(+)-Borneol, the main component of "Natural Borneol" in the Chinese Pharmacopoeia, is a high-end spice and precious medicine. Plant extraction cannot meet the increasing demand for (+)-borneol, while microbial biosynthesis offers a sustainable supply route. However, its production was extremely low compared with other monoterpenes, even with extensively optimizing the mevalonate pathway. We found that the key challenge is the complex and unusual dephosphorylation reaction of bornyl diphosphate (BPP), which suffers the side-reaction and the competition from the cellular dephosphorylation process, especially lipid metabolism, thus limiting (+)-borneol synthesis. Here, we systematically optimized the dephosphorylation process by identifying, characterizing phosphatases, and balancing cellular dephosphorylation metabolism. For the first time, we identified two endogenous phosphatases and seven heterologous phosphatases, which significantly increased (+)-borneol production by up to 152%. By engineering BPP dephosphorylation and optimizing the MVA pathway, the production of (+)-borneol was increased by 33.8-fold, which enabled the production of 753 mg/L under fed-batch fermentation in shake flasks, so far the highest reported in the literature. This study showed that rewiring dephosphorylation metabolism was essential for high-level production of (+)-borneol in Saccharomyces cerevisiae, and balancing cellular dephosphorylation is also helpful for efficient biosynthesis of other terpenoids since all whose biosynthesis involves the dephosphorylation procedure.

Objective:To establish reference values for clot waveform analysis (CWA) and analyze their diagnostic efficacy in distinguishing acquired hemophilia A (AHA) and lupus anticoagulant (LA)-positive patients.Methods:Case-Control Study. A total of 391 healthy individuals(260 males and 131 females) with a mean age of 45.53±14.85 years were enrolled at Nanyang central Hospital between January 6, 2023 and October 10, 2024. Prothrombin time (PT), activated partial thromboplastin time (APTT), and thrombin time (TT) were measured to establish reference ranges for the CWA parameters, including maximal reaction velocity (Min1), maximal reaction acceleration (Min2), and maximal reaction deceleration (Max2). A total of 158 definitively diagnosed AHA and LA-positive patients (mean age:42.46±14.83 years), including 34 AHA patients and 124 LA-positive patients, were recruited. The Mann Whitney U test was used to analyze the differences in the CWA parameters between the two groups. The diagnostic efficacy of CWA parameters in distinguishing AHA and LA-positive patients was evaluated using the area under the receiver operating characteristic(ROC) curve AUC and the cut-off values were calculated. Results:The reference values for PT-Min1, APTT-Min1, APTT-Min2, APTT-Max2, TT-Min1, TT-Min2, TT-Max2 were 203.41-516.89, 144.63-324.03, 526.46-1 190.03, -404.96±157.22, 159.17±60.34, 272.29-686.99, and -289.47--113.76, respectively. Compared with the CWA parameters in AHA patients, APTT-Max2 was significantly lower in LA-positive patients [-422.74(-577.50, -239.22) vs. -68.87(-92.85,30.28), Z=-7.43, P<0.01], while PT-Min1, APTT-Min1, APTT-Min2, TT-Min1, TT-Min2 were significantly elevated [287.01(188.03, 382.50) vs. 107.45(90.20, 151.39), 972.88(601.20, 1 351.19) vs. 229.10(118.38, 371.67), Z=6.68, 6.69, all P<0.01]. ROC analysis demonstrated the APTT-CWA parameter exhibited high diagnostic efficacy in patients with AHA (AUC>0.900 for both).Additionally, APTT-Min1 and APTT-Max2 were found to be useful in distinguishing between AHA patients and those with LA-positive status accompanied by APTT prolongation (AUC=0.660, 0.700, respectively). Conclusions:Reference values for CWA parameters were successfully established. The APTT-CWA is useful for differentiating between AHA and LA-positive patients and APTT-Max2 demonstrated a good diagnostic value in differentiating AHA patients from those with LA-positive status accompanied by APTT prolongation.

OBJECTIVE To introduce the Dutch system of pharmacy academic education， professional practice and continuing education， and provide new ideas for constructing a “demand-driven， industry-education integrated， and sustainably developing” Chinese-style pharmacy education system. METHODS Through literature and public data retrieval， as well as collection of field visit materials， the study systematically combed the stage characteristics， institutional design， and innovative practices of Dutch pharmacy education， extracted its features and advantages， and proposed suggestions for pharmacy education reform in China. RESULTS & CONCLUSIONS The Dutch pharmacy academic education system is characterized by stepped competency-based training， integrating basic theory with early clinical practice at the undergraduate level， emphasizing specialized division of labor and strengthening clinical competence at the master’s level， and promoting industry-university-research collaborative innovation at the doctoral level. The practice qualification certification and continuing education exhibit multi-dimensional synergy. Specifically， the practice qualification certification process adheres to the guiding principle of “evidence-based competency”， implementing an access system centered on competency assessment， which requires passing national examinations and registration. The continuing education for hospital pharmacists is guided by patient safety， while continuing education for community pharmacists and other pharmacists （such as industrial pharmacists， regulatory science pharmacists， etc.） is guided by the frameworks of “digital situational learning” and a “triple tracks encompassing industry， regulation， and emerging fields”， respectively. China may draw on the five-dimensional path of Dutch pharmacy education in “early integration， vertical coherence， unified standards， industry-university-research collaboration， and intelligent empowerment” to reform its pharmacy education in aspects such as curriculum design， credit systems， evaluation criteria， training models， and training methods， aiming to cultivate pharmacy professionals aligned with China’s practical E-mail：cqqianyan@hospital.cqmu.edu.cn requirements.

Objective:To explore the clinical and pathological features and survival outcomes of patients with early-onset intrahepatic cholangiocarcinoma (EOICC).Methods:This is a multicenter, retrospective cohort study. Data of 1 160 intrahepatic cholangiocarcinoma patients undergoing radical resection in 14 tertiary Grade A hospitals in China from January 2010 to November 2021 were retrospectively collected. The cohort included 632 males and 528 females, aged( M (IQR)) 61 (14) years (range: 22 to 93 years). ICC aged ≤50 years at the time of diagnosis was defined as EOICC and >50 years as late-onset intrahepatic cholangiocarcinoma (LOICC). Of these, there were 247 cases in the EOICC group and 913 cases in the LOICC. The clinical and pathological characteristics of both groups were analyzed and compared using the independent sample t-test, Mann-Whitney U test or Kaplan-Meier method. Univariate and multivariate Cox regression models for patient outcomes were constructed and forest graphed. Results:Compared with the patients in the LOICC group, patients in the EOICC group had lower carcinoembryonic antigen levels (2.5(4.0) μg/L vs. 3.1(5.2)μg/L, U=124 899, P=0.009) and CA19-9 level (63.4(524.7)U/ml vs. 77.9(611.3)U/ml, U=120 320, P=0.013), higher levels of ALT (29(35)U/L vs. 24(26)U/L, U=101 214, P=0.013), a lower score of the Eastern US Cooperative Oncology Group (0 score patients: 54.7% vs. 44.1%, χ2=12.472, P=0.014), higher TNM stage ( χ2=11.807, P=0.038), and proportion of lymph node dissection (62.3% vs. 54.1%, χ2=5.355, P=0.021). Patients in the two groups in sex, first diagnosis symptoms, intrahepatic bile duct stone history, nail protein, albumin, total bilirubin, transaminase, liver function Child-Pugh grade, T stage, stage, N stage, preoperative laparoscopic exploration proportion, tumor diameter, vascular invasion proportion, differentiation, margin, intraoperative bleeding, postoperative complications, postoperative hospital days were no statistical significance (all P>0.05). Patients in the EOICC group had better outcomes than the LOICC group (median survival time: 29.7 months vs. 25.0 months, 3-year overall survival: 45.1% vs. 37.8%, P=0.027). Conclusion:EOICC patients are better than LOICC patients in carcinoembryonic antigen, CA19-9, ALT, physical strength status and TNM stage, and the long-term prognosis is also better than LOICC patients.

Objective To investigate the effectiveness and safety of biological patch in minimally invasive inguinal hernia surgery.Methods From July 2019 to July 2021,100 inguinal hernia patients were divided into two groups based on the actual type of patch received.Biological patch was used in the experimental group(50 cases),and polypropylene patch was used in the control group(50 cases).The operation method was laparoscopic transabdominal preperitoneal(TAPP)hernia repair.Operating time,bleeding volume during operation,hospital stay after operation,hernia recurrence rate,incision infection rate,patch infection rate,and complication rate were compared between the two groups.Results Two groups of patients had no recurrence of hernia within 3 years after surgery,and didn't experience incision infection or patch infection after surgery.There were no significant differences in operating time,bleeding volume during operation,hospital stay after operation,seroma rate and chronic pain rate between the two groups(P>0.05).The incidence rate of foreign body sensation in the control group was higher than that in the experimental group,with statistical difference(P<0.05).Conclusion In conclusion,biological patch is safe and effective in laparoscopic TAPP hernia repair,and can reduce the incidence of postoperative foreign body sensation,providing a new option for laparoscopic inguinal hernia repair.

Objective To investigate the possible association between cross-domain associative memory(AM)impairment and hippocampal subfield volumes in patients with schizophrenia(SCZ).Methods We enrolled 28 SCZ patients from Shanghai Mental Health Center,Shanghai Jiao Tong University School of Medicine,and 28 healthy controls(HCs)between 2019 and 2021.Based on an innovative AM paradigm and automated segmentation,3D-T1 weighted data of the objects were processed with PhiPipe and FreeSurfer.Differences in subfield volums between the two groups were analyzed using ANCOVA,while their relationship with AM scores was assessed using Pearson correlation.Results SCZ patients exhibited significantly poorer AM performance across three conditions compared with HCs.Marginally significant reductions were observed in the total volume of bilateral hippocampus,encompassing both the hippocampal head and body.Significant volume reductions were identified in the bilateral presubiculum and parasubiculum.The volumes of bilateral presubiculum head(r=0.273,P=0.042),parasubiculum(r=0.397,P=0.002),and CA1 head(r=0.382,P=0.004)exhibited positive correlations with cross-domain AM performance.Conclusion The bilateral presubiculum and parasubiculum,as hippocampal subregions significantly associated with cross-modal AM deficits in SCZ,may play a crucial role in the pathology of AM.

Objective To investigate the possible association between cross-domain associative memory(AM)impairment and hippocampal subfield volumes in patients with schizophrenia(SCZ).Methods We enrolled 28 SCZ patients from Shanghai Mental Health Center,Shanghai Jiao Tong University School of Medicine,and 28 healthy controls(HCs)between 2019 and 2021.Based on an innovative AM paradigm and automated segmentation,3D-T1 weighted data of the objects were processed with PhiPipe and FreeSurfer.Differences in subfield volums between the two groups were analyzed using ANCOVA,while their relationship with AM scores was assessed using Pearson correlation.Results SCZ patients exhibited significantly poorer AM performance across three conditions compared with HCs.Marginally significant reductions were observed in the total volume of bilateral hippocampus,encompassing both the hippocampal head and body.Significant volume reductions were identified in the bilateral presubiculum and parasubiculum.The volumes of bilateral presubiculum head(r=0.273,P=0.042),parasubiculum(r=0.397,P=0.002),and CA1 head(r=0.382,P=0.004)exhibited positive correlations with cross-domain AM performance.Conclusion The bilateral presubiculum and parasubiculum,as hippocampal subregions significantly associated with cross-modal AM deficits in SCZ,may play a crucial role in the pathology of AM.

Objective To investigate the effectiveness and safety of biological patch in minimally invasive inguinal hernia surgery.Methods From July 2019 to July 2021,100 inguinal hernia patients were divided into two groups based on the actual type of patch received.Biological patch was used in the experimental group(50 cases),and polypropylene patch was used in the control group(50 cases).The operation method was laparoscopic transabdominal preperitoneal(TAPP)hernia repair.Operating time,bleeding volume during operation,hospital stay after operation,hernia recurrence rate,incision infection rate,patch infection rate,and complication rate were compared between the two groups.Results Two groups of patients had no recurrence of hernia within 3 years after surgery,and didn't experience incision infection or patch infection after surgery.There were no significant differences in operating time,bleeding volume during operation,hospital stay after operation,seroma rate and chronic pain rate between the two groups(P>0.05).The incidence rate of foreign body sensation in the control group was higher than that in the experimental group,with statistical difference(P<0.05).Conclusion In conclusion,biological patch is safe and effective in laparoscopic TAPP hernia repair,and can reduce the incidence of postoperative foreign body sensation,providing a new option for laparoscopic inguinal hernia repair.

Objective:To establish reference values for clot waveform analysis (CWA) and analyze their diagnostic efficacy in distinguishing acquired hemophilia A (AHA) and lupus anticoagulant (LA)-positive patients.Methods:Case-Control Study. A total of 391 healthy individuals(260 males and 131 females) with a mean age of 45.53±14.85 years were enrolled at Nanyang central Hospital between January 6, 2023 and October 10, 2024. Prothrombin time (PT), activated partial thromboplastin time (APTT), and thrombin time (TT) were measured to establish reference ranges for the CWA parameters, including maximal reaction velocity (Min1), maximal reaction acceleration (Min2), and maximal reaction deceleration (Max2). A total of 158 definitively diagnosed AHA and LA-positive patients (mean age:42.46±14.83 years), including 34 AHA patients and 124 LA-positive patients, were recruited. The Mann Whitney U test was used to analyze the differences in the CWA parameters between the two groups. The diagnostic efficacy of CWA parameters in distinguishing AHA and LA-positive patients was evaluated using the area under the receiver operating characteristic(ROC) curve AUC and the cut-off values were calculated. Results:The reference values for PT-Min1, APTT-Min1, APTT-Min2, APTT-Max2, TT-Min1, TT-Min2, TT-Max2 were 203.41-516.89, 144.63-324.03, 526.46-1 190.03, -404.96±157.22, 159.17±60.34, 272.29-686.99, and -289.47--113.76, respectively. Compared with the CWA parameters in AHA patients, APTT-Max2 was significantly lower in LA-positive patients [-422.74(-577.50, -239.22) vs. -68.87(-92.85,30.28), Z=-7.43, P<0.01], while PT-Min1, APTT-Min1, APTT-Min2, TT-Min1, TT-Min2 were significantly elevated [287.01(188.03, 382.50) vs. 107.45(90.20, 151.39), 972.88(601.20, 1 351.19) vs. 229.10(118.38, 371.67), Z=6.68, 6.69, all P<0.01]. ROC analysis demonstrated the APTT-CWA parameter exhibited high diagnostic efficacy in patients with AHA (AUC>0.900 for both).Additionally, APTT-Min1 and APTT-Max2 were found to be useful in distinguishing between AHA patients and those with LA-positive status accompanied by APTT prolongation (AUC=0.660, 0.700, respectively). Conclusions:Reference values for CWA parameters were successfully established. The APTT-CWA is useful for differentiating between AHA and LA-positive patients and APTT-Max2 demonstrated a good diagnostic value in differentiating AHA patients from those with LA-positive status accompanied by APTT prolongation.

Objective:To explore the clinical and pathological features and survival outcomes of patients with early-onset intrahepatic cholangiocarcinoma (EOICC).Methods:This is a multicenter, retrospective cohort study. Data of 1 160 intrahepatic cholangiocarcinoma patients undergoing radical resection in 14 tertiary Grade A hospitals in China from January 2010 to November 2021 were retrospectively collected. The cohort included 632 males and 528 females, aged( M (IQR)) 61 (14) years (range: 22 to 93 years). ICC aged ≤50 years at the time of diagnosis was defined as EOICC and >50 years as late-onset intrahepatic cholangiocarcinoma (LOICC). Of these, there were 247 cases in the EOICC group and 913 cases in the LOICC. The clinical and pathological characteristics of both groups were analyzed and compared using the independent sample t-test, Mann-Whitney U test or Kaplan-Meier method. Univariate and multivariate Cox regression models for patient outcomes were constructed and forest graphed. Results:Compared with the patients in the LOICC group, patients in the EOICC group had lower carcinoembryonic antigen levels (2.5(4.0) μg/L vs. 3.1(5.2)μg/L, U=124 899, P=0.009) and CA19-9 level (63.4(524.7)U/ml vs. 77.9(611.3)U/ml, U=120 320, P=0.013), higher levels of ALT (29(35)U/L vs. 24(26)U/L, U=101 214, P=0.013), a lower score of the Eastern US Cooperative Oncology Group (0 score patients: 54.7% vs. 44.1%, χ2=12.472, P=0.014), higher TNM stage ( χ2=11.807, P=0.038), and proportion of lymph node dissection (62.3% vs. 54.1%, χ2=5.355, P=0.021). Patients in the two groups in sex, first diagnosis symptoms, intrahepatic bile duct stone history, nail protein, albumin, total bilirubin, transaminase, liver function Child-Pugh grade, T stage, stage, N stage, preoperative laparoscopic exploration proportion, tumor diameter, vascular invasion proportion, differentiation, margin, intraoperative bleeding, postoperative complications, postoperative hospital days were no statistical significance (all P>0.05). Patients in the EOICC group had better outcomes than the LOICC group (median survival time: 29.7 months vs. 25.0 months, 3-year overall survival: 45.1% vs. 37.8%, P=0.027). Conclusion:EOICC patients are better than LOICC patients in carcinoembryonic antigen, CA19-9, ALT, physical strength status and TNM stage, and the long-term prognosis is also better than LOICC patients.