Alzheimer's disease(AD)is the most common neurodegenerative disease in the elderly,and its main pathological manifestations include senile plaques formed by β-amyloid deposition and neuronal fibrillar nodules formed by hyperphosphorylation of tau proteins.Lysosome is an important organelle in eukaryotic cells,containing a variety of hydrolytic enzymes that can break down proteins and other biomolecules.It is closely related to intracellular transport and autophagy,and is important for maintaining cellular homeostasis.This review summarizes the interaction between lysosomal dysfunction and the development and progression of AD and the potential therapeutic mechanisms in treating AD by regulating and restoring the functions of lysosomes.Lysosomal dysfunction can lead to neurodegenerative diseases such as AD.Modulation of lysosomal function is a promising treatment strategy for AD.It is expected that more drugs and therapeutic regimens based on this mechanism can be used in the clinical treatment for AD patients in the future.

Objective To discuss the short-term efficacy of endovascular recanalization for symptomatic non-acute internal carotid artery occlusion.Methods A total of 90 patients with symptomatic non-acute internal carotid artery occlusion,who were admitted to the Department of Neurology of Tianjin Municipal Teda Hospital of China from August 2017 to December 2021,were selected as the research objects.The patients were divided into study group(n=45)and control group(n=45).Percutaneous endovascular recanalization of internal carotid artery occlusion was performed for the patients of the study group,and standardized antiplatelet aggregation and anti-lipid therapy(including oral aspirin,clopidogrel bisulphate and atorvastatin)was adopted for the patients of the control group.The symptom recurrence rate at one year after treatment in both groups was analyzed.Results Of the 45 patients in the control group,4 were lost in touch,and 41 completed the one-year follow-up.Of the 45 patients in the study group,2 patients had failure of surgery,one patient had lost contact visit,and 42 completed the one-year follow-up.Postoperative intracranial hemorrhage occurred in 2 patients.After one year of follow-up,in the control group 26 patients(63.41％)developed recurrence of symptoms,presenting as transient ischemic attack(TIA,n=13,31.7％)and cerebral infarction(n=13,31.7％),and in the study group 8 patients(4.76％)developed recurrence of symptoms,presenting as TIA(n=6,14.3％)and cerebral infarction(n=2,4.8％);the incidence of cerebral infarction in the study group was strikingly lower than that in the control group,and the difference between the two groups was statistically significant(P＜0.05).In the patients with grade Ⅲ compensation,the recurrence rate of symptoms was remarkably decreased after endovascular recanalization of internal carotid artery occlusion,and the difference between the two groups was statistically significant(P＜0.05).However,in the patients with grade Ⅰ or grade Ⅱ compensation,although the recurrence rate of symptoms was decreased after endovascular recanalization of internal carotid artery occlusion,the difference between the two groups was not statistically significant(P＞0.05).Conclusion For the treatment of patients with symptomatic non-acute internal carotid artery occlusion,percutaneous endovascular recanalization of internal carotid artery occlusion is clinically safe,it can significantly decrease the recurrence rate of symptoms.

Objective: To explore the mechanism of action of hepatic leukemia factor (HLF) in diabetes mellitus and to construct a conditional animal model of mice with islet β ⁃cell⁃specific HLF gene knockout. Methods: At the cellular level , the effects of HLF inhibition or overexpression on the proliferation of MIN6 cells was verified by the CCK⁃8 assay. The effects of HLF inhibition or overexpression were detected at the mRNA level and protein level by Cre + / - mice (C57BL/6J) to obtain offspring mice. The genotypes of the mice were identified by the PCR method.The differences in the expression levels of the HLF gene at the mRNA and protein levels in islet β ⁃cell knockout mice (HLFflox/flox Cre + / - ) and control mice (HLFflox/flox ) were detected by RT⁃qPCR technology and Western blot technology to verify the knockout effect. At the same time , the islet tissues of the mice in two groups were taken to make paraffin sections and analyzed by hematoxylin⁃eosin (HE) staining. Results: HLF gene inhibition or overex⁃pression had no significant effect on the proliferation of MIN6 cells. When the HLF gene was inhibited in MIN6 cells , the mRNA expression level decreased by 74% compared with the control group , and the protein expression level decreased by 60% compared with the control group. After overexpressing the HLF gene , the mRNA expres⁃sion level was 2. 13 times compared with that of the control group , and the protein expression level was 1. 8 times compared with that of the control group. The mRNA expression level of the HLF gene in the knockout mice de⁃creased by 89% compared with the control group , and the protein expression level decreased by 65% compared with the control group. The results of HE staining showed that there was no significant difference in the cell mor⁃phology in the islet tissues between the knockout mice and the control mice. Inhibiting HLF increased the glycogen content in MIN6 cells by approximately 20% . Conclusion The HLF gene knockout mice are successfully con⁃structed , providing an animal model for studying the role of HLF in the pathogenesis of diabetes mellitus.

Background It is a research hotspot to study the changes of metabolites and metabolic pathways in the process of coal worker's pneumoconiosis (CWP) by metabonomics and to explore its pathogenesis. Objective To study the change of metabolites in bronchoalveolar lavage fluid (BALF) of patients with CWP and explore the metabolic regulation mechanism of the disease. Methods Patients with CWP who met the national diagnostic criteria according to Diagnosis of occupational pneumoconiosis (GBZ 70-2015) and underwent massive whole lung lavage were selected as the case group, and patients with tracheostenosis who underwent bronchoscopy were selected as the control group. BALF samples were collected from the cases and the controls. After filtering out large particles and mucus, the supernatant was stored in a −80 ℃ refrigerator. The samples were detected and analyzed by liquid chromatography-mass spectrometry after adding extraction solution, cold bath ultrasonication, and high-speed centrifugation, and the metabolic profiles and related data of CWP patients were obtained. The differential metabolites related to the occurrence and development of CWP were screened by multiple statistical analysis; furthermore, we searched the Kyoto Encyclopedia of Genes and Genomes (KEGG) database for potential metabolic pathways involved in the progression. Results There was no significant difference in the general conditions of the subjects, such as weight, height, age, and length of service among the stage I group, the stage II group, the stage III group, and the control group (P˃0.05). When comparing the CWP stage I group with the control group, 48 differential metabolites were screened out, among which 14 were up-regulated and 34 were down-regulated. A total of 66 differential metabolites were screened out between the patients with CWP stage II and the controls, 14 up-regulated and 52 down-regulated differential metabolites. Compared with the control group, 63 differential metabolites were screened out in the patients with CWP stage III, including 11 up-regulated and 52 down-regulated differential metabolites. There were 36 differential metabolites that may be related to the occurrence of CWP, among which 11 differential metabolites were up-regulated, and 25 were down-regulated. Four significant differential metabolic pathways were identified through KEGG database query: linoleic acid metabolic pathway, alanine metabolic pathway, sphingolipid metabolic pathway, and glycerophospholipid metabolic pathway. Conclusion The metabolomic study of BALF show that there are 36 different metabolites in the occurrence and development of CWP, mainly associating with linoleic acid metabolism, alanine metabolism, sphingolipid metabolism, and glycerophospholipid metabolism pathways.

Background Pneumoconiosis is a widespread occupational disease in China at present. As a type of lung diseases, its pathological damage is mainly irreversible fibrotic changes in the lungs. Several studies have shown that the occurrence and development of lung diseases such as coal workers' pneumoconiosis are closely related to intestinal flora. Objective To observe intestinal flora of coal workers' pneumoconiosis patients based on the results of 16SrDNA high-throughput sequencing and evaluate the changes of intestinal flora after treatment with tetrandrine tablets. Methods A total of 80 patients with coal workers' pneumoconiosis attending the outpatient clinic of the Department of Occupational Diseases of the Emergency General Hospital from April to July 2022 were enrolled. All patients were treated with tetrandrine tablets for 4 weeks, with group A before the treatment of tetrandrine tablets and group B after the treatment. In the same period, 24 healthy controls (group C) were set up. Stool samples were collected before and after the treatment. Using 16SrDNA high-throughput sequencing, gene V3-V4 sequencing technology, and bioinformatic analysis platform, we evaluated the intestinal flora after treatment by groups. Results The dominant flora at the phylum level and genus level were the same across three groups. The relative abundances of phylum Bacteroidetes, Bifidobacterium, Bacteroides, and Facealibacterium in groups B and C were higher than those in group A, and the relative abundances of phy-lum Actinobacteria, genus Blautia, and genus Romboutsia in groups B and C were lower than those in group A (P＜0.05). The relative abundances of genus Clostridium, genus Megamonas, and genus Lactobacillus in group C was lower than that in groups A and B (P＜0.05). The alpha diversity analysis showed that the Chao1 index was higher in group A than in group C (P＜0.01). Compared with group A, the Shannon index was higher in group B, and the increases of Simpson index were all statistically significant in stage I patients (P＜0.05), but the differences in Chao1 index were not statistically significant (P＞0.05). The differences in the values of Chao1 index, Shannon index, and Simpson index in stage Ⅱ and stage III patients were not statistically significant (P＞0.05). The beta diversity analysis showed that the difference in flora structure between group A and group C was statistically significant (P＜0.05); the differences in flora structure before and after treatment in the same stage patients were statistically significant (P＜0.05). The partial least squares discriminant analysis (PLS-DA) showed that there were significant differences between group A and group C, and between group A and group B. The LEfSe analysis showed that the significant markers contributing to the differences were basically the same in stage I, stage Ⅱ, and stage Ⅲ after treatment, which were mainly phylum Bacteroidetes and its subordinate groups, class Negativicutes, or-der Selenomonas, and genus Facealibacterium. Conclusion There are differences in the distribution of flora between coal workers' pneumoconiosis patients and healthy individuals, and the structure and relative abundance of intestinal flora are changed and the number of beneficial flora is increased after treatment with tetrandrine tablets.

Objective:To investigate the effect of tripartite motif-containing protein 59 (TRIM59) on glucose metabolism in macrophages and its role in regulating hypoxia-inducible factor-1α (HIF-1α)/IL-10 axis in macrophages under inflammatory conditions.Methods:The differentially expressed genes between macrophages with high expression of TRIM59 and control cells transfected with empty TRIM59 plasmid were analyzed by GO and KEGG. The expression of HIF-1α by RAW264.7 macrophages with high expression of TRIM59 was detected at different time points after lipopolysaccharide (LPS) stimulation by RT-qPCR and Western blot. Bone marrow was isolated from TRIM59-cKO and TRIM59 flox/flox mice and induced to differentiate into bone marrow-derived macrophages (BMDMs). These BMDMs were stimulated with LPS and the supernatants of cell culture were collected at 3, 6, 12 and 24 h after stimulation to detect IL-10 level by ELISA. In addition, mouse models of cecal ligation and puncture (CLP) were established, and bronchoalveolar lavage fluid (BALF) samples were collected at the same time points to detect IL-10 level by ELISA. Histopathological changes in lung tissues were observed after HE staining. Results:There was a significant change in glucose metabolism-related genes in macrophages with high expression of TRIM59, and the content of lactic acid increased significantly. Compared with the control group, the expression of HIF-1α at mRNA level in BMDMs from TRIM59-cKO mice decreased after LPS stimulation ( P<0.05); the level of IL-10 increased at 3 h and 24 h in the TRIM59-cKO group, but there was no significant difference in IL-10 level at 6 h or 12 h between the two groups. In the TRIM59-cKO mouse model of CLP, the levels of IL-10 in the BALF samples increased with time, but decreased at 24 h. The level of IL-10 was higher in the TRIM59-cKO mouse model group than that in the control group at each time point ( P<0.05 or P<0.01). Conclusions:TRIM59 can inhibit inflammation and lung injury by decreasing HIF-1α-mediated lactate secretion and IL-10 expression in macrophages. This study provides a new idea for developing novel anti-sepsis drugs based on TRIM59.

Background Multi-slice spiral computerized tomography (MSCT) can be used as an auxiliary diagnosis of chest radiography in diagnosis of pneumoconiosis, but there are few studies on the correlations between interstitial images and stage classification of coal workers' pneumoconiosis in the existing literature. Objective To present MSCT imaging manifestations and distribution characteristics of coal workers' pneumoconiosis and complications, evaluate correlations between coal workers' pneumoconiosis stages and pulmonary interstitial lesions, and provide a reliable imaging diagnosis basis for pneumoconiosis interstitial lesions. Methods From June 2022 to June 2023, a total of 1002 patients with coal workers' pneumoconiosis confirmed by the pneumoconiosis diagnostic and identification group in the Department of Occupational Diseases of the Emergency General Hospital were enrolled. MSCT was used to observe the abnormal imaging manifestations of the lungs of coal workers' pneumoconiosis patients and the diseases of pulmonary fibrosis related to their own diseases (thickening of the interlobular septum, bronchial perivascular interstitial mass thickening, parenchymal banding, subpleural line, intralobular interstitial thickening, honeycomb, and subpleural interstitial thickening), the occurrence of coal workers' pneumoconiosis and complications (old tuberculosis, active tuberculosis, pneumonia, atelectasis, lung cancer, bronchiectasis), and the density, size, and location of pneumoconiosis nodules. Imaging data were analyzed and statistically processed. Results All 1002 patients were male, with an average age of (60.71±6.87) years and an average dust exposure time of (23.01±7.80) years. Among them, there were 470 patients with stage I, 422 patients with stage II, and 110 patients with stage III. There were significant differences in the distribution of thickening of the interlobular septum, bronchial perivascular interstitial mass thickening, parenchymal banding, intralobular interstitial thickening, subpleural interstitial thickening, and honeycomb across different stages (P<0.05). Statistically significant differences in p, q, and r subsets of round nodules were found in patients with pneumoconiosis at different stages (P<0.05). Observed nodule types included solid nodules, pure ground-glass shadow nodules, and partial solid nodules. There were statistically significant differences in pulmonary tuberculosis and bronchiectasis among different stages of coal workers' pneumoconiosis (P<0.05). There were statistically significant differences in interstitial shadows and patches combined with interstitial shadows among different stages of pneumoconiosis complicated with pneumonia (P<0.05). Conclusion MSCT provides images of the progression of coal workers' pneumoconiosis and have a certain relationship with the stages of coal workers' pneumoconiosis, which is conducive to the formulation of reasonable treatment plans in the early clinical stage. Therefore, in the diagnosis and treatment of pneumoconiosis, a great attention should be paid to the imaging technology of chest computerized tomography, especially the use of MSCT examination.

Objective To analyze the effect of a high salt diet on ovarian mitochondrial function.Methods Twenty female ICR mice were randomly divided into a normal salt diet(NSD)group and a high salt diet(HSD)group(n = 10 each).The NSD group was given a normal salt diet and the HSD group was given an 8%NaCl diet for 4 weeks.A high salt-treated cell model was established by inducing COV-434 cells cultured in vitro with NaCl.Western blotting was used to detect the protein expression of superoxide dismutase(SOD)and ComplexesⅠ-Ⅴ.The activity of SOD and succinate dehydrogenase(SDH)was detected kinetically.A chemiluminescence assay was used to detect adenosine triphosphate(ATP)levels.Results Compared with the NSD,the HSD significantly reduced the expression level of ComplexⅠin ovarian mitochondria(P＜0.01),significantly increased the expression level of ComplexⅤ(P＜0.05),and significantly reduced the activity of SDH and content of ATP(P＜0.01).The expression level of ComplexesⅠandⅡdecreased significantly(P＜0.05),expression level of ComplexⅤ increased significantly(P＜0.05),activity of SDH decreased significantly(P＜0.01),and content of ATP was insufficient(P＜0.01)in COV-434 cells cultured under high salt conditions.Conclusion High salt can lead to mitochondrial dys-function in the mouse ovary,such as imbalanced oxidative homeostasis,changed expression level of electron transport chain complexes,blocked tricarboxylic acid cycle,and insufficient ATP level.

Background At present, the practice of pulmonary rehabilitation for pneumoconiosis in China is in a primary stage. The basis for formulating an individualized comprehensive pulmonary rehabilitation plan is still insufficient, which is one of the factors limiting the development of community-level rehabilitation work. Objective To formulate an exercise prescription based on maximum heart rate measured by cardiopulmonary exercise test (CPET), conduct an individualized comprehensive pulmonary rehabilitation program with the exercise prescription for patients with stable pneumoconiosis, and evaluate its role in improving exercise endurance and quality of life, thus provide a basis for the application and promotion of pulmonary rehabilitation. Methods A total of 68 patients were recruited from the Occupational Disease Prevention Hospital of Jinneng Holding Coal Industry Group Co., Ltd. from April to August 2022 , and were divided into an intervention group and a control group by random number table method, with 34 cases in each group. All the pneumoconiosis patients participated in a baseline test. The control group was given routine drug treatment, while the intervention group received multidisciplinary comprehensive pulmonary rehabilitation treatment on the basis of routine drug treatment, including health education, breathing training, exercise training, nutrition guidance, psychological intervention, and sleep management, whose exercise intensity was determined according to the maximum heart rate provided by CPET. The rehabilitation training lasted for 24 weeks. Patients were evaluated at registration and the end of study respectively. CPET was used to measure peak oxygen uptake per kilogram (pVO₂/kg), anaerobic threshold (AT), carbon dioxide equivalent of ventilation (EqCO₂), maximum metabolic equivalent (METs), and maximum work (W_max). The modified British Medical Research Council Dyspnea Questionnaire (mMRC), Self-rating Anxiety Scale (SAS), Self-rating Depression Scale (SDS), Pittsburgh Sleep Quality Index (PSQI), Chronic Obstructive Pulmonary Disease Assessment Test (CAT), and Short Form of Health Survey (SF-36) were used to evaluate the potential effect of the comprehensive pulmonary rehabilitation program. Results Among the included 68 patients, 63 patients were having complete data, then 31 cases were assigned in the control group and 32 cases in the interventional group. Before the intervention, there was no significant difference in pVO₂/kg, AT, EqCO₂, METs, or W_max between the two groups (P>0.05). At the end of the trail, the indicators like pVO₂/kg [(19.81±2.38) mL·(min·kg)⁻¹], AT [(14.48±2.33) mL·(min·kg)⁻¹], METs (5.64±0.69), and W_max [(85.25±14) W] of patients in the intervention group were all higher than those [(13.90±2.37) mL·(min·kg)⁻¹, (11.70±1.94) mL·(min kg)⁻¹, (3.97±0.70), and (61.77±14.72) W, respectively] in the control group (P<0.001); there was no significant difference in EqCO₂ between the two groups (P=0.083). Before the trial, there was no significant difference in mMRC, SAS, SDS, PSQI, or CAT scores between the two groups (P>0.05). At the end of the trail, the mMRC score (1.16±0.57), SAS score (27.93±2.12), SDS score (26.48±1.44), PSQI score (1.08±0.88), and CAT score (4.34±3.28) of patients in the intervention group were lower than those [(2.03±0.83), (35.87±6.91), (34.23±6.65), (5.37±3.03), and (13.87±7.53), respectively] in the control group (P<0.001). The SF-36 scores of bodily pain (94.13±10.72), general health (87.50±5.68), vitality (95.31±5.53), mental health (99.88±0.71), and health changes (74.22±4.42) in the intervention group were higher than those [(71.87±32.72), (65.81±15.55), (74.52±16.45), (86.97±16.56), and (29.84±13.50), respectively] in the control group (P<0.001), and no significant difference was found in social functioning and role emotional scores (P>0.05). Conclusion Comprehensive pulmonary rehabilitation can increase the oxygen intake and exercise endurance of pneumoconiosis patients, ameliorate dyspnea symptoms, elevate psychological state and sleep quality, and improve the quality of life.

With the vigorous development of the nuclear industry, the perfection and professionalization of China’s nuclear emergency response system are becoming increasingly crucial. The national nuclear emergency response system is divided into three levels: the national level, the level of provinces (autonomous regions or centrally administered municipalities) with nuclear installations, and the level of operators of nuclear installations. Nuclear emergency response organizations in prefecture-level cities play an indispensable role within the provincial nuclear emergency response organizations and are the vanguard force responsible for off-site nuclear emergency response, with advantages such as familiarity with the off-site environment and rapid response initiation. As the number of nuclear power units increases, especially with a single prefecture-level city hosting multiple nuclear bases, the existing nuclear emergency response capabilities and systems in prefecture-level cities urgently need to be updated and strengthened. Through in-depth research on the nuclear emergency response organization systems, professional team capabilities, and emergency response resource allocation of a typical prefecture-level city and its county-level cities, issues such as incomplete organizational systems, unclear interface relationships, unprofessional talent teams, and imperfect resource allocation have been identified, which affect the effectiveness of emergency response. To address these challenges, a systematic enhancement of nuclear emergency response capabilities in prefecture-level cities was proposed from four aspects: institutional system, core capabilities, team mechanisms, and resource allocation. The perfection of the institutional system is the foundation, the strengthening of core capabilities is the key, and the soundness of team mechanisms is the safeguard. Prefecture-level cities should promote the systematization, specialization, and standardization of nuclear emergency response capability construction with a task-oriented, coordinated, and compatible philosophy and principles, thereby solidifying the cornerstone of China’s nuclear safety.