BACKGROUND:The Twin-block orthodontic appliance is commonly used for the correction of Class Ⅱ malocclusion.Its mechanism of action in stimulating mandibular growth has been confirmed in many studies,but its impact on maxillary growth is not very clear. OBJECTIVE:By establishing a finite element model to analyze the stress distribution of the maxillary complex,surrounding bone sutures,and maxillary dentition in patients with Class Ⅱ malocclusion wearing Twin-block orthodontic appliances. METHODS:One patient with Class Ⅱ malocclusion who underwent orthodontic treatment at Qingdao Hospital/Qingdao Municipal Hospital of Shandong Rehabilitation University was selected.The bite force data of the patient when wearing the Twin-block orthodontic appliance was measured,and CBCT data were collected.A finite element model was established,including the maxillary complex,peripheral sutures,Twin-block orthodontic appliance,and maxillary dentition.ABAQUS software was used to simulate the stress distribution in the maxilla and maxillary dentition when the patient was wearing the Twin-block appliance. RESULTS AND CONCLUSION:The equivalent stress on the maxillary anterior teeth was significantly smaller than that on the posterior teeth,and the maximum equivalent stress on both sides of the teeth were 4.797 5 Mpa and 8.716 1 Mpa,respectively,which were located at the first premolar.The maximum displacements were presented at the maxillary incisors on both sides of the teeth,which were 0.080 5 mm and 0.081 0 mm,respectively.The maximum equivalent stress on the bone suture was 1.284 Mpa,which was mainly concentrated in the pterygopalatine suture and the frontal-maxillary suture on both sides,and there was almost no difference in the force of the rest of bone sutures;the maximum displacement of the bone suture was 0.07 mm,with the pterygopalatine suture having the largest displacement,followed by the frontal-maxillary suture.The maximal equivalent stress on the maxillary complex was 27.18 Mpa,which was mainly concentrated on both sides of the anterior pyriform foramen of the maxilla,around the nasofrontal suture and around the pterygopalatine suture at the posterior part of the jaws.The maximal displacement of the maxilla was 0.07 mm,which was mainly concentrated on the maxillary alveolar bone.All these findings show that the occlusal force acts on the maxillary complex through the Twin-block appliance,resulting in clockwise rotation of the maxilla and steepening of the dentition plane.Measures should be taken to compensate for this tendency,for example,by considering maxillary molar elongation and intrusion in the process of occlusion,which are not only able to flatten the occlusal plane,but facilitate the mandibular protraction,thereby further improving Class Ⅱ malocclusion orthodontic treatment.

Distinct from the complementary inhibition mechanism through binding to the target with three-dimensional conformation of small molecule inhibitors, targeted protein degradation technology takes tremendous advantage of endogenous protein degradation pathway inside cells to degrade plenty of “undruggable” target proteins, which provides a novel route for the treatment of many serious diseases, mainly including proteolysis-targeting chimeras, lysosome-targeting chimeras, autophagy-targeting chimeras, antibody-based proteolysis-targeting chimeras, etc. Unlike proteolysis-targeting chimeras first found in 2001, which rely on ubiquitin-proteasome system to mainly degrade intracellular proteins of interest, lysosome-targeting chimeras identified in 2020, which was act as the fastly developing technology, utilize cellular lysosomal pathway through endocytosis mediated by lysosome-targeting receptor to degrade both extracellular and membrane proteins. As an emerging biomedical technology, nucleic acid-driven lysosome-targeting chimeras utilize nucleic acids as certain components of chimera molecule to replace with ligand to lysosome-targeting receptor or protein of interest, exhibiting broad application prospects and potential clinical value in disease treatment and drug development. This review mainly introduced present progress of nucleic acid-driven lysosome-targeting chimeras technology, including its basic composition, its advantages compared with antibody or glycopeptide-based lysosome-targeting chimeras, and focused on its chief application, in terms of the type of lysosome-targeting receptors. Most research about the development of nucleic acid-driven lysosome-targeting chimeras focused on those which utilized cation-independent mannose-6-phosphonate receptor as the lysosome-targeting receptor. Both mannose-6-phosphonate-modified glycopeptide and nucleic aptamer targeting cation-independent mannose-6-phosphonate receptor, even double-stranded DNA molecule moiety can be taken advantage as the ligand to lysosome-targeting receptor. The same as classical lysosome-targeting chimeras, asialoglycoprotein receptor can also be used for advance of nucleic acid-driven lysosome-targeting chimeras. Another new-found lysosome-targeting receptor, scavenger receptor, can bind dendritic DNA molecules to mediate cellular internalization of complex and lysosomal degradation of target protein, suggesting the successful application of scavenger receptor-mediated nucleic acid-driven lysosome-targeting chimeras. In addition, this review briefly overviewed the history of lysosome-targeting chimeras, including first-generation and second-generation lysosome-targeting chimeras through cation-independent mannose-6-phosphonate receptor-mediated and asialoglycoprotein receptor-mediated endocytosis respectively, so that a clear timeline can be presented for the advance of chimera technique. Meantime, current deficiency and challenge of lysosome-targeting chimeras was also mentioned to give some direction for deep progress of lysosome-targeting chimeras. Finally, according to faulty lysosomal degradation efficiency, more cellular mechanism where lysosome-targeting chimeras perform degradation of protein of interest need to be deeply explored. In view of current progress and direction of nucleic acid-driven lysosome-targeting chimeras, we discussed its current challenges and development direction in the future. Stability of natural nucleic acid molecule and optimized chimera construction have a great influence on the biological function of lysosome-targeting chimeras. Discovery of novel lysosome-targeting receptors and nucleic aptamer with higher affinity to the target will greatly facilitate profound advance of chimera technique. In summary, nucleic acid-driven lysosome-targeting chimeras have many superiorities, such as lower immunogenicity, expedient synthesis of chimera molecules and so on, in contrast to classical lysosome-targeting chimeras, making it more valuable. Also, the chimera technology provides new ideas and methods for biomedical research, drug development and clinical treatment, and can be used more widely through further research and optimization.

ObjectiveRecent studies have highlighted the critical role of NUDT19 in the initiation, progression, and prognosis of specific cancer types. However, its involvement in pan-cancer analysis has not been fully characterized. This study aims to systematically explore the expression patterns, clinical significance, and immune-related functions of NUDT19 in various cancer types through multi-omics analysis, further revealing its potential role in cancer, particularly its functional and therapeutic target value in leukemia. MethodsTo achieve this goal, various bioinformatics approaches were employed to evaluate the expression patterns, clinical significance, and immune-related functions of NUDT19 in tumors and normal tissues. Additionally, we analyzed the mutation characteristics of NUDT19 and its relationship with epigenetic modifications. Using the single-cell analysis tool SingleCellBase, we explored the distribution of NUDT19 across different cell subpopulations in tumors. To validate these findings, qRT-PCR was used to measure NUDT19 expression levels in specific tumor cell lines, and we established acute myeloid leukemia (AML) cell lines (HL-60 and THP-1) to conduct NUDT19 knockdown and overexpression experiments, assessing its effects on leukemia cell proliferation, apoptosis, and invasion. ResultsPan-cancer analysis revealed the dysregulated expression of NUDT19 across multiple cancer types, which was closely associated with poor prognosis, clinical staging, and diagnostic markers. Furthermore, NUDT19 was significantly correlated with tumor biomarkers, immune-related genes, and immune cell infiltration in different cancers. Mutation analysis showed that multiple mutations in NUDT19 were significantly associated with epigenetic changes. Single-cell analysis revealed the heterogeneity of NUDT19 expression in cancer cells, suggesting its potentially diverse functional roles in different cell subpopulations. qRT-PCR experiments confirmed the significant upregulation of NUDT19 in various tumor cell lines. In AML cell lines, NUDT19 knockdown led to reduced cell proliferation and invasion, with increased apoptosis, while NUDT19 overexpression significantly enhanced cell proliferation and invasion while reducing apoptosis. ConclusionThis study demonstrates the diverse roles of NUDT19 in various cancer types, with a particularly prominent functional role in leukemia. NUDT19 is not only associated with tumor initiation and progression but may also influence cancer progression through the regulation of immune microenvironment and epigenetic mechanisms. Our research highlights the potential of NUDT19 as a therapeutic target, particularly for targeted therapies in malignancies such as leukemia, with significant clinical application prospects.

OBJECTIVES: To study the epidemiological characteristics of respiratory syncytial virus (RSV) infection in hospitalized children with community-acquired pneumonia (CAP) in Hebei Province. METHODS: Hospitalized children with CAP who tested positive for RSV and were admitted to Hebei Children's Hospital from various cities and counties across Hebei Province between January 2019 and December 2023 were included in the study. Clinical data were collected and analyzed to assess epidemiological characteristics. RESULTS: The clinical data of 43 978 children with CAP were collected, with an overall RSV detection rate of 25.98%. The detection rate was higher during the implementation of non-pharmaceutical interventions (NPIs) (30.60%) than in the non-NPIs period. Winter and spring were the primary epidemic seasons for RSV each year except in 2022. The detection rate in males (26.62%) was higher than in females (25.06%) (P<0.001). The highest detection rate (59.18%) was found in infants aged 29 days to <1 year. Single RSV infection was more common, with rhinovirus being the most frequent co-infection. CONCLUSIONS The overall RSV detection rate in Hebei Province is influenced by NPIs, being higher during their implementation. RSV predominantly circulates in winter and spring. The detection rate of RSV is higher in males and infants. RSV infection is primarily single, most often co-occurring with rhinovirus.
Humans ; Respiratory Syncytial Virus Infections/epidemiology* ; Female ; Male ; Infant ; Child, Preschool ; Seasons ; China/epidemiology* ; Infant, Newborn ; Community-Acquired Infections/epidemiology* ; Child

Neuropathic pain, often featuring allodynia, imposes significant physical and psychological burdens on patients, with limited treatments due to unclear central mechanisms. Addressing this challenge remains a crucial unsolved issue in pain medicine. Our previous study, using protein kinase C gamma (PKCγ)-tdTomato mice, highlights the spinal feedforward inhibitory circuit involving PKCγ neurons in gating neuropathic allodynia. However, the regulatory mechanisms governing this circuit necessitate further elucidation. We used diverse transgenic mice and advanced techniques to uncover the regulatory role of the descending serotonin (5-HT) facilitation system on spinal PKCγ neurons. Our findings revealed that 5-HT neurons from the rostral ventromedial medulla hyperpolarize spinal inhibitory interneurons via 5-HT_2C receptors, disinhibiting the feedforward inhibitory circuit involving PKCγ neurons and exacerbating allodynia. Inhibiting spinal 5-HT_2C receptors restored the feedforward inhibitory circuit, effectively preventing neuropathic allodynia. These insights offer promising therapeutic targets for neuropathic allodynia management, emphasizing the potential of spinal 5-HT_2C receptors as a novel avenue for intervention.
Animals ; Neuralgia/physiopathology* ; Protein Kinase C/metabolism* ; Receptor, Serotonin, 5-HT2C/metabolism* ; Hyperalgesia/physiopathology* ; Mice, Transgenic ; Mice ; Spinal Cord/metabolism* ; Serotonin/metabolism* ; Male ; Neurons/metabolism* ; Mice, Inbred C57BL

Aconiti Lateralis Radix Praeparata (Fuzi) represents a significant traditional Chinese medicine (TCM) that exhibits both notable pharmacological effects and toxicity. Various processing methods are implemented to reduce the toxicity of raw Fuzi by modifying its toxic and effective components, primarily diterpenoid alkaloids. To comprehensively analyze the chemical variations between different Fuzi products, ultra-high performance liquid chromatography-linear ion trap quadrupole Orbitrap mass spectrometry (UHPLC-LTQ-Orbitrap MS) was employed to systematically characterize Shengfuzi, Heishunpian and Baifupian. A total of 249 diterpenoid alkaloids present in Shengfuzi were identified, while only 111 and 61 in Heishunpian and Baifupian were detected respectively, indicating substantial differences among these products. An untargeted metabolomics approach combined with multivariate statistical analysis revealed 42 potential chemical markers. Through subsequent validation using 52 batches of commercial Heishunpian and Baifupian samples, 8 robust markers distinguishing these products were identified, including AC1-propanoic acid-3OH, HE-glucoside, HE-hydroxyvaleric acid-2OH, dihydrosphingosine, N-dodecoxycarbonylvaline and three unknown compounds. Additionally, the MS imaging (MSI) technique was utilized to visualize the spatial distribution of chemical constituents in raw Fuzi, revealing how different processing procedures affect the chemical variations between Heishunpian and Baifupian. The distribution patterns of different diterpenoid alkaloid subtypes partially explained the chemical differences among products. This research provides valuable insights into the material basis for future investigations of different Fuzi products.
Diterpenes/chemistry* ; Alkaloids/chemistry* ; Chromatography, High Pressure Liquid/methods* ; Aconitum/chemistry* ; Drugs, Chinese Herbal/chemistry* ; Metabolomics ; Mass Spectrometry/methods* ; Plant Roots/chemistry* ; Molecular Structure

OBJECTIVE: To identify prognostic genes associated with lysosome-dependent cell death (LDCD) in patients with gastric cancer (GC). METHODS: Differentially expressed genes (DEGs) were identified using The Cancer Genome Atlas - Stomach Adenocarcinoma. Weighted gene co-expression network analysis was performed to identify the key module genes associated with LDCD score. Candidate genes were identified by DEGs and key module genes. Univariate Cox regression analysis, and least absolute shrinkage and selection operator regression and multivariate Cox regression analyses were performed for the selection of prognostic genes, and risk module was established. Subsequently, key cells were identified in the single-cell dataset (GSE183904), and prognostic gene expression was analyzed. Cell proliferation and migration were assessed using the Cell Counting Kit-8 assay and the wound healing assay. RESULTS: A total of 4,465 DEGs, 95 candidate genes, and 4 prognostic genes, including C19orf59, BATF2, TNFAIP2, and TNFSF18, were identified in the analysis. Receiver operating characteristic curves indicated the excellent predictive power of the risk model. Three key cell types (B cells, chief cells, and endothelial/pericyte cells) were identified in the GSE183904 dataset. C19orf59 and TNFAIP2 exhibited predominant expression in macrophage species, whereas TNFAIP2 evolved over time in endothelial/pericyte cells and chief cells. Functional experiments confirmed that interfering with C19orf59 inhibited proliferation and migration in GC cells. CONCLUSION C19orf59, BATF2, TNFAIP2, and TNFSF18 are prognostic genes associated with LDCD in GC. Furthermore, the risk model established in this study showed robust predictive power.
Stomach Neoplasms/pathology* ; Humans ; Prognosis ; Lysosomes/physiology* ; RNA-Seq ; Cell Death ; Single-Cell Analysis ; Gene Expression Regulation, Neoplastic ; Cell Proliferation ; Single-Cell Gene Expression Analysis

OBJECTIVE To investigate the effect of Banxia Xiexin decoction(BXD) on colitis associated cancer(CAC) mice and its related mechanism. METHODS Seventy-five C57BL/6 mice were randomly divided into normal group, model group, Banxia Xiexin decoction low-dose group, high-dose group and mesalazine group. Except for the normal group, the mice in the other groups were intraperitoneally injected with azoxymethane combined with oral dextran sodium sulfate to establish the CAC model. BXD and mesalazine were given respectively for intervention. The general conditions of all mice were observed and recorded, and the changes of body weight, disease activity index, colon length and tumor number were monitored. HE staining was utilized to observe the pathological changes of colon tissue. The expression levels of PCNA, NF-κB P65 and IκB-α were detected by immunohistochemistry. The mRNA levels of IL-17A, N-cadherin, E-cadherin and Bcl-2 were detected by qRT-PCR. Macrophage infiltration was measured using immunostaining analysis. Western blotting was applied to analyze the expression of NF-κB, E-cadherin and N-cadherin proteins in colon tissues of each group. RESULTS There was no significant tumor occurrence in the normal group, while the body weight of the model group mice was significantly reduced and the number of colon tumors increased. The colon length, number of tumors, and degree of inflammatory cell infiltration in the BXD group were significantly improved compared to the model group. Immunohistochemical results showed that the expression of PCNA, NF-κB P65 and IκB-α protein in colon tissue of model group was remarkably increased (P<0.01). Immunofluorescence results showed that the number of F4/80, CD80 and CD206 positive macrophages in the colon tissue of the model group increased (P<0.05 or P<0.01). The results of RT-PCR demonstrated that the levels of IL-17A, N-cadherin and Bcl-2 mRNA in the colon tissue of the model group were significantly increased (P<0.01), while the level of E-cadherin mRNA was fundamentally decreased (P<0.01). Western blotting results displayed that the expression levels of NF-κB and N-cadherin protein in colon tissue of model group were up-regulated (P<0.01), while E-cadherin was significantly down-regulated (P<0.01). Compared with the model group, the changes of the above indexes in the BXD and mesalazine groups were ameliorated, with statistical differences (P<0.05 or P<0.01), and the changes in the BXD high-dose group were more significant. CONCLUSION BXD exhibits strong anti-inflammatory and anti-tumor benefits in CAC mice, inhibiting macrophage activation in colon tissue and promoting M2 polarization, while reducing the expression of tumor associated proteins PCNA and Bcl-2, and block the progression of EMT related proteins (E-cadherin and N-cadherin). The mechanism may connect to suppressing NF-κB P65 and IκB-α activation to regulate the NF-κB signaling pathway.

OBJECTIVE To investigate the effect of Banxia Xiexin decoction(BXD) on colitis associated cancer(CAC) mice and its related mechanism. METHODS Seventy-five C57BL/6 mice were randomly divided into normal group, model group, Banxia Xiexin decoction low-dose group, high-dose group and mesalazine group. Except for the normal group, the mice in the other groups were intraperitoneally injected with azoxymethane combined with oral dextran sodium sulfate to establish the CAC model. BXD and mesalazine were given respectively for intervention. The general conditions of all mice were observed and recorded, and the changes of body weight, disease activity index, colon length and tumor number were monitored. HE staining was utilized to observe the pathological changes of colon tissue. The expression levels of PCNA, NF-κB P65 and IκB-α were detected by immunohistochemistry. The mRNA levels of IL-17A, N-cadherin, E-cadherin and Bcl-2 were detected by qRT-PCR. Macrophage infiltration was measured using immunostaining analysis. Western blotting was applied to analyze the expression of NF-κB, E-cadherin and N-cadherin proteins in colon tissues of each group. RESULTS There was no significant tumor occurrence in the normal group, while the body weight of the model group mice was significantly reduced and the number of colon tumors increased. The colon length, number of tumors, and degree of inflammatory cell infiltration in the BXD group were significantly improved compared to the model group. Immunohistochemical results showed that the expression of PCNA, NF-κB P65 and IκB-α protein in colon tissue of model group was remarkably increased (P<0.01). Immunofluorescence results showed that the number of F4/80, CD80 and CD206 positive macrophages in the colon tissue of the model group increased (P<0.05 or P<0.01). The results of RT-PCR demonstrated that the levels of IL-17A, N-cadherin and Bcl-2 mRNA in the colon tissue of the model group were significantly increased (P<0.01), while the level of E-cadherin mRNA was fundamentally decreased (P<0.01). Western blotting results displayed that the expression levels of NF-κB and N-cadherin protein in colon tissue of model group were up-regulated (P<0.01), while E-cadherin was significantly down-regulated (P<0.01). Compared with the model group, the changes of the above indexes in the BXD and mesalazine groups were ameliorated, with statistical differences (P<0.05 or P<0.01), and the changes in the BXD high-dose group were more significant. CONCLUSION BXD exhibits strong anti-inflammatory and anti-tumor benefits in CAC mice, inhibiting macrophage activation in colon tissue and promoting M2 polarization, while reducing the expression of tumor associated proteins PCNA and Bcl-2, and block the progression of EMT related proteins (E-cadherin and N-cadherin). The mechanism may connect to suppressing NF-κB P65 and IκB-α activation to regulate the NF-κB signaling pathway.

Objective To observe the alteration of thoracic and lumbar physiological curvature in adolescent idiopathic scoliosis(AIS)and the difference of physiological curvature between different types of scoliosis.Methods A retrospective analysis was conducted on 305 adolescent patients taken full spine X-ray in our hospital from January 2017 to December 2021.The patients were divided into normal group and scoliosis group.The normal group was composed of 179 patients,79 males and 100 females,aged 10 to 18 years old with an average of(12.84±2.10)years old,with cobb agle less than 10 degrees.The scol-iosis group was composed of 126 patients,33 males and 93 females,aged 10 to 18 years old with an average of(13.92±2.20)years old.The gender,age,Risser sign,thoracic kyphosis(TK)and lumbar lordosis(LL)in 2 groups were compared,and the TK and LL were also compared between different genders,different degrees of scoliosis and different segments of scoliosis.Re-sults The female ratio(P=0.001)and age(P＜0.001)in scoliosis group were higher than them in normal group;the ratio of low-grade ossification was higher in normal group than in scoliosis group(P=0.038).TK was significantly smaller in scoliosis group than in normal group(P＜0.001),but there was no significant difference in LL between the 2 groups(P=0.147).There were no significant difference in TK and LL between male and female.The TK was significantly bigger in mild AIS patients than in moderate AIS patients(P＜0.05),but there was no significant difference in LL between mild and moderate patients(P＞0.05).The TK and LL in different segments scoliosis were not found significant difference.Conclusion The physiological curvature of thoracic and lumbar spine is independent of gender.The thoracic physiological curvature becomes smaller in AIS patients,but lumbar curvature remains unchanged.The thoracic physiological curvature in mild AIS patients is greater than that in moderate AIS patients,but the lumbar curvature is almost unchanged between mild and moderate scoliosis and is similar with that in normal adolescent.The alteration of thoracic and lumbar physiological curvature in AIS patients may be related to relative an-terior spinal overgrowth,and the specific detailed mechanism needs to be further studied.