Objective: To characterize longitudinal trajectories of testicular development in boys and breast development in girls, so as to provide reference data for understanding patterns of pubertal sexual maturation. Methods: Based on the Shanghai Pudong New Area Cohort Study on Growth, Development and Health in Children and Adolescents, a baseline survey was conducted in 2020 using a mult stage cluster random sampling method. A total of 2 184 children who completed all follow ups during the primary school period from 13 elementary schools in Pudong New Area,Shanghai,with annual follow ups during 2021-2025. Testicular volume and Tanner stage of breast development were assessed by professional physicians using standardized visual inspection and palpation. The age distribution of testicular volume and breast development was fitted by using cumulative link mixed models and Turnbull s nonparametric maximum likelihood estimation method. Results: Median ages for testicular volumes of 2, 3, 4 and 5 mL in boys were 7.07, 9.24, 10.29, and 11.57 years old, respectively. Median ages for Tanner breast stages Ⅱ, Ⅲ, Ⅳ, and Ⅴ in girls were 8.55 , 10.17, 11.18, and 13.78 years old, respectively. Based on overweight and obesity, stratified analysis showed that earlier pubertal onset among overweight/obesity children, and the key milestones for pubertal initiation were testicular volume reaching 4 mL in boys and breast Tanner II in girls for 10.29, 10.83; 8.18, 9.00 years. Conclusion Overweight and obesity are associated with earlier pubertal initiation,but there are certain gender and developmental stage specific patterns.

The Type III Secretion System (T3SS) serves as a pivotal virulence apparatus for numerous Gram-negative bacterial pathogens, enabling them to infect both animal and plant hosts. Functioning as a molecular syringe, the T3SS directly translocates bacterial effector proteins from the bacterial cytoplasm into the interior of eukaryotic host cells. These effectors are central weapons that precisely manipulate a wide spectrum of host cellular physiological processes, ranging from cytoskeletal dynamics to immune signaling, to establish a favorable niche for bacterial survival and proliferation. Among the diverse arsenal of T3SS effectors, the YopJ family constitutes a critical group of virulence factors. Members of this family are characterized by a conserved catalytic triad structure—a hallmark of the CE clan of cysteine proteases that has been evolutionarily repurposed to confer acetyltransferase activity. A defining and intriguing feature of these enzymes is their stringent dependence on a host-derived eukaryotic cofactor, inositol hexakisphosphate (IP₆), for allosteric activation. This requirement acts as a sophisticated molecular safeguard, ensuring enzymatic activity only within the appropriate host environment, thereby preventing detrimental effects on the bacterium itself. While seminal studies on individual members such as Yersinia’s YopJ and Salmonella’s AvrA have provided deep mechanistic insights, a systematic and integrative understanding of the structure-function relationships across the entire family remains fragmented. Key questions persist regarding how a conserved catalytic core has diverged to recognize distinct host substrates in different kingdoms of life. To address this gap, this article provides a systematic review of the YopJ family, focusing on three interconnected aspects: their structural features, their catalytic mechanism, and their divergent immunosuppressive strategies in animal versus plant hosts. By conducting a comparative analysis of the sequences and resolved three-dimensional structures of three representative members (e.g., HopZ1a, PopP2, AvrA), we elucidate regions of significant variation embedded within the conserved core catalytic architecture. These variable regions, often involving surface loops and substrate-binding interfaces, are crucial determinants of target specificity and functional specialization. The functional divergence of this effector family is most apparent when comparing their modes of action in different hosts. In animal hosts, YopJ-family effectors primarily sabotage innate immune signaling pathways. They achieve this by acetylating key serine and threonine residues within the activation loops of critical kinases in the MAPK and NF‑κB pathways. This post-translational modification blocks the phosphorylation and subsequent activation of these kinases, leading to potent suppression of inflammatory cytokine production. Conversely, in plant hosts, the strategy broadens to dismantle the two-tiered plant immune system. YopJ homologs target a more diverse set of substrates, including immune-associated receptor-like cytoplasmic kinases (RLCKs), microtubule networks via tubulin acetylation (which disrupts cellular trafficking and signaling), and transcription factors central to defense gene regulation. This multi-target approach effectively suppresses both Pattern-Triggered Immunity (PTI) and Effector-Triggered Immunity (ETI). In conclusion, this synthesis aims to deepen the mechanistic understanding of YopJ family-mediated pathogenesis by integrating structural biology with cellular function across host kingdoms. Elucidating the precise molecular basis for substrate selection—how conserved platforms achieve target diversity—is a major frontier. Furthermore, this knowledge provides a vital theoretical foundation for developing novel anti-virulence strategies. Targeting the conserved IP₆-binding pocket or the catalytic acetyltransferase activity itself represents a promising avenue for designing broad-spectrum inhibitors that could disarm this critical family of bacterial effectors, potentially offering new therapeutic approaches against a range of pathogenic bacteria.

The present study aimed to investigate the effects of eccentric treadmill exercise on adaptive hypertrophy of skeletal muscle in rats. Thirty-two 3-month-old Sprague Dawley (SD) rats were selected and randomly assigned to one of the four groups based on their body weights: 2-week quiet control group (2C), 2-week downhill running exercise group (2E), 4-week quiet control group (4C), and 4-week downhill running exercise group (4E). The downhill running protocol for rats in the exercise groups involved slope of -16°, running speed of 16 m/min, training duration of 90 min, and 5 training sessions per week. Twenty-four hours after the final session of training, all the four groups of rats underwent an exhaustion treadmill exercise. After resting for 48 h, all the rats were euthanized and their gastrocnemius muscles were harvested for analysis. HE staining was used to measure the cross-sectional area (CSA) and diameter of muscle fibers. Transmission electron microscope was used to observe the ultrastructural changes in muscle fibers. Purithromycin surface labeling translation method was used to measure protein synthesis rate. Immunofluorescence double labeling was used to detect the colocalization levels of lysosomal-associated membrane protein 2 (Lamp2)-leucyl-tRNA synthetase (LARS) and Lamp2-mammalian target of rapamycin (mTOR). Western blot was used to measure the protein expression levels of myosin heavy chain (MHC) IIb and LARS, as well as the phosphorylation levels of mTOR, p70 ribosomal protein S6 kinase (p70S6K), and eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1). The results showed that, compared with the 2C group rats, the 2E group rats showed significant increases in wet weight of gastrocnemius muscle, wet weight/body weight ratio, running distance, running time, pre- and post-exercise blood lactate levels, myofibrillar protein content, colocalization levels of Lamp2-LARS and Lamp2-mTOR, and LARS protein expression. Besides these above changes, compared with the 4C group, the 4E group further exhibited significantly increased fiber CSA, fiber diameter, protein synthesis rate, and phosphorylation levels of mTOR, p70S6K, and 4E-BP1. Compared with the quiet control groups, the exercise groups exhibited ultrastructural damage of rat gastrocnemius muscle, which was more pronounced in the 4E group. These findings suggest that eccentric treadmill exercise may promote mTOR translocation to lysosomal membrane, activating mTOR signaling via up-regulating LARS expression. This, in turn, increases protein synthesis rate through the mTOR-p70S6K-4E-BP1 signaling pathway, promoting protein deposition and inducing adaptive skeletal muscle hypertrophy. Although the ultrastructural changes of skeletal muscle are more pronounced, the relatively long training cycles during short-term exercise periods have a more significant effect on promoting gastrocnemius muscle protein synthesis and adaptive hypertrophy.
Animals ; Rats, Sprague-Dawley ; Physical Conditioning, Animal/physiology* ; Rats ; Muscle, Skeletal/metabolism* ; TOR Serine-Threonine Kinases/metabolism* ; Male ; Hypertrophy ; Adaptation, Physiological/physiology* ; Adaptor Proteins, Signal Transducing/metabolism* ; Ribosomal Protein S6 Kinases, 70-kDa/metabolism* ; Intracellular Signaling Peptides and Proteins

Objective To investigate the distribution and antimicrobial resistance profiles of clinically isolated Haemophilus influenzae and Moraxella catarrhalis in hospitals across China from 2015 to 2021,and provide evidence for rational use of antimicrobial agents.Methods Data of H.influenzae and M.catarrhalis strains isolated from 2015 to 2021 in CHINET program were collected for analysis,and antimicrobial susceptibility testing was performed by disc diffusion method or automated systems according to the uniform protocol of CHINET.The results were interpreted according to the CLSI breakpoints in 2022.Beta-lactamases was detected by using nitrocefin disk.Results From 2015 to 2021,a total of 43 642 strains of Haemophilus species were isolated,accounting for 2.91％of the total clinical isolates and 4.07％of Gram-negative bacteria in CHINET program.Among the 40 437 strains of H.influenzae,66.89％were isolated from children and 33.11％were isolated from adults.More than 90％of the H.influenzae strains were isolated from respiratory tract specimens.The prevalence of β-lactamase was 53.79％in H.influenzae strains.The H.influenzae strains isolated from children showed higher resistance rate than the strains isolated from adults.Overall,779 strains of H.influenzae did not produce β-lactamase but were resistant to ampicillin(BLNAR).Beta-lactamase-producing strains showed significantly higher resistance rates to these antimicrobial agents than the β-lactamase-nonproducing strains.Of the 16 191 M.catarrhalis strains,80.06％were isolated from children and 19.94％isolated from adults.M.catarrhalis strains were mostly susceptible to both amoxicillin-clavulanic acid and cefuroxime,evidenced by resistance rate lower than 2.0％.Conclusions The emergence of antibiotic-resistant H.influenzae due to β-lactamase production poses a challenge for clinical anti-infective treatment.Therefore,it is very important to implement antibiotic resistance surveillance for H.influenzae and guide rational antibiotic use.All local clinical microbiology laboratories should actively improve antibiotic susceptibility testing and strengthen antibiotic resistance surveillance for H.influenzae.

Objective:To investigate the characteristics of Internet addiction(IA)in adolescents with depression and explore its relationship with impulsivity and aggressive personality traits.Methods:A total of 71 adolescent patients with depressive disorders were recruited from the Child Psychiatry Outpatient Clinic of Peking University Sixth Hospital between April 2021 and November 2022 (15 males, 56 females; median age 14 [13, 15] years) as the depressive disorder group. Additionally, 83 healthy adolescents (27 males, 56 females; median age 14 [13, 17] years) were recruited as the control group during the same period. Internet addiction was assed using the Chinese version of Young′s Internet Addiction Test (YIAT), with a total score≥50 indicating internet addiction. Impulsivity was evaluated using the Barratt Impulsiveness Scale-11(BIS-11), and aggression was measured with the Buss-Perry Aggression Questionnaire(BPAQ). Differences in internet addiction, impulsivity, and aggression between the depression group and the control group were analyzed. Pearson correlation analysis was used to explore the correlation between internet addiction and impulsivity, aggression. Hierarchical linear regression models were used to analyze the factors influencing internet addiction, and a parallel mediation model was used to examine the mediating effect of impulsivity and aggressive personality traits in the relationship between depressive disorders and internet addiction.Results:The prevalence of IA was significantly higher in adolescents with depression than the healthy control group [57.75%(41/71) vs 31.33%(26/83); χ 2=10.87, P<0.001]. Adolescents with depressive disorders also exhibited higher impulsivity (65.5±9.2 vs 57.0±9.2, t=-5.72, P<0.001) and aggression (56.3±16.0 vs 42.4±15.1, t=-5.13, P<0.001) compared to the control group. Internet addiction was positively correlated with aggression ( r=0.47, P<0.01) and impulsivity ( r=0.57, P<0.01). Hierarchical regression analysis with the YIAT total score as the dependent variable revealed that impulsivity ( β=0.48, P<0.001) and aggression ( β=0.24, P<0.001) significantly predicted internet addiction. Mediation analysis indicated that depressive disorders indirectly indirectly influenced internet addiction through parallel paths of impulsivity and aggression, with a total indirect effect of 0.543 (95% CI: 0.362-0.761). Conversely, internect addiction influenced depressive disorders through reverse parallel pathway of impulsivity and aggression with a total indirect effect of 0.038 (95% CI: 0.021-0.067). Direct effects were not significant in either direction. Conclusion:Adolescents with depressive disorders exhibit more internet addiction. Impulsivity and aggressive personality traits play bidirectional mediating roles in the relationship between depressive disorders and internet addiction.

Objective To investigate the therapeutic effect of hypericin on acute pancreatitis(AP)in mice and its effect on NLRP3 inflammasome signaling pathway.Methods The AP model in mice was established with caerulein(CER).The mice were divided into the normal control group,the model group(AP group),the low-dose HY group(CER+HY 5 mg/kg group),the medium-dose HY group(CER+HY 10 mg/kg group)and the high-dose HY group(CER+HY 20 mg/kg group),with 10 mice in each group.The 266-6 mouse pancreatic acinar cancer cells were treated with cholecystokinin(CCK)and divided into the control group,the AP group,the CCK+HY 1 μmol/L group,the CCK+HY 2 μmol/L group and the CCK+HY 4 μmol/L group.The activities of amylase(AMS),lipase,trypsin and myeloperoxidase(MPO)in the serum of each group of mice,and levels of inflammatory factors interleukin(IL)-1β and tumor necrosis factor(TNF)-α were detected by enzyme-linked immunosorbent assay(ELISA).The expression of NOD-like receptor family protein 3(NLRP3)was detected by Western blot assay.The mRNA levels of NLRP3,caspase(Caspase)-1,IL-1β,TNF-α and IL-18 in pancreatic tissue of mice were detected by real-time quantitative PCR(q-PCR).The cell survival rate of cells in each group was detected by CCK8 method.The mRNA expression levels of NLRP3,Caspase-1 and IL-18 in each group of cells were detected by q-PCR.Results Compared with the normal control group,the levels of AMS,lipase,MPO,trypsin,IL-1β and TNF-α in serum of the model group,and the mRNA and protein expression levels of NLRP3,IL-1β,TNF-α,IL-18 and Caspase-1 in pancreatic tissue were increased(P＜0.01).Compared with the model group,the levels of AMS,IL-1β and TNF-α,the enzymatic activity of trypsin in serum,and the mRNA levels of IL-1β,TNF-α,IL-18 and Caspase-1 in pancreatic tissue were decreased in the low-,medium-and high-dose HY groups.The serum levels of lipase and MPO and the mRNA expression levels of NLRP3 in pancreatic tissue were decreased in the medium-and high-dose HY groups(P＜0.05).Compared with the AP group,the cell survival rates were increased in the CCK+HY 1 μmol/L group,the CCK+HY 2 μmol/L group and the CCK+HY 4 μmol/L group,and the mRNA levels of NLRP3,IL-18 and Caspase-1 were decreased in a dose-dependent manner(P＜0.05).Conclusion Hypericin can effectively treat AP in vivo and in vitro,and its therapeutic effect may be related to the regulation of NLRP3 inflammasome signaling pathway.

The purpose of this study was to clarify the effect of Huotan Jiedu Tongluo Decoction on atherosclerosis(AS) injury in ApoE~(-/-) mice by regulating the ferroptosis pathway. Seventy-five ApoE~(-/-) mice were randomly divided into model group, low-, medium-, and high-dose of Huotan Jiedu Tongluo Decoction groups, and evolocumab group(n=15), and 15 C57BL/6J mice were selected as the blank group. Mice in the blank group were fed with a normal diet, and those in the other groups were fed with a high-fat diet to induce AS. From the 9th week, mice in Huotan Jiedu Tongluo Decoction groups were administrated with Huotan Jiedu Tongluo Decoction at corresponding doses by gavage, and those in the blank group and the model group were given an equal volume of distilled water. Mice in the evolocumab group were treated with evolocumab 18.2 mg·kg~(-1 )by subcutaneous injection every 2 weeks. After 8 weeks of continuous intervention, oil red O staining and hematoxylin-eosin(HE) staining were employed to observe the lipid deposition and plaque formation in the aortic root. Masson staining was used to evaluate the collagen content in the aortic root. The serum levels of total cholesterol(TC), triglycerides(TG), high-density lipoprotein cholesterol(HDL-C), and low-density lipoprotein cholesterol(LDL-C) were determined by biochemical kits. The levels of Fe~(2+), superoxide dismutase(SOD), malondialdehyde(MDA), and glutathione(GSH) in the aorta were measured by colorimetry. The protein and mRNA levels of nuclear factor erythroid 2-related factor 2(Nrf2), glutathione peroxidase 4(GPX4), solute carrier family 7 member 11(SLC7A11), and acyl-CoA synthetase long chain family member 4(ACSL4) in the aorta were detected by Western blot and RT-qPCR, respectively. The expression of Nrf2, GPX4, and SLC7A11 was localized by immunofluorescence. The results showed that low-, medium-, and high-dose Huotan Jiedu Tongluo Decoction reduced the plaque formation of aortic root and increased the collagen content in AS mice. At the same time, Huotan Jiedu Tongluo Decoction improved the lipid metabolism by lowering the levels of TC, LDL-C, and TG and elevating the level of HDL-C in the serum. Huotan Jiedu Tongluo Decoction enhanced the antioxidant capacity by elevating the levels of GSH and SOD and lowering the level of MDA in the aorta and inhibiting the accumulation of Fe~(2+) in the aorta. In addition, Huotan Jiedu Tongluo Decoction up-regulated the protein and mRNA levels of Nrf2, GPX4, and SLC7A11, while down-regulating the protein and mRNA levels of ACSL4. In summary, Huotan Jiedu Tongluo Decoction can effectively alleviate AS lesions in ApoE~(-/-) mice by activating the Nrf2/GPX4 pathway, reducing lipid peroxidation, and inhibiting ferroptosis.
Animals ; Ferroptosis/drug effects* ; Atherosclerosis/metabolism* ; Drugs, Chinese Herbal/administration & dosage* ; NF-E2-Related Factor 2/genetics* ; Mice ; Mice, Inbred C57BL ; Apolipoproteins E/metabolism* ; Male ; Phospholipid Hydroperoxide Glutathione Peroxidase/genetics* ; Signal Transduction/drug effects* ; Humans ; Mice, Knockout

OBJECTIVE: To screen anti-tumor drugs that improve antigen processing and presentation in acute myeloid leukemia (AML) cells. METHODS: A TCR-like or TCR mimic antibody that can specifically recognize HLA-A*0201:WT1_126-134 ( RMFPNAPYL) complex (hereafter referred to as HLA-A2:WT1) was synthesized to evaluate the function of antigen processing and presentation machinery (APM) in AML cells. AML cell line THP1 was incubated with increasing concentrations of IFN-γ, hypomethylating agents (HMA), immunomodulatory drugs (IMiD), proteasome inhibitors (PI) and γ-secretase inhibitors (GSI), followed by measuring of HLA-ABC, HLA-A2 and HLA-A2:WT1 levels by flow cytometry at consecutive time points. RESULTS: The TCR-like antibody we generated only binds to HLA-A*0201⁺WT1⁺ cells, indicating the specificity of the antibody. HLA-A2:WT1 level of THP-1 cells detected with the TCR-like antibody was increased significantly after co-incubation with IFN-γ, showing that the HLA-A2:WT1 TCR like antibody could evaluate the function of APM. Among the anti-tumor agents screened in this study, GSI (LY-411575) and HMA (decitabine and azacitidine) could significantly increase the HLA-A2:WT1 level. The IMiD lenalidomide and pomalidomide could aslo upregulate the expression of HLA-A2:WT1 complex under certain concentrations of the drugs and incubation time. As proteasome inhibitors, carfilzomib could significantly decreased the expression of HLA-A2:WT1, while bortezomib had no significant effect on HLA-A2:WT1 expression. CONCLUSION HLA-A2:WT1 TCR-like antibody can effectively reflect the APM function. Some of the anti-tumor drugs can affect the APM function and immunogenicity of tumor cells.
Humans ; Leukemia, Myeloid, Acute/immunology* ; Antineoplastic Agents/pharmacology* ; Antigen Presentation/drug effects* ; HLA-A2 Antigen/immunology* ; Receptors, Antigen, T-Cell/immunology* ; Cell Line, Tumor ; Interferon-gamma

Objective:To explore the effect and safety profile of psycho-cardiology model combined with phased re-habilitation exercise on psychological state,cardiac function,sleep quality,cognitive function and quality of life of patients with coronary heart disease(CHD)after percutaneous coronary intervention(PCI).Methods:This ran-domized controlled study enrolled 150 CHD patients with anxiety and sleep disorder who underwent PCI in the Psy-cho-cardiology Medical Center of Beijing Anzhen Hospital,Capital Medical University between January 2023 and April 2023.Patients were randomly divided into control group(n=75)and intervention group(n=75).Patients in the control group received routine management mode intervention after PCI,comparing to those in the intervention group receiving psycho-cardiology model combined with phased rehabilitation exercise intervention after PCI.Both groups were intervened for 2 months and followed up for 6 months.Mental state,heart function,sleep quality,cog-nitive function,quality of life and incidence of adverse events were compared between two groups.Results:Com-pared to those in control group,patients in intervention group had significant lower scores of generalized anxiety dis-order-7(GAD-7)[(5.16±1.19)points vs.(7.53±1.68)points],patient health questionaire-9(PHQ-9)[(7.63±1.03)points vs.(10.41±1.54)points],Athens insomnia scale(AIS)[(3.69±1.35)points vs.(6.43±2.11)points]and left ventricular end diastolic diameter(LVEDd)[(44.50±2.86)mm vs.(54.11±3.46)mm](P＜0.001 all),and significant higher left ventricular ejection fraction(LVEF)[(60.06±3.05)％vs.(53.90±3.05)％],scores of Seattle angina questionnaire(SAQ)[(83.31±6.59)points vs.(52.75±5.66)points]and mini-mental state examination(MMSE)[(26.44±4.68)points vs.(23.23±4.01)points](P＜0.001 all).We detec-ted significant lower incidence of adverse events in intervention group compared to control group(4.29％vs.16.44％,P=0.018).Conclusion:Psycho-cardiology model combined with phased rehabilitation exercise may im-prove psychological state,heart function,sleep quality,cognitive function and quality of life in CHD patients with anxiety and sleep disorder after PCI with considerable safety.

Aim To predict and verify the potential mechanism of the compatibility of"ginseng-astragalus-pueraria"in protecting islet morphology and improving insulin resistance by using network pharmacology.Methods The active ingredients and targets of the horn medicine were obtained from three platforms:TC-MSP,TCMIP,and BATMAN.The targets of type 2 dia-betes mellitus(T2DM)were obtained from three plat-forms:TTD,OMIM,and disgeNET.The PPI network was constructed by using the STRING database and Cy-toscape 3.9.1;GO and KEGG analysis were per-formed;POCASA 1.1 was used to predict protein binding sites,and AutoDock Vina1.1.2 was used for docking and experimental verification.Results"Gin-seng-astragalus-pueraria"screened out 2 021 targets,of which 152 were closely related to T2DM,and 10 key genes and the AGE-RAGE signaling pathway were i-dentified.Molecular docking showed that quercetin had good binding to RAGE,INS,and PI3K.Experi-ments showed that the horn drug increased insulin binding rate and secretion index and reduced serum in-sulin level and insulin resistance index.These data benefited from"ginseng-astragalus-pueraria"reducing the expression of AGE-RAGE,activating PI3K-Akt,in-hibiting NF-κB,and reducing the expression of IL-6,IL-1β and TNF-α.Conclusion The study suggests that"ginseng-astragalus-pueraria"regulates the AGE-RAGE/PI3K-Akt/NF-κB signaling pathway,repairs damaged islet morphology,and improves insulin resist-ance.