ObjectiveTo explore the mechanism of Huoxue Rongluo prescription （HXRLP） in repairing the blood-brain barrier （BBB） after ischemic stroke （IS）. MethodsMale C57BL/6 mice were randomly divided into sham operation （Sham） group， cerebral infarction model （MCAO） group， environmental circadian disruption with cerebral infarction model （ECD-MCAO） group， low-， medium-， and high-dose HXRLP （HXRLP-L， M， and H） groups （8.5， 17， 34 g·kg^-1·d^-1， respectively）， and positive drug butylphthalide （NBP） group （0.23 mL·d^-1）. In the Sham group， only the exposed blood vessels were isolated without suture insertion. In the other groups， the middle cerebral artery occlusion （MCAO） model of mice was prepared. In the ECD-MCAO group， HXRLP groups， and NBP group， the environmental circadian disruption （ECD） model was prepared. The mice in the Sham group， MCAO group， and ECD-MCAO group were given the same volume of soybean oil by gavage， while those in the other groups were given the corresponding drugs by gavage. Samples were collected after 7 consecutive days of administration. The mNSS score was used to evaluate the repair effect of HXRLP on neurological deficits after IS. Hematoxylin-eosin （HE） staining was used to assess the impact of HXRLP on the pathological damage of brain tissue after IS. 2，3，5-Triphenyltetrazolium chloride （TTC） staining and cerebral blood perfusion status were used to evaluate the repair effect of HXRLP on brain tissue damage after IS. Evans blue staining and transmission electron microscopy were used to evaluate the improvement effect of HXRLP on the permeability injury of BBB after IS. Immunofluorescence （IF） staining was used to observe the expression of von Willebrand Factor （vWF）， brain and muscle Arnt-like 1 （Bmal1）， and Occludin in brain tissue. Western blot was used to detect the protein expression of Bmal1， Occludin， tight junction protein （Claudin-5）， vascular endothelial growth factor （VEGF）， and angiopoietins（Ang）， and related analysis was conducted. ResultsCompared with the Sham group， the MCAO group exhibited significantly aggravated neurological deficits， cerebral infarction volume， brain pathological damage， and BBB leakage （P0.01） and significantly reduced cerebral blood perfusion （P0.01）. The expression of Bmal1， vWF， vascular endothelial growth factor A （VEGFA）， and Ang in brain tissue was significantly enhanced （P0.01）， while the expression of Occludin and Claudin-5 was significantly weakened （P0.01）. Compared with the MCAO group， the ECD-MCAO group showed significantly aggravated neurological deficits， cerebral infarction volume， and BBB leakage （P0.01）， obviously worsened brain pathological damage （P0.05）， significantly reduced cerebral blood perfusion （P0.01）， and significantly decreased expression of Bmal1， vWF， VEGFA， Ang， Occludin， and Claudin-5 in brain tissue （P0.01）. Compared with the ECD-MCAO group， the HXRLP groups of all doses presented significantly improved neurological deficits， cerebral infarction volume， brain pathological damage， and BBB leakage （P0.01）， significantly increased cerebral blood perfusion （P0.01）， and enhanced expression levels of Bmal1， vWF， VEGFA， Ang， Occludin， and Claudin-5 in brain tissue （P0.01）. ConclusionHXRLP can regulate the clock protein Bmal1 and promote the expression of VEGFA， Ang， Occludin， and Claudin-5， thereby improving BBB damage after IS.

Humans ; Gastrointestinal Microbiome ; Constipation/therapy* ; Probiotics/therapeutic use* ; Patients

Humans ; Aged ; Lung Diseases ; Pneumonia/drug therapy* ; Adrenal Cortex Hormones/therapeutic use* ; Pulmonary Disease, Chronic Obstructive/drug therapy* ; Administration, Inhalation ; Community-Acquired Infections/drug therapy*

Since the 1970s, the laboratory animal industry in Suzhou has gone through five stages: its inception, emergence, growth, transformation, and scaling up. It began with the manufacturing of caging equipment for laboratory animals, initially by imitation and later through independent innovation. The industry evolved from sporadic factories to clustered enterprises, gradually growing and opening up the export market for caging equipment. In the 21st century, with industrial upgrading and transformation, purification systems and related products began to develop, and industry organizations emerged. As China has modernized, the rise of automation and intelligent production has led to technological innovation in enterprises and the emergence of various outsourcing services in the laboratory animal industry, driving the large-scale development of the industrial chain. After nearly half a century of growth, the laboratory animal industry in Suzhou has formed a complete industrial chain, including the production of laboratory animals, caging equipment, feed and bedding materials, design and construction of laboratory animal facilities, quality testing of laboratory animals and environments, and animal experimentation services. Laboratory animal breeding equipment, the core of the industry, has reached the level of developed countries, and the industry's scale and influence are unmatched in China. Since the 21st century, biopharmaceuticals have become the "No.1 industry" in the development of Suzhou. With government support, the guidance of the local economy, and the assistance from universities and research institutes, the animal experiment outsourcing industry has begun to cluster in Suzhou. The continuous influx of CROs has driven the construction of large-scale laboratory animal facilities, and key research projects have been initiated, significantly enhancing the industry's R&D capabilities. The Suzhou laboratory animal industry has quickly expanded alongside the "No. 1 industry," creating a unique "Suzhou Path" for laboratory animals. Over nearly fifty years, the laboratory animal industry in Suzhou has been essential to the rapid development of the biopharmaceutical industry in Suzhou and China.

Objective To analyze the magnetic resonance images (MRI) of patients with spinal epidural lipomatosis (SEL) in high-altitude areas and to determine the optimal cut-off value for diagnosis with epidural fat thickness. Methods This retrospective study included patients who underwent lumbosacral MRI examination for lumbosacral pain in Ping’an District Hospital of Traditional Chinese Medicine, Haidong City, China from January 1, 2021 to December 31, 2022. The epidural fat thickness in vertebral segments T12/L1 to L5/S1 was compared between the SEL group and the non-SEL group. The diagnostic efficacy with different cut-off values at each vertebral segment was evaluated. Between-group comparisons were performed using the t-test, Mann-Whitney U test, chi-square test, or modified chi-square test. The area under the receiver operating characteristic (AUC) was used to evaluate the diagnostic efficiency. The DeLong test was used to compare AUC between the two groups. Results A total of 370 patients were included (60 in the SEL group and 310 in the non-SEL group). There were no significant differences in age, sex, height, body weight, and body mass index between the two groups (all P > 0.05). At different vertebral segments, the epidural fat thickness was significantly higher in the SEL group than in the non-SEL group (all P < 0.05). The cut-off values for SEL diagnosis with epidural fat thickness in segments T12/L1 to L5/S1 were 2.23, 4.25, 4.85, 5.57, 7.21, and 8 mm, respectively. The AUC of MRI SEL diagnosis with epidural fat thickness in segment L5/S1 was the highest (0.945, 95% confidence interval [CI]: 0.916-0.966, P < 0.001). SEL diagnosis with epidural fat thickness > 8 mm in segment L5/S1 was the most accurate, with an AUC of 0.931 (95% CI: 0.901-0.955, P < 0.001), a sensitivity of 95.0%, and a specificity of 91.3%; this AUC was significantly higher than those of diagnosis with other cut-off values (all P < 0.05). Conclusion SEL patients have significantly increased epidural fat in the spinal canal. Epidural fat thickness > 8 mm in segment L5/S1 can be used for diagnosis of SEL with improved efficiency and accuracy.

Bone formation and deposition are initiated by sensory nerve infiltration in adaptive bone remodeling. Here, we focused on the role of Semaphorin 3A (Sema3A), expressed by sensory nerves, in mechanical loads-induced bone formation and nerve withdrawal using orthodontic tooth movement (OTM) model. Firstly, bone formation was activated after the 3rd day of OTM, coinciding with a decrease in sensory nerves and an increase in pain threshold. Sema3A, rather than nerve growth factor (NGF), highly expressed in both trigeminal ganglion and the axons of periodontal ligament following the 3rd day of OTM. Moreover, in vitro mechanical loads upregulated Sema3A in neurons instead of in human periodontal ligament cells (hPDLCs) within 24 hours. Furthermore, exogenous Sema3A restored the suppressed alveolar bone formation and the osteogenic differentiation of hPDLCs induced by mechanical overload. Mechanistically, Sema3A prevented overstretching of F-actin induced by mechanical overload through ROCK2 pathway, maintaining mitochondrial dynamics as mitochondrial fusion. Therefore, Sema3A exhibits dual therapeutic effects in mechanical loads-induced bone formation, both as a pain-sensitive analgesic and a positive regulator for bone formation.
Humans ; Bone Remodeling ; Cell Differentiation ; Osteogenesis ; Semaphorin-3A/pharmacology* ; Trigeminal Ganglion/metabolism*

ObjectiveUltra-performance liquid chromatography-quadrupole/electrostatic field orbitrap high resolution mass spectrometry（UPLC-Q-Exactive Orbitrap MS/MS） was used to investigate the metabolism and distribution of nardosinone in rats， then metabolic pathways were speculated. MethodRats were administered with 30 mg·kg^-1 of nardosinone suspension by gavage for 3 consecutive days， and plasma， urine， feces， and tissues of heart， liver， spleen， lung， kidney， brain， stomach， and intestine were collected at predetermined time points. After treatment， the samples were processed for UPLC-Q-Exactive Orbitrap MS/MS， and the MS data were analyzed using Xcalibur 2.2 software. The metabolites were searched by comparing the base peak chromatogram and extracted ion chromatogram between the treated group and blank group， and based on the relative retention time（t_R）， quasi-molecular ion peak， precise molecular mass， and fragment ions of MS/MS， the elemental composition were searched using databases such as SciFinder and PubChem， as well as referring to relevant literature， the possible metabolites were identified and the metabolic pathways were inferred. ResultA total of 30 metabolites of nardosinone were identified， including 15， 19， 12， 7， 4， 11， 8， 13， 13， 8 and 12 metabolites in urine， feces， plasma， brain， heart， liver， spleen， lung， kidney， stomach and intestine， respectively. The main metabolic pathways of nardosinone in rats were hydroxylation， dehydroxylation， reduction， dehydrogenation， hydration， dehydration， carboxylation， glucuronidation， and dehydroxy-isopropyl. ConclusionNardosinone can be metabolized by phase Ⅰ and phase Ⅱ metabolism in rats， and the metabolites are widely distributed in the major organs. The results of this study can provide a basis for further research on the pharmacodynamic material basis， pharmacological mechanism and clinical application of nardosinone.

OBJECTIVE To explore the independent risk factors of voriconazole （VCZ）-related liver injury in elderly patients with hypoproteinemia. METHODS Elderly patients with invasive fungal infection and hypoproteinemia who were hospitalized in the respiratory intensive care unit of our hospital and treated with VCZ from August 2020 to July 2023 were selected. They were divided into group A （liver injury group） and group B （non-liver injury group） based on whether the liver injury occurred after using VCZ. Pearson correlation analysis was used to analyze the correlation between minimum concentration （cmin） of VCZ and inflammatory factor[C-reactive protein （CRP）， procalcitonin （PCT）， interleukin-6 （IL-6）]， as well as liver function [alanine transaminase （ALT）， aspartate transaminase （AST）， alkaline phosphatase （ALP）， gamma-glutamyl transpeptidase （GGT）， total bilirubin （TBIL）]； univariate analysis was performed by using χ 2 test； Logistic regression analysis was used to analyze the independent risk factors affecting the occurrence of liver injury. RESULTS A total of 320 patients were included in the study， of whom 56 developed liver injury， with an incidence of 17.50%. The VCZ cmin in group A was significantly higher than group B （P＝ 0.021）. CRP， PCT， IL-6， and TBIL were correlated with VCZ cmin （P＜0.05）. CRP， PCT， IL-6， and TBIL had a significant impact on VCZ cmin （P＜0.05）. VCZ cmin， PCT， and TBIL were independent risk factors for liver injury （P＜0.05）. The patients with VCZ cmin≥3.76 mg/L had a significantly increased risk of liver injury. CONCLUSIONS VCZ cmin， PCT， and TBIL are independent risk factors for the occurrence of liver injury in elderly patients with hypoproteinemia. For patients with high PCT and TBIL， VCZ cmin and liver function should be closely monitored during VCZ treatment to reduce the risk of liver injury.

Objective: To analyze the longitudinal association between mobile phone dependence and depressive symptoms in college students, so as to provide a theoretical basis for psychological health education among college students. Methods: From November 2021 to June 2023, 2 515 first year students from 2 universities in Yunnan Province were surveyed with a questionnaire by a cluster random sampling method, including baseline survey (November 2021, T1) and three follow up visits (June 2022, T2; November 2022, T3; June 2023, T4). The Self rating Questionnaire for Adolescent Problematic Mobile Phone Use and the Depression Anxiety Stress Scales-21 (DASS-21) were used to evaluate mobile phone dependence and depressive symptoms of college students. The χ 2 test was used to analyze the difference in depressive symptoms among different demographic groups, and a generalized estimation equation model was established to analyze the association between mobile phone dependence symptoms and depressive symptoms. Results: The detection rates of depressive symptoms among university students in Yunnan Province at time points T1, T2, T3, and T4 were 23.02%, 33.36%, 34.79% and 35.51%, respectively. There were statistically significant differences in the detection rates of depressive symptoms among college students with different sacademic burden (T1, T2, T3, T4), different number of close friends (T1, T2, T3), as well as their father s educational level (T1), mothers educational level (T2, T4), gender (T4), major (T3, T4), education (T2, T3, T4), family residency (T1, T2), and family economic conditions (T1, T2, T4) ( χ 2= 59.68 , 49.38, 16.70, 39.31; 55.35, 26.01, 16.69; 10.22; 14.87, 11.51; 14.90; 27.81, 50.28; 9.75, 7.42, 24.76; 6.06, 4.47 ; 15.88, 14.58, 15.85, P < 0.05 ). After controlling for demographic variables and confounding factors in the generalized estimation equation model, mobile phone dependence ( β =0.11), withdrawal symptoms of mobile phone dependence ( β =0.14), and the physical and mental effects of mobile phone dependence ( β =0.14) were all positively correlated with depressive symptoms ( P <0.01). Further gender analysis showed that depressive symptoms in both boys ( β =0.13, 0.13, 0.18) and girls ( β =0.10, 0.13, 0.13 ) were associated with mobile phone dependence, withdrawal symptoms of mobile phone dependence and the physical and mental effects of mobile phone dependence ( P <0.01). Conclusions Depressive symptoms of college students are positively correlated with mobile phone dependence, and family economic conditions, academic burden and number of close friends are factors that continued to affect depressive symptoms. College students should be guided to pay attention to the impact of excessive use of mobile phones on their physical and mental health, use mobile phones reasonably to reduce the incidence of depressive symptoms among college students.

Objective To explore the characteristics and mechanism of phase separation between TAR DNA binding protein-43(TDP-43)and ubiquitin.Methods The TARDBP gene and its truncated genes were inserted into vectors to construct recombinant plasmids for expression and protein purification.The phase separation system of ubiquitin and TDP-43 was constructed in vitro.The characteristics of the droplets formed via liquid-liquid phase separation were observed by fluorescence microscopy.The plasmids of ubiquitin and TDP-43 were co-transfected into HEK293T cells to observe aggregates containing TDP-43 and ubiquitin and find out whether TDP-43 could be ubiquitinated.Results The GFP-8Ub,TDP-43 full-length(FL)and truncated proteins were purified.TDP-43 FL and C-terminal domain(CTD)proteins were able to form droplets via phase separation with ubiquitin.The droplets changed into solid-like aggregates after prolonged incubation.Insolvable aggregates containing TDP-43 and ubiquitin were formed.TDP-43 was ubiquitinated under stress conditions in HEK293T cells after being co-transfected with ubiquitin and TDP-43 recombinant plasmids.Conclusion TDP-43 undergoes co-phase separation with ubiquitin,mainly driven by the multivalent interaction between TDP-43′s CTD structural domain and ubiquitin.The droplets finally form aggregates with solid-like properties.Under stress conditions,especially when the protein homeostasis is disrupted,TDP-43 and ubiquitin form aggregates while TDP-43 is ubiquitinated.This study reveals the basic mechanism of TDP-43 co-phase separation with ubiquitin and liquid-solid transformation.