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In summer, convective activity over the Tibetan Plateau (TP) is vigorous, with some of it moving eastward and vacating the plateau [defined as the eastward-moving type (EMT)]. Although the EMT only accounts for a small proportion, it is closely related to heavy precipitation east of the TP. This study investigates EMT impacts based on a series of composite semi-idealized simulations and piecewise potential vorticity (PV) inversion. The main results are as follows. (i) An EMT begins to affect downstream precipitation before it vacates the TP. A weaker EMT tends to cause the main downstream rainband to reduce in intensity and move southward. (ii) The EMT contributes to the formation of an eastward-moving plateau vortex (PLV) by enhancing convergence-induced stretching. Over the TP, the PLV mainly enhances/maintains the EMT, whereas during the vacating stage, the PLV dissipates (since convergence decreases rapidly when sensible heating from the TP reduces), which substantially reduces the intensity of the EMT. (iii) After PLV dissipation, a southwest vortex (SWV) forms around the Sichuan basin mainly due to convergence-induced stretching, convection-related tilting, and background transport. Piecewise PV inversion indicates that an EMT can directly contribute to SWV formation via lowering geopotential height and enhancing cyclonic wind perturbations around the Sichuan basin (even before its vacating stage), while neither of them governs the SWV formation. Sensitivity runs show that an EMT is not necessary for SWV formation, but can modify the SWV formation time and location, as well as its displacement, which significantly affects downstream precipitation.

Senescence of vascular smooth muscle cells (VSMCs) contributes to aging-related cardiovascular diseases by promoting arterial remodelling and stiffness. Ferroptosis is a novel type of regulated cell death associated with lipid oxidation. Here, we show that pro-ferroptosis signaling drives VSMCs senescence to accelerate vascular NAD + loss, remodelling and aging. Pro-ferroptotic signaling is triggered in senescent VSMCs and arteries of aged mice. Furthermore, the activation of pro-ferroptotic signaling in VSMCs not only induces NAD + loss and senescence but also promotes the release of a pro-senescent secretome. Pharmacological or genetic inhibition of pro-ferroptosis signaling, ameliorates VSMCs senescence, reduces vascular stiffness and retards the progression of abdominal aortic aneurysm in mice. Mechanistically, we revealed that inhibition of pro-ferroptotic signaling facilitates the nuclear-cytoplasmic shuttling of proliferator-activated receptor-γ and, thereby impeding nuclear receptor coactivator 4-ferrtin complex-centric ferritinophagy. Finally, the activated pro-ferroptotic signaling correlates with arterial stiffness in a human proof-of-concept study. These findings have significant implications for future therapeutic strategies aiming to eliminate vascular ferroptosis in senescence- or aging-associated cardiovascular diseases. Ferroptosis is a novel form of regulated cell death associated with lipid oxidation. Here, the authors demonstrate that the proferroptosis signal is activated and drives vascular aging by inducing senescence in vascular smooth muscle cells.

Extratropical cyclones play a crucial role in balancing the global momentum, energy, and moisture, and also, they shape the extreme weather events over the extra-tropics. As the strongest category of the extratropical cyclones, the explosive extratropical cyclones (EECs) frequently induce severe disasters through their strong surface winds. During the entire lifespan of an EEC, there is a maximum value of its surface wind (i.e. the maximum surface wind; MSW), which processes the greatest destructive power. After nearly a century of research on the EECs, key features about their MSWs still remain vague. In this study, we systematically investigate the EECs’ MSWs over the North Atlantic storm track (NAST) based on the ERA-Interim reanalysis. It is found that, the average intensity of EECs’ MSWs shows a significant increasing trend of ∼0.3 m s −1 per 10a. More importantly, for the last 20 years, even larger increasing rates of 1.5 m s −1 and 3.5 m s −1 per 10a are found in the average and maximum intensities of the EECs’ MSWs, respectively, implying the EECs’ risks increase notably for the NAST. We further clarify the physical mechanisms governing the production of EECs’ MSWs, and then establish a mechanism-based statistical model, which has the potential to predict the MSWs’ annual average intensity. In summary, our study fills a knowledge gap for the EECs’ MSWs, which would have broad implication of the economics and society.

Immune checkpoint inhibitor (ICI)-induced myocarditis involves intensive immune/inflammation activation; however, its molecular basis is unclear. Here, we show that gasdermin-E (GSDME), a gasdermin family member, drives ICI-induced myocarditis. Pyroptosis mediated by GSDME, but not the canonical GSDMD, is activated in myocardial tissue of mice and cancer patients with ICI-induced myocarditis. Deficiency of GSDME in male mice alleviates ICI-induced cardiac infiltration of T cells, macrophages, and monocytes, as well as mitochondrial damage and inflammation. Restoration of GSDME expression specifically in cardiomyocytes, rather than myeloid cells, in GSDME-deficient mice reproduces ICI-induced myocarditis. Mechanistically, quantitative proteomics reveal that GSDME-dependent pyroptosis promotes cell death and mitochondrial DNA release, which in turn activates cGAS-STING signaling, triggering a robust interferon response and myocardial immune/inflammation activation. Pharmacological blockade of GSDME attenuates ICI-induced myocarditis and improves long-term survival in mice. Our findings may advance the understanding of ICI-induced myocarditis and suggest that targeting the GSDME-cGAS-STING-interferon axis may help prevent and manage ICI-associated myocarditis. One-sentence summary GSDME inflames ICI-associated myocarditis. ICI-induced myocarditis is fatal, but its mechanism is unclear. Here, the authors identify GSDME as a key driver by promoting cGAS-STING signaling, enhancing our understanding of its pathogenesis.

Nicotinamide adenine dinucleotide (NAD )-boosting therapy has emerged as a promising strategy to treat various health disorders, while the underlying molecular mechanisms are not fully understood. Here, we investigated the involvement of fibronectin type III domain containing 5 (Fndc5) or irisin, which is a novel exercise-linked hormone, in the development and progression of nonalcoholic fatty liver disease (NAFLD). NAD -boosting therapy was achieved by administrating of nicotinamide riboside (NR) in human and mice. The Fndc5/irisin levels in tissues and blood were measured in NR-treated mice or human volunteers. The therapeutic action of NR against NAFLD pathologies induced by high-fat diet (HFD) or methionine/choline-deficient diet (MCD) were compared between wild-type (WT) and mice. Recombinant Fndc5/irisin was infused to NALFD mice via osmotic minipump to test the therapeutic action of Fndc5/irisin. Various biomedical experiments were conducted and to know the molecular mechanisms underlying the stimulation of Fndc5/irisin by NR treatment. NR treatment elevated plasma level of Fndc5/irisin in mice and human volunteers. NR treatment also increased Fndc5 expression in skeletal muscle, adipose and liver tissues in mice. In HFD-induced NAFLD mice model, NR displayed remarkable therapeutic effects on body weight gain, hepatic steatosis, steatohepatitis, insulin resistance, mitochondrial dysfunction, apoptosis and fibrosis; however, these actions of NR were compromised in mice. Chronic infusion of recombinant Fndc5/irisin alleviated the NAFLD pathological phenotypes in MCD-induced NAFLD mice model. Mechanistically, NR reduced the lipid stress-triggered ubiquitination of Fndc5, which increased Fndc5 protein stability and thus enhanced Fndc5 protein level. Using shRNA-mediated knockdown screening, we found that NAD -dependent deacetylase SIRT2, rather than other sirtuins, interacts with Fndc5 to decrease Fndc5 acetylation, which reduces Fndc5 ubiquitination and stabilize it. Treatment of AGK2, a selective inhibitor of SIRT2, blocked the therapeutic action of NR against NAFLD pathologies and NR-induced Fndc5 deubiquitination/deacetylation. At last, we identified that the lysine sites K127/131 and K185/187/189 of Fndc5 may contribute to the SIRT2-dependent deacetylation and deubiquitination of Fndc5. The findings from this research for the first time demonstrate that NAD -boosting therapy reverses NAFLD by regulating SIRT2-deppendent Fndc5 deacetylation and deubiquitination, which results in a stimulation of Fndc5/irisin, a novel exerkine. These results suggest that Fndc5/irisin may be a potential nexus between physical exercise and NAD -boosting therapy in metabolic pathophysiology.

Drug‐induced liver injury (DILI) is a significant global health issue that poses high mortality and morbidity risks. One commonly observed cause of DILI is acetaminophen (APAP) overdose. GSDME is an effector protein that induces non‐canonical pyroptosis. In this study, the activation of GSDME, but not GSDMD, in the liver tissue of mice and patients with APAP‐DILI is reported. Knockout of GSDME, rather than GSDMD, in mice protected them from APAP‐DILI. Mice with hepatocyte‐specific rescue of GSDME reproduced APAP‐induced liver injury. Furthermore, alterations in the immune cell pools observed in APAP‐induced DILI, such as the replacement of TIM4+ resident Kupffer cells (KCs) by monocyte‐derived KCs, Ly6C+ monocyte infiltration, MerTk+ macrophages depletion, and neutrophil increase, reappeared in mice with hepatocyte‐specific rescue of GSDME. Mechanistically, APAP exposure led to a substantial loss of interferon‐stimulated gene 15 (ISG15), resulting in deISGylation of carbamoyl phosphate synthetase‐1 (CPS1), promoted its degradation via K48‐linked ubiquitination, causing ammonia clearance dysfunction. GSDME deletion prevented these effects. Delayed administration of dimethyl‐fumarate inhibited GSDME cleavage and alleviated ammonia accumulation, mitigating liver injury. This findings demonstrated a previously uncharacterized role of GSDME in APAP‐DILI by promoting pyroptosis and CPS1 deISGylation, suggesting that inhibiting GSDME can be a promising therapeutic option for APAP‐DILI. Acetaminophen (APAP) overdose is the most common cause of drug‐induced liver failure (DILI), representing a significant global health issue with high mortality and morbidity risks. This study reveals that GSDME, a non‐canonical pyroptosis effector, is triggered and activated in the liver tissue of both mice and patients with APAP‐DILI, whereas the canonical pyroptosis effector GSDMD is not involved. Notably, GSDME expression in hepatocytes, rather than myeloid cells, governs pyroptosis and ammonia clearance by regulating CPS1 deISGylation and degradation. Administration of dimethyl fumarate inhibits GSDME cleavage and mitigates ammonia accumulation, thereby alleviating liver injury. These findings suggest that inhibiting GSDME holds promise as a therapeutic option for APAP‐DILI.

The southwest vortices (SWVs) are a unique type of mesoscale vortex that frequently induce torrential rainfall in China. In this study, we focused a long‐lived quasi‐stationary SWV, which was the primary system for producing an extremely heavy rainstorm within/around Sichuan (the maximum hourly precipitation was ~103.8 mm) in Mid July 2021. After reproduced the SWV's formation by using Weather Research and Forecasting model, we conducted trajectory analyses and topography sensitivity simulations to understand the effects of complicated topography on the vortex's formation. It is found that, the regions south and southwest of the SWV acted as the most important source regions for the air clusters that formed the SWV (proportion ≥ 65%), and the air clusters originated from the upper layer contributed the most (≥60%). Of these, the air clusters sourced from the upper layer southwest and south of the SWV played the most important role in the SWV's formation, as their increase in cyclonic vorticity and their contributions to trajectory number and vorticity were all much larger than those of the others. Sensitivity simulations indicated that, detailed topography features around the Sichuan Basin were crucial in determining the structure, intensity and precipitation of the SWV, whereas, the topography features were not a decisive factor for the SWV's formation. In summary, our findings are useful to enrich the current understanding of the SWVs' formation, which would be helpful to improve the related forecasts. The air particles sourced from the upper layer southwest and south of the southwest vortices (SWV) contributed the most to the SWV's formation, as their increase in cyclonic vorticity and their contributions to trajectory number and vorticity were all the largest. Although the detailed topography features were not a decisive factor for the SWV's formation, they exerted notable impacts on the structure, intensity, and precipitation of the SWV. The SWV's formation was the most sensitive to the topography south of the vortex, whereas, it was relatively insensitive to the topography southwest of the vortex.

Senescence contributes to the pathology of abdominal aortic aneurysm (AAA); however, the regulation of senescence in AAA remains unclear. Here, we sought to determine the role of gasdermin-E (GSDME)-dependent non-canonical pyroptosis in AAA. GSDME-dependent non-canonical pyroptosis is activated in the lesioned vascular walls of mouse models and patients with AAA. GSDME deficiency inhibits vascular senescence and AAA progression. Combined analyses of single-cell RNA sequencing (scRNA-seq), bulk RNA-seq, and multiplex flow cytometry demonstrate that GSDME is essential for the reprogramming of vascular smooth muscle cells (VSMCs) and the shift in immune statuses of macrophages, monocytes, and neutrophils in AAA. Reintroduction of GSDME in VSMCs, but not in myeloid cells, in mice with a GSDME deletion background, recapitulates the induced vascular senescence and AAA, which is abolished by senolytic therapy with dasatinib plus quercetin. These results indicate that GSDME-dependent non-canonical pyroptosis in VSMCs may be a ‘master switch’ in AAA and a potential therapeutic target for managing AAA. Here they show that gasdermin-E (GSDME) acts as a key driver of abdominal aortic aneurysm (AAA) by triggering senescence in vascular smooth muscle cells, a process reversible with senolytic drugs, highlighting a promising therapeutic target of AAA.

Regions around Dabie Mountain (DBM) in the Yangtze River basin (YRB) are the source of a mesoscale vortex: the Dabie vortex (DBV). Based on a 14-yr statistical study, 11 long-lived heavy-rain-producing DBVs were composited for convection-permitting semi-idealized simulations. A control simulation, initialized 12 h before the composite vortex formation, successfully reproduced a DBV, with all the salient characteristics of the 11 events. Sensitivity experiments were designed to understand the impacts of large-scale environmental conditions, regional topography, and latent heating on DBV formation. The main results were as follows: (i) Supposition of a 500-hPa shortwave trough with an east–west-oriented lower-level transversal trough around the DBM is crucial for the formation of vortices. A nocturnal lower-level jet on the southern side of the transversal trough accelerates DBV formation by enhancing convergence, triggering/sustaining convection, and producing cyclonic vorticity. (ii) During the simulation period, the topography east of the second-step mountain ranges, including the DBM, significantly affects nearby precipitation and convective activity, whereas this is not crucial for DBV formation. (iii) Latent heating is not required for generating DBVs, but it enhances the intensity, longevity, and eastward progression of these vortices along the shear line associated with the transversal trough. (iv) The vorticity budget suggests the convergence-related (horizontal) shrinking and vertical transport dominate the cyclonic-vorticity increase associated with DBVs, whereas tilting and horizontal transport mainly act in the opposite manner.

Mesoscale vortices (MVs) play an important role in balancing global atmospheric momentum, moisture, and energy, and can induce almost all types of disastrous weather. To enhance the understanding of MVs, there is a need to identify them from various types of grid data. Despite the higher detection accuracy, manual identification is gradually being replaced by numerical methods, because the former has enormous time and manpower requirements. However, after decades of research to accurately detect MVs using numerical algorithms the process remains challenging. This study proposed the use of restricted vorticity (RV) as a new metric for numerical MV identification, based on which a numerical algorithm was developed. Compared with ∼1800 manually identified MVs, the new algorithm had a hit rate of over 97%, and a Heidke skill score of above 0.9. This indicates that RV will be of great practical value, and is suitable for popularizing and applying immediately.