ObjectiveTo clarify whether METTL14 mediates the core role of acupuncture at Neiguan (PC6) in promoting myelination and improving behavior in young autistic rats through gene intervention technology. MethodsThe ASD model was established by intraperitoneal injection of valproic acid (VPA) in pregnant rats. Male offspring were intracerebroventricularly injected with adenovirus-packaged METTL14 shRNA (sh-METTL14) or its control (sh-NC) on postnatal day 1, with a model group set as well. Subsequently, the juvenile rats were divided into model group, acupuncture group, acupuncture+sh-NC group, and acupuncture+sh-METTL14 group. The acupuncture group received acupuncture at Neiguan (PC6) from postnatal day 7, once daily for 21 consecutive days. Neurobehavioral changes were evaluated by behavioral tests; METTL14 knockdown efficiency and the expression of METTL14, METTL3, and PTEN were detected by quantitative real-time PCR (qRT-PCR) and Western blot (WB); PTEN m⁶A levels were measured by RNA immunoprecipitation-qPCR (RIP-qPCR); myelin ultrastructure, expression of myelin basic protein (MBP) and neurofascin 155 (NF155), and dendritic spine density were observed using transmission electron microscopy (TEM), enzyme-linked immunosorbent assay (ELISA), immunofluorescence, qRT-PCR, and primary neuron culture. ResultsBehaviorally, knockdown of METTL14 significantly counteracted the beneficial effects of acupuncture in improving self-grooming, open field exploration, three-chamber social interaction, and Morris water maze learning and memory (P<0.05, P<0.01). Compared with the acupuncture+sh-NC group, the acupuncture+sh-METTL14 group showed significantly decreased mRNA and protein expression of hippocampal METTL14 (P<0.01), and the upregulating effects of acupuncture on METTL3 and PTEN expression were reversed (P<0.01). Meanwhile, knockdown of METTL14 significantly inhibited the acupuncture-induced increase in PTEN m⁶A levels (P<0.01). Morphologically, knockdown of METTL14 attenuated the improvement of myelin structure by acupuncture, reversed the downregulation of MBP and upregulation of NF155 induced by acupuncture, and blocked the increase in dendritic spine density (P<0.05, P<0.01). ConclusionMETTL14 is a key molecule mediating the therapeutic effect of acupuncture at Neiguan. Acupuncture at Neiguan upregulates METTL14, thereby enhancing m⁶A methylation modification of PTEN mRNA to stabilize its expression, ultimately promoting myelin development and improving behavioral symptoms in ASD juvenile rats. This preliminarily reveals the modern biological connotation of “opening Xuanfu and dredging myelin”.

ObjectiveTo clarify whether METTL14 mediates the core role of acupuncture at Neiguan (PC6) in promoting myelination and improving behavior in young autistic rats through gene intervention technology. MethodsThe ASD model was established by intraperitoneal injection of valproic acid (VPA) in pregnant rats. Male offspring were intracerebroventricularly injected with adenovirus-packaged METTL14 shRNA (sh-METTL14) or its control (sh-NC) on postnatal day 1, with a model group set as well. Subsequently, the juvenile rats were divided into model group, acupuncture group, acupuncture+sh-NC group, and acupuncture+sh-METTL14 group. The acupuncture group received acupuncture at Neiguan (PC6) from postnatal day 7, once daily for 21 consecutive days. Neurobehavioral changes were evaluated by behavioral tests; METTL14 knockdown efficiency and the expression of METTL14, METTL3, and PTEN were detected by quantitative real-time PCR (qRT-PCR) and Western blot (WB); PTEN m⁶A levels were measured by RNA immunoprecipitation-qPCR (RIP-qPCR); myelin ultrastructure, expression of myelin basic protein (MBP) and neurofascin 155 (NF155), and dendritic spine density were observed using transmission electron microscopy (TEM), enzyme-linked immunosorbent assay (ELISA), immunofluorescence, qRT-PCR, and primary neuron culture. ResultsBehaviorally, knockdown of METTL14 significantly counteracted the beneficial effects of acupuncture in improving self-grooming, open field exploration, three-chamber social interaction, and Morris water maze learning and memory (P<0.05, P<0.01). Compared with the acupuncture+sh-NC group, the acupuncture+sh-METTL14 group showed significantly decreased mRNA and protein expression of hippocampal METTL14 (P<0.01), and the upregulating effects of acupuncture on METTL3 and PTEN expression were reversed (P<0.01). Meanwhile, knockdown of METTL14 significantly inhibited the acupuncture-induced increase in PTEN m⁶A levels (P<0.01). Morphologically, knockdown of METTL14 attenuated the improvement of myelin structure by acupuncture, reversed the downregulation of MBP and upregulation of NF155 induced by acupuncture, and blocked the increase in dendritic spine density (P<0.05, P<0.01). ConclusionMETTL14 is a key molecule mediating the therapeutic effect of acupuncture at Neiguan. Acupuncture at Neiguan upregulates METTL14, thereby enhancing m⁶A methylation modification of PTEN mRNA to stabilize its expression, ultimately promoting myelin development and improving behavioral symptoms in ASD juvenile rats. This preliminarily reveals the modern biological connotation of “opening Xuanfu and dredging myelin”.

Metabolic diseases characterized by an imbalance in energy homeostasis represent a significant global health challenge. Individuals with metabolic diseases often suffer from complications related to disorders in lipid metabolism, such as obesity and non-alcoholic fatty liver disease (NAFLD). Understanding core genes involved in lipid metabolism can advance strategies for the prevention and treatment of these conditions. Stearoyl-CoA desaturase 1 (SCD1) is a key enzyme in lipid metabolism that converts saturated fatty acids into monounsaturated fatty acids. SCD1 plays a crucial regulatory role in numerous physiological and pathological processes, including energy homeostasis, glycolipid metabolism, autophagy, and inflammation. Abnormal transcription and epigenetic activation of Scd1 contribute to abnormal lipid accumulation by regulating multiple signaling axes, thereby promoting the development of obesity, NAFLD, diabetes, and cancer. This review comprehensively summarizes the key role of SCD1 as a metabolic hub gene in various (patho)physiological contexts. Further it explores potential translational avenues, focusing on the development of novel SCD1 inhibitors across interdisciplinary fields, aiming to provide new insights and approaches for targeting SCD1 in the prevention and treatment of metabolic diseases.
Stearoyl-CoA Desaturase/metabolism* ; Humans ; Metabolic Diseases/physiopathology* ; Lipid Metabolism/physiology* ; Animals ; Obesity/enzymology* ; Non-alcoholic Fatty Liver Disease

This article reports the clinical features and gene mutation types of a large family with Nascimento form of syndromic X-linked intellectual developmental disorder (MRXSN), involving 9 individuals across 3 generations, and a literature review was conducted. In this family, 9 individuals had similar manifestations including mental retardation and unusual facies, and 4 of them had passed away. Genetic testing showed that the proband had the deletion of exons 2-3 of the UBE2A gene, which was inherited from the mother. Fluorescent quantitative polymerase chain reaction showed that the proband and his uncle had the deletion of exons 2-3 of the UBE2A gene; the proband's mother, grandmother, and great-aunt had a heterozygous deletion of exons 2-3 of the UBE2A gene; the proband's father, sister, and aunt had a normal copy number of exons 2-3 of the UBE2A gene. The 34 patients reported in the literature had diverse clinical phenotypes, and UBE2A gene mutations (22/34, 65%) and large fragment deletions (12/34, 35%) were the main mutation types. Moderate to severe mental retardation (34/34, 100%), speech and language impairment (33/34, 97%), and unusual facies (32/34, 94%) were the main clinical manifestations of MRXSN patients. The disease has obvious phenotypic heterogeneity, and early diagnosis facilitates optimal prenatal and postnatal management to improve reproductive outcomes.
Humans ; Male ; Ubiquitin-Conjugating Enzymes/genetics* ; Female ; X-Linked Intellectual Disability/genetics* ; Gene Deletion ; Child ; Pedigree ; Child, Preschool ; Adult

Objective:This study aims to investigate the risk factors of venous thromboembolism(VTE)in patients with chronic heart failure(CHF),and establish a model for predicting the risk of VTE.Methods:A nested case-control study was conducted on CHF patients admitted in Pengzhou People's Hospital between June 2022 and June 2023.A total of 66 patients were diagnosed with VTE among the 960 CHF patients.Then another 66 patients paired by age and gender to those with VTE were selected from the remaining non-VTE patients as control group.Gener-al data,D dimer(D-D),thrombin-antithrombin complex(TAT),plasmin-α2-antiplasmin complex(PIC),tissue plasminogen activator-inhibitor complex(t-PAIC),thrombomodulin(TM)and Padua score were compared between two groups.Multivariate Logistic regression analysis was used to screen the independent risk factors of VTE in CHF patients.The receiver operating characteristic(ROC)curve analysis was applied to assess the efficacy of each indicator in predicting the risk of VTE in CHF patients.Results:Compared to patients in the non-VTE group,those in the VTE group had significantly higher D-D[3.26(1.87,6.19)mg/L vs.0.81(0.56,1.26)mg/L],TAT[5.60(4.90,8.80)ng/ml vs.2.60(1.70,3.30)ng/ml],TM[16.40(13.50,20.03)TU/ml vs.9.65(7.60,11.20)TU/ml],PIC[1.24(0.94,1.68)μg/ml vs.0.84(0.65,1.22)μg/ml],t-PAIC[12.60(9.38,17.05)ng/ml vs.7.70(5.53,9.70)ng/ml],proportion of atrial fibrillation/flutter(54.5％vs.22.7％)and Padua score[4(3,4)points vs.3(2,3)points](P＜0.001 all),and significantly lower lymphocyte count[0.99(0.60,1.38)×109/Lvs.1.20(0.76,1.67)×109/L,P=0.020].Multivariate Logistic regression analysis indicated that after adjusting confounders,TM(OR=2.456,95％CI 1.389～14.296,P=0.012)and Padua score(OR=3.257,95％CI 1.270～13.073,P=0.037)were independent risk factors for VTE in CHF patients.A predictive model was constructed using above-mentioned two indexes.The area under the ROC curve(AUC)of the combined prediction was 0.941(95％CI 0.901～0.980),which was significantly higher than those of TM(AUC=0.889,95％CI 0.833～0.945)and Padua score(AUC=0.801,95％CI 0.731～0.871)alone(Z=2.672,4.063,P=0.008,＜0.001).Conclusion:Padua score and TM were independent risk factors for VTE in CHF patients,and their combined detec-tion could better predict the risk of VTE in these patients.

Gastric cancer remains one of the most prevalent and lethal malignancies of the digestive tract worldwide,underscoring the urgent need for more effective targeted therapeutic strategies.Poly(ADP-ri-bose)polymerase(PARP)inhibitors have demonstrated remarkable efficacy in tumors with homologous recombination repair(HRR)deficiency;however,their clinical application in gastric cancer remains limited.Clinical evidence suggests that patients harboring Helicobacter pylori infection in combination with HRR gene mutations exhibit a significantly elevated risk of developing gastric cancer,thereby supporting the potential benefit of PARP inhibition in this setting.In this study,a kinase inhibitor library was screened in combination with the PARP inhibitor olaparib in gastric cancer cells.And we identify the cy-clin-dependent kinase 8/19(CDK8/19)inhibitor Senexin A as a compound that synergistically enhances the cytotoxic effect of PARP inhibition(P<0.05).Phenotypic validation using CCK-8 and colony for-mation assays demonstrated that the combination treatment significantly suppressed cellular proliferation and clonogenic potential compared to either monotherapy(P<0.0001).Mechanistically,alkaline comet assays revealed a significant increase in DNA damage in the combination treatment group relative to either single-agent group(P<0.0001),suggesting that the synergistic effect results from the exacerbation of DNA damage via impaired DNA repair mechanisms.In addition,treatment with CDK8/19 inhibitors a-lone markedly increased the formation of γH2AX and 53BP1 foci in irradiated gastric cancer cells(P<0.0001),indicating inhibition of DNA damage repair pathways.Transcriptome sequencing further re-vealed that CDK8/19 inhibition impacts critical cellular pathways,including DNA repair,cell cycle reg-ulation,and RNA splicing.Co-immunoprecipitation assays confirmed that inhibition of CDK8/19 kinase activity significantly reduces the phosphorylation level of PARP1,suggesting a potential regulatory inter-action.Immunohistochemical analysis of tumor and adjacent non-tumor tissues from gastric cancer pa-tients demonstrated that CDK8 is significantly overexpressed in tumor tissues,supporting its potential as both a prognostic biomarker and a therapeutic target.Collectively,this study elucidates a mechanistic ba-sis by which CDK8/19 inhibition enhances the sensitivity of gastric cancer cells to PARP inhibitors.These findings provide a strong rationale for the combined use of CDK8/19 and PARP inhibitors as a tar-geted therapeutic strategy and offer promising translational implications for advancing personalized medi-cine in gastric cancer treatment.

Objective To evaluate the consumption of opioid and postoperative analgesia of intercostal nerve block(ICNB)and paravertebral block(PVB)for autologuous rib cartilage graft for auricular reconstruction in children with microtia.Methods A total of 120 patients scheduled for autologuous rib cartilage graft for auricular reconstruction were enrolled.According to randomized blocks,patients were allocated into three groups(n=40 in each group):general anesthesia group(GA group),ultrasound-guided intercostal nerve block group(ICNB group)and ultrasound-guided PVB group(PVB group).GA group only received general anesthesia,while ICNB group and PVB group received single-shot nerve block with lidocaine after induction of general anesthesia.All groups were received patient-controlled intravenous analgesia(PCIA)for 48 hours postoperatively.Intraoperative opioid requirement was recorded.Heart rate(HR)and mean arterial pressure(MAP)were recorded at different time points during surgery.Time of the first visual analogue scale(VAS)obtained and duration of postanesthesia care unit(PACU)stay were evaluated.The VAS scores of chest and ear during deep breath and at rest were recorded during 48 hours postoperatively.Opioid consumption and postoperative analgesia-related adverse events were compared among the three groups during 48 hours after surgery.Results Compared with those in GA group,intraoperative fentanyl consumption(P=0.02,P<0.01),time of the first VAS obtained(P<0.01,P=0.02),duration of PACU stay(P<0.01,P<0.01)and HR when harvesting the first rib cartilage(P=0.04,P<0.01)were statistically lower in ICNB group and PVB group than those in GA group,but no statistical difference was found between these two groups.There were no statistical differences in VAS scores,opioid consumption and analgesia-related adverse events among the three groups.Conclusion Ultrasound-guided single-shot ICNB and PVB with lidocaine provide similar efficacy of reducing intraoperative opioid consumption,maintaining intraoperative hemodynamic stability and faster awakening,but fail to alleviate postoperative pain.

Bovine rotavirus(BRV)is an important pathogen causing diarrhea in calves.To understand the genomic charac-teristics and genetic variations in bovine rotavirus,and to further enrich data on the biological characteristics of rotavirus,we aimed to amplify 11 gene segments of the isolated and cultured G6P[1]bovine rotavirus BLL strain,perform whole genome se-quencing,and analyze the molecular characteristics.MEGA7.0 and DNAMAN software were used for homology and typing a-nalysis,and the whole genome phylogenetic tree was constructed to analyze genetic evolution relationships.The complete geno-type of the BLL strain was G6-P[1]-I2-R2-C2-M2-A3-N2-T6-E2-H3.Phylogenetic analysis of the VP7 and VP4 genes of the BLL strain showed that the VP7 gene had the highest homology with RVA/Cow-wt/HB01/China/2021,and the VP4 gene of the BLL strain was in the same branch as RVA/Human-tc/ISR/Ro8059/1995.From the sequence alignment of VP8*amino acids,the sialic acid domain of the BLL strain was found to be similar to that in other P[1]strains,but different from those in other types of strains,except for residue 189,which was the same as that in Ro8059 but different from that in other strains.The results suggested that the BLL strain might potentially infect humans.Therefore,continued monitoring and study of the biological characteristics of this strain are necessary to provide more information and evidence supporting further research on the cross-species transmission of group A rotavirus in China.

Objective To investigate the expression of ferritinophagy-related gene ELAV-like RNA binding protein 1(ELAVL1)in multiple myeloma(MM)and elucidate its diagnostic and prognostic value for MM.Methods First,we analyzed ELAVL1 expression level in healthy controls and MM patients using data from the GEO and TCGA databases.Subsequently,bone marrow specimens were collected from 28 newly diagnosed MM patients and 20 healthy controls,and qRT-PCR was employed to validate ELAVL1 expression.The diagnostic and prognostic potential of ELAVL1 was assessed using ROC curve analysis and Kaplan-Meier survival curves.Additionally,univariate and multivariate COX regression analyses were performed to identify independent risk factors for MM prognosis.Finally,KEGG and GO enrichment analyses were performed using the DAVID online platform.Results The level of ELAVL1 expression was significantly higher in newly diagnosed MM patients and refractory/relapsed MM patients than in the healthy controls(P＜0.001).Moreover,ELAVL1 expression was positively correlated with the International Staging System(ISS)stage of MM(P＜0.01).Furthermore,qRT-PCR validation confirmed that ELAVL1 expression was elevated in the 28 newly diagnosed MM patients compared to the 20 healthy controls(P＜0.001).ROC curve analysis demonstrated that ELAVL1 could effectively differentiate between newly diagnosed MM patients,healthy controls,and MGUS patients(P＜0.001 and P=0.000 2,respectively).Survival analysis revealed that high ELAVL1 expression was associated with shorter progression-free survival(P=0.0141)and overall survival(P=0.008 0).Univariate and multivariate COX regression analyses identified high ELAVL1 expression as an independent risk factor for poor MM prognosis(P=0.005 0).KEGG analysis suggested that ELAVL1 might be involved in the Hippo and MAPK signaling pathways.Conclusion High ELAVL1 expression in MM may serve as a biomarker for diagnosis and poor prognosis.ELAVL1 may promote MM initiation and progression via the Hippo and MAPK signaling pathways.