Objective To introduce the modeling method of pendulum-like modified rat abdominal heart heterotopic transplantation model and evaluate the quality of the model. Methods An operator without transplantation experience performed 15 consecutive models, recorded the time of each step, changes in body weight and modified Stanford scores, and calculated the surgical success rate, postoperative 1-week survival rate and technical success rate. Ultrasound examinations was performed in 1 week postoperatively. Results The times for donor heart acquisition, donor heart processing, recipient preparation and transplantation anastomosis were (14.3±1.4) min, (3.5±0.6) min, (13.6±2.1) min and (38.3±5.2) min respectively. The surgical success rate was 87% (13/15), and the survival rate 1 week after operative was 100% (13/13). The improved Stanford score indicated a technical success rate of 92% (12/13), and the postoperative 1-week ultrasound examination showed that grafts with Stanford scores ≥3 had detectable pulsation and blood flow signals. Conclusions The pendulum-like modified rat abdominal heart heterotopic transplantation improved model further optimizes the operational steps with a high success rate and stable quality, may be chosen as a modeling option for basic research in heart transplantation in the future.

Diterpenoid ferruginol is a key intermediate in biosynthesis of active ingredients such as tanshinone and carnosic acid.However, the traditional process of obtaining ferruginol from plants is often cumbersome and inefficient. In recent years, the increasingly developing gene editing technology has been gradually applied to the heterologous production of natural products, but the production of ferruginol in microbe is still very low, which has become an obstacle to the efficient biosynthesis of downstream chemicals, such as tanshinone. In this study, miltiradiene was produced by integrating the shortened diterpene synthase fusion protein,and the key genes in the MVA pathway were overexpressed to improve the yield of miltiradiene. Under the shake flask fermentation condition, the yield of miltiradiene reached about(113. 12±17. 4)mg·L~(-1). Subsequently, this study integrated the ferruginol synthase Sm CYP76AH1 and Sm CPR1 to reconstruct the ferruginol pathway and thereby realized the heterologous synthesis of ferruginol in Saccharomyces cerevisiae. The study selected the best ferruginol synthase(Il CYP76AH46) from different plants and optimized the expression of pathway genes through redox partner engineering to increase the yield of ferruginol. By increasing the copy number of diterpene synthase, CYP450, and CPR, the yield of ferruginol reached(370. 39± 21. 65) mg·L~(-1) in the shake flask, which was increased by 21. 57-fold compared with that when the initial ferruginol strain JMLT05 was used. Finally, 1 083. 51 mg·L~(-1) ferruginol was obtained by fed-batch fermentation, which is the highest yield of ferruginol from biosynthesis so far. This study provides not only research ideas for other metabolic engineering but also a platform for the construction of cell factories for downstream products.
Saccharomyces cerevisiae/genetics* ; Diterpenes/metabolism* ; Metabolic Engineering ; Fermentation ; Abietanes

Colorectal cancer(CRC) is a common malignant tumor worldwide. Due to the treatment intolerance and side effects, CRC rank the top among various cancers regarding the incidence and mortality rates. Therefore, exploring new therapies is of great significance for the treatment of CRC. Aerobic glycolysis(AEG) plays an important role in the microenvironment formation, proliferation, metastasis, and recurrence of CRC and other tumor cells. It has been confirmed that intervening in the AEG pathway can effectively curb CRC. The active ingredients and compound prescriptions of traditional Chinese medicine(TCM) can effectively inhibit the proliferation, metastasis, and drug resistance and regulate the apoptosis of tumor cells by modulating AEG-associated transport proteins [eg, glucose transporters(GLUT)], key enzymes [hexokinase(HK) and phosphofructokinase(PFK)], key genes [hypoxia-inducible factor 1(HIF-1) and oncogene(c-Myc)], and signaling pathways(MET/PI3K/Akt/mTOR). Accordingly, they can treat CRC, reduce the recurrence, and improve the prognosis of CRC. Although AEG plays a key role in the development and progression of CRC, the specific mechanisms are not yet fully understood. Therefore, this article delves into the intrinsic connection of the targets and mechanisms of the AEG pathway with CRC from the perspective of tumor cell glycolysis and explores how active ingredients(oxymatrine, kaempferol, and dioscin) and compound prescriptions(Quxie Capsules, Jiedu Sangen Decoction, and Xianlian Jiedu Prescription) of TCM treat CRC by intervening in the AEG pathway. Additionally, this article explores the shortcomings in the current research, aiming to provide reliable targets and a theoretical basis for treating CRC with TCM.
Humans ; Colorectal Neoplasms/genetics* ; Drugs, Chinese Herbal/therapeutic use* ; Glycolysis/drug effects* ; Animals ; Medicine, Chinese Traditional ; Signal Transduction/drug effects*

Sigma-1 receptor (σ ₁R) has become a focus point of drug discovery for central nervous system (CNS) diseases. A series of novel 1-phenylethan-1-one O-(2-aminoethyl) oxime derivatives were synthesized. In vitro biological evaluation led to the identification of 1a, 14a, 15d and 16d as the most high-affinity (K _i < 4 nmol/L) and selective σ ₁R agonists. Among these, 15d, the most metabolically stable derivative exhibited high selectivity for σ ₁R in relation to σ ₂R and 52 other human targets. In addition to low CYP450 inhibition and induction, 15d also exhibited high brain permeability and excellent oral bioavailability. Importantly, 15d demonstrated effective antipsychotic potency, particularly for alleviating negative symptoms and improving cognitive impairment in experimental animal models, both of which are major challenges for schizophrenia treatment. Moreover, 15d produced no significant extrapyramidal symptoms, exhibiting superior pharmacological profiles in relation to current antipsychotic drugs. Mechanistically, 15d inhibited GSK3β and enhanced prefrontal BDNF expression and excitatory synaptic transmission in pyramidal neurons. Collectively, these in vivo proof-of-concept findings provide substantial experimental evidence to demonstrate that modulating σ ₁R represents a potential new therapeutic approach for schizophrenia. The novel chemical entity along with its favorable drug-like and pharmacological profile of 15d renders it a promising candidate for treating schizophrenia.

Objective:The study aimed to investigate the factors of pregnancy failures in patients with low ser-um anti-Müllerian hormone(AMH)level after in vitro fertilization(IVF)or intracytoplasmic sperm injection(ICSI).Method:The clinical outcome of 1184 cycles in 931 patients with serum AMH＜1.1 ng/ml undergoing IVF/ICSI at the Department of Reproductive Medicine of West China Second Hospital,Sichuan University between January 1,2020 and December 31,2020,was retrospectively studied.In total,503 patients(525 cycles)underwent embryo transfer,including clinical pregnant group in 193 patients(193 cycles)and clinical non-pregnant group in 310 pa-tients(332 cycles).All of the patients were divided into three different groups according to their chronological age(＜35,35-＜40,40-51 years old)and five different serum AMH levels(＜0.06 ng/ml,0.06-＜0.20 ng/ml,0.20-＜0.50 ng/ml,0.50-＜0.80 ng/ml,0.80-＜1.10 ng/ml),to explore the relationship with IVF pregnancy outcomes.Multivariate Logistic regression analysis was carried out to explore factors affecting pregnancy out-comes afer IVF/ICSI.Results:①Compared with the clinical pregnancy group,the clinical non-pregnant patients were older,AMH level and antral follicle count(AFC)were lower,the number of MII,2PN,available embryos and top quality embryos were also lower,and endometrial thickness at oocyte pickup(OPU)was thinner,and differ-ences above were statistically significant(P＜0.05).②AMH level,AFC,BMI,total Gn and MII number were signifi-cantly different among different age groups(P＜0.05).The clinical pregnancy rate per transplantation cycle,per oocyte pickup cycle and per ovulation induction cycle also had statistically significant differences(P＜0.001),and the pregnancy rate showed a decreasing trend with the increase of age.③There were significant differences in clinical pregnancy rate per transplantation cycle,per oocyte pickup cycle and per ovulation induction cycle among different ranges of low level AMH(P＜0.05).④Multivariable Logistic regression analysis confirmed that the prob-ability of pregnancy in patients with low AMH level after transfering embryo was significantly affected by patients'age(P=0.002).Receiver operating characteristic(ROC)curve showed that the best cut-off value for predicting clinical pregnancy was 35.5 years,the area under the curve(AUC)was 0.634(95%CI 0.586-0.682,P＜0.001).Conclusions:Patients with low AMH level(＜1.1 ng/ml)still have a good chance of pregnancy after IVF/ICSI treatment,and the most notable influencing factor is the patient's chronological age,rather than AMH.When the actual age of patients is less than 35.5 years,the clinical pregnancy outcome after transferring embryo is better e-ven with low AMH level.

Objective:The study aimed to investigate the factors of pregnancy failures in patients with low ser-um anti-Müllerian hormone(AMH)level after in vitro fertilization(IVF)or intracytoplasmic sperm injection(ICSI).Method:The clinical outcome of 1184 cycles in 931 patients with serum AMH＜1.1 ng/ml undergoing IVF/ICSI at the Department of Reproductive Medicine of West China Second Hospital,Sichuan University between January 1,2020 and December 31,2020,was retrospectively studied.In total,503 patients(525 cycles)underwent embryo transfer,including clinical pregnant group in 193 patients(193 cycles)and clinical non-pregnant group in 310 pa-tients(332 cycles).All of the patients were divided into three different groups according to their chronological age(＜35,35-＜40,40-51 years old)and five different serum AMH levels(＜0.06 ng/ml,0.06-＜0.20 ng/ml,0.20-＜0.50 ng/ml,0.50-＜0.80 ng/ml,0.80-＜1.10 ng/ml),to explore the relationship with IVF pregnancy outcomes.Multivariate Logistic regression analysis was carried out to explore factors affecting pregnancy out-comes afer IVF/ICSI.Results:①Compared with the clinical pregnancy group,the clinical non-pregnant patients were older,AMH level and antral follicle count(AFC)were lower,the number of MII,2PN,available embryos and top quality embryos were also lower,and endometrial thickness at oocyte pickup(OPU)was thinner,and differ-ences above were statistically significant(P＜0.05).②AMH level,AFC,BMI,total Gn and MII number were signifi-cantly different among different age groups(P＜0.05).The clinical pregnancy rate per transplantation cycle,per oocyte pickup cycle and per ovulation induction cycle also had statistically significant differences(P＜0.001),and the pregnancy rate showed a decreasing trend with the increase of age.③There were significant differences in clinical pregnancy rate per transplantation cycle,per oocyte pickup cycle and per ovulation induction cycle among different ranges of low level AMH(P＜0.05).④Multivariable Logistic regression analysis confirmed that the prob-ability of pregnancy in patients with low AMH level after transfering embryo was significantly affected by patients'age(P=0.002).Receiver operating characteristic(ROC)curve showed that the best cut-off value for predicting clinical pregnancy was 35.5 years,the area under the curve(AUC)was 0.634(95%CI 0.586-0.682,P＜0.001).Conclusions:Patients with low AMH level(＜1.1 ng/ml)still have a good chance of pregnancy after IVF/ICSI treatment,and the most notable influencing factor is the patient's chronological age,rather than AMH.When the actual age of patients is less than 35.5 years,the clinical pregnancy outcome after transferring embryo is better e-ven with low AMH level.

The breakage pattern of unit particles during the production of oral solid dosage forms (OSD) is closely related to the quality of intermediate or final products. To accurately characterize the particles and study the evolution law of particle breakage, the Bonding model of the discrete element method (DEM) was used to investigate the breakage patterns of model parameters, particle shape and process conditions (loading mode and loading rate) on the dynamic breakage, force-time curve, breakage rate, maximum breakage size ratio and fracture strength of particles. The results showed that the particle breakage force was positively correlated with normal strength and bonded disk scale, negatively correlated with normal stiffness per unit area and tangential stiffness per unit area, and weakly correlated with tangential strength. The particle breakage rate was negatively correlated with the aspect ratio of the particles, and the maximum breakage size ratio was positively correlated with the aspect ratio of the particles; among the three loading modes, the breakage rate of compression breakage model was the largest, the breakage rate of shear breakage model was the second largest, and the breakage rate of wear breakage model was the smallest; the maximum breakage size ratio was positively correlated with the loading rate, the loading mode and the loading rate had no mutual influence on particle breakage rate, but had mutual influence on the maximum breakage size ratio. The research results will provide a theoretical basis for the shift of OSD from batch manufacturing to advanced manufacturing.

Objective:The study aimed to investigate the factors of pregnancy failures in patients with low ser-um anti-Müllerian hormone(AMH)level after in vitro fertilization(IVF)or intracytoplasmic sperm injection(ICSI).Method:The clinical outcome of 1184 cycles in 931 patients with serum AMH＜1.1 ng/ml undergoing IVF/ICSI at the Department of Reproductive Medicine of West China Second Hospital,Sichuan University between January 1,2020 and December 31,2020,was retrospectively studied.In total,503 patients(525 cycles)underwent embryo transfer,including clinical pregnant group in 193 patients(193 cycles)and clinical non-pregnant group in 310 pa-tients(332 cycles).All of the patients were divided into three different groups according to their chronological age(＜35,35-＜40,40-51 years old)and five different serum AMH levels(＜0.06 ng/ml,0.06-＜0.20 ng/ml,0.20-＜0.50 ng/ml,0.50-＜0.80 ng/ml,0.80-＜1.10 ng/ml),to explore the relationship with IVF pregnancy outcomes.Multivariate Logistic regression analysis was carried out to explore factors affecting pregnancy out-comes afer IVF/ICSI.Results:①Compared with the clinical pregnancy group,the clinical non-pregnant patients were older,AMH level and antral follicle count(AFC)were lower,the number of MII,2PN,available embryos and top quality embryos were also lower,and endometrial thickness at oocyte pickup(OPU)was thinner,and differ-ences above were statistically significant(P＜0.05).②AMH level,AFC,BMI,total Gn and MII number were signifi-cantly different among different age groups(P＜0.05).The clinical pregnancy rate per transplantation cycle,per oocyte pickup cycle and per ovulation induction cycle also had statistically significant differences(P＜0.001),and the pregnancy rate showed a decreasing trend with the increase of age.③There were significant differences in clinical pregnancy rate per transplantation cycle,per oocyte pickup cycle and per ovulation induction cycle among different ranges of low level AMH(P＜0.05).④Multivariable Logistic regression analysis confirmed that the prob-ability of pregnancy in patients with low AMH level after transfering embryo was significantly affected by patients'age(P=0.002).Receiver operating characteristic(ROC)curve showed that the best cut-off value for predicting clinical pregnancy was 35.5 years,the area under the curve(AUC)was 0.634(95%CI 0.586-0.682,P＜0.001).Conclusions:Patients with low AMH level(＜1.1 ng/ml)still have a good chance of pregnancy after IVF/ICSI treatment,and the most notable influencing factor is the patient's chronological age,rather than AMH.When the actual age of patients is less than 35.5 years,the clinical pregnancy outcome after transferring embryo is better e-ven with low AMH level.

Objective:The study aimed to investigate the factors of pregnancy failures in patients with low ser-um anti-Müllerian hormone(AMH)level after in vitro fertilization(IVF)or intracytoplasmic sperm injection(ICSI).Method:The clinical outcome of 1184 cycles in 931 patients with serum AMH＜1.1 ng/ml undergoing IVF/ICSI at the Department of Reproductive Medicine of West China Second Hospital,Sichuan University between January 1,2020 and December 31,2020,was retrospectively studied.In total,503 patients(525 cycles)underwent embryo transfer,including clinical pregnant group in 193 patients(193 cycles)and clinical non-pregnant group in 310 pa-tients(332 cycles).All of the patients were divided into three different groups according to their chronological age(＜35,35-＜40,40-51 years old)and five different serum AMH levels(＜0.06 ng/ml,0.06-＜0.20 ng/ml,0.20-＜0.50 ng/ml,0.50-＜0.80 ng/ml,0.80-＜1.10 ng/ml),to explore the relationship with IVF pregnancy outcomes.Multivariate Logistic regression analysis was carried out to explore factors affecting pregnancy out-comes afer IVF/ICSI.Results:①Compared with the clinical pregnancy group,the clinical non-pregnant patients were older,AMH level and antral follicle count(AFC)were lower,the number of MII,2PN,available embryos and top quality embryos were also lower,and endometrial thickness at oocyte pickup(OPU)was thinner,and differ-ences above were statistically significant(P＜0.05).②AMH level,AFC,BMI,total Gn and MII number were signifi-cantly different among different age groups(P＜0.05).The clinical pregnancy rate per transplantation cycle,per oocyte pickup cycle and per ovulation induction cycle also had statistically significant differences(P＜0.001),and the pregnancy rate showed a decreasing trend with the increase of age.③There were significant differences in clinical pregnancy rate per transplantation cycle,per oocyte pickup cycle and per ovulation induction cycle among different ranges of low level AMH(P＜0.05).④Multivariable Logistic regression analysis confirmed that the prob-ability of pregnancy in patients with low AMH level after transfering embryo was significantly affected by patients'age(P=0.002).Receiver operating characteristic(ROC)curve showed that the best cut-off value for predicting clinical pregnancy was 35.5 years,the area under the curve(AUC)was 0.634(95%CI 0.586-0.682,P＜0.001).Conclusions:Patients with low AMH level(＜1.1 ng/ml)still have a good chance of pregnancy after IVF/ICSI treatment,and the most notable influencing factor is the patient's chronological age,rather than AMH.When the actual age of patients is less than 35.5 years,the clinical pregnancy outcome after transferring embryo is better e-ven with low AMH level.

Objective:The study aimed to investigate the factors of pregnancy failures in patients with low ser-um anti-Müllerian hormone(AMH)level after in vitro fertilization(IVF)or intracytoplasmic sperm injection(ICSI).Method:The clinical outcome of 1184 cycles in 931 patients with serum AMH＜1.1 ng/ml undergoing IVF/ICSI at the Department of Reproductive Medicine of West China Second Hospital,Sichuan University between January 1,2020 and December 31,2020,was retrospectively studied.In total,503 patients(525 cycles)underwent embryo transfer,including clinical pregnant group in 193 patients(193 cycles)and clinical non-pregnant group in 310 pa-tients(332 cycles).All of the patients were divided into three different groups according to their chronological age(＜35,35-＜40,40-51 years old)and five different serum AMH levels(＜0.06 ng/ml,0.06-＜0.20 ng/ml,0.20-＜0.50 ng/ml,0.50-＜0.80 ng/ml,0.80-＜1.10 ng/ml),to explore the relationship with IVF pregnancy outcomes.Multivariate Logistic regression analysis was carried out to explore factors affecting pregnancy out-comes afer IVF/ICSI.Results:①Compared with the clinical pregnancy group,the clinical non-pregnant patients were older,AMH level and antral follicle count(AFC)were lower,the number of MII,2PN,available embryos and top quality embryos were also lower,and endometrial thickness at oocyte pickup(OPU)was thinner,and differ-ences above were statistically significant(P＜0.05).②AMH level,AFC,BMI,total Gn and MII number were signifi-cantly different among different age groups(P＜0.05).The clinical pregnancy rate per transplantation cycle,per oocyte pickup cycle and per ovulation induction cycle also had statistically significant differences(P＜0.001),and the pregnancy rate showed a decreasing trend with the increase of age.③There were significant differences in clinical pregnancy rate per transplantation cycle,per oocyte pickup cycle and per ovulation induction cycle among different ranges of low level AMH(P＜0.05).④Multivariable Logistic regression analysis confirmed that the prob-ability of pregnancy in patients with low AMH level after transfering embryo was significantly affected by patients'age(P=0.002).Receiver operating characteristic(ROC)curve showed that the best cut-off value for predicting clinical pregnancy was 35.5 years,the area under the curve(AUC)was 0.634(95%CI 0.586-0.682,P＜0.001).Conclusions:Patients with low AMH level(＜1.1 ng/ml)still have a good chance of pregnancy after IVF/ICSI treatment,and the most notable influencing factor is the patient's chronological age,rather than AMH.When the actual age of patients is less than 35.5 years,the clinical pregnancy outcome after transferring embryo is better e-ven with low AMH level.