Compulsory schooling system and equity in education: An analysis on intergenerational transmission of education.

This paper uses the China Family Panel Studies' micro-level data and the ordered logit model to study intergenerational transmission of education and examines whether the nine-year compulsory schooling system affects equity in education. The results show that when parents have higher educational attainments, their children will have higher educational attainments. Full-sample results show that when the mother has higher education, the probability that her children have higher education increases by 7.97%, whereas for the sub-sample after the compulsory schooling policy carried out, the probability increases by 22.42%. We find that the compulsory schooling system strengthens intergenerational transmission of education in the level of higher education. An implication is that the compulsory schooling system may promote equity in compulsory education but does not promote equity in higher education.

The Application of the Nurse-Led Sedation and Analgesia Management in ICU after Heart Surgeries.

Aim: Traditional sedation management consists of doctors adjusting the dosage of sedative drugs or adding other drugs in combination according to the evaluation of nurses; the nurses then execute the orders. The nurses' passive execution in the process is not the ideal model for continuous evaluation and observation of sedation. This study aims to investigate the application and effects of nurse-provided procedural sedation and analgesia for patients in intensive care unit. Methods: The experimental group consisted of 354 heart surgery patients who received procedural sedation and analgesia from nurses from November 2020 to August 2021. The control group consisted of 301 patients who had had heart surgery and received the traditional sedation management program from January to October 2020. The differences in levels of the sedative effect, delirium, and unplanned extubation of patients between these two groups were compared. Results: There were no significant differences in baseline characteristics between the two groups (P > 0.05). It was found that both insufficient sedation and excessive sedation decreased in the experimental group when compared to the control group, while the appropriate proportion of sedation increased (72.41% versus 37.98%); the difference was statistically significant (P < 0.05). The incidence of delirium was lower for patients in the experimental group than for patients in the control group (37.01% versus 66.45%); the difference was statistically significant (P < 0.05). The incidence of unplanned extubation caused by patient factors was lower for the experimental group than for the control group, but the difference was not statistically significant (P > 0.05). Conclusion: The programmed sedation scheme led by nurses can improve the sedation effect and reduce the incidence of delirium. Implications for Practice. The management team gives the sedative goal and establishes the standard flowchart. The sedation management led by the nurse according to the goal and flowchart is better than the traditional sedation management.

MCPIP1 negatively regulate cellular antiviral innate immune responses through DUB and disruption of TRAF3-TBK1-IKKε complex.

IFNß innate immune plays an essential role in antiviral immune. Previous reports suggested that many important regulatory proteins in innate immune pathway may be modified by ubiquitin and that many de-ubiquitination (DUB) proteins may affect immunity. Monocyte chemotactic protein-inducing protein 1 (MCPIP1), one of the CCCH Zn finger-containing proteins, was reported to have DUB function, but its effect on IFNß innate immune was not fully understood. In this study, we uncovered a novel mechanism that may explain how MCPIP1 efficiently inhibits IFNß innate immune. It was found that MCPIP1 negatively regulates the IFNß expression activated by RIG-I, STING, TBK1, IRF3. Furthermore, MCPIP1 inhibits the nuclear translocation of IRF3 upon stimulation with virus, which plays a key role in type I IFN expression. Additionally, MCPIP1 interacts with important modulators of IFNß expression pathway including IPS1, TRAF3, TBK1 and IKKε. Meanwhile, the interaction between the components in TRAF3-TBK1-IKKε complex was disrupted by MCPIP1. These results collectively suggest MCPIP1 as an innate immune regulator encoded by the host and point to a new mechanism through which MCPIP1 negatively regulates IRF3 activation and type I IFNß expression.

Autophagy relieves the function inhibition and apoptosis­promoting effects on osteoblast induced by glucocorticoid.

Autophagy may be a major mechanism by which osteoblasts (OBs) protect against the negative effects of chronic glucocorticoid (GC) usage. OBs are closely associated with the remodeling that occurs in GC­induced osteoporosis (GIO). In osteocytes, in response to stress induced by GCs, several pathways are activated, including cell necrosis, apoptosis and autophagy. However, the role of autophagy in OBs following treatment with excess GCs has not been addressed. In the current study, confocal microscopy observation of green fluorescent protein­microtubule­associated protein 1 light chain 3ß (LC3) punctuate, and western blotting for LC3Ⅱ and Beclin 1 were performed for detection of autophagy in the MC3T3­E1 osteoblastic cell line. Flow cytometry and western blotting were used for the examination of apoptosis and expression of BAX apoptosis regulator (Bax)/apoptosis regulator Bcl­2 (Bcl­2). The expression of genes associated with osteoblastic function, runt­related transcription factor 2, α­1 type 1 collagen and osteocalcin, were measured by reverse transcription­quantitative polymerase chain reaction. The results indicated that autophagy was induced in OBs during dexamethasone (Dex) treatment in a dose­dependent manner. The level of autophagy did not continue to increase over time, but peaked at 48 h and then decreased gradually. Subsequently, flow cytometry was used to demonstrate that inhibition of autophagy induced apoptosis in OBs under Dex treatment, and was associated with the upregulation of Bax and the downregulation of Bcl­2 protein expression. Furthermore, the data suggested that the inhibition of autophagy also suppressed the expression of osteoblastic genes. By contrast, the stimulation of autophagy maintained the gene expression level under Dex treatment. The data revealed that autophagy is an important regulator of osteoblastic apoptosis through its interaction with Bax/Bcl­2, and maintains the osteoblastic function of MC3T3­E1 cells following GC exposure. In addition, these results indicated that the suppression of autophagy in OBs under chronic GC therapy may increase the prevalence of GIO and fragility fractures.

SlnR is a positive pathway-specific regulator for salinomycin biosynthesis in Streptomyces albus.

Salinomycin, a polyether antibiotic produced by Streptomyces albus, is widely used in animal husbandry as an anticoccidial drug and growth promoter. Situated within the salinomycin biosynthetic gene cluster, slnR encodes a LAL-family transcriptional regulator. The role of slnR in salinomycin production in S. albus was investigated by gene deletion, complementation, and overexpression. Gene replacement of slnR from S. albus chromosome results in almost loss of salinomycin production. Complementation of slnR restored salinomycin production, suggesting that SlnR is a positive regulator of salinomycin biosynthesis. Overexpression of slnR in S. albus led to about 25 % increase in salinomycin production compared to wild type. Quantitative RT-PCR analysis revealed that the expression of most sal structural genes was downregulated in the ΔslnR mutant but upregulated in the slnR overexpression strain. Electrophoretic mobility gel shift assays (EMSAs) also revealed that SlnRDBD binds directly to the three intergenic regions of slnQ-slnA1, slnF-slnT1, and slnC-slnB3. The SlnR binding sites within the three intergenic regions were determined by footprinting analysis and identified a consensus-directed repeat sequence 5'-ACCCCT-3'. These results indicated that SlnR modulated salinomycin biosynthesis as an enhancer via interaction with the promoters of slnA1, slnQ, slnF, slnT1, slnC, and slnB3 and activates the transcription of most of the genes belonging to the salinomycin gene cluster but not its own transcription.

p53 degradation by a coronavirus papain-like protease suppresses type I interferon signaling.

Infection by human coronaviruses is usually characterized by rampant viral replication and severe immunopathology in host cells. Recently, the coronavirus papain-like proteases (PLPs) have been identified as suppressors of the innate immune response. However, the molecular mechanism of this inhibition remains unclear. Here, we provide evidence that PLP2, a catalytic domain of the nonstructural protein 3 of human coronavirus NL63 (HCoV-NL63), deubiquitinates and stabilizes the cellular oncoprotein MDM2 and induces the proteasomal degradation of p53. Meanwhile, we identify IRF7 (interferon regulatory factor 7) as a bona fide target gene of p53 to mediate the p53-directed production of type I interferon and the innate immune response. By promoting p53 degradation, PLP2 inhibits the p53-mediated antiviral response and apoptosis to ensure viral growth in infected cells. Thus, our study reveals that coronavirus engages PLPs to escape from the innate antiviral response of the host by inhibiting p53-IRF7-IFNß signaling.

Coronavirus membrane-associated papain-like proteases induce autophagy through interacting with Beclin1 to negatively regulate antiviral innate immunity.

Autophagy plays important roles in modulating viral replication and antiviral immune response. Coronavirus infection is associated with the autophagic process, however, little is known about the mechanisms of autophagy induction and its contribution to coronavirus regulation of host innate responses. Here, we show that the membrane-associated papain-like protease PLP2 (PLP2-TM) of coronaviruses acts as a novel autophagy-inducing protein. Intriguingly, PLP2-TM induces incomplete autophagy process by increasing the accumulation of autophagosomes but blocking the fusion of autophagosomes with lysosomes. Furthermore, PLP2-TM interacts with the key autophagy regulators, LC3 and Beclin1, and promotes Beclin1 interaction with STING, the key regulator for antiviral IFN signaling. Finally, knockdown of Beclin1 partially reverses PLP2-TM's inhibitory effect on innate immunity which resulting in decreased coronavirus replication. These results suggested that coronavirus papain-like protease induces incomplete autophagy by interacting with Beclin1, which in turn modulates coronavirus replication and antiviral innate immunity.

SARS coronavirus papain-like protease inhibits the type I interferon signaling pathway through interaction with the STING-TRAF3-TBK1 complex.

SARS coronavirus (SARS-CoV) develops an antagonistic mechanism by which to evade the antiviral activities of interferon (IFN). Previous studies suggested that SARS-CoV papain-like protease (PLpro) inhibits activation of the IRF3 pathway, which would normally elicit a robust IFN response, but the mechanism(s) used by SARS PLpro to inhibit activation of the IRF3 pathway is not fully known. In this study, we uncovered a novel mechanism that may explain how SARS PLpro efficiently inhibits activation of the IRF3 pathway. We found that expression of the membrane-anchored PLpro domain (PLpro-TM) from SARS-CoV inhibits STING/TBK1/IKKε-mediated activation of type I IFNs and disrupts the phosphorylation and dimerization of IRF3, which are activated by STING and TBK1. Meanwhile, we showed that PLpro-TM physically interacts with TRAF3, TBK1, IKKε, STING, and IRF3, the key components that assemble the STING-TRAF3-TBK1 complex for activation of IFN expression. However, the interaction between the components in STING-TRAF3-TBK1 complex is disrupted by PLpro-TM. Furthermore, SARS PLpro-TM reduces the levels of ubiquitinated forms of RIG-I, STING, TRAF3, TBK1, and IRF3 in the STING-TRAF3-TBK1 complex. These results collectively point to a new mechanism used by SARS-CoV through which PLpro negatively regulates IRF3 activation by interaction with STING-TRAF3-TBK1 complex, yielding a SARS-CoV countermeasure against host innate immunity.

Radiosurgery inhibition of the Notch signaling pathway in a rat model of arteriovenous malformations.

OBJECT: Notch signaling has been suggested to promote the development and maintenance of arteriovenous malformations (AVMs), but whether radiosurgery inhibits Notch signaling pathways in AVMs is unknown. The aim of this study was to examine molecular changes of Notch signaling pathways following radiosurgery and to explore mechanisms of radiosurgical obliteration of "nidus" vessels in a rat model of AVMs. METHODS: One hundred eleven rats received common carotid artery-to-external jugular vein anastomosis to form an arteriovenous fistula (AVF) model. Six weeks postoperatively, dilated small vessels and capillaries formed a nidus. The rats with AVFs received 25-Gy radiosurgery. The expression of Notch1 and Notch4 receptors and their ligands, Delta-like1 and Delta-like4, Jagged1, Notch downstream gene target HES1, and an apoptotic marker caspase-3 in nidus vessels in the AVF rats was examined immunohistochemically and was quantified using LAS-AF software at 7 time points over a period of 42 days postradiosurgery. The interaction events between Notch1 receptor and Jagged1, as well as Notch4 receptor and Jagged1, were quantified in nidus vessels in the AVF rats using proximity ligation assay at different time points over 42 days postradiosurgery. RESULTS: The expression of Notch1 and Notch4 receptors, Delta-like1, Delta-like4, Jagged1, and HES1 was observed in nidus vessels in the AVF rats pre- and postradiosurgery. Radiosurgery enhanced apoptotic activity (p < 0.05) and inhibited the expression of Notch1 and Notch4 receptors and Jagged1 in the endothelial cells of nidus vessels in the AVF rats at 1, 2, 3, 7, 21, 28, and 42 days postradiosurgery (p < 0.05). Radiosurgery suppressed the interaction events between Notch1 receptor and Jagged1 (p < 0.001) as well as Notch4 receptor and Jagged1 (p < 0.001) in the endothelial cells of nidus vessels in the AVF rats over a period of 42 days postradiosurgery. Radiosurgery induced thrombotic occlusion of nidus vessels in the AVF rats. There was a positive correlation between the percentage of fully obliterated nidus vessels and time after radiosurgery (r = 0.9324, p < 0.001). CONCLUSIONS: Radiosurgery inhibits endothelial Notch1 and Notch4 signaling pathways in nidus vessels while inducing thrombotic occlusion of nidus vessels in a rat model of AVMs. The underlying mechanisms of radiosurgery-induced AVM shrinkage could be a combination of suppressing Notch receptor signaling in blood vessel endothelial cells, leading to a reduction in nidus vessel size and thrombotic occlusion of nidus vessels.

Proteolytic processing, deubiquitinase and interferon antagonist activities of Middle East respiratory syndrome coronavirus papain-like protease.

The emerging Middle East respiratory syndrome coronavirus (MERS-CoV) causes severe pulmonary disease in humans and represents the second example of a highly pathogenic coronavirus (CoV) following severe acute respiratory syndrome coronavirus (SARS-CoV). Genomic studies revealed that two viral proteases, papain-like protease (PLpro) and 3C-like protease (3CLpro), process the polyproteins encoded by the MERS-CoV genomic RNA. We previously reported that SARS-CoV PLpro acts as both deubiquitinase (DUB) and IFN antagonist, but the function of the MERS-CoV PLpro was poorly understood. In this study, we characterized MERS-CoV PLpro, which is a protease and can recognize and process the cleavage sites (CS) of nsp1-2, nsp2-3 and nsp3-4. The LXGG consensus cleavage sites in the N terminus of pp1a/1ab, which is generally essential for CoV PLpro-mediated processing, were also characterized in MERS-CoV. MERS-CoV PLpro, like human SARS-CoV PLpro and NL63-CoV PLP2, is a viral deubiquitinating enzyme. It acts on both K48- and K63-linked ubiquitination and ISG15-linked ISGylation. We confirmed that MERS-CoV PLpro acts as an IFN antagonist through blocking the phosphorylation and nuclear translocation of IFN regulatory factor 3 (IRF3). These findings indicate that MERS-CoV PLpro acts as a viral DUB and suppresses production of IFN-ß by an interfering IRF3-mediated signalling pathway, in addition to recognizing and processing the CS at the N terminus of replicase polyprotein to release the non-structural proteins. The characterization of proteolytic processing, DUB and IFN antagonist activities of MERS-CoV PLpro would reveal the interactions between MERS-CoV and its host, and be applicable to develop strategies targeting PLpro for the effective control of MERS-CoV infection.