Studies have suggested that the nucleus accumbens (NAc) is implicated in the pathophysiology of major depression; however, the regulatory strategy that targets the NAc to achieve an exclusive and outstanding anti-depression benefit has not been elucidated. Here, we identified a specific reduction of cyclic adenosine monophosphate (cAMP) in the subset of dopamine D1 receptor medium spiny neurons (D1-MSNs) in the NAc that promoted stress susceptibility, while the stimulation of cAMP production in NAc D1-MSNs efficiently rescued depression-like behaviors. Ketamine treatment enhanced cAMP both in D1-MSNs and dopamine D2 receptor medium spiny neurons (D2-MSNs) of depressed mice, however, the rapid antidepressant effect of ketamine solely depended on elevating cAMP in NAc D1-MSNs. We discovered that a higher dose of crocin markedly increased cAMP in the NAc and consistently relieved depression 24 h after oral administration, but not a lower dose. The fast onset property of crocin was verified through multicenter studies. Moreover, crocin specifically targeted at D1-MSN cAMP signaling in the NAc to relieve depression and had no effect on D2-MSN. These findings characterize a new strategy to achieve an exclusive and outstanding anti-depression benefit by elevating cAMP in D1-MSNs in the NAc, and provide a potential rapid antidepressant drug candidate, crocin.

Objective:To summary the clinical phenotype and genotype characteristics of 2 cases of autosomal dominant mental retardation (MRD) caused by TRIO gene variation. Methods:Retrospective study of the clinical data of 2 cases of autosomal dominant MRD caused by TRIO gene mutations diagnosed at the Department of Neurology, Children′s Hospital Affiliated to Zhengzhou University in April 2019 and January 2023 was conducted. The clinical features were summarized and gene analysis and follow-up were carried out. Results:The 2 patients were 6 years and 5 months old and 5 months old males, respectively. Clinical manifestations included seizures, cognitive and motor disorders, low intelligent development; case 1 had microcephaly, attention deficit disorder, ataxia, and aggressive behavior, and case 2 had macrocephaly. Brain magnetic resonance imaging revealed cerebellar atrophy in case 1, and non-specific dilation of the subarachnoid space and hypoplasia of the corpus callosum in case 2. Analysis of chromosome karyotype and chromosome copy number variation in 2 children showed no abnormalities. Whole exome sequencing revealed novel missense mutations in the TRIO gene in both patients [NM_007118:c.4289C>A(p.Thr1430Lys), c.4111C>A(p.His1371Asn), respectively]. The application of rehabilitation function training and a variety of anti-seizure medications can not fully and effectively control the seizure. Conclusion:TRIO gene c.4289C>A(p.Thr1430Lys), c.4111C>A(p.His1371Asn) de novo missense variants were the genetic etiology of the 2 probands,causing rare autosomal dominant MRD type 44 and 63.

Heart failure is the leading cause of death worldwide. Compound Danshen Dripping Pill (CDDP) or CDDP combined with simvastatin has been widely used to treat patients with myocardial infarction and other cardiovascular diseases in China. However, the effect of CDDP on hypercholesterolemia/atherosclerosis-induced heart failure is unknown. We constructed a new model of heart failure induced by hypercholesterolemia/atherosclerosis in apolipoprotein E (ApoE) and LDL receptor (LDLR) dual deficient (ApoE^-/-LDLR^-/-) mice and investigated the effect of CDDP or CDDP plus a low dose of simvastatin on the heart failure. CDDP or CDDP plus a low dose of simvastatin inhibited heart injury by multiple actions including anti-myocardial dysfunction and anti-fibrosis. Mechanistically, both Wnt and lysine-specific demethylase 4A (KDM4A) pathways were significantly activated in mice with heart injury. Conversely, CDDP or CDDP plus a low dose of simvastatin inhibited Wnt pathway by markedly up-regulating expression of Wnt inhibitors. While the anti-inflammation and anti-oxidative stress by CDDP were achieved by inhibiting KDM4A expression and activity. In addition, CDDP attenuated simvastatin-induced myolysis in skeletal muscle. Taken together, our study suggests that CDDP or CDDP plus a low dose of simvastatin can be an effective therapy to reduce hypercholesterolemia/atherosclerosis-induced heart failure.

Hepatocellular carcinoma (HCC) is a common malignant tumor of the liver characterized by a high incidence rate, rapid progression, and poor prognosis. In recent years, it has been found that non-coding RNA (ncRNA) participates in the regulation of tumor immunity in tumor microenvironment (TME) and in turn affects the biological behavior of HCC. This article briefly describes the regulatory effect of ncRNA on immune cells in TME and introduces the potential value of ncRNA in the diagnosis and treatment of HCC, in order to provide potential diagnostic and treatment strategies for HCC.

Transcatheter aortic valve replacement is the effective treatment for severe aortic stenosis. PhaseⅠ cardiac rehabilitation is the key period for the recovery of cardiac function, the establishment of rehabilitation consciousness and rehabilitation education, which has important clinical significance. This article reviews the content and research status of Phase I cardiac rehabilitation after transcatheter aortic valve replacement and the nursing mode led by specialist nurses of Phase I cardiac rehabilitation after transcatheter aortic valve replacement, so as to provide reference for improving nursing effect of Phase I cardiac rehabilitation after transcatheter aortic valve replacement.

Methods:Two thousand standard sections images werre collected from 2 000 clinical retrospective pediatric hip ultrasound videos from January 2019 to January 2021. All standard sections were annotated by the annotation team through the self-designed software based on Python 3.6 environment for image cross-media data annotation and manual review standardization process with unified standards. Among them, 1 753 were randomly selected for training the deep learning system, and the remaining 247 were used for testing the system. Further, 200 standard sections were randomly selected from the test set, and 8 clinicians independently completed the film reading annotation. The 8 independent results were then compared with the AI results.Results:The testing set consists of 247 patients. Compared with the clinician's measurements, the area under the receiver operating characteristic curve (AUC) of diagnosing hip joint maturity was 0.865, the sensitivity was 76.19%, and the specificity was 96.9%. The AUC of AI system interpretation under Graf detailed typing was 0.575, the sensitivity was 25.90%, the specificity was 89.10%. The 95% LoA of α-angle determined by Bland-Altman method, of -4.7051° to 6.5948° ( Bias -0.94, P<0.001), compared with clinicians' measurements. The 95% LoA of β-angle, of -7.7191 to 6.8777 ( Bias -0.42, P=0.077). Compared with those from 8 clinicians, the results of AI system interpretation were more stable, and the β-angle effect was more prominent. Conclusion:The AI system can quickly and accurately measure the Graf correlation index of standard DDH ultrasonic standard diagnosis plane.

Objective:To investigate the etiological diagnostic value of metagenomic sequencing in central nervous system (CNS) infectious diseases.Methods:A total of 170 patients with central nervous system infection admitted to the First Affiliated Hospital of Zhengzhou University from January 2018 to June 2020 were selected as the study subjects according to inclusion and exclusion criteria. General clinical data and pathogen test results were collected. All included patients underwent routine examination and mNGS test, and were divided into the conventional method test group and mNGS test group according to the test results. The measurement data conforming to normal distribution were represented by ± s; The measurement data that did not conform to normal distribution were represented by median and interquartile range. The classification data were expressed by the number of cases and percentage( n,%), and were compared by χ2 test or Fisher's exact test. Consistency test was represented by Kappa value. The detection of pathogenic microorganisms by the two methods and the rule of pathogen spectrum were compared and analyzed. Results:The overall positive rate of mNGS in CNS infectious diseases was higher than that of conventional methods (58.23% vs. 18.82%), and the difference was statistically significant ( P<0.01). Among the 20 samples which were both positive by the two methods, 10 cases were completely pathogenic, 5 cases were partially consistent and 5 cases were completely inconsistent. In the detection of tuberculous nervous system infection, the positive rates were 66.7%, 53.8%, 44.0%, 40.0%, 4.0% in blood T-SPOT, cerebrospinal fluid mNGS, ADA, Mycobacterium tuberculosis DNA and tuberculous specific antibody, respectively. The positive rate of acid-fast staining was 0. The positive rate of mNGS combined with conventional method was 80.8%. Conclusions:The detection rate of mNGS in CNS infection is better than that of conventional methods. However, it does not show obvious superiority in the detection rate of Mycobacterium tuberculosis associated nervous system infection. In general, mNGS detection of pathogenic bacteria is more extensive, which is conducive to a thorough and comprehensive understanding of the bacterial characteristics of central nervous system infection. The combination of the two methods can make up for the deficiency of clinical routine detection to a certain extent, and can maximize the detection rate.

Objective:Clamping bilateral renal arteries with refined surgical methods to establish the rat renal ischemia-reperfusion injury (RIRI) model, and study the protective mechanism of ischemic preconditioning renal (IPC) tubular cell-derived exosomes in RIRI.Methods:25 female Sprague Dawley (SD) rats were divided into sham group, model group, inactivated group, normoxic group, IPC group. In the sham operation group, after bilateral renal arteries were dissociated, the back incision was disinfected and closed. The model group established RIRI model; RIRI models were established in inactivated group, normoxia group and IPC group, and then 200 μg of inactivated exosomes, normal exosomes and IPC exosomes were injected into the caudal vein 24 hours after operation. Serum creatinine (Scr) and urea nitrogen (BUN) levels were detected. The pathological changes of renal tissue were observed under light microscope. Transmission electron microscopy (TEM) was used to observe the shape and size of renal tubular exosomes. Nanoparticle tracking analysis (NTA)was used to detect the concentration and size of renal tubular exosomes.Results:Compared with the sham group, the Scr and BUN levels in the model group were significantly elevated ( P<0.01). Renal pathological changes in the model group showed damaged of the tubular structure, necrosis and shedding of tubular epithelial cells, and a large number of inflammatory cells accumulated in the renal interstitial tissue with varying degrees of edema. Compared with the inactivated group, the Scr and BUN levels significantly decreased in the normoxic group and IPC group ( P<0.01). Renal pathological changes in the normoxic group and IPC group showed that the renal tubular cell necrosis alleviated, inflammatory was reduced, the improved edema. Compared with the normoxic group, the Scr and BUN levels in the IPC group were further reduced ( P<0.01). Renal pathological changes in the IPC group showed that the inflammatory cells were significantly reduced, the cell edema was significantly improved, and the cell apoptosis was significantly reduced. Conclusions:Clamping bilateral renal arteries with refined surgical methods is the main and optimal way to build a rat model of RIRI. IPC tubular cell-derived exosomes have protective and repair effects on RIRI.

Objective:To establish a mouse model of intra-jugular arteriovenous fistula (AVF) to screen differentially expressed genes in the process of intimal stenosis of AVF for investigating the abnormal expression signaling pathways and the mechanisms.Methods:Forty-six male C57BL/6 mice were randomly divided into AVF group ( n=23) and sham-operated group ( n=23). The AVF group underwent internal jugular arteriovenous fistuloplasty, and the sham-operated group separated the right external jugular vein and common carotid artery and then sutured the incision. The whole-genome sequences of mice with AVF stenosis were determined by transcriptomic reversible chain terminator and synthetic sequencing. The microarray data set was established, and the Benjamini & Hochberg method of gene microarray data analysis was applied to screen the differentially expressed genes. The differentially expressed genes were screened by R-language enrichment analysis. Then, gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) were performed. The subcellular localization of the differentially expressed genes was performed by BUSCA software. The protein network interaction of differentially expressed genes was analyzed by using STRING database and Cytoscape software. Results:In the AVF group, 21 mice were successfully modeled and 2 mice failed. Therefore, there were 21 mice in the AVF group and only 21 mice in the sham-operated group. This mouse internal jugular AVF model was innovated using the continuous-interrupted suture method, which improved the success rate of modeling this model. The differential gene sequencing analysis showed that there were 2 514 differentially expressed genes in the AVF process, including 1 323 up-regulated genes and 1 191 down-regulated genes. GO functional enrichment analysis showed that the differential genes were mainly enriched in metabolic process, activation, redox, mitochondria and so on. KEGG pathway enrichment analysis showed that the differential genes were enriched in metabolism, energy substance synthesis, diabetes, oxidative stress and so on. Statistical analysis of subcellular localization showed that the differences were mainly in mitochondrial proteins (24.24%), cytoplasmic proteins (17.51%), nuclear proteins (13.13%), cell membrane proteins (11.45%), and extracellular proteins (10.77%).Conclusions:Mitochondrial oxidative stress injury may be involved in the pathological damage process of endothelial proliferation stenosis in the AVF.

Objective:To investigate the effects and underlying mechanisms of phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/NF-κB signaling pathway in human kidney-2(HK-2) cells of hyperuricemic nephropathy.Methods:HK-2 cells were cultured in vitro and randomly divided into control group and experimental group. The experimental group was induced by high uric acid (720 μmol/L) immersion for 48 h to establish a cell model of hyperuricemic nephropathy in vitro and subsequently divided into hyperuricemic group, overexpressed protease activated receptor 2 (PAR2) and knockdown PAR2 group. The expressions of PAR2, PI3K, AKT, NF-κB mRNA were measured by real-time PCR. The expressions of PAR2, PI3K, AKT and NF-κB protein were measured by Western blotting. The expressions of tumor necrosis factor-α (TNF-α), monocyte chemotactic protein-1 (MCP-1), interleukin-6 (IL-6), pro-interleukin-1β (pro-IL-1β), interleukin-1β (IL-1β) and transforming growth factor-β1 (TGF-β1) were detected by enzyme linked immunosorbent assay (ELISA). Results:(1) Compared with the control group, the expressions of PAR2, PI3K, AKT and NF-κB mRNA and protein in hyperuricemic group were significantly increased (all P<0.05), the expressions of TNF-α, MCP-1, IL-6, pro-IL-1β, IL-1β and TGF-β1 in the supernatant in hyperuricemic group were significantly increased (all P<0.01). (2) Compared with the hyperuricemic group, the expressions of PAR2, PI3K, AKT and NF-κB mRNA and protein in overexpressed PAR2 group were significantly increased (all P<0.05), the expressions of TNF-α, MCP-1, IL-6, IL-1β and TGF-β1 in the supernatant were significantly increased (all P<0.05). (3) Compared with the hyperuricemic group, the expression of PAR2, PI3K, AKT and NF-κB mRNA and protein in knockdown PAR2 group were significantly decreased (all P<0.05), the expressions of IL-6, pro-IL-1β, IL-1β and TGF-β1 in the supernatant were significantly decreased (all P<0.05). Conclusions:In the process of uric acid-induced HK-2 cell damage, uric acid significantly up-regulates the expression of PI3K/AKT/NF-κB signaling pathway by activating PAR2, leading to a marked increase in inflammatory damage. Knocking down PAR2 inhibits the expression of PI3K/AKT/NF-κB signaling pathway, which can effectively reduce the inflammatory damage of HK-2 cells.