Thermodynamic Inhibition of Microbial Sulfur Disproportionation in a Multisubunit Designed Sulfur-Siderite Packed Bioreactor.

Sulfur disproportionation (S0DP) poses a challenge to the robust application of sulfur autotrophic denitrification due to unpredictable sulfide production, which risks the safety of downstream ecosystems. This study explored the S0DP occurrence boundaries with nitrate loading and temperature effects. The boundary values increased with the increase in temperature, exhibiting below 0.15 and 0.53 kg-N/m3/d of nitrate loading at 20 and 30 °C, respectively. A pilot-scale sulfur-siderite packed bioreactor (150 m3/d treatment capacity) was optimally designed with multiple subunits to dynamically distribute the loading of sulfur-heterologous electron acceptors. Operating two active and one standby subunit achieved an effective denitrification rate of 0.31 kg-N/m3/d at 20 °C. For the standby subunit, involving oxygen by aeration effectively transformed the facultative S0DP functional community from S0DP metabolism to aerobic respiration, but with enormous sulfur consumption resulting in ongoing sulfate production of over 3000 mg/L. Meanwhile, acidification by the sulfur oxidation process could reduce the pH to as low as 2.5, which evaluated the Gibbs free energy (ΔG) of the S0DP reaction to +2.56 kJ, thermodynamically suppressing the S0DP occurrence. Therefore, a multisubunit design along with S0DP inhibition strategies of short-term aeration and long-term acidification is suggested for managing S0DP in various practical sulfur-packed bioreactors.

N-acetylserotonin alleviates retinal ischemia-reperfusion injury via HMGB1/RAGE/NF-κB pathway in rats.

AIM: To observe the effects of N-acetylserotonin (NAS) administration on retinal ischemia-reperfusion (RIR) injury in rats and explore the underlying mechanisms involving the high mobility group box 1 (HMGB1)/receptor for advanced glycation end-products (RAGE)/nuclear factor-kappa B (NF-κB) signaling pathway. METHODS: A rat model of RIR was developed by increasing the pressure of the anterior chamber of the eye. Eighty male Sprague Dawley were randomly divided into five groups: sham group (n=8), RIR group (n=28), RIR+NAS group (n=28), RIR+FPS-ZM1 group (n=8) and RIR+NAS+ FPS-ZM1 group (n=8). The therapeutic effects of NAS were examined by hematoxylin-eosin (H&E) staining, and retinal ganglion cells (RGCs) counting. The expression of interleukin 1 beta (IL-1ß), HMGB1, RAGE, and nod-like receptor 3 (NLRP3) proteins and the phosphorylation of nuclear factor-kappa B (p-NF-κB) were analyzed by immunohistochemistry staining and Western blot analysis. The expression of HMGB1 protein was also detected by enzyme-linked immunosorbent assay (ELISA). RESULTS: H&E staining results showed that NAS significantly reduced retinal edema and increased the number of RGCs in RIR rats. With NAS therapy, the HMGB1 and RAGE expression decreased significantly, and the activation of the NF-κB/NLRP3 pathway was antagonized along with the inhibition of p-NF-κB and NLRP3 protein expression. Additionally, NAS exhibited an anti-inflammatory effect by reducing IL-1ß expression. The inhibitory of RAGE binding to HMGB1 by RAGE inhibitor FPS-ZM1 led to a significant decrease of p-NF-κB and NLRP3 expression, so as to the IL-1ß expression and retinal edema, accompanied by an increase of RGCs in RIR rats. CONCLUSION: NAS may exhibit a neuroprotective effect against RIR via the HMGB1/RAGE/NF-κB signaling pathway, which may be a useful therapeutic target for retinal disease.

Inducement mechanism and control of self-acidification in elemental sulfur fluidizing bioreactor.

The sulfur fluidizing bioreactor (S0FB) has significant superiorities in treating nitrate-rich wastewater. However, substantial self-acidification has been observed in engineering applications, resulting in frequent start-up failures. In this study, self-acidification was reproduced in a lab-scale S0FB. It was demonstrated that self-acidification was mainly induced by sulfur disproportionation process, accounting for 93.4 % of proton generation. Supplying sufficient alkalinity to both the influent (3000 mg/L) and the bulk (2000 mg/L) of S0FB was essential for achieving a successful start-up. Furthermore, the S0FB reached 10.3 kg-N/m3/d of nitrogen removal rate and 0.13 kg-PO43-/m3/d of phosphate removal rate, respectively, surpassing those of the documented sulfur packing bioreactors by 7-129 times and 26-65 times. This study offers a feasible and practical method to avoid self-acidification during restart of S0FB and highlights the considerable potential of S0FB in the treatment of nitrate-rich wastewater.

STAT5 promotes PD-L1 expression by facilitating histone lactylation to drive immunosuppression in acute myeloid leukemia.

Immunotherapy is a revolutionized therapeutic strategy for tumor treatment attributing to the rapid development of genomics and immunology, and immune checkpoint inhibitors have successfully achieved responses in numbers of tumor types, including hematopoietic malignancy. However, acute myeloid leukemia (AML) is a heterogeneous disease and there is still a lack of systematic demonstration to apply immunotherapy in AML based on PD-1/PD-L1 blockage. Thus, the identification of molecules that drive tumor immunosuppression and stratify patients according to the benefit from immune checkpoint inhibitors is urgently needed. Here, we reported that STAT5 was highly expressed in the AML cohort and activated the promoter of glycolytic genes to promote glycolysis in AML cells. As a result, the increased-lactate accumulation promoted E3BP nuclear translocation and facilitated histone lactylation, ultimately inducing PD-L1 transcription. Immune checkpoint inhibitor could block the interaction of PD-1/PD-L1 and reactive CD8+ T cells in the microenvironment when co-culture with STAT5 constitutively activated AML cells. Clinically, lactate accumulation in bone marrow was positively correlated with STAT5 as well as PD-L1 expression in newly diagnosed AML patients. Therefore, we have illustrated a STAT5-lactate-PD-L1 network in AML progression, which demonstrates that AML patients with STAT5 induced-exuberant glycolysis and lactate accumulation may be benefited from PD-1/PD-L-1-based immunotherapy.

Effect of hydraulic regime on sulfur-packed bed performance: Denitrification and disproportionation.

Sulfur-packed beds (SPBs) have been increasingly incorporated into constructed wetland systems to overcome limitations in achieving satisfactory nitrate removal efficiency. However, the underlying impact of hydraulic regimes on SPB performance remains understudied. This study investigated the performance of a pilot-scale SPB, encompassing sulfur autotrophic denitrification (SAD) and sulfur disproportionation (SDP) processes, under various horizontal flow (HF) and vertical flow (VF) regimes. The HF regime exhibited superior SAD efficiency, achieving 3.1-4.4 mg-N/L of nitrate removal compared to 0.9-2.8 mg-N/L under VF regimes. However, greater sulfide production of 3.8-5.6 mg/L was observed, in contrast to only 1.5-2.3 mg/L under VF regimes when SDP occurred. Employing current computational fluid dynamics simulations could predict general regimes but lacked precision in detailing sulfur layer dynamics. In contrast, determining the spatial distribution of SAD substrates and SDP products offered a viable solution, revealing stagnate, short-circuit, and back flows. Moreover, the feasibility of an aeration approach to reduce sulfide emissions below 0.5 mg/L in case of accidental SDP occurrence was confirmed. This study offers a method for assessing detailed hydraulic regimes within SPBs. Additionally, it provides guidance on optimizing the packing of sulfur-based materials when implementing SPBs in constructed wetland systems and presents a strategy for mitigating excessive sulfide emissions.

Managing microbial sulfur disproportionation for optimal sulfur autotrophic denitrification in a pilot-scale elemental sulfur packed-bed bioreactor.

Elemental sulfur packed-bed (S0PB) bioreactors for autotrophic denitrification have gained more attention in wastewater treatment due to their organic carbon-free operation, low operating cost, and minimal carbon emissions. However, the rapid development of microbial S0-disproportionation (MS0D) in S0PB reactor during deep denitrification poses a significant drawback to this new technology. MS0D, the process in which sulfur is used as both an electron donor and acceptor by bacteria, plays a crucial role in the microbial-driven sulfur cycle but remains poorly understood in wastewater treatment setups. In this study, we induced MS0D in a pilot-scale S0PB reactor capable of denitrifying over 1000 m3/d nitrate-containing wastewater. Initially, the S0PB reactor stably removed 6.6 mg-NO3--N/L nitrate at an empty bed contact time (EBCT) of 20 mins, which was designated the S0-denitrification stage. To induce MS0D, we reduced the influent nitrate concentrations to allow deep nitrate removal, resulted in the production of large quantities of sulfate and sulfide (SO42-:S2- 3.2 w/w). Meanwhile, other sulfur-heterologous electron acceptors (SHEAs), e.g., nitrite and DO, were also kept at trace levels. The negative correlations between the SHEAs concentrations and the sulfide productions indicated that the absence of SHEAs was a primary inducing factor to MS0D. The microbial community drastically diverged in response to the depletion of SHEAs during the switch from S0-denitrification to S0-disproportionation. An evident enrichment of sulfur-disproportionating bacteria (SDBs) was found at the S0-disproportionation stage, accompanied by the decline of sulfur-oxidizing bacteria (SOBs). In the end, we discovered that shortening the EBCT and increasing the reflux ratio could inhibit sulfide production by reducing it from 43.9 mg/L to 3.2 mg/L or 25.5 mg/L. In conclusion, our study highlights the importance of considering MS0D when designing and optimizing S0PB reactors for sustainable autotrophic sulfur denitrification in real-life applications.

Response of sulfur-metabolizing biofilm to external sulfide in element sulfur-based denitrification packed-bed reactor.

Dosing sulfide into the sulfur-packed-bed (S0PB) has great potential to enhance the denitrification efficiency by providing compensatory electron donors, however, the response of sulfur-metabolizing biofilm to various sulfide dosages has never been investigated. In this study, the S0PB reactor was carried out with increasing sulfide dosages by 3.6 kg/m3/d, presenting a decreasing effluent nitrate from 14.2 to 2.7 mg N/L with accelerated denitrification efficiency (k: 0.04 to 0.27). However, 6.5 mg N/L of nitrite accumulated when the sulfide dosage exceeded 0.9 kg/m3/d (optimum value). The increasing electron export contribution of sulfide a maximum of 85.5% illustrated its competition with the in-situ sulfur. Meanwhile, over-dosing sulfide caused serious biofilm expulsion with significant decreases in the total biomass, live cell population, and ATP by 90.2%, 86.7%, and 54.8%, respectively. This study verified the capacity of dosing sulfide to improve the denitrification efficiency in S0PB but alerted the negative effect of exceeded dosing.

Effect of sulfur particle morphology on the performance of element sulfur-based denitrification packed-bed reactor.

The effect of particle morphology on denitrification performance in element sulfur-based denitrification (ESDeN) packed-bed process is a gap. In this study, three different types of commercial sulfur particles were selected to build the ESDeN reactors. The results showed the reactors filled with rougher sulfur particles took shorter time to reach stable denitrification performance in the start-up stage. The reactors filled with cap-shape sulfur particles received the maximum nitrate removal rate of 849.49 ± 79.29 g N m-3 d-1 at empty bed contact time of 0.50 h, which was 2.34 times higher than that with ball-shape sulfur particles in the steady stage. The superior denitrification performance in the cap-shape particles set linked to its larger effective volumetric surface area (ωe, 1.67 times larger) and to the longer actual hydraulic retention time (AHRT, 1.80 times longer). This study extends the knowledge of the dependency of sulfur particle properties on denitrification performance in ESDeN packed-bed reactor.

Mutant C/EBPα p30 alleviates immunosuppression of CD8+ T cells by inhibiting autophagy-associated secretion of IL-1ß in AML.

OBJECTIVES: Mutant C/EBPα p30 (mp30), the product of C/EBPα double mutations (DM), lacks transactivation domain 1 and has C-terminal loss-of-function mutation. Acute myeloid leukaemia (AML) patients harbouring C/EBPα DM could be classified as a distinct subgroup with favourable prognosis. However, the underlying mechanism remains elusive. MATERIALS AND METHODS: Autophagy regulated by mp30 was detected by western blot and immunofluorescence. Immune infiltration analysis and GSEA were performed to investigate autophagic and inflammatory status of AML patients from the GSE14468 cohort. Flow cytometry was applied to analyse T cell activation. RESULTS: Mp30 inhibited autophagy by suppressing nucleus translocation of NF-κB. Autophagy-associated secretion of IL-1ß was decreased in mp30-overexpressed AML cells. Bioinformatic analysis revealed that inflammatory status was attenuated, while CD8+ T cell infiltration was upregulated in C/EBPα DM AML patients. Consistently, the proportion of CD8+ CD69+ T cells in peripheral blood mononuclear cells (PBMCs) was upregulated after co-culture with mp30 AML cell conditional culture medium. Knock-out of IL-1ß in AML cells also enhanced CD8+ T cell activation. Accordingly, IL-1ß expression was significantly reduced in the bone marrow (BM) cells of C/EBPα DM AML patients compared to the wildtype, while the CD8+ CD69+ T cell proportion was specifically elevated. CONCLUSIONS: C/EBPα DM alleviates immunosuppression of CD8+ T cells by inhibiting the autophagy-associated secretion of IL-1ß, which elucidated that repression of autophagy-related inflammatory response in AML patients might achieve a favourable clinical benefit.

Thiosulfate as external electron donor accelerating denitrification at low temperature condition in S0-based autotrophic denitrification biofilter.

This study was carried out to determine the inhibition of low temperature on the performance of S0-based autotrophic denitrification (S0-SAD) biofilter, and proposed to enhance the nitrate removal efficiency with thiosulfate as external electron donor. With the decline of temperature from 30 °C to 10 °C at 0.25 h of empty bed contact time (EBCT), the nitrate removal rate presented a logarithmical drop, and the effluent nitrate dramatically increased from 9.19 mg L-1 to 15.13 mg L-1. EBCT was prolonged until 0.33 h for 20 °C, 0.66 h for 15 °C and 1.5 h for 10 °C, respectively, to maintain the effluent nitrate below 10 mg L-1. Such excessive variation of EBCT for different temperature is undoubtedly incredible for practical engineering. Thiosulfate, as the external electron donor, was adopted to compensate the efficiency loss during temperature decrease, which significantly prompted nitrate removal rate to 0.59, 0.53 and 0.31 kg N m-3 d-1 at 20 °C, 15 °C and 10 °C conditions, respectively, even at a short EBCT of 0.25 h. It not only acted as compensatory electron donor for nitrate removal, but also promoted the contribution of elemental sulfur via accelerating the DO consumption and extended larger effective volume of S0-layer for denitrification. Meanwhile, the significant enrichment of Sulfurimonas and Ferritrophicum provided biological evidences to the enhancement process. However, the incomplete consumption of thiosulfate was observed especially at EBCT of 0.25 h and 10 °C, and the thiosulfate runoff needs to be concerned in case of contaminating the effluent. Herein, approximately extending EBCT to 0.66 h and decreasing thiosulfate dosage were conducted simultaneously, thereby achieving 100% thiosulfate utilization efficiency and expected nitrate removal. This study provided a fundamental guidance to design and operate S0-SAD biofilter in response to seasonal temperature variation for practical engineering.

Mitigating nitrite accumulation during S0-based autotrophic denitrification: Balancing nitrate-nitrite reduction rate with thiosulfate as external electron donor.

This study was carried out to determine the effect of influent nitrate loading on nitrite accumulation during elemental-sulfur based denitrification process, and proposed to enhance the nitrogen removal efficiency by mitigating nitrite accumulation with thiosulfate as external electron donor. Along with increasing the nitrate influent loading (from 0.09 kg N/m3/d to 1.73 kg N/m3/d) by shortening the empty bed contact time (EBCT) (from 5 h to 0.25 h), the nitrate removal loading increased from 0.08 to 0.83 kg N/m3/d. Meanwhile, the raise of the nitrate influent loading obviously aggravated the nitrite accumulation. Herein, nitrite began to accumulate since the nitrate influent loading was over 0.86 kg N/m3/d, and a maximum nitrite accumulation of 2.39 mg/L was observed under the 0.25 h of EBCT and 15 mg/L of nitrate influent concentration condition. Thiosulfate was used as the external electron donor to accelerate the nitrite reduction rate in order to mitigate the nitrite accumulation. As a result, the nitrite accumulation significantly decreased from 2.39 mg/L to 0.17 mg/L with the thiosulfate dosage of 13.36 mg/L. However, the nitrite accumulation bounced with the on-going increase of the thiosulfate dosage, indicating that the nitrate reduction rate and nitrite reduction rate were accelerated alternatively. After dosing thiosulfate, the relative abundances of sulfurimonas and ferritrophicum grew up significantly.

Association of changes in waist circumference with cardiovascular disease and all-cause mortality among the elderly Chinese population: a retrospective cohort study.

BACKGROUND: To examine the association of baseline waist circumference (WC) and changes in WC with cardiovascular disease (CVD) and all-cause mortality among elderly people. METHODS: A total of 30,041 eligible participants were included from a retrospective cohort in China. The same questionnaire, anthropometric and laboratory measurements were performed at baseline (2010) and the first follow-up (2013). The percent change in WC between baseline and the first follow-up was calculated to evaluate three years change of WC. We collected the occurrence of CVD and all-cause death from the first follow-up to December 31, 2018. Restricted cubic splines and Cox proportional-hazards regression models were used to evaluate the relationship between baseline WC/ changes in WC and mortality. RESULTS: The dose-response relationships between baseline WC and CVD mortality were U- or J-shaped. In low WC group, compared with stable group, the fully adjusted hazard ratio (aHR) for CVD mortality was 1.60 (95% CI: 1.24-2.06) in WC gain group among men. In normal WC group, the CVD mortality risk increased with WC gain (men: aHR = 1.86, 95% CI: 1.36-2.56; women: aHR = 1.83, 95% CI: 1.29-2.58). In moderate-high WC group, the CVD mortality risk increased with WC gain (men: aHR = 1.76, 95% CI: 1.08-2.88; women: aHR = 1.46, 95% CI: 1.04-2.05) and risk decreased with WC loss (men: aHR = 0.54, 95% CI: 0.30-0.98; women: aHR = 0.59, 95% CI: 0.37-0.96). CONCLUSIONS: For the elderly population, WC gain may increase CVD mortality risk regardless of baseline WC, whereas WC reduction could decrease the risk only in the moderate-high WC group.

[Effect of different melatonin treatment regimens on white matter damage in neonatal rats with hypoxic-ischemic brain damage].

OBJECTIVE: To study the effect of different melatonin treatment regimens on long-term behavior and white matter damage in neonatal rats with hypoxic-ischemic brain damage (HIBD), and to seek an optimal melatonin treatment regimen. METHODS: Healthy Sprague-Dawley rats, aged 7 days, were randomly divided into four groups: sham-operation, HIBD, single-dose immediate treatment (SDIT), and 7-day continuous treatment (7DCT), with 8 rats in each group. A neonatal rat model of HIBD was prepared according to the classical Rice-Vannucci method. On day 21 after HIBD, the Morris water maze test was used to evaluate spatial learning and memory abilities. On day 70 after HIBD, immunofluorescence assay was used to measure the expression of neuronal nuclear antigen (NeuN) in the cerebral cortex and the hippocampal CA1 region of neonatal rats, and double-label immunofluorescence was used to measure the expression of myelin basic protein (MBP) and neurofilament 200 (NF200) in the corpus striatum and the corpus callosum. RESULTS: The results of the Morris water maze test showed that the SDIT and 7DCT groups had a significantly shorter mean escape latency than the HIBD group, and the 7DCT group had a significantly shorter mean escape latency than the SDIT group (P < 0.05). The results of immunofluorescence assay for NeuN showed that the SDIT and 7DCT groups had a significantly higher number of NeuN+ cells in the cerebral cortex and the hippocampal CA1 region than the HIBD group, and the 7DCT group had a significantly higher number than the SDIT group (P < 0.05). MBP/NF200 double-label immunofluorescence showed that compared with the HIBD group, the SDIT group and the 7DCT group had significantly higher fluorescence intensities of MBP and NF200 in the corpus striatum, and the 7DCT group had significantly higher fluorescence intensities than the SDIT group (P < 0.05); the 7DCT group had significantly higher fluorescence intensities of MBP and NF200 in the corpus callosum than the SDIT and HIBD groups (P < 0.05). CONCLUSIONS: Both SDIT and 7DCT can improve long-term behavior and reduce white matter damage in neonatal rats with HIBD, and 7DCT is more effective than SDIT.

MCCC2 promotes HCC development by supporting leucine oncogenic function.

BACKGROUND: The role of methylcrotonoyl-CoA carboxylase 2 (MCCC2) in the development of tumors is well-established, and the involvement of leucine in the liver is well-known. However, the role of MCCC2 and the correlation between MCCC2 and leucine in the progression of hepatocellular carcinoma (HCC) have not yet been reported. METHODS: In this study, the Gepia database was used to evaluate the prognostic value of MCCC2 in HCC. The expression and localization of MCCC2 in HCC cells were determined by western blot and immunofluorescence assays. Flow cytometry and CCK-8 and transwell assays were carried out to explore the effect of MCCC2 on cell proliferation, migration, and invasion. In addition, mass spectrometry analysis was used to predict the potential cell function of MCCC2 in HCC. RESULTS: We found that the expression of MCCC2 increased in HCC tissues and that high expression of MCCC2 could predict poor outcomes in HCC patients. Knockdown expression of MCCC2 in HCC cells could reduce cell proliferation, migration, and invasion ability in vitro and could inhibit HCC cell proliferation in vivo. Interestingly, we found that HCC cells transfected with MCCC2-sgRNA failed to respond to leucine deprivation. Meanwhile, leucine deprivation inhibited cell proliferation, migration, and invasion in HCC cells where MCCC2 was present rather than in cells where MCCC2 was absent. In addition, knockdown of MCCC2 significantly reduced the glycolysis markers, glucose consumption, lactate secretion, and acetyl-CoA level, which is a product of leucine metabolism. Furthermore, we found that MCCC2 promotes the activation of ERK. Profiling the MCCC2 binding proteins revealed that MCCC2-associated proteins are enriched in biological processes, such as protein metabolism, energy pathway, and metabolism in HCC cells. CONCLUSIONS: Our findings revealed that MCCC2 plays a critical role in the development of HCC, and the leucine metabolism pathway might be a novel target in HCC treatment.

Melatonin-mediated regulation of anthocyanin biosynthesis and antioxidant defense confer tolerance to arsenic stress in Camellia sinensis L.

Arsenic is a toxic metalloid for both animals and plants. The signaling molecule melatonin can enhance abiotic stress tolerance, but the effects of As and melatonin on tea plants and the mechanisms of resilience remain unclear. Here we report that excess As causes severe oxidative stress in tea leaves as revealed by significantly reduced maximal photochemical efficiency of photosystem-II, and increased reactive oxygen species accumulation and lipid peroxidation. However, exogenous melatonin application alleviated the As phytotoxicity and increased the anthocyanin content upto 69.4 % by selectively upregulating the expression of its biosynthetic genes such as CsCHS and CsANS. Comparison of As tolerance between two tea genotypes differing in basal levels of anthocyanin revealed that a tea cultivar with increased anthocyanin content, Zijuan (ZJ), showed enhanced tolerance to As stress compared with Longjing 43 (LJ43) that contained relatively low levels of anthocyanin. Interestingly, exogenous anthocyanin also enhanced As tolerance in LJ43, but exogenous melatonin did not improve As tolerance in ZJ genotype. Analysis of As content in tea leaves revealed that melatonin significantly reduced As content in LJ43 but not in ZJ, suggesting that melatonin-enhanced tolerance to As stress is largely dependent on the basal levels of anthocyanin in tea plants.

Association of level of leisure-time physical activity with risks of all-cause mortality and cardiovascular disease in an elderly Chinese population: a prospective cohort study.

BACKGROUND: Implementing the current guidelines for leisure-time physical activity (LTPA) provides significant health benefits, especially for middle-aged adults, but it is unclear whether LTPA also translates into cardiovascular health benefits among elderly people. Therefore, we aimed to assess the association of LTPA with the risks of cardiovascular disease (CVD), including coronary heart disease (CHD) and stroke, and all-cause mortality in an elderly population. METHODS: In this prospective cohort study, 32, 942 participants aged 60 years or older who participated in a health check-up programme in China between 2010 and 2018 were included. We evaluated the morbidity and mortality risks through the Cox regression model, competing risk model and restricted cubic spline model. RESULTS: During a median of 6.84 years of follow-up, there were 6, 857 elderly people with incident CVD; a total of 6, 324 deaths occurred due to all causes and 2, 060 deaths occurred due to CVD. Compared with the inactive group, reductions in CVD morbidity and mortality were observed, with hazard ratios (HRs) of 0.89 (95% CI: 0.83-0.96) and 0.81 (95% CI: 0.71-0.92) in the insufficiently active group, 0.86 (95% CI: 0.80-0.92) and 0.79 (95% CI: 0.69-0.90) in the sufficiently active group, and 0.79 (95% CI: 0.70-0.89) and 0.58 (95% CI: 0.45-0.76) in the highly active group, respectively; but no significant reductions were observed in the very highly active group, with HRs of 0.87 (95% CI: 0.71-1.06) and 0.99 (95% CI: 0.70-1.40), respectively. Compared with the inactive group, reductions in all-cause mortality were also observed, with a HR of 0.90 (95% CI: 0.84-0.97) in the insufficiently active group, 0.82 (95% CI: 0.77-0.89) in the sufficiently active group, 0.77 (95% CI: 0.67- 0.87) in the highly active group, and 0.80 (95% CI: 0.64-0.98) in the very highly active group. A restricted cubic spline diagram showed that there was an L-shaped association between LTPA and the risk of all-cause mortality but a U-shaped or reverse J-shaped relationship between LTPA and the risk of CVD morbidity and mortality, especially stroke. In addition, a subgroup analysis showed that elderly population who consistently performed LTPA for ten years or more had a lower risk of morbidity and mortality. CONCLUSIONS: In an elderly population, even insufficient activity is associated with a decreased risk of all-cause mortality and CVD, and moderate levels of LTPA may be optimal for CVD prevention. In addition, elderly people who consistently perform LTPA over several years may experience greater health benefits.

Aurora kinase inhibitor restrains STAT5-activated leukemic cell proliferation by inducing mitochondrial impairment.

Current chemotherapy regimens on acute myeloid leukemia (AML) still have some drawbacks, such as intolerance and drug resistance, which calls need for the development of targeted therapy. Signal transducer and activator of transcription 5 (STAT5) is often overexpressed or abnormally activated in leukemia and involved in cell self-renewal, proliferation, and stress adaptation. Overexpressed Aurora A (AURKA) is associated with poor prognosis in tumors, and inhibitors against AURKA are already in clinical trials. However, it has rarely been reported whether AURKA inhibitors restrain STAT5-activated leukemia cells. In this study, we constructed STAT5 constitutively activated (cS5) cells and found that STAT5 promoted cell proliferation and colony formation. Moreover, cS5 cells showed elevated reactive oxygen species (ROS) and adenosine triphosphate (ATP) levels, which indicated higher mitochondrial metabolism in cS5 cells. A novel AURKA inhibitor AKI604 was synthesized and showed significant inhibitory effects to the proliferation and colony formation in both STAT5 constitutively activated and nonactivated AML cells. AKI604 induced mitochondrial impairment, leading to the disruption of mitochondrial membrane potential and the elevation of ROS as well as cellular calcium (Ca2+ ) levels. AKI604 could also decline basal oxygen consumption rate and ATP biosynthesis, indicating the damage of oxidative phosphorylation. Furthermore, AKI604 exhibited significant antitumor effect in the HL-60 cS5 xenograft model of the BALB/c nude mice without an obvious influence on mice body weight and other healthy indicators. This study suggested that AKI604 was a potential strategy to overcome STAT5-induced leukemic proliferation in AML treatment by inducing mitochondrial impairment.

Epigallocatechin-3-gallate enhances tomato resistance to tobacco mosaic virus by modulating RBOH1-dependent H2O2 signaling.

Tobacco mosaic virus (TMV) is one of the most damaging plant viruses from an economic and research point of view. Epigallocatechin-3-Gallate (EGCG), a flavonoid type secondary metabolite can selectively improve plant defense against pathogens; however, the effect of EGCG on plant defense against TMV and the underlying mechanism(s) remain elusive. In this study, exogenous EGCG application increased plant resistance to TMV as revealed by significantly decreased transcript levels of TMV-coat protein (CP) in tomato leaves. A time-course of H2O2 concentrations in tomato leaves showed that TMV inoculation rapidly increased the H2O2 accumulation, reaching its peak at 3 days post-inoculation (dpi) which remained the highest until 6 dpi. However, the combined treatment of EGCG and TMV remarkably decreased the concentrations of H2O2 at 3 and 6 dpi. Meanwhile, the transcript levels of RESPIRATORY BURST OXIDASE HOMOLOG 1 (SlRBOH1) were significantly increased by either EGCG or TMV inoculation, but the EGCG treatment along with TMV caused a further upregulation in the SlRBOH1 transcripts compared with that in only TMV-inoculated plants. Chemical scavenging of H2O2 or silencing SlRBOH1 both compromised the EGCG-induced enhanced resistance to TMV. Furthermore, EGCG-induced elevation in the activity of antioxidant enzymes was abolished by SlRBOH1 silencing, suggesting that EGCG enhanced defense against TMV by increasing the antioxidant enzyme activity via RBOH1-dependent H2O2 signaling. Taken together, our results suggest that EGCG functioned to maintain a delicate balance between ROS signaling and ROS scavenging via RBOH1, which enhanced tomato resistance to TMV.

Measurement of morphological parameters of giant cell tumor of bone in the knee.

The aim of the present study was to characterize the morphological parameters of giant cell tumor of bone (GCTB) in the knee. The imaging data of 250 patients with GCTB in the knee were retrospectively reviewed, and the morphological parameters were analyzed. The study included 137 cases with GCTB in the distal femur and 113 cases with GCTB in the proximal tibia. The maximal longitudinal diameter of the tumor was 6.616±2.322 cm in the femur group and 5.738±2.278 cm in the tibia group (P=0.003). The maximal transverse diameter in the two groups was 4.865±1.525 and 4.313±1.309 cm, respectively (P=0.003). The shortest distance from the articular surface (SDAS) in the two groups was 0.381±0.404 and 0.280±0.328 cm, respectively (P=0.035), whereas the longest distance from the articular surface in the two groups was 6.924±2.135 and 5.878±1.825 cm, respectively (P=0.001). There were statistically significant differences between the two groups in terms of the range of SDAS (P=0.043). Additionally, the incidence of pathological fractures in the femur was higher compared with that in the tibia (P=0.001), and the incidence of pathological fractures in the two groups gradually increased with the increase in lesion diameter. GCTB in the distal femur was larger compared with that in the proximal tibia, whereas GCTB in the tibia was closer to the articular surface compared with that in the femur. Furthermore, the incidence of pathological fractures in the femur was higher compared with that in the tibia.

High expression of Anxa2 and Stat3 promote progression of hepatocellular carcinoma and predict poor prognosis.

AIM: To elucidate whether the interaction between Anxa2 and Stat3 could promote the progression of hepatocellular carcinoma (HCC) and that high co-expression of Anxa2 and Stat3 could predict poor prognosis in HCC patients. METHODS: We investigated Anxa2 and Stat3 expression using Western blot analysis in 4 HCC and adjacent nontumor tissues and using immunohistochemistry in 100 patients' paraffin sections. Then we assessed the expression of Stat3, Anxa2 and co-expression of Stat3 and Anxa2 with relevant clinical pathological parameters and their prognostic value in HCC patients. The recurrence and overall survival rates were estimated using the Kaplan-Meier method and compared with the log-rank test. The prognostic analysis was carried out with univariate and multivariate Cox regressions models. RESULTS: The incidence of high Stat3 expression in HCC tissues (35%) was significantly higher than that in non-HCC tissues (8%) (P < 0.001). The same result was observed in Anxa2 (P < 0.001). Also, the overexpression of Stat3 or Anxa2 showed a significant relationship with the recurrence of the 100 HCC patients (P = 0.012; P = 0.003). Additionally, tumor size >3 cm in diameter, multiple tumor number, and the presence of microvascular tumor thrombus were also significantly associated with recurrence in 100 patients. Then, all enrolled patients were divided into four groups according to IHC score of Stat3 and Anxa2, and the results indicated a significant difference in recurrence time between the subgroups (P < 0.001). What's more, co-highexpression of Stat3 and Anxa2 was related to the presence of microvascular tumor thrombus (P = 0.003) and poor tumor differentiation (P < 0.001), but not relevant with other clinical features (All P > 0.05). CONCLUSION: The expression of Stat3, Anxa2, or co-high-expression of the two proteins was associated with HCC recurrence and survival.