Objective:To summarize the clinical and genetic characteristics of pseudoachondroplasia and multiple epiphyseal dysplasia caused by COMP gene variants in pediatric patients.Methods:This retrospective study concluded 15 pediatric patients with COMP-related pseudoachondroplasia and multiple epiphyseal dysplasia at Shanghai Children′s Medical Center, Shanghai Jiao Tong University School of Medicine from July 2013 to August 2024. This paper analyzed clinical manifestations, laboratory findings and genetic testing.Results:This cohort comprised 15 pediatric patients (8 males and 7 females) with a diagnostic age of 5.3 (1.8,9.3) years. The major clinical presentations included abnormal gait (15/15), brachydactyly (11/15), genu varum (12/15), irregular metaphyseal changes (14/14) and epiphyseal dysplasia (14/14). Genetic analysis revealed 13 cases of pseudoachondroplasia and 2 multiple epiphyseal dysplasias cases associated with COMP gene variants. Fifteen variants were identified (8 pathogenic and 7 likely pathogenic), including 2 novel variants (c.1223A>G, c.1378G>C). Thirteen of these patients had variations clustered in exons 8-14 encoding the calmodulin-like domains, with c.1414_1419dupGACGAC emerging as a hotspot variant.Conclusions:COMP-related pseudoachondroplasia and multiple epiphyseal dysplasia predominantly manifest with gait abnormalities and skeletal deformities. COMP gene pathogenic variations were mainly located in calmodulin-like domains.

This study was aimed at predicting and analyzing the structural and functional properties of the persistence-associated secretory protein PaaX in Mycobacterium tuberculosis(M.tb),identifying its interacting partners,and elucidating its biological roles.Bioinformatics analysis revealed that PaaX comprises 240 amino acids with a molecular mass of 26.54 kDa(C1158H1866N354O334S14).The protein lacks transmembrane domains but contains a signal peptide.Its secondary structure is dominated by α-helices(53.33%),fol-lowed by random coils(36.25%)and extended strands(10.42%),thereby forming a homotetrameric spatial configuration.Potential PaaX-interacting proteins,including Rv0406c,EchA4,EchA5,HsaE,FadE8,LpqP,and End,were predicted.These candidate genes and the paaX gene were cloned into bacterial two-hybrid vectors and co-transformed into Escherichia coli BTH101 cells.Colony PCR and sequencing confirmed the accuracy of the recombinant constructs.Bacterial two-hybrid assays demonstrated direct interac-tions of PaaX with EchA4,HsaE,FadE8,and LpqP.Moreover,gradient dilution experiments indicated that the strongest binding af-finity occurred between PaaX and EchA4.AlphaFold 3 modeling further validated these interactions,thus providing high-confidence predictions of binding interfaces.Our findings revealed that PaaX,a secreted α-helix-rich protein,engages in specific interactions with key metabolic enzymes(EchA4,HsaE,and FadE8)and a lipoprotein(LpqP),thus suggesting its potential involvement in lipid metabolism,stress adaptation,and host-pathogen interactions.This study provides novel insights into PaaX's contribution to M.tb per-sistence and pathogenicity,and highlights its value as a potential target for tuberculosis diagnostics and therapeutic development.

This study was aimed at predicting and analyzing the structural and functional properties of the persistence-associated secretory protein PaaX in Mycobacterium tuberculosis(M.tb),identifying its interacting partners,and elucidating its biological roles.Bioinformatics analysis revealed that PaaX comprises 240 amino acids with a molecular mass of 26.54 kDa(C1158H1866N354O334S14).The protein lacks transmembrane domains but contains a signal peptide.Its secondary structure is dominated by α-helices(53.33%),fol-lowed by random coils(36.25%)and extended strands(10.42%),thereby forming a homotetrameric spatial configuration.Potential PaaX-interacting proteins,including Rv0406c,EchA4,EchA5,HsaE,FadE8,LpqP,and End,were predicted.These candidate genes and the paaX gene were cloned into bacterial two-hybrid vectors and co-transformed into Escherichia coli BTH101 cells.Colony PCR and sequencing confirmed the accuracy of the recombinant constructs.Bacterial two-hybrid assays demonstrated direct interac-tions of PaaX with EchA4,HsaE,FadE8,and LpqP.Moreover,gradient dilution experiments indicated that the strongest binding af-finity occurred between PaaX and EchA4.AlphaFold 3 modeling further validated these interactions,thus providing high-confidence predictions of binding interfaces.Our findings revealed that PaaX,a secreted α-helix-rich protein,engages in specific interactions with key metabolic enzymes(EchA4,HsaE,and FadE8)and a lipoprotein(LpqP),thus suggesting its potential involvement in lipid metabolism,stress adaptation,and host-pathogen interactions.This study provides novel insights into PaaX's contribution to M.tb per-sistence and pathogenicity,and highlights its value as a potential target for tuberculosis diagnostics and therapeutic development.

Objective:To summarize the clinical and genetic characteristics of pseudoachondroplasia and multiple epiphyseal dysplasia caused by COMP gene variants in pediatric patients.Methods:This retrospective study concluded 15 pediatric patients with COMP-related pseudoachondroplasia and multiple epiphyseal dysplasia at Shanghai Children′s Medical Center, Shanghai Jiao Tong University School of Medicine from July 2013 to August 2024. This paper analyzed clinical manifestations, laboratory findings and genetic testing.Results:This cohort comprised 15 pediatric patients (8 males and 7 females) with a diagnostic age of 5.3 (1.8,9.3) years. The major clinical presentations included abnormal gait (15/15), brachydactyly (11/15), genu varum (12/15), irregular metaphyseal changes (14/14) and epiphyseal dysplasia (14/14). Genetic analysis revealed 13 cases of pseudoachondroplasia and 2 multiple epiphyseal dysplasias cases associated with COMP gene variants. Fifteen variants were identified (8 pathogenic and 7 likely pathogenic), including 2 novel variants (c.1223A>G, c.1378G>C). Thirteen of these patients had variations clustered in exons 8-14 encoding the calmodulin-like domains, with c.1414_1419dupGACGAC emerging as a hotspot variant.Conclusions:COMP-related pseudoachondroplasia and multiple epiphyseal dysplasia predominantly manifest with gait abnormalities and skeletal deformities. COMP gene pathogenic variations were mainly located in calmodulin-like domains.

The orphan nuclear receptor Nur77 is emerging as an attractive target for cancer therapy, and activating Nur77's non-genotypic anticancer function has demonstrated strong therapeutic potential. However, few Nur77 site B ligands have been identified as excellent anticancer compounds. There are no co-crystal structures of effective anticancer agents at Nur77 site B, which greatly limits the development of novel Nur77 site B ligands. Moreover, the lack of pharmaceutical ligands restricts Nur77's therapeutic proof of concept. Herein, we developed a first-in-class Nur77 site B ligand (NB1) that significantly inhibited cancer cells by mediating the Nur77/Bcl-2-related apoptotic effect at mitochondria. The X-ray crystallography suggests that NB1 is bound to the Nur77 site B with a distinct binding mode. Importantly, NB1 showed favorable pharmacokinetic profiles and safety, as evidenced by its good oral bioavailability in rats and lack of mortality, bodyweight loss, and pathological damage at the 512.0 mg/kg dose in mice. Furthermore, oral administration of NB1 demonstrated remarkable in vivo anticancer efficacy in an MDA-MB-231 xenograft model. Together, our work discovers NB1 as a new generation Nur77 ligand that activates the Nur77/Bcl-2 apoptotic pathway with a safe and effective cancer therapeutic potency.

OBJECTIVES: To analyze the clinical and genetic characteristics of children with autosomal dominant neurodevelopmental disorders caused by kinesin family member 1A (KIF1A) gene variation. METHODS: Clinical and genetic testing data of 6 children with KIF1A gene de novo heterozygous variation diagnosed in Shanghai Children's Medical Center Affiliated to Shanghai Jiao Tong University School of Medicine from the year 2018 to 2020 were retrospectively analyzed. Pathogenic variants were identified based on whole exome sequencing, and verified by Sanger sequencing. Moreover, the effect of variants on three-dimensional structure and stability of protein was analyzed by bioinformatics. RESULTS: Among 6 patients there were 4 males and 2 females, and the age of consultation varied from 7 months to 18 years. All cases had varying degrees of motor developmental delay since childhood, and 4 of them had gait abnormalities or fell easily. In addition, 2 children were accompanied by delayed mental development, epilepsy and abnormal eye development. Genetic tests showed that all 6 cases had heterozygous de novo variations of KIF1A gene, including 4 missense mutations c.296C>T (p.T99M), c.761G>A (p.R254Q), c.326G>T (p.G109V), c.745C>G (p.L249V) and one splicing mutation c.798+1G>A, among which the last three variants have not been previously reported. Bioinformatics analysis showed that G109V and L249V may impair their interaction with the neighboring amino acid residues, thereby impacting protein function and reducing protein stability, and were assessed as "likely pathogenic". Meanwhile, c.798+1G>A may damage an alpha helix in the motor domain of the KIF1A protein, and was assessed as "likely pathogenic". CONCLUSIONS KIF1A-associated neurological diseases are clinically heterogeneous, with motor developmental delay and abnormal gait often being the most common clinical features. The clinical symptoms in T99M carriers are more severe, while those in R254Q carriers are relatively mild.
Male ; Female ; Humans ; Child ; Retrospective Studies ; China ; Mutation ; Epilepsy/genetics* ; Neurodevelopmental Disorders/genetics* ; Kinesins/genetics*

Humans ; Sodium-Calcium Exchanger ; Carrier Proteins ; Pain ; Calcium/metabolism*

Objective To investigate the association of energy metabolic markers with the risk of spontaneous bacterial peritonitis (SBP) in patients with decompensated hepatitis B virus-related liver cirrhosis (HBV-LC). Methods A retrospective analysis was performed for the clinical data of the patients with decompensated HBV-LC who were admitted to Mengchao Hepatobiliary Hospital of Fujian Medical University from November 2017 to November 2019, and baseline clinical parameters and energy metabolic markers were compared between the patients with SBP and those without SBP within 2 weeks after admission. A multivariate logistic regression analysis was performed to investigate the risk factors for SBP. The t -test was used for comparison of normally distributed continuous data between two groups, and the Kruskal-Wallis H test was used for comparison of non-normally distributed continuous data between two groups; the Fisher's exact test was used for comparison of categorical data between two groups. The receiver operating characteristic (ROC) curve was plotted to evaluate the diagnostic efficiency of the newly established logistic regression model, and with the corresponding point of Youden index as the cut-off value, the DeLong test was used to compare the area under the ROC curve (AUC). Results A total of 50 patients with decompensated HBV-LC were included, among whom 23 (46%) developed SBP within 2 weeks after admission and 27 (54%) had no SBP during hospitalization. Compared with the non-SBP patients, the SBP patients had significantly lower triglyceride, prealbumin, and prothrombin time activity (PTA) and significantly higher international normalization ratio, C-reactive protein (CRP), and Model for End-Stage Liver Disease score (all P < 0.05). Comparison of baseline energy metabolic markers showed that compared with the non-SBP patients, the SBP patients had significantly lower respiratory quotient (RQ) [0.79(0.76-0.86) vs 0.85(0.79-0.91), P =0.041] and carbohydrate oxidation (CHO) rate [20.50%(15.25%-41.05%) vs 41.6%(22.25%-68.05%), P =0.041]. The multivariate logistic regression analysis showed that PTA was an independent risk factor for SBP in the patients with decompensated HBV-LC during hospitalization (odd ratio=0.004, P =0.008), and the regression model established based on the variables including PTA, CRP, RQ, and CHO had an AUC of 85.0% and a cut-off value of 0.60 at the maximum Youden index, with a specificity of 85.19% and a sensitivity of 73.91%, suggesting that this model had a better discriminatory ability than CRP (AUC=74.5%, P =0.049) and procalcitonin (AUC=56.4%, P < 0.01). Conclusion There are significant reductions in the energy metabolic markers RQ and CHO in the patients with decompensated HBV-LC who develop SBP within a short term, and their combination with PTA, CRP, and CHO/RQ ratio can help clinicians identify the patients at a high risk of SBP in the early stage and enhance nutrition support for such patients.

Objective:To characterize the histopathological subtypes and their clinicopathological parameters of gender and onset age by common, rare and sparse primary esophageal malignant tumors (PEMT).Methods:A total of 272 437 patients with PEMT were enrolled in this study, and all of the patients were received radical surgery. The clinicopathological information of the patients was obtained from the database established by the State Key Laboratory of Esophageal Cancer Prevention & Treatment from September 1973 to December 2020, which included the clinical treatment, pathological diagnosis and follow-up information of esophagus and gastric cardia cancers. All patients were diagnosed and classified by the criteria of esophageal tumor histopathological diagnosis and classification (2019) of the World Health Organization (WHO). The esophageal tumors, which were not included in the WHO classification, were analyzed separately according to the postoperative pathological diagnosis. The χ 2 test was performed by the SPSS 25.0 software on count data, and the test standard α=0.05. Results:A total of 32 histopathological types were identified in the enrolled PEMT patients, of which 10 subtypes were not included in the WHO classification. According to the frequency, PEMT were divided into common (esophageal squamous cell carcinoma, ESCC, accounting for 97.1%), rare (esophageal adenocarcinoma, EAC, accounting for 2.3%) and sparse (mainly esophageal small cell carcinoma, malignant melanoma, etc., accounting for 0.6%). All the common, rare, and sparse types occurred predominantly in male patients, and the gender difference of rare type was most significant (EAC, male∶ female, 2.67∶1), followed with common type (ESCC, male∶ female, 1.78∶1) and sparse type (male∶ female, 1.71∶1). The common type (ESCC) mainly occurred in the middle thoracic segment (65.2%), while the rare type (EAC) mainly occurred in the lower thoracic segment (56.8%). Among the sparse type, malignant melanoma and malignant fibrous histiocytoma were both predominantly located in the lower thoracic segment (51.7%, 66.7%), and the others were mainly in the middle thoracic segment.Conclusion:ESCC is the most common type among the 32 histopathological types of PEMT, followed by EAC as the rare type, and esophageal small cell carcinoma and malignant melanoma as the major sparse type, and all of which are mainly occur in male patients. The common type of ESCC mainly occur in the middle thoracic segment, while the rare type of EAC mainly in the lower thoracic segment. The mainly sparse type of malignant melanoma and malignant fibrous histiocytoma predominately occur in the lower thoracic segment, and the remaining sparse types mainly occur in the middle thoracic segment.

Objective:To investigate and analyze the energy metabolism characteristics and the correlation between energy metabolism and the risk of secondary bacterial infection in patients with hepatitis B virus-related chronic liver disease (HBV-CLD).Methods:Data of 183 cases admitted to the Mengchao Hepatobiliary Hospital of Fujian Medical University from November 2017 to November 2020 were retrospectively analyzed. 79 cases of chronic hepatitis B, 51 cases of hepatitis B-related liver cirrhosis, and 53 cases of hepatitis B-related liver failure were collected. Among them patients with liver failure and decompensated liver cirrhosis were defined as severe liver disease group. The Quark RMR indirect calorimetry (COSMED Corporation, Italy) was used to exam the patients' energy metabolism condition, and the incidences of secondary bacterial infection of the patients during hospitalization were recorded. Shapiro-Wilk test and normal QQ plot were used to analyze the normal distribution of continuous variable data, which was consistent with the normal distribution and was described by mean ± standard deviation. In addition, if it did not conform to the normal distribution, the median and interquartile distance were used to describe it. Levene’s test was used to test the homogeneity of variance of the data, which was consistent with the normal distribution. The t-test was used to compare the means of the two groups of samples. One-way analysis of variance was used to compare the mean values of the three groups of samples, and then the Tukey's test was used to compare the two groups. If the variance was uneven or did not conform to the normal distribution, the Wilcoxon rank sum test was used to compare the differences between the two groups. Kruskal-Wallis test (H test) was used to compare the differences between the three groups of samples, and then the Dunnett’s test (Z test) was used for comparison between the two groups. Categorical variable data were analyzed using chi-square test. Logistic regression analysis was used to screen independent risk factors, and the criteria for variable inclusion ( P < 0.05). Results:The respiratory entropy (RQ) and non-protein respiratory entropy (npRQ) of the three groups had statistically significant difference ( P < 0.05). Among them, the RQ and npRQ of the chronic hepatitis B group were higher than hepatitis B-related liver cirrhosis group and hepatitis B-related liver failure group. There were statistically significant differences in fat oxidation rate (FAT%) and carbohydrate oxidation rate (CHO%) between the three groups ( P < 0.05). Compared with hepatitis B-related liver cirrhosis group and hepatitis B-related liver failure group, chronic hepatitis B group ( P < 0.05) had lower FAT% and higher CHO%. There were no statistically significant differences in the measured and predicted resting energy expenditure and protein oxidation rate (PRO%) between the three groups. The incidence of secondary bacterial infection in patients with severe liver disease was 48.39% (45/93). Compared with the non-infected group, the RQ and npRQ values ??of the infected group were significantly decreased ( P < 0.05), while FAT% was significantly increased ( P < 0.05). Logistic regression analysis showed that glutamyltransferase, cholesterol, and npRQ were independent risk factors for secondary bacterial infections in patients with severe liver disease. Glutamyltransferase elevation, and cholesterol and npRQ depletion had suggested an increased risk of secondary bacterial infection. Subgroup analysis of patients with hepatitis B-related liver failure also showed that compared with non-infected group, RQ value and npRQ value of secondary bacterial infection group were significantly decreased ( P < 0.05), while FAT% was significantly increased ( P < 0.05). Conclusion:Patients with hepatitis B virus-related chronic liver disease generally have abnormal energy metabolism. Low RQ, npRQ, CHO% and high FAT% are related to the severity of the disease; while npRQ reduction is related to the risk of secondary bacterial infection in patients with severe liver disease, and thus can be used as a clinical prognostic indicator.