Caspase-1 activated in inflammasomes triggers a programmed necrosis called pyroptosis, which is mediated by gasdermin D (GSDMD). However, GSDMD-deficient cells are still susceptible to ...caspase-1-mediated cell death. Therefore, here, we investigate the mechanism of caspase-1-initiated cell death in GSDMD-deficient cells. Inflammasome stimuli induce apoptosis accompanied by caspase-3 activation in GSDMD-deficient macrophages, which largely relies on caspase-1. Chemical dimerization of caspase-1 induces pyroptosis in GSDMD-sufficient cells, but apoptosis in GSDMD-deficient cells. Caspase-1-induced apoptosis involves the Bid-caspase-9-caspase-3 axis, which can be followed by GSDME-dependent secondary necrosis/pyroptosis. However, Bid ablation does not completely abolish the cell death, suggesting the existence of an additional mechanism. Furthermore, cortical neurons and mast cells exhibit little or low GSDMD expression and undergo apoptosis after oxygen glucose deprivation and nigericin stimulation, respectively, in a caspase-1- and Bid-dependent manner. This study clarifies the molecular mechanism and biological roles of caspase-1-induced apoptosis in GSDMD-low/null cell types.
IL-1α serves as a pro-inflammatory cytokine. Although pro-IL-1α has cytokine activity, proteolytic maturation increases its potency and release from cells. IL-1α maturation occurs in a ...caspase-1-dependent manner following inflammasome activation. However, pro-IL-1α is not a substrate of caspase-1, and it remains unclear what mediates the maturation of this cytokine downstream of inflammasomes. Here, we show that gasdermin D (GSDMD), an executor of pyroptosis, is required for the rapid induction of IL-1α maturation by non-particulate inflammasome activators. Ablation of GSDMD abrogates the maturation of IL-1α, but not of IL-1β. Inflammasome-induced maturation of IL-1α relies on extracellular Ca2+ and calpains. Ca2+ influx and calpain activation are induced in a GSDMD-dependent manner. Glycine, which inhibits cell lysis, but not GSDMD pore formation, does not affect IL-1α maturation. These results suggest that during inflammasome activation, GSDMD processed by caspase-1 forms plasma membrane pores that mediate Ca2+ influx, resulting in the calpain-dependent maturation of IL-1α.
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•Maturation of IL-1α increases its release from cells upon inflammasome activation•Inflammasome-induced IL-1α maturation and release depend on GSDMD and calpains•GSDMD pores mediate Ca2+ influx and consequent calpain activation
Tsuchiya et al. demonstrate that rapid processing and release of IL-1α induced by non-particulate activators of canonical and non-canonical inflammasomes depend on GSDMD. They demonstrate that plasma membrane GSDMD pores mediate Ca2+ influx and calpain activation, resulting in IL-1α maturation, which can be mechanistically uncoupled from IL-1β maturation.
Background:We compared postoperative outcomes in hemodialysis (HD) patients who underwent isolated coronary artery bypass grafting (CABG) for multivessel disease using either bilateral or single ...skeletonized internal thoracic artery.Methods and Results:Among 1,486 patients who underwent isolated CABG between 2002 and 2020, 145 HD patients were retrospectively analyzed. After inverse probability of treatment weighting, there were no significant differences in the preoperative characteristics. No significant differences in 30-day mortality (P=0.551) or postoperative deep sternal wound infection (P=0.778) were observed. However, the bilateral internal thoracic artery grafting group had a lower postoperative stroke rate (0% vs. 4.0%, P=0.019). No significant differences in freedom from all-cause death (P=0.760) and cardiac death (P=0.863) were found. In the multivariate Cox proportional hazards models, bilateral internal thoracic artery grafting was not associated with all-cause death (P=0.246) or cardiac death (P=0.435).Conclusions:Bilateral internal thoracic artery grafting in HD patients did not improve mid-term outcomes, but it was also not associated with worse postoperative outcomes. Use of the bilateral internal thoracic artery may be an important option in patients with limited conduits to prevent postoperative complications.
In the mobile era, place attachment among rural migrants and returnees has become dynamic and diversified. However, research on place attachment to native place among rural migrants and returnees is ...limited. The focus of previous research has primarily been on the destination place attachment of rural migrants, which makes it difficult to gain a comprehensive understanding of the place attachment among both rural migrants and returnees. This study aims to investigate the state of place attachment to both native and destination places among rural migrants and returnees originating from the same birthplace. It explores their place attachment after migrating from rural areas to cities. A quantitative research approach was adopted, garnering questionnaire responses from 274 rural migrants and returnees, all born in Shuangfeng County, Hunan Province. The questionnaire encompassed a Likert scale for measuring place attachment, as well as sociodemographic statistical information. Exploratory factor analysis and confirmatory factor analysis were conducted to ascertain the reliability and validity of the questionnaire. Based on the factor scores of place attachment to both places from migrants and returnees, a two-step cluster analysis identified three types of migrants and two types of returnees. Chi-square tests revealed significant differences among migrants in terms of property ownership, educational level, marital status, presence of children, age at departure, and time away from hometown. The study discovered that, regardless of being a migrant or returnee, the overall attachment to hometown was stronger than that to the current or previously inhabited city. In the context of existing literature primarily concerned with the integration of rural migrants into urban areas, this paper offers a fresh research perspective, highlighting the significance of emotional ties to one's hometown for rural migrants. The findings of this paper provide direction and a theoretical basis for rural areas to attract return migration and for urban regions to facilitate the integration of migrants.
Octogenarians are often declined an emergency operation for acute type A aortic dissection on grounds of high mortality rate and short life expectancy. Our policy is to accept all patients at any ...time and never to refuse an emergency operation, even for octogenarians.
From April 2004 to September 2017, 319 patients underwent surgical repair for acute type A aortic dissection at our institution. We compared the clinical results between the 55 elderly patients (≥80 years old; older group) and the 264 nonelderly patients (≤79 years old; younger group). The primary end point was early mortality, and the secondary end point was long-term mortality.
The older group had a higher proportion of women (74.5% vs 46.6%), a lower body mass index (21.4 vs 23.8 kg/m
), and a lower proportion of smokers (20.0% vs 46.2%). In the two groups (older vs younger), postoperative stroke occurred in 12.7% versus 11.4% and hospital mortality in 10.2% versus 10.9%, with no significant statistical difference. In multivariate analysis, older age of 80 years or older was not a significant risk factor for hospital mortality. Among the hospital survivors, the actuarial survival rate at 8 years was 52.5% in the older group and 85.0% in the younger group (p = 0.005).
Emergency surgical repair for type A aortic dissection in octogenarians without patient selection resulted in similar rates of mortality and morbidity as younger patients. Octogenarians should not be refused this life-saving emergency operation.
Abstract
The evolution of a random directional wave in deep water was studied in a laboratory wave tank (50 m long, 10 m wide, 5 m deep) utilizing a directional wave generator. A number of ...experiments were conducted, changing the various spectral parameters (wave steepness 0.05 < ɛ < 0.11, with directional spreading up to 36° and frequency bandwidth 0.2 < δk/k < 0.6). The wave evolution was studied by an array of wave wires distributed down the tank. As the spectral parameters were altered, the wave height statistics change. Without any wave directionality, the occurrence of waves exceeding twice the significant wave height (the freak wave) increases as the frequency bandwidth narrows and steepness increases, due to quasi-resonant wave–wave interaction. However, the probability of an extreme wave rapidly reduces as the directional bandwidth broadens. The effective Benjamin–Feir index (BFIeff) is introduced, extending the BFI (the relative magnitude of nonlinearity and dispersion) to incorporate the effect of directionality, and successfully parameterizes the observed occurrence of freak waves in the tank. Analysis of the high-resolution hindcast wave field of the northwest Pacific reveals that such a directionally confined wind sea with high extreme wave probability is rare and corresponds mostly to a swell–wind sea mixed condition. Therefore, extreme wave occurrence in the sea as a result of quasi-resonant wave–wave interaction is a rare event that occurs only when the wind sea directionality is extremely narrow.
Background: Patients with end-stage renal disease on hemodialysis (ESRD-HD) have a lifelong risk of atrial fibrillation-related stroke. We compared clinical outcomes in ESRD-HD patients undergoing ...coronary artery bypass grafting (CABG) with and without concomitant left atrial appendage (LAA) closure.Methods and Results: Of 2,783 consecutive patients undergoing isolated CABG between 2002 and 2020, 242 patients had ESRD-HD with sinus rhythm. The primary outcome was a composite of death and stroke. An inverse probability (IP)-weighted cohort was created based on the propensity score. The 2 IP-weighted groups had well-balanced baseline and surgical backgrounds, with an equivalent follow-up. Five-year stroke-free survival was significantly higher in patients with LAA closure (log-rank test, P=0.035). The adjusted hazard ratio of LAA closure for death and stroke was 0.43 (95% confidence interval CI 0.20–0.92; P=0.023). Competing risk analysis showed that LAA closure was significantly associated with a risk reduction of stroke (subhazard ratio 0.26; 95% CI 0.08–0.96; P=0.028). No significant difference was observed in adjusted risk ratios for reoperation for bleeding, new atrial fibrillation, 30-day mortality, and readmission for heart failure.Conclusions: Concomitant LAA closure during CABG can reduce the risk of death and stroke in ESRD-HD patients with normal sinus rhythm.
Background: We compared the location of the false lumen within the medial layer between acute intramural hematoma (AIH) and acute aortic dissection (AAD) using microscopic images of aortic specimens ...and examined the associations with patient characteristics, CT findings, and late outcomes.Methods and Results: Among 293 patients undergoing surgery for Stanford type A acute aortic syndrome between 2008 and 2018, 45 patients had neither an identifiable intimal tear, flow to the false lumen on preoperative CT or intimal tear by intraoperative observation (AIH group), and 98 patients with patent false lumen were enrolled (AAD group). The AIH group had a significantly thinner outer media thickness (OMT) than the AAD group. The AIH group showed more pericardial effusion, but distal progression of dissection and branch vessel involvement were limited. The change in aortic diameter after surgery was insignificant in the AIH group, whereas in the AAD group it continued to increase. Cumulative incidence of aortic adverse events was significantly higher among AAD patients, but no significant difference was observed in survival between groups.Conclusions: The AIH group had a significantly thinner OMT than the AAD group, which was significantly associated with a large amount of pericardial effusion, greater false lumen diameter, and limited progression of aortic dissection.
Cigarette smoking induces vascular endothelial dysfunction characterized by impaired nitric oxide (NO) bioavailability. There are two types of soluble guanylate cyclase (sGC), which is a cellular ...target of NO: NO-sensitive reduced form (the heme moiety with a ferrous iron) and NO-insensitive oxidized (the heme moiety with a ferric iron)/heme-free form. This study investigated the influence of cigarette smoking on NO-sensitive and NO-insensitive sGC-mediated vascular tone regulation in organ chamber experiments with isolated rat and human arteries. The rats were subcutaneously administered phosphate-buffered saline (PBS), nicotine-free cigarette smoke extract (N(-)-CSE) or nicotine-containing cigarette smoke extract (N(+)-CSE) for 4 weeks. Plasma thiobarbituric acid reactive substance (TBARS) levels were higher in the N(+)-CSE group than those in the N(-)-CSE group, and TBARS levels for these groups were higher than those for the PBS group. In the aorta and the pulmonary artery in rats administered N(-)-CSE or N(+)-CSE, acetylcholine-induced relaxation was significantly impaired compared with that in rats administered PBS; there was no significant difference in the relaxation between the N(-)-CSE and N(+)-CSE groups. However, sodium nitroprusside (NO-sensitive sGC stimulant)- and BAY 60-2770 (NO-insensitive sGC stimulant)-induced relaxations were not different among the three groups, regardless of the vessel type. In addition, in the human gastroepiploic artery, the relaxant responses to these sGC-targeting drugs were identical between nonsmokers and smokers. These findings suggest that NO-sensitive and NO-insensitive sGC-mediated vascular tone regulation functions normally even in blood vessels damaged by cigarette smoking.
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