Objective To explore the impact of peptidylarginine deiminase 2(Padi2)-knockout on depressive-like behaviors in socially isolated mice.Methods Using CRISPR/Cas9 technology,a Padi2-knockout(Padi2-/-)mouse model with a C57BL/6J background was established,and the effect of Padi2 knockout was identified by genotyping and RT-qPCR detection.Six-week-old male Padi2-/- mice and wild-type C57BL/6J mice were selected and divided into normal rearing and social isolation groups,with 15 mice per group.The normal rearing group mice were housed with 5 mice per cage,and the social isolation group was housed with 1 mouse per cage,and weighed once a week.After 4 weeks,forced swimming and open field tests were conducted.After the behavioral experiments,brain tissues were taken from mice in each group,and changes in microglia in the brains were detected by immunofluorescence.Results We successfully established Padi2-/- mice.There was no difference in behavior between Padi2-/- mice and C57BL/6J mice in the normal rearing group.After social isolation,compared with C57BL/6J mice,Padi2-/- mice showed a significant increase in depressive symptoms,obvious weight gain,and a significant increase in the number of microglia in brain tissue.Conclusions Padi2 knockout exacerbated depressive-like behaviors and obesity in socially isolated mice,indicating that Padi2 is involved in the progression of depression and may be an effective target for the prevention and treatment of depression.

Objective:To assess the relationship between basophil levels and mortality in patients with intra-abdominal infection.Methods:Information on patients with intraperitoneal infection admitted to the intensive care unit were extracted from the MIMIC database.A time-dependent Cox regression model was used to adjust for confounders associated with 28-day mortality.Propensity score matching(PSM)was used to balance the baseline differences be-tween groups with different basophil levels,and a restricted cube chart(RCS)was used to show the relationship between basophil count and 28-day mortality in patients with intra-abdominal infection.Results:A total of 4403 patients with intra-abdominal infection were enrolled in the MIMIC database.Patients with high basophil levels have lower mortality than those with low basophil levels.There was an L-shaped curve between basophil level and 28-day mortality,with a cut-off value of 0.47×109/L.Cox regression analysis showed that basophil levels were an independent protective factor for mortal-ity in patients with intra-abdominal infection after adjusting for potential confounders(HR=0.586,95%CI:0.443-0.769).Protective factors for death at basophil levels remained after PSM adjusted for potential confounders(HR=0.628,95%CI:0.470-0.832).Conclusion:Basophil level is an independent protective factor for mortality in patients with intra-abdominal infection,and basophil levels should be dynamically monitored to better evaluate the prognosis of patients.

Objective To develop a toolkit suitable for assisting community health institutions in the early identification and inter-vention of mild cognitive impairment(MCI)among older adults.Methods A literature review was conducted to construct a draft of the identification and intervention toolkit.Tools with an expert approval rate above 70%were included after expert consultation.The final version of the toolkit was developed by integrating these tools with officially recommended tools in China.Results The expert consultation yielded an authority coefficient of 0.84.The finalized toolkit included the assessment tools of Mini-Mental State Examination,Montreal Cognitive Assessment,General Practitioner Assessment of Cognition,Cognitive Abilities Screening Instrument and Clock Drawing Test,and 18 intervention measures in-cluding pharmacological treatment,cognitive training and psychological interventions,etc.Conclusion The MCI Identification-Intervention Toolkit may serve as a reference for guiding the identification and inter-vention of MCI among older adults for community health institutions.

Under the background of forensic medicine becoming a first-level discipline,the opportuni-ties and challenges of discipline development coexist.Starting from the actual situation and characteris-tics of local medical colleges and universities,this paper discusses the problems and solutions for the development of forensic medicine discipline from the perspective of building a regional high-level medical university.Combined with the experiences of carrying out forensic medicine education in our college,this paper supplies our thoughts and practices on improving the discipline system,enhancing the ability to serve society,perfecting the talent cultivation model and promoting forensic culture,to provide reference and inspiration for the development of forensic medicine in other universities,jointly promote the advancement of forensic medicine in China to a new stage,and contribute the wisdom and strength of forensic medical experts to the construction of a law-based China,a safe China and a healthy China.

Interfering hepatitis B virus (HBV) capsid assembly holds promise as a therapeutic approach for chronic hepatitis B (CHB). Novel anti-HBV agents are urgently needed to overcome drug resistance challenges, with targeted protein degradation (TPD) emerging as a hopeful strategy. Herein, we report the first degradation of HBV core protein (HBC), a multifunctional structural protein, using small-molecule degraders developed by hydrophobic tagging (HyT) technology. Structure-activity relationship (SAR) analysis identified compound HyT-S7, featuring an adamantyl group, exhibiting potent inhibitory activity (EC₅₀ = 0.46 μmol/L, HepAD38 cells) and degradation ability (DC₅₀ = 3.02 ± 0.54 μmol/L) in a dose- and time-dependent manner. Mechanistic studies demonstrated that the autophagy-lysosome pathway was a potential driver of HyT-S7-induced HBC degradation. Remarkably, HyT-S7 effectively degraded 11 drug-resistant mutants, including highly resistant strains P25G and T33N, to Phase III drug GLS4. Furthermore, cellular thermal shift assay, surface plasmon resonance assay, and molecular dynamics simulations revealed the precise mode of HyT-S7 binding to HBC with the adamantyl group potentially mimicking protein misfolding to facilitate HBC degradation. This first proof-of-concept study highlights the potential of HyT-mediated TPD in HBC as a promising avenue for discovering novel HBV and other antiviral agents with favorable drug resistance profiles.

Cervical spine health issues not only seriously affect patients' quality of life but also impose a heavy burden on the social healthcare system. Existing guidelines lack sufficient clinical guidance on lifestyle and work habits, such as exercise, posture, daily routine, and diet, making it difficult to meet practical needs. To address this, relying on the China Association of Chinese Medicine, Wangjing Hospital of China Academy of Chinese Medical Sciences took the lead and joined hands with more than ten institutions to form a multidisciplinary guideline development group. For the first time, the group developed the Guidelines for Cervical Spine Health Intervention based on evidence-based medicine methods, strictly following the standardized procedures outlined in the World Health Organization Handbook for Guideline Development and the Guiding Principles for the Formulation/Revision of Clinical Practice Guidelines in China (2022 Edition). This proposal systematically explains the methods and steps for developing the guideline, aiming to make the guideline development process scientific, standardized, and transparent.
Humans ; Practice Guidelines as Topic/standards* ; Cervical Vertebrae ; China

PURPOSE: To assess the relationship between dislocation and functional outcomes in supination-external rotation (SER) ankle fractures. METHODS: A retrospective case series study was performed on patients with ankle fractures treated surgically at a large trauma center from January 2015 to December 2021. The inclusion criteria were young and middle-aged patients of 18 - 65 years with SER ankle fractures that can be classified by Lauge-Hansen classification and underwent surgery at our trauma center. Exclusion criteria were serious life-threatening diseases, open fractures, fractures delayed for more than 3 weeks, fracture sites ≥ 2, etc. Then patients were divided into dislocation and no-dislocation groups. Patient demographics, injury characteristics, surgery-related outcomes, and postoperative functional outcomes were collected and analyzed. The functional outcomes of SER ankle fractures were assessed postoperatively at 1-year face-to-face follow-up using the foot and ankle outcome score (FAOS) and American Orthopedic Foot and Ankle Society ankle hindfoot score and by 2 experienced orthopedic physicians. Relevant data were analyzed using SPSS version 22.0 by Chi-square or t-test. RESULTS: During the study period, there were 371 ankle fractures. Among them, 190 (51.2%) were SER patterns with 69 (36.3%) combined with dislocations. Compared with the no-dislocation group, the dislocation group showed no statistically significant differences in gender, age composition, fracture type, diabetes, or smoking history, preoperative waiting time, operation time, and length of hospital stay (all p > 0.05), but a significantly higher Lauge-Hansen injury grade (p < 0.001) and syndesmotic screw fixation rate (p = 0.033). Moreover, the functional recovery was poorer, revealing a significantly lower FAOS in the sport/rec scale (p < 0.001). Subgroup analysis showed that among SER IV ankle fracture patients, FAOS was much lower in pain (p = 0.042) and sport/rec scales (p < 0.001) for those with dislocations. American Orthopedic Foot and Ankle Society ankle hindfoot score revealed no significant difference between dislocation and no-dislocation patients. CONCLUSION Dislocation in SER ankle fractures suggests more severe injury and negatively affects functional recovery, mainly manifested as more pain and poorer motor function, especially in SER IV ankle cases.
Humans ; Ankle Fractures/physiopathology* ; Male ; Female ; Retrospective Studies ; Adult ; Middle Aged ; Supination ; Aged ; Young Adult ; Rotation ; Joint Dislocations/surgery* ; Fracture Fixation, Internal/methods* ; Adolescent ; Recovery of Function ; Treatment Outcome

Pancreatic cancer is characterized by significant drug resistance,and despite continuous advancements in treatment regimens,the 5-year survival rate of patients remains low.The nuclear factor-κB(NF-κB)signaling pathway,frequently mutated in tumors,has been identified as a critical factor in triggering drug resistance.Multiple studies have demonstrated that strategies targeting NF-κB signaling transduction exhibit promising outcomes in pancreatic cancer treatment.Therefore,exploring the relationship between the NF-κB signaling pathway and drug resistance in pancreatic cancer has become a research hotspot in pancreatic cancer treatment.This review summarizes recent advances in the relationship between NF-κB signaling pathway and tumor drug resistance,as well as its role in pancreatic cancer treatment.Specifically,the mechanisms by which the NF-κB signaling pathway mediates drug resistance in pancreatic cancer are elaborated from two perspectives:chemotherapy and immunotherapy,aiming to provide insights for pancreatic cancer treatment and future research.

Objective To investigate the effects and mechanisms of ubiquitin-associated domain-containing protein 2(UBAC2)mediated by m6A methylation modification on the invasion and migration abilities of colorectal cancer cells.Methods The GEPIA2.0 database was utilized to analyze the expression differences of UBAC2 mRNA between colorectal cancer tissues and adjacent normal tissues,as well as its expression in colorectal cancer tissues at different stages.The correlation between Wilms tumor 1-associated protein(WTAP)and UBAC2 expression was analyzed.The Kaplan-Meier plotter online tool was applied to analyze the correlation between UBAC2 and the overall survival rate of colorectal cancer patients.The RMVar and SRAMP databases were employed to predict potential m6A methylation modification sites in the UBAC2 gene.Quantitative real-time PCR(qRT-PCR)and Western blotting were performed to detect the expression levels of UBAC2 mRNA and protein in colorectal cancer cell lines.For UBAC2 knockdown experiments,SW480 cells were divided into control group(no treatment),sh-NC group(transfected with sh-NC negative control plasmid),and sh-UBAC2 group(transfected with sh-UBAC2 plasmid).For WTAP knockdown experiments,groups included control group(no treatment),si-NC group(transfected with negative control siRNA),and si-WTAP group(transfected with WTAP-targeting siRNA).For UBAC2 overexpression experiments,groups were control group(no treatment),si-WTAP group(transfected with pcDNA3.1 empty plasmid),and si-WTAP+OE-UBAC2 group(transfected with UBAC2 overexpression plasmid pcDNA3.1-UBAC2).Western blotting was used to detect the protein expression levels of UBAC2,WTAP,E-cadherin,N-cadherin,and Vimentin;qRT-PCR was applied to detect the expression level of UBAC2 mRNA;Transwell assays were conducted to assess cell invasion and migration abilities.MeRIP-qPCR was employed to detect the m6A methylation modification of UBAC2 mRNA;RIP-qPCR experiments were conducted to verify the binding of WTAP to UBAC2 mRNA.In nude mouse colorectal cancer lung metastasis experiments,groups included LV-sh-NC group(tail vein injection of SW480 cells stably infected with LV-sh-NC)and LV-sh-UBAC2 group(tail vein injection of SW480 cells stably infected with LV-sh-UBAC2).After 42 d of tumor-implantation in nude mice,lung tissues were harvested:the number of lung nodules observed by hematoxylin/eosin(HE)staining,and the expression level of Luc2 mRNA detected by qRT-PCR.Results GEPIA2.0 database analysis revealed that the expression level of UBAC2 mRNA in colorectal cancer tissues was significantly higher than that in adjacent normal tissues,and it gradually increased with the progression of tumor stage(P<0.05).The expression levels of UBAC2 mRNA and protein in multiple colorectal cancer cell lines were significantly higher than those in normal colonic epithelial cells(P<0.05).Compared with sh-NC group,sh-UBAC2 group showed significantly increased E-cadherin protein expression,significantly decreased N-cadherin and Vimentin protein expression,and significantly reduced number of invaded and migrated SW480 cells(P<0.05).GEPIA2.0 database analysis results indicated a positive correlation between WTAP and UBAC2 expression(r=0.24,P<0.001).Compared with si-NC group,si-WTAP group showed significantly decreased expression levels of WTAP and UBAC2 mRNA and protein in SW480 cells(P<0.05).MeRIP-qPCR results demonstrated that the m6A modification level of UBAC2 mRNA in si-WTAP group was significantly lower than that in si-NC group(P<0.05).RIP-qPCR further confirmed that WTAP could bind to UBAC2 mRNA.Compared with control group,si-WTAP group showed significantly increased E-cadherin protein expression and significantly decreased N-cadherin and Vimentin protein expression in SW480 cells(P<0.05);compared with si-WTAP group,si-WTAP+OE-UBAC2 group showed significantly decreased E-cadherin protein expression and significantly increased N-cadherin and Vimentin protein expression in SW480 cells(P<0.05).The number of lung nodules in LV-sh-UBAC2 group was significantly fewer than that in LV-sh-NC group,and the expression level of Luc2 mRNA in lung tissues was significantly lower than that in LV-sh-NC group(P<0.05).Conclusion UBAC2 mediated by m6A methylation modification can regulate the epithelial-mesenchymal transition(EMT)process in colorectal cancer cells,thereby affecting the invasion and migration abilities of colorectal cancer cells.

Objective To investigate the effect of electroacupuncture(EA)on the behaviors of lipopolysaccharide(LPS)-induced depression-like mice and explore the potential molecular mechanism of the antidepressant effect of EA using transcriptomics sequencing technology.Methods Thirty-six male specific pathogen-free-grade C57BL/6J mice were divided into the normal,the model,and the EA groups using the random number table method,with 12 mice per group.The EA group received a daily 20-minute EA at the"Baihui"and"Yintang"acupoints for 7 days.After 7 days of EA treatment,1.5 mg/kg LPS was injected intraperitoneally into the model and EA groups,whereas the normal group received an injection of an equal volume of saline solution.Depressive behaviors were assessed using the open-field test,tail-suspension test,and other relevant tests.Pathologic morphology of the hippocampus tissue was determined using hematoxylin-eosin staining.Transcriptomics technology was used to identify differentially expressed genes in the hippocampus,and bioinformatics analysis was performed.Real-time fluorescence quantitative PCR was performed to detect the mRNA expressions of hematopoietic cell kinase(Hck),adhesion G protein-coupled receptor E1(Adgre1),Toll-like receptor 2(Tlr2),and Gm49037 in the hippocampus.Results Compared to the normal group,mice in the model group exhibited a decrease in total travel distance,central travel distance,center area time(P＜0.01),as well as an increase in tail-suspension immobility time(P＜0.05).Hippocampal neurons were loosely arranged,and some neurons had blurred boundaries.Compared to the model group,mice in the EA group showed an increase in open-field total travel distance,central travel distance,center area time(P＜0.05),as well as a decrease in tail-suspension immobility time(P＜0.01);Additionally,hippocampal neurons were more tightly arranged,exhibiting clearer morphology and structure.Transcriptomic analysis revealed that 779 differentially expressed genes were identified in the model group compared to the normal group,whereas 172 genes differed between the EA and model groups.Nineteen genes were upregulated in the model group but downregulated in the EA group,and ten genes were down-regulated in the model group but up-regulated in the EA group.Gene Ontology Functional Analysis indicated that these genes primarily function in immune responses,Toll-like receptor activity,cell surface receptor signaling pathways,and interleukin-10 production.Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed enrichment in inflammation-related pathways,including Toll-like receptor signaling pathway and tumor necrosis factor signaling pathway.Compared to the normal group,Hck,Adgre1,and Tlr2 mRNA expressions were elevated in the model group(P＜0.01),whereas there was a decrease tendency for Gm49037 mRNA expression and there was no significant difference(P＞0.05);compared to the model group,Hck,Adgre1,and Tlr2 mRNA expressions were decreased in the EA group(P＜0.05),whereas there was an increase tendency for Gm49037 mRNA expression and there was no significant difference(P＞0.05).Conclusion EA alleviated depressive-like behavior and pathological damage in the hippocampus in LPS-induced mice,which may be related to attenuating hippocampal inflammatory pathways,and Hck,Adgre1,and Tlr2 genes may be the potential targets for its effect.