Artificial intelligence （AI） and population pharmacokinetics （PPK） technologies have demonstrated significant potential in the personalized medication of immunosuppressants after organ transplantation, enabling precise prediction of drug dosages. This article provides a comprehensive review of the application status of AI and PPK in the individualized administration of immunosuppressants after organ transplantation， focuses on monitoring blood drug concentration， predicting efficacy/adverse reactions， and establishing individualized dosing models for organ transplant recipients after immunosuppressant administration， and analyzes and compares the application characteristics of different methods in different organ transplant patients as well as the integration and future development of AI and PPK technologies. AI and PPK technologies can not only significantly reduce the dependence on human resources， but also greatly improve the level of individualized treatment of immunosuppressants after organ transplantation， and reduce the discomfort and burden caused by frequent blood concentration monitoring to patients.

Glucagon-like peptide-1 （GLP-1） receptor agonists are a novel class of antidiabetic drugs that also possess lipid- lowering and cardiovascular protective effects， with liraglutide and semaglutide being their representative medications. Based on a systematic literature search， this review summarizes the lipid-lowering mechanisms by which liraglutide and semaglutide exert direct effects on the liver and kidney （regulating autophagy， key lipid metabolism pathways， reverse cholesterol transport， etc.）， direct actions on adipose tissue （affecting adipocyte proliferation and differentiation， expression of lipid metabolism proteins， and gene transcription）， activation of sympathetic pathways through the central nervous system， and modulation of the gut microbiota. Additionally， it summarizes the clinical evidence of their lipid-lowering effects in populations with type 2 diabetes mellitus， overweight individuals， and others. These findings indicate that GLP-1 receptor agonists exert lipid-lowering effects by acting on multiple tissues or systems， providing crucial evidence for further elucidating the molecular mechanisms of these drugs in lipid regulation and exploring potential new ideas for their clinical applications.

Idiopathic pulmonary fibrosis (IPF), a chronic interstitial lung disease, is characterized by aberrant wound healing, excessive scarring and the formation of myofibroblastic foci. Although the role of alternative splicing (AS) in the pathogenesis of organ fibrosis has garnered increasing attention, its specific contribution to pulmonary fibrosis remains incompletely understood. In this study, we identified an up-regulation of serine/arginine-rich splicing factor 7 (SRSF7) in lung fibroblasts derived from IPF patients and a bleomycin (BLM)-induced mouse model, and further characterized its functional role in both human fetal lung fibroblasts and mice. We demonstrated that enhanced expression of Srsf7 in mice spontaneously induced alveolar collagen accumulation. Mechanistically, we investigated alternative splicing events and revealed that SRSF7 modulates the alternative splicing of pyruvate kinase (PKM), leading to metabolic dysregulation and fibroblast activation. In vivo studies showed that fibroblast-specific knockout of Srsf7 in conditional knockout mice conferred resistance to bleomycin-induced pulmonary fibrosis. Importantly, through drug screening, we identified lomitapide as a novel modulator of SRSF7, which effectively mitigated experimental pulmonary fibrosis. Collectively, our findings elucidate a molecular pathway by which SRSF7 drives fibroblast metabolic dysregulation and propose a potential therapeutic strategy for pulmonary fibrosis.

Hepatic stellate cells (HSCs) are the primary fibrogenic cells in the liver, and their activation plays a crucial role in the development and progression of hepatic fibrosis. Here, we report that retinoid X receptor-alpha (RXRα), a unique member of the nuclear receptor superfamily, is a key modulator of HSC activation and liver fibrosis. RXRα exerts its effects by modulating calcium/calmodulin-dependent protein kinase kinase β (CaMKKβ)-mediated activation of AMP-activated protein kinase-alpha (AMPKα). In addition, we demonstrate that K-80003, which binds RXRα by a unique mechanism, effectively suppresses HSC activation, proliferation, and migration, thereby inhibiting liver fibrosis in the CCl₄ and amylin liver NASH (AMLN) diet animal models. The effect is mediated by AMPKα activation, promoting mitophagy in HSCs. Mechanistically, K-80003 activates AMPKα by inducing RXRα to form condensates with CaMKKβ and AMPKα via a two-phase process. The formation of RXRα condensates is driven by its N-terminal intrinsic disorder region and requires phosphorylation by CaMKKβ. Our results reveal a crucial role of RXRα in liver fibrosis regulation through modulating mitochondrial activities in HSCs. Furthermore, they suggest that K-80003 and related RXRα modulators hold promise as therapeutic agents for fibrosis-related diseases.

Tauopathies, including Alzheimer's disease (AD), are a series of neurodegenerative diseases characterized by pathological accumulation of the microtubule-associated protein tau. Since the abnormal modification and deposition of tau in nerve cells are crucial for tauopathy etiology, methods for reducing tau levels, such as promoting tau degradation, may become effective strategies for disease treatment. Herein, we identified that sorafenib significantly reduced total tau and phosphorylated tau levels through screening FDA-approved drugs. We showed that sorafenib treatment attenuated cognitive deficits and tau pathologies in PS19 tauopathy model mice. Mechanistically, we found that sorafenib inhibited multiple kinases involved in tau phosphorylation and promoted autophagy. Importantly, we further demonstrated that sorafenib also promoted the expression of the E3 ubiquitin ligase FBXW7, which could bind tau and mediate tau degradation through the ubiquitin-proteasome pathway. Finally, we showed that FBXW7 expression decreased in the brains of AD patients and tauopathy model mice, and that overexpression of FBXW7 in the hippocampus attenuated cognitive deficits and tau pathologies in PS19 mice. These results suggest that sorafenib may be a promising treatment option for tauopathies by promoting tau degradation and reducing tau phosphorylation, and that targeting FBXW7 could also serve as an alternative therapeutic strategy for tauopathies.

Glucose oxidase (GOD) is an oxygen-consuming dehydrogenase that can catalyze the production of gluconic acid hydrogen peroxide from glucose, and its specific mechanism of action makes it promising for applications, while the low catalytic activity and poor thermostability have become the main factors limiting the industrial application of this enzyme. In this study, we used the glucose oxidase AtGOD reported with the best thermostability as the source sequence for phylogenetic analysis to obtain the GOD with excellent performance. Six genes were screened and successfully synthesized for functional validation. Among them, the glucose oxidase AhGODB derived from Aspergillus heteromorphus was expressed in Pichia pastoris and showed better thermostability and catalytic activity, with an optimal temperature of 40 ℃, a specific activity of 112.2 U/mg, and a relative activity of 47% after 5 min of treatment at 70 ℃. To improve its activity and thermal stability, we constructed several mutants by directed evolution combined with rational design. Compared with the original enzyme, the mutant T72R/A153P showcased the optimum temperature increasing from 40 to 50 ℃, the specific activity increasing from 112.2 U/mg to 166.1 U/mg, and the relative activity after treatment at 70 ℃ for 30 min increasing from 0% to 33%. In conclusion, the glucose oxidase mutants obtained in this study have improved catalytic activity and thermostability, and have potential for application.
Glucose Oxidase/chemistry* ; Enzyme Stability ; Aspergillus/genetics* ; Pichia/metabolism* ; Temperature ; Catalysis ; Fungal Proteins/metabolism* ; Hot Temperature

Postoperative pain seriously affects the recovery process of patients, resulting in prolonged hospital stay and increased care costs. Appropriate application of patient-controlled analgesia devices can effectively relieve perioperative acute pain. In 1994 patient-controlled analgesia began to be used in Peking Union Medical College Hospital, and the Acute Pain Service Working Group was established in 2004. With the cooperation of anesthesiologists and specialist nurses, the group jointly has implemented the whole process and standardized management based on patient-controlled analgesia, and constantly improved and innovated working methods, laying a solid foundation for the development of postoperative pain management. This paper systematically reviews and summarizes the work from the aspects of clinical focus, nursing management experience, promotion and dissemination of pain treatment concepts, and development of acute pain service model under the new situation, with the hope of providing valuable reference for comprehensively strengthening pain management in the process of diagnosis and treatment, and enhancing patients' satisfaction with perioperative analgesia services.

Objective:To explore the regulatory role of the melanin-concentrating hormone (MCH) neural pathway from the lateral hypothalamus (LHA) to the nucleus accumbens (NAc) in modulating anxiety-like behavior in mice.Methods:Totally 37 male SPF-grade C57BL/6J mice, aged 6 to 8 weeks and weighed 18-22 g, were used for the following experiment: (1) Five mice received an injection of Fluoro-Gold (FG) into the NAc, followed by retrograde tracing combined with immunofluorescence staining after one week to observe the coexistence of FG and MCH immunopositive neurons in the LHA.(2)Thirty-two mice were injected with adeno-associated virus which could activate the MCH neurons into the LHA.After two weeks, they were randomly divided into four groups and received different drug injections: normal saline (NS, intraperitoneal injection)+ NS (1.5 μL, injection in the NAc) group, NS(intraperitoned injection) + SNAP94847 (SNAP, 2 mg/mL, 1.5 μL, injection in the NAc) group, chlorprothixene N-oxide (CNO, 0.15 mg/kg, intraperitoned injection) + NS(1.5 μL, injection in the NAc) group, and CNO(intraperitoned injection) + SNAP(1.5 μL injection in the NAc) group, and the SNAP94847 was an antagonist for MCH typel receptor.The open field test (OFT), elevated plus maze (EPM), and marble burial test (MBT) were employed to assess the impact of chemogenetic activation of MCH neurons on anxiety-related behavior in mice.Results:(1) The results of FG retrograde tracing combined with immunofluorescence histochemistry showed that MCH neurons in the LHA project their neural fibers to NAc neurons.(2) In the chemogenetic experiment, there was no significant interaction effect between CNO and SNAP in terms of the duration of stay ( Finteraction=2.899, P>0.05) and the distance moved ( Finteraction=1.603, P>0.05) in the central area during OFT experiments.However, the main effects of both CNO and SNAP intervention were significant in the duration of stay ( FCNO=6.767, FSNAP=7.656, both P<0.05) and the distance moved ( FCNO=12.480, FSNAP=7.999, both P<0.01) in the central area.Compared to the NS+ NS group, mice in the CNO+ NS group exhibited a shortened duration of stay ((89.00±19.16)s, (63.75±13.58)s, P<0.05) and a decrease in distance moved ((593.79±108.18)cm, (426.81±66.14)cm, P<0.05) in the central area.In contrast, mice in the CNO+ SNAP group had an extended duration of stay ((87.38±16.57)s) and an increase in distance moved ((569.27±73.20)cm) in the central area compared to the CNO+ NS group.There was no significant interaction effect between CNO and SNAP in the number of entries ( Finteraction=2.79, P>0.05) and the dwell time ( Finteraction=2.871, P>0.05) into the open arms of EPM experiments.However, the main effects of both CNO and SNAP interventions in the number of entries ( FCNO=10.43, P<0.01; FSNAP=4.96, P<0.05) and the dwell time ( FCNO=5.232, FSNAP=7.597, both P<0.05) into the open arms were significant.Compared to the NS+ NS group, mice in the CNO+ NS group showed a decrease in the number of entries ((13.13±3.36), (7.63±3.70), P<0.01) and a decrease in open arm dwell time ((37.68±11.37) s, (22.98±7.00) s, P<0.05) into the open arms.The CNO+ SNAP group had an increased number of entries (12.00±3.02) and an increased dwell time ((39.41±10.58)s) into the open arms compared to the CNO+ NS group(both P<0.05).There was no significant interaction effect between CNO and SNAP in the MBT experiment ( Finteraction=2.746, P>0.05).However, the main effects of both CNO and SNAP interventions were significant ( FCNO=8.125, P<0.01; FSNAP=5.383, P<0.05).Compared to the NS+ NS group, the number of buried beads increased in the CNO+ NS group ((16.13±2.10), (11.88±3.23), P<0.05).Conversely, the number of buried beads decreased in the CNO+ SNAP group compared to the CNO+ NS group ((12.38±2.33), (16.13±2.10), P<0.05). Conclusion:Enhanced activity in the MCHergic neural pathway from LHA to NAc can promote anxiety-like behavior in mice, providing new insights into the mechanisms underlying anxiety.

Objective:To investigate the role of p-AKT-mTOR-P70S6K signaling pathway in radiation therapy for polyploid cervical cancer cells.Methods:Human cervical cancer HeLa cell lines were selected and HeLa cells were radiated under 7 Gy of 6 MV X-ray. The morphological changes of the cells were observed with an inverted microscope on day 5 after radiation induction. All cells were divided into the 7 Gy group (7 Gy X-ray radiation but not transfected polyploidy HeLa cells) and the control group (the non-radiation-induced and not transfected HeLa cells). In addition, the plasmid carrying pcDNA3 negative control sequence and the plasmid carrying pcDNA3-TT-AKT sequence were transfected into HeLa cells, respectively, which were induced by 7 Gy X-ray radiation after 48 h of transfection, and then they were recorded as the pcDNA3 + 7 Gy group and the pcDNA3-TT-AKT + 7 Gy group. Cell proliferation ability was detected by using CCK-8 assay, cell cycle was detected by using flow cytometry, cell apoptosis was detected by using mitochondrial membrane potential assay, the relative expression levels of cell proliferation, cell cycle, apoptosis and autophagy related proteins were tested by using Western blot.Results:Most of the normal HeLa cells in the 7 Gy group died on day 5 after radiation induction, and only a few surviving cells increased in size with multiple nuclei. The results of Western blot showed that the relative expression levels of p-AKT, p-mTOR and p-P70S6K in HeLa cells of the 7 Gy group were lower than those of the control group (all P < 0.05). CCK-8 assay showed that the absorbance ( A) values were 0.45±0.06, 0.65±0.06 after 48 h of culture and 0.75±0.05, 1.05±0.02 after 72 h of culture, respectively in the pcDNA3 + 7 Gy group and the pcDNA3-TT-AKT + 7 Gy group, and the differences were statistically significant (all P < 0.05), and the A values in the pcDNA3-TT-AKT + 7 Gy group were all higher than those in the pcDNA3 +7 Gy group. Flow cytometry results showed that the proportion of cells was (29.2±3.6)%, (26.7±1.7)% in G 0/G 1 phase and (29.6±1.6)%, (30.3±0.6)% in G 2/M phase, respectively in the pcDNA3 + 7 Gy group and the pcDNA3-TT-AKT + 7 Gy group, and the differences were not statistically significant (all P > 0.05); the proportion of cells in S phase was (10.2±0.9)% and (14.6±1.5)%, respectively in the pcDNA3 + 7 Gy group and the pcDNA3-TT-AKT + 7 Gy group, and the differences were statistically significant ( t = 2.86, P = 0.043). Mitochondrial membrane potential assay showed that the green fluorescence proportion was (23.1±2.5)% and (14.3±1.9)%, respectively in the pcDNA3 + 7 Gy group and the pcDNA3-TT-AKT + 7 Gy group, and the different was statistically significant ( t = 4.82, P = 0.009). Western blot results showed that the relative expression level of p-cdc25c (Ser216) in the pcDNA3-TT-AKT+7 Gy group was higher than that in the pcDNA3+7 Gy group ( P < 0.001); and the relative expression levels of Bak and LC3-Ⅱ/Ⅰ in the pcDNA3-TT-AKT+7Gy group were lower than those in the pcDNA3 +7 Gy group, respectively (all P < 0.05). Conclusions:The p-AKT-mTOR-P70S6K signaling pathway may be involved in the regulation of radiation-induced polyploidy HeLa cell proliferation, cell cycle and cell apoptosis.

Objective To compare the success rates of two methods for endobronchial intubation:the left-sided double-lumen tube(DLT)rotated 90° counter-clockwise with the patient head at the mid positon and the tube rotated 180°counter-clockwise with the patient head turned to the right.Methods Six hundred and forty-eight patients were enrolled in this study,who were to undergo elective thoracic surgery by left-sided DLT intuba-tion in the Peking Union Medical College Hospital from December 2021 to June 2022.They were randomized into a 90° group and a 180° group,with 324 patients in each group.In the 90° group,with the patient head kept at the mid position,the left-sided DLT was advanced until the bronchial cuff passed the vocal cords and then rotated 90° counter-clockwise.In the 180°group,with the left mandible angle of each patient in the straight line with the ster-num,the tube was advanced until the bronchial cuff passed the vocal cords and then rotated 180° counter-clock-wise.The intubation success rate and the intubation-related complications such as carina mucosal injuries were com-pared between the two groups.Results The 648 patients included 336 males and 312 females,with the age ran-ging from 39.0 to 75.0 years old and the average age of(54.6±9.0)years old.The success rate of first intubation was 80.3% in the 90°group and 75.0% in the 180°group,which showed no significant difference(P =0.109).The success rate of second intubation was higher in the 180°group than in the 90°group(P<0.001).The rate of carina mucosal injuries was 23.8% in the 90° group and 25.6% in the 180° group,which showed no significant difference(P =0.585).Conclusions Compared with the conventional method(90°),the intubation of the left-sided DLT rotated 180° counter-clockwise with the patient head turned to the right cannot improve the success rate of the first intubation.However,it could improve the success rate of reintubation as a remedy.