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Background: Delirium is an acute or subacute change in mental status caused by various factors. We evaluated the causal relationship between leisure sedentary behaviors (LSBs) and delirium., Methods: A two-sample Mendelian randomization (MR) study was performed to evaluate the causal relationship between sedentary behaviors (time spent watching television, time spent using computer, and time spent driving) and delirium. Statistical information for the associations between single nucleotide polymorphisms (SNPs) and the traits of interest was obtained from independent consortia that focused on European populations. The dataset for LSBs was acquired from genome-wide association studies (GWAS) comprising a substantial sample size: 437887 samples for time spent watching television, 360,895 for time spent using computer, and 310,555 for time spent driving. A GWAS with 1269 delirium cases and 209,487 controls was used to identify genetic variation underlying the time of LSBs. We used five complementary MR methods, including inverse variance weighted method (IVW), MR-Egger, weighted median, weighted mode, and simple mode., Results: Genetically predicted time spent watching television (odds ratio [OR]: 2.921, 95 % confidence interval [CI]: 1.381-6.179) demonstrated significant association with delirium (P = 0.005), whereas no significant associations were observed between time spent using computer (OR: 0.556, 95 % CI: 0.246-1.257, P = 0.158) and time spent driving (OR: 1.747, 95 % CI: 0.09-3. 40, P = 0.713) and delirium. Sensitivity analyses supported a causal interpretation, with limited evidence of significant bias from genetic pleiotropy. Moreover, our MR assumptions appeared to be upheld, enhancing the credibility of our conclusions., Limitations: Larger sample sizes are needed to validate the findings of our study., Conclusion: Time spent watching television is a significant risk factor for delirium. Reducing television time may be an important intervention for those at higher risk of delirium., Competing Interests: Declaration of competing interest The authors declare no competing interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Pulmonary arterial hypertension (PAH) is a pathophysiological syndrome that is extremely difficult to manage, and there is currently no effective treatment. We want to elucidate the therapeutic effect of ethyl pyruvate (EP) on PAH and its possible mechanism. Pulmonary artery endothelial cells (PAECs) were cultured in conventional low-oxygen environments, and cellular proliferation was monitored after treatment with EP. Expression of p-PI3K/Akt, LC3-II, and Beclin-1 was detected by Western blot. After hyperkinetic PAH rabbits' models were treated with EP, hemodynamic data were collected. Right ventricular hypertrophy and pulmonary vascular remodeling were evaluated. Expression of p-PI3K/Akt, LC3-II, and Beclin-1 protein was also detected after using autophagy inhibitor and agonists. We found that EP could inhibit PAECs proliferation. After EP treatment, expression of p-PI3K/Akt was upregulated in vitro and in vivo. LC3-II and Beclin-1 were inhibited and their expression was lower after autophagy inhibitor was given, while after administration of autophagy agonists, their expression was higher than that in the EP alone group. Besides, EP attenuated PAH, and right ventricular hypertrophy and pulmonary vascular remodeling were also reversed. EP can reduce PAH and reverse vascular remodeling which is associated with inhibition of autophagy in PAECs based on PI3K-Akt signaling pathway. The results of this study can provide surgical opportunities for patients with severe PAH caused by congenital heart disease in clinical cardiovascular surgery., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Delayed gastric emptying (DGE) commonly occurs after pancreaticoduodenectomy (PD). Risk factors for DGE have been reported in open PD but are rarely reported in laparoscopic PD (LPD). This study was designed to evaluate the perioperative risk factors for DGE and secondary DGE after LPD in a single center., Methods: This retrospective cohort study included patients who underwent LPD between October 2014 and April 2023. Demographic data, preoperative, intraoperative, and postoperative data were collected. The risk factors for DGE and secondary DGE were analyzed., Results: A total of 827 consecutive patients underwent LPD. One hundred and forty-two patients (17.2%) developed DGE of any type. Sixty-five patients (7.9%) had type A, 62 (7.5%) had type B, and the remaining 15 (1.8%) had type C DGE. Preoperative biliary drainage (p = 0.032), blood loss (p = 0.014), and 90-day any major complication with Dindo-Clavien score ≥ III (p < 0.001) were independent significant risk factors for DGE. Seventy-six (53.5%) patients were diagnosed with primary DGE, whereas 66 (46.5%) patients had DGE secondary to concomitant complications. Higher body mass index, soft pancreatic texture, and perioperative transfusion were independent risk factors for secondary DGE. Hospital stay and drainage tube removal time were significantly longer in the DGE and secondary DGE groups., Conclusion: Identifying patients at an increased risk of DGE and secondary DGE can be used to intervene earlier, avoid potential risk factors, and make more informed clinical decisions to shorten the duration of perioperative management., (© 2024. The Author(s).)

Centrifugal blood pumps are important devices used to treat heart failure. However, they are prone to high-risk suction events that pose a threat to human health when operating at high speeds. To address these issues, a normal suction detection method and a suction suppression method based on the FFT-GAPSO-LSTM model and speed modulation were proposed. The innovation of this suction detection method lies in the application of the genetic particle swarm optimisation (GAPSO) and the fast Fourier transform (FFT) feature extraction method to the long-term and short-term memory (LSTM) model, thereby improving the accuracy of suction detection. After detecting signs of suction, the suction suppression method designed in this study based on variable-speed modulation immediately takes effect, enabling the centrifugal blood pump to quickly return to its normal state by controlling the speed. The suction detection method was divided into four steps. First, a mathematical model of the coupling of the cardiovascular system and the centrifugal blood pump was established, and a real-time blood flow curve was obtained through model simulation. Second, the signal was preprocessed by adding Gaussian white noise and low-pass filtering to make the blood flow signal close to actual working conditions while retaining the original characteristics. Subsequently, through fast Fourier transform (FFT) analysis of the processed curve, the spectral characteristics that can characterise the working state of the centrifugal blood pump were extracted. Finally, the parameters of the LSTM model were optimised using the GAPSO, and the improved LSTM model was used to train and test the blood flow spectrum feature set. The results show that the suction detection method of the FFT-GAPSO-LSTM model can effectively detect whether centrifugal blood pump suction occurs and has certain advantages over other methods. In addition, the simulation results of the suction suppression were excellent and could effectively suppress the occurrence of suction. These results provide a reference for the design of centrifugal blood pump control systems., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Hongyi Qu reports financial support was provided by The Institute of Electrical Engineering, CAS (E155420201)., (© 2024 The Authors. Published by Elsevier Ltd.)

Aim: Hyperkinetic pulmonary arterial hypertension (PAH) is a complication of congenital heart disease. Gene therapy is a new experimental treatment for PAH, and ultrasound-mediated gene-carrying microbubble targeted delivery is a promising development for gene transfer., Methods: This study successfully established a hyperkinetic PAH rabbit model by a common carotid artery and jugular vein shunt using the cuff style method. Liposome microbubbles carrying the hepatocyte growth factor (HGF) gene were successfully constructed. An in vitro experiment evaluated the appropriate intensity of ultrasonic radiation by Western blots and 3H-TdR incorporation assays. In an in vivo experiment, after transfection of ultrasound-mediated HGF gene microbubbles, catheterisation was applied to collect haemodynamic data. Hypertrophy of the right ventricle was evaluated by measuring the right ventricle hypertrophy index. Western blot and immunohistochemistry analyses were used to detect the expression of human (h)HGF and angiogenic effects, respectively., Results: The most appropriate ultrasonic radiation intensity was 1.0 W/cm 2 for 5 minutes. Two weeks after transfection, both systolic pulmonary arterial pressure and mean pulmonary arterial pressure were attenuated. Hypertrophy of the right ventricle was reversed. hHGF was transplanted into the rabbits, resulting in a high expression of hHGF protein and an increase in the number of small pulmonary arteries. Ultrasound-mediated HGF gene microbubble therapy was more effective at attenuating PAH and increasing the density of small pulmonary arteries than single HGF plasmid transfection., Conclusions: Ultrasound-mediated HGF gene microbubbles significantly improved the target of gene therapy in a rabbit PAH model and enhanced the tropism and transfection rates. Thus, the technique can effectively promote small pulmonary angiogenesis and play a role in the treatment of PAH without adverse reactions., (Copyright © 2023 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.)

The term "peri-implantitis" (peri-implantitis) refers to an inflammatory lesion of the mucosa surrounding an endosseous implant and a progressive loss of the peri-implant bone that supports the implant. Recently, it has been suggested that the increased sensitivity of implants to infection and the quick elimination of supporting tissue after infection may be caused by a dysregulated peri-implant mucosal immune response. Macrophages are polarized in response to environmental signals and play multiple roles in peri-implantitis. In peri-implantitis lesion samples, recent investigations have discovered a considerable increase in M1 type macrophages, with M1 type macrophages contributing to the pro-inflammatory response brought on by bacteria, whereas M2 type macrophages contribute to inflammation remission and tissue repair. In an effort to better understand the pathogenesis of peri-implantitis and suggest potential immunomodulatory treatments for peri-implantitis in the direction of macrophage polarization patterns, this review summarizes the research findings related to macrophage polarization in peri-implantitis and compares them with periodontitis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Li, Li, Guo, Meng, Feng, Zhang and Pan.)

In this paper, we proposed a sliding mode control method for the bearingless permanent magnet slice motor for the blood pump based on the genetic particle swarm algorithm, which aims to solve the problems of strong coupling, strong interference, nonlinearity and uncertainty. Firstly, the mathematical model of rotor torque and suspension force of the bearingless permanent magnet slice motor is established. Secondly, the structure of sliding mode observer is deduced by designing sliding mode surface and control law. And, the performance parameters of sliding mode observer are optimized by the genetic particle swarm optimization algorithm. Thirdly, electromagnetic torque and suspension force control under this control method is studied by Simulink. Finally, the control method is applied to the control of the blood flow of the blood pump, and the rotation speed can effectively control the blood flow. The results indicate that compared with PID control and traditional sliding mode control methods, the sliding mode control method optimized by the genetic particle swarm optimization algorithm greatly improves the control performance of bearingless permanent magnet slice motor. The results show that the blood flow can meet expectations with a small error, which fully meets the blood perfusion requirements of the blood pump., (© 2023. The Author(s).)

Introduction: CT imaging analysis of mitral annulus (MA), coronary sinus (CS) and left circumflex artery (LCX) is critical to transcatheter mitral annuloplasty (TMA), which, however, is scantly reported. We aimed to comprehensively assess MA, CS and LCX anatomy and geometry in mitral regurgitation (MR) based on 3-D reconstruction of cardiac CT images., Methods: Patients with primary or secondary MR and patients without MR were recruited and underwent cardiac CT examination. MR severity was evaluated by echocardiography. 3-D reconstruction of cardiac CT images was done by the Mimics Research 21.0 software. A MA-centered two dimensional coordinate system, a CS plane, a MA plane and a series of auxiliary planes along the posterior MA were created for the measurement of parameters defining MA, CS and LCX anatomy and geometry during the cardiac cycle., Results: The secondary MR group had a significantly higher MA perimeter index than the other two groups during the cardiac cycle. The CS diameters at most sites, and the posterior MA radian were substantially greater in the two MR groups. Distances between the CS and MA at some locations were significant different among the three groups. The secondary MR group had a significantly smaller CS-MA plane angle than the other two groups during systole, and than control group during diastole. The site where the CS crossed LCX was pinpointed., Conclusion: The comprehensive information from this study may help improve the results of TMA and enhance the design of devices for a better annuloplasty effect., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Hypertrophic cardiomyopathy is a commonly inherited heart disease. In addition, single coronary artery (SCA) is a rare congenital anomaly of the coronary arteries. And SCA concomitant with severe hypertrophic obstructive cardiomyopathy (HOCM) has seldom been reported in the literature. However, such cases have not been reported to be treated with the Morrow procedure., Case Presentation: Herein, we presented a case of a 64-year-old female diagnosed with a single left coronary artery with severe HOCM. The HOCM was treated with the Morrow procedure. The patient was discharged on the seventh postoperative day and was asymptomatic during the follow-up., Conclusion: To our knowledge, this is the first study reporting a single left coronary artery with severe HOCM treated with the Morrow procedure. In addition, myocardial protection by cardioplegia antegrade perfusion was safe for the patient with SCA and HOCM., (© 2022. The Author(s).)

Background: Outcomes of pancreaticojejunostomy without pancreatic duct during open pancreaticoduodenectomy (OPD) are unknown and controversial, and corresponding reports in laparoscopic surgery are lacking., Methods: Patients were evaluated at West China Hospital, and standard laparoscopic pancreaticoduodenectomy (LPD) was planned. A prospective randomized trial was conducted, in which the patients were randomly assigned to the no-stent and internal-stent groups in a single-center trial. The primary outcomes were the incidence of clinically relevant postoperative pancreatic fistula (CR-POPF) and 90-day mortality. Preliminary results were reported., Results: From November 2019 to March 2021, we enrolled 90 patients (41 in the no-stent group and 49 in the internal-stent group) in the study. All baseline parameters of both groups, including age, sex ratio, pancreatic duct diameter, and intraoperative blood loss, were comparable between the two groups except for pathological diagnosis and the texture of remnants. Twenty-seven (65.9%) and 19 (38.8%) patients in the no-stent and internal-stent groups, respectively, had soft pancreatic remnants (P = 0.010). The total incidence of CR-POPF was 5.6% and included two patients (4.9%) in the no-stent group and three patients (6.1%) in the internal-stent group (P = 1.000). Only one patient in the internal-stent group died of heart failure within 90 days after the operation. No significant difference in other postoperative complications was observed between the groups except for biochemical fistula [no-stent group vs. internal-stent group = 31.7% vs. 12.2%, (P = 0.024)]., Conclusions: In a high-volume LPD center, duct-to-mucosa pancreaticojejunostomy without pancreatic duct stent is safe and reliable. In addition, duct-to-mucosa pancreaticojejunostomy without pancreatic duct stent was more challenge. We recommend using the stent during anastomosis and pulling it out after the procedure., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: The present study aims to assess the preliminary outcomes of the effectiveness of wrapping the ligamentum teres hepatis (LTH) around the gastroduodenal artery stump for the prevention of erosion hemorrhage after laparoscopic pancreaticoduodenectomy (LPD)., Methods: We reviewed 247 patients who had undergone LPD between January 2016 and April 2019. The patients were divided into two groups according to whether LTH wrapped the stump of the gastroduodenal artery: group A (119 patients) who underwent the LTH wrapping procedure, and group B (128 patients) who did not undergo the procedure. The perioperative data from the two groups were reviewed to assess the effectiveness of the LTH procedure for the prevention of postpancreatectomy hemorrhage (PPH) and other complications., Results: No differences were observed in the clinical characteristics between the two groups. The data from 247 patients were acceptable for analysis: 119 patients underwent wrapping, and 128 patients did not. The incidence of clinically relevant pancreatic fistula (8.4% vs 3.9%), biliary fistula (2.5% vs 1.6%), intra-abdominal infection (10.1% vs 3.9%) and delayed gastric emptying (13.4% vs 16.4%) showed no significant difference between group A and group B. The 90-day mortality and 90-day reoperation rates (0.8% vs 0.8% and 5.0% vs 3.1%) were also similar between group A and group B. Furthermore, postpancreatectomy hemorrhage of Grade B and C occurred in 0 patients (0.0%) in the wrapping group, which was significantly less frequent than the occurrence in the nonwrapping group (7 patients; 5.5%, P = 0.02)., Conclusions: Wrapping the LTH around the gastroduodenal artery stump after LPD does not reduce the incidence of clinically relevant pancreatic fistula, biliary fistula or delayed gastric emptying. However, this procedure has a trend of reducing the rate of PPH of Grade B and C after LPD and is simple to perform.

Background: With the recent emerge of dynamic prediction model on the use of diabetes, cardiovascular diseases and renal failure, and its advantage of providing timely predicted results according to the fluctuation of the condition of the patients, we aim to develop a dynamic prediction model with its corresponding risk assessment chart for clinically relevant postoperative pancreatic fistula after laparoscopic pancreaticoduodenectomy by combining baseline factors and postoperative time-relevant drainage fluid amylase level and C-reactive protein-to-albumin ratio., Methods: We collected data of 251 patients undergoing LPD at West China Hospital of Sichuan University from January 2016 to April 2019. We extracted preoperative and intraoperative baseline factors and time-window of postoperative drainage fluid amylase and C-reactive protein-to-albumin ratio relevant to clinically relevant pancreatic fistula by performing univariate and multivariate analyses, developing a time-relevant logistic model with the evaluation of its discrimination ability. We also established a risk assessment chart in each time-point., Results: The proportion of the patients who developed clinically relevant postoperative pancreatic fistula after laparoscopic pancreaticoduodenectomy was 7.6% (19/251); preoperative albumin and creatine levels, as well as drainage fluid amylase and C-reactive protein-to-albumin ratio on postoperative days 2, 3, and 5, were the independent risk factors for clinically relevant postoperative pancreatic fistula. The cut-off points of the prediction value of each time-relevant logistic model were 14.0% (sensitivity: 81.9%, specificity: 86.5%), 8.3% (sensitivity: 85.7%, specificity: 79.1%), and 7.4% (sensitivity: 76.9%, specificity: 85.9%) on postoperative days 2, 3, and 5, respectively, the area under the receiver operating characteristic curve was 0.866 (95% CI 0.737-0.996), 0.896 (95% CI 0.814-0.978), and 0.888 (95% CI 0.806-0.971), respectively., Conclusions: The dynamic prediction model for clinically relevant postoperative pancreatic fistula has a good to very good discriminative ability and predictive accuracy. Patients whose predictive values were above 14.0%, 8.3%, and 7.5% on postoperative days 2, 3, and 5 would be very likely to develop clinically relevant postoperative pancreatic fistula after laparoscopic pancreaticoduodenectomy.

Background: Laparoscopic pancreaticoduodenectomy (LPD) technique with artificial vascular graft reconstruction for patients with borderline resectable pancreatic cancer has been rarely reported since it is a very challenging technique. However, preliminary experience for the technique has been reported at the Department of Pancreatic Surgery, West China Hospital, Sichuan University.1,2 The rising popularity of neoadjuvant chemotherapy for pancreatic cancer patients may result in the increase of operative difficulty due to tissue edema and many other factors caused by the chemotherapy. The main aim of this study was to demonstrate the feasibility, safety, and key surgical procedure for LPD using video evidence., Methods: A three-dimensional upper abdominal computed tomography angiography (CTA) scan done to a 51-year-old man brought to the center with upper abdominal pain showed a mass in the uncinate process of the pancreas, with over 180-degree involvement of the superior mesenteric vein. Percutaneous transhepatic cholangial drainage (PTCD) was performed to reduce jaundice while endoscopic ultrasound and fine-needle aspiration (EUS-FNA) were done to confirm the diagnosis of adenocarcinoma. The patient underwent two cycles of neoadjuvant chemotherapy using albumin-bound paclitaxel gemcitabine + program. The chemotherapy helped in significantly relieving the symptoms where CA 199 reduced from 586.7 IU/ml to 36.73 IU/ml, and the tumor maximum diameter was reduced from 4.3 cm to 2.2 cm. The violated superior mesenteric vein (SMV) and the tumor were en bloc resected, and a 4.0-cm artificial vascular graft was placed for reconstruction. Bing's anastomosis was performed using pancreaticojejunostomy3 while cholangiojejunostomy was performed using continuous stitching. The gastroduodenal artery (GDA) stump was wrapped with ligamentum teres hepatis after the completion of gastrointestinal anastomosis. The specimen was then removed through the extended umbilical incision (4 cm) and the operation was completed after the drainage tube was placed., Results: The length of intraoperative excisional SMV, duration of artificial vascular graft reconstruction, operation time, and volume of intraoperative blood loss were 4.0 cm, 30 min, 520 min, and 800 mL, respectively. Histopathological examination of ypT2N1 indicated that 1 of the 27 lymph nodes was positive. Pathological results showed a moderately differentiated adenocarcinoma with all margins being negative., Conclusions: This study demonstrated the feasibility of total laparoscopic pancreaticoduodenectomy combined with vascular resection and artificial vascular graft reconstruction in properly selected cases of pancreatic cancer with vein involvement after neoadjuvant chemotherapy. It is worth noting that skilled laparoscopic technicians and effective teamwork are necessities for safe completion of the procedure.

Objective: The aim of the study was to evaluate the effect of age on outcomes with pancreatic ductal adenocarcinoma (PDAC) undergoing laparoscopic pancreaticoduodenectomy (LPD)., Methods: We retrospectively collected clinical data of consecutive patients with PDAC undergoing LPD from January 2012 to April 2019. The patients were divided into 2 groups according to age at admission for LPD: younger than 70 and 70 years or older., Results: A total of 147 patients were included (<70 years, n = 96; ≥70 years, n = 51). The elderly LPD patients had lower serum albumin levels (mean, 37.9 [standard deviation, 4.8] g/L vs 40.7 [standard deviation, 6.8] g/L, P = 0.004) and a larger frequency of comorbidities (62.7% vs 36.5%, P = 0.002) than younger patients. The short-term outcomes showed no significant differences. The median overall survival time of the younger patients was not significantly greater than that of the elderly patients (20.0 [95% confidence interval, 16.1-23.9] months vs 19.0 [95% confidence interval, 13.8-24.2] months, P = 0.902)., Conclusions: The short- and long-term outcomes of elderly patients with PDAC after LPD were similar to those of younger patients, despite a higher prevalence of multiple chronic illnesses and poorer nutritional conditioning among the elderly patients. These results show that LPD can be applied safely to elderly patients.

The effects of Makgeolli, dry yeast (DY), sourdough with dry yeast (SDDY) and sourdough with Makgeolli (SDMG) on the quality of fermented rice cakes (FRCs) stored at 23 °C for 3 days were determined. The acidity of SDDY and SDMG significantly increased with increasing fermentation time. The FRCs supplemented with sourdough had slightly higher moisture contents than others. The addition of DY and SDDY increased the specific volume of the FRC, in which its texture was softer. The addition of DY and sourdoughs significantly decreased the firming rate of crumb and improved the sensory qualities. The sourdoughs retarded amylopectin retrogradation, indicating their anti-staling effect on the FRC. Compared to the control, the shelf-lives of FRCs made with DY and SDDY were extended by 0.7 and 0.5 days based on the instrumental hardness, respectively. DY and SDDY effectively improved the appearance and texture of FRC and extended its shelf-life., Competing Interests: Conflict of interestThe authors declare that they have no conflict of interest., (© The Korean Society of Food Science and Technology 2020.)

The extrapyramidal side effects of schizophrenia treatment can be significantly reduced by simultaneously targeting dopamine D 2 and serotonin 5-HT 2A receptors. In this study, three-dimensional quantitative structure-activity relationship (3D-QSAR) models of D 2 receptor (CoMFA-1, q 2 = 0.767, r 2 = 0.969; CoMSIA-1, q 2 = 0.717, r 2 = 0.978) and 5-HT 2A receptor antagonists (CoMFA-2, q 2 = 0.703, r 2 = 0.946; CoMSIA-2, q 2 = 0.675, r 2 = 0.916) were successfully constructed using 35 tetrahydropyridopyrimidinone derivatives. Topomer CoMFA and HQSAR models were then constructed to further validate and supplement above models. Results showed that all models had good predictive power and stability. Contour map analysis revealed that the electrostatic and hydrophobic fields played vital roles in the bioactivity of dual antagonists. Molecular docking and molecular dynamic studies also suggested that the hydrogen bonding, electrostatic and hydrophobic interactions played key roles in the formation of stable binding sites. Meanwhile, several key residues like ASP114, TRP100, PHE389 of dopamine D 2 receptor and ASP134, PHE328, TRP324 of serotonin 5-HT 2A receptor were identified. Based on above findings, seven compounds were obtained through bioisostere replacement and ten compounds were designed by contour map analysis, in which the predicted activity of compounds S6 and DS2 were equivalent to that of the template compound 15 . 3D-QSAR and ADMET predictions indicated that all newly designed compounds had great biological activity and physicochemical properties. Moreover, based on the best pharmacophore model, four compounds ( Z1 , Z2 , Z3 and Z4 ) with new backbones were obtained by virtual screening. Overall, this study could provide theoretical guidance for the structural optimization, design and synthesis of novel dopamine D 2 and serotonin 5-HT 2A receptors dual antagonists. Abbreviations3D-QSARThree-dimensional quantitative structure-activity relationship5-HT 2A RSerotonin 5-hydroxytryptamine 5-HT 2A receptor5-HT 2C RSerotonin 5-hydroxytryptamine 5-HT 2C receptor receptorCADDComputer-aided drug designCoMFAComparative molecular field analysisCoMSIAComparative molecular similarity index analysisD 2 RDopamine D(2) receptorGPCRG-protein coupled receptorPLSPartial least squares regressionHQSARHologram quantitative structure-activity relationship. Communicated by Ramaswamy H. Sarma.

Tri-block copolymers have exhibited great potentials in small interfering RNA (siRNA) therapeutics. To reveal structure-activity relationships, we here synthesized a series of tri-block copolymers with different hydrophobic segments, PEG-PAMA-P(C6A x -C7A y -DPA z -DBA m ) (EAAS) and PEG-PDAMAEMA-P(C6A x -C7A y -DPA z -DBA m ) (EDAS), termed from EAASa to EAASh and EDASa to EDASh, with pKa ranging from 5.2 to 7.0. Our data showed that the better gene silencing efficiency was located in pKa of 5.8-6.2, which was contributed from higher endosomal escape observed with confocal images and hemolysis assay. EAASc, the leader polymer, showed excellent gene knockdown at w/w ratio of 14.5 on HepG2 (89.94%), MDA-MB-231 (92.45%), 293A (83.06%), and Hela cells (80.27%), all better than lipofectamine 2000. Besides, EAASc mediated effective gene silencing in tumor when performed peritumoral injection. This work found out that polymers with pKa ranging from 5.8 to 6.2 were efficient in siRNA delivery, which provided an optimization strategy for siRNA delivery systems, especially for tri-block copolymers., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)