Objective To explore the correlation between the triglyceride glucose-waist-to-height ratio (TyG-WHtR) and advanced cardiovascular-kidney-metabolic (CKM) syndrome. Methods Data from the National Health and Nutrition Examination Survey (NHANES) 2007–2018 were used and analyzed, including a total of 14 322 adult participants. The CKM syndrome is classified into 5 stages, with stages 0-2 categorized as the early phase and stages 3-4 as the advanced phase, which were subjected to dichotomous classification analysis. The TyG-WHtR was calculated using triglycerides, glucose, waist circumference, and height. Multivariate logistic regression was used to analyze the correlation between TyG-WHtR and advanced CKM syndrome, adjusting for variables such as age, sex, race, education level, poverty-income ratio (PIR), smoking status, and alcohol consumption. Restricted cubic spline (RCS) analysis was conducted to evaluate the nonlinear relationship between the TyG-WHtR and advanced CKM syndrome. Results Among the 14 322 participants, advanced CKM syndrome accounted for 16.99%. The TyG-WHtR level in the advanced CKM syndrome group was significantly higher than that in the early CKM syndrome group (5.60±0.03 vs 5.02±0.02, P＜0.001). Logistic regression showed that TyG-WHtR was an independent related factor for advanced CKM syndrome (OR＝1.48, 95%CI 1.36-1.61, P＜0.001). Subgroup analyses revealed that the TyG-WHtR was consistently associated with advanced CKM syndrome across different sex, rase, and age groups, with no significant interaction effects observed. RCS analysis revealed a nonlinear positive association between TyG-WHtR and advanced CKM syndrome (P_overall＜0.001, P_nonlinear＝0.014). When the TyG-WHtR exceeded 5, the risk of advanced-stage CKM syndrome showed a significant elevation. Conclusions The TyG-WHtR is an independent related factor for advanced CKM syndrome, with a particularly significant risk increase when TyG-WHtR exceeds 5.

Objective To evaluate myocardial microvascular lesions in patients with type 2 diabetes mellitus(T2DM)by 2D-speckle tracking echocardiography(2D-STE)and myocardial contrast echocar-diography(MCE).Methods A total of 45 T2DM patients admitted to the Endocrine Department of The First Affiliated Hospital of Air Force Military Medical University from August to November 2022 were enrolled in this study.All the patients were divided into two groups:simple T2DM group(n=22)and T2DM with microvascular complication group(MIC,n=23).In addition,24 healthy subjects were included as normal control(NC)group.2D-STE obtained the global longitudinal strain(GLS)and global circumferential strain(GCS);MCE obtained the average acoustic intensity(A),perfusion slope(b)of left ventricular segment,then myocardial blood flow(Aβ)was calculated and compared between groups.Results Compared with NC group,GLS,GCS,β and Aβ were lower in T2DM and MIC group(P＜0.05).Among the parameters of 2D-STE and MCE,GLS and Aβ have high diagnostic performance(P＜0.05)and GCS and β have medium diagnostic performance(P＜0.05).ROC curve analysis showed that the early warning values of myocardial microcirculation disorders were-17.63%(GLS),-21.55%(GCS),0.845 s-1(β),7.045 dB/s(Aβ)in patients with T2DM.Conclusion The mechanical strain and perfusion of myocar-dium in T2DM patients have already decreased even no lesion was shown in the peripheral micro-vessels.2D-STE combined with MCE can assess the changes of myocardial elasticity and microcirculation in T2DM in real time,which is helpful for early clinical diagnosis of diabetes cardiomyopathy and intervention guidance.

Objective To explore the radiosensitizing effect of arsenic trioxide (ATO) in cervical cancer, and to further explore the underlying mechanism related to DNA damage repair. Methods Human cervical cancer cells (Siha and Hela cells) were cultured in vitro, treated with different concentrations of ATO, and the cell proliferation was detected by CCK-8 assay. The cells were divided into four groups: control group, radiotherapy (IR) group, ATO group, and radiotherapy + ATO (IR + ATO) group. Radiosensitization ratio was determined by plate cloning assay, cell cycle and apoptosis by flow cytometry, the expression of γH2AX by immunofluorescence, the expression of Cyclin B1, PTEN, and RAD51 by Western blot, and the expression of RAD51 mRNA by reverse transcription quantitative polymerase chain reaction (RT-qPCR). Results CCK-8 showed that ATO at concentrations of 1 μM and higher could significantly inhibit the proliferation of Siha and HeLa cells. Plate cloning showed that ATO had a radiosensitizing effect on cervical cancer, and the radiosensitization ratios were 1.37 and 1.30, respectively. Flow cytometry showed that the proportion of cell cycle arrest was significantly higher in the IR + ATO group than that in the control group (P < 0.001). The apoptosis rate was significantly higher in the IR + ATO group than that in the control group (P < 0.01). Western blotting showed that the expression levels of PTEN and RAD51 proteins significantly decreased (P < 0.05) and the expression level of Cyclin B1 protein significantly increased (P < 0.05) in the IR + ATO group. Conclusion ATO achieves radiosensitization in cervical cancer through blocking the DNA homologous recombination repair pathway by consuming PTEN.

Objective:To explore the genetic etiology of a pedigree with intellectual disability and explore its pathogenesis.Methods:A Chinese pedigree which had presented at the Henan Provincial People′s Hospital in March 2023 was selected as the study subject. Clinical data of the pedigree were collected, along with peripheral venous blood samples from its members. Whole exome sequencing (WES) was carried out, and candidate variants were verified by Sanger sequencing. Amniotic fluid was collected for prenatal diagnosis. This study was approved by the Medical Ethics Committee of the Henan Provincial People′s Hospital (No. 2019-134).Results:Both the proband (a 6-year-old male) and his mother (30 years old) had various degrees of intellectual and motor impairment. WES revealed that the proband has harbored a de novo heterozygous c. 2563_2567dup (p.Lys856fs) variant of the UBE3A gene, while his mother, maternal grandmother and fetus had all harbored a novel heterozygous c. 409+ 1G>A variant of the RNF13 gene. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), both variants were predicted to be pathogenic (PVS1+ PS1+ PM2_Supporting; PVS1+ PM2_Supporting+ PP3). Conclusion:Based on the clinical manifestations and the result of genetic testing, the heterozygous c.2563_2567dup (p.Lys856fs) variant of the UBE3A gene probably underlay the intellectual disability and developmental delay in the proband, whilst the heterozygous c. 409+ 1G>A variant of the RNF13 gene may underlie the intellectual disability in the proband′s mother and grandmother. Above results have enabled genetic counseling and prenatal diagnosis for this pedigree.

Objective To compare the early embryonic developmental potential and clinical outcomes of oocytes matured in vivo and those matured by modified in vitro maturation(LVM)technology during the same controlled ovarian hyperstimulation(COH)cycle,and to explore the clinical application of melatonin-supplemented IVM technology.Methods 159 patients were recruited into the study.920 mature oocytes were collected during their COH cycles processed for conventional IVF/ICSI protocols,while 1 283 immature oocytes from the same cycles were matured in a melatonin-supplemented IVM medium before ICSI was performed.A retrospective analysis was conducted to compare the impact of conventional assisted reproductive technology and improved IVM technology on the outcomes of assisted reproductive therapy and pregnancy outcomes.Results Compared with mature oocytes collected from COH cycles treated with conventional IVF/ICSI,oocytes promoted by improved melatonin-supple-mented IVM technology had a lower rate of high-quality blastocyst formation.However,after embryo transfer,there was no significant difference in the clinical outcomes of mature oocytes obtained through two methods,including clinical pregnancy rate,full-term birth rate,neonatal length,and neonatal Apgar score.Conclusion The applica-tion of melatonin-supplemented IVM significantly increases the utilization of immature oocytes collected from COH cycles,improving the pregnancy outcomes of patients assisted by assisted reproductive technology.

Objective To analyze the interactions between different structural types of volatile oil compo-nents(VOCs)and skin lipid molecules,and investigate the mechanism of volatile oil in Chi-nese materia medica(VOCMM)as penetration enhancers. Methods In this study,210 different structural types of VOCs were selected from the VOCMM penetration enhancer database,and the molecular docking experiments were conducted with three main lipid molecules of skin:ceramide 2(CER2),cholesterol(CHL),and free fatty acid(FFA).Each VOC was docked individually with each lipid molecule.Cluster analysis was used to explore the relationship between the binding energy of VOCs and their molecular struc-tures.Nine specific pathogen-free(SPF)Sprague Dawley(SD)rats were randomly divided in-to Control,Nootkatone,and 3-Butylidenephthalide groups for in vitro percutaneous experi-ments,with three rats in each group.The donor pool solutions were 3%gastrodin,3%gas-trodin+3%nootkatone,and 3%gastrodin+3%3-butylidenephthalide,respectively.The pen-etration enhancing effects of VOCs with higher binding energy were evaluated by comparing the 12-hour cumulative percutaneous absorption of gastrodin(Q12,μg/cm2). Results(i)Most of the VOCs were non-hydrogen bonded to the hydrophobic parts of CHL and FFA,and hydrogen bonded to the head group of CER2.Among them,sesquiterpene ox-ides showed the most pronounced binding affinity to CER2.The VOCs with 2-4 rings(in-cluding carbon rings,benzene rings,and heterocycles)demonstrated stronger binding affini-ty for three skin lipid molecules compared with the VOCs without intramolecular rings(P<0.01).(ii)According to the cluster analysis,most of the VOCs that bond well to CER2 had 2-3 intramolecular rings.The non-oxygenated VOCs were bonded to CER2 in a hydrophobic manner.The oxygenated VOCs were mostly bonded to CER2 by hydrogen bonding.(iii)The results of Franz diffusion cell experiment showed that the Q12 of Control group was 260.60±25.09 μg/cm2,and the transdermal absorption of gastrodin was significantly increased in Nootkatone group(Q12=5 503.00±1 080.00 μg/cm2,P<0.01).The transdermal absorption of gastrodin was also increased in 3-Butylidenephthalide group(Q12=495.40±56.98 μg/cm2,P>0.05).(iv)The type of oxygen-containing functional groups in VOCs was also an influencing factor of binding affinity to CER2. Conclusion The interactions between different types of VOCs with different structures in the VOCMM and three skin lipid molecules in the stratum corneum were investigated at the molecular level in this paper.This research provided theoretical guidance and data support for the screening of volatile oil-based penetration enhancers,and a simple and rapid method for studying the penetration-enhancing mechanism of volatile oils.

Objective:To analyze clinical characteristics of and causative genes in two families with dystrophic epidermolysis bullosa, and to reveal the pathogenesis of the disease and mechanisms underlying phenotypic differences between patients.Methods:DNA was extracted from peripheral blood samples of members from two families with dystrophic epidermolysis bullosa, and subjected to high-throughput sequencing and Sanger sequencing.Results:The clinical manifestations of the 2 probands in the 2 families were consistent with the diagnosis of dystrophic epidermolysis bullosa, and the symptoms of the proband in family 1 were more serious than those of other patients in the family. Genetic testing showed that all patients in family 1 carried a mutation c.6082G>C (p.G2028R) in the COL7A1 gene, and the proband and her phenotypically normal mother and uncle also carried a splice-site mutation c.7068+2 (IVS91) T>G in the COL7A1 gene, both of which were first reported. The proband in family 2 carried the mutations c.6081_6082 ins C (p.G2028Rfs*71) and c.1892G>A (p.W631X, first reported) in the COL7A1 gene, which were inherited from her father and mother, respectively.Conclusion:The two pathogenic mutations may be the molecular mechanism underlying the severe clinical phenotype in the proband in family 1; the first reported mutations enriched the mutation spectrum of the COL7A1 gene.

OBJECTIVE: To explore the genetic etiology for a child featuring mental retardation and speech delay. METHODS: Clinical data of the child was collected. DNA was extracted from peripheral blood samples of the child and members of his pedigree. Whole exome sequencing was carried out for the child, and candidate variants were verified by Sanger sequencing. Prenatal diagnosis was provided for his mother upon her subsequent pregnancy. RESULTS: The child has mainly featured mental retardation, speech delay, ptosis, strabismus, photophobia, hyperactivity, and irritability. Whole exome sequencing revealed that he has harbored a pathogenic heterozygous variant of the KAT6A gene, namely c.5314dupA (p.Ser1772fs*20), which was not detected in either of his parents. The child was diagnosed with Arboleda-Tham syndrome. The child was also found to harbor a hemizygous c.56T>G (p.Leu19Trp) variant of the AIFM1 gene, for which his mother was heterozygous and his phenotypically normal maternal grandfather was hemizygous. Pathogenicity was excluded. Prenatal diagnosis has excluded the c.5314dupA variant of the KAT6A gene in the fetus. CONCLUSION The heterozygous c.5314dupA (p.Ser1772fs*20) variant of the KAT6A gene probably underlay the Arboleda-Tham syndrome in this child. Above finding has enabled genetic counseling and prenatal diagnosis for this pedigree.
Child ; Humans ; Male ; Pregnancy ; Histone Acetyltransferases ; Intellectual Disability/genetics* ; Language Development Disorders ; Pedigree

OBJECTIVE: To detect the mutation site in a pedigree affected with autosomal dominant polycystic kidney disease (ADPKD) and verify its impact on the protein function. METHODS: Peripheral blood samples were collected from the proband and his pedigree members for the extraction of genomic DNA. Mutational analysis was performed on the proband through whole-exome sequencing. Suspected variant was verified by Sanger sequencing. A series of molecular methods including PCR amplification, restriction enzyme digestion, ligation and transformation were also used to construct wild-type and mutant eukaryotic expression vectors of the PKD2 gene, which were transfected into HEK293T and HeLa cells for the observation of protein expression and cell localization. RESULTS: The proband was found to harbor a c.2051dupA (p. Tyr684Ter) frame shift mutation of the PKD2 gene, which caused repeat of the 2051st nucleotide of its cDNA sequence and a truncated protein. Immunofluorescence experiment showed that the localization of the mutant protein within the cell was altered compared with the wild-type, which may be due to deletion of the C-terminus of the PKD2 gene. CONCLUSION The c.2051dupA (p. Tyr684Ter) mutation of the PKD2 gene probably underlay the pathogenesis of ADPKD in this pedigree.
DNA Mutational Analysis ; Female ; Frameshift Mutation ; HEK293 Cells ; HeLa Cells ; Humans ; Male ; Pedigree ; Polycystic Kidney, Autosomal Dominant/physiopathology* ; Protein Kinases/genetics* ; Protein Transport/genetics* ; Whole Exome Sequencing

OBJECTIVE: To analyze the pathogenic variant of preaxial polydactyly in a Chinese Han pedigree and identify the cause of polydactyly. METHODS: The peripheral blood DNA of the proband and her parents was extracted. The polydactyly-related genes were detected by trio whole exome sequencing, and the suspected pathogenic gene was screened out. Sanger sequencing was applied to other members of the pedigree. RESULTS: The results of gene sequencing showed that the LMBR1 gene had a heterozygous variant of c.423+4909(IVS5)C>T in 6 patients of the pedigree. The same variant was not detected in family members with normal phenotype. Based on the ACMG guidelines, c.423+4909(IVS5)C>T of the LMBR1 gene was predicted to be pathogenic (PM1+PM2+PP1-S(PS)+PP4+PP5). CONCLUSION The heterozygous C>T variant at position 4909 of intron 5 of the LMBR1 gene probably underlies the disease in this pedigree.
China ; Female ; Humans ; Mutation ; Pedigree ; Polydactyly/genetics* ; Thumb ; Whole Exome Sequencing