Objective:To investigate the clinical characteristics of infantile cholestasis caused by IFT122 gene variants and the molecular mechanism underlying its impact on primary cilia.Methods:The clinical data of an infant with cholestasis from the Children′s Hospital of Fudan University in September 2022 were retrospectively analyzed. The whole-exome sequencing was performed to identify candidate variants, which were validated by Sanger sequencing in the family. Immortalized cell lines were generated using lentiviral infection, followed by immunofluorescence staining to assess the impact of the variants on primary cilia. Intergroup comparisons were performed using the independent sample t-test and Mann-Whitney U test .Results:The proband was a 4-month-old male infant presenting with jaundice, distinctive facial features, and sagittal craniosynostosis. Blood biochemistry indicated elevated direct bilirubin, total bile acids, and transaminases, with markedly increased γ-glutamyltransferase (GGT). Liver pathology demonstrated giant cell hepatitis with cholestasis and bile duct dysplasia. Genetic analysis identified compound heterozygous variants in IFT122 (NM_052989.3) gene c.88G>C (p.Ala30Pro) and c.240G>C (p.Trp80Cys), which co-segregated with the disease in the family. Immunofluorescence analysis demonstrated that the IFT122 gene compound heterozygous missense variants not only significantly reduced the proportion of cilia-positive cells but also led to aberrant ciliary localization of ADP-ribosylation factor-like protein 13B (ARL13B).In addition, ciliary deposition with phosphatidylinositol polyphosphate 5-phosphatase type Ⅳ (INPP5E) was reduced. All differences were statistically significant (all P<0.05). Conclusion:The compound heterozygous missense variants in IFT122 gene not only impair ciliogenesis but also disrupt the ciliary localization of ARL13B and INPP5E, ultimately resulting in high-GGT infantile cholestasis.

Objective:To investigate the clinical characteristics of infantile cholestasis caused by IFT122 gene variants and the molecular mechanism underlying its impact on primary cilia.Methods:The clinical data of an infant with cholestasis from the Children′s Hospital of Fudan University in September 2022 were retrospectively analyzed. The whole-exome sequencing was performed to identify candidate variants, which were validated by Sanger sequencing in the family. Immortalized cell lines were generated using lentiviral infection, followed by immunofluorescence staining to assess the impact of the variants on primary cilia. Intergroup comparisons were performed using the independent sample t-test and Mann-Whitney U test .Results:The proband was a 4-month-old male infant presenting with jaundice, distinctive facial features, and sagittal craniosynostosis. Blood biochemistry indicated elevated direct bilirubin, total bile acids, and transaminases, with markedly increased γ-glutamyltransferase (GGT). Liver pathology demonstrated giant cell hepatitis with cholestasis and bile duct dysplasia. Genetic analysis identified compound heterozygous variants in IFT122 (NM_052989.3) gene c.88G>C (p.Ala30Pro) and c.240G>C (p.Trp80Cys), which co-segregated with the disease in the family. Immunofluorescence analysis demonstrated that the IFT122 gene compound heterozygous missense variants not only significantly reduced the proportion of cilia-positive cells but also led to aberrant ciliary localization of ADP-ribosylation factor-like protein 13B (ARL13B).In addition, ciliary deposition with phosphatidylinositol polyphosphate 5-phosphatase type Ⅳ (INPP5E) was reduced. All differences were statistically significant (all P<0.05). Conclusion:The compound heterozygous missense variants in IFT122 gene not only impair ciliogenesis but also disrupt the ciliary localization of ARL13B and INPP5E, ultimately resulting in high-GGT infantile cholestasis.

BACKGROUND:Studies have shown that there is a close relationship between dendritic spine plasticity and Alzheimer's disease,and that resistance or aerobic exercise has some efficacy in improving cognitive dysfunction,but the mechanism of action is unclear.OBJECTIVE:To investigate the effect of aerobic exercise or resistance exercise on dendritic spine plasticity in the hippocampal CA1 region of APP/PS1 transgenic mice.METHODS:Thirty 3-month-old male APP/PS1 mice were selected and randomly divided into three groups:a model group,a resistance exercise group,and an aerobic exercise group.The same litter of 3-month-old C57BL/6J mice were selected as a blank group.Mice in the resistance exercise group were subjected to ladder-climbing exercise and those in the aerobic exercise group were subjected to treadmill exercise for 12 weeks.At the end of the exercise intervention,the water maze experiment and the new arm of the Y maze were used to assess behavioral changes in mice.Hematoxylin-eosin staining,Nissl staining,Golgi staining,and electron microscopy were performed to observe neuronal morphology,Nissl bodies,dendritic spines,and ultrastructural changes in the synapses of the hippocampal region of the mouse brain.The protein expression levels of hippocampal amyloid-beta1-42,Ras,and Drebrin were measured using Western blot analysis.RESULTS AND CONCLUSION:Mice in the model group exhibited a prolonged escape latency over 5 consecutive days(P＜0.05,P＜0.01)and significantly fewer entries into the new arm of the Y maze(P＜0.01).Dendritic spine density in the CA1 region of the hippocampus,as well as Ras and Drebrin expression in the hippocampal tissues of mice in the model group,were lower than those in the normal group(P＜0.01),and amyloid-beta1-42 expression in the hippocampal tissues was higher in the model group compared with the normal group(P＜0.01).Mice in the resistance exercise group and the aerobic exercise group displayed a shortened escape latency over the same 5-day period(P＜0.05,P＜0.01)and showed a significantly greater number of entries into the new arm of the Y maze compared with the normal group(P＜0.01).Dendritic spine density in the CA1 region of the hippocampus,as well as Ras and Drebrin expression in the hippocampal tissues,were higher in both the resistance exercise group and the aerobic exercise group compared with the model group(P＜0.01).Amyloid-beta1-42 expression in the hippocampal tissue was lower in both exercise groups than in the model group(P＜0.01).To conclude,long-term regular aerobic or resistance exercise interventions can increase dendritic spine density and synaptic plasticity in the CA1 region of the hippocampus,enhancing spatial learning and memory abilities in a mouse model of Alzheimer's disease.These effects may be associated with increased expression of Ras and Drebrin proteins in the hippocampus.

Objective:To analyze the clinical characteristics of mannose phosphate isomerase-congenital disorders of glycosylation (MPI-CDG) and evaluated the outcomes following D-mannose treatment.Methods:This case-series study analyzed clinical manifestations, laboratory findings, imaging results, genetic data, and outcomes after D-mannose therapy in 5 children with MPI-CDG diagnosed at the Children′s Hospital of Fudan University between December 2014 and December 2024.Results:The age of onset ranged from 0.3 to 0.4 years in all 5 children, who initially presented with diarrhea and hypoglycemia. Associated manifestations included short stature (3 cases), anemia (3 cases), splenomegaly (3 cases), hepatomegaly (4 cases), elevated transaminases (4 cases), and hypoalbuminemia (4 cases). Liver pathology revealed hepatic fibrosis in 3 cases. Genetic testing identified 8 variants in the MPI gene, including 2 novel variants. Following D-mannose treatment, diarrhea and hypoglycemia resolved within 1-2 weeks in all children, with concurrent improvement in anemia. Notably except for Patient 1, who developed progressive splenomegaly, worsening hepatic fibrosis, and portal hypertension despite persistently normal transaminase and albumin levels, the other 4 children showed improvement in transaminase levels, resolution of hypoalbuminemia and amelioration of imaging abnormalities.Conclusions:MPI-CDG typically manifests in infancy with diarrhea and hypoglycemia, often accompanied by multi-system involvement. D-mannose treatment significantly improves metabolic abnormalities and most organ damages. However, close surveillance of liver status is warranted due to the risk of hepatic fibrosis progression in some cases.

Parkinson's disease (PD), a chronic and common neurodegenerative disease, is characterized by the progressive loss of dopaminergic neurons in the dense part of the substantia nigra and abnormal aggregation of alpha-synuclein. Type 2 diabetes mellitus (T2DM) is a metabolic disease characterized by chronic insulin resistance and deficiency in insulin secretion. Extensive evidence has confirmed shared pathogenic mechanisms underlying PD and T2DM, such as oxidative stress caused by insulin resistance, mitochondrial dysfunction, inflammation, and disorders of energy metabolism. Conventional drugs for treating T2DM, such as metformin and glucagon-like peptide-1 receptor agonists, affect nerve repair. Even drugs for treating PD, such as levodopa, can affect insulin secretion. This review summarizes the relationship between PD and T2DM and related therapeutic drugs from the perspective of insulin signaling pathways in the brain.
Humans ; Parkinson Disease/drug therapy* ; Diabetes Mellitus, Type 2/pathology* ; Signal Transduction/physiology* ; Receptor, Insulin/metabolism* ; Animals ; Insulin Resistance/physiology* ; Insulin/metabolism*

ObjectiveTo explore the effect of Yishen Tongluo prescription on sperm DNA fragmentation index （DFI） and sperm mitochondrial membrane potential （MMP） in patients with asymptomatic idiopathic asthenospermia infertility. MethodsA total of 128 patients with asymptomatic idiopathic asthenospermia were randomly assigned to an experimental group （64 cases） and a control group （64 cases）. The experimental group received Yishen Tongluo prescription， while the control group was treated with Wuzi Yanzongwan combined with L-carnitine oral solution. One treatment course lasted 12 weeks. Spouse pregnancy rate， sperm progressive motility （PR）， total sperm motility （PR+NP）， sperm function （sperm tail hypotonic swelling rate， sperm acrosin activity）， sperm DFI， and sperm MMP were compared between the two groups before and after treatment. Adverse reactions were observed and recorded during the study， and clinical efficacy and safety were systematically evaluated. ResultsA total of 121 patients completed the study， including 61 in the experimental group and 60 in the control group. The spouse pregnancy rate in the experimental group was 14.75% （9/61）， higher than that in the control group at 6.67% （4/60）， though the difference was not statistically significant. Clinical efficacy in the experimental group was superior to that in the control group （P<0.05）. Compared with the results before treatment， sperm PR， PR + NP， sperm tail hypotonic swelling rate， sperm acrosin activity， sperm DFI， and sperm MMP were significantly improved in both groups after treatment （P<0.05）， with greater improvements in the experimental group （P<0.05）. However， there was no significant change in sperm concentration in either group after treatment. During the study， no abnormal safety indicators or significant adverse reactions occurred in either group. ConclusionThe kidney-tonifying and collateral-dredging method shows good clinical efficacy in the treatment of asymptomatic idiopathic asthenospermia infertility. Yishen Tongluo prescription can improve sperm motility， increase spouse pregnancy rate， enhance sperm function， and demonstrates good safety. Its mechanism may be related to reducing sperm DFI and increasing sperm MMP.

Objective:To analyze the clinical characteristics of mannose phosphate isomerase-congenital disorders of glycosylation (MPI-CDG) and evaluated the outcomes following D-mannose treatment.Methods:This case-series study analyzed clinical manifestations, laboratory findings, imaging results, genetic data, and outcomes after D-mannose therapy in 5 children with MPI-CDG diagnosed at the Children′s Hospital of Fudan University between December 2014 and December 2024.Results:The age of onset ranged from 0.3 to 0.4 years in all 5 children, who initially presented with diarrhea and hypoglycemia. Associated manifestations included short stature (3 cases), anemia (3 cases), splenomegaly (3 cases), hepatomegaly (4 cases), elevated transaminases (4 cases), and hypoalbuminemia (4 cases). Liver pathology revealed hepatic fibrosis in 3 cases. Genetic testing identified 8 variants in the MPI gene, including 2 novel variants. Following D-mannose treatment, diarrhea and hypoglycemia resolved within 1-2 weeks in all children, with concurrent improvement in anemia. Notably except for Patient 1, who developed progressive splenomegaly, worsening hepatic fibrosis, and portal hypertension despite persistently normal transaminase and albumin levels, the other 4 children showed improvement in transaminase levels, resolution of hypoalbuminemia and amelioration of imaging abnormalities.Conclusions:MPI-CDG typically manifests in infancy with diarrhea and hypoglycemia, often accompanied by multi-system involvement. D-mannose treatment significantly improves metabolic abnormalities and most organ damages. However, close surveillance of liver status is warranted due to the risk of hepatic fibrosis progression in some cases.

The accuracy of orthodontic bracket bonding directly affects the treatment effect,and intelligent orthodontics is gradually advancing clinical practice toward precision.Mixed reality(MR),a new digital holographic imaging simulation technology,enables interactive scenarios between 3D data and the real world,allowing precise identification and localization of dental roots and jaw ana-tomical structures.This study constructs an oral visualization model via multimodal image fusion,establishes a virtual-real registra-tion algorithm combining target detection and point cloud registration for high-dynamic scenarios,and develops an MR-based intelli-gent auxiliary and teaching system for orthodontic bracket bonding.The system achieves clinical training and intraoperative naviga-tion for bracket positioning and bonding,accurately identifies dental root and jaw information,and is of significant importance for improving the precision,intelligence,and digitization of orthodontic clinical practice.

The accuracy of orthodontic bracket bonding directly affects the treatment effect,and intelligent orthodontics is gradually advancing clinical practice toward precision.Mixed reality(MR),a new digital holographic imaging simulation technology,enables interactive scenarios between 3D data and the real world,allowing precise identification and localization of dental roots and jaw ana-tomical structures.This study constructs an oral visualization model via multimodal image fusion,establishes a virtual-real registra-tion algorithm combining target detection and point cloud registration for high-dynamic scenarios,and develops an MR-based intelli-gent auxiliary and teaching system for orthodontic bracket bonding.The system achieves clinical training and intraoperative naviga-tion for bracket positioning and bonding,accurately identifies dental root and jaw information,and is of significant importance for improving the precision,intelligence,and digitization of orthodontic clinical practice.

BACKGROUND:Studies have shown that there is a close relationship between dendritic spine plasticity and Alzheimer's disease,and that resistance or aerobic exercise has some efficacy in improving cognitive dysfunction,but the mechanism of action is unclear.OBJECTIVE:To investigate the effect of aerobic exercise or resistance exercise on dendritic spine plasticity in the hippocampal CA1 region of APP/PS1 transgenic mice.METHODS:Thirty 3-month-old male APP/PS1 mice were selected and randomly divided into three groups:a model group,a resistance exercise group,and an aerobic exercise group.The same litter of 3-month-old C57BL/6J mice were selected as a blank group.Mice in the resistance exercise group were subjected to ladder-climbing exercise and those in the aerobic exercise group were subjected to treadmill exercise for 12 weeks.At the end of the exercise intervention,the water maze experiment and the new arm of the Y maze were used to assess behavioral changes in mice.Hematoxylin-eosin staining,Nissl staining,Golgi staining,and electron microscopy were performed to observe neuronal morphology,Nissl bodies,dendritic spines,and ultrastructural changes in the synapses of the hippocampal region of the mouse brain.The protein expression levels of hippocampal amyloid-beta1-42,Ras,and Drebrin were measured using Western blot analysis.RESULTS AND CONCLUSION:Mice in the model group exhibited a prolonged escape latency over 5 consecutive days(P＜0.05,P＜0.01)and significantly fewer entries into the new arm of the Y maze(P＜0.01).Dendritic spine density in the CA1 region of the hippocampus,as well as Ras and Drebrin expression in the hippocampal tissues of mice in the model group,were lower than those in the normal group(P＜0.01),and amyloid-beta1-42 expression in the hippocampal tissues was higher in the model group compared with the normal group(P＜0.01).Mice in the resistance exercise group and the aerobic exercise group displayed a shortened escape latency over the same 5-day period(P＜0.05,P＜0.01)and showed a significantly greater number of entries into the new arm of the Y maze compared with the normal group(P＜0.01).Dendritic spine density in the CA1 region of the hippocampus,as well as Ras and Drebrin expression in the hippocampal tissues,were higher in both the resistance exercise group and the aerobic exercise group compared with the model group(P＜0.01).Amyloid-beta1-42 expression in the hippocampal tissue was lower in both exercise groups than in the model group(P＜0.01).To conclude,long-term regular aerobic or resistance exercise interventions can increase dendritic spine density and synaptic plasticity in the CA1 region of the hippocampus,enhancing spatial learning and memory abilities in a mouse model of Alzheimer's disease.These effects may be associated with increased expression of Ras and Drebrin proteins in the hippocampus.