Acetylcholine (ACh) is an important neuromodulator in various cognitive functions. However, it is unclear how ACh influences neural circuit dynamics by altering cellular properties. Here, we investigated how ACh influences reverberatory activity in cultured neuronal networks. We found that ACh suppressed the occurrence of evoked reverberation at low to moderate doses, but to a much lesser extent at high doses. Moreover, high doses of ACh caused a longer duration of evoked reverberation, and a higher occurrence of spontaneous activity. With whole-cell recording from single neurons, we found that ACh inhibited excitatory postsynaptic currents (EPSCs) while elevating neuronal firing in a dose-dependent manner. Furthermore, all ACh-induced cellular and network changes were blocked by muscarinic, but not nicotinic receptor antagonists. With computational modeling, we found that simulated changes in EPSCs and the excitability of single cells mimicking the effects of ACh indeed modulated the evoked network reverberation similar to experimental observations. Thus, ACh modulates network dynamics in a biphasic fashion, probably by inhibiting excitatory synaptic transmission and facilitating neuronal excitability through muscarinic signaling pathways.
Cholinergic Agents/pharmacology* ; Acetylcholine/metabolism* ; Neurons/metabolism* ; Synaptic Transmission/physiology*

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*

Objective To explore the differences in the effectiveness of using different blood indicators individually,in combination,and for dynamic monitoring in the diagnosis,differential diagnosis,and prognosis of bacterial infections.Methods 1843 cases with infectious symptoms or signs from January 2015 to September 2022 at the People's Hospital of Yuxi City were selected as the case group,and 2298 uninfected individuals during the same period were selected as the control group.Blood indicators of the two groups were collected.Variables were grouped according to gender,age group,specimen type,etc.SPSS 24.0 and Medcalc 20.0 were used for statistical analysis.Results The individual diagnostic efficacy of various blood indicators for detecting infection ranges from 0.656 to 0.937.When used together,the efficacy ranges from 0.907 to 0.987.The efficacy of distinguishing between G+c and G-b in different specimens is as follows:when PCT is used alone in blood,the AUC is 0.875 for males and 0.769 for females.However,the individual diagnostic efficacy in male mucous secretions,sterile body fluids,and non-adult male sputum is all≤0.7.Yet,when used together,the efficacy is AUC(0.789,0.737,0.86)respectively.The dynamic monitoring of PCT,IL-6,CRP,WBC,and LAC in adult patients at 24 h,48 h,and 72 h after admission shows statistically significant differences in prognostic efficacy for G+c and G-b(P<0.05).Conclusions Blood indicators have a certain diagnostic value for determining whether there is a bacterial infection,and there are gender differences.The combined use of these indicators is more effective.The diagnostic value of using blood indicators alone or in combination for distinguishing between G+c and G-b in different types of specimens varies.The use of PCT alone in blood specimens is the most effective.For adult males,the combined use of body surface mucous secretions and sterile body fluids is most effective,while for underage males,the combined use of sputum is most effective.The combined use for females is not effective.Dynamic monitoring of PCT,CRP,IL-6,LAC,and WBC has a high value for evaluating the prognosis and therapeutic effect of infections.The evaluation of G+c infection is most effective at 24 hours for IL-6,and for G-b infection,it is most effective at 72 hours for PCT.

Objective: The relationship between serum uric acid (SUA) levels and glycemic indices, including plasma glucose (FPG), 2-hour postload glucose (2h-PG), and glycated hemoglobin (HbA1c), remains inconclusive. We aimed to explore the associations between glycemic indices and SUA levels in the general Chinese population. Methods: The current study was a cross-sectional analysis using the first follow-up survey data from The China Cardiometabolic Disease and Cancer Cohort Study. A total of 105,922 community-dwelling adults aged ≥ 40 years underwent the oral glucose tolerance test and uric acid assessment. The nonlinear relationships between glycemic indices and SUA levels were explored using generalized additive models. Results: A total of 30,941 men and 62,361 women were eligible for the current analysis. Generalized additive models verified the inverted U-shaped association between glycemic indices and SUA levels, but with different inflection points in men and women. The thresholds for FPG, 2h-PG, and HbA1c for men and women were 6.5/8.0 mmol/L, 11.0/14.0 mmol/L, and 6.1/6.5, respectively (SUA levels increased with increasing glycemic indices before the inflection points and then eventually decreased with further increases in the glycemic indices). Conclusion An inverted U-shaped association was observed between major glycemic indices and uric acid levels in both sexes, while the inflection points were reached earlier in men than in women.
Aged ; Asian Continental Ancestry Group ; Blood Glucose/analysis* ; China/epidemiology* ; Cohort Studies ; Diabetes Mellitus/blood* ; Female ; Glucose Tolerance Test ; Glycated Hemoglobin A/analysis* ; Glycemic Index ; Humans ; Male ; Middle Aged ; Uric Acid/blood*

Adult ; Cesarean Section/statistics & numerical data* ; China/epidemiology* ; Female ; Humans ; Pregnancy ; Pregnancy Outcome/epidemiology* ; Risk Factors ; Trial of Labor ; Young Adult

Objective: To investigate the clinical value of lymph node dissection (LND) in the radical resection of intrahepatic cholangiocarcinoma (ICC). Methods: The propensity score matching and retrospective cohort study was conducted. The clinicopathological data of 448 patients with ICC who were admitted to 12 medical centers from December 2011 to December 2017 were collected, including 279 in the Eastern Hepatobiliary Surgery Hospital of Navy Medical University, 32 in the Mengchao Hepatobiliary Hospital of Fujian Medical University, 21 in the First Hospital Affiliated to Army Medical University, 20 in the Cancer Hospital Chinese Academy of Medical Science and Peking Union Medical College, 19 in the West China Hospital of Sichuan University, 18 in the Second Hospital Affiliated to Zhejiang University School of Medicine, 18 in the Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine, 16 in the Beijing Friendship Hospital Affiliated to Capital Medical University, 10 in the Xuanwu Hospital Affiliated to Capital Medical University, 7 in the Tongji Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology, 5 in the Beijing Tiantan Hospital Affiliated to Capital Medical University, and 3 in the Affiliated Hospital of North Sichuan Medical College. There were 281 males and 167 females, aged from 22 to 80 years, with a median age of 57 years. Of the 448 patients, 143 with routinely intraoperative LND were divided into LND group and 305 without routinely intraoperative LND were divided into control group, respectively. Observation indicators: (1) the propensity score matching conditions and comparison of general data between the two groups after matching; (2) intraoperative and postoperative situations; (3) follow-up; (4) survival analysis. Patients were followed up by outpatient examination, telephone interview and email to detect survival of patients and tumor recurrence up to October 31, 2018 or death. Follow-up was conducted once every 3 months within postoperative 1-2 years, once every 6 months within postoperative 2-5 years, and once a year after 5 years. The propensity score matching was realized using the nearest neighbor method with 1∶1 ratio. Measurement data with normal distribution were represented as Mean±SD, and comparison between groups was analyzed using the t test. Measurement data with skewed distribution were represented as M (range), and comparison between groups was analyzed using the Mann-Whitney U test. Count data were described as absolute numbers, and comparison between groups was analyzed using the chi-square test or Fisher exact probability. Kaplan-Meier method was used to calculate survival rates and draw survival curve, and Log-rank test was used to perform survival analysis. Univariate analysis and multivaraiate analysis were conducted using the Log-rank test and COX regression model, respectively. Results: (1) The propensity score matching conditions and comparison of general data between the two groups after matching: 286 of 448 patients had successful matching, including 143 in each group. The number of males and females, cases with hepatitis, cases with grade A and B of Child-Pugh classification, cases with distance from margin to tumor <1 cm and ≥1 cm, cases with highly, moderately, and poorly differentiated tumor, cases with anatomical hepatectomy and nonanatomical hepatectomy before propensity score matching were 77, 66, 33, 96, 47, 70, 73, 105, 38, 79, 64 in the LND group, and 204, 101, 121, 165, 140, 207, 98, 251, 54, 124, 181 in the control group, respectively, showing significant differences in the above indices between the two groups (χ²=7.079, 11.885, 7.098, 14.763, 5.184, 8.362, P<0.05). After propensity score matching, the above indices were 77, 66, 33, 96, 47, 70, 73, 105, 38, 79, 64 in the LND group, and 79, 64, 29, 88, 55, 71, 72, 112, 31, 74, 69 in the control group, respectively, showing no significant difference in the above indices between the two groups (χ²=0.056, 0.329, 2.158, 0.014, 0.936, 1.400, P>0.05). (2) Intraoperative and postoperative situations: the operation time, volume of intraoperative blood loss, cases with intraoperative blood transfusion, cases with postoperative complications, and duration of postoperative hospital stay were 265 minutes (range, 160-371 minutes), 300 mL (range, 200-500 mL), 37, 46, 12 days (range, 9-17 days) for the LND group, and 59 minutes (range, 46-250 minutes), 200 mL (range, 100-400 mL), 24, 25, 9 days (range, 7-11 days) for the control group, respectively. There was no significant difference in the volume of intraoperative blood loss or cases with intraoperative blood transfusion between the two groups (Z=1.700, χ²=3.520, P>0.05). There were significant differences in the operation time, cases with postoperative complications, and duration of postoperative hospital stay (Z=6.520, χ²=8.260, Z=4.270, P<0.05). (3) Follow-up: 143 patients in the LND group was followed up for 18-26 months. The 1-, 3-, 5-year survival rates were 66.9%, 32.8%, 25.0%, and the median survival time was 22.0 months (range, 18.0-26.0 months). In the control group, 143 patients were followed up for 11-32 months. The 1-, 3-, 5-year survival rates were 71.7%, 38.0%, 31.0%, and the median survival time was 22.0 months (range, 11.0-32.0 months). There was no significant difference in the overall survival between the two groups (χ²=0.466, P>0.05). (4) Survival analysis: results of univariate analysis showed that distance from margin to tumor, tumor diameter, the number of tumors, microvascular tumor thrombus, and lymph node metastasis by pathological examination were related factors for prognosis of patients undergoing radical resection of ICC (χ²=10.662, 9.477, 16.944, 6.520, 11.633, P<0.05). Results of multivariate analysis showed that distance from margin to tumor<1 cm, tumor diameter>5 cm, multiple tumors, microvascular tumor thrombus, positive lymph node metastasis by pathological examination were independent risk factors for prognosis of patients undergoing radical resection of ICC (hazard ratio=0.600, 1.571, 1.601, 1.750, 1.723, 95% confidence interval: 0.430-0.837, 1.106-2.232, 1.115-2.299, 1.083-2.829, 1.207-2.460, P<0.05). Conclusion Lymph node metastasis is an independent risk factor affecting the prognosis of ICC patients, and it is necessary to perform LND in radical resection for patients with ICC and lymph node metastasis.

This study engineered β-carotene ketolase CrtW and β-carotene hydroxylase CrtZ to improve biosynthesis of astaxanthin in Escherichia coli. Firstly, crtW was randomly mutated to increase CrtW activities on conversion from β-carotene to astaxanthin. A crtW* mutant with A6T, T105A and L239M mutations has improved 5.35-fold astaxanthin production compared with the wild-type control. Secondly, the expression levels of crtW* and crtZ on chromosomal were balanced by simultaneous modulation RBS regions of their genes using RBS library. The strain RBS54 selected from RBS library, directed the pathway exclusively towards the desired product astaxanthin as predominant carotenoid (99%). Lastly, the number of chromosomal copies of the balanced crtW-crtZ cassette from RBS54 was increased using a Cre-loxP based technique, and a strain with 30 copies of the crtW*-crtZ cassette was selected. This final strain DL-A008 had a 9.8-fold increase of astaxanthin production compared with the wild-type control. Fed-batch fermentation showed that DL-A008 produced astaxanthin as predominant carotenoid (99%) with a specific titer of 0.88 g·L without addition of inducer. In conclusion, through constructing crtW mutation, balancing the expression levels between crtW* and crtZ, and increasing the copy number of the balanced crtW*-crtZ cassette, the activities of β-carotene ketolase and β-carotene hydroxylase were improved for conversion of β-carotene to astaxanthin with higher efficiency. The series of conventional and novel metabolic engineering strategies were designed and applied to construct the astaxanthin hetero-producer strain of E. coli, possibly offering a general approach for the construction of stable hetero-producer strains for other natural products.

Based on domestic and international guidelines,clinical researches and expert consensus,it is stated that fetal growth restriction is the fetal low weight,clinically accompanied by abnormal placenta and umbilical cord blood flow.This paper summarized the significance and clinical value of the color Doppler detection during perinatal period,and discussed the measures to reduce the adverse outcome of fetal growth restriction during delivery.

Objective In order to meet the needs of maxillofacical bone defect repair, the aim of this study was to synthesize graphene oxide(GO) modified three-dimensional conneted nano- zirconia(ZrO₂) bone tissue engineering scaffold and evaluate its surface morphology, compressive strength and cytocompatibility. Methods GO was synthesized by a modified Hummers method and then was testified by scanning electron microscope, transmission electron microscopy and fourier transform infrared spectroscopy. ZrO₂ scaffold was modified by different concentrations(0.5,1.0,1.5mg/mL) of GO dispersion via a silane-mediated method. The composite scaffold with uniform GO coating was chosen for compressive strength test and co-cultured with human dental pulp stem cells(hDPSCs). Actin staining was used to observe the growth of the cells on the scaffold, and MTS was used to detect the cell activity. Results The characterization results showed that, under scanning electron microscope, the GO was flaky and the surface morphology of folds could be seen. Part of the GO layer folds up at the edge. Under transmission electron microscopy, the GO was clearly observed to have a gossylike, translucent and slightly wrinkled lamellar structure. The crystal structure in this area in the high-resolution filter image showed a six-member ring structure like graphite. Under high power electron microscope, the 1.0mg/ml GO-ZrO₂ scaffold could be seen to deposit a thin layer of GO at the crack of the scaffold skeleton, connecting the two ends of the crack, and lamellar GO with folds could be observed on the surface of ceramic particles. The comparison of mechanical properties showed that the compression strength of GO-ZrO₂ scaffold was sgnificantly increased compared with that of ZrO₂ scaffold[（1.292±0.087）vs（1.031±0.076）, P<0.05]. Compared with the simple ZrO₂ scaffold, the GO-ZrO₂ scaffold showed more dense extension and adhesion to the surface of scaffolds, showing more active cell proliferation. The cell viability test showed that the viability of hDPSCs was significantly improved on GO-ZrO₂ scaffold after 1, 3 and 5 days of proliferation compared with the simple ZrO₂ scaffold(P<0.05). Conclusion The ZrO₂ scaffold modified by GO improved compressive strength, promoted the early proliferation of hDPSCs with good cytocompatibility.

Objective To investigate the cell morphology and expression of 5-hydroxytryptamine transporter(5-HTT) in hippocampal CA1 region of depression rats induced by adolescent and post-adult stress,and to observe the inter-vention effect of modified Sini San (MSS). Methods One hundred and thirty-two Wistar rats were randomly divided into blank group,model group,JSS group,and fluoxetine group,33 rats in each group. And then the rats in each group were randomly subdivided into adolescent group, adult group, post-adult group acaccording to the age day, 11 rats in each subgroup. Age day 44,56 and 78 were used as the sampling time points for adolescent group,adult group,post-adult group respectively. Chronic unpredictable mild stress(CUMS)rat model was used. From day 21 to 44 and from day 57 to 78, the rats were modeled and given medication, but from day 44 to 55, the rats were fed normally. The rat general condition and body mass of various groups were observed,the cell morphology of hippocampal CA1 region was observed by hematoxylin-eosin (HE) staining , and the distribution of 5-hydroxytryptamine transporter (5-HTT)positive cells in CA1 region of hippocampus was observed by immunohistochemical staining. Results The general condition of the rats at different age stages in the model group was poor,while that in MSS group and fluoxetine group was improved obviously. The body mass of rats at different age stages in the model group was obviously decreased (P<0.01 compared with the blank group). After adulthood stage,the body mass of rats in model group, MSS group, and fluoxetine group was lower than that of the blank group(P < 0.01), but there was no difference between the 3 groups (P > 0.05). In aspect of cell morphological manifestation in hippocampal CA1 region, rats in the adolescent model group had more deeply-staining atrophy neurons, with unclear hyperchromatic nucleus and cytoplasm. The morphological manifestations in modeled rats at adult stage and post-adulthood stage showed progressive aggravation,manifested as a large amount of neurons stained deeply with unclear nucleus and cytoplasm, and a small amount of glial cells proliferated. Compared with the model group at the same stage,the neuronal atrophy and deeply staining decreased in fluoxetine group and MSS group. The average optical density value of 5-HTT expression in the model group was decreased significantly at the adult stage and after adulthood stage(P<0.05 or P<0.01 compared with the blank group). Compared with the model group, the average optical density value of 5-HTT expression in MSS group after adulthood stage, and in the fluoxetine group at the adult stage and after adulthood stage were increased (P<0.05 or P<0.01). Conclusion Rats suffering CUMS in adolescence presents depressive behavior, and post-adult stimulation can aggravates depression. 5-HTT expression in hippocampus may be an important pathway for MSS to achieve the therapeutic efficacy.