and adjacent normal tissues were measured by quantitative real-time PCR (qRT-PCR), Western blot, and immunohistochemistry. Colony formation, Cell Counting Kit-8 (CCK-8), trypan blue exclusion assay, flow cytometry, and nude mice tumorigenesis assay were performed to explore the effects of ADNP on growth of BC in vivo and in vitro. The impacts of ADNP on AKT signaling pathways were measured by Western blot.ResultsThe expression of ADNP mRNA and protein was significantly upregulated in BC tissues compared with adjacent normal tissues. Immunohistochemical analysis of 221 BC and 51 adjacent normal tissue paraffin sections indicated that ADNP expression was significantly associated with histological classification and pathological T and N stages. Survival analysis revealed that patients with high ADNP expression have worse prognosis with respect to overall survival and progression-free disease. ADNP knockdown markedly delayed propagation of BC in vitro and the development of BC in vivo. ADNP overexpression showed the opposite effect. In addition, ADNP can markedly promote G1-S cell cycle transition in BC cells. On the molecular level, we confirmed that ADNP mediated acceleration of G1-S transition was associated with activation of the AKT pathways in BC.ConclusionADNP is overexpressed in BC and promotes BC growth partly through AKT pathways. ADNP is crucial in predicting the outcome of BC patients and may be a potential therapeutic target in BC.

A major challenge for managing impacts and implementing effective mitigation measures and adaptation strategies for coastal zones affected by future sea level (SL) rise is our limited capacity to predict SL change at the coast on relevant spatial and temporal scales. Predicting coastal SL requires the ability to monitor and simulate a multitude of physical processes affecting SL, from local effects of wind waves and river runoff to remote influences of the large-scale ocean circulation on the coast. Here we assess our current understanding of the causes of coastal SL variability on monthly to multi-decadal timescales, including geodetic, oceanographic and atmospheric aspects of the problem, and review available observing systems informing on coastal SL. We also review the ability of existing models and data assimilation systems to estimate coastal SL variations and of atmosphere-ocean global coupled models and related regional downscaling efforts to project future SL changes. We discuss (1) observational gaps and uncertainties, and priorities for the development of an optimal and integrated coastal SL observing system, (2) strategies for advancing model capabilities in forecasting short-term processes and projecting long-term changes affecting coastal SL, and (3) possible future developments of sea level services enabling better connection of scientists and user communities and facilitating assessment and decision making for adaptation to future coastal SL change.

Research on the coupling of membrane separation (MS) and electrochemical advanced oxidation processes (EAOPs) has been a hot area in water pollution control for decades. This coupling aims to greatly improve water quality and focuses on the challenges in practical application to provide a promising solution to water shortage problems. This article provides a summary of the coupling configurations of MS and EAOPs, including two-stage and one-pot processes. The two-stage process is a combination of MS and EAOPs where one process acts as a pretreatment for the other. Membrane fouling is reduced when setting EAOPs before MS, while mass transfer is promoted when placing EAOPs after MS. A one-pot process is a kind of integration of two technologies. The anode or cathode of the EAOPs is fabricated from porous materials to function as a membrane electrode; thus, pollutants are concurrently separated and degraded. The advantages of enhanced mass transfer and the enlarged electroactive area suggest that this process has excellent performance at a low current input, leading to much lower energy consumption. The reported conclusions illustrate that the coupling of MS and EAOPs is highly applicable and may be widely employed in wastewater treatment in the future.

Anaerobic dechlorination of chlorophenols often subjects to their toxicity and recalcitrance, presenting low loading rate and poor degradation efficiency. In this study, in order to accelerate p-chlorophenol (p-CP) reduction and extracellular electron transfer in an anaerobic system, three iron-oxide nanoparticles, namely hematite, magnetite and ferrihydrite, were coupled into an anaerobic system, with the performance and underlying role of iron-oxide nanoparticles elucidated. The reductive dechlorination of p-CP was notably improved in the anaerobic systems coupled by hematite and magnetite, although ferrihydrite did not plays a positive role. Enhanced dechlorination of p-CP in hematite or magnetite coupled anaerobic system was linked to the obvious accumulation of acetate, lower oxidation–reduction potential and pH, which were beneficial for reductive dechlorination. Electron transfer could be enhanced by Fe2+/Fe3+ redox couple on the iron oxides surface formed through dissimilatory iron-reduction. This study demonstrated that the coupling of iron-oxide nanoparticles such as hematite and magnetite could be a promising alternative to the conventional anaerobic reduction process for the removal of CPs from wastewater.

During the CINDY/DYNAMO field campaign (fall/winter 2011), intensive measurements of the upper ocean, including an array of several surface moorings and ship observations for the area around 75°E–80°E, Equator-10°S, were conducted. In this study, large-scale upper ocean variations surrounding the intensive array during the field campaign are described based on the analysis of satellite-derived data. Surface currents, sea surface height (SSH), sea surface salinity (SSS), surface winds and sea surface temperature (SST) during the CINDY/DYNAMO field campaign derived from satellite observations are analyzed. During the intensive observation period, three active episodes of large-scale convection associated with the Madden-Julian Oscillation (MJO) propagated eastward across the tropical Indian Ocean. Surface westerly winds near the equator were particularly strong during the events in late November and late December, exceeding 10 m/s. These westerlies generated strong eastward jets (>1 m/s) on the equator. Significant remote ocean responses to the equatorial westerlies were observed in both Northern and Southern Hemispheres in the central and eastern Indian Oceans. The anomalous SSH associated with strong eastward jets propagated eastward as an equatorial Kelvin wave and generated intense downwelling near the eastern boundary. The anomalous positive SSH then partly propagated westward around 4°S as a reflected equatorial Rossby wave, and it significantly influenced the upper ocean structure in the Seychelles-Chagos thermocline ridge about two months after the last MJO event during the field campaign. For the first time, it is demonstrated that subseasonal SSS variations in the central Indian Ocean can be monitored by Aquarius measurements based on the comparison with in situ observations at three locations. Subseasonal SSS variability in the central Indian Ocean observed by RAMA buoys is explained by large-scale water exchanges between the Arabian Sea and Bay of Bengal through the zonal current variation near the equator.

This article discusses the challenges of developing a regional ocean prediction model for the Philippine Archipelago, a complex area in terms of geometry, bathymetry-dominated dynamics and variability, and strong local and remote wind forcing, where there are limited temporal and spatial ocean measurements. We used the Regional Ocean Modeling System (ROMS) for real-time forecasting during the Philippines Experiment (2007–2009) observational program. The article focuses on the prediction experiments before and during the exploratory cruise period, June 6–July 3, 2007. The gathered observations were not available in real time, so the 4-Dimensional Variational (4D-Var) data assimilation experiments were carried out in hindcast mode. The best estimate of ocean state (nowcast) is determined by combining satellite-derived products for sea surface temperature and height, and subsurface temperature and salinity measurements from several hydrographic assets over a sequential five-day data assimilation window. The largest source of forecast uncertainty is from the prescribed lateral boundary conditions in the nearby Pacific Ocean, especially excessive salt flux. This result suggests that remote forcing and inflows from the Pacific are crucial for predicting ocean circulation in the Philippine Archipelago region. The lateral boundary conditions are derived from 1/12° global Hybrid Coordinate Ocean Model (HYCOM) daily snapshots. The incremental, strong-constraint 4D-Var data assimilation successfully decreased temperature and salinity errors of the real-time, nonassimilative control forecast by 38% and 49%, respectively.

Previous studies suggest that anthropogenic warming has affected the multi-decadal trend patterns of sea level over the Indian Ocean (IO). This effect, however, has not been quantified. Using observational datasets combined with large ensemble experiments from two climate models, this paper assesses the effects of natural internal variability versus external forcing on the observed, multi-decadal trend pattern and the decadal sea level anomaly (SLA) of the IO since the 1960s. Because the global mean sea level rise (SLR), which results largely from external forcing, has been removed before the examination, the paper focuses on the regionally uneven distribution of trend and SLA. The impacts of climate modes are quantified using a Bayesian Dynamic Linear Model. For the regional trend pattern of 1958–2005, the effects of internal variability dominate external forcing. Over the Seychelles area where sea-level variations obtain the maximum, internal variability (external forcing) contributes 81% (19 ± 2.4%) of the observed trend. For decadal SLA, internal variability is the predominant cause, with a standard deviation (STD) ratio of externally forced/observed SLA being 18 ± 17% over Seychelles and 17 ± 11% near the Indonesian Throughflow (ITF) area. Climate modes account for most observed SLA during boreal winter, with the total effects of decadal ENSO, Indian Ocean Dipole (IOD), and monsoon accounting for 78–86% of the observed STD near the Seychelles region, ITF area, and coasts of Sumatra and the Bay of Bengal. During summer, climate modes explain 95% of observed STD near the ITF but only 58–67% in other regions. Decadal ENSO dominates the SLA in the south tropical IO for both seasons and near the coasts of Sumatra and the Bay during winter. Decadal IOD and monsoon, however, control the coastal SLA during summer. Remote and local winds over the IO are the main drivers for decadal SLA, while the Pacific influence via the ITF is strong mainly in the southeast basin.

During the CINDY/DYNAMO field campaign, exceptionally large upper ocean responses to strong westerly wind events associated with the Madden–Julian oscillation (MJO) were observed in the central equatorial Indian Ocean. Strong eastward equatorial currents in the upper ocean lasted more than one month from late November 2011 to early January 2012. The remote ocean response to these unique MJO events are investigated using a high resolution (1/25°) global ocean general circulation model along with the satellite altimeter data. The local ocean response to the MJO events are realistically simulated by the global model based on the comparison with the data collected during the field campaign. The satellite altimeter data show that anomalous sea surface height (SSH) associated with the strong eastward jets propagated eastward as an equatorial Kelvin wave. The positive SSH anomalies then partly propagate westward as a reflected Rossby wave. The SSH anomalies associated with the reflected Rossby wave in the southern hemisphere propagate all the way to the western boundary. These remote ocean responses are well simulated by the global model. The analysis of the model simulation indicates the significant influence of reflected Rossby waves on sub-seasonal variability of Somali current system near the equator. The analysis further suggests that the reflected Rossby wave causes a substantial change in the structure of the Seychelles–Chagos thermocline ridge, which contributes to significant SST anomalies.

Glycoconjugate is one of the most efficacious and safest vaccines against bacterial pathogens. Previous studies of glycoconjugates against pathogen E. coli O157:H7 focused more on the humoral responses they elicited. However, little was known about their cellular responses. In this study, we exploited a novel approach based on bacterial protein N-linked glycosylation system to produce glycoconjugate containing Escherichia coli O157:H7 O-antigen linked with maltose-binding protein and examined its humoral and cellular responses in BALB/c mice. The transfer of E. coli O157:H7 O-antigen to MBP was confirmed by western blot and MALDI-TOF MS. Mice injected with glycoconjugate O-Ag-MBP elicited serum bactericidal antibodies including anti-E. coli O157:H7 O-antigen IgG and IgM. Interestingly, O-Ag-MBP also stimulated the secretion of anti-E. coli O157:H7 O-antigen IgA in intestine. In addition, O-Ag-MBP stimulated cellular responses by recruiting Th1-biased CD4+ T cells, CD8+ T cells. Meanwhile, O-Ag-MBP induced the upregulation of Th1-related IFN-γ and downregulation of Th2-related IL-4, and the upregulation of IFN-γ was stimulated by MBP in a dose-dependent manner. MBP showed TLR4 agonist-like properties to activate Th1 cells as carrier protein of O-Ag-MBP. Thus, glycoconjugate vaccine E. coli O157:H7-specific O-Ag-MBP produced by bacterial protein N-linked glycosylation system was able to elicit both humoral and Th1-biased cellular responses.

OBJECTIVES: This study investigates the effects on aortic stiffness and vasodilation by arotinolol and the underlying mechanisms in spontaneously hypertensive rats (SHR). METHODS: The vasodilations of rat aortas, renal and mesenteric arteries were evaluated by isometric force recording. Nitric oxide (NO) was measured in human aortic endothelial cells (HAECs) by fluorescent probes. Sixteen-week old SHRs were treated with metoprolol (200 mg·kg-1·d⁻¹), arotinolol (30 mg·kg-1·d⁻¹) for 8 weeks. Central arterial pressure (CAP) and pulse wave velocity (PWV) were evaluated via catheter pressure transducers. Collagen was assessed by immunohistochemistry and biochemistry assay, while endothelial nitric oxide synthase (eNOS) and eNOS phosphorylation (p-eNOS) of HAECs or aortas were analyzed by western blotting. RESULTS: Arotinolol relaxed vascular rings and the relaxations were attenuated by Nω-nitro-L-arginine methyl ester (L-NAME, NO synthase inhibitor) and the absence of endothelium. Furthermore, arotinolol-induced relaxations were attenuated by 4-aminopyridine (4-AP, Kv channels blocker). Arotinolol produced more nitric oxide compared to metoprolol and increased the expression of p-eNOS in HAECs. These results indicated that arotinolol-induced vasodilation involves endothelium-derived NO and Kv channels. The treatement with arotinolol in 8 weeks, but not metoprolol, markedly decreased CAP and PWV. Biochemistry assay and immunohistochemistry showed that aortic collagen depositions in the arotinolol groups were reduced compared with SHRs with metoprolol. Moreover, eNOS phosphorylation was significantly increased in aortinolol-treated SHR compared with SHRs with metoprolol. CONCLUSIONS: Arotinolol improves arterial stiffness in SHR, which involved in increasing NO and decreasing collagen contents in large arteries.

Wild-type p53-induced phosphatase (Wip1 or PPM1D) has been reported to be aberrantly expressed in various cancers and correlated with the malignant behavior of cancer cells. However, the function of Wip1 in RCC remains unclear. The present study investigated its abnormal expression and dysfunctions in clear cell renal cell carcinoma (ccRCC) in vitro. With the combination of immunohistochemistry, western blotting, immunofluorescence, qRT-PCR, and cell proliferation, migration and invasion assays, we found that levels of Wip1 mRNA and protein were dramatically increased in human ccRCC tissues (P

BACKGROUND: Wind setdown is the drop in water level caused by wind stress acting on the surface of a body of water for an extended period of time. As the wind blows, water recedes from the upwind shore and exposes terrain that was formerly underwater. Previous researchers have suggested wind setdown as a possible hydrodynamic explanation for Moses crossing the Red Sea, as described in Exodus 14. METHODOLOGY/PRINCIPAL FINDINGS: This study analyzes the hydrodynamic mechanism proposed by earlier studies, focusing on the time needed to reach a steady-state solution. In addition, the authors investigate a site in the eastern Nile delta, where the ancient Pelusiac branch of the Nile once flowed into a coastal lagoon then known as the Lake of Tanis. We conduct a satellite and modeling survey to analyze this location, using geological evidence of the ancient bathymetry and a historical description of a strong wind event in 1882. A suite of model experiments are performed to demonstrate a new hydrodynamic mechanism that can cause an angular body of water to divide under wind stress, and to test the behavior of our study location and reconstructed topography. CONCLUSIONS/SIGNIFICANCE: Under a uniform 28 m/s easterly wind forcing in the reconstructed model basin, the ocean model produces an area of exposed mud flats where the river mouth opens into the lake. This land bridge is 3-4 km long and 5 km wide, and it remains open for 4 hours. Model results indicate that navigation in shallow-water harbors can be significantly curtailed by wind setdown when strong winds blow offshore.