Water availability, which can be represented by soil water content (SWC), plays a crucial role in plant growth and productivity across the cold and arid Qinghai-Tibetan Plateau. However, the indirect ...effects of SWC are less well understood, and a more comprehensive understanding of its regulating effects may enhance the recognition of its importance, as this factor is pivotal for accurately predicting the future response of alpine ecosystems to climate change. In this study, in situ eddy covariance observation data from typical alpine ecosystems and satellite data covering the Qinghai-Tibetan region were used to comprehensively reveal the effects of SWC on ecosystem productivity. The results indicated that SWC played an important role in regulating the responses of gross primary productivity (GPP) to other environmental factors over both time and space, especially in terms of the responses of GPP to vapor pressure deficit (VPD). The regulating effect can be summarized as follows: there was a specific SWC value (SWC = 0.24 m3 m−3 on the Qinghai-Tibetan Plateau) above which SWC was no longer the primary limiting factor. The responses of GPP to certain environmental factors shifted from negative to positive when the SWC increased above this value. The responses of GPP to VPD exhibited the highest sensitivity to the regulating effects of SWC, with a general response pattern found across different temporal and spatial scales. The findings revealed divergent responses of GPP to environmental factors under different SWC conditions and between arid and humid regions, emphasizing the importance of soil water conditions. These findings suggest that water conditions should be given primary consideration in global change studies.
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•The soil water content (SWC) controlled the alpine ecosystem productivity (GPP).•The responses of GPP to other factors shifted by an SWC threshold of 0.24 m3 m−3.•SWC threshold (0.24) was verified and applicable at multiple spatiotemporal scales.•From arid to humid, the VPD shifted from a negative factor to a positive factor.•SWC would determine the responses of alpine ecosystems to future climate change.
•Droughts enhanced the control effects of biotic factors on carbon and water fluxes.•Droughts induced changes in the driving paths of biotic and abiotic factors on RUE.•RUE responded differently to ...droughts in different periods in the growing season.•Droughts in the mid-growing season reduced the RUE.
Drought is a threat universally faced by global terrestrial ecosystems under global climate change. The habitat of alpine ecosystems is harsh, and they necessitate to use the limited resources efficiently to survive. However, drought occurred frequently during the short growing season, which greatly affected their resource use efficiency (RUE). In this study, based on long-term flux and microclimate observations in a typical alpine meadow ecosystem in northern Tibet, the effects of drought on RUE, including water use efficiency (WUE), light use efficiency (LUE), and carbon use efficiency (CUE), were studied. The results indicate that droughts could change the driving paths of abiotic and biotic factors on carbon and water fluxes and hence affect RUE. When vegetation exhibits robust physiological activity, droughts could enhance the control effects of biotic factors. The droughts that occurred at different periods of the growing season showed divergent effects on RUE. In the early-growing season, the strong photosynthetic capacity of the nascent leaves facilitated enhancements in WUE and LUE in response to drought conditions. However, the CUE did not increase significantly due to the heightened consumption of organic matter by respiration. The mid-growing season droughts led to a sharp decrease in gross primary productivity (GPP), consequently leading to a decline in WUE, LUE and CUE. During the late-growing season, droughts together with the decomposition of chlorophyll reduced the photosynthetic capacity and led to a significant decrease in LUE. The diminished physiological activity of the senescent leaves led to insensitive responses of WUE and CUE to droughts. These findings indicate that RUE might primarily be regulated by factors affecting GPP rather than others. This study would be beneficial for assessing the responses and adaptation characteristics of alpine meadow ecosystems to future climate change and could help accurately predict their possible evolution trends.
Evidence is still limited for the role of long-term PM2.5 exposure in cerebrovascular diseases among residents in high pollution regions. The study is aimed to investigate the long-term effects of ...PM2.5 exposure on stroke mortality, and further explore the effect modification of temperature variation on the PM2.5-mortality association in northern China. Based on a cohort data with an average follow-up of 9.8 years among 38,435 urban adults, high-resolution estimates of PM2.5 derived from a satellite-based model were assigned to each participant. A Cox regression model with time-varying exposures and strata of geographic regions was employed to assess the risks of stroke mortality associated with PM2.5, after adjusting for individual risk factors. The cross-product term of PM2.5 exposure and annual temperature range was further added into the regression model to test whether the long-term temperature variation would modify the association of PM2.5 with stroke mortality. Among the study participants, the annual mean level of PM2.5 concentration was 66.3 μg/m3 ranging from 39.0 μg/m3 to 100.6 μg/m3. For each 10 μg/m3 increment in PM2.5, the hazard ratio (HR) was 1.31 (95% CI: 1.04–1.65) for stroke mortality after multivariable adjustment. In addition, the HRs of PM2.5 decreased gradually as the increase of annual temperature range with the HRs of 1.95 (95% CI: 1.36–2.81), 1.53 (95% CI: 1.06–2.22), and 1.11 (95% CI: 0.75–1.63) in the low, middle, and high group of annual temperature range, respectively. The findings provided further evidence of long-term PM2.5 exposure on stroke mortality in high-exposure settings such as northern China, and also highlighted the view that assessing the adverse health effects of air pollution might not ignore the role of temperature variations in the context of climate change.
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•The cohort data was combined with satellite-based PM2.5 at 1-km spatial resolution.•High levels of PM2.5 exposure increased risk of stroke mortality in northern China.•The stroke mortality-PM2.5 association was modified by annual temperature range.
Epithelial-mesenchymal transition (EMT) of lens epithelial cells (LECs) is a predominant pathological process underlying fibrotic cataracts. Here we investigated the role and mechanism of lanosterol ...synthase (LSS), a key rate-limiting enzyme in sterol biosynthesis, in EMT of LECs.
Human lens epithelial explants, primary rabbit LECs, and whole rat lenses were treated with TGFβ2. RNA-sequencing was conducted to explore genetic changes during fibrosis of human lens epithelial explants. Loss- and gain-of-function studies were performed in primary LECs to investigate roles and mechanisms of LSS, lanosterol and sterol regulatory element binding transcription protein 1 (SREBP1) in EMT. Rat lenses were applied to evaluate the potential effect of lanosterol on lens fibrosis. Expression of LSS, SREBP1, EMT-related regulators, and markers were analyzed by Western blot, qRT-PCR, or immunofluorescent staining.
LSS and steroid biosynthesis were downregulated in TGFβ2-induced lens fibrosis. LSS inhibition directly triggered EMT by inducing Smad2/3 phosphorylation and nucleus translocation, an overexpression of LSS protected LECs from EMT by inhibiting Smad2/3 activation. Moreover, LSS inhibition decreased the expression of SREBP1, which regulated EMT via intervening TGFβ2/Smad2/3 transduction. Furthermore, lanosterol protected LECs from EMT caused by both TGFβ2 treatment and LSS inhibition via suppressing Smad2/3 activation and maintained lens transparency by preventing fibrotic plaques formation.
We first identified that LSS protected LECs from EMT and played an antifibrotic role to maintain lens transparency. Additionally, lanosterol and sterol biosynthesis regulation might be promising strategies for preventing and treating fibrotic cataracts.
Several literatures have examined the risk of chronic respiratory diseases in association with short-term ambient PM2.5 exposure in China. However, little evidence has examined the chronic impacts of ...PM2.5 exposure on morbidity of chronic respiratory diseases in cohorts from high pollution countries. Our study aims to investigate the associations. Based on a retrospective cohort among adults in northern China, a Cox regression model with time-varying PM2.5 exposure and a concentration-response (C-R) curve model were performed to access the relationships between incidence of chronic respiratory diseases and long-term PM2.5 exposure during a mean follow-up time of 9.8 years. Individual annual average PM2.5 estimates were obtained from a satellite-based model with high resolution. The incident date of a chronic respiratory disease was identified according to self-reported physician diagnosis time and/or intake of medication for treatment. Among 38,047 urban subjects analyzed in all-cause chronic respiratory disease cohort, 482 developed new cases. In CB (38,369), asthma (38,783), and COPD (38,921) cohorts, the onsets were 276, 89, and 14, respectively. After multivariable adjustment, hazard ratio and 95% confidence interval for morbidity of all-cause chronic respiratory disease, CB, asthma, and COPD were 1.15 (1.01, 1.31), 1.20 (1.00, 1.42), 0.76 (0.55, 1.04), and 0.66 (0.29, 1.47) with each 10 μg/m3 increment in PM2.5, respectively. Stronger effect estimates were suggested in alcohol drinkers across stratified analyses. Additionally, the shape of C-R curve showed an increasing linear relationship before 75.00 μg/m3 concentrations of PM2.5 for new-onset all-cause chronic respiratory disease, and leveled off at higher levels. These findings indicated that long-term exposure to high-level PM2.5 increased the risks of incident chronic respiratory diseases in China. Further evidence of C-R curves is warranted to clarify the associations of adverse chronic respiratory outcomes involving air pollution.
•The first cohort study of PM2.5 and incidence of chronic respiratory diseases in China.•PM2.5 estimate was derived from the satellite-based data at 1-km spatial resolution.•C-R curve was performed for all-cause chronic respiratory disease linked to PM2.5.•Long-term high PM2.5 exposure increased morbidity of chronic respiratory diseases.
Human CUB and Sushi multiple domains (CSMD1) is considered a crucial role in cancer progression, but the specific function in esophageal squamous cell carcinoma (ESCC) is not clear. Understanding the ...role of CSMD1 in ESCC progression may lead to a novel strategy for ESCC treatment. Here, we found that both CSMD1 mRNA and protein levels were downregulated in ESCC tissues. Reduced CSMD1 expression was correlated with a poor prognosis in ESCC patients. CSMD1 expression inhibited proliferation, migration and invasion in ESCC cell lines in vitro. CSMD1 deficiency in established xenografted tumors increases tumor size and weight. We further found that CSMD1-overexpression cells are more sensitive to chemotherapy. Moreover, we addressed the role of CSMD1 in the CD8+ T cell immune response. An in vitro killing assay showed that the cytotoxicity of CD8+ T cells was inhibited in CSMD1-overexpression tumor cells. In vivo, in CSMD1 deficiency tumor-bearing mice activation and expansion of CD8+ T cells were increased. Further investigation showed that CSMD1 expression on tumor cells was positively correlated with CD8+ T cells infiltration and cytokines secretion. These findings highlight that CSMD1 is a tumor suppressor gene in ESCC patients and a positive regulator of CD8+ T cells expansion and activation, and could increase cytokines secretion, indicating that tumor cell-associated CSMD1 might be a target for ESCC.
•CSMD1 is a novel suppressor gene in ESCC.•CSMD1 promotes ESCC cell lines to sensitize to chemotherapy.•CSMD1 induces immunosuppression in ESCC by increasing CD8+ T cells and cytokines secretion.
Aims The present study was designed to investigate whether the beneficial effects of β-blocker propranolol are related to regulation of microRNA miR-1. Methods and results We demonstrated that ...propranolol reduced the incidence of arrhythmias in a rat model of myocardial infarction by coronary artery occlusion. Overexpression of miR-1 was observed in ischaemic myocardium and strikingly, administration of propranolol reversed the up-regulation of miR-1 nearly back to the control level. In agreement with its miR-1-reducing effect, propranolol relieved myocardial injuries during ischaemia, restored the membrane depolarization and cardiac conduction slowing, by rescuing the expression of inward rectifying K+ channel subunit Kir2.1 and gap junction channel connexin 43. Our results further revealed that the β-adrenoceptor–cAMP–Protein Kinase A (PKA) signalling pathway contributed to the expression of miR-1, and serum response factor (SRF), which is known as one of the transcriptional enhancers of miR-1, was up-regulated in ischaemic myocardium. Moreover, propranolol inhibited the β-adrenoceptor–cAMP–PKA signalling pathway and suppressed SRF expression. Conclusion We conclude that the β-adrenergic pathway can stimulate expression of arrhythmogenic miR-1, contributing to ischaemic arrhythmogenesis, and β-blockers produce their beneficial effects partially by down-regulating miR-1, which might be a novel strategy for ischaemic cardioprotection.
Autophagy has been reported to play an essential role in fibrotic disorders. Known as fibrotic cataract, posterior capsular opacification (PCO) result from pathological epithelial-mesenchymal ...transition (EMT) of lens epithelial cells (LECs). This study aims to identify the role and potential mechanism of autophagy in TGF-β2-induced EMT in LECs.
Primary rabbit LECs were treated with TGF-β2 to induce EMT as a model of fibrotic cataract in vitro. 3-methyladenine, chloroquine, bafilomycin A1, and gene silencing of autophagy-related protein 7 (ATG7) were treated in LECs for autophagy inhibition, while rapamycin was utilized for autophagy activation. The expression levels of EMT/autophagy-associated markers were analyzed by qRT-PCR, western blotting, immunofluorescence and transmission electron microscopy. We additionally examined cell migration ability with transwell migration assay and wound healing assay.
TGF-β2 promoted autophagy flux during EMT progression of LECs in a time-dependent manner. Autophagy activation by rapamycin enhanced TGF-β2-triggered fibrogenic responses and cell migration in LECs, whereas pharmacological inhibition of autophagy alleviated TGF-β2-induced increases of EMT markers and cell migration of LECs. In addition, the phosphorylation of Smad2/3 induced by TGF-β2 was suppressed through autophagy inhibition, while it was promoted upon autophagy activation, indicating that TGF-β2/Smad signaling was involved in the modulation of autophagy on EMT in LECs. Furthermore, ATG7-silenced LECs exerted anti-fibrosis effect induced by TGF-β2 through downregulation of autophagy.
Intervention/inhibition of autophagy could attenuate TGF-β2-induced EMT in LECs, which provides autophagy-related insights on preventing and treating the fibrotic cataract or other fibrotic diseases.
•Autophagy is activated in TGF-β2-induced EMT in LECs.•Autophagy activation enhances TGF-β2-triggered fibrogenic responses in LECs.•Pharmacological inhibition of autophagy alleviates TGF-β2-induced EMT in LECs.•TGF-β/Smad signaling is involved in the modulation of autophagy on EMT in LECs.•ATG7 knockdown abrogates TGF-β2-induced EMT in LECs.
PurposeDiabetic cataract (DC) is a visual disorder arising from diabetes mellitus (DM). Autophagy, a prosurvival intracellular process through lysosomal fusion and degradation, has been implicated in ...multiple diabetic complications. Herein, we performed in vivo and in vitro assays to explore the specific roles of the autophagy-lysosome pathway in DC. MethodsStreptozotocin-induced DM and incubation in high glucose (HG) led to rat lens opacification. Protein Simple Wes, Western blot, and immunoassay were utilized to investigate autophagic changes in lens epithelial cells (LECs) and lens fiber cells (LFCs). RNA-sequencing (RNA-seq) was performed to explore genetic changes in the lenses of diabetic rats. Moreover, autophagy-lysosomal functions were examined using lysotracker, Western blot, and immunofluorescence analyses in HG-cultured primary rabbit LECs. ResultsFirst, DM and HG culture led to fibrotic LECs, swelling LFCs, and eventually cataracts. Further analysis showed aberrant autophagic degradation in LECs and LFCs during cataract formation. RNA-seq data revealed that the differentially expressed genes (DEGs) were enriched in the lysosome pathway. In primary LECs, HG treatment resulted in decreased transcription factor EB (TFEB) and cathepsin B (CTSB) activity, and increased lysosomal size and pH values. Moreover, TFEB-mediated dysfunctional lysosomes resulted from excessive oxidative stress in LECs under HG conditions. Furthermore, TFEB activation by curcumin analog C1 alleviated HG-induced cataracts through enhancing lysosome biogenesis and activating protective autophagy, thereby attenuating HG-mediated oxidative damage. ConclusionsIn summary, we first identified that ROS-TFEB-dependent lysosomal dysfunction contributed to autophagy blockage in HG-induced cataracts. Additionally, TFEB-mediated lysosomal restoration might be a promising therapeutic method for preventing and treating DC through mitigating oxidative stress.
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