BACKGROUND:It has also been confirmed that ferroptosis is closely related to a variety of musculoskeletal diseases,such as rheumatoid arthritis,osteosarcoma,and osteoporosis.The pathophysiological mechanisms of ferroptosis and osteoporosis need to be further studied and elucidated to broaden our understanding of iron metabolism and osteoporosis.It will provide research ideas for the future elucidation of new mechanisms of osteoporosis and the development of new technologies and drugs for the treatment of osteoporosis. OBJECTIVE:To provide an overview of the current status of research on ferroptosis in osteoporosis,to provide a new direction for future research on the specific molecular mechanisms of osteoporosis,and to provide more effective and better options for osteoporosis treatment strategies. METHODS:The first author used the computer to search the literature published from 2000 to 2024 in CNKI,WanFang,VIP,and PubMed databases with search terms"ferroptosis,iron metabolism,osteoporosis,osteoblast,osteoclast,bone metabolism,signal pathway,musculoskeletal,review"in Chinese and English.A total of 68 articles were finally included according to the selection criteria. RESULTS AND CONCLUSION:(1)Ferroptosis is a new type of cell death discovered in recent years,which is usually accompanied by a large amount of iron accumulation and lipid peroxidation during cell death,and its occurrence is iron-dependent.This is distinctly different from several types of cell death that are currently being hotly studied(e.g.,cellular pyroptosis,necrotic apoptosis,cuproptosis,and autophagy).(2)Intracellular iron homeostasis is manifested as a balance between iron uptake,export,utilization,and storage.The body's iron regulatory system includes systemic and intracellular regulation.The main factor of systemic regulation is hepcidin produced by hepatic secretion,and cellular regulation depends on the iron regulatory protein/iron response element system.Of course,intracellular iron homeostasis can be controlled by other factors,such as hypoxia,cytokines,and hormones.(3)Lipid peroxidation causes oxidative damage to biological membranes(plasma membrane and internal organelle membranes),lipoproteins,and other lipid-containing molecules.Polyunsaturated fatty acid-containing phospholipids are important targets of lipid peroxidation.Free polyunsaturated fatty acid is an important substrate for lipid oxidation and can bind to the phospholipid bilayer,leading to over-oxidation and thus triggering lipid apoptosis.(4)Several studies have shown that osteoblasts are overloaded with iron in different ways,resulting in the accumulation of unstable ferrous iron and the generation of reactive oxygen species and lipid peroxides,causing ferroptosis of osteoblasts and ultimately a decrease in bone formation,affecting bone homeostasis and the development of osteoporosis.(5)Osteoclasts are large multinucleated cells formed by the fusion of mononuclear macrophage cell lines or bone marrow mesenchymal stem cells induced by nuclear factor-κB ligand receptor activator,and they have the function of bone resorption.Iron ions can promote osteoclast differentiation and bone resorption through the production of intracellular lipid reactive oxygen species,while iron chelators can inhibit osteoclast formation in vitro and thus affect the occurrence and development of osteoporosis.

Metachromatic leukodystrophy (MLD) is an inherited disease caused by a deficiency of the enzyme arylsulfatase A (ARSA). Lentivirus-modified autologous hematopoietic stem cell gene therapy (HSCGT) has recently been approved for clinical use in pre and early symptomatic children with MLD to increase ARSA activity. Unfortunately, this advanced therapy is not available for most patients with MLD who have progressed to more advanced symptomatic stages at diagnosis. Patients with late-onset juvenile MLD typically present with a slower neurological progression of symptoms and represent a significant burden to the economy and healthcare system, whereas those with early onset infantile MLD die within a few years of symptom onset. We conducted a pilot study to determine the safety and benefit of HSCGT in patients with postsymptomatic juvenile MLD and report preliminary results. The safety profile of HSCGT was favorable in this long-term follow-up over 9 years. The most common adverse events (AEs) within 2 months of HSCGT were related to busulfan conditioning, and all AEs resolved. No HSCGT-related AEs and no evidence of distorted hematopoietic differentiation during long-term follow-up for up to 9.6 years. Importantly, to date, patients have maintained remarkably improved ARSA activity with a stable disease state, including increased Functional Independence Measure (FIM) score and decreased magnetic resonance imaging (MRI) lesion score. This long-term follow-up pilot study suggests that HSCGT is safe and provides clinical benefit to patients with postsymptomatic juvenile MLD.
Humans ; Leukodystrophy, Metachromatic/genetics* ; Pilot Projects ; Genetic Therapy/methods* ; Hematopoietic Stem Cell Transplantation ; Male ; Follow-Up Studies ; Female ; Lentivirus/genetics* ; Child ; Child, Preschool ; Hematopoietic Stem Cells/metabolism* ; Cerebroside-Sulfatase/metabolism* ; Adolescent

AIM:To identify transcriptional differences between the ocular surface ectoderm(OSE)and surface ectoderm(SE)using RNA-seq, and elucidate the OSE transcriptome landscape and the regulatory networks involved in its development.METHODS:OSE and SE cells were differentiated from human embryonic stem(hES)cells. Differentially expressed genes(DEGs)between OSE and SE were analyzed using RNA-seq. Based on the DEGs, we performed gene ontology(GO)analysis, Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analysis, and protein-protein interaction(PPI)network analysis. Transcription factors(TFs)and hub genes were screened. Subsequently, TF-gene and TF-miRNA regulatory networks were constructed using the NetworkAnalyst platform.RESULTS:A total of 4 182 DEGs were detected between OSE and SE cells, with 2 771 up-regulated and 1 411 down-regulated genes in OSE cells. GO-BP analysis revealed that up-regulated genes in OSE were enriched in the regulation of ion transmembrane transport, axon development, and modulation of chemical synaptic transmission. Down-regulated genes were primarily involved in nuclear division, chromosome segregation, and regulation of cell cycle phase transition. KEGG analysis indicated that up-regulated genes in OSE cells were enriched in signaling pathways such as cocaine addiction, axon guidance, and amphetamine addiction, while down-regulated genes were enriched in proteoglycans in cancer, ECM-receptor interaction, protein digestion and absorption, and cytokine-cytokine receptor interaction. Additionally, compared with SE, 204 TFs(including FOS, EGR1, POU5F1, SOX2, and PAX6)were up-regulated, and 80 TFs(including HAND2, HOXB6, HOXB5, HOXA5, and HOXB8)were down-regulated in OSE cells. Furthermore, we identified 6 up-regulated and 9 down-regulated hub genes in OSE cells, and constructed TF-gene and TF-miRNA regulatory networks based on these hub genes.CONCLUSIONS:The transcriptome characteristics of OSE and SE cells were elucidated through RNA-seq analysis. These findings may provide a novel insight for studies on the development and in vitro directed induction of OSE and corneal epithelial cells.

Birth cohort is an effective method to explore the relationship between various prepregnant and pregnant exposures and the health of fetuses, infants and young children. It is a long construction period to build a birth cohort and the quality of research may be affected by many factors. This paper reviews the quality assurance and quality control measures in the process of China National Birth Cohort (CNBC), and summarizes the construction experience. We aim to provide experience for related cohort studies, which could improve the quality of cohort studies through removing the impact of related factors. CNBC adopted a series of measures to ensure the quality of research in the top-level design of quality assurance, including screening research center, developing member management system, formulating standard operating procedures and training staff by it. In terms of quality control, it includes real-time, timely and timing quality control for the process of data generation, full-cycle quality control for biological sample collection, processing, storage and comprehensive three-dimensional quality control for staff training, supervision and quantitative assessment.

Birth cohort is an important observational study which can continuously and dynamically collect the exposure changes and health outcomes from gametophyte development to adolescence and even old age. However, because of its complex design and difficult implementation, how to construct birth cohort with high quality and high efficiency is the main difficulty faced by epidemiologists at home and abroad. In 2016, China National Birth Cohort was officially launched. The network and information technology were used to explore, and a set of "cloud-based information platform" was established to support this queue construction, containing 16 units in China. After four years of development, the platform has formed a complete set of programs about the construction of cohort information platform, which including recruitment and follow-up management of participants, real-time data interaction, queue quality control, multi-level authority management and function division. The relevant design framework and functional elements provide the references to the future information construction of large-scale birth cohort and even population-based research in China.

Objective:To explore the association between polygenic risk score (PRS) and age at onset and early-onset risk of gastric cancer (GC).Methods:Gastric cancer cases from existing genome-wide association study were included, and 112 single nucleotide polymorphisms associated with GC risk were used to derive individual PRS. Analysis of variance and Pearson correlation test was used to depict the relationship between PRS and GC onset age. Cases diagnosed before 50 years old were defined as early-onset gastric cancer. Cox proportional hazard model was used to test the association between PRS and early-onset GC risk with early-onset age as the timescale and low genetic risk (PRS ≤20%) as the reference group.Results:A total of 8 629 cases, including 6 284 males (72.82%) and 2 345 females (27.18%), were included, and the mean age was (60.61±10.80) years old. The PRS was negatively correlated with age of GC onset ( r=-0.05, P<0.001). The mean age of gastric cancer cases with low, intermediate, and high genetic risk were (61.68±10.33), (60.53±10.79), (59.80±11.20), respectively. PRS was significantly associated with the risk of early-onset GC in a dose-response manner (intermediate genetic risk: HR=1.19, 95% CI: 1.03-1.39, P=0.022; high genetic risk: HR=1.44, 95% CI: 1.20-1.71, P<0.001). Conclusions:PRS may contribute to the risk of both GC and early-onset GC. PRS can be used as a measurable indicator for risk prediction for occurrence and early-onset of GC.

Significantly increasing crop yield is a major and worldwide challenge for food supply and security. It is well-known that rice cultivated at Taoyuan in Yunnan of China can produce the highest yield worldwide. Yet, the gene regulatory mechanism underpinning this ultrahigh yield has been a mystery. Here, we systematically collected the transcriptome data for seven key tissues at different developmental stages using rice cultivated both at Taoyuan as the case group and at another regular rice planting place Jinghong as the control group. We identified the top 24 candi-date high-yield genes with their network modules from these well-designed datasets by developing a novel computational systems biology method, i.e., dynamic cross-tissue (DCT) network analysis. We used one of the candidate genes, OsSPL4, whose function was previously unknown, for gene editing experimental validation of the high yield, and confirmed that OsSPL4 significantly affects panicle branching and increases the rice yield. This study, which included extensive field phenotyping, cross-tissue systems biology analyses, and functional validation, uncovered the key genes and gene regulatory networks underpinning the ultrahigh yield of rice. The DCT method could be applied to other plant or animal systems if different phenotypes under various environments with the common genome sequences of the examined sample. DCT can be downloaded from https://github.com/zt-pub/DCT.

BACKGROUND AND PURPOSE: Large cohort studies on relationship between family history of stroke (FHS) and stroke risk are lacking in Asians. We aimed to systematically evaluate the association of FHS with stroke risk in a cohort study of 0.5 million Chinese adults. METHODS: Information about FHS was self-reported. The median follow-up time was 7.16 years and the end-point of follow-up was incident stroke, which was entered directly into the China Kadoorie Biobank system. Multivariate analyses were performed with Cox proportional hazards model, and interaction analyses were carried using likelihood-ratio tests. RESULTS: Compared with participants without FHS, the hazard ratio (HR) (95% confidence interval, CI) of stroke for participants with FHS was 1.50 (1.46-1.55). The HRs increased with the number of first degree relatives with stroke (HRs=1.41, 1.98 and 2.47 for 1, 2 and ≥3 relatives, respectively, P(trend) <0.001). The HRs were 1.57 (95% CI: 1.50-1.66) and 1.49 (95% CI: 1.45-1.54) for sibling history and parental history, respectively. Similar associations with offspring stroke risk were observed between paternal history (HR=1.48, 95% CI: 1.43-1.54) and maternal history (HR=1.49, 95% CI: 1.43-1.55). Moreover, significant interactions were detected between FHS and health-risk behaviors (tobacco smoking and alcohol drinking). CONCLUSIONS: FHS is an independent risk factor for stroke in Chinese. The more first degree relatives are affected by stroke, the higher are individuals’ risk of suffering from stroke. The management of the health-risk behaviors for reducing stroke should be highlighted, especially for the individuals with FHS.
Adult ; Asian Continental Ancestry Group ; China* ; Cohort Studies* ; Follow-Up Studies ; Humans ; Multivariate Analysis ; Parents ; Proportional Hazards Models ; Risk Factors ; Siblings ; Smoke ; Smoking ; Stroke*

Objective To investigate the diagnostic value of plasma B-type natriuretic peptide(BNP) in left to right shunt congenital heart disease accompanied by heart failure in PICU.Methods We retrospectively reviewed the clinical data of 52 cases diagnosed left to right shunt congenital heart disease in the PICU of Shengjing Hospital of China Medical University from January 2012 to June 2014.The cases were divided into negative control group(n=18) and heart failure group(n=34) according to the criteria for the diagnosis of pediatric heart failure.We respectively compared plasma BNP,size of heart defects,left ventricular end-diastolic volume index(LVEDVI),ratio of left ventricular early diastolic filling blood flow velocity and left ventricular late diastolic filling blood flow velocity(E/A),left ventricular ejection fraction(LVEF),pulmonary artery systolic pressure(PASP),and cardiothoracic ratio between the two groups.We analyzed the correlation between plasma BNP and the size of heart defects,LVEDVI,E/A,cardiothoracic ratio,LVEF,PASP.The receiver operating characteristic curve was used to determine the optimal cut-off value of plasma BNP to diagnose heart failure.Results Plasma BNP were 87.7(22.7,165.7)pg/ml in negative control group and 716.5(326.8,1813.0)pg/ml in heart failure group.The plasma BNP level of heart failure group was significantly higher than that of negative control group(Z=5.3,P<0.01).Size of heart defects were 5.0(3.0,6.8) mm in negative control group and 7.4(5.5,9.0)mm in heart failure group.Size of heart defects of heart failure group was significantly higher than that of negative control group(Z=3.5,P<0.01).LVEDVI were (44.6±18.3)ml/m3 in negative control group and (70.8±38.4)ml/m3 in heart failure group.LVEDVI of heart failure group was significantly higher than that of negative control group(t=2.7,P=0.01).E/A were 1.3±0.3 in negative control group and 1.1±0.3 in heart failure group.E/A of negative control group was significantly higher than that of heart failure group(t=2.2,P=0.04).Plasma BNP had a positive relation with cardiothoracic ratio(r=0.49,P=0.01) and a negative correlation with E/A(r=-0.28,P=0.04).The optimal cut-off value of plasma BNP was 181.8 pg/ml.The sensitivity of diagnosis of heart failure was 94% and the specificity was 88%.The area under the receiver operating characteristic curve was 0.951.Conclusion Plasma BNP may comprise a sensitive marker for heart failure of left to right shunt congenital heart disease.It is recommended that 181.8 pg/ml is the optimal cut-off value to diagnose heart failure of left to right shunt congenital heart disease.

Objective To investigate the high risk factors of new dysfunction in Pediatric Intensive Care Unit.Methods A retrospective cohort case control analysis was performed in order to investigate the 906 patients admitted to the Pediatric Intensive Care Unit of Shengjing Hospital of China Medical University from January 2015 to January 2016.Assessment of Functional Status Scale(FSS) was performed at both admission and discharge.According to the new dysfunction diagnostic criteria,all cases were divided into new dysfunction group and control group.The 2 groups were compared in gender,glucocorticoids application time,mechanical ventilation application time,sedation application time,neuromuscular blockers application time,albumin,alanine aminotransferase,aspartate aminotransferase,creatine kinase,creatine kinase isoenzyme,leukocyte,hemoglobin and C-reactive protein.Multivariate Logistic regression was used to screen the risk factors leading to new dysfunction.All cases were divided into high risk factors group and control group according to the risk factors.The 2 groups were compared in initial FSS,FSS of discharge,ΔFSS and the discharge FSS of mental status domain,FSS of sensory domain,FSS of communication domain,FSS of motor domain,FSS of feeding domain,and FSS of respiratory domain.Results Among the 906 cases,547 cases were male and 359 cases were female,and average age was (28.1-± 1.9) months.There were 81 cases in new dysfunction group and 825 cases in control group.Factors such as mechanical ventilation application time [(3.7 ±-0.5) d vs.(1.1 ±-0.1) d],glucocorticoid application time [(3.2-±0.6) d vs.(1.7-±0.1) d],sedation application time[(4.7 ±0.7) d vs.(1.7 ±0.1)d],neuromuscular blockers application time [(0.7 ± 0.3) d vs.(0.1 ± 0.03) d],albumin [(35.6 ± 0.8) g/L vs.(40.5 ± 0.2) g/L],creatine kinase isoenzyme [(75.8 ± 12.4) U/L vs.(49.7 ± 2.6) U/L] had significant differences between the new dysfunction group and the control group(all P ＜ 0.05).Multivariate Logistic regression analysis revealed that more than 7 days of mechanical ventilation,more than 7 days of glucocorticoids application,more than 7 days of sedation application,hypoalbuminemia were risk factors to develop new dysfunction [OR =0.69 (95％ CI:0.62-0.78),OR=0.62 (95％ CI:0.75-0.94),0R=0.75 (95％ CI:0.68-0.84),0R=0.68 (95％ CI:1.06-1.16),all P ＜0.05].In the more than 7 days of mechanical ventilation group,FSS at discharge,FSS of mental status,FSS of sensory,FSS of communication,FSS of motor,FSS of feeding,FSS of respiratory were significantly different from those of the mechanical ventilation application time ≤ 7 d group (all P ＜ 0.05).In the more than 7 days of glucocorticoids application group,FSS of mental status,FSS of sensory,FSS of communication were significantly different from those of the glucocorticoids application time ≤7 d group (all P ＜ 0.05).In the more than 7 days of sedation application group,FSS at discharge,FSS of mental status,FSS of sensory,FSS of communication,FSS of motor were significantly different from those of the sedation application time ≤7 d group(all P ＜ 0.05).Concltsion More than 7 days of mechanical ventilation,glucocorticoids application and sedation application not only increase the incidence of new dysfunction,but also affect mental,sensory,communication,motor function,the muscle and cognitive function at discharge and prognosis.