Neddylation is a crucial posttranslational modification that involves the attachment of neural precursor cell-expressed developmentally downregulated protein 8 (NEDD8) to a lysine residue in the substrate via the sequential actions of the E1 NEDD8-activating enzyme (NAE) (E1), E2 NEDD8-conjugating enzyme (E2), and E3 NEDD8-ligase (E3). The most extensively studied substrates of neddylation are members of the cullin family, which act as scaffold components for cullin ring E3 ubiquitin ligases (CRLs). Since cullin neddylation activates CRLs, which are frequently overactive in tumors, inhibiting neddylation has emerged as a promising strategy for developing novel antitumor therapies. This review explores the antitumor effects of inhibiting neddylation that leads to the inactivation of CRLs and provides a summary of known inhibitors that target protein-protein interactions (PPIs) within the neddylation enzymatic cascade.

ObjectiveTo investigate the current status and related factors of maternal influenza vaccination willingness among pregnant and postpartum women in Shanghai and Liaoning Province, China, and to explore the facilitators and barriers affecting vaccination uptake, so as to provide references for future practices in promoting maternal influenza immunization in China. MethodsA convergent mixed-methods research was conducted. From January to March 2024, a questionnaire survey was conducted among women attending prenatal and postnatal care at 7 medical institutions in Shanghai and Dalian, Liaoning Province, which aimed to assess pregnant women’s knowledge about influenza vaccine and their willingness to vaccination during pregnancy, as well as to identify the related factors. In addition, purposive sampling method was used to conduct in-depth interviews with pregnant women and perinatal healthcare service providers to explore their perspectives on influenza vaccination during pregnancy, including the reasons for their willingness or unwillingness to receive ( or recommend) the vaccine, and the relevant facilitators and barriers to vaccination. ResultsA total of 366 pregnant and postpartum women participated in the questionnaire survey, and 9.56% (35/366) of them were willing to receive the influenza vaccine during pregnancy. The results of multivariate logistic stepwise regression analyses showed that primipara (aOR=0.158, 95%CI: 0.037‒0.671, P=0.012), family members’ support for influenza vaccination during pregnancy (aOR=0.015, 95%CI: 0.003‒0.082, P<0.001) were associated with higher willingness to receive influenza vaccine during pregnancy. Absence of influenza infection during pregnancy (aOR=5.383, 95%CI: 1.801‒16.092, P<0.001), and lack of knowledge regarding influenza vaccination during pregnancy (aOR=11.294, 95%CI: 3.593‒35.496, P<0.01) were associated with lower willingness to receive influenza vaccine during pregnancy. Qualitative findings indicated that the facilitators to vaccination willingness among pregnant and postpartum women included the recommendation of healthcare service providers, adequate knowledge of influenza vaccine information and family members’ support for vaccination. Conversely, the barriers to vaccination willingness included low recommendation from the healthcare service providers, lack of knowledge about the safety of influenza vaccine during pregnancy and inadequate attention to influenza and influenza vaccine. ConclusionThe willingness to receive influenza vaccination among pregnant and postpartum women in Shanghai and Liaoning Province is relatively low. It is recommended that China should promptly improve the evidence-based system for the safety and efficacy of influenza vaccines for pregnant and postpartum women, along with an establishment of the mechanism for addressing adverse reactions. Furthermore, it is essential to enhance educational outreach to pregnant and postpartum women, their families, and healthcare service providers, thereby increasing the accessibility of information regarding influenza vaccination, which are expected to enhance the willingness of pregnant and postpartum women to receive the vaccine.

Objective:To explore the effects and potential mechanisms of cell growth regulator 1 ( CGREF1) with an EF hand domain in colorectal cancer proliferation and migration. Methods:Fifty paraffin specimens of colorectal cancer tissues and corresponding paracancerous tissues were selected from January 2023 to January 2024 from the Northern Jiangsu People's Hospital Affiliated to Yangzhou University for analysis, and TCGA, GDSC, KMPLOT and STRING databases were used to explore the expression, prognosis, immune microenvironment, drug sensitivity and related signaling pathway functions of CGREF1 in colorectal cancer. Tissue and cellular expression levels of CGREF1 were analyzed by immunohistochemistry and qRT-PCR. Lentiviral-mediated CGREF1 overexpression in SW-620 cells (OE- CGREF1 vs NC groups) was functionally characterized through CCK-8 proliferation assays, colony formation tests, and scratch wound healing migration assays, with mechanistic investigation via Western blot analysis of apoptosis markers, invasion-related proteins, and RAS/RAF/ERK pathway components. In vivo tumorigenicity was assessed by subcutaneous injection of control or CGREF1-overexpressing SW620 cells in nude mice ( n=3 per group) with tumor growth monitoring. Software of GraphPad Prism 9 was used for statistical analysis of experimental data. Results:CGREF1CGREF1RASERK Studies based on databases, clinical samples and colorectal cancer cell line analyses demonstrated that CGREF1 is downregulated in colorectal cancer, where low CGREF1 expression showed positive correlation with tumor diameter and invasion depth. CGREF1 is closely related to tumor immune infiltration microenvironment and sensitivity to multiple anti-tumor drugs. Overexpression of CGREF1 promoted cell apoptosis while inhibiting cell proliferation, invasion and migration. Overexpression of CGREF1 downregulated the expression levels of RAS, ERK and P-P38/MAPK pathway proteins. CGREF1 inhibited tumor growth in vivo. Conclusion:CGREF1 can inhibit the proliferation, colony formation, and migration of CRC cells through the RAS/ERK/MAPK pathway.

Neddylation is a crucial posttranslational modification that involves the attachment of neural precursor cell-expressed developmentally downregulated protein 8(NEDD8)to a lysine residue in the substrate via the sequential actions of the E1 NEDD8-activating enzyme(NAE)(E1),E2 NEDD8-conjugating enzyme(E2),and E3 NEDD8-ligase(E3).The most extensively studied substrates of neddylation are members of the cullin family,which act as scaffold components for cullin ring E3 ubiquitin ligases(CRLs).Since cullin neddylation activates CRLs,which are frequently overactive in tumors,inhibiting neddylation has emerged as a promising strategy for developing novel antitumor therapies.This review explores the antitumor effects of inhibiting neddylation that leads to the inactivation of CRLs and provides a summary of known inhibitors that target protein-protein interactions(PPIs)within the neddylation enzymatic cascade.

Objective Under the operation background of Diagnosis-Intervention Packet(DIP),whether there is interaction between reducing medical cost and average length of stay combined with pre-hospitalization mode,and whether there is difference between different departments and diseases in interaction.Methods Based on real-world data from 71 453 patients admitted to Guizhou Provincial People's Hospital from July to December 2021,a two-way analysis of variance was employed.When the interaction effect was statistically significant,parameter estimation was used to determine the magnitude and direction of the interaction effect,followed by subgroup analyses by department and disease.Results Without adjustment,both total medical costs and average length of stay exhibited a negative interaction effect(P＜0.05).Subgroup analyses revealed that in terms of total medical costs,the effect size for the surgical system was 0.18％,lower than that for the internal medicine system(0.70％);for core diseases,it was 6.62％,lower than that for comprehensive diseases(7.71％).Regarding average length of stay,the effect size for the surgical system was 0.55％,better than that for the internal medicine system(0.22％);for core diseases,it was 8.70％,higher than that for comprehensive diseases(2.90％).Conclusion The combination of DIP payment reform and pre-admission management model demonstrates a synergistic effect,effectively reducing patients' medical costs and length of stay.This effect is influenced by disease complexity and the standardization of diagnostic and treatment processes.

Objective Under the operation background of Diagnosis-Intervention Packet(DIP),whether there is interaction between reducing medical cost and average length of stay combined with pre-hospitalization mode,and whether there is difference between different departments and diseases in interaction.Methods Based on real-world data from 71 453 patients admitted to Guizhou Provincial People's Hospital from July to December 2021,a two-way analysis of variance was employed.When the interaction effect was statistically significant,parameter estimation was used to determine the magnitude and direction of the interaction effect,followed by subgroup analyses by department and disease.Results Without adjustment,both total medical costs and average length of stay exhibited a negative interaction effect(P＜0.05).Subgroup analyses revealed that in terms of total medical costs,the effect size for the surgical system was 0.18％,lower than that for the internal medicine system(0.70％);for core diseases,it was 6.62％,lower than that for comprehensive diseases(7.71％).Regarding average length of stay,the effect size for the surgical system was 0.55％,better than that for the internal medicine system(0.22％);for core diseases,it was 8.70％,higher than that for comprehensive diseases(2.90％).Conclusion The combination of DIP payment reform and pre-admission management model demonstrates a synergistic effect,effectively reducing patients' medical costs and length of stay.This effect is influenced by disease complexity and the standardization of diagnostic and treatment processes.

Objective:To investigate the changes of dynamic functional brain network connectivity in patients with Parkinson disease(PD) using Hidden Markov model(HMM), and to analyze the correlation between dynamic functional parameters and clinical parameters.Methods:Forty-eight PD patients(PD group) and thirty-three healthy controls(HC group) were included from 2019 to 2023. The cognitive function was assessed using the Montreal cognitive assessment (MoCA), and motor status was assessed using the unified Parkinson's disease rating scale Ⅲ(UPDRS-Ⅲ) in PD group.HMM technique was used to analyze the dynamic functional brain network connectivity, and the dynamic higher-order index fractional occupancy(FO), switching rate(SR), and mean dwell time(MDT) were obtained. Two independent samples t-test was used to calculate the differences between groups of functional connectivity matrices in different states, and Mann-Whitney U test was used to calculate the differences between groups of dynamic higher-order indicators in different states. Spearman correlation analysis was used to calculate the correlation between dynamic higher-order parameters and clinical parameters in the PD group. Results:The HMM was used to construct 6 spatial states for all subjects.MDT was significantly higher in PD group(24.93(19.73)) in state 1 sparse junctions than that in HC group(17.63(14.80)) ( Z=-2.030, P=0.042), but significantly lower MDT was showed in PD group(6.00(3.00)) in state 5 tight junctions than that in HC group(9.75(7.70)) ( Z=-2.210, P=0.027).FO in state 3 was negatively correlated with MoCA score in PD group( r=-0.331, P=0.022).FO in state 5 was positively correlated with UPDRS-Ⅲ score in PD patients( r=0.412, P=0.004), and MDT in state 5 was positively correlated with UPDRS-Ⅲ score( r=0.448, P=0.001). Conclusion:HMM can capture the transient changes of dynamic brain network, which can provide some value for the study of dynamic brain network in patients with Parkinson disease.

Objective To investigate the mechanism underlying gasdermin E(GSDME)-mediated pyroptosis in radiation-induced intestinal injury and to find out whether gasdermin(GSDM)family members regulate pyroptosis through similar signaling pathways.Methods Human normal colon epithelial cells(NCM460)and human colon cancer cells(HT-29)were exposed to radiation of different doses and durations before pyroptosis indicators were evaluated by observing pyroptotic bubbles,cell survival,and the cleavage of pyroptosis execution proteins.HT-29 cells overexpressing GSDME were subjected to radiation,followed by enrichment analysis of pyroptosis-related differentially expressed genes using RNA-seq.Results Radiation induced substantial pyroptosis in NCM460 cells.Overexpression of GSDME in HT-29 cells resulted in substantial radiation-induced pyroptosis.The pyroptosis state of human intestinal cells was simulated in the HT-29 model cell line.Overexpressions of GSDME-N and GSDMD-N resulted in the expression of more than 50％ of the differentially expressed genes in the pyroptosis state.Sequencing analysis showed that the genes in the pyroptosis state were mainly overrepresented in immune response,inflammatory response,and Rapl signaling pathway.Conclusion GSDME activation can mediate radiation-induced pyroptosis by producing GSDME-N fragments.GSDM family members participate in pyroptosis in a similar mode of regulation.Furthermore,radiation-induced activation of GSDME/D may regulate pyroptosis through immune response,inflammatory response,and Rap1 signaling pathway.

Objective To analyse the risk factors for postoperative infection in traumatic tibial plateau fractures and to construct a Nomogram prediction model.Methods One hundred and forty-eight patients with traumatic tibial plateau fractures who underwent surgery in our hospital from October 2019 to August 2021 were selected for the study,and were divided into an infected group(n=20)and an uninfected group(n=128)according to whether they developed infection after surgery.The general data of the two groups were compared;the predictive value of statistically significant continuous variables was analysed using the ROC experiment;the risk factors affecting postoperative infection in traumatic tibial plateau fractures were analysed using the logistic regression experiment;and the clinical efficacy of the Nomogram model was verified using internal data.Results In the comparison of general data such as age and gender between the two groups,the differences were not statistically significant(P＞0.05).Compared with the uninfected group,patients in the infected group had a higher percentage of diabetes mellitus,open fracture type,and osteofascial compartment syndrome,and longer operative time and hospital stay(P＜0.05);diabetes(yes),fracture type(open),osteofascial compartment syndrome(yes),and operative time(＞3 h)were risk factors affecting postoperative infection in traumatic tibial plateau fractures.The AUCs for operative time and hospital stay were not 0.792 and 0.651;the optimal stage values were not 3 h and 13 d(P＜0.05);the Nomogram model predicted a C-index of 0.744(0.651-0.807)for the risk of postoperative infection in traumatic tibial plateau fractures.The model predicted the risk of infection after traumatic tibial plateau fracture at a threshold of＞0.09.Conclusion Diabetes mellitus(yes),fracture type(open),osteofascial compartment syndrome(yes),and operative time(＞3 h)were risk factors affecting postoperative infection in traumatic tibial plateau fractures,and the Nomogram model constructed based on the above variables had good predictive value.

Diarrhea-predominant irritable bowel syndrome(IBS-D)is a clinically common functional gastrointestinal disease,the"SCFAs-intestinal barrier"pathway plays an important role in the pathogenesis of IBS-D.Traditional Chinese medicine monomers/compounds or Chinese medicine compound can treat IBS-D by regulating the"SCFAs-intestinal barrier"through multiple pathways and multiple targets.This article takes the relationship between SCFAs and the four major intestinal barriers,as well as the mediating effect of IBS-D,as the starting point to systematically review and sort out the relevant literature on the targeted regulation of"SCFAs-intestinal barrier"in the treatment of IBS-D by Traditional Chinese medicine monomers/compounds and Chinese medicine compound;explores the theoretical basis of IBS-D caused by"SCFAs-intestinal barrier"from the perspective of"Large intes-tine dominating fluid",in order to provid ideas for Traditional Chinese medicine to establish a precision treatment system with Chinese medicine characteristics.