Understanding the dynamics and underlying mechanism of carbon exchange between terrestrial ecosystems and the atmosphere is one of the key issues in global change research. In this study, we ...quantified the carbon fluxes in different terrestrial ecosystems in China, and analyzed their spatial variation and environmental drivers based on the long‐term observation data of ChinaFLUX sites and the published data from other flux sites in China. The results indicate that gross ecosystem productivity (GEP), ecosystem respiration (ER), and net ecosystem productivity (NEP) of terrestrial ecosystems in China showed a significantly latitudinal pattern, declining linearly with the increase of latitude. However, GEP, ER, and NEP did not present a clear longitudinal pattern. The carbon sink functional areas of terrestrial ecosystems in China were mainly located in the subtropical and temperate forests, coastal wetlands in eastern China, the temperate meadow steppe in the northeast China, and the alpine meadow in eastern edge of Qinghai‐Tibetan Plateau. The forest ecosystems had stronger carbon sink than grassland ecosystems. The spatial patterns of GEP and ER in China were mainly determined by mean annual precipitation (MAP) and mean annual temperature (MAT), whereas the spatial variation in NEP was largely explained by MAT. The combined effects of MAT and MAP explained 79%, 62%, and 66% of the spatial variations in GEP, ER, and NEP, respectively. The GEP, ER, and NEP in different ecosystems in China exhibited ‘positive coupling correlation’ in their spatial patterns. Both ER and NEP were significantly correlated with GEP, with 68% of the per‐unit GEP contributed to ER and 29% to NEP. MAT and MAP affected the spatial patterns of ER and NEP mainly by their direct effects on the spatial pattern of GEP.
Compared to natural enzymes, nanomaterial-based artificial enzymes have attracted immense attention because of their high stability and cost-effectiveness. In this study, cobalt nitride (Co4N) as a ...noble-metal-free artificial enzyme exhibiting highly intrinsic peroxidase-like activity and good stability was reported. Kinetic studies revealed that the resultant Co4N nanowires (NWs) exhibited a stronger affinity for 3,3′,5,5′-tetramethylbenzidine (TMB) and H2O2 than HRP. Compared to Co3O4 NWs, Co4N NWs exhibited highly improved catalytic activities, with H2O2 exhibiting an apparent K m approximately 2 orders of magnitude less than that of Co3O4. In particular, the peroxidase-like activity of Co4N was maintained well over a wide range of temperatures and ionic strength. A Co4N-based method was further developed for the detection of glucose with good sensitivity and reliability. Because of advantages such as easy storage, cost-effectiveness, high sensitivity, and outstanding stability, Co4N NWs demonstrate the potential for replacing noble-metal-based peroxidase mimetics in a wide range of promising applications.
Urban greening has been widely regarded as one of the most effective strategies for alleviating the risk of urban heat island (UHI). In this study, the metropolitan region of Beijing in China, was ...chosen as the study area. We used urban blocks as the special units for spatial analysis, and 17 landscape factors, including both landscape composition and configuration metrics, were chosen as the explanation variables for seasonal land surface temperature (LST). Based on these, we examined the potential differences in the relationship between urban LST and the landscape characteristics of urban green space (UGS) in different seasons and UGS gradients. Our results confirmed the significant cooling effect by UGS at a city-block-scale. However, the roles of UGS landscape composition and configuration on impacting LST varied in different seasons and UGS gradients. Generally, the cooling effect of UGS is more significant in locations with warmer climate or lower UGS coverage, and the landscape composition characteristics of UGS had a dominant effect on the variation of LST. On the contrary, in cold seasons or higher UGS ratios, the landscape configuration characteristics of UGS, such as the edge density of urban forest patches, would predominantly function to alleviate UHI than landscape composition in urban blocks. Moreover, the geometry features of urban blocks were also found to have a certain influence on LST. These findings demonstrated that the influence of UGS landscape features on urban surface thermal environment is very complex at city-block-scale. Therefore, for UHI mitigation, a prerequisite for multifactor analysis must be taken into consideration during the implementation of urban greening.
Stimulator-of-interferon genes (STING) is vital for sensing cytosolic DNA and initiating innate immune responses against microbial infection and tumors. Redox homeostasis is the balance of oxidative ...and reducing reactions present in all living systems. Yet, how the intracellular redox state controls STING activation is unclear. Here, we show that cellular redox homeostasis maintained by glutathione peroxidase 4 (GPX4) is required for STING activation. GPX4 deficiency enhanced cellular lipid peroxidation and thus specifically inhibited the cGAS-STING pathway. Concordantly, GPX4 deficiency inhibited herpes simplex virus-1 (HSV-1)-induced innate antiviral immune responses and promoted HSV-1 replication in vivo. Mechanistically, GPX4 inactivation increased production of lipid peroxidation, which led to STING carbonylation at C88 and inhibited its trafficking from the endoplasmic reticulum (ER) to the Golgi complex. Thus, cellular stress-induced lipid peroxidation specifically attenuates the STING DNA-sensing pathway, suggesting that GPX4 facilitates STING activation by maintaining redox homeostasis of lipids.
Treponema pallidum (Tp) has a well-known ability to evade the immune system and can cause neurosyphilis by invading the central nervous system (CNS). Microglia are resident macrophages of the CNS ...that are essential for host defense against pathogens, this study aims to investigate the interaction between Tp and microglia and the potential mechanism. Here, we found that Tp can exert significant toxic effects on microglia in vivo in Tg (mpeg1: EGFP) transgenic zebrafish embryos. Single-cell RNA sequencing results showed that Tp downregulated autophagy-related genes in human HMC3 microglial cells, which is negatively associated with apoptotic gene expression. Biochemical and cell biology assays further established that Tp inhibits microglial autophagy by interfering with the autophagosome-lysosome fusion process. Transcription factor EB (TFEB) is a master regulator of lysosome biogenesis, Tp activates the mechanistic target of rapamycin complex 1 (mTORC1) signaling to inhibit the nuclear translocation of TFEB, leading to decreased lysosomal biogenesis and accumulated autophagosome. Importantly, the inhibition of autophagosome formation reversed Tp-induced apoptosis and promoted microglial clearance of Tp. Taken together, these findings show that Tp blocks autophagic flux by inhibiting TFEB-mediated lysosomal biosynthesis in human microglia. Autophagosome accumulation was demonstrated to be a key mechanism underlying the effects of Tp in promoting apoptosis and preventing itself from clearing by human microglia. This study offers novel perspectives on the potential mechanism of immune evasion employed by Tp within CNS. The results not only establish the pivotal role of autophagy dysregulation in the detrimental effects of Tp on microglial cells but also bear considerable implications for the development of therapeutic strategies against Tp, specifically involving mTORC1 inhibitors and autophagosome formation inhibitors, in the context of neurosyphilis patients.
Abstract
Background
Sorafenib is a kinase inhibitor that is used as a first-line therapy in advanced hepatocellular carcinoma (HCC) patients. However, the existence of sorafenib resistance has ...limited its therapeutic effect. Through RNA sequencing, we demonstrated that miR-138-1-3p was downregulated in sorafenib resistant HCC cell lines. This study aimed to investigate the role of miR-138-1-3p in sorafenib resistance of HCC.
Methods
In this study, quantitative real-time PCR (qPCR) and Western Blot were utilized to detect the levels of PAK5 in sorafenib-resistant HCC cells and parental cells. The biological functions of miR-138-1-3p and PAK5 in sorafenib-resistant cells and their parental cells were explored by cell viability assays and flow cytometric analyses. The mechanisms for the involvement of PAK5 were examined via co-immunoprecipitation (co-IP), immunofluorescence, dual luciferase reporter assay and chromatin immunoprecipitation (ChIP). The effects of miR-138-1-3p and PAK5 on HCC sorafenib resistant characteristics were investigated by a xenotransplantation model.
Results
We detected significant down-regulation of miR-138-1-3p and up-regulation of PAK5 in sorafenib-resistance HCC cell lines. Mechanistic studies revealed that miR-138-1-3p reduced the protein expression of PAK5 by directly targeting the 3′-UTR of PAK5 mRNA. In addition, we verified that PAK5 enhanced the phosphorylation and nuclear translocation of β-catenin that increased the transcriptional activity of a multidrug resistance protein ABCB1.
Conclusions
PAK5 contributed to the sorafenib resistant characteristics of HCC via β-catenin/ABCB1 signaling pathway. Our findings identified the correlation between miR-138-1-3p and PAK5 and the molecular mechanisms of PAK5-mediated sorafenib resistance in HCC, which provided a potential therapeutic target in advanced HCC patients.
To investigate the factors associated with the duration of severe acute respiratory syndrome coronavirus 2 RNA shedding in patients with coronavirus disease 2019 (COVID‐19). A retrospective cohort of ...COVID‐19 patients admitted to a designated hospital in Beijing was analyzed to study the factors affecting the duration of viral shedding. The median duration of viral shedding was 11 days (IQR, 8‐14.3 days) as measured from illness onset. Univariate regression analysis showed that disease severity, corticosteroid therapy, fever (temperature>38.5°C), and time from onset to hospitalization were associated with prolonged duration of viral shedding (P < .05). Multivariate regression analysis showed that fever (temperature>38.5°C) (OR, 5.1, 95%CI: 1.5‐18.1), corticosteroid therapy (OR, 6.3, 95%CI: 1.5‐27.8), and time from onset to hospitalization (OR, 1.8, 95%CI: 1.19‐2.7) were associated with increased odds of prolonged duration of viral shedding. Corticosteroid treatment, fever (temperature>38.5°C), and longer time from onset to hospitalization were associated with prolonged viral shedding in COVID‐19 patients.
Highlights
Corticosteroid treatment was associated with prolonged viral shedding in COVID‐19 patients
More favorable treatment against epithelial ovarian cancer (EOC) is urgently needed because of its insidious nature at an early stage and a low rate of five-year survival. The current primary ...treatment, extensive surgery combined with chemotherapy, exhibits limited benefits for improving prognosis. Chimeric antigen receptor T (CAR-T) cell technology as novel immunotherapy has made breakthrough progress in the treatment of hematologic malignancies, and there were also benefits shown in a partial solid tumor in previous research. Therefore, CAR-T cell technology may be a promising candidate as an immunotherapeutic tool against EOC. However, there are some weaknesses in targeting one antigen from the previous preclinical assay, such as on-target off-tumor cytotoxicity. The dual-target CAR-T cell may be a better choice.
We constructed tandem PD1-antiMUC16 dual-CAR, PD1 single-CAR, and anti-MUC16 single-CAR fragments by PCR and genetic engineering, followed by preparing CAR-T cells via lentiviral infection. The expression of CAR molecules on single and dual CAR-T cells was detected by flow cytometry. The killing capacity and activation of CAR-T cells were measured by cytotoxic assays and cytokines release assays in vitro. The therapeutic capacity of CAR-T cells was assessed by tumor-bearing mice model assay in vivo.
We successfully constructed CARs lentiviral expression vectors and obtained single and dual CAR-T cells. CAR-T cells demonstrated robust killing capacity against OVCAR-3 cells in vitro. Meanwhile, CAR-T cells released plenty of cytokines such as interleukin-2(IL-2), interferon-γ (IFN-γ) and tumor necrosis factor-α(TNF-α). CAR-T cells showed a therapeutic benefit against OVCAR-3 tumor-bearing mice and significantly prolonged the survival time. Dual CAR-T cells were shown to be two to four times more efficacious than single CAR-T cells in terms of survival time.
Although exhibiting a similar ability as single CAR-T cells against OVCAR-3 cells in vitro, dual CAR-T cells demonstrated enhanced killing capacity against OVCAR-3 cells as compared to single CAR-T cells in vivo and significantly prolonged the survival time of tumor-bearing mice. PD1-antiMUC16 CAR-T cells showed more potent antitumor activity than single CAR-T cells in vivo. The present experimental data may support further research work that will have the potential to lead to clinical studies.
The nutritional components in oat and tartary buckwheat had been assessed to have cholesterollowering effects. However, The effect of oat and tartary buckwheat based-food (OF) on cholesterol-lowering ...and gut microbiota in hypercholesterole hamsters was still limited studied because they are usually consumed in whole gran as well as after being processed. In this study, normal diets, high fat diet (HFD) with/without OF were fed to hamsters for 30 days respectively and growth parameters, metabolic parameters, and gut microbiota were investigated, respectively. It was found that OF significantly decreased plasma total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-cholesterol), lowered liver TC, cholesterol ester (CE), and triglycerides (TG) concentrations, and increased fecal weight and bile acids (BA) concentrations, compared with HFD (p < 0.05). Moreover, the concentrations of acetate, propionate, butyrate and total short-chain fatty acids (SCFAs) were significantly increased in hamsters fed with OF, compared with HFD (p < 0.05). OF changed the overall structure of gut microbiota. The relative abundances of Erysipelotrichaceae, Ruminococcaceae, and Lachnospiraceae were decreased and the relative abundance of Eubacteriaceae was increased, compared with HFD. These results suggested that OF could reduce the concentrations of plasma lipid by inhibiting cholesterol absorption in liver and promoting excretions of fecal lipid and BA. And it also increased SCFAs and modulated the gut microbiota effectively to exert the hypocholesterolemic effects.
Objective. To evaluate the incidence and safety of clinical complications associated with percutaneous endoscopic lumbar discectomy (PELD) for the treatment of recurrent lumbar disc herniation (RLDH) ...by meta-analysis. Methods. PubMed, Embase, The Cochrane Library, and Web of Science electronic databases were searched for clinical studies on complications related to the treatment of RLDH with PELD. The search time extended from the databases’ inception until May 2021. RevMan5.4 software was used for meta-analysis after two researchers independently scanned the literature, gathered data, and assessed the bias risk of the included studies. Results. A total of 8 clinical studies, including 1 randomized controlled trial and 7 cohort studies including 906 individuals, were included. According to the results of the meta-analysis, the overall complications (OR=0.18, 95% CI: 0.04-0.83, p=0.03) and dural tear rates (OR=0.11, 95% CI: 0.01-0.92, p=0.04) of PELD were lower than those of traditional fenestration nucleus pulposus removal. Moreover, the PELD group had a greater recurrence rate compared to the MIS-TLIF group (OR=19.71, 95% CI: 3.68-105.62, p=0.0005), and the difference was statistically significant. However, compared with MED and MIS-TLIF, there were no significant differences in the incidence of overall complications, dural tear, nerve root injury, and incomplete nucleus pulposus removal (P>0.05). Conclusion. PELD is an effective and safe method for the treatment of recurrent lumbar disc herniation, with a lower incidence of complications and higher safety profile than traditional fenestration nucleus pulposus removal.
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