Dopamine D₃ receptor (D₃R) is implicated in multiple psychotic symptoms. Increasing the D₃R selectivity over dopamine D₂ receptor (D₂R) would facilitate the antipsychotic treatments. Herein, novel carbazole and tetrahydro-carboline derivatives were reported as D₃R selective ligands. Through a structure-based virtual screen, ZLG-25 (D₃R K_i = 685 nmol/L; D₂R K_i > 10,000 nmol/L) was identified as a novel D₃R selective bitopic ligand with a carbazole scaffold. Scaffolds hopping led to the discovery of novel D₃R-selective analogs with tetrahydro-β-carboline or tetrahydro-γ-carboline core. Further functional studies showed that most derivatives acted as hD₃R-selective antagonists. Several lead compounds could dose-dependently inhibit the MK-801-induced hyperactivity. Additional investigation revealed that 23j and 36b could decrease the apomorphine-induced climbing without cataleptic reaction. Furthermore, 36b demonstrated unusual antidepressant-like activity in the forced swimming tests and the tail suspension tests, and alleviated the MK-801-induced disruption of novel object recognition in mice. Additionally, preliminary studies confirmed the favorable PK/PD profiles, no weight gain and limited serum prolactin levels in mice. These results revealed that 36b provided potential opportunities to new antipsychotic drugs with the multiple antipsychotic-like properties.

ObjectiveTo explore the therapeutic effect and mechanism of Yiqi Huoxue Tongbian prescription on slow transit constipation （STC） in rats. MethodThe rat model of STC was established by gavage of loperamide hydrochloride. Rats were assigned into control， model， mosapride， low-， medium-， and high-dose （3.51， 7.02， and 14.04 g·kg^-1， respectively） Yiqi Huoxue Tongbian prescription groups. The changes of general signs， fecal moisture content， and intestinal propulsion rate were measured after model establishment and drug administration. The colonic mucosal changes were observed by hematoxylin eosin staining. Enzyme-linked immunosorbent assay was employed to determine the content of substance P （SP） and vasoactive intestinal peptide （VIP） in the colon of rats in each group. The gray values of aquaporin （AQP） 3， AQP4， AQP8， and c-Kit in rat colon tissue were measured by immunohistochemistry and Western blot， and the changes of intestinal flora were detected by 16S rRNA high-throughput sequencing. ResultCompared with the model group， 10 days of treatment with Yiqi Huoxue Tongbian prescription increased the fecal moisture content and intestinal propulsion rate （P<0.01）. The medium- and high-dose Yiqi Huoxue Tongbian prescription groups and the mosapride group showed no obvious mucosal inflammation and neat arrangement of goblet cells with a large number in the colon tissue. Moreover， the three groups showed increased SP content （P<0.01） and decreased VIP content （P<0.01） in the serum. The medium- and high-dose Yiqi Huoxue Tongbian prescription groups showed down-regulated protein levels of AQP3， AQP4， and AQP8 （P<0.01） and up-regulated protein level of c-Kit （P<0.01）. The drug administration groups presented slightly increased observed species， Chao1， ACE， and Shannon， Simpson， and PD whole tree. The principal component analysis showed that the control group had a short distance with the high- and medium-dose Yiqi Huoxue Tongbian prescription groups， indicating that high- and medium-dose Yiqi Huoxue Tongbian prescription can recover the intestinal flora to that in the control group. ConclusionYiqi Huoxue Tongbian prescription can alleviate the defecation status of rats with slow transit constipation by down-regulating the expression of AQP3， AQP4， and AQP8 to reduce the absorption of water in the intestine， up-regulating the expression of c-Kit to increase the number and distribution of Cajal interstitial cells， and regulating the balance of flora in the colon tissue.

Patients who initiated peritoneal dialysis (PD) in Sichuan Provincial People's Hospital from January 1, 2001 to December 31, 2013 were enrolled in the single center and retrospective study. Clinical and laboratory data were collected to analyze the long-term survival rates, technique survival rates and associated influencing factors. Patients were followed up until December 31, 2021 or endpoints occurred (death or stopping PD treatment). Kaplan-Meier survival curves were used to estimate survival rates and technique survival rates. Cox proportional hazards regression model was used to analyze the risk factors of death and technique failure in PD patients. A total of 373 patients were enrolled in the study, with age of (52.1±15.8) years old and 199 (53.4%) males. During the follow-up, 154 (41.3%) patients died, 72 (19.3%) patients transferred to hemodialysis, and 40 (10.7%) patients received kidney transplant. Kaplan-Meier survival curves revealed that overall survival rates of PD patients at 1, 3, 5, 7, and 10 years were 92.2%, 76.6%, 66.0%, 52.4% and 38.6%, respectively. Technique survival rates were 93.5%, 84.8%, 74.2%, 62.8% and 44.5% at 1, 3, 5, 7, and 10 years, respectively. Multivariate Cox regression model results showed that age ( HR=1.055, 95% CI 1.039-1.073, P<0.001), transfer from hemodialysis ( HR=2.212, 95% CI 1.514-3.231, P<0.001), episodes of peritonitis ( HR=2.141, 95% CI 1.194-3.837, P=0.011), Charlson comorbidity index ( HR=1.525, 95% CI 1.305-1.783, P<0.001), and baseline albumin ( HR=0.951, 95% CI 0.925-0.978, P<0.001) were independent influencing factors of survival in PD patients. Episodes of peritonitis ( HR=2.327, 95% CI 1.274-4.250, P=0.006) and Charlson comorbidity index ( HR=1.244, 95% CI 1.035-1.496, P=0.020) were independent influencing factors of technique survival in PD patients. PD patients have good early survival rates and technical survival rates, but long-term outcomes need to be further improved. Peritonitis is a major risk factor for low long-term survival rates and technical survival rates in PD patients.

Objective:To understand the prevalence of human parechovirus (HPeV) in neonates of Hunan Provincial People’s Hospital, and analyze genetic evolutionary characteristics.Methods:From June to September 2021, fecal samples of inpatient neonates were collected in Hunan Provincial People′s Hospital. TaqMan real-time qPCR and RT-PCR were used for HPeV screening and genotyping. High-throughput sequencing and PCR were used to obtain whole genomes. Phylogenetic analysis was performed after sequencing.Results:A total of 123 fecal samples of neonates were collected, of which 22 were HPeV positive, with 17.89% positive rate. All the strains belonged to the HPeV-1 genotype. One full-length genomic sequence of 7 269 bp were obtained, and provisionally named Hunan/HPeV/2021, which has the highest nucleotide identity with known HPeV-1 genotype, with 86.6%-91.9% nucleotide identity. The nucleotide and amino acid identity of open reading frame (ORF) with known similar sequences were 90.3%-92.6% and 97.3%-98.3%, respectively. The phylogenetic analysis showed that Hunan/HPeV/2021 belongs to the HPeV-1 genotype, which is clustered into the same clade as the popular HPeV-1 strains in China.Conclusions:HPeV has a high prevalence in inpatient neonates of Hunan Provincial People’s Hospital and belong to the HPeV-1 genotype.

Objective:To evaluate the effectiveness and safety of coronavirus disease 2019 (COVID-19) vaccines for dialysis patients with chronic kidney disease.Methods:PubMed, Medline, Embase databases and CNKI, VIP, Wanfang databases were searched systematically. The deadline was April 25, 2022. The search terms included haemodialysis, peritoneal dialysis, vaccine, seroresponse, COVID-19, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The main outcome included the positive rate after vaccination, antibody titer, antibody changes during follow-up, infection rate of SARS-CoV-2, hospitalization rate and mortality.Results:A total of 154 195 patients were analyzed in 26 studies. The results of meta-analysis showed that the positive rate of serum IgG antibody in patients with chronic kidney disease was 48% after the first dose of vaccine, 89% and 96% after the second dose and third dose, respectively. After vaccination with COVID-19 vaccines, there was no significant difference in serum antibody and titer between hemodialysis patients and peritoneal dialysis patients. However, compared with the healthy control group, the antibody positive rate and antibody titer of dialysis patients after vaccination were lower (both P<0.05). In the follow-up, the antibody positive rate at the third month decreased by 12% compared with at the first month, at the sixth month decreased by 15% compared with at the third month, and at the sixth month decreased by 20% compared with at the first month. The serum antibody positive rate after the third dose of vaccine increased by 38% ( RR=1.38, 95% CI 1.12-1.70, P<0.001), and the antibody titer increased significantly ( SMD=1.46, 95% CI 0.31-2.61, P<0.001). Although the vaccines could not reduce the infection rate of SARS-CoV-2 in dialysis patients, it could significantly reduce the hospitalization rate and mortality after infection. Conclusions:After vaccination with COVID-19 vaccines, dialysis patients can produce strong serum antibodies, which can reduce the hospitalization rate and mortality after SARS-CoV-2 infection. However, the duration of antibody is short and the titer level is low, so it is necessary to timely vaccinate booster vaccine dose to obtain stronger immunogenicity.

ObjectiveTo clarify the spatial distribution characteristics of medicinal plant resources in Gansu province， analyze the causes， changing trends， and driving factors of the spatial differentiation， and thus lay a scientific basis for the rational development and sustainable development of medicinal plant resources in this province. MethodBased on the data of The Fourth National Survey of Chinese Medicine Resources， the richness and spatial distribution difference of medicinal plant resources in 87 counties （districts） of Gansu province were analyzed via the global spatial autocorrelation analysis， trend surface analysis， local spatial autocorrelation analysis， and hotspot analysis. Moreover， the correlation of vegetation type， soil texture， annual average temperature， annual average precipitation， and altitude with the spatial distribution pattern of the medicinal plant resources was discussed. ResultCounties （districts） with high or low richness of medicinal plant resources in Gansu province were respectively clustered together. To be specific， counties （districts） with high richness of the medicinal resources were mainly in southeastern Gansu， while those with low richness in northwestern Gansu. The leading driving factors affecting the cold and hot spots included vegetation type， soil texture， and average annual rainfall. ConclusionThe species richness of medicinal plant resources in Gansu province rises from west to east and from north to south. The natural driving factors are the key to the diversity and spatial distribution pattern of medicinal plant resources， which show significant influence on them.

Objective:To optimize and evaluate the pretreatment method for high-throughput sequencing of fecal and tissue samples to improve the sensitivity of high-throughput sequencing in the study of virome.Methods:For fecal samples, five virus-positive samples that have been detoxified from feces were selected, mixed as the simulated samples, and filters made of different materials were used, different processing times were set for nucleases, and different kits were used to extract nucleic acid. For tissue samples, two virus-positive samples that have been detected in animal tissues, filter and nuclease treatment were used, and different extraction method were used to extract nucleic acid. TaqMan real-time PCR was used to quantitatively evaluate the impact of each treatment on the virus and the advantages and disadvantages were compared. We used the SYBR Green real-time PCR quantitative method to evaluate the removal effect of the above method on bacteria 16S rRNA and host 12S rRNA genome.Results:For fecal samples, the 0.22 μm PES filter showed a better filtering effect, and the PVDF material filter reduces the sample volume; 2 h nuclease digestion was better than 1 h digestion to remove bacteria, and the virus loss was less; the use of RPMK kits can effectively reduce bacteria, but the effect of extracting some viruses was poor, and the MVSK kit has a better effect of extracting viral nucleic acid. For tissue samples, 0.22 μm PES filter filtration, nuclease digestion for 1 h and VNAEK II kit extraction of nucleic acid were the best, Trizol LS combined with the RPMK method was better for gDNA removal, but the virus loss was larger. The virus loss of the whole process of the pretreatment method of feces and tissue samples was (1.7-3.0) Ct and (1.6-2.5) Ct, respectively.Conclusions:The optimal method for fecal samples was to filter with a PES filter, then digest with nuclease for 2 hours, and then extract nucleic acids using the MVSK kit; the optimal method for tissue samples was to filter with a PES filter, then perform 1 h nuclease digestion, and then use VNAEK II kit to extract nucleic acids.

Objective:To study the effect of baseline weight and its change on new-onset albuminuria or increased urine albumin/creatinine ratio (ACR) in the physical examination population.Methods:The subjects of this study were those who completed two or more physical examinations at the Physical Examination Center of Sichuan Provincial People's Hospital from September 1, 2013 to September 1, 2018. The general information and laboratory examination results at the first and last physical examinations were collected. According to body mass index (BMI), they were divided into normal BMI group and overweight/obese group. The differences in general clinical data and laboratory test results between the two groups were compared. The primary endpoint events were new-onset albuminuria or urine ACR increase≥30%. Stepwise multiple linear regression method was used to analyze the influencing factors for ACR increase, and Cox proportional hazard model method was used to analyze the impact of baseline weight and its change on new-onset albuminuria or ACR increase ≥30%.Results:A total of 1 761 physical examination subjects were included in this study. The follow-up time was (16.54±7.87) months. There were 59 patients with new-onset albuminuria, 30 patients with ACR increase≥30%, and 35 patients with albuminuria reversal. Multiple linear regression analysis showed that BMI was an independent influencing factor for ACR ( β=0.127, P<0.001). Cox regression analysis showed that the older age ( HR=1.041, 95% CI 1.018-1.064, P<0.001), hypertension ( HR=2.035, 95% CI 1.278-3.242, P=0.003), diabetes ( HR=2.081, 95% CI 1.310-3.305, P=0.002) and hyperuricemia ( HR=1.700, 95% CI 1.084-2.668, P=0.021) were independent influencing factors for new-onset albuminuria or ACR increase≥30%, while BMI ( HR=1.053, 95% CI 0.975-1.137, P=0.191) and weight change rate ( HR=1.030, 95% CI 0.972-1.092, P=0.322) were not independent influencing factors for endpoint events. Subgroup analysis indicated that overweight/obesity had interactions with age, hypertension, diabetes, and hyperuricemia, respectively ( P for interaction<0.05), and the effects of overweight/obesity on the pre-set primary endpoint events in each subgroup were basically consistent. There were interactions between weight gain and hypertension and diabetes ( P for interaction<0.05). Weight gain increased the risk of the primary endpoint events of women ( HR=3.355, 95% CI 1.164-9.670, P=0.025), and the effects of overweight/obesity on the pre-set primary endpoint events of each subcomponent were basically the same (all P>0.05). The incidence of albuminuria reversal in the group with obvious weight loss was slightly higher than that in the group with obvious weight gain, but the difference was not statistically significant ( P>0.05), which might be related to the small weight loss range (-6.08%±3.51%). Conclusions:Overweight or obesity may increase the risk of albuminuria, and people with diabetes, hypertension, and hyperuricemia may be more likely to occur. Mild weight loss is not enough to reverse albuminuria.

Objective: During the 2016 winter season, GII.2 norovirus(NoV) suddenly emerged in China. To elucidate its mechanism of epidemic, this study focused on characteristics of binding between the P protein of capsid and histo-blood group antigens (HBGAs). Methods: The research object was GⅡ.2 ZTX strain which had an outbreaks by the end of 2016 in Beijing. Recombinant prokaryotic expression plasmid was constructed, and the expression of virus P protein was determined and purified. The P protein characteristics of binding to HBGAs was studied through saliva and oligosaccharide binding experiments. Results: Soluble P protein was successfully obtained, and combined with type A, B, AB saliva. Conclusions The result illuminate the combination with new outbreaks of NoV and salivary types, which provided a basis for its pathogenic mechanism and prevention and control measures.

Objective To investigate the influences of drop components on the"coffee ring" test of DNA. Methods The DNA-EB drops containing SDS, NaCl, etc, were evaporated on glass slides. After evaporation, the fluorescent Deposition Pattern (DP) and Integrated Optical Density (IOD) was acquired with a gel imaging system. The dose-effect relationship was analyzed. Result When the non-DNA components concentration is low, the DP was still characteristiced by peripheral rings, subtle component-specific differences, such as tree-ring like structure and radial crack, existed. At high concentrations, DP was various, which may be ring + scattered dots (NaCl), central spot + small weak ring (SDS), concentric/tree-ring (TritonX-100) or ring + spot (H+), et al. Non-DNA components had little effect on IOD(0.5~2 times). Conclusion Non-DNA components in DNA-EB drops influences both the DP and IOD, but rough estimation of DNA concentrations is still effective. Moreover, analyzing the DP can provide more informations about sample purity and residue.