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Abstract The unfolded protein response (UPR) is a conserved and adaptive intracellular pathway that relieves the endoplasmic reticulum (ER) stress by activating ER transmembrane stress sensors. As a consequence of ER stress, the inhibition of nonsense-mediated mRNA decay (NMD) is due to an increase in the phosphorylation of eIF2α, which has the effect of inhibiting translation. However, the role of NMD in maintaining ER homeostasis remains unclear. In this study, we found that the three NMD factors, up-frameshift (UPF)1, UPF2, or UPF3B, were required to negate the UPR. Among these three NMD factors, only UPF3B interacted with inositol-requiring enzyme-1α (IRE1α). This interaction inhibited the kinase activity of IRE1α, abolished autophosphorylation, and reduced IRE1α clustering for ER stress. BiP and UPF3B jointly control the activation of IRE1α on both sides of the ER membrane. Under stress conditions, the phosphorylation of UPF3B was increased and the phosphorylated sites were identified. Both the UPF3BY160D genetic mutation and phosphorylation at Thr169 of UPF3B abolished its interaction with IRE1α and UPF2, respectively, leading to activation of ER stress and NMD dysfunction. Our study reveals a key physiological role for UPF3B in the reciprocal regulatory relationship between NMD and ER stress.

Scientific evaluation of water resources metabolism efficiency (WME) has essential theoretical and practical value for regional water resources security and sustainable utilization. Based on the framework of the water resources metabolism process and construction of the indicator system of WME, the spatiotemporal variations of WME were analyzed using the weighted summation method in the Eastern, Central, and Western regions of China during the period from 1990 to 2020 with heterogeneous resource endowments. The exploratory spatial data analysis (ESDA) and spatial Durbin model were applied to analyze the spatial autocorrelation patterns and reveal spillovers of the WME. The results show that (1) The WME increased at different speeds in the Eastern, Central, and Western regions from 1990 to 2020 with heterogeneous resource endowment, and the spatial variation of WME in the Eastern and Central regions was significantly higher than in the Western regions. (2) The WME had significant spatial autocorrelation except in 2015, indicating obvious spatial agglomeration characteristics and spatial heterogeneity simultaneously. (3) The spatial spillover effects analysis indicated that the waste virtual recycling use ratio, the ratio of output virtual water and input virtual water, and industrial water ratio were the primary factors influencing WME. HIGHLIGHTS The indicator system of water resources metabolism efficiency (WME) was constructed based on the material flow analysis.; The spatiotemporal variations of WME were analyzed using the weighted summation method.; Using Moran's I and spatial Durbin model to indicate spatial autocorrelation and reveal spatial spillover effects of WME.; Spatial spillover effects of WME are obvious in the study area.;

IntroductionHypoxic-ischemic encephalopathy (HIE) is one of severe neonatal brain injuries, resulting from inflammation and the immune response after perinatal hypoxia and ischemia. IgG N-glycosylation plays a crucial role in various inflammatory diseases through mediating the balance between anti-inflammatory and pro-inflammatory responses. This study aimed to explore the effect of IgG N-glycosylation on the development of HIE.MethodsThis case-control study included 53 HIE patients and 57 control neonates. An ultrahigh-performance liquid chromatography (UPLC) method was used to determine the features of the plasma IgG N-glycans, by which 24 initial glycan peaks (GPs) were quantified. Multivariate logistic regression was used to examine the association between initial glycans and HIE, by which the significant parameters were used to develop a diagnostic model. Though receiver operating characteristic (ROC) curves, area under the curve (AUC) and 95% confidence interval (CI) were calculated to assess the performance of the diagnostic model.ResultsThere were significant differences in 11 initial glycans between the patient and control groups. The levels of fucosylated and galactosylated glycans were significantly lower in HIE patients than in control individuals, while sialylated glycans were higher in HIE patients (p < 0.05). A prediction model was developed using three initial IgG N-glycans and fetal distress, low birth weight, and globulin. The ROC analysis showed that this model was able to discriminate between HIE patients and healthy individuals [AUC = 0.798, 95% CI: (0.716–0.880)].DiscussionIgG N-glycosylation may play a role in the pathogenesis of HIE. Plasma IgG N-glycans are potential noninvasive biomarkers for screening individuals at high risk of HIE.

BackgroundLupus nephritis (LN) is a crucial complication of systemic lupus erythematosus (SLE) and has important clinical implications in guiding treatment. N-glycosylation of immunoglobulin G (IgG) plays a key role in the development of SLE by affecting the balance of anti-inflammatory and proinflammatory responses. This study aimed to evaluate the performance of IgG N-glycosylation for diagnosing LN in a sample of female SLE patients.MethodsThis case-control study recruited 188 women with SLE, including 94 patients with LN and 94 age-matched patients without LN. The profiles of plasma IgG N-glycans were detected by hydrophilic interaction chromatography with ultra-performance liquid chromatography (HILIC-UPLC). A multivariate logistic regression model was used to explore the associations between IgG N-glycans and LN. A diagnostic model was developed using the significant glycans as well as demographic factors. The performance of IgG N-glycans in the diagnosis of LN was evaluated by receiver operating characteristic (ROC) curve analysis, and the area under the curve (AUC) and its 95% confidence interval (CI) were calculated.ResultsThere were significant differences in 9 initial glycans (GP2, GP4, GP6, GP8, GP10, GP14, GP16, GP18 and GP23) between women with SLE with and without LN (P < 0.05). The levels of sialylated, galactosylated and fucosylated glycans were significantly lower in the LN patients than in the control group, while bisected N-acetylglucosamine (GlcNAc) glycans were increased in LN patients (P < 0.05). GP8, GP10, GP18, and anemia were included in our diagnostic model, which performed well in differentiating female SLE patients with LN from those without LN (AUC = 0.792, 95% CI: 0.727 to 0.858).ConclusionOur findings indicate that decreased sialylation, galactosylation, and core fucosylation and increased bisecting GlcNAc might play a role in the development of LN by upregulating the proinflammatory response of IgG. IgG N-glycans can serve as potential biomarkers to differentiate individuals with LN among SLE patients.

BackgroundAtherosclerosis is considered a crucial component in the pathogenesis of decreased cognitive function, as occurs in vascular cognitive impairment (VCI). Inflammation and the immune response play a significant role in the development of many chronic diseases. Immunoglobulin G (IgG) N-glycosylation has been implicated in the development of a variety of diseases by affecting the anti-inflammatory and proinflammatory responses of IgG. This study aimed to investigate the association between IgG N-glycosylation and VCI in a sample of patients with atherosclerosis through a case-control study.MethodWe recruited a total of 330 patients with atherosclerosis to participate in this case-control study, including 165 VCI patients and 165 sex- and age-matched participants with normal cognitive function. The plasma IgG N-glycans of participants were separated by ultrahigh-performance liquid chromatography. An enzyme-linked immunosorbent assay (ELISA) kit was used to determine the corresponding serum inflammatory factors. Atherosclerosis was diagnosed by carotid ultrasound, and the diagnosis of VCI was based on the “Guidelines for the Diagnosis and Treatment of Vascular Cognitive Impairment in China (2019)”. A multivariate logistic regression model was used to explore the association between IgG N-glycans and VCI. We also analyzed the relationship between IgG N-glycans and the inflammatory state of VCI through canonical correlation analysis (CCA).ResultsThrough the multivariate logistic regression analysis, 8 glycans and 13 derived traits reflecting decreased sialylation and galactosylation and increased bisecting GlcNAc significantly differed between the case and control groups after adjusting for confounding factors (P < 0.05, q < 0.05). Similarly, the differences in TNF-α, IL-6, and IL-10 were statistically significant between the case and control groups after adjusting for the effects of confounding factors (P < 0.05, q < 0.05). The CCA results showed that VCI-related initial N-glycans were significantly correlated with VCI-related inflammatory factors (r = 0.272, P = 0.004). The combined AUC value (AUCcombined = 0.885) of 7 initial glycans and inflammatory factors was higher than their respective values (AUCinitial glycans = 0.818, AUCinflammatory factors = 0.773).ConclusionThe findings indicate that decreased sialylation and galactosylation and increased bisecting GlcNAc reflected by IgG N-glycans might affect the occurrence of VCI in patients with atherosclerosis though promoting the proinflammatory function of IgG. IgG N-glycans may serve as potential biomarkers to distinguish VCI in individuals with atherosclerosis.

Abstract Background Qiliqiangxin (QLQX) is a preparation refined from a traditional Chinese medicine compound. It plays an important role in protecting cardiac function after myocardial infarction (MI). However, the underline mechanism of QLQX action is not clear. The purpose of this study was to detect the effects of QLQX on mitophagy after MI. Methods Male FVB/NJ mice aged 8–10 weeks were underwent left coronary artery ligation and were orally administered either QLQX (0.25 g/kg/d) or saline. Twenty-eight days after surgical operation, the cardiac function of mice was detected by echocardiography. Electron Microscopy was used to observe the microstructure of cardiomyocytes. Myocardial apoptosis was examined by TdT-mediated dUTP Nick-End Labeling (TUNEL) and western blot. H9c2 cells were cultured in a hypoxic incubator chamber (5% CO2, 1% O2, 94% N2) for 12 h and pretreated with or without QLQX (0.5 mg/mL). The cell apoptosis, reactive oxygen species (ROS), mitochondrial membrane potential and mitophagy were detected. Results When compared to sham group, the cardiac function of MI mice decreased significantly, and their cardiomyocyte apoptosis and mitochondrial damage were more serious. These MI-induced cardiac changes could be reversed by QLQX treatment. In vitro experiments also confirmed that QLQX could protect cardiomyocytes from hypoxia-induced apoptosis and mitochondrial damage. Further study indicated that QLQX could increase the expression of Pink1 and Parkin in cardiomyocytes. Conclusion Qiliqiangxin could reduce cardiomyocytes apotosis and improved heart function in infarcted heart through Pink1-mediated mitochondrial autophagy.