Neurodegenerative diseases constitute a group of chronic disorders characterized by the progressive loss of neurons. Major neurodegenerative conditions include Alzheimer's disease, Parkinson's disease, Huntington's disease, frontotemporal lobar degeneration, and amyotrophic lateral sclerosis. Pathologically, these diseases are marked by the accumulation of aggregates formed by pathological proteins such as amyloid-β, tau, α-synuclein, and TAR DNA-binding protein 43. These proteins assemble into amyloid fibrils that undergo prion-like propagation and dissemination, ultimately inducing neurodegeneration. Understanding the biology of these protein aggregates is fundamental to elucidating the pathophysiology of neurodegenerative disorders. In this review, we summarize the molecular mechanisms underlying the aggregation and transmission of pathological proteins, the processes through which these protein aggregates trigger neurodegeneration, and the interactions between different pathological proteins. We also provide an overview of the current diagnostic approaches and therapeutic strategies targeting pathological protein aggregates.
Humans ; Neurodegenerative Diseases/metabolism* ; alpha-Synuclein/metabolism* ; Amyloid beta-Peptides/metabolism* ; tau Proteins/metabolism* ; Protein Aggregation, Pathological/metabolism* ; DNA-Binding Proteins/metabolism* ; Animals ; Protein Aggregates/physiology*

Vascular damage plays a significant role in the onset and progression of Alzheimer's disease (AD). However, the precise molecular mechanisms underlying the induction of neuronal injury by vascular damage remain unclear. The present study aimed to examine the impact of fibrinogen (Fg) on tau pathology. The results showed that Fg deposits in the brains of tau P301S transgenic mice interact with tau, enhancing the cytotoxicity of pathological tau aggregates and promoting tau phosphorylation and aggregation. Notably, Fg-modified tau fibrils caused enhanced neuronal apoptosis and synaptic damage compared to unmodified fibrils. Furthermore, intrahippocampal injection of Fg-modified tau fibrils worsened the tau pathology, neuroinflammation, synaptic damage, neuronal apoptosis, and cognitive dysfunction in tau P301S mice compared to controls. The present study provides compelling evidence linking Fg and tau, thereby connecting cerebrovascular damage to tau pathology in AD. Consequently, inhibiting Fg-mediated tau pathology could potentially impede the progression of AD.
Animals ; tau Proteins/metabolism* ; Alzheimer Disease/metabolism* ; Fibrinogen/metabolism* ; Mice, Transgenic ; Mice ; Disease Models, Animal ; Memory Disorders/metabolism* ; Male ; Mice, Inbred C57BL ; Brain/metabolism* ; Hippocampus/metabolism* ; Protein Aggregation, Pathological/metabolism* ; Apoptosis ; Phosphorylation

Objective:To evaluate the clinical efficacy of methylation sensitive-high resolution melting curve (MS-HRM) detection of IFN-induced protein 44-like (IFI44L) gene methylation in the diagnosis of systemic lupus erythematosus (SLE), as well as the relationship between IFI44L gene markers and the early onset of SLE.Methods:From February 2020 to September 2022, the MS-HRM was used to detect the methylation level of the IFI44L gene in peripheral blood mononuclear cells of 602 SLE patients and 524 other autoimmune disease patients (excluding SLE) from Beijing Peking Union Medical College Hospital, Guangdong Provincial People′s Hospital, and Shenzhen People′s Hospital, totaling 1 126 patients. Compared with the 2012 SLICC criteria, the suspected cases were followed up for 6 months until the onset and clinical diagnosis of SLE were confirmed. The measurement data of normal distribution were expressed as mean±SD, and the consistency analysis was performed using the Kappa consistency test. The clinical diagnostic efficacy indicators were calculated using the receiver operating characteristic (ROC) curve. Results:RR (95% CI) of early suspected cases was 17.06 (9.43, 30.82). The results of IFI44L gene methylation level were in good agreement with the 2012 SLICC criteria, and the sensitivity, specificity and total coincidence rate were 90.53%, 92.56% and 91.47%, respectively. The Kappa value (95% CI) was 0.829(0.796, 0.862) ( P<0.001). The diagnostic efficiency of IFI44L gene methylation level ( Kappa value 0.817) was superior to anti-nuclear antibody, anti-SM antibody and anti-dsDNA antibody ( Kappa value 0.418, 0.216 and 0.440, respectively). The Kappa values (95% CI) of methylation between MS-HRM and pyrosequencing was 0.861(0.806, 0.916), P<0.001. Conclusion:The hypomethylation of IFI44L gene methylation level detected by MS-HRM is closely related to the occurrence and development of SLE, and its diagnostic performance is better than that of three autoantibodies in SLE diagnosis, which can be used for the early diagnosis of SLE.

Objective:To explore the safety and efficacy of transesophageal echocardiography(TEE)-guided percutaneous patent foramen ovale(PFO)closure in treating migraine.Methods:A total of 78 patients with migraine who underwent TEE-guided percutaneous PFO closure at The Third Hospital of Mianyang between March 2021 and August 2023 were included in the study.The impact of headache on daily life was assessed using the Headache Impact Test(HIT-6)score.Preoperatively conventional examination included TEE,right heart acoustic imaging,and contrast transcranial Doppler(c-TCD)were conducted to assess the situation of foramen ovale and right-to-left shunt(RLS).PFO closure was completed under TEE monitoring in surgery,and TEE examination was immediately implemented after surgery so as to evaluate the effect of closure.The transthoracic TTE,right heart acoustic imaging and c-TCD were adopted to conduct follow-up for the form and position of occluder,and the situation of residual shunt at the 1st,3rd and 6th month after surgery.HIT-6 score was used to assess whether the headache of patients was improved.Results:Transesophageal echocardiography(TEE)-guided PFO closure was successfully performed in 75 patients(success rate was 96%),while 3 cases was failure in closure.There was not major surgical complications in all patients.During follow-up,TTE demonstrated the position and form of occluder were well,and there was not pericardial effusion.The results of right heart acoustic imaging and c-TCD showed the RLS obviously reduced or even disappeared after closure.HIT-6 scores showed the number of patients,whose scores were less than 50 scores,increased at the 1st,3rd and 6th after closure,which were respectively 44 cases,49 cases and 64 cases,and the differences of them were significant(x2=49.912,82.041,96.189,P＜0.05).Conclusion:The single TEE-guided percutaneous PFO closure is safe,which short-term outcomes is favorable for migraine.This technique is worth in clinical application.

Objective To investigate the application of catheterization laboratory risk management in the interventional treatment of children with congenital heart disease(CHD),aiming to construct a comprehensive and practical risk management intervention plan to enhance treatment safety and child patient experience.Methods A total of 120 pediatric patients who underwent interventional treatment in the Pediatric Cardiovascular Department of the Interventional Center of Imaging and Nuclear Medicine,the Second Affiliated Hospital of Wenzhou Medical University from January 2021 to December 2022 were randomly divided into two groups(60 cases in each group).Child patients in control group received routine care,while child patients in observation group were subjected to a risk management strategy of the catheterization laboratory on the basis of control group,which included preoperative assessment,psychological intervention,intraoperative monitoring and prevention,stress management and postoperative care.Mental health status of the children,incidence of risk events and nursing disputes,as well as satisfaction of two groups were compared.Results Under the risk management strategy,the levels of anxiety and depression in observation group significantly decreased,with anxiety score dropping from(56.8±4.6)before treatment to(30.8±2.6)after treatment,and depression score falling from(55.8±2.5)to(31.4±1.6),demonstrating a significant improvement(P＜0.01).After implementing the risk management strategy,the incidence of risk events in observation group was notably lower than that in control group(5.0％vs.15.0％),and medical disputes were also significantly reduced(3.3％vs.11.7％).The overall satisfaction rate in observation group was 95.0％,significantly higher than 78.3％in control group(P=0.0012).Conclusion A comprehensive risk management plan can effectively reduce the incidence of risk events and medical disputes in the interventional treatment of pediatric CHD,significantly improving child patient satisfaction and mental health status.This confirms the vital role of risk management strategies in optimizing the treatment process,reducing adverse events,and enhancing doctor-patient harmony,providing clinical reference of safer interventional treatment services for children with CHD.

Objective:To explore the safety and efficacy of transesophageal echocardiography(TEE)-guided percutaneous patent foramen ovale(PFO)closure in treating migraine.Methods:A total of 78 patients with migraine who underwent TEE-guided percutaneous PFO closure at The Third Hospital of Mianyang between March 2021 and August 2023 were included in the study.The impact of headache on daily life was assessed using the Headache Impact Test(HIT-6)score.Preoperatively conventional examination included TEE,right heart acoustic imaging,and contrast transcranial Doppler(c-TCD)were conducted to assess the situation of foramen ovale and right-to-left shunt(RLS).PFO closure was completed under TEE monitoring in surgery,and TEE examination was immediately implemented after surgery so as to evaluate the effect of closure.The transthoracic TTE,right heart acoustic imaging and c-TCD were adopted to conduct follow-up for the form and position of occluder,and the situation of residual shunt at the 1st,3rd and 6th month after surgery.HIT-6 score was used to assess whether the headache of patients was improved.Results:Transesophageal echocardiography(TEE)-guided PFO closure was successfully performed in 75 patients(success rate was 96%),while 3 cases was failure in closure.There was not major surgical complications in all patients.During follow-up,TTE demonstrated the position and form of occluder were well,and there was not pericardial effusion.The results of right heart acoustic imaging and c-TCD showed the RLS obviously reduced or even disappeared after closure.HIT-6 scores showed the number of patients,whose scores were less than 50 scores,increased at the 1st,3rd and 6th after closure,which were respectively 44 cases,49 cases and 64 cases,and the differences of them were significant(x2=49.912,82.041,96.189,P＜0.05).Conclusion:The single TEE-guided percutaneous PFO closure is safe,which short-term outcomes is favorable for migraine.This technique is worth in clinical application.

Objective To investigate the application of catheterization laboratory risk management in the interventional treatment of children with congenital heart disease(CHD),aiming to construct a comprehensive and practical risk management intervention plan to enhance treatment safety and child patient experience.Methods A total of 120 pediatric patients who underwent interventional treatment in the Pediatric Cardiovascular Department of the Interventional Center of Imaging and Nuclear Medicine,the Second Affiliated Hospital of Wenzhou Medical University from January 2021 to December 2022 were randomly divided into two groups(60 cases in each group).Child patients in control group received routine care,while child patients in observation group were subjected to a risk management strategy of the catheterization laboratory on the basis of control group,which included preoperative assessment,psychological intervention,intraoperative monitoring and prevention,stress management and postoperative care.Mental health status of the children,incidence of risk events and nursing disputes,as well as satisfaction of two groups were compared.Results Under the risk management strategy,the levels of anxiety and depression in observation group significantly decreased,with anxiety score dropping from(56.8±4.6)before treatment to(30.8±2.6)after treatment,and depression score falling from(55.8±2.5)to(31.4±1.6),demonstrating a significant improvement(P＜0.01).After implementing the risk management strategy,the incidence of risk events in observation group was notably lower than that in control group(5.0％vs.15.0％),and medical disputes were also significantly reduced(3.3％vs.11.7％).The overall satisfaction rate in observation group was 95.0％,significantly higher than 78.3％in control group(P=0.0012).Conclusion A comprehensive risk management plan can effectively reduce the incidence of risk events and medical disputes in the interventional treatment of pediatric CHD,significantly improving child patient satisfaction and mental health status.This confirms the vital role of risk management strategies in optimizing the treatment process,reducing adverse events,and enhancing doctor-patient harmony,providing clinical reference of safer interventional treatment services for children with CHD.

Objective:To evaluate the clinical efficacy of methylation sensitive-high resolution melting curve (MS-HRM) detection of IFN-induced protein 44-like (IFI44L) gene methylation in the diagnosis of systemic lupus erythematosus (SLE), as well as the relationship between IFI44L gene markers and the early onset of SLE.Methods:From February 2020 to September 2022, the MS-HRM was used to detect the methylation level of the IFI44L gene in peripheral blood mononuclear cells of 602 SLE patients and 524 other autoimmune disease patients (excluding SLE) from Beijing Peking Union Medical College Hospital, Guangdong Provincial People′s Hospital, and Shenzhen People′s Hospital, totaling 1 126 patients. Compared with the 2012 SLICC criteria, the suspected cases were followed up for 6 months until the onset and clinical diagnosis of SLE were confirmed. The measurement data of normal distribution were expressed as mean±SD, and the consistency analysis was performed using the Kappa consistency test. The clinical diagnostic efficacy indicators were calculated using the receiver operating characteristic (ROC) curve. Results:RR (95% CI) of early suspected cases was 17.06 (9.43, 30.82). The results of IFI44L gene methylation level were in good agreement with the 2012 SLICC criteria, and the sensitivity, specificity and total coincidence rate were 90.53%, 92.56% and 91.47%, respectively. The Kappa value (95% CI) was 0.829(0.796, 0.862) ( P<0.001). The diagnostic efficiency of IFI44L gene methylation level ( Kappa value 0.817) was superior to anti-nuclear antibody, anti-SM antibody and anti-dsDNA antibody ( Kappa value 0.418, 0.216 and 0.440, respectively). The Kappa values (95% CI) of methylation between MS-HRM and pyrosequencing was 0.861(0.806, 0.916), P<0.001. Conclusion:The hypomethylation of IFI44L gene methylation level detected by MS-HRM is closely related to the occurrence and development of SLE, and its diagnostic performance is better than that of three autoantibodies in SLE diagnosis, which can be used for the early diagnosis of SLE.

Objective: To understand sleep quarity among primary and middle school students in Shenzhen City, so as to provide data support for sleeping quality improvement. Methods: A survey was conducted among 8 742 children selected from two 12 year schools in Longhua District of Shenzhen City, by purposive sampling method from December 22, 2020 to January 15, 2021. The general information was investigated with the self designed questionnaire, and sleep disturbance was investigated and evaluated with the Sleep Disturbance Scale for Children (SDSC). And Chi square test was applied for data analysis. Results: About 47.61 % of primary and middle school students in Shenzhen City reported sleep disturbance, 10.84% of students had moderate to severe sleep disturbance. The overall rate of sleep disturbance and moderate and to severe sleep disturbance among primary school students (48.03%, 10.04%), junior middle schools (45.89%, 11.30%), senior middle schools (52.61%, 16.83%) were found of statistically significant differences ( χ 2=8.89, 27.05, P <0.05). The time to fall asleep for primary school students, junior school students and senior school students at night during the study period were 22:00-23:00 (90.35%), 22:00-23:00 (62.37%), and 23:00-01:00 (61.44%), respectively, and the time to fall asleep of the different stages students were found of statistically significant differences ( χ 2=1 470.17, P <0.01). About 41.04% of students could fall asleep within 15 minutes and 50.57% could fall asleep within 15 to 30 minutes, and the differences in the latency for different stages students to fall asleep at night were of statistical significance ( χ 2=82.92, P <0.01); 8.03% of primary and middle school students had a night sleep time of over 9 hours, and 45.97 % had a night sleep time of 8-9 hours, and the differences in the night sleep time among different stages students were of statistical significance ( χ 2=1 292.86, P <0.01). Conclusions The main sleep problems among primary and secondary school students in Shenzhen City are insufficient sleep and poor sleep quality. The relevant departments should emphasize the sleep health education among children and their parents, so as to improve their sleep quality.

Objective:To elucidate the quasispecies variation of 3′ half-length genome in HIV-1 CRF103_01B-infected patients in Beijing using single genome amplification (SGA).Methods:This study enrolled six CRF103_01B-infected patients who were diagnosed during a drug resistance monitoring for newly diagnosed cases or newly treated cases with antiviral therapy in Beijing from 2017 to 2020. RNA was extracted from their plasma samples, and 3′ end of cDNA was diluted by serial dilution method after reverse transcription. Nested PCR was used to amplify the 3′ half-length genome sequences of HIV-1 quasispecies. MEGA 11 was used to construct Neighbor-Joining (NJ) tree and calculate the intrahost genetic distance. Genetic variation in HIV-1 quasispecies was visualized by online Highlighter tool. BootScan analysis was performed using Simplot 3.5 software to analyze inter-quasispecies recombination. Virus tropism was predicted by online Geno2pheno tool.Results:Among the six CRF103_01B-infected patients, five were men who have sex with men. A total of 144 3′ half-length genome SGA sequences (19-36 sequences/case) were obtained. The NJ tree based on the 3′ half-length genome of HIV-1 quasispecies revealed different degrees of genetic diversity. The HIV-1 quasispecies in BL4748-00 case of acute infection has the least variation with the intrahost distance of 0.002±0.000, showing genetic homogeneity. The quasispecies sequences from BL4981-00, BL3150-00 and BL3558-00 cases formed at least three subclusters, respectively, with different evolutionary directions, and their intrahost distance ranked from 0.031±0.004 to 0.016±0.002 (BL3150-00>BL3558-00>BL4981-00). The quasispecies sequences from the couple BL3022-00 (female) and BL3023-00 clustered into a large monophyletic cluster (bootstrap value=100%), and the intrahost distance of the latter (0.025±0.003) was higher than that of the former (0.019±0.002). Inter-quasispecies recombination was observed in BL3558-00 case. The quasispecies from the six patients were CCR5-tropic viruses.Conclusions:The diversity of quasispecies variation in CRF103_01B-infected patients is related to disease progress. Genetic homogeneity is observed in acute HIV infection, while multiple evolutionary directions are detected in chronic infection. Co-infection or superinfection cases are not found, but there are recombination events among quasispecies in some cases.