Objective:To detect itching,anxiety,depression behaviors in chronic itch models of mice and observe the activation of γ-aminobutiric acid(GABA)neurons in the ventral sector of the zona incerta(ZIv),and provide mor-phological evidence for their involvement in the modulation of itch information.Methods:Diphenylcyclopropenone(DCP)was used in glutamic acid decarboxylase 67-green fluorescent protein(GAD67-GFP)knock-in mice to establish chronic itch model.Itch behaviors were detected by video tracking system to verify whether the models were successfully established.The anxiety,depression behaviors of chronic itch model mice were detected by using elevated plus maze test(EPM)and tail suspention test(TST).By using GAD67-GFP mice,the distribution of GABAergic neurons in va-rious sectors of the zona incerta(ZI)was observed.And combined with immunofluorescence staining method,double labeling of GABAergic neurons with FOS in ZIv were observed respectively in control and DCP group mice.Results:In brain slices of GAD67-GFP mice,GABAergic neurons can be observed within all sectors of ZI and are more concentrat-ed in ZIv.Compared with control group mice,DCP group mice showed a significant increase in the bouts of scratching(P＜0.001).The time of immobility in TST was significantly higher in DCP group mice than in control group mice,which displayed depression-like behavior.The EPM test showed that the numbers of entries and proportion of time in the cross region in DCP group mice were less than in control group mice.EPM test revealed that DCP group mice exhibited anxiety-like behavior.The results of immunofluorescence staining showed that the number of FOS-positive cells in ZIv was significantly higher in DCP group mice than in control group mice,and abundant co-labeled neurons of FOS and GABAergic neurons were observed in ZIv.Conclusion:GABAergic neurons were predominantly distributed in ZI,and were more concentrated in ZIv.The activation of GABAergic neurons in ZIv of DCP group mice provides morphological evidence on the involvement of GABAergic neurons in chronic itch and associated negative emotions.

Objective To analyze the relationship between expression level of protein O-fucosyltransferase 1(POFUT1)and tumor immune infiltration level and prognosis of patients,and explore the value of POFUT1 in tumor immunotherapy.Methods Based on the pan-cancer data,R software was used to analyze the changes in POFUT1 expression levels of various tumor tissues and their correlation with the risk ratio of various tumor patients,and screen for tumor types related to patient prognosis and POFUT1 expression.Through the String database,a protein interaction network was constructed,POFUT1-associated genes were screened,and functional enrichment analysis was performed.The estimate software package was used to analyze the correlation between POFUT1 expression and immune infiltration score in selected tumor tissues.The TIMER database was used to analyze the correlation between the expression level of POFUT1 and various levels of immune cell infiltration,and the correlation between the infiltration level of immune cells and the prognosis of patients.Results The expression levels of POFUT1 were significantly high in 14 types of tumors(P<0.05),and were associated with poor prognosis of low-grade gliomas,lung adenocarcinoma,and thyroid cancer(Hazard Ratio>1,P<0.05).POFUT1 and its associated genes were highly involved in Notch signaling pathway,lymphocyte activation and immune regulation processes.The expression level of POFUT1 was positively correlated with the infiltration degree of B cells,CD8+T cells,CD4+T cells,macrophages,neutrophils and dendritic cells in low-grade gliomas,as well as positively associated with the infiltration level of neutrophils in LUAD,and B cells,CD4+ T cells and macrophages in thyroid cancer(|r|>0.2,P<0.05).The high infiltration levels of the above 6 types of immune cells were correlated with the poor prognosis of patients with low-grade glioma(Hazard Ratio>1,P<0.05).Conclusion POFUT1 was highly involved in the process of immune regulation,affecting the immune infiltration level of some tumors and further influencing patient prognosis.It may have the potential to become a target for tumor immunotherapy.

Objective:To investigate the clinical and genetic characteristics and predictive role of the severe liver disease phenotype in patients with hepatolenticular degeneration (HLD).Methods:Inpatients with HLD confirmed at Xinhua Hospital affiliated with Shanghai Jiao Tong University School of Medicine from January 1989 to December 2022 were selected as the research subjects. Clinical classification was performed according to the affected organs. Patients with liver disease phenotypes were classified into the liver disease group and further divided into the severe liver disease group and the ordinary liver disease group. The clinical characteristics and genetic variations were compared in each group of patients. The predictive indicators of patients with severe liver disease were analyzed by multiple regression. Statistical analysis was performed using the t-test, Mann-Whitney U test, or χ2 test according to different data. Results:Of the 159 HLD cases, 142 were in the liver disease group (34 in the severe liver disease group and 108 in the ordinary liver disease group), and 17 were in the encephalopathy group. The median age of onset was statistically significantly different between the liver disease group and the encephalopathy group [12.6 (7.0, 13.3) years versus 16.9 (11.0, 21.5) years, P<0.01]. 156 ATP7B gene mutation sites were found in 83 cases with genetic testing results, of which 54 cases carried the p.Arg778Leu gene mutation (allele frequency 46.2%). Compared with patients with other types of gene mutations ( n=65), patients with homozygous p.Arg778Leu mutations ( n=18) had lower blood ceruloplasmin and albumin levels, a higher prognostic index, Child-Pugh score, an international normalized ratio, and prothrombin time ( P<0.05). Hemolytic anemia, corneal K-F ring, homozygous p.Arg778Leu mutation, and multiple laboratory indexes in the severe liver disease group were statistically significantly different from those in the ordinary liver disease group ( P<0.05). Multivariate logistic regression analysis showed that the predictive factors for severe liver disease were homozygous p.Arg778Leu mutation, total bilirubin, and bile acids ( ORs=16.512, 1.022, 1.021, 95% CI: 1.204-226.425, 1.005-1.039, and 1.006-1.037, respectively, P<0.05). The drawn ROC curve demonstrated a cutoff value of 0.215 3, an AUC of 0.953 2, and sensitivity and specificity of 90.91% and 92.42%, respectively. Conclusion:Liver disease phenotypes are common in HLD patients and have an early onset. Total bilirubin, bile acids, and the homozygous p.Arg778Leu mutation of ATP7B is related to the severity of liver disease in HLD patients, which aids in predicting the occurrence and risk of severe liver disease.

Patients with severe trauma require an extremely timely treatment and transfusion plays an irreplaceable role in the emergency treatment of such patients. An increasing number of evidence-based medicinal evidences and clinical practices suggest that patients with severe traumatic bleeding benefit from early transfusion of low-titer group O whole blood or hemostatic resuscitation with red blood cells, plasma and platelet of a balanced ratio. However, the current domestic mode of blood supply cannot fully meet the requirements of timely and effective blood transfusion for emergency treatment of patients with severe trauma in clinical practice. In order to solve the key problems in blood supply and blood transfusion strategies for emergency treatment of severe trauma, Branch of Clinical Transfusion Medicine of Chinese Medical Association, Group for Trauma Emergency Care and Multiple Injuries of Trauma Branch of Chinese Medical Association, Young Scholar Group of Disaster Medicine Branch of Chinese Medical Association organized domestic experts of blood transfusion medicine and trauma treatment to jointly formulate Chinese expert consensus on blood support mode and blood transfusion strategies for emergency treatment of severe trauma patients ( version 2024). Based on the evidence-based medical evidence and Delphi method of expert consultation and voting, 10 recommendations were put forward from two aspects of blood support mode and transfusion strategies, aiming to provide a reference for transfusion resuscitation in the emergency treatment of severe trauma and further improve the success rate of treatment of patients with severe trauma.

Currently, in precision cardiac surgery, there are still some pressing issues that need to be addressed. For example, cardiopulmonary bypass remains a critical factor in precise surgical treatment, and many core aspects still rely on the experience and subjective judgment of cardiopulmonary bypass specialists and surgeons, lacking precise data feedback. With the increasing elderly population and rising surgical complexity, precise feedback during cardiopulmonary bypass becomes crucial for improving surgical success rates and facilitating high-complexity procedures. Overcoming these key challenges requires not only a solid medical background but also close collaboration among multiple interdisciplinary fields. Establishing a multidisciplinary team encompassing professionals from the medical, information, software, and related industries can provide high-quality solutions to these challenges. This article shows several patents from a collaborative medical and electronic information team, illustrating how to identify unresolved technical issues and find corresponding solutions in the field of precision cardiac surgery while sharing experiences in applying for invention patents.

  Objective  By summarizing the clinical characteristics and follow-up outcomes of 5 patients with immune checkpoint inhibitor induced diabetes mellitus (ICI-DM) and reviewing the relevant literatures, the article aims at providing reference to clinicians in the diagnosis and treatment of the ICI-DM.  Methods  Clinical data of 5 patients with ICI-DM who were admitted to Peking Union Medical College Hospital from December 2018 to February 2023 and did retrospectively analyzed.  Results  Five patients with a mean age of (65±7)years received treatment by the programmed cell death 1 (PD-1) or its ligand inhibitor (PD-L1). The median time from the first immunotherapy to the discovery of elevated plasma glucose was 100 (43, 210)days, and the median cycle of immunotherapy was 7 (2.5, 10.5). The onset of the illness of all the 5 patients started with diabetic ketosis or ketoacidosis. At the onset, urine ketone bodies were positive, random plasma glucose was (36.36±15.89)mmol/L, glycosylated hemoglobin A1c (HbA1c)was (8.6%±0.66%), arterial blood pH was (7.28±0.16), and the median fasting C-peptide level was 0.09 (0.05, 0.32)μg/L. Five patients had an onset plasma glucose level of grade 3 or 4.Then, ICI treatment was discontinued in all patients and insulin therapy started. The daily dosage of insulin was (56±20)IU, supplemented with hypoglycemic drugs. After treatment, urine ketone body turned negative, pH value increased to normal range, and random plasma glucose decreased significantly (the median difference of random blood glucose before and after treatment was 21.30 mmol/L, P=0.043) showing that the treatment was effective. During the follow-up, all patients continued to use insulin. The PD-1 or PD-L1 inhibitors were restarted after hyperglycemia remission. The tumor condition was under control.  Conclusions  ICI-DM mainly occurs in patients who receive treatment with PD-1 or PD-L1 inhibitors usually with acute hyperglycemia whose laboratory tests indicate insulin secretion defects. Some patients had positive islet cell antibodies, glutamic acid decarboxylase antibodies and autoantibodies.Patients with positive autoantibodies needed early diagnosis and continuous insulin treatment. ICI treatment can be restarted after endocrinologists brought the blood glucose under control.

Objective:Both type 1 diabetes and type 2 diabetes are associated with abnormal bone metabolism, but they have different pathogenic mechanisms. Sclerostin(SOST), Dickkopf-related protein 1(DKK-1), and irisin are newly discovered factors involved in the regulation of bone metabolism. This study aims to compare the differences in serum levels of SOST, DKK-1, and irisin between patients with type 1 diabetes and type 2 diabetes.Methods:This cross-sectional study included 101 patients with type 1 diabetes who visited the Endocrinology Department of Peking Union Medical College Hospital from 2017 to 2019, as well as 55 patients with type 2 diabetes and 59 individuals with normal glucose tolerance who were confirmed through an oral glucose tolerance test as part of the Beijing Changping Community Type 2 Diabetes Management Program from 2014 to 2015. Enzyme-linked immunosorbent assay(ELISA) was used to measure the levels of SOST, DKK-1, and irisin.Results:There were more female participants than male participants, with an average age of 49 years. The group with type 1 diabetes had a longer duration of illness( P<0.001) and higher HbA 1C levels( P<0.001) compared to the group with type 2 diabetes, and there was no statistical difference in age between the two groups. Both the type 1 diabetes and type 2 diabetes groups had lower levels of serum procollagen type 1 N-terminal propeptide(P1NP) compared to the control group [(8 579±400)pg/mL, (7 268±552)pg/mL vs(10 051±618)pg/mL, P=0.039, P=0.001]; But the β isomer of C-terminal cross-linking telopeptide of type 1 collagen(β-CTX) showed no statistical difference compared to the control group. Patients with type 1 diabetes and type 2 diabetes had higher SOST than controls [(129.7±6.8)pg/mL, (104.8±6.8)pg/mL vs(85.9±5.3)pg/mL, P<0.001, P=0.030], the differences between the type 1 diabetes group and the control group lost statistical significance after adjusting for factors such as fasting blood glucose and lipid levels. There was no significant difference in SOST between type 1 diabetes and type 2 diabetes groups. There was no significant difference in DKK-1 among three groups, but DKK-1 in type 1 diabetes group was lower or tended to be lower than that in type 2 diabetes group. Serum irisin in patients with type 1 diabetes was higher than that in controls and patients with type 2 diabetes[(16.6±0.7)ng/mL vs (9.6±0.6)ng/mL, (9.8±0.6)ng/mL, both P<0.001], but there was no significant difference in irisin level between type 2 diabetes and controls. Conclusions:Patients with both type 1 and type 2 diabetes showed inhibition of the bone formation marker P1NP, while the bone resorption marker β-CTX did not significantly change. SOST levels were elevated or showed an increasing trend in both type 1 and type 2 diabetes patients, which may be related to the inhibition of bone formation. Additionally, type 1 diabetes patients had increased levels of irisin, which may be involved in abnormal bone turnover.

BACKGROUND: Plasminogen activator inhibitor-1 (PAI-1) plays an important role in the pathophysiology of sepsis, but the exact mechanism remains debatable. In this study, we investigated the associations among the serum levels of PAI-1, the incidence of 4G/5G promoter PAI-1 gene polymorphisms, immunological indicators, and clinical outcomes in septic patients. METHODS: A total of 181 patients aged 18-80 years with sepsis between November 2016 and August 2018 in the intensive care unit in the Xinhua Hospital were recruited in this retrospective study, with 28-day mortality as the primary outcome. The initial serum level of PAI-1 and the presence of rs1799768 single nucleotide polymorphisms (SNPs) were examined. Univariate logistic regression and multivariate analyses were performed to determine the factors associated with different genotypes of PAI-1, serum level of PAI-1, and 28-day mortality. RESULTS: The logistic analysis suggested that a high serum level of PAI-1 was associated with the rs1799768 SNP of PAI-1 (4G/4G and 4G/5G) (Odds ratio [OR]: 2.49; 95% confidence interval [CI]: 1.09, 5.68). Furthermore, a high serum level of PAI-1 strongly influenced 28-day mortality (OR 3.36; 95% CI 1.51, 7.49). The expression and activation of neutrophils (OR 0.96; 95% CI 0.93, 0.99), as well as the changes in the expression patterns of cytokines and chemokine-associated neutrophils (OR: 1.00; 95% CI: 1.00, 1.00), were both regulated by the genotype of PAI-1. CONCLUSIONS Genetic polymorphisms of PAI-1 can influence the serum levels of PAI-1, which might contribute to mortality by affecting neutrophil activity. Thus, patients with severe sepsis might clinically benefit from enhanced neutrophil clearance and the resolution of inflammation via the regulation of PAI-1 expression and activity.
Adolescent ; Adult ; Aged ; Aged, 80 and over ; Humans ; Middle Aged ; Young Adult ; Genotype ; Neutrophils ; Plasminogen Activator Inhibitor 1/genetics* ; Polymorphism, Single Nucleotide/genetics* ; Retrospective Studies ; Sepsis/genetics*

The eukaryotic genome is folded into higher-order conformation accompanied with constrained dynamics for coordinated genome functions. However, the molecular machinery underlying these hierarchically organized three-dimensional (3D) chromatin architecture and dynamics remains poorly understood. Here by combining imaging and sequencing, we studied the role of lamin B1 in chromatin architecture and dynamics. We found that lamin B1 depletion leads to detachment of lamina-associated domains (LADs) from the nuclear periphery accompanied with global chromatin redistribution and decompaction. Consequently, the inter-chromosomal as well as inter-compartment interactions are increased, but the structure of topologically associating domains (TADs) is not affected. Using live-cell genomic loci tracking, we further proved that depletion of lamin B1 leads to increased chromatin dynamics, owing to chromatin decompaction and redistribution toward nucleoplasm. Taken together, our data suggest that lamin B1 and chromatin interactions at the nuclear periphery promote LAD maintenance, chromatin compaction, genomic compartmentalization into chromosome territories and A/B compartments and confine chromatin dynamics, supporting their crucial roles in chromatin higher-order structure and chromatin dynamics.
Chromatin ; Chromosomes ; Genome ; Humans ; Lamin Type B/genetics*

Recent research indicates that lactate promotes the switching of vascular smooth muscle cells (VSMCs) to a synthetic phenotype, which has been implicated in various vascular diseases. This study aimed to investigate the effects of lactate on the VSMC phenotype switch and the underlying mechanism. The CCK-8 method was used to assess cell viability. The microRNAs and mRNAs levels were evaluated using quantitative PCR. Targets of microRNA were predicted using online tools and confirmed using a luciferase reporter assay. We found that lactate promoted the switch of VSMCs to a synthetic phenotype, as evidenced by an increase in VSMC proliferation, mitochondrial activity, migration, and synthesis but a decrease in VSMC apoptosis. Lactate inhibited miR-23b expression in VSMCs, and miR-23b inhibited VSMC's switch to the synthetic phenotype. Lactate modulated the VSMC phenotype through downregulation of miR-23b expression, suggesting that overexpression of miR-23b using a miR-23b mimic attenuated the effects of lactate on VSMC phenotype modulation. Moreover, we discovered that SMAD family member 3 (SMAD3) was the target of miR-23b in regulating VSMC phenotype. Further findings suggested that lactate promotes VSMC switch to synthetic phenotype by targeting SMAD3 and downregulating miR-23b. These findings suggest that correcting the dysregulation of miR-23b/ SMAD3 or lactate metabolism is a potential treatment for vascular diseases.