ObjectiveTo elucidate the effects of autonomic neuromodulators [calcium chloride (CaCl₂)-acetylcholine (ACh)] on atrial electrical remodeling and histopathological changes in rats, thereby providing evidence for further investigation into the pathological mechanisms by which autonomic imbalance induces atrial fibrillation (AF). MethodsTen 8-week-old male Sprague-Dawley (SD) rats were randomly divided into experimental and control groups, with 5 rats in each group. The experimental group received daily tail vein injections of a CaCl₂-ACh mixed solution for 28 days, while the control group received an equal volume of saline. Surface electrocardiograms were recorded before and after daily administration. On day 28 of administration, under isoflurane inhalation anesthesia, echocardiography was performed, and then the rats were euthanized by exsanguination under isoflurane anesthesia for tissue collection. Body weight and heart weight of rats were measured, and electrophysiological parameters including AF inducibility, conduction velocity, and conduction dispersion in isolated rat hearts were monitored using the MappingLab multichannel electrophysiological mapping system. HE staining was performed to evaluate atrial tissue architecture and inflammatory cell infiltration. The expression levels of matrix metalloproteinase 9 (MMP-9) and interleukin-1 beta (IL-1β) were analyzed by Western blotting. Masson staining was used to quantitatively analyze the proportional distribution of collagen fibers and myocardial fibers, and to calculate the area of collagen deposition, thereby evaluating the degree of myocardial fibrosis. Wheat germ agglutinin (WGA) staining was used to evaluate morphological changes of cardiomyocytes. Dihydroethidium (DHE) staining was used to detect the level of oxidative stress in atrial myocytes. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining was used to detect atrial cell apoptosis. ResultsCompared with the control group, the experimental group showed obvious arrhythmias on electrocardiograms. Echocardiography after 28 days of administration revealed significant structural remodeling in the experimental group, with a marked increase in left atrial anteroposterior diameter (P < 0.05), and also showed cardiac dysfunction, with significant decreases in left ventricular ejection fraction and left ventricular fractional shortening (P < 0.01). Compared with the control group, the experimental group showed a significantly increased heart weight-to-body weight ratio (P < 0.05), a markedly higher AF inducibility (P < 0.001), a significantly slowed atrial conduction velocity (P < 0.05), an uneven isochronal map with irregular directions, and a significantly increased conduction dispersion (P < 0.01). HE staining showed that atrial myocytes in the experimental group were disorganized, with slight inflammatory cell infiltration. Western blotting showed that the expression levels of MMP-9 and IL-1β in the atrial tissue of the experimental group were significantly upregulated (P < 0.05). Masson staining showed a significant increase in collagen deposition and a significant increase in fibrosis area in the atrial tissue of the experimental group (P < 0.001). WGA staining showed that cardiomyocytes in the experimental group were significantly hypertrophied compared with the control group (P < 0.05). DHE staining and TUNEL staining revealed that the level of oxidative stress in atrial myocytes (P < 0.001) and the apoptotic rate (P < 0.01) were both significantly increased. Conclusion Daily tail vein injections of the autonomic neuromodulator CaCl₂-ACh mixed solution for 28 days can successfully induce AF in rats, accompanied by significant atrial structural remodeling, electrical remodeling, and oxidative stress.

OBJECTIVES: To study the clinical and genetic characteristics of osteopetrosis (OPT) in children. METHODS: A retrospective analysis was performed on the clinical data of 14 children with OPT. Whole-exome sequencing was used to detect pathogenic genes, and clinical phenotypes and genotypic features were summarized. RESULTS: Among the 14 children (10 males and 4 females), the median age at diagnosis was 8 months. Clinical manifestations included systemic osteosclerosis (14 cases, 100%), anemia (12 cases, 86%), infections (10 cases, 71%), thrombocytopenia (9 cases, 64%), hepatosplenomegaly (8 cases, 57%), and developmental delay (5 cases, 36%). Malignant osteopetrosis (MOP) cases had lower platelet counts, creatine kinase isoenzyme, and serum calcium levels, but higher white blood cell counts, lactate dehydrogenase, and alkaline phosphatase levels compared to non-MOP cases (P<0.05). Genetic testing identified 15 variants in 12 patients, including 8 variants in the CLCN7 gene (53%), 6 in the TCIRG1 gene (40%), and 1 in the TNFRSF11A gene (7%). Three novel CLCN7 variants were identified: c.2351G>C, c.1215-43C>T, and c.1534G>A. All four patients with TCIRG1 variants exhibited MOP clinical phenotypes. Of the seven patients with CLCN7 variants, 4 presented with intermediate OPT, 2 with benign OPT, and 1 with MOP. CONCLUSIONS Clinical phenotypes of OPT in children are heterogeneous, predominantly involving CLCN7 and TCIRG1 gene variants, with a correlation between clinical phenotypes and genotypes.
Humans ; Osteopetrosis/genetics* ; Male ; Female ; Infant ; Child, Preschool ; Retrospective Studies ; Vacuolar Proton-Translocating ATPases/genetics* ; Child ; Chloride Channels/genetics* ; Mutation ; Receptor Activator of Nuclear Factor-kappa B

Ferroptosis has received great attention as an iron-dependent programmed cell death for efficient cancer therapy. However, with the accumulation of iron in tumor cells, the antioxidant system is activated by reducing glutathione (GSH) with glutathione peroxidase 4 (GPX4), which critically limits the ferroptosis therapeutic effect. Herein, an iron and GPX4 silencing siRNA (siGPX4) co-encapsulated ferritin nanocage (HFn@Fe/siGPX4) was developed to enhance ferroptosis by disruption of redox homeostasis and inhibition of antioxidant enzyme synergistically. The siGPX4 were loaded into the nanocages by pre-incubated with iron, which could significantly improve the loading efficiency of the gene drugs when compared with the reported gene drug loading strategy by ferritin nanocages. And more iron was overloaded into the ferritin through the diffusion method. When HFn@Fe/siGPX4 was taken up by human breast cancer cell MCF-7 in a TfR1-mediated pathway, the excess iron ions in the drug delivery system could for one thing induce ferroptosis by the production of reactive oxygen species (ROS), for another promote siGPX4 escaping from the lysosome to exert gene silencing effect more effectively. Both the in vitro and in vivo results demonstrated that HFn@Fe/siGPX4 could significantly inhibit tumor growth by synergistical ferroptosis. Thus, the developed HFn@Fe/siGPX4 afforded a combined ferroptosis strategy for ferroptosis-based antitumor as well as a novel and efficient gene drug delivery system.

Objective:To analyze two families with inherited dysfibrinogenemia,and explore the molecular pathogenic mechanisms.Methods:The coagulation indexes of the probands and their family members were detected.The FGA,FGB,and FGG exons and their flanking sequences were amplified by PCR,and the mutation sites were identified by sequencing.SIFT,PolyPhen2,LRT,ReVe,MutationTaster,phyloP,and phastCons bioinformatics software were used to predict the functional impact of the mutation sites.Protein structure and amino acid conservation analysis of the variant were conducted using PyMOL and Clustal X software.Results:The thrombin time(TT)of the proband in family 1 was prolonged to 37.00 s,and Fg:C decreased to 0.52 g/L.The TT of the proband in family 2 was 20.30 s,and Fg:C was 1.00 g/L,which was lower than the normal range.Genetic analysis revealed that the proband in family 1 had a heterozygous mutation c.80T＞C in FGA,resulting in the substitution of phenylalanine 27 with serine(Phe27Ser).The proband in family 2 had a heterozygous mutation c.1007T＞A in FGG,resulting in the substitution of methionine 336 with lysine(Met336Lys).Bioinformatics software prediction analysis indicated that both mutations were deleterious variants.PyMOL mutation models revealed that the Aα chain mutation(Phe27Ser)in family 1 and y chain mutation(Met336Lys)in family 2 resulted in alterations in spatial structure and reduced protein stability.Clustal X results showed that both Aα Phe27 and γMet336 were highly conserved across homologous species.Conclusion:Heterozygous mutations of FGA gene c.80T＞C and FGG gene c.1007T＞A are both pathogenic variants,causing inherited dysfibrinogenemia.

This study was aimed at investigating the pathogenic and molecular characteristics of Klebsiella pneumoniae(KP)in fecal samples of diarrhea cases in a district of Beijing.Fecal samples from diarrhea cases in an outpatient department in a district of Beijing from 2018 to 2021 were collected,and used for isolation and culture of KP.The KP strains isolated strains were subjected to drug resistance phenotype testing and whole-genome sequencing.Multilocus sequence typing and whole-genome phyletic evolution analysis were performed on the sequencing results.The cases'epidemiological and clinical characteristics were analyzed.From 2018 to 2021,1 103 fecal samples were collected and detected.The total detection rate of KP was 10.43％(115/1 103),and the infection rate of KP mixed with other diarrhea-causing pathogens was 42.61％(49/115).The positivity rate was slightly high(12.47％,61/489)a-mong females and was highest in young adults 16-45 years of age.Small peaks were observed in January,April to May,and August to September.The gastrointestinal symptoms in cases were mainly nausea and watery stool,and the suspicious food was unknown.Ampicillin,tetracycline,and sulfafurazole were the top three antibiotics to which these 115 KP strains showed resistance,and 29 strains were resistant to multiple antibiotics.The strains were divided into 72 sequence types,among which ST23 was dominant.According to the phylogenetic tree,the strains were divided into four main branches,among which 14 ST23 strains had a very close genetic relationship with the highly virulent NTUH-K2044 reference strain.KP infection persisted in fecal samples from diarrhea cases in the district of Beijing.Women and young adults were particularly susceptible.The drug resistance of KP strains in this region was very serious,and the ST types were diverse.Moreover,the ST23 pathogenic strains were closely related to high virulence strains.

In order to investigate the mechanism of 3-hydroxy-3-methylglutaryl-CoA reductase(HMGCR)on liver bile acid(BAs)and lipid metabolism of dairy cows with fatty liver,A liver lip-id accumulation model was established by isolating primary calf hepatocytes and treating them with high concentration of non-esterified fatty acids(NEFA)in vitro.Then,HMGCR overex-pressed adenovirus(Ad-HMGCR)and overexpressed adenovirus control(Ad-GFP)were added.Hepatocyte triglyceride(TAG)was detected by the kit,lipid droplet changes were detected by lip-id droplet fluorescence,and BAs synthesis,fatty acid synthesis and oxidation factor changes were detected by real-time fluorescence quantitative PCR.The results showed that TAG content and lip-id droplet fluorescence were significantly reduced in Ad-HMGCR+NEFA group compared with Ad-GFP+NEFA group.Real-time fluorescence quantitative PCR results showed that CYP7A1,CYP8B1,CYP7B1 and CYP27A1 of hepatocyte BAs synthesis factors in Ad-HMGCR+NEFA group,BAs transporters ABCC2 and ABCB11 and fatty acid synthesis factors ACC1,FAS and SREBP1C were significantly lower than those in Ad-GFP+NEFA group.The levels of BAs syn-thesis factor FXR and lipid oxidation factor CPT1A in Ad-HMGCR+NEFA group were higher than those in Ad-GFP+NEFA group.The results showed that overexpression of HMGCR could significantly reduce BAs and lipid accumulation in the liver of dairy cows with fatty liver.

Objective: Self-determination theory (SDT) deems that people have three causality orientations: autonomy orientation, control orientation, and impersonal orientation. Previous studies suggested that lower autonomy orientation or higher control and impersonal orientations may be associated with more addictive behaviors. Our study aimed to investigate if these associations exist in Internet gaming disorder (IGD), and if sensation seeking, anxiety, and depression could influence the associations between causality orientations and IGD symptoms. Methods: A total of 1,400 college students completed the Internet Gaming Disorder Scale, General Causality Orientation Scale, Brief Sensation Seeking Scale, Generalized Anxiety Disorder Scale, and Patient Health Questionnaire. Correlation, multiple linear regressions, structural equation model (SEM) analyses, and moderation analyses were conducted to explore the associations. Results: The control and impersonal orientations were positively associated with IGD symptoms, while the autonomy orientation was negatively associated with them. Moreover, SEM analyses showed that the autonomy-IGD relationship was totally mediated by anxiety and depression, the impersonal-IGD relationship was partially mediated by anxiety, and the control-IGD relationship was partially mediated by depression. Finally, the effects of causality orientations on IGD were moderated by sensation seeking. Conclusion Overall, autonomy orientation is linked to fewer gaming problems, whereas control and impersonal orientations are associated with more gaming problems. Moreover, the relationships between causality orientations and IGD symptoms are mediated by anxiety and depression and moderated by sensation seeking. Our findings inform theory on the motivations of gaming behaviors and may shed light on the prevention and intervention of IGD from the perspective of SDT.

The breakage pattern of unit particles during the production of oral solid dosage forms (OSD) is closely related to the quality of intermediate or final products. To accurately characterize the particles and study the evolution law of particle breakage, the Bonding model of the discrete element method (DEM) was used to investigate the breakage patterns of model parameters, particle shape and process conditions (loading mode and loading rate) on the dynamic breakage, force-time curve, breakage rate, maximum breakage size ratio and fracture strength of particles. The results showed that the particle breakage force was positively correlated with normal strength and bonded disk scale, negatively correlated with normal stiffness per unit area and tangential stiffness per unit area, and weakly correlated with tangential strength. The particle breakage rate was negatively correlated with the aspect ratio of the particles, and the maximum breakage size ratio was positively correlated with the aspect ratio of the particles; among the three loading modes, the breakage rate of compression breakage model was the largest, the breakage rate of shear breakage model was the second largest, and the breakage rate of wear breakage model was the smallest; the maximum breakage size ratio was positively correlated with the loading rate, the loading mode and the loading rate had no mutual influence on particle breakage rate, but had mutual influence on the maximum breakage size ratio. The research results will provide a theoretical basis for the shift of OSD from batch manufacturing to advanced manufacturing.

Objective:This study aimed to analyze the genomic characteristics of Varicella-Zoster Virus (VZV) strains circulating in Jilin province from 2010 to 2023.Methods:Vesicle fluid from 78 sporadic cases with VZV infection were collected in Jilin province from 2010 to 2023, after detecting by Real-time PCR, 26 specimens (CT<25) were detected by PCR. Open reading frame 22(ORF22), ORF38 and ORF62 were amplified and analyzed. Genotyping was confirmed by SNPs ORF22 (37902, 38019, 38055, 38081 and 38177) and ORF38 (69424). Vaccine strains were indentified from wild-type strains according to ORF38 (69349) and ORF62 (106262, 107252, and 108111). Sequences were analyzed by homologous comparison and phylogenetic analysis.Results:The comparison with Dumas sequence revealed that SNPs (37902, 38055, 38081 and 38177) in ORF22 and ORF38 (69424) have mutations similar to the pOka strain, which belong to clade 2. Compared to the Dumas and Baike strains, all 26 samples were wild-type strains. JL2016-4 strain changes from threonine to asparaginyl at position 38059, JL2021-4 strain changes from arginine to proline at position 37933, from aspartic acid to tyrosine at position 37935, and from aspartic acid at base 38031 to tyrosine. JL2023-1 strain changes from arginine to leucine at position 37933.Conclusions:VZV has been prevalent for 14 years in Jilin province. The main epidemic strains belong to the clade 2. We should strengthen the monitoring of VZV outbreaks and raise the coverage rate of VZV vaccination.

Purpose::This study evaluated the methods and clinical effects of multidisciplinary collaborative treatment for occlusal reconstruction in patients with old jaw fractures and dentition defects.Methods::Patients with old jaw fractures and dentition defects who underwent occlusal reconstruction at the Third Affiliated Hospital of Air Force Military Medical University from January 2018 to December 2022 were enrolled. Clinical treatment was classified into 3 phases. In phase I, techniques such as orthognathic surgery, microsurgery, and distraction osteogenesis were employed to reconstruct the correct 3-dimensional (3D) jaw position relationship. In phase II, bone augmentation and soft tissue management techniques were utilized to address insufficient alveolar bone mass and poor gingival soft tissue conditions. In phase III, implant-supported overdentures or fixed dentures were used for occlusal reconstruction. A summary of treatment methods, clinical efficacy evaluation, comparative analysis of imageological examinations, and satisfaction questionnaire survey were utilized to evaluate the therapeutic efficacy in patients with traumatic old jaw fractures and dentition defects. All data are summarized using the arithmetic mean ± standard deviation and compared using independent sample t-tests. Results::In 15 patients with old jaw fractures and dentition defects (an average age of 32 years, ranging from 18 to 53 years), there were 7 cases of malocclusion of single maxillary fracture, 6 of malocclusion of single mandible fracture, and 2 of malocclusion of both maxillary and mandible fractures. There were 5 patients with single maxillary dentition defects, 2 with single mandibular dentition defects, and 8 with both maxillary and mandibular dentition defects. To reconstruct the correct 3D jaw positional relationship, 5 patients underwent Le Fort I osteotomy of the maxilla, 3 underwent bilateral sagittal split ramus osteotomy of the mandible, 4 underwent open reduction and internal fixation for old jaw fractures, 3 underwent temporomandibular joint surgery, and 4 underwent distraction osteogenesis. All patients underwent jawbone augmentation, of whom 4 patients underwent a free composite vascularized bone flap (26.66%) and the remaining patients underwent local alveolar bone augmentation. Free gingival graft and connective tissue graft were the main methods for soft tissue augmentation (73.33%). The 15 patients received 81 implants, of whom 11 patients received implant-supported fixed dentures and 4 received implant-supported removable dentures. The survival rate of all implants was 93.82%. The final imageological examination of 15 patients confirmed that the malocclusion was corrected, and the clinical treatment ultimately achieved occlusal function reconstruction. The patient satisfaction questionnaire survey showed that they were satisfied with the efficacy, phonetics, aesthetics, and comfort after treatment.Conclusion::Occlusal reconstruction of old jaw fractures and dentition defects requires a phased sequential comprehensive treatment, consisting of 3D spatial jaw correction, alveolar bone augmentation and soft tissue augmentation, and implant-supported occlusal reconstruction, achieving satisfactory clinical therapeutic efficacy.