The p21-activated kinase 4 (PAK4), a key regulator of malignancy, is negatively correlated with immune infiltration and has become an emergent drug target of cancer therapy. Given the lack of high efficacy PAK4 inhibitors, we herein reported the identification of a novel inhibitor 13 bearing a tetrahydrobenzofuro[2,3-c]pyridine tricyclic core and possessing high potency against MIA PaCa-2 and Pan02 cell lines with IC₅₀ values of 0.38 and 0.50 μmol/L, respectively. This compound directly binds to PAK4 in a non-ATP competitive manner. In the mouse Pan02 model, compound 13 exhibited significant tumor growth inhibition at a dose of 100 mg/kg, accompanied by reduced levels of PAK4 and its phosphorylation together with immune infiltration in mice tumor tissue. Overall, compound 13 is a novel allosteric PAK4 inhibitor with a unique tricyclic structural feature and high potency both in vitro and in vivo, thus making it worthy of further exploration.

Objective To explore the clinical efficacy of Chinese herbal medicine with the actions of invigorating spleen,activating blood and resolving phlegm in the treatment of senile insomnia based on the theory of"muscular atrophy,qi-passage blockage"recorded in Huang Di Nei Jing(The Yellow Emperor's Inner Classic,shortened as Nei Jing).Methods A total of 120 elderly patients with insomnia were randomly divided into observation group and control group,with 60 cases in each group.The control group was treated with oral use of Dexzopiclone Tablets,and the observation group was treated with oral use of decoction of Chinese herbal medicine for invigorating spleen,activating blood and resolving phlegm.The course of treatment covered 4 weeks.Before and after treatment,the two groups were observed in the changes of Pittsburgh Sleep Quality Index(PSQI)score,Insomnia Severity Index(ISI)score,polysomnography(PSG)related parameters of total sleep time(TST),number of awakenings(AN)and sleep latency(SL),mean blood flow velocity of anterior cerebral artery(ACA),middle cerebral artery(MCA),and posterior cerebral artery(PCA),and serum levels of 5-hydroxytryptamine(5-HT)and melatonin(MT).After treatment,the clinical efficacy and safety of the two groups were evaluated.Results(1)After 4 weeks of treatment,the total effective rate of the observation group was 93.33%(56/60),which was slightly higher than 90.00%(54/60)of the control group,but the difference was not statistically significant(P＞0.05).(2)After treatment,the item scores and total scores of PSQI in the two groups were lower than those before treatment(P＜0.05),and the decrease of the scores of sleep quality,sleep time,sleep efficiency,and daytime function as well as total scores in the observation group was significantly superior to that in the control group(P＜0.05).However,there was no significant difference of time for falling asleep and sleep disorder scores between the two groups(P＞0.05).After 4 weeks of drug withdrawal,the item scores of PSQI in the observation group continued to decrease compared with those after treatment(P＜0.05),but there was no significant difference in the control group(P＜0.05).(3)After treatment,the ISI scores in the two groups were decreased when compared with those before treatment(P＜0.05),and the decrease in the observation group was superior to that in the control group(P＜0.05).After 4 weeks of drug withdrawal,the ISI score of the observation group continued to decrease compared with that after treatment(P＜0.05),while the control group had no significant change,and the difference was not statistically significant(P＞0.05).(4)After treatment,the PSG related parameters such as TST,AN and SL in the two groups were improved when compared with those before treatment(P＞0.05),and the improvement of TST and AN in the observation group was superior to that in the control group(P＞0.05).(5)After treatment,the mean blood flow velocity of ACA,MCA and PCA in the observation group was improved compared with that before treatment(P＜0.05),while there was no significant change in the control group compared with that before treatment(P＞0.05).The improvement of the mean blood flow velocity of ACA,MCA and PCA in the observation group was significantly superior to that in the control group(P＜0.05).(6)After treatment,the levels of serum 5-HT and MT in the two groups were increased when compared with those before treatment(P＜0.05),and the increase in the observation group was superior to that in the control group(P＜0.05).(7)The incidence of adverse reactions in the observation group was 5.00%(3/60),which was slightly lower than 13.33%(8/60)in the control group,but the difference was not statistically significant(P＞0.05).Conclusion Based on the theory of"muscular atrophy,qi-passage blockage"recorded in Nei Jing,the Chinese herbal medicine for invigorating spleen,activating blood and resolving phlegm exerts certain effect in treating senile insomnia.It can effectively improve the sleep quality and daytime function of patients,enhance sleep efficiency,increase sleep time,reduce the number of awakenings,alleviate the severity of insomnia,improve brain function,and regulate the level of neurotransmitters,with remarkably long-term effect and reliable safety.

Objective: To determine the causal association between long-term Nitrogen dioxide (NO₂) exposure and the risk of cardiovascular hospitalization. Methods: Based on a sub-cohort of a community-based prospective cohort study, a total of 36 271 participants were recruited from 35 communities randomly selected in Guangzhou in 2015. The annual average exposure of NO₂, demographic characteristics, lifestyle factors, and information on the causes of hospitalization was collected. We applied marginal structural Cox models to investigate the effect of NO₂ on cardiovascular hospitalization. Demographic and behavioral factors also stratified results. Results: The mean age of participants in the present study was (50.9±17.8) years, and the cardiovascular admission rate was 8.7%, with 203 822 person-years of follow-up. The annual mean NO₂ concentration was 48.7 μg/m³ during 2015-2020. For each 10 μg/m³ increase in NO₂ concentrations, the HRs (95%CIs) of total cardiovascular hospitalization, cardiovascular hospitalization, and cerebrovascular hospitalization were 1.33 (1.16-1.52), 1.36 (1.16-1.60) and 1.25 (1.00-1.55), respectively. Participants who were never married/married, with secondary education, high exercise frequency, or non-smokers/current smokers may be more susceptible than their counterparts. Conclusion: Long-term exposure to NO₂ significantly increased hospitalization risk for cardiovascular disease.
Humans ; Adult ; Middle Aged ; Aged ; Nitrogen Dioxide ; Prospective Studies ; Cardiovascular Diseases/epidemiology* ; Causality ; Hospitalization

Objective: To investigate the factors influencing total bilirubin elevation and its correlation with UGT1A1 gene polymorphism in the early postoperative period of transjugular intrahepatic portosystemic shunt (TIPS). Methods: 104 cases with portal hypertension and esophageal variceal hemorrhage (EVB) treated with elective TIPS treatment were selected as the study subjects and were divided into a bilirubin-elevated group and a normal bilirubin group according to the total bilirubin elevation level during the early postoperative period. Univariate analysis and logistic regression were used to analyze the factors influencing total bilirubin elevation in the early postoperative period. PCR amplification and first-generation sequencing technology were used to detect the polymorphic loci of the UGT1A1 gene promoter TATA box, enhancer c.-3279 T > G, c.211G > A, and c.686C > A. Logistic regression was used to analyze the correlation of four locus alleles and genotypes with elevated total bilirubin in the early postoperative period. Results: Among the 104 cases, 47 patients were in the bilirubin elevated group, including 35 males (74.5%) and 12 females (25.5%), aged (50.72 ± 12.56) years. There were 57 cases in the normal bilirubin group, including 42 males (73.7%) and 15 females (26.3%), aged (51.63 ± 11.10) years. There was no statistically significant difference in age (t = -0.391, P = 0.697) and gender (χ(2) = 0.008, P = 0.928) between the two groups of patients. Univariate analysis revealed that preoperative alanine transaminase (ALT) level (χ(2) = 5.954, P = 0.015), total bilirubin level (χ(2) = 16.638, P < 0.001), MELD score (χ(2) = 10.054, P = 0.018), Child-Pugh score (χ(2) = 6.844, P = 0.022), and postoperative portal vein branch development (χ(2) = 6.738, P = 0.034) were statistically significantly different between the two groups. Logistic regression analysis showed that preoperative ALT level, total bilirubin level, and portal vein branch development after TIPS were correlated with the elevated total bilirubin in the early postoperative period. The polymorphism of the c.211G > A locus of the UGT1A1 gene correlation had elevated total bilirubin in the early postoperative period of TIPS. The risk of elevated total bilirubin was increased in the population carrying allele A (P = 0.001, OR = 4.049) in the early postoperative period. Allelic polymorphisms in the TATA box promoter region and enhancer c.-3279 T > G and c.686C > A had no statistically significant difference between the bilirubin-elevated group and the normal bilirubin group. Conclusion: The preoperative ALT level, total bilirubin level, and portal vein branch development are correlated with the elevated total bilirubin in early postoperative patients. The polymorphisms of the UGT1A1 gene and enhancer c.211G > A are correlated with the occurrence of elevated total bilirubin in the early postoperative period of TIPS. Allele A carrier may have a higher risk of elevated total bilirubin in the early postoperative period.
Female ; Humans ; Male ; Bilirubin ; Esophageal and Gastric Varices ; Gastrointestinal Hemorrhage/surgery* ; Portasystemic Shunt, Transjugular Intrahepatic ; Postoperative Period ; Retrospective Studies ; Treatment Outcome ; Adult ; Middle Aged ; Glucuronosyltransferase/genetics*

Based on the technology of platelet proteomics, the key regulatory proteins and pathogenesis of coronary heart disease with phlegm and blood stasis syndrome were explored and analyzed. Based on the previous laboratory research, the model of coronary heart disease in mini-swine with phlegm-stasis cementation syndrome was duplicated. The model was judged by the changes in blood lipid and myocardial tissue characteristics. Furthermore, the platelet proteins were studied by quantitative proteomics, and the differentially expressed proteins were screened. The critical regulatory proteins and biological pathways of coronary heart disease with phlegm-stasis cementation syndrome were analyzed by bioinformatics. After ten weeks of modeling, the levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), very low density lipoprotein (VLDL-C), triglyceride (TG), creatine kinase (CK) and creatine kinase-MB (CK-MB) in the model group were significantly increased, reflecting the pathological changes such as increased blood lipid, abnormal coagulation function and myocardial ischemia in the model group. In addition, compared with the sham group, there were 26 up-regulated proteins and 8 down-regulated proteins in the platelets of the model group. Combined with bioinformatics analysis, it was found that differential proteins mainly involved in glycolysis/gluconeogenesis, pyruvate metabolism, lipid and atherosclerosis, Ras protein signal transduction. Among them, lactate dehydrogenase B (LDHB), alcohol dehydrogenase 5 (ADH5), neuroblastoma ratsarcoma viral oncogene homolog (NRAS) and Kirsten ratsarcoma viral oncogene homolog (KRAS) play a central role when interacting with other proteins and simultaneously participate in multiple action pathways. The results showed that LDHB, ADH5, NRAS, and KRAS may be the marker proteins in CHD with phlegm-stasis cementation syndrome by regulating glycolysis/gluconeogenesis, pyruvate metabolism, lipid and atherosclerosis, Ras protein signal transduction and other biological processes.

Humans ; Diabetes Mellitus, Type 2/epidemiology* ; Air Pollution/adverse effects* ; Air Pollutants/toxicity* ; Risk Assessment ; Particulate Matter ; Environmental Exposure

Asthenoteratozoospermia is one of the most severe types of qualitative sperm defects. Most cases are due to mutations in genes encoding the components of sperm flagella, which have an ultrastructure similar to that of motile cilia. Coiled-coil domain containing 103 (CCDC103) is an outer dynein arm assembly factor, and pathogenic variants of CCDC103 cause primary ciliary dyskinesia (PCD). However, whether CCDC103 pathogenic variants cause severe asthenoteratozoospermia has yet to be determined. Whole-exome sequencing (WES) was performed for two individuals with nonsyndromic asthenoteratozoospermia in a consanguineous family. A homozygous CCDC103 variant segregating recessively with an infertility phenotype was identified (ENST00000035776.2, c.461A>C, p.His154Pro). CCDC103 p.His154Pro was previously reported as a high prevalence mutation causing PCD, though the reproductive phenotype of these PCD individuals is unknown. Transmission electron microscopy (TEM) of affected individuals' spermatozoa showed that the mid-piece was severely damaged with disorganized dynein arms, similar to the abnormal ultrastructure of respiratory ciliary of PCD individuals with the same mutation. Thus, our findings expand the phenotype spectrum of CCDC103 p.His154Pro as a novel pathogenic gene for nonsyndromic asthenospermia.
Asthenozoospermia/pathology* ; Dyneins/genetics* ; Homozygote ; Humans ; Male ; Microtubule-Associated Proteins ; Mutation ; Mutation, Missense ; Sperm Tail/metabolism*

Objective:To study the effect of medical social workers combined with ICU diary on the prevention and treatment of post-traumatic stress disorder in ICU traffic accident patients, and to explore the application of continuing nursing services and ICU diary to ICU traffic accident patients.Methods:A total of 47 patients who were admitted to the ICU of Suzhou Science and Technology City Hospital from January to December 2019 due to traffic accidents were selected by convenient sampling method. Twenty-three patients admitted to the hospital in the first 6 months were selected as the control group (before the introduction of medical social workers and ICU diaries) for routine ICU treatment and nursing mode. Twenty-four patients admitted to the hospital in the last 6 months were selected as the experimental group (after the introduction of medical social workers and ICU diaries), and the medical social workers combined with the ICU diary were intervened. The scores of the Self-rating Anxiety Scale (SAS) and Self-rating Depression Scale (SDS) were compared between the two groups of patients when they were admitted to the ICU, stayed in the ICU for a week, and transferred out of the ICU. The incidence of post-traumatic stress disorder was evaluated and compared by the scores of the Impact of Event Scale-Revised of the two groups of patients one month after leaving the ICU, three months after leaving the ICU, and six months after leaving the ICU.Results:The scores of SAS in the experimental group were 58.67 ± 7.45, 44.13 ± 5.47 and 39.08 ± 5.52 when they were admitted to the ICU, stayed in the ICU for a week, and transferred out of the ICU, and were 58.17 ± 6.75, 50.87 ± 6.35 and 42.74 ± 4.85, respectively in the control group. There was no statistical difference in the scores of the SAS between the two groups of patients when they were admitted to the ICU ( P>0.05), but there was a time difference between the two groups with time changes and different interventions ( Ftime = 110.98, P<0.01), there were also differences between groups ( Fbetween groups = 5.91, P<0.05). Compared with the control group, the SAS score of the experimental group decreased more significantly( Finteraction = 0.28, P<0.05). The scores of SDS in the experimental group were 57.75 ± 4.06, 45.29 ± 3.39 and 36.63 ± 3.49 when they were admitted to the ICU, stayed in the ICU for a week, and transferred out of the ICU, and were 57.48 ± 2.29, 49.04 ± 5.65 and 43.57 ± 4.07 respectively in the control group. There was no statistical difference in the scores of the SDS between the two groups of patients when they were admitted to the ICU ( P>0.05), but there was a time difference between the two groups of patients with time changes and different interventions ( Ftime = 248.24, P<0.01), there are also differences between groups ( Fbetween groups = 24.39, P<0.05). Compared with the control group, the SDS score of the experimental group decreased more significantly ( Finteraction=10.44, P<0.05). The incidences of post-traumatic stress disorder in the experimental group were 9, 8, 6 cases at one month, three months and six months after leaving the ICU, which were lower than 12, 11, 8 cases in the control group. The generalized estimation equation showed that the difference was statistically significant ( χ2=4.21, P<0.05). Conclusions:The intervention model of medical social workers combined with ICU diary is conducive to the use of ICU diary and the development of continuous nursing, which improves patients′negative emotions and reduces the incidence of post-traumatic stress disorder.

Objective To investigate the diversity and composition of microflora in laboratory-reared Aedes albopictus at different developmental stages and larval habitat waters. Methods The larval habitat waters and different developmental stages of laboratory-reared A. albopictus were collected, and the V3 and V4 regions of the bacterial 16S rRNA gene were sequenced using Illumina Miseq next-generation sequencing. The abundance and diversity of the microflora were examined using alpha diversity index in A. albopictus at different developmental stages, and the difference in the microflora compositions was compared in A. albopictus at different developmental stages using principal component analysis (PCA). In addition, the species composition and relative abundance of microflora in A. albopictus at different developmental stages were described using histograms and Venn diagrams. Results A total of 16 phyla, 30 classes, 72 orders, 129 families and 224 genera of bacteria were detected in larval habitat waters and different developmental stages of A. albopictus. The highest bacterial diversity was seen in larval A. albopictus, with Chao index of 125.20 ± 30.48 and Shannon diversity index of 2.04 ± 0.39, which were comparable to those (Chao index of 118.52 ± 15.07 and Shannon diversity index of 2.15 ± 0.30) in larval habitat waters (t = 0.35 and -0.41, both P values > 0.05). The bacterial abundance and evenness were significantly greater in female adults than in male adults (Chao index: 42.50 ± 3.54 vs. 18.50 ± 2.13, t = 8.23, P < 0.05; Shannon diversity index: 1.25 ± 1.67 vs. 0.50 ± 0.05, t = 6.00, P < 0.05). Proteobacteria, Bacteroidota, Actinobacteriota and Finnicutes were four common phyla of bacteria at each developmental stage of A. albopictus, with Proteobacteria dominated at the pupal stage (90.36%), Bacteroidota dominated at the adult stage (46.01% in female adults and 86.11% in male adults), and Actinobacteriota dominated at the larval stage (32.10%). Elizabethkingia and Rahnella 1 were common dominant genera of bacteria at each developmental stage of A. albopictus, with Rahnellal as the major component at the pupal stage (87.56%), Elizabethkingia as the main component at the adult stage (46.01% in female adults and 86.11% in male adults, respectively), and Microbacteria as the dominant bacterial genus at the larval stage (12.11%). In addition, Delftia, Elizabethkingia, Romboutsia, Serratia, Rahnella 1, Enterococcus and Microbacterium were common genera of bacteria at each developmental stage of A. albopictus, with Edaphobaculum dominated at the larval stage (17.54%) and Sphingobacterium dominated in larval habitat waters (13.93%). Conclusions There are differences in the composition of symbiotic bacteria at different developmental stages of A. albopictus; however, similar microflora diversity is maintained at the phylum level. The microflora diversity is comparable in larvae and larval habitat waters of A. albopictus.