2D-Like Catalyst with a Micro-nanolinked Functional Surface for Water Purification.

In water purification, the performance of heterogeneous advanced oxidation processes significantly relies upon the utilization of the catalyst's specific surface area (SSA). However, the presence of the structural "dead volume" and pore-size-induced diffusion-reaction trade-off limitation restricts the functioning of the SSA. Here, we reported an effective approach to make the best SSA by changing the traditional 3D spherule catalyst into a 2D-like form and creating an in situ micro-nanolinked structure. Thus, a 2D-like catalyst was obtained which was characterized by a mini "paddy field" surface, and it exhibited a sharply decreased dead volume, a highly available SSA and oriented flexibility. Given its paddy-field-like mass-transfer routine, the organic capture capability was 7.5-fold higher than that of the catalyst with mesopores only. Moreover, such a catalyst exhibited a record-high O3-to-·OH transition rate of 2.86 × 10-8 compared with reported millimetric catalysts (metal base), which contributed to a 6.12-fold higher total organic removal per catalyst mass than traditional 3D catalysts. The facile scale preparation, performance stability, and significant material savings with the 2D-like catalyst were also beneficial for practical applications. Our findings provide a unique and general approach for designing potential catalysts with excellent performance in water purification.

A single-centre, open-label, single-arm, fixed-sequence pharmacokinetic study of SHR3680 on repaglinide and bupropion in prostate cancer patients.

To evaluate the pharmacokinetic effects of SHR3680 on repaglinide and bupropion and its metabolite hydroxybupropion. METHODS: A single-centre, open-label, single-arm, fixed-sequence clinical trial in 18 patients with prostate cancer. RESULTS: After a single oral dose of 0.5 mg repaglinide and SHR3680, geometric mean peak plasma concentration (Cmax ) of plasma repaglinide was 14.240 and 5.887 ng/mL, geometric mean area under the concentration-time curve (AUC0-t )was 20.577 and 7.320 h ng/mL, geometric mean AUC0-∞ was 20.949 and 7.451 h ng/mL, mean half-life (t1/2 ) was 1.629 and 1.195 hours, and geometric mean oral clearance (CL/F) was 23.867 and 67.107 L/h, respectively. After a single oral administration of 150 mg bupropion and SHR3680, geometric mean Cmax of plasma bupropion was 85.430 and 33.747 ng/mL, geometric mean AUC0-t was 1003.896 and 380.158 h ng/mL, geometric mean AUC0-∞ was 1038.054 and 401.387 h ng/mL, mean t1/2 was 22.533 and 17.733 hours, and geometric mean CL/F was 144.501 and 373.705 L/h, respectively. The plasma geometric mean Cmax of its main active metabolic hydroxybupropion was 268.113 and 177.318 ng/mL, geometric mean AUC0-t was 14 283.087 and 5420.219 h ng/mL, geometric mean AUC0-∞ was 15 218.158 and 5364.625 h ng/mL, mean t1/2 were 36.069 and 16.688 hours, and geometric mean CL/F was 8.623 L/h and 27.961 L/h, respectively. CONCLUSION: Coadministration of SHR3680 with repaglinide or bupropion significantly shortened the elimination half-lives, significantly increased the apparent clearance rate, and significantly decreased the in vivo exposure of repaglinide, bupropion and hydroxybupropion compared with single administration of repaglinide or bupropion.

An extra-chelator-free fenton process assisted by electrocatalytic-induced in-situ pollutant carboxylation for target refractory organic efficient treatment in chemical-industrial wastewater.

For traditional Fenton processes, the quenching behavior of radical contenders (e.g., most aliphatic hydrocarbons) on hydroxyl radicals (·OH) usually hinders the removal of target refractory pollutants (aromatic/heterocyclic hydrocarbons) in chemical industrial wastewater, leading to excess energy consumption. Herein, we proposed an electrocatalytic-assisted chelation-Fenton (EACF) process, with no extra-chelator addition, to significantly enhance target refractory pollutant (pyrazole as a representative) removal under high ·OH contender (glyoxal) levels. Experiments and theoretical calculations proved that superoxide radical (·O2-) and anodic direct electron transfer (DET) effectively converted the strong ·OH-quenching substance (glyoxal) to a weak radical competitor (oxalate) during the electrocatalytic oxidation process, promoting Fe2+ chelation and therefore increasing radical utilization for pyrazole degradation (reached maximum of ∼43-fold value upon traditional Fenton), which appeared more obviously in neutral/alkaline Fenton conditions. For actual pharmaceutical tailwater treatment, the EACF achieved 2-folds higher oriented-oxidation capability and ∼78% lower operation cost per pyrazole removal than the traditional Fenton process, demonstrating promising potential for future practical applications.

Rezvilutamide versus bicalutamide in combination with androgen-deprivation therapy in patients with high-volume, metastatic, hormone-sensitive prostate cancer (CHART): a randomised, open-label, phase 3 trial.

BACKGROUND: Rezvilutamide, a novel androgen-receptor inhibitor with low blood-brain barrier penetration, has shown potent antitumour activity against metastatic castration-resistant prostate cancer. In this study, we aimed to evaluate the efficacy and safety of rezvilutamide versus bicalutamide in combination with androgen-deprivation therapy (ADT) for high-volume, metastatic, hormone-sensitive prostate cancer. METHODS: CHART is a randomised, open-label, phase 3 study done at 72 hospitals in China, Poland, Czech Republic, and Bulgaria. Eligible patients were aged 18 years or older, had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and had high-volume metastatic, hormone-sensitive prostate cancer. Previous chemotherapy or other localised treatment for prostate cancer were not allowed. Patients were randomly assigned (1:1) to receive ADT plus either rezvilutamide (240 mg) or bicalutamide (50 mg) orally once daily. Randomisation was done via an interactive response technology system (block size of four) and stratified according to ECOG performance status and presence of visceral metastasis (excluding lymph nodes). Herein, we present the results of the preplanned interim analyses for the two co-primary endpoints of radiographic progression-free survival assessed by a blinded independent review committee and overall survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study medication. This study is ongoing, but is closed to recruitment. This trial is registered with ClinicalTrials.gov, NCT03520478. FINDINGS: Between June 28, 2018, and Aug 6, 2020, 792 patients were screened and 654 patients were randomly assigned to receive rezvilutamide plus ADT (n=326) or bicalutamide plus ADT (n=328). At the preplanned interim analysis for radiographic progression-free survival (data cutoff May 16, 2021), the median follow-up duration was 21·2 months (IQR 16·6-25·8). Rezvilutamide significantly improved radiographic progression-free survival compared with bicalutamide (median radiographic progression-free survival not reached [95% CI not reached-not reached] vs 25·1 months [95% CI 15·7-not reached]; hazard ratio [HR] 0·44 [95% CI 0·33-0·58]; p<0·0001). At the preplanned interim analysis for overall survival (data cutoff Feb 28, 2022), the median follow-up duration was 29·3 months (IQR 21·0-33·3). Rezvilutamide significantly improved overall survival compared with bicalutamide (HR 0·58 [95% CI 0·44-0·77]; p=0·0001; median overall survival was not reached [95% CI not reached-not reached] vs not reached [36·2-not reached]). The most common grade 3 or worse adverse events of any cause in the safety population were hypertension (26 [8%] of 323 patients in the rezvilutamide group vs 24 [7%] of 324 patients in the bicalutamide group), hypertriglyceridaemia (24 [7%] vs seven [2%]), increased weight (20 [6%] vs 12 [4%]), anaemia (12 [4%] vs 16 [5%]), and hypokalaemia (11 [3%] vs four [1%]). Serious adverse events were reported in 90 (28%) of 323 patients in the rezvilutamide group and 69 (21%) of 324 patients in the bicalutamide group. No treatment-related deaths occurred in patients in the rezvilutamide group; one treatment-related death of unknown specific cause (<1%) occurred in the bicalutamide group. INTERPRETATION: In the two interim analyses, rezvilutamide plus ADT significantly improved radiographic progression-free survival and overall survival compared with bicalutamide plus ADT in patients with high-volume, metastatic, hormone-sensitive prostate cancer, with a tolerable safety profile. FUNDING: Jiangsu Hengrui Pharmaceuticals.

Stromal cell-derived factor-1 exerts opposing roles through CXCR4 and CXCR7 in angiotensin II-induced adventitial remodeling.

Recent studies have emphasized the role of vascular adventitia inflammation and immune response in hypertension. It has been reported that stromal cell-derived factor-1 (SDF-1) plays various biological functions through its receptors C-X-C motif chemokine receptor 4 (CXCR4) and CXCR7 in tumor growth and tissue repair. However, it is unclear that whether SDF-1/CXCR4/CXCR7 axis is involved in hypertensive vascular remodeling. In the present study, the involvement of SDF-1/CXCR4/CXCR7 axis was evaluated with lentivirus-mediated shRNA of SDF-1 and CXCR7, CXCR4 antagonist AMD3100 and CXCR7 agonist VUF11207 in angiotensin II (AngII)-induced hypertensive mice and in cultured adventitial fibroblasts (AFs). Results showed that AngII infusion markedly increased SDF-1 expressed in vascular adventitia, but not in media and endothelium. Importantly, blockade of SDF-1/CXCR4 axis strikingly potentiated AngII-induced adventitial thickening and fibrosis, as indicated by enhanced collagen I deposition. In contrast, CXCR7 shRNA largely attenuated AngII-induced adventitial thickness and fibrosis, whereas CXCR7 activation with VUF11207 significantly potentiated AngII-induced adventitial thickening and fibrosis. In consistent with these in vivo study, CXCR4 inhibition with AMD3100 and CXCR7 activation with VUF11207 aggravated AngII-induced inflammation, proliferation and migration in cultured AFs. In summary, these results suggested that SDF-1 exerted opposing effects through CXCR4 and CXCR7 in AngII-induced vascular adventitial remodeling.

Activity and safety of SHR3680, a novel antiandrogen, in patients with metastatic castration-resistant prostate cancer: a phase I/II trial.

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.

Bifunctional anti-PD-L1/TGF-ßRII agent SHR-1701 in advanced solid tumors: a dose-escalation, dose-expansion, and clinical-expansion phase 1 trial.

BACKGROUND: Dual inhibition of PD-1/PD-L1 and TGF-ß 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-ß 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.

Efficient removal of Sb(â ¤) from water using sulphidated ferrihydrite via tripuhyite (FeSbO4) precipitation and complexation.

Elevated concentrations of antimony (Sb) in the ecological environment have received considerable attention due to the harmful consequence involved. This study synthesized sulphidated ferrihydrite with different S:Fe molar ratios to efficiently remove Sb(V) from water. As the S:Fe molar ratio ranged from 0.00 to 1.48, the removal efficiency of Sb(V) by sulphidated ferrihydrite first decreased before increasing considerably. Sulphidated ferrihydrite with an S:Fe molar ratio of 0.74 exhibited a strong affinity towards Sb(V) with an optimal removal capacity of 963.74 mg Sb/g, which was 3.2-fold higher than that of ferrihydrite. In the kinetic experiments, the removal behavior of Sb(V) was well described by the pseudo-second-order model, suggesting that the removal process was controlled via chemisorption. Moreover, Sb(V) was efficiently removed over a wide pH range of 3.00-11.00, and coexisting anions (NO3-, Cl-, SO42-, SiO32-, CO32- and PO43-) exhibited marginal impact on the Sb(V) removal by sulphidated ferrihydrite (S:Fe ≥ 0.44). The characterization results of XRD, SEM, TEM mapping and etched XPS revealed goethite to be the dominant phase of sulphidated ferrihydrite with an S:Fe molar ratio of 0.15, while a mixed constitution of mixed-valent iron (hydro)oxides and iron sulphide was formed when the S:Fe molar ratio exceeded 0.44. Moreover, sulphidated ferrihydrite acted as a donor for Fe and S for the effective retention of Sb(V) by two main pathways: precipitation (tripuhyite, FeSbO4) and complexation (≡S-H and ≡Fe-OH). Therefore, sulphidated ferrihydrite is a promising material for eliminating Sb(V) contamination from water.

The clinical research of 5 steps sequential method for whole treatment of hemorrhagic radiation cystitis in china.

Background: Curing hemorrhagic cystitis remains a challenge. We explore a continuous and effective treatment for hemorrhagic radiation cystitis. Methods: The data of patients in 6 provincial cancer hospital urology departments between April 2015 and December 2019 was reviewed retrospectively. Patients were classified as moderate and severe groups. The 5-steps sequential method was adopted. Two groups were initiated with step 1 and step 3 respectively. Step 1 was symptomatic treatment. Thrombin solution or sodium hyaluronate was administrated for bladder irrigation in step 2. Step 3 was transurethral electrocoagulation. Step 4 was interventional embolization. Step 5 was HBO therapy. OABSS was used to assess the improvement of patients' symptoms. The outcome was evaluated after at least 6 months of follow-up. Results: A total of 650 patients (56 men and 594 women), mean age 71.2 years, were enrolled in the 5 steps sequential method. 582 patients were classified as moderate and 68 severe group. In moderate group, the cure rate of step 1 was 61.2% (356/582), 80.4% (468/582) after step 2, 93.1% (542/582) after step 3, 96.2% (560/582) after step 4, and 99.8% (581/582) after step 5. In severe group, the cure rate was 54.4% (37/68) after step 3, 76.5% (52/68) after step 4, and 94.1% (64/68) after the step 5 respectively. The mean OABSS scores of both groups significantly decreased after 5 steps sequential method treatment (P<0.01). Conclusions: Our results show hemorrhagic radiation cystitis can be cured in 5 steps, and the 5 steps sequential method is welcomed and effective. Therapy efficacy depends on the number of steps adopted and the severity of hematuria.

Neural Crest Cells Differentiate Into Brown Adipocytes and Contribute to Periaortic Arch Adipose Tissue Formation.

OBJECTIVE: Periaortic arch adipose tissue (PAAT) plays critical roles in regulating vascular homeostasis; however, its anatomic features, developmental processes, and origins remain unclear. Approach and Results: Anatomic analysis and genetic lineage tracing of Wnt1 (wingless-type MMTV [mouse mammary tumor virus] integration site family member 1)-Cre+;Rosa26RFP/+ mice, Myf5 (myogenic factor 5)-Cre+;Rosa26RFP/+ mice, and SM22α-Cre+;Rosa26RFP/+ mice are performed, and the results show that PAAT has unique anatomic features, and the developmental processes of PAAT are independent of the others periaortic adipose tissues. PAAT adipocytes are mainly derived from neural crest cells (NCCs) rather than from Myf5+ progenitors. Most PAAT adipocyte progenitors expressed SM22α+ (smooth muscle protein 22-alpha) during development. Using Wnt1-Cre+;PPARγflox/flox mice, we found that knockout of PPAR (peroxisome proliferator-activated receptor)-γ in NCCs results in PAAT developmental delay and dysplasia, further confirming that NCCs contribute to PAAT formation. And we further indicated PAAT dysplasia aggravates Ang II (angiotensin II)-induced inflammation and remodeling of the common carotid artery close to aorta arch. We also found that NCCs can be differentiated into both brown and white adipocytes in vivo and in vitro. RNA sequencing results suggested NCC-derived adipose tissue displays a distinct transcriptional profile compared with the non-NCC-derived adipose tissue in PAAT. CONCLUSIONS: PAAT has distinctive anatomic features and developmental processes. Most PAAT adipocytes are originated from NCCs which derive from ectoderm. NCCs are progenitors not only of white adipocytes but also of brown adipocytes. This study indicates that the PAAT is derived from multiple cell lineages, the adipocytes derived from different origins have distinct transcriptional profiles, and PAAT plays a critical role in Ang II-induced common carotid artery inflammation and remodeling.Visual OvervieW: An online visual overview is available for this article.

Membrane raft redox signalling contributes to endothelial dysfunction and vascular remodelling of thoracic aorta in angiotensin II-infused rats.

NEW FINDINGS: What is the central question of this study? Is the membrane raft redox signalling pathway involved in blood pressure increase, endothelial dysfunction and vascular remodelling in an angiotensin II-induced hypertensive animal model? What is the main finding and its importance? The membrane raft redox signalling pathway was involved in endothelial dysfunction and medial remodelling in angiotensin II-induced hypertension. ABSTRACT: The membrane raft (MR) redox pathway is characterized by NADPH oxidase activation via the clustering of its subunits through lysosome fusion and the activation of acid sphingomyelinase (ASMase). Our previous study shows that the MR redox signalling pathway is associated with angiontensin II (AngII)-induced production of reactive oxygen species (ROS) and endothelial dysfunction in rat mesenteric arteries. In the present study, we hypothesized that this signalling pathway is involved in blood pressure increase, endothelial dysfunction and vascular remodelling in an AngII-induced hypertensive animal model. Sixteen-week-old male Sprague-Dawley rats were subjected to AngII infusion for 2 weeks with or without treatment with the lysosome fusion inhibitor bafilomycin A1 and ASMase inhibitor amitriptyline. After treatments, aortas were harvested for further study. The results showed that the MR redox signalling pathway was activated as indicated by the increase of MR formation, ASMase activity and ROS production in aorta from AngII-infused rats compared with that from control rats. MR formation and ROS production were significantly inhibited in thoracic aorta from AngII-induced rats treated with bafilomycin A1 and amitriptyline. Both treatments significantly attenuated blood pressure increase, endothelial dysfunction and vascular remodelling including medial hypertrophy, and increased collagen and fibronectin deposition in thoracic aortas from AngII-infused rats. Finally, both treatments significantly prevented the increase of inflammatory factors including monocyte chemotactic protein 1, intercellular adhesion molecule 1 and tumour necrosis factor α in thoracic aorta from AngII-infused rats. In conclusion, the present study demonstrates that the MR redox signalling pathway was involved in endothelial dysfunction and medial remodelling in AngII-induced hypertension.

[Low expressions of EHD2 and E-cadherin correlate with a poor prognosis for clear cell renal cell carcinoma].

OBJECTIVE: To explore roles of expressions of EHD2 and E-cadherin in clear cell renal cell carcinoma (ccRCC).
 Methods: Four couples of fresh ccRCC tissues and adjacent non-cancerous tissues were collected to evaluate the expression of EHD2 and E-cadherin protein by Western blotting. A total of 65 paraffin-embedded renal ccRCC tissues were collected, and immunohistochemical assay was used to detect the expression of EHD2 and E-cadherin in the samples. The correlation between their expression and clinical and pathological indicators of ccRCC was analyzed, and the relationship between EHD2 and E-cadherin proteins and prognosis for patients with ccRCC was also explored.
 Results: The results of Western blotting showed that the expression levels of EHD2 and E-cadherin were low in 4 ccRCC tissues compared with the adjacent noncancerous tissues. Immunohistochemical results revealed that the expressions of EHD2 and E-cadherin were higher in the localized ccRCC tissues than those in the metastatic ccRCC tissues; the expression levels of EHD2 and E-cadherin were decreased, while the TNM staging and Fuhrman grade were increased (P<0.05 or P<0.01). There was positive correlation between the expressions of EHD2 and E-cadherin in ccRCC (r=0.390, P<0.01). The progression-free survival in ccRCC patients with lower expression of both EHD2 and E-cadherin was better than that in ccRCC patients with higher expressions of EHD2 and E-cadherin (P<0.05). 
 Conclusion: The low expressions of EHD2 and E-cadherin are the potential indicators for the ccRCC patients with poor prognosis.

Membrane rafts-redox signalling pathway contributes to renal fibrosis via modulation of the renal tubular epithelial-mesenchymal transition.

KEY POINTS: Membrane rafts (MRs)-redox signalling pathway is activated in response to transforming growth factor-ß1 (TGF-ß1) stimulation in renal tubular cells. This pathway contributes to TGF-1ß-induced epithelial-mesenchymal transition (EMT) in renal tubular cells. The the MRs-redox signalling pathway is activated in renal tubular cells isolated from angiotensin II (AngII)-induced hypertensive rats. Inhibition of this pathway attenuated renal inflammation and fibrosis in AngII-induced hypertension. ABSTRACT: The membrane rafts (MRs)-redox pathway is characterized by NADPH oxidase subunit clustering and activation through lysosome fusion, V-type proton ATPase subunit E2 (encoded by the Atp6v1e2 gene) translocation and sphingomyelin phosphodiesterase 1 (SMPD1, encoded by the SMPD1 gene) activation. In the present study, we hypothesized that the MRs-redox-derived reactive oxygen species (ROS) are involved in renal inflammation and fibrosis by promoting renal tubular epithelial-mesenchymal transition (EMT). Results show that transforming growth factor-ß1 (TGF-ß1) acutely induced MR formation and ROS production in NRK-52E cells, a rat renal tubular cell line. In addition, transfection of Atp6v1e2 small hairpin RNAs (shRNA) and SMPD1 shRNA attenuated TGF-ß1-induced changes in EMT markers, including E-cadherin, α-smooth muscle actin (α-SMA) and fibroblast-specific protein-1 (FSP-1) in NRK-52E cells. Moreover, Erk1/2 activation may be a downstream regulator of the MRs-redox-derived ROS, because both shRNAs significantly inhibited TGF-ß1-induced Erk1/2 phosphorylation. Further in vivo study shows that the renal tubular the MRs-redox signalling pathway was activated in angiotensin II (AngII)-induced hypertension, as indicated by the increased NADPH oxidase subunit Nox4 fraction in the MR domain, SMPD1 activation and increased ROS content in isolated renal tubular cells. Finally, renal transfection of Atp6v1e2 shRNA and SMPD1 shRNA significantly prevented renal fibrosis and inflammation, as indicated by the decrease of α-SMA, fibronectin, collagen I, monocyte chemoattractant protein-1 (MCP-1), intercellular cell adhesion molecule-1 (ICAM-1) and tumour necrosis factor-α (TNF-α) in kidneys from AngII-infused rats. It was concluded that the the MRs-redox signalling pathway is involved in TGF-ß1-induced renal tubular EMT and renal inflammation/fibrosis in AngII-induced hypertension.

Simultaneous pyridine biodegradation and nitrogen removal in an aerobic granular system.

Simultaneous pyridine biodegradation and nitrogen removal were successfully achieved in a sequencing batch reactor (SBR) based on aerobic granules. In a typical SBR cycle, nitritation occurred obviously after the majority of pyridine was removed, while denitrification occurred at early stage of the cycle when oxygen consumption was aggravated. The effect of several key operation parameters, i.e., air flow rate, influent NH4+-N concentration, influent pH and pyridine concentration, on nitritation, pyridine degradation and total nitrogen (TN) removal, was systematically investigated. The results indicated that high air flow rate had a positive effect on both pyridine degradation and nitritation but a negative impact of overhigh air flow rate. With the increase of NH4+ dosage, both nitritation and TN removal could be severely inhibited. Slightly alkaline condition, i.e., pH7.0-8.0, was beneficial for both pyridine degradation and nitritation. High pyridine dosage often resulted in the delay of both pyridine degradation and nitritation. Besides, extracellular polymeric substances production was affected by air flow rate, NH4+ dosage, pyridine dosage and pH. In addition, high-throughput sequencing analysis demonstrated that Bdellovibrio and Paracoccus were the dominant species in the aerobic granulation system. Coexistence of pyridine degrader, nitrification related species, denitrification related species, polymeric substances producer and self-aggregation related species was also confirmed by high-throughput sequencing.

Electrospun flexible poly(bisphenol A carbonate) nanofibers decorated with Ag nanoparticles as effective 3D SERS substrates for trace TNT detection.

A flexible 3D hybrid PC/Ag surface-enhanced Raman scattering (SERS) substrate was fabricated through the combination of electrospinning and in situ chemical reduction. Due to the rough surface morphology and the intricate 3D structure, a high density of Raman "hotspots" was formed at the junctions of cross-linked nanofibers, resulting in excellent sensitivity to a probe molecule (4-aminothiophenol). The nanofibers were modified with l-cysteine to capture TNT molecules by the formation of a Meisenheimer complex, after which positively charged 4-ATP-labelled AgNPs were introduced to the system, which both generated more hotspots and led to a linear relationship between the TNT concentration and the SERS intensity of the labelled molecules. As a result, a good linear response ranging from 10-8 to 10-12 M was achieved, and the detection limit for TNT was as low as 2.05 × 10-13 M. This strategy demonstrates an ultra-sensitive approach for the detection of trace amounts of TNT, and a promising method for the detection of many other analogous explosives.

Reuse of Fenton sludge as an iron source for NiFe2O4 synthesis and its application in the Fenton-based process.

The potentially hazardous iron-containing sludge from the Fenton process requires proper treatment and disposal, which often results in high treatment cost. In this study, a novel method for the reuse of Fenton sludge as an iron source for the synthesis of nickel ferrite particles (NiFe2O4) is proposed. Through a co-precipitation method followed by sintering at 800°C, magnetic NiFe2O4 particles were successfully synthesized, which was confirmed by powder X-ray diffraction (XRD), scanning electronic microscopy (SEM), energy dispersive spectroscopy (EDS), Fourier transform infrared spectroscopy (FT-IR) and Raman spectroscopy. The synthesized NiFe2O4 could be used as an efficient catalyst in the heterogeneous Fenton process. In phenol degradation with H2O2 or NiFe2O4 alone, the phenol removal efficiencies within the reaction time of 330min were as low as 5.9%±0.1% and 13.5%±0.4%, respectively. However, in the presence of both NiFe2O4 and H2O2, phenol removal efficiency as high as 95%±3.4% could be achieved, indicating the excellent catalytic performance of NiFe2O4 in the heterogeneous Fenton process. Notably, a rapid electron exchange between NiII and FeIII ions in the NiFe2O4 structure could be beneficial for the Fenton reaction. In addition, the magnetic catalyst was relatively stable, highly active and recoverable, and has potential applications in the Fenton process for organic pollutant removal.

Protease-activated receptor 1 and 2 contribute to angiotensin II-induced activation of adventitial fibroblasts from rat aorta.

Adventitial fibroblasts (AFs) can be activated by angiotensin II (Ang II) and exert pro-fibrotic and pro-inflammatory effects in vascular remodeling. Protease-activated receptor (PAR) 1 and 2 play a significant role in fibrogenic and inflammatory diseases. The present study hypothesized that PAR1 and PAR2 are involved in Ang II-induced AF activation and contribute to adventitial remodeling. We found that direct activation of PAR1 and PAR2 with PAR1-AP and PAR2-AP led to AF activation, including proliferation and differentiation of AFs, extracellular matrix synthesis, as well as production of pro-fibrotic cytokine TGF-ß and pro-inflammatory cytokines IL-6 and MCP-1. Furthermore, PAR1 and PAR2 mediated Ang II-induced AF activation, since both PAR1 and PAR2 antagonists inhibited Ang II-induced proliferation, migration, differentiation, extracellular matrix synthesis and production of pro-fibrotic and pro-inflammatory cytokines in AFs. Finally, mechanistic study showed that Ang II, via Ang II type I receptor (AT1R), upregulated both PAR1 and PAR2 expression, and transactivated PAR1 and PAR2, as denoted by internalization of both proteins. In conclusion, our results suggest that PAR1 and PAR2 play a critical role in Ang II-induced AF activation, and this may contribute to adventitia-related pathological changes.

Asp141 and the Hydrogen-Bond Chain Asp141-Asn109-Asp33 Are Respectively Essential for GT80 Sialyltransferase Activity and Structural Stability.

Sialyltransferases are key enzymes involved in the biosynthesis of biologically and pathologically important sialic acid-containing molecules in nature. In this study, the activity of a putative sialyltransferase (Pm0160) harboring an inherent mutation D141Y in the conserved DDG motif, which has been identified in GT52 and GT80 families, was restored by reverse mutation. More interestingly, a hydrogen-bond chain was found to form between three conserved residues (Asp141, Asn109, and Asp33) of GT80 sialyltransferases based on recently determined crystal structures. Our mutagenesis experiments demonstrated that the hydrogen-bond chain connecting the general base Asp141 with Nß4, Nß1, and Nα1 plays an essential role in maintaining protein structural stability other than keeping the general base Asp141 in a productive orientation for sialic acid transfer.

Role of the Bering Strait on the hysteresis of the ocean conveyor belt circulation and glacial climate stability.

Abrupt climate transitions, known as Dansgaard-Oeschger and Heinrich events, occurred frequently during the last glacial period, specifically from 80-11 thousand years before present, but were nearly absent during interglacial periods and the early stages of glacial periods, when major ice-sheets were still forming. Here we show, with a fully coupled state-of-the-art climate model, that closing the Bering Strait and preventing its throughflow between the Pacific and Arctic Oceans during the glacial period can lead to the emergence of stronger hysteresis behavior of the ocean conveyor belt circulation to create conditions that are conducive to triggering abrupt climate transitions. Hence, it is argued that even for greenhouse warming, abrupt climate transitions similar to those in the last glacial time are unlikely to occur as the Bering Strait remains open.

Hypoxia-inducible factor prolyl-hydroxylase-2 mediates transforming growth factor beta 1-induced epithelial-mesenchymal transition in renal tubular cells.

Transforming growth factor beta 1 (TGF-ß1)-induced epithelial-mesenchymal transition (EMT) in kidney epithelial cells plays a key role in renal tubulointerstitial fibrosis in chronic kidney diseases. As hypoxia-inducible factor (HIF)-1α is found to mediate TGF-ß1-induced signaling pathway, we tested the hypothesis that HIF-1α and its upstream regulator prolyl hydroxylase domain-containing proteins (PHDs) are involved in TGF-ß1-induced EMT using cultured renal tubular cells. Our results showed that TGF-ß1 stimulated EMT in renal tubular cells as indicated by the significant decrease in epithelial marker P-cadherin, and the increase in mesenchymal markers α-smooth muscle actin (α-SMA) and fibroblast-specific protein 1 (FSP-1). Meanwhile, we found that TGF-ß1 time-dependently increased HIF-1α and that HIF-1α siRNA significantly inhibited TGF-ß1-induced EMT, suggesting that HIF-1α mediated TGF-ß1 induced-EMT. Real-time PCR showed that PHD1 and PHD2, rather than PHD3, could be detected, with PHD2 as the predominant form of PHDs (PHD1:PHD2=0.21:1.0). Importantly, PHD2 mRNA and protein, but not PHD1, were decreased by TGF-ß1. Furthermore, over-expression of PHD2 transgene almost fully prevented TGF-ß1-induced HIF-1α accumulation and EMT marker changes, indicating that PHD2 is involved in TGF-ß1-induced EMT. Finally, Smad2/3 inhibitor SB431542 prevented TGF-ß1-induced PHD2 decrease, suggesting that Smad2/3 may mediate TGF-ß1-induced EMT through PHD2/HIF-1α pathway. It is concluded that TGF-ß1 decreased PHD2 expression via an Smad-dependent signaling pathway, thereby leading to HIF-1α accumulation and then EMT in renal tubular cells. The present study suggests that PHD2/HIF-1α is a novel signaling pathway mediating the fibrogenic effect of TGF-ß1, and may be a new therapeutic target in chronic kidney diseases.