Objective:To explore the prevalence, clinical features, genetic characteristics and prognosis of Citrin deficiency in Henan province of China.Methods:A total of 986 565 neonates screened by tandem mass spectrometry at the Third Affiliated Hospital of Zhengzhou University from January 2013 to December 2021 were retrospectively analyzed. Analysis of SLC25A13 gene variants and parental verification were carried out for neonates suspected for Citrin deficiency by next-generation sequencing. The clinical, biochemical and genetic characteristics of Citrin deficiency patients were integrated to guide the diet treatment and follow up the growth and development. Paired- t test was used to compare the amino acid levels in the peripheral blood samples before and after the treatment. Results:Nine cases of Citrin deficiency were diagnosed among the 986 565 neonates. Specific elevation of citrulline was observed in all of the 9 cases. Six variants were detected by genetic sequencing, among which c. 852_855delTATG, c. 615+ 5G>A, c. 550C>T and IVS16ins3kb were known pathogenic variants, whilst c. 1111_1112delAT and c. 837T>A were unreported previously. The detection rate for c. 852_855delTATG was the highest (61.6%, 11/18), followed by IVS16ins3kb (16.7%, 3/18). The clinical symptoms of all patients were relieved after the treatment, and the blood amino acid profile and biochemical parameters were significantly improved by gradually falling within the normal range. By June 2022, all patients had shown a good prognosis.Conclusion:The prevalence of Citrin deficiency among neonates from Henan Province by tandem mass spectrometry is 1/109 618, and the carrier rate for the pathogenic variants of the SLC25A13 gene was 1/166. The c. 852_855delTATG may be a hot spot variant among the patients. Discovery of the novel variants has enriched the mutational spectrum of the SLC25A13 gene. Above results have provided a basis for the early diagnosis, treatment, prognosis and genetic counseling for the affected families.

Objective:To explore the genetic basis of a child with mental retardation and developmental delay.Methods:A child who had attended the genetic clinic of Linyi People′s Hospital from October 2023 to April 2024 was selected as the study subject. Intelligence and development were assessed with simplified Peabody scale. Electroencephalogram and imaging data were collected. Peripheral blood samples of the child and her parents were collected for the screening of genetic metabolic diseases, chromosomal karyotyping, and trio-whole genome sequencing (trio-WGS) analysis. Candidate variant was verified by Sanger sequencing, and RNAseq was carried out to verify the alternative splicing due to the candidate variant. This study has been approved by the Medical Ethics Committee of Linyi People′s Hospital (No. YX200083).Results:The patient was an 8-year-and-11-month-old girl. Both of her parents had normal phenotypes. The child was assessed by the simplified Peabody scale as having intellectual disability and developmental delay. MRI showed no definite abnormal signals within the brain parenchyma, and electroencephalogram was normal. Screening of genetic metabolic diseases showed no obvious abnormality. Chromosomal karyotype was normal. Trio-WGS has detected a c. 697+ 1G>A variant in the intron 4 of the NFIX gene, along with 9 other variants within eight genes. The c. 697+ 1G>A variant may cause abnormal splicing of the NFIX gene transcript. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the c. 697+ 1G>A variant was predicted to be pathogenic (PVS1+ PS2+ PM2_Supporting), while the evidence for pathogenicity of the other 9 variants was insufficient. Conclusion:The novel de novo c. 697+ 1G>A variant of the NFIX gene probably underlay the pathogenesis of the child, which may have caused the disease by leading to abnormal splicing.

Inflammation-driven endothelial dysfunction is the major initiating factor in atherosclerosis, while the underlying mechanism remains elusive. Here, we report that the non-canonical stimulator of interferon genes (STING)-PKR-like ER kinase (PERK) pathway was significantly activated in both human and mice atherosclerotic arteries. Typically, STING activation leads to the activation of interferon regulatory factor 3 (IRF3) and nuclear factor-kappa B (NF-κB)/p65, thereby facilitating IFN signals and inflammation. In contrast, our study reveals the activated non-canonical STING-PERK pathway increases scaffold protein bromodomain protein 4 (BRD4) expression, which encourages the formation of super-enhancers on the proximal promoter regions of the proinflammatory cytokines, thereby enabling the transactivation of these cytokines by integrating activated IRF3 and NF-κB via a condensation process. Endothelium-specific STING and BRD4 deficiency significantly decreased the plaque area and inflammation. Mechanistically, this pathway is triggered by leaked mitochondrial DNA (mtDNA) via mitochondrial permeability transition pore (mPTP), formed by voltage-dependent anion channel 1 (VDAC1) oligomer interaction with oxidized mtDNA upon cholesterol oxidation stimulation. Especially, compared to macrophages, endothelial STING activation plays a more pronounced role in atherosclerosis. We propose a non-canonical STING-PERK pathway-dependent epigenetic paradigm in atherosclerosis that integrates IRF3, NF-κB and BRD4 in inflammatory responses, which provides emerging therapeutic modalities for vascular endothelial dysfunction.

Chimeric antigen receptor T cell(CAR-T)therapy has produced remarkable results in the treatment of hematological tumors.The BCMA antigen is widely expressed on the surface of multiple myeloma cells and is a suitable,efficient target for CAR-T therapy.BCMA CAR-T cell therapy has a high response rate for relapsed or refractory patients in particular,and CAR-T cells are still detectable in most patients 1 year after infusion.However,drug resistance and disease recurrence remain key problems in clinical management.In this paper,we discuss the response factors and resistance induction mechanism of BCMA CAR-T cell therapy from several perspectives,such as the immune es-cape of multiple myeloma cells,CAR-T product factors,previous treatment regimens,and tumor immune microenvironment inhibition.We also propose possible optimization strategies in order to provide reference for future exploration.

BACKGROUND: Congenital scoliosis (CS) is a complex spinal malformation of unknown etiology with abnormal bone metabolism. Fibroblast growth factor 23 (FGF23), secreted by osteoblasts and osteocytes, can inhibit bone formation and mineralization. This research aims to investigate the relationship between CS and FGF23. METHODS: We collected peripheral blood from two pairs of identical twins for methylation sequencing of the target region. FGF23 mRNA levels in the peripheral blood of CS patients and age-matched controls were measured. Receiver operator characteristic (ROC) curve analyses were conducted to evaluate the specificity and sensitivity of FGF23. The expression levels of FGF23 and its downstream factors fibroblast growth factor receptor 3 (FGFr3)/tissue non-specific alkaline phosphatase (TNAP)/osteopontin (OPN) in primary osteoblasts from CS patients (CS-Ob) and controls (CT-Ob) were detected. In addition, the osteogenic abilities of FGF23-knockdown or FGF23-overexpressing Ob were examined. RESULTS: DNA methylation of the FGF23 gene in CS patients was decreased compared to that of their identical twins, accompanied by increased mRNA levels. CS patients had increased peripheral blood FGF23 mRNA levels and decreased computed tomography (CT) values compared with controls. The FGF23 mRNA levels were negatively correlated with the CT value of the spine, and ROCs of FGF23 mRNA levels showed high sensitivity and specificity for CS. Additionally, significantly increased levels of FGF23, FGFr3, OPN, impaired osteogenic mineralization and lower TNAP levels were observed in CS-Ob. Moreover, FGF23 overexpression in CT-Ob increased FGFr3 and OPN levels and decreased TNAP levels, while FGF23 knockdown induced downregulation of FGFr3 and OPN but upregulation of TNAP in CS-Ob. Mineralization of CS-Ob was rescued after FGF23 knockdown. CONCLUSIONS Our results suggested increased peripheral blood FGF23 levels, decreased bone mineral density in CS patients, and a good predictive ability of CS by peripheral blood FGF23 levels. FGF23 may contribute to osteopenia in CS patients through FGFr3/TNAP / OPN pathway.
Humans ; Osteopontin/genetics* ; Alkaline Phosphatase/metabolism* ; Receptor, Fibroblast Growth Factor, Type 3/metabolism* ; Scoliosis/genetics* ; Osteoblasts/metabolism* ; Calcinosis ; RNA, Messenger/metabolism* ; Bone Diseases, Metabolic/metabolism* ; Fibroblast Growth Factors/genetics*

Objective To investigate the clinical,endoscopic and pathological features of gastritis cystica profunda (GCP).Methods A total of 40 patients with GCP confirmed by pathology who received endoscopic or surgical treatment at Renji Hospital,School of Medicine,Shanghai Jiaotong University from May 2013 to May 2018,were included in the retrospective analysis.The clinical data such as population composition,clinical manifestations,endoscopic findings and pathological results were summarized and analyzed.Results Among the 40 patients were predominantly males (75.0％,30/40),and the mean age of onset was 61.2 years.The most common sites were cardia (32.5％,13/40) and gastric antrum (30.0％,12/40).The clinical symptoms of the patients were atypical and it was difficult to diagnose GCP with routine endoscopy examination.The endoscopic findings were mostly type 0-Ⅱ (50.0％,20/40).GCP with neoplastic lesions accounted for 55％ (22/40).Unconditional logistic regression analysis showed that male (P =0.013,OR =31.093,95％ CI:2.079-464.976) and Helicobacter pylori infection (P =0.041,OR =10.225,95％ CI:1.096-95.411) were risk factors for GCP with neoplastic lesions.Conclusion GCP commonly occurs in middle-aged and elderly men,and varies in different manifestations under white light endoscopy.GCP is not a benign lesion,but can also coexist with neoplastic lesions,which are mostly differentiated intramucosal cancer.

BACKGROUND: Simple nanotube surface modification of titanium implant has been shown to promote adhesion, proliferation and differentiation of osteoblasts. Collagen coating can promote osteoblast adhesion and osseointegration in vivo. OBJECTⅠVE: To observe the effects of type collagen combined titanium dioxide nanotube composite coating modified titanium surface on osteoblast adhesion in vitro and osseointegration in vivo. METHODS: The titanium dioxide nanotube was fabricated on the pure titanium surface, then type Ⅰ collagen was combined with the nanotube structure to form composite coating. Scanning electron microscope observation was used to characterize the surface topography of the pure titanium, titanium dioxide nanotube and type Ⅰ collagen combined titanium dioxide nanotube surfaces. Contact angle test was employed to evaluate the hydrophilicity of different samples. MC3 T3-E1 murine preosteoblasts were seeded on the three kinds of materials for 4 hours. Cell adhesion morphology was examined by scanning electron microscope. Adherent cell counting was detected under inverted fluorescence microscope. Expression of actin cytoskeleton and vinculin was observed under laser scanning confocal microscope. The gene expression of vinculin and osteoprotegerin mRNA was detected by real-time quantitative PCR. The three kinds of samples were implanted into the tibia of Sprague-Dawley rats (provided by Laboratory Animal Center, Ⅰnstitute of Radiation Medicine, Chinese Academy of Medical Sciences) , and tibia samples were removed after 4 weeks of implantation for biological push-out test and histological observation. RESULTS AND CONCLUSⅠON: (1) Scanning electron microscope: There was mechanical scratch on the pure titanium surface. There was controllable, and uniform vertical arrangement of nanotubular structures with a diameter of approximately 70 nm on the titanium dioxide nanotube surface, and collagen adhered surrounding the nanotubular structures on the type Ⅰ collagen combined titanium dioxide nanotube substrate, and partial tubule orifices were closed. (2) The hydrophicility of type Ⅰ collagen combined titanium dioxide nanotube was significantly larger than those of the other two materials (P < 0.05) . (3) Compared with the pure titanium and titanium dioxide nanotube surfaces, the type Ⅰ collagen combined titanium dioxide nanotube substrate displayed increased adherent cell number, much well-organized cytoskeleton, enhanced immunofluorescence intensity of vinculin protein staining, and increased expression levels of vinculin and osteoprotegerin mRNA levels (all P < 0.05) . (4) Ⅰn vivo test revealed that the maximum push-out force in the type Ⅰ collagen combined titanium dioxide nanotube group was significantly higher than that in the pure titanium and titanium dioxide nanotube groups (P < 0.05) . Hematoxylin-eosin staining results showed that there were few bones, but many fibrous connective tissue surrounding the implant in the pure titanium group; there were more newly-born bones, and less fibrous connective tissue surrounding the implant in the titanium dioxide nanotube group; there were dense newly-born bones, and few thin fibrous connective tissue surrounding the implant in the type Ⅰ collagen combined titanium dioxide nanotube group. (5) These results indicate that type Ⅰ collagen combined titanium dioxide nanotube surface can facilitate osteoblast cell adhesion and promote osseointegration in vivo.

OBJECTIVETo evaluate the clinical efficacy of YANG's pricking-cupping therapy for knee osteoar thritis (KOA). Methods This was a multi-center randomized parallel controlled trial. One hundred and seventy one patients with KOA were randomly allocated to a pricking-cupping group (89 cases) and a conventional acu puncture group (82 cases). Neixiyan (EX-LE 4), Dubi (ST 35) and ashi points were selected in the two groups. Patients in the pricking-cupping group were treated with YANG's pricking-cupping therapy; the seven-star needles were used to perform pricking at acupoints, then cupping was used until slight bleeding was observed. Patients in the conventional acupuncture group were treated with semi-standardized filiform needle therapy. The treatment was given for 4 weeks (from a minimum of 5 times to a maximum of 10 times). The follow-up visit was 4 weeks. The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and the visual analogue scale (VAS) were adopted for the efficacy assessments.

RESULTSThe pain score, stiffness score, physical function score and total score of WOMAC were all reduced after 4-week treatment and during follow-up visit in the two groups (all P<0. 0001). Except that the difference of stiffness score between the two groups was not significant after 4-week treatment (P>0. 05), each score and total score of WOMAC in the pricking-cupping group were lower than those in the conventional acupuncture group after 4-week treatment and during follow-up visit (P<0. 0001, P<0. 01). After 2-week treatment, 4-week treatment and during follow-up visit, the VAS was all reduced compared with that before treatment (all P<0. 0001) ; with the increase of the treatment, the reducing trend of VAS was more significant (P<0. 0001). The scores of VAS in the pricking-cupping group were lower than those in the conventional acupuncture group after 4-week treatment and during follow-up visit (P < 0. 01, P <0. 0001). CONCLUSION The YANG's pricking-cupping and conventional acupuncture therapy can both significantly improve knee joint pain and function in patients with KOA, which are relatively safe. The pricking cupping therapy is superior to conventional acupuncture with the identical selection of acupoints.

Acupuncture Therapy ; Adult ; Aged ; Arthralgia ; physiopathology ; therapy ; Combined Modality Therapy ; Female ; Humans ; Knee Joint ; physiopathology ; Male ; Medicine, Chinese Traditional ; methods ; Middle Aged ; Osteoarthritis, Knee ; physiopathology ; therapy ; Treatment Outcome

MicroRNAs (miRNAs) are critical for both development and function of the central nervous system. Significant evidence suggests that abnormal expression of miRNAs is associated with neurodevelopmental disorders. MeCP2 protein is an epigenetic regulator repressing or activating gene transcription by binding to methylated DNA. Both loss-of-function and gain-of-function mutations in the MECP2 gene lead to neurodevelopmental disorders such as Rett syndrome, autism and MECP2 duplication syndrome. In this study, we demonstrate that miR-130a inhibits neurite outgrowth and reduces dendritic spine density as well as dendritic complexity. Bioinformatics analyses, cell cultures and biochemical experiments indicate that miR-130a targets MECP2 and down-regulates MeCP2 protein expression. Furthermore, expression of the wild-type MeCP2, but not a loss-of-function mutant, rescues the miR-130a-induced phenotype. Our study uncovers the MECP2 gene as a previous unknown target for miR-130a, supporting that miR-130a may play a role in neurodevelopment by regulating MeCP2. Together with data from other groups, our work suggests that a feedback regulatory mechanism involving both miR-130a and MeCP2 may serve to ensure their appropriate expression and function in neural development.
Animals ; Dendrites ; genetics ; metabolism ; Dendritic Spines ; genetics ; metabolism ; Down-Regulation ; physiology ; Methyl-CpG-Binding Protein 2 ; biosynthesis ; genetics ; MicroRNAs ; genetics ; metabolism ; Rats

Objective To analyze the correlation of carotid artery stenosis(CAS)with postoperative cognitive dysfunc?tion(POCD)in patients who underwent off-pump coronary artery bypass grafting(OPCABG). Methods Between March 2014 and October 2014, a total of 157 patients who underwent OPCABG in our hospital were enrolled and divided into POCD group and non-POCD group according to their performance respondent to MMSE questionnaire survey conducted 5 days before operation. LOTCA questionnaire survey was conducted at the first day and 7th days pre-and post-operation re?spectively in order to investigate the influence of CAS on POCD in patients. Results The incidence of POCD was 30.6%(48 out of 157). Advanced age, diabetes,cultural level,carotid artery stenosis, Hb level after operation, score of LOTCA question?naire survey conducted before surgery,time of respirator and the time spend in ICU were significant predictive factors for POCD. However, multivariate logistic regression analysis showed that age, CAS and the time spend in ICU were independent risk factors for POCD, especially CAS(OR=5.078,95%CI:2.211-11.662, P<0.001). Patients with severe CAS suffer from a significant decline in cognitive function on space, time, action and ideation. Conclusion CAS is a predominant risk factor for POCD in patients undergoing OPCABG.