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

Nipah virus (NiV) and related viruses form a distinct henipavirus genus within the Paramyxoviridae family. NiV continues to spillover into the humans causing deadly outbreaks with increasing human-bat interaction. NiV encodes the large protein (L) and phosphoprotein (P) to form the viral RNA polymerase machinery. Their sequences show limited homologies to those of non-henipavirus paramyxoviruses. We report two cryo-electron microscopy (cryo-EM) structures of the Nipah virus (NiV) polymerase L-P complex, expressed and purified in either its full-length or truncated form. The structures resolve the RNA-dependent RNA polymerase (RdRp) and polyribonucleotidyl transferase (PRNTase) domains of the L protein, as well as a tetrameric P protein bundle bound to the L-RdRp domain. L-protein C-terminal regions are unresolved, indicating flexibility. Two PRNTase domain zinc-binding sites, conserved in most Mononegavirales, are confirmed essential for NiV polymerase activity. The structures further reveal anchoring of the P protein bundle and P protein X domain (XD) linkers on L, via an interaction pattern distinct among Paramyxoviridae. These interactions facilitate binding of a P protein XD linker in the nucleotide entry channel and distinct positioning of other XD linkers. We show that the disruption of the L-P interactions reduces NiV polymerase activity. The reported structures should facilitate rational antiviral-drug discovery and provide a guide for the functional study of NiV polymerase.
Nipah Virus/chemistry* ; Cryoelectron Microscopy ; Viral Proteins/genetics* ; RNA-Dependent RNA Polymerase/genetics* ; Phosphoproteins/genetics* ; Humans ; Models, Molecular ; Protein Binding

Objective To screen out the indexes of medical insurance fund under China Healthcare Security Diagno-sis Related Groups(CHS-DRG)payment based on Delphi method and improve the efficiency of medical insurance fund supervision.Methods Using the Delphi method,32 experts in the medical insurance field were selected and 2 rounds of expert questionnaires were conducted to design an evaluation scale for the monitoring indicators of medi-cal insurance funds under CHS-DRG payment.The consultation results were evaluated from three aspects of motiva-tion,authority,and coordination.Results A medical insurance fund supervision index system based on three dimen-sions of medical insurance fund use quality,efficiency and safety supervision is constructed,including 3 first-level indicators,7 second-level indicators and 44 third-level indicators.Results The construction ofmedical insurance fund supervision index system under CHS-DRG payment should respect the actual clinical diagnosis and treatment,strengthen the intelligent supervision method,and timely intervene in medical insurance fund management risks.

Objective:To explore the protocol for handgrip exercise stress echocardiography by comparing different maximal voluntary contraction（MVC）handgrip groups with bicycle exercise stress.Methods:Forty-one healthy volunteers were enrolled prospectively from June to October 2024 in Tangdu Hospital and utilized a color Doppler echocardiography system，supine cycle ergometer，and handgrip dynamometer to collect echocardiographic data at baseline，during handgrip exercises at 20%（3 min），30%（3 min），and 40%（2 min）of MVC，and spine bicycle exercise stress at peak. Parameters measured included left ventricular ejection fraction（EF），stroke volume（SV），cardiac output（CO），mitral inflow E-wave and A-wave velocities，lateral and septal mitral annular e' velocities，E/A and E/e' ratios，global longitudinal strain（GLS），left atrial reservoir strain（LAS R），conduit strain（LAS CD），and contractile strain（LAS CT）. The non-invasive myocardial work indices were also assessed，including global work index（GWI），global constructive work（GCW），global wasted work（GWW），and global work efficiency（GWE）. Statistical analyses were performed using repeated measures analysis of variance，with corrected paired t-test for comparisons between two exercise stress states. Results:Compared with the baseline state，heart rate，blood pressure，CO、GWI、GCW、GWW and LAS CT gradually increased，while EF、E/A、GLS、GWE、LAS R and LAS CD gradually decreased under 20%，30% and 40% of MVC states. The changes were most obvious at 40% of MVC state，which was selected for the handgrip exercise stress echocardiography protocol.Compared with the peak of bicycle exercise，at 40% of MVC，heart rate was significantly lower［（81.2 ± 9.7）bpm vs.（164.6 ± 11.3）bpm， P<0.05）］，systolic blood pressure was slightly lower［（152.9 ± 13.2）mmHg vs.（165.1 ± 20.4）mmHg， P<0.05］，diastolic blood pressure was higher［（96.0 ± 9.5）mmHg vs.（89.5 ± 10.9）mmHg， P<0.05］，GLS was lower［（19.1 ± 1.5）% vs.（23.5 ± 1.7）%， P<0.05］，GWI was similar［（2 254.2 ± 417.3）mmHg% vs.（2 227.5 ± 389.0）mmHg%， P>0.05］，but GWE was higher［（95.3 ± 2.0）% vs.（93.7 ± 2.0）%， P<0.05］，and LAS R was lower［（39.4 ± 4.2）% vs.（43.9 ± 4.1）%， P<0.05］. Conclusions:The 40% of MVC lasting 2 min can cause the most significant handgrip-related changes in cardiac function and can be used as the standard protocol for handgrip exercise stress echocardiography. Handgrip stress exercise can cause significant changes in cardiac systole，diastole，and work performance，showing different characteristics compared with bicycle exercise stress.

Objective:To investigate the diagnostic efficacy of artificial intelligence(AI)software combined with contrast-enhanced ultrasound(CEUS)on portal hypertension of cirrhosis.Methods:A retrospective analysis was conducted on 106 patients with cirrhosis who admitted to Handan Communicable Disease Hospital from January 2024 to June 2024 and were confirmed by surgical pathology.In them,60 cases with positive portal hypertension were included in positive group,and 46 cases with negative portal hypertension were included in negative group.The receiver operating characteristic(ROC)curve was used to analyze the diagnostic values of ultrasound characteristics via preoperative AI quantization,enhanced ultrasound mode and the combination of them for portal hypertension of cirrhosis.Results:The mean peak intensity,mean vessel density and branching morphology index of AI software were respectively 201.23±10.18,0.62±0.11 and 1.23±0.24 in diagnosing portal hypertension of positive group,all of which were significantly higher than those of negative group(t=8.551,3.707,2.054,P<0.05).However,the mean peak reaching time,uniformity of flow perfusion,mean flow velocity and uniformity of microcirculation perfusion of the positive group were respectively(18.22±2.18)seconds,(75.22±5.46)%,(10.09±2.22)cm/s,(80.78±5.11)%,all of which were significantly lower than those in the negative group(t=3.729,5.237,4.969,4.491,P<0.05).The enhancement speed and degree of liver parenchyma,the enhancement speed of portal vein,and the enhancement speed and degree of spleen in CEUS of positive group were significantly higher than those of negative group,and the differences were significant(t=4.770,12.781,7.313,5.501,4.645,7.513,P<0.05).ROC curve analysis showed that the area under curve(AUC)value of CEUS combined with AI algorithm was 0.926 in diagnosis,which was significantly better than single CEUS and single AI analysis(0.853,0.925).Conclusion:CEUS technique combines with AI software can show higher diagnostic efficacy in the diagnosis for portal hypertension of cirrhosis,which diagnostic effect was better than single either of two methods.

Background: Bone cancer pain (BCP) is not adequately addressed by current treatment methods, making the exploration of effective management strategies a topic of significant interest. Bone marrow mesenchymal stem cells (BMSCs) seem to be a potential way for managing BCP, yet little is known about the mechanisms underlying the efficacy of this potential treatment. Methods: We established the male C57BL/6 mice BCP models. Behavioral tests, X-ray, bone histology, western blotting, and immunofluorescence were used to verify the analgesic effect of BMSCs. Results: Intramedullary injection of Lewis lung carcinoma cells into the femur successfully generated the mice BCP models. The number of c-Fos-positive neurons and phosphorylated mitogen-activated protein kinase (MAPK) proteins in the spinal dorsal horn of the BCP mice increased. Intrathecal injection of BMSCs temporarily improved the BCP mice’s mechanical and thermal hyperalgesia without affecting motor function. This effect may be related to inhibiting spinal microglia and p-p38 MAPK activation. The analgesic effect of BMSCs may be related to the homing effect mediated by CXCR4. Conclusions Intrathecal injection of BMSCs can temporarily inhibit mechanical and thermal hyperalgesia in BCP mice without affecting motor function. This effect may be related to the inhibition of p-p38 protein expression and the inhibition of microglia but not to p-ERK and p-JNK.

Background: Bone cancer pain (BCP) is not adequately addressed by current treatment methods, making the exploration of effective management strategies a topic of significant interest. Bone marrow mesenchymal stem cells (BMSCs) seem to be a potential way for managing BCP, yet little is known about the mechanisms underlying the efficacy of this potential treatment. Methods: We established the male C57BL/6 mice BCP models. Behavioral tests, X-ray, bone histology, western blotting, and immunofluorescence were used to verify the analgesic effect of BMSCs. Results: Intramedullary injection of Lewis lung carcinoma cells into the femur successfully generated the mice BCP models. The number of c-Fos-positive neurons and phosphorylated mitogen-activated protein kinase (MAPK) proteins in the spinal dorsal horn of the BCP mice increased. Intrathecal injection of BMSCs temporarily improved the BCP mice’s mechanical and thermal hyperalgesia without affecting motor function. This effect may be related to inhibiting spinal microglia and p-p38 MAPK activation. The analgesic effect of BMSCs may be related to the homing effect mediated by CXCR4. Conclusions Intrathecal injection of BMSCs can temporarily inhibit mechanical and thermal hyperalgesia in BCP mice without affecting motor function. This effect may be related to the inhibition of p-p38 protein expression and the inhibition of microglia but not to p-ERK and p-JNK.

Background: Bone cancer pain (BCP) is not adequately addressed by current treatment methods, making the exploration of effective management strategies a topic of significant interest. Bone marrow mesenchymal stem cells (BMSCs) seem to be a potential way for managing BCP, yet little is known about the mechanisms underlying the efficacy of this potential treatment. Methods: We established the male C57BL/6 mice BCP models. Behavioral tests, X-ray, bone histology, western blotting, and immunofluorescence were used to verify the analgesic effect of BMSCs. Results: Intramedullary injection of Lewis lung carcinoma cells into the femur successfully generated the mice BCP models. The number of c-Fos-positive neurons and phosphorylated mitogen-activated protein kinase (MAPK) proteins in the spinal dorsal horn of the BCP mice increased. Intrathecal injection of BMSCs temporarily improved the BCP mice’s mechanical and thermal hyperalgesia without affecting motor function. This effect may be related to inhibiting spinal microglia and p-p38 MAPK activation. The analgesic effect of BMSCs may be related to the homing effect mediated by CXCR4. Conclusions Intrathecal injection of BMSCs can temporarily inhibit mechanical and thermal hyperalgesia in BCP mice without affecting motor function. This effect may be related to the inhibition of p-p38 protein expression and the inhibition of microglia but not to p-ERK and p-JNK.

Background: Bone cancer pain (BCP) is not adequately addressed by current treatment methods, making the exploration of effective management strategies a topic of significant interest. Bone marrow mesenchymal stem cells (BMSCs) seem to be a potential way for managing BCP, yet little is known about the mechanisms underlying the efficacy of this potential treatment. Methods: We established the male C57BL/6 mice BCP models. Behavioral tests, X-ray, bone histology, western blotting, and immunofluorescence were used to verify the analgesic effect of BMSCs. Results: Intramedullary injection of Lewis lung carcinoma cells into the femur successfully generated the mice BCP models. The number of c-Fos-positive neurons and phosphorylated mitogen-activated protein kinase (MAPK) proteins in the spinal dorsal horn of the BCP mice increased. Intrathecal injection of BMSCs temporarily improved the BCP mice’s mechanical and thermal hyperalgesia without affecting motor function. This effect may be related to inhibiting spinal microglia and p-p38 MAPK activation. The analgesic effect of BMSCs may be related to the homing effect mediated by CXCR4. Conclusions Intrathecal injection of BMSCs can temporarily inhibit mechanical and thermal hyperalgesia in BCP mice without affecting motor function. This effect may be related to the inhibition of p-p38 protein expression and the inhibition of microglia but not to p-ERK and p-JNK.

AIM: To analyze the factors affecting non-contact intraocular pressure(IOPNCT)measurements after femtosecond laser-assisted small incision lenticule extraction(SMILE), explore the correlation of IOPNCT with central corneal thickness(CCT)and corneal curvature after SMILE, and construct the corresponding regression model which will provide scientific basis for clinical evaluation of the true IOP of patients after SMILE.METHODS: Data from a retrospective analysis of 107 myopic patients(206 eyes)who underwent SMILE and 107 myopic patients(201 eyes)received femtosecond laser-assisted in situ keratomileusis(FS-LASIK)surgery from June 2023 to May 2024 were examined. IOPNCT, CCT, and corneal curvature before surgery and at 1 and 3 mo were collected. The preoperative and postoperative IOPNCT, CCT and corneal curvature were analyzed by ANOVA and Pearson correlation analysis, and multiple linear regression models were constructed to evaluate the association of postoperative changes of IOPNCT, CCT and corneal curvature.RESULTS: There were significant differences in IOPNCT, CCT, and corneal curvature of both SMILE and FS-LASIK patients(all P<0.001), there was no significant difference between two groups and interaction effects(all P>0.05), and the IOPNCT, CCT and corneal curvature at 1 and 3 mo post-surgery were significantly lower than preoperative(all P<0.05). Pearson correlation analysis showed a positive correlation between IOPNCT and CCT at 1 and 3 mo after SMILE(r=0.261, 0.267, all P<0.001), but no significant correlation with corneal curvature(all P>0.05). Multiple linear regression analysis of IOPNCT with CCT and corneal curvature at 1 mo after SMILE indicated that the regression equation was: Y=3.426+0.019X1-0.058X2(Y represents IOPNCT, X1 represents the CCT, and X2 represents the corneal curvature), with statistical significant difference in the equation(F=7.654, P=0.001); the regression equation for 3 mo after surgery was: Y=2.056+0.020X1-0.038 X2(Y represents IOPNCT, X1 represents the CCT, and X2 represents the corneal curvature), with statistically significance in the equation(F=7.903, P<0.001). The regression equation of postoperative IOPNCT change(△IOPNCT)and intraoperative cutting corneal thickness(△CCT)and corneal curvature at 1 mo was Y=-2.252+0.008X1+0.587X2(Y represents △IOPNCT, X1 stands for the △CCT, X2 represents the corneal curvature change value), with statistical significant difference in the equation(F=17.550, P<0.001); the regression equation for 3 mo after surgery was: Y=-2.168+0.024X1+0.281X2(Y represents △IOPNCT, X1 represents △CCT, X2 indicates the corneal curvature change values), with statistical significant difference in the equation(F=16.030, P<0.001).CONCLUSION: After SMILE and FS-LASIK surgery, the IOPNCT value of patients was mainly affected by CCT compared with preoperative surgery, and the short-term use of hormone eye drops, fluorometholone, did not cause a significant increase in IOP; both the IOP correction formula at 1 and 3 mo postoperatively can be used clinically to evaluate and correct actual IOP in patients after SMILE.