Ocean eddies produce strong vertical heat flux(VHF)in the upper ocean,exerting profound influences on the climate and ecosystem.Currently,mooring array provides a standard way to estimate the eddy-induced VHF(EVHF)bas...Ocean eddies produce strong vertical heat flux(VHF)in the upper ocean,exerting profound influences on the climate and ecosystem.Currently,mooring array provides a standard way to estimate the eddy-induced VHF(EVHF)based on the adiabatic potential density equation.Apart from the validity of adiabatic assumption,it remains unclear to what extent the estimated EVHF at a single location within a limited time period is representative of its climatological mean value.In this study,we analyzed the above issue by systematically evaluating the variability of EVHF simulated by a 1-km ocean model configured over the Kuroshio Extension.It is found that the EVHF at a single location exhibits pronounced variability.Even averaged over one year that is comparable to the current maintenance capacity of mooring array,the EVHF still deviates significantly from its climatological mean value.For more than 49%of locations in our computational domain(31°-40°N,149°-166°E),the discrepancy between the one-year mean EVHF and its climatological mean value at the peaking depth is larger than the climatological mean itself.The mesoscale eddies play a dominant role in the variability of EVHF but contribute little to the climatological mean EVHF;the opposite is true for submesoscale eddies.Our findings indicate that nested mooring array allowing for isolating the effects of submesoscale eddies will be useful to obtain climatological mean EVHF.展开更多
Pulmonary hypertension (PH) is a fatal disorder characterized by pulmonary vascular remodeling and obstruction. The phosphodiesterase 4 (PDE4) family hydrolyzes cyclic AMP (cAMP) and is comprised of four subtypes (PD...Pulmonary hypertension (PH) is a fatal disorder characterized by pulmonary vascular remodeling and obstruction. The phosphodiesterase 4 (PDE4) family hydrolyzes cyclic AMP (cAMP) and is comprised of four subtypes (PDE4A–D). Previous studies have shown the beneficial effects of pan-PDE4 inhibitors in rodent PH;however, this class of drugs is associated with side effects owing to the broad inhibition of all four PDE4 isozymes. Here, we demonstrate that PDE4B is the predominant PDE isozyme in lungs and that it was upregulated in rodent and human PH lung tissues. We also confirmed that PDE4B is mainly expressed in the lung endothelial cells (ECs). Evaluation of PH in Pde4b wild type and knockout mice confirmed that Pde4b is important for the vascular remodeling associated with PH. In vivo EC lineage tracing demonstrated that Pde4b induces PH development by driving endothelial-to-mesenchymal transition (EndMT), and mechanistic studies showed that Pde4b regulates EndMT by antagonizing the cAMP-dependent PKA–CREB–BMPRII axis. Finally, treating PH rats with a PDE4B-specific inhibitor validated that PDE4B inhibition has a significant pharmacological effect in the alleviation of PH. Collectively, our findings indicate a critical role for PDE4B in EndMT and PH, prompting further studies of PDE4B-specific inhibitors as a therapeutic strategy for PH.展开更多
Silicosis is a leading cause of occupational disease-related morbidity and mortality worldwide,but the molecular basis underlying its development remains unclear.An accumulating body of evidence supports gasdermin D(G...Silicosis is a leading cause of occupational disease-related morbidity and mortality worldwide,but the molecular basis underlying its development remains unclear.An accumulating body of evidence supports gasdermin D(GSDMD)-mediated pyroptosis as a key component in the development of various pulmonary diseases.However,there is little experimental evidence connecting silicosis and GSDMD-driven pyroptosis.In this work,we investigated the role of GSDMD-mediated pyroptosis in silicosis.Single-cell RNA sequencing of healthy and silicosis human and murine lung tissues indicated that GSDMD-induced pyroptosis in macrophages was relevant to silicosis progression.Through microscopy we then observed morphological alterations of pyroptosis in macrophages treated with silica.Measurement of interleukin-1βrelease,lactic dehydrogenase activity,and real-time propidium iodide staining further revealed that silica induced pyroptosis of macrophages.Additionally,we verified that both canonical(caspase-1-mediated)and non-canonical(caspase-4/5/11-mediated)signaling pathways mediated silica-induced pyroptosis activation,in vivo and in vitro.Notably,Gsdmd knockout mice exhibited dramatically alleviated silicosis phenotypes,which highlighted the pivotal role of pyroptosis in this disease.Taken together,our results demonstrated that macrophages underwent GSDMD-dependent pyroptosis in silicosis and inhibition of this process could serve as a viable clinical strategy for mitigating silicosis.展开更多
Silicosis is the most prevalent and fatal occupational disease with no effective therapeutics,and currently used drugs cannot reverse the disease progress.Worse still,there are still challenges to be addressed to full...Silicosis is the most prevalent and fatal occupational disease with no effective therapeutics,and currently used drugs cannot reverse the disease progress.Worse still,there are still challenges to be addressed to fully decipher the intricated pathogenesis.Thus,specifying the essential mechanisms and targets in silicosis progression then exploring anti-silicosis pharmacuticals are desperately needed.In this work,multi-omics atlas was constructed to depict the pivotal abnormalities of silicosis and develop targeted agents.By utilizing an unbiased and time-resolved analysis of the transcriptome,proteome and phosphoproteome of a silicosis mouse model,we have verified the significant differences in transcript,protein,kinase activity and signaling pathway level during silicosis progression,in which the importance of essential biological processes such as macrophage activation,chemotaxis,immune cell recruitment and chronic inflammation were emphasized.Notably,the phosphorylation of EGFR(p-EGFR)and SYK(pSYK)were identified as potential therapeutic targets in the progression of silicosis.To inhibit and validate these targets,we tested fostamatinib(targeting SYK)and Gefitinib(targeting EGFR),and both drugs effectively ameliorated pulmonary dysfunction and inhibited the progression of inflammation and fibrosis.Overall,our drug discovery with multi-omics approach provides novel and viable therapeutic strategies for the treatment of silicosis.展开更多
To the Editor:Cancer has been recognized as an independent predisposing factor of venous thromboembolism(VTE),including pulmonary embolism(PE)and deep vein thrombosis(DVT).Patients with cancer have a sevenfold increas...To the Editor:Cancer has been recognized as an independent predisposing factor of venous thromboembolism(VTE),including pulmonary embolism(PE)and deep vein thrombosis(DVT).Patients with cancer have a sevenfold increased risk of VTE compared with those without cancer.[1]Evidence from autopsy in cancer patients showed that PE is an important disease complication in patients with cancer.[2]Optimal management of PE patients with cancer has become a major concern that challenges clinicians in daily clinical practice.Understanding the risk factors of all-cause death in PE patients with cancer in the real world may enable optimal management and improve their survival.Therefore,this study was performed to characterize cancerassociated PE and evaluate the clinical predictors of inhospital death based on the data of PE patient population in China.展开更多
基金The Taishan Scholar Fund under contract No.tsqn201909052。
文摘Ocean eddies produce strong vertical heat flux(VHF)in the upper ocean,exerting profound influences on the climate and ecosystem.Currently,mooring array provides a standard way to estimate the eddy-induced VHF(EVHF)based on the adiabatic potential density equation.Apart from the validity of adiabatic assumption,it remains unclear to what extent the estimated EVHF at a single location within a limited time period is representative of its climatological mean value.In this study,we analyzed the above issue by systematically evaluating the variability of EVHF simulated by a 1-km ocean model configured over the Kuroshio Extension.It is found that the EVHF at a single location exhibits pronounced variability.Even averaged over one year that is comparable to the current maintenance capacity of mooring array,the EVHF still deviates significantly from its climatological mean value.For more than 49%of locations in our computational domain(31°-40°N,149°-166°E),the discrepancy between the one-year mean EVHF and its climatological mean value at the peaking depth is larger than the climatological mean itself.The mesoscale eddies play a dominant role in the variability of EVHF but contribute little to the climatological mean EVHF;the opposite is true for submesoscale eddies.Our findings indicate that nested mooring array allowing for isolating the effects of submesoscale eddies will be useful to obtain climatological mean EVHF.
基金This work was supported by Beijing Natural Science Foundation[Z220019 to Jing Wang,China]National High Level of Hospital Clinical Research Funding[2022-PUMCH-D-002 to Jing Wang,China]+3 种基金National Key Research and Development Program of China Grants[2019YFA0801703 and 2019YFA0801804 to Jing Wang]Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences[2022-I2M-JB-007 to Chen Wang,2021-I2M-1-016 to Hongmei Zhao,2021-I2M-1-049 to Jing Wang,2021-I2M-1-005 to Yanjiang Xing,China]Haihe Laboratory of Cell Ecosystem Innovation Fund[22HHXBSS00010 to Jing Wang,China]National Natural Science Foundation of China[82241004 to Jing Wang].
文摘Pulmonary hypertension (PH) is a fatal disorder characterized by pulmonary vascular remodeling and obstruction. The phosphodiesterase 4 (PDE4) family hydrolyzes cyclic AMP (cAMP) and is comprised of four subtypes (PDE4A–D). Previous studies have shown the beneficial effects of pan-PDE4 inhibitors in rodent PH;however, this class of drugs is associated with side effects owing to the broad inhibition of all four PDE4 isozymes. Here, we demonstrate that PDE4B is the predominant PDE isozyme in lungs and that it was upregulated in rodent and human PH lung tissues. We also confirmed that PDE4B is mainly expressed in the lung endothelial cells (ECs). Evaluation of PH in Pde4b wild type and knockout mice confirmed that Pde4b is important for the vascular remodeling associated with PH. In vivo EC lineage tracing demonstrated that Pde4b induces PH development by driving endothelial-to-mesenchymal transition (EndMT), and mechanistic studies showed that Pde4b regulates EndMT by antagonizing the cAMP-dependent PKA–CREB–BMPRII axis. Finally, treating PH rats with a PDE4B-specific inhibitor validated that PDE4B inhibition has a significant pharmacological effect in the alleviation of PH. Collectively, our findings indicate a critical role for PDE4B in EndMT and PH, prompting further studies of PDE4B-specific inhibitors as a therapeutic strategy for PH.
基金supported by Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences(CIFMSNos.2021-1-I2M-049 and 2018-I2M-1-001,China)+1 种基金the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences(Nos.2019RC330001 and 2021RC310002,China)National Natural Science Foundation of China(No.82090010)。
文摘Silicosis is a leading cause of occupational disease-related morbidity and mortality worldwide,but the molecular basis underlying its development remains unclear.An accumulating body of evidence supports gasdermin D(GSDMD)-mediated pyroptosis as a key component in the development of various pulmonary diseases.However,there is little experimental evidence connecting silicosis and GSDMD-driven pyroptosis.In this work,we investigated the role of GSDMD-mediated pyroptosis in silicosis.Single-cell RNA sequencing of healthy and silicosis human and murine lung tissues indicated that GSDMD-induced pyroptosis in macrophages was relevant to silicosis progression.Through microscopy we then observed morphological alterations of pyroptosis in macrophages treated with silica.Measurement of interleukin-1βrelease,lactic dehydrogenase activity,and real-time propidium iodide staining further revealed that silica induced pyroptosis of macrophages.Additionally,we verified that both canonical(caspase-1-mediated)and non-canonical(caspase-4/5/11-mediated)signaling pathways mediated silica-induced pyroptosis activation,in vivo and in vitro.Notably,Gsdmd knockout mice exhibited dramatically alleviated silicosis phenotypes,which highlighted the pivotal role of pyroptosis in this disease.Taken together,our results demonstrated that macrophages underwent GSDMD-dependent pyroptosis in silicosis and inhibition of this process could serve as a viable clinical strategy for mitigating silicosis.
基金funded by Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences(CIFMS)(grant number:2021-I2M-1-049)National Key Research and Development Program of China Grants(grant numbers:2021YFC2500700)the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences(grant number:2021RC31002,2018RC31001).
文摘Silicosis is the most prevalent and fatal occupational disease with no effective therapeutics,and currently used drugs cannot reverse the disease progress.Worse still,there are still challenges to be addressed to fully decipher the intricated pathogenesis.Thus,specifying the essential mechanisms and targets in silicosis progression then exploring anti-silicosis pharmacuticals are desperately needed.In this work,multi-omics atlas was constructed to depict the pivotal abnormalities of silicosis and develop targeted agents.By utilizing an unbiased and time-resolved analysis of the transcriptome,proteome and phosphoproteome of a silicosis mouse model,we have verified the significant differences in transcript,protein,kinase activity and signaling pathway level during silicosis progression,in which the importance of essential biological processes such as macrophage activation,chemotaxis,immune cell recruitment and chronic inflammation were emphasized.Notably,the phosphorylation of EGFR(p-EGFR)and SYK(pSYK)were identified as potential therapeutic targets in the progression of silicosis.To inhibit and validate these targets,we tested fostamatinib(targeting SYK)and Gefitinib(targeting EGFR),and both drugs effectively ameliorated pulmonary dysfunction and inhibited the progression of inflammation and fibrosis.Overall,our drug discovery with multi-omics approach provides novel and viable therapeutic strategies for the treatment of silicosis.
基金supported by grants from the CAMS Innovation Fund for Medical Sciences(Nos.2021-I2M-1-061 and 2021-I2M-1-001)the National Key Research and Development Program of China(No.2016YFC0905600)
文摘To the Editor:Cancer has been recognized as an independent predisposing factor of venous thromboembolism(VTE),including pulmonary embolism(PE)and deep vein thrombosis(DVT).Patients with cancer have a sevenfold increased risk of VTE compared with those without cancer.[1]Evidence from autopsy in cancer patients showed that PE is an important disease complication in patients with cancer.[2]Optimal management of PE patients with cancer has become a major concern that challenges clinicians in daily clinical practice.Understanding the risk factors of all-cause death in PE patients with cancer in the real world may enable optimal management and improve their survival.Therefore,this study was performed to characterize cancerassociated PE and evaluate the clinical predictors of inhospital death based on the data of PE patient population in China.
