Objective To investigate the mechanism of action of macrophage-derived exosomes(Exo)in peripheral nerve injury(PNI).Methods Exo were extracted following the polarization of macrophages to either the M1 or M2 phenotype to determine their effects on Schwann cells(SCs),using cell proliferation,quantitative real-time polymerase chain reaction,flow cytometry,RNA sequencing,and Western blot.A sciatic nerve extrusion model was established in vivo.PBS,M1-exo and M2-exo treatment groups were injected with PBS,M1-exo,and M2-exo,respectively,and a separate normal group was set up.The sciatic nerve function index(SFI),wet weight ratio,and staining of neuromuscular tissue were evaluated on a weekly basis in each experimental group following surgical intervention.Results M1-exo facilitated SC migration and upregulated glial-derived nerve growth factor,whereas M2-exo promoted SC proliferation and migration and upregulated brain-derived nerve growth factor and nerve growth factor.The biomarkers,myelin protein zero,glial fibrillary acidic protein,nerve growth factor receptor(NGFR)and S100 calcium-binding protein B(S100)were also detected.In the in vivo experiments,the SFI,wet weight ratio,neuromuscular tissues,and fluorescent areas of nerve axons(marker NF200)and SCs(marker S100)were all significantly better in the M2-exo treatment group at week 4 compared with the PBS treatment group,while there were no significant differences between the M1-exo and PBS treatment groups.Both the in vivo and ex vivo experiments demonstrated that M2-exo facilitated the proliferation of SCs via phosphorylation of the serine/threonine kinase AKT,resulting in downregulation of the cell cycle protein WEE 1.Conclusions M2-exo has been demonstrated to promote up-regulation of genes associated with nerve regeneration by SCs and promote SC proliferation and migration,thereby facilitating nerve regeneration via the AKT-WEE1 pathway.

Objective:To assess the efficacy and safety profile of antaitasvir phosphate combined with yiqibuvir in the treatment of chronic hepatitis C (CHC) of various genotypes, without cirrhosis or with compensated cirrhosis.Methods:394 cases with CHC from 22 centers were collected from October 2021 to April 2023. They were randomly assigned to receive either the experimental drugs (antaitasvir phosphate 100 mg+yiqibuvir 600 mg) or placebo treatment in a 3∶1 ratio. The patients were administered drugs once a day for 12 consecutive weeks, and then followed up for 24 weeks after treatment cessation. All subjects were unblinded at the four-week follow-up following drug discontinuation, with the experimental drug group continuing to complete subsequent post-discontinuation follow-up. The placebo group was switched to receive the experimental drugs for a repeated 12-week treatment period and followed up for another 24 weeks after discontinuation of the drug (placebo delayed treatment phase).The sustained virologic response rate (SVR12) was observed for subjects in the double-blind phase and the placebo delayed-treatment phase at 12 weeks after treatment cessation.Virological resistance analysis was performed on subjects who failed treatment. The primary efficacy endpoint was SVR12. The number and percentage of subjects who achieved "HCV RNA

Objective To investigate the mechanism of action of macrophage-derived exosomes(Exo)in peripheral nerve injury(PNI).Methods Exo were extracted following the polarization of macrophages to either the M1 or M2 phenotype to determine their effects on Schwann cells(SCs),using cell proliferation,quantitative real-time polymerase chain reaction,flow cytometry,RNA sequencing,and Western blot.A sciatic nerve extrusion model was established in vivo.PBS,M1-exo and M2-exo treatment groups were injected with PBS,M1-exo,and M2-exo,respectively,and a separate normal group was set up.The sciatic nerve function index(SFI),wet weight ratio,and staining of neuromuscular tissue were evaluated on a weekly basis in each experimental group following surgical intervention.Results M1-exo facilitated SC migration and upregulated glial-derived nerve growth factor,whereas M2-exo promoted SC proliferation and migration and upregulated brain-derived nerve growth factor and nerve growth factor.The biomarkers,myelin protein zero,glial fibrillary acidic protein,nerve growth factor receptor(NGFR)and S100 calcium-binding protein B(S100)were also detected.In the in vivo experiments,the SFI,wet weight ratio,neuromuscular tissues,and fluorescent areas of nerve axons(marker NF200)and SCs(marker S100)were all significantly better in the M2-exo treatment group at week 4 compared with the PBS treatment group,while there were no significant differences between the M1-exo and PBS treatment groups.Both the in vivo and ex vivo experiments demonstrated that M2-exo facilitated the proliferation of SCs via phosphorylation of the serine/threonine kinase AKT,resulting in downregulation of the cell cycle protein WEE 1.Conclusions M2-exo has been demonstrated to promote up-regulation of genes associated with nerve regeneration by SCs and promote SC proliferation and migration,thereby facilitating nerve regeneration via the AKT-WEE1 pathway.

Objective:To assess the efficacy and safety profile of antaitasvir phosphate combined with yiqibuvir in the treatment of chronic hepatitis C (CHC) of various genotypes, without cirrhosis or with compensated cirrhosis.Methods:394 cases with CHC from 22 centers were collected from October 2021 to April 2023. They were randomly assigned to receive either the experimental drugs (antaitasvir phosphate 100 mg+yiqibuvir 600 mg) or placebo treatment in a 3∶1 ratio. The patients were administered drugs once a day for 12 consecutive weeks, and then followed up for 24 weeks after treatment cessation. All subjects were unblinded at the four-week follow-up following drug discontinuation, with the experimental drug group continuing to complete subsequent post-discontinuation follow-up. The placebo group was switched to receive the experimental drugs for a repeated 12-week treatment period and followed up for another 24 weeks after discontinuation of the drug (placebo delayed treatment phase).The sustained virologic response rate (SVR12) was observed for subjects in the double-blind phase and the placebo delayed-treatment phase at 12 weeks after treatment cessation.Virological resistance analysis was performed on subjects who failed treatment. The primary efficacy endpoint was SVR12. The number and percentage of subjects who achieved "HCV RNA

Objective:To evaluate the efficacy and safety of antaitasvir phosphate 100 mg or 200 mg combined with yiqibuvir for 12 weeks in patients with various genotypes of chronic hepatitis C, without cirrhosis or compensated stage cirrhosis.Methods:Patients with chronic hepatitis C (without cirrhosis or compensated stage cirrhosis) were randomly assigned to the antaitasvir phosphate 100 mg+yiqibuvir 600 mg group (100 mg group) or the antaitasvir phosphate 200 mg+yiqibuvir 600 mg group (200 mg group) in a 1∶1 ratio. The drugs were continuously administered once a day for 12 weeks and observed for 24 weeks after drug withdrawal. The drug safety profile was assessed concurrently with the observation of the sustained virological response (SVR12) in the two patient groups 12 weeks following the drug cessation. The intention-to-treat concept was used to define as closely as possible a full analysis set, including all randomized cases who received the experimental drug at least once. The safety set was collected from all subjects who received the experimental drug at least once (regardless of whether they participated in the randomization group) in this study. All efficacy endpoints and safety profile data were summarized using descriptive statistics. The primary efficacy endpoint was SVR12. The primary analysis was performed on a full analysis set. The frequency and proportion of cases were calculated in the experimental drug group (antaitasvir phosphate capsules combined with yiqibuvir tablets) that achieved "HCV RNA

Here, we report a previously unrecognized syndromic neurodevelopmental disorder associated with biallelic loss-of-function variants in the RBM42 gene. The patient is a 2-year-old female with severe central nervous system (CNS) abnormalities, hypotonia, hearing loss, congenital heart defects, and dysmorphic facial features. Familial whole-exome sequencing (WES) reveals that the patient has two compound heterozygous variants, c.304C>T (p.R102*) and c.1312G>A (p.A438T), in the RBM42 gene which encodes an integral component of splicing complex in the RNA-binding motif protein family. The p.A438T variant is in the RRM domain which impairs RBM42 protein stability in vivo. Additionally, p.A438T disrupts the interaction of RBM42 with hnRNP K, which is the causative gene for Au-Kline syndrome with overlapping disease characteristics seen in the index patient. The human R102* or A438T mutant protein failed to fully rescue the growth defects of RBM42 ortholog knockout ΔFgRbp1 in Fusarium while it was rescued by the wild-type (WT) human RBM42. A mouse model carrying Rbm42 compound heterozygous variants, c.280C>T (p.Q94*) and c.1306_1308delinsACA (p.A436T), demonstrated gross fetal developmental defects and most of the double mutant animals died by E13.5. RNA-seq data confirmed that Rbm42 was involved in neurological and myocardial functions with an essential role in alternative splicing (AS). Overall, we present clinical, genetic, and functional data to demonstrate that defects in RBM42 constitute the underlying etiology of a new neurodevelopmental disease which links the dysregulation of global AS to abnormal embryonic development.
Female ; Animals ; Mice ; Humans ; Child, Preschool ; Intellectual Disability/genetics* ; Heart Defects, Congenital/genetics* ; Facies ; Cleft Palate ; Muscle Hypotonia

Objective:To study the differences of intestinal flora between neonatal rats with intrauterine hypoxia and healthy neonatal rats using high-throughput sequencing technology to determine the effects of intrauterine hypoxia on neonatal intestinal flora.Methods:Intrauterine hypoxia model were established in neonatal rats. On d1 and d7 after birth, intestinal samples were collected from intrauterine hypoxic group and normal control group and assigned into INH1 group (intrauterine hypoxia d1), INH7 group (intrauterine hypoxia d7), NOR1 group (normal control d1) and NOR7 group (normal control d7). 16S rRNA sequencing were conducted using these samples and the differences in the diversity, richness and composition of the flora among the groups were compared.Results:(1) The Alpha diversity of the intestinal flora in the INH1 group was higher than the NOR1 group. Specifically, both sobs and chao indices, representing the richness of the flora, in INH1 group were significantly higher than the NOR1 group (sobs index: 114.5±35.6 vs. 50.5±21.3, chao index: 135.6±38.5 vs. 73.9±28.8)( P<0.05). Compared with the NOR7 group, the mean values of sobs, ace, chao, simpson and shannon indices in the INH7 group showed no significant differences ( P>0.05). (2) At the phylum and genus level, the dominant bacterial groups in the intrauterine hypoxia group on d1 were firmicutes and streptococcus and proteus and escherichia for the normal control group. The difference of intestinal flora between intrauterine hypoxia group and the normal control group on d7 was smaller than the difference between the two groups on d1. Compared with INH1 group, the INH7 group had increased escherichia composition and decreased streptococcus composition. Conclusions:Intrauterine hypoxia changes the initial colonization and later affects the abundance and structural composition of the intestinal flora in newborn rats.

Objective:To provide a scientific basis for reducing the rate of invalid ambulance attendance and the establishment of grades dispatch system through a retrospective analysis of the invalid ambulance attendance in prehospital emergency care.Methods:The data of the invalid ambulance attendance was collected in Huazhong University of Science and Technology Union Shenzhen Hospital (the only tertiary hospital of in Nanshan District) from 2014 to 2018, and the reasons of the invalid ambulance attendance, the time period during the invalid ambulance attendance occurred (every 3 hours was divided into one time period), and the reasons of ambulance calling were statistically analyzed.Results:① The invalid ambulance attendance rates showed a fluctuating decrease trend year by year from 2014 to 2018, the rates were 31.22% (2 515/8 055), 26.94% (2 147/7 970), 29.80% (2 398/8 046), 25.69% (1 844/7 177) and 21.89% (1 686/7 703), respectively. The total invalid ambulance attendance rate was 27.19% (10 590/38 951) in the five years. ② The top three reasons for the invalid ambulance attendance were cancelled calls, departure before the ambulance arrived, and going to hospital by themselves, accounting for 36.87%, 25.08%, and 17.03%, respectively. The constituent ratios of the causes of invalid ambulance attendance in each year were different with statistical significance (χ 2 = 217.626, P < 0.001). ③ The top three time period of invalid ambulance attendance occurred at 21:00-23:59, 18:00-20:59 and 09:00-11:59, accounting for 16.86%, 14.95% and 13.54%, respectively. There was no statistical significance in the distribution of time period in each year (χ 2 = 32.571, P = 0.252). ④ The top five reasons for ambulance calling of invalid ambulance attendance were fainting/syncope, trauma, alcoholism, traffic accident injuries, and brawls, accounting for 20.13%, 15.67%, 9.97%, 8.64%, and 6.45%, respectively, and there was statistically significant difference in the distribution of the reason for ambulance calls in each year (χ 2 = 194.213, P < 0.001). Conclusion:The invalid ambulance attendance rate is high in Nanshan District of Shenzhen. Improving the professional level and triage ability of the dispatchers, improving the system construction of prehospital emergency care system and increasing social education are conducive to reduce invalid ambulance attendance rate.

Objective:To investigate the functional connectivity of resting-state networks in young depressed patients with suicide attempts and its association with suicide attempt as well as to better understand the underlying neural mechanism of suicide.Methods:Hamilton Depression Scale-17 items （HAMD 17），Beck Depression Inventory （BDI）, Suicide Attitude Questionnaire （SAQ）, Barratt Impulsiveness Scale （BIS）, Beck Hopelessness Scale （BHS） and Scale for Suicide Ideation （SSI）were used to assess the severity of depressive symptoms and suicidal characteristics in 35 young depressed patients with suicide attempts (SU group), 18 patients with non-suicide attempt （NSU group） and 47 gender, age, and education matched healthy controls (HC group). The alterations of intra-and internetwork connectivity among SU, NSU and HC group were analyzed with functional magnetic resonance imaging and independent component analysis（ICA）. Pearson correlation was adopted to analyze the association between functional network connectivity and clinical psychological scales .Results:(1)There were significant differences in functional network connectivity within the default mode network （DMN），salience network (SN) and bilateral frontal-parietal network （FPN） among three groups. Compared with NSU group, SU showed significantly decreased internetwork connectivity between anterior default mode network （aDMN）, salience network （SN）（ t=-2.63, P=0.036）, and right frontal-parietal network （rFPN）( t=-3.42, P=0.048). However, enhanced internetwork connectivity between the SN and the right fronto-parietal network (rFPN) was found in SU group （ t=3.07, P=0.038）. In addition，decreased aDMN-rFPN connectivity was negatively correlated with BHS scores ( r=-0.353； P=0.037), and the differences in SN-rFPN and aDMN-pDMN connectivity were negatively associated with the HAMD score in the SU group ( r=-0.369, P=0.029； r=-0.372, P=0.028). Conclusions:These findings suggest that SU experience reorganization at the level of large-scale brain networks. Suicide attempt is correlated with abnormal functional network connectivity within and among these RSNs.

Objective:To investigate the functional connectivity of resting-state networks in young depressed patients with suicide attempts and its association with suicide attempt as well as to better understand the underlying neural mechanism of suicide.Methods:Hamilton Depression Scale-17 items （HAMD 17），Beck Depression Inventory （BDI）, Suicide Attitude Questionnaire （SAQ）, Barratt Impulsiveness Scale （BIS）, Beck Hopelessness Scale （BHS） and Scale for Suicide Ideation （SSI）were used to assess the severity of depressive symptoms and suicidal characteristics in 35 young depressed patients with suicide attempts (SU group), 18 patients with non-suicide attempt （NSU group） and 47 gender, age, and education matched healthy controls (HC group). The alterations of intra-and internetwork connectivity among SU, NSU and HC group were analyzed with functional magnetic resonance imaging and independent component analysis（ICA）. Pearson correlation was adopted to analyze the association between functional network connectivity and clinical psychological scales .Results:(1)There were significant differences in functional network connectivity within the default mode network （DMN），salience network (SN) and bilateral frontal-parietal network （FPN） among three groups. Compared with NSU group, SU showed significantly decreased internetwork connectivity between anterior default mode network （aDMN）, salience network （SN）（ t=-2.63, P=0.036）, and right frontal-parietal network （rFPN）( t=-3.42, P=0.048). However, enhanced internetwork connectivity between the SN and the right fronto-parietal network (rFPN) was found in SU group （ t=3.07, P=0.038）. In addition，decreased aDMN-rFPN connectivity was negatively correlated with BHS scores ( r=-0.353； P=0.037), and the differences in SN-rFPN and aDMN-pDMN connectivity were negatively associated with the HAMD score in the SU group ( r=-0.369, P=0.029； r=-0.372, P=0.028). Conclusions:These findings suggest that SU experience reorganization at the level of large-scale brain networks. Suicide attempt is correlated with abnormal functional network connectivity within and among these RSNs.