Effect of recombinant CYP3A4 variants and interaction on imatinib metabolism in vitro.

The aim of this study was to investigate the catalytic activity of 26 Cytochrome P450 3A4 (CYP3A4) variants and drug interactions on imatinib metabolism in recombinant insect microsomes. This study was designed with an appropriate incubation system and carried out in the constant temperature water. By using ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) to measure the quantities of its metabolite N-desmethyl imatinib, to elucidate the impacts of the CYP3A4 genetic polymorphism and drug interactions on the metabolism of imatinib. Consequently, as compared to CYP3A4.1, the intrinsic clearance (CLint) values of the variations were dramatically changed, rising from 2.34 % to 120.57 %. CYP3A4.14 showed an increase in CLint in comparison to CYP3A4.1, and the remaining 24 variants demonstrated decreases in catalytic activity for the metabolism of imatinib. In addition, the metabolism of imatinib was decreased to varied degrees by ketoconazole, itraconazole, and fluconazole in CYP3A4.1 and CYP3A4.18. Moreover, most of CYP3A4 variants showed similar trend of enzyme activity under different substrates of imatinib and cabozantinib, except 6 variants (CYP3A4.3,.4,.10,.15,.29 and.31). The first study of the effects of 26 CYP3A4 variants on imatinib metabolism will contribute to the clinical evaluation of imatinib and help personalize therapy in clinical settings.

Engineered Extracellular Vesicles for Combinatorial TNBC Therapy: SR-SIM-Guided Design Achieves Substantial Drug Dosage Reduction.

Triple negative breast cancer is an aggressive subtype of breast cancer that has no therapeutic targets, relies on chemotherapeutics for treatment, and is in dire need of novel therapeutic approaches for improved patient outcomes. Extracellular vesicles serve as intercellular communicators and have been proposed as ideal drug delivery vehicles. Here, extracellular vesicles were engineered with RNA nanotechnology to develop Triple negative breast cancer tumor inhibitors. Utilizing Super Resolved-Structured Illumination Microscopy, extracellular vesicles were optimized for precise Survivin siRNA conjugated to chemotherapeutics loading and CD44 aptamer ligand decoration, thereby enhancing specificity towards triple negative breast cancer cells. Conventional treatments typically employ chemotherapy drugs Gemcitabine and Paclitaxel at dosages on the order of mg/kg respectively, per injection (IV) in mice. In contrast, engineered extracellular vesicles encapsulating these drugs saw functional tumor growth inhibition at significantly reduced concentrations: 2.2 µg/kg for Gemcitabine or 5.6 µg/kg for Paclitaxel, in combination with 21.5 µg/kg Survivin-siRNA in mice. The result is a substantial decrease of chemotherapeutic dose required, by orders of magnitude, compared to standard regimens. In vivo and in vitro evaluations in a triple negative breast cancer orthotopic xenograft mouse model demonstrated the efficacy of this reduced dosage strategy, indicating potential for decreased chemotherapy-associated toxicity.

Multiscale Spatial-Temporal Feature Fusion Neural Network for Motor Imagery Brain-Computer Interfaces.

Motor imagery, one of the main brain-computer interface (BCI) paradigms, has been extensively utilized in numerous BCI applications, such as the interaction between disabled people and external devices. Precise decoding, one of the most significant aspects of realizing efficient and stable interaction, has received a great deal of intensive research. However, the current decoding methods based on deep learning are still dominated by single-scale serial convolution, which leads to insufficient extraction of abundant information from motor imagery signals. To overcome such challenges, we propose a new end-to-end convolutional neural network based on multiscale spatial-temporal feature fusion (MSTFNet) for EEG classification of motor imagery. The architecture of MSTFNet consists of four distinct modules: feature enhancement module, multiscale temporal feature extraction module, spatial feature extraction module and feature fusion module, with the latter being further divided into the depthwise separable convolution block and efficient channel attention block. Moreover, we implement a straightforward yet potent data augmentation strategy to bolster the performance of MSTFNet significantly. To validate the performance of MSTFNet, we conduct cross-session experiments and leave-one-subject-out experiments. The cross-session experiment is conducted across two public datasets and one laboratory dataset. On the public datasets of BCI Competition IV 2a and BCI Competition IV 2b, MSTFNet achieves classification accuracies of 83.62% and 89.26%, respectively. On the laboratory dataset, MSTFNet achieves 86.68% classification accuracy. Besides, the leave-one-subject-out experiment is performed on the BCI Competition IV 2a dataset, and MSTFNet achieves 66.31% classification accuracy. These experimental results outperform several state-of-the-art methodologies, indicate the proposed MSTFNet's robust capability in decoding EEG signals associated with motor imagery.

Transcutaneous Immunization of 1D Rod-Like Tobacco-Mosaic-Virus-Based Peptide Vaccine via Tip-Loaded Dissolving Microneedles.

Peptide vaccines induce specific neutralizing antibodies and are effective in disease prevention and treatment. However, peptide antigens have a low immunogenicity and are unstable, requiring efficient vaccine carriers to enhance their immunogenicity. Here, we develop a tobacco mosaic virus (TMV)-based peptide vaccine for transdermal immunization using a tip-loaded dissolving microneedle (MN) patch. TMV is decorated with the model peptide antigen PEP3. The prepared TMV-PEP3 promotes dendritic cell maturation and induces dendritic cells to overexpress MHC II, costimulatory factors, and pro-inflammatory factors. By encapsulation of TMV-PEP3 in the tips of a trehalose MN, TMV-PEP3 can be delivered by MN and significantly promote local immune cell infiltration. In vivo studies show that both subcutaneous injection and MN administration of TMV-PEP3 increase the production of anti-PEP3 IgG antibodies and the harvested serum can induce complement-dependent cytotoxicity. This work provides a promising strategy for constructing efficient and health-care-friendly peptide vaccines.

Inhibitory effects of calcium channel blockers nisoldipine and nimodipine on ivacaftor metabolism and their underlying mechanism.

Ivacaftor is the first potentiator of the cystic fibrosis transmembrane conductance regulator (CFTR) protein approved for use alone in the treatment of cystic fibrosis (CF). Ivacaftor is primarily metabolized by CYP3A4 and therefore may interact with drugs that are CYP3A4 substrates, resulting in changes in plasma exposure to ivacaftor. The study determined the levels of ivacaftor and its active metabolite M1 by ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). We screened 79 drugs and 19 severely inhibited ivacaftor metabolism, particularly two cardiovascular drugs (nisoldipine and nimodipine). In rat liver microsomes (RLM) and human liver microsomes (HLM), the half-maximal inhibitory concentrations (IC50) of nisoldipine on ivacaftor metabolism were 6.55 µM and 9.10 µM, respectively, and the inhibitory mechanism of nisoldipine on ivacaftor metabolism was mixed inhibition; the IC50 of nimodipine on ivacaftor metabolism in RLM and HLM were 4.57 µM and 7.15 µM, respectively, and the inhibitory mechanism of nimodipine on ivacaftor was competitive inhibition. In pharmacokinetic experiments in rats, it was observed that both nisoldipine and nimodipine significantly altered the pharmacokinetic parameters of ivacaftor, such as AUC(0-t) and CLz/F. However, this difference may not be clinically relevant. In conclusion, this paper presented the results of studies investigating the interaction between these drugs and ivacaftor in vitro and in vivo. The objective is to provide a rationale for the safety of ivacaftor in combination with other drugs.

Effect of isavuconazole on the pharmacokinetics of sunitinib and its mechanism.

BACKGROUND: Sunitinib, a newly developed multi-targeted tyrosine kinase inhibitor (TKI), has become a common therapeutic option for managing advanced renal cell carcinoma (RCC). Examining the mechanism underlying the interaction between sunitinib and isavuconazole was the aim of this effort. METHODS: The concentrations of sunitinib and its primary metabolite, N-desethyl sunitinib, were analyzed and quantified using ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). Our study evaluated the potential interaction between isavuconazole and sunitinib using rat liver microsomes (RLM), human liver microsomes (HLM), and in vivo rat models. For the in vivo study, two groups (n = 5) of Sprague-Dawley (SD) rats were randomly allocated to receive sunitinib either with or without co-administration of isavuconazole. Additionally, the effects of isavuconazole on the metabolic stability of sunitinib and N-desethyl sunitinib were studied in RLM in vitro. RESULTS: Our findings demonstrated that in RLM, isavuconazole exhibited a mixed non-competitive and competitive inhibition mechanism, with an IC50 (half maximal inhibitory concentration) value of 1.33 µM. Meanwhile, in HLM, isavuconazole demonstrated a competitive inhibition mechanism, with an IC50 of 5.30 µM. In vivo studies showed that the presence of isavuconazole significantly increased the pharmacokinetic characteristics of sunitinib, with the AUC(0→t), AUC(0→∞), and Tmax rising to approximately 211.38%, 203.92%, and 288.89%, respectively, in contrast to the control group (5 mg/kg sunitinib alone). The pharmacokinetic characteristics of the metabolite N-desethyl sunitinib in the presence of isavuconazole remained largely unchanged compared to the control group. Furthermore, in vitro metabolic stability experiments revealed that isavuconazole inhibited the metabolic processing of both sunitinib and N-desethyl sunitinib. CONCLUSIONS: Isavuconazole had a major impact on sunitinib metabolism, providing fundamental information for the precise therapeutic administration of sunitinib.

Effects of three flavonoids on the metabolism of lenvatinib.

Lenvatinib is a first-line therapy for the treatment of hepatocellular carcinoma (HCC), an active multi-target tyrosine kinase inhibitor (TKI). The interaction between Traditional Chinese Medicine (TCM) and chemicals has increasingly become a research hotspot. The objective of this study was to pinpoint the effects of three flavonoids on the metabolism of lenvatinib. Enzyme reaction system was established and optimized in vitro, and in vivo experiments were conducted in Sprague-Dawley (SD) rats, where the analytes were detected by ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). We found that among three flavonoids, luteolin and myricetin had strong inhibitory effects on lenvatinib metabolism, with half-maximal inhibitory concentration (IC50) values of 11.36 ± 0.46 µM and 11.21 ± 0.81 µM in rat liver microsomes (RLM), respectively, and 6.89 ± 0.43 µM and 12.32 ± 1.21 µM in human liver microsomes (HLM), respectively. In Sprague-Dawley rats, the combined administration of lenvatinib and luteolin obviously expanded the exposure to lenvatinib; however, co-administered with myricetin did not have any changes, which may be due to the poor bioavailability of myricetin in vivo. Furthermore, the inhibitory type of luteolin on lenvatinib showed an un-competitive in RLM and a mixed in HLM. Collectively, flavonoids with liver protection, especially luteolin, may inhibit lenvatinib metabolism in vitro and in vivo.

Application of the modified Byars staged procedure for severe hypospadias repair.

This study aimed to introduce a modified Byars staged procedure and investigate its application value in patients with severe hypospadias. We retrospectively analyzed the clinical data of patients with severe hypospadias admitted to the First Affiliated Hospital of Sun Yat-sen University (Guangzhou, China) between October 2012 and October 2022. In total, 31 patients underwent the conventional Byars procedure (conventional group), and 45 patients underwent the modified Byars staged procedure (modified group). Our modified strategy was built upon the standard Byars procedure by incorporating glansplasty during the first stage and employing a Y-shaped flap in conjunction with a glandular tunnel for urethroplasty during the second stage. Notably, there were no statistically significant differences in the preoperative baseline characteristics, duration of surgery, amount of blood loss, or occurrence of postoperative complications, including urethral fistula, stricture and diverticulum, or penile curvature, between the conventional and modified groups. However, there was a significantly lower incidence of coronal sulcus fistula (0 vs 16.1%, P = 0.02) and glans dehiscence (0 vs 12.9%, P = 0.02) in the surgical group than that in the conventional group. In addition, the modified group exhibited a notably greater rate of normotopic urethral opening (100.0% vs 83.9%, P = 0.01) and a higher mean score on the Hypospadias Objective Penile Evaluation (HOPE; mean ± standard error of mean: 8.6 ± 0.2 vs 7.9 ± 0.3, P = 0.02) than did the conventional group. In conclusion, the modified Byars staged procedure significantly reduced the risks of glans dehiscence and coronal sulcus fistula. Consequently, it offers a promising approach for achieving favorable penile esthetics, thereby providing a reliable therapeutic option for severe hypospadias.

A Bibliometric study of the top 100 most-cited papers in high tibial osteotomy.

Background: High tibial osteotomy (HTO) is a well-established surgical procedure employed to treat medial compartment knee osteoarthritis by modifying the mechanical axis of the lower limb, thereby reducing the load on the affected joint. It has gained increased attention in recent years, resulting in numerous research advancements in this field. Methods: The top 100 most-cited papers on HTO, published between 1970 and 2023, were identified by searching the Web of Science Core Collection database. Data, including the title, author, keywords, journal, publication year, country, and institution, were extracted. Subsequently, a bibliometric analysis was performed. Results: The 100 papers collectively garnered a total of 15 833 citations, with a median of 122 and an average of 158.33 citations per article. Since the onset of the 21st century, there has been a significant increase in the number of publications and citations. Lobenhoffer authored the most published papers. The majority of papers originated from the USA. Hannover Medical School produced the most papers. Analysis of keywords in the articles revealed several research hotspots, including open-wedge osteotomy, biomechanical study, tibial slope, patellar height, Puddu plate, TomoFix plate, stability, complications, and accuracy. Conclusion: This study offers bibliometric insights into HTO, underscoring that the USA is a prominent leader in this field. HTO has garnered increasing attention since the onset of the 21st century and is expected to remain a significant research area in the future. Concurrently, the authors advise focusing on potential research hotspots, such as the navigation system, to augment the accuracy of the correction.

Bone controls browning of white adipose tissue and protects from diet-induced obesity through Schnurri-3-regulated SLIT2 secretion.

The skeleton has been suggested to function as an endocrine organ controlling whole organism energy balance, however the mediators of this effect and their molecular links remain unclear. Here, utilizing Schnurri-3-/- (Shn3-/-) mice with augmented osteoblast activity, we show Shn3-/-mice display resistance against diet-induced obesity and enhanced white adipose tissue (WAT) browning. Conditional deletion of Shn3 in osteoblasts but not adipocytes recapitulates lean phenotype of Shn3-/-mice, indicating this phenotype is driven by skeleton. We further demonstrate osteoblasts lacking Shn3 can secrete cytokines to promote WAT browning. Among them, we identify a C-terminal fragment of SLIT2 (SLIT2-C), primarily secreted by osteoblasts, as a Shn3-regulated osteokine that mediates WAT browning. Lastly, AAV-mediated Shn3 silencing phenocopies the lean phenotype and augmented glucose metabolism. Altogether, our findings establish a novel bone-fat signaling axis via SHN3 regulated SLIT2-C production in osteoblasts, offering a potential therapeutic target to address both osteoporosis and metabolic syndrome.

Development of UPLC-MS/MS method for studying the pharmacokinetic interactions of fuzuloparib with curcumin in rats.

Fuzuloparib is a novel orally bioactive poly-ADP-ribose polymerase inhibitor (PARPi), which was approved by the Chinese Regulatory Agency (CRA) in 2020 for the treatment of platinum-sensitive recurrent ovarian, fallopian tube, and primary peritoneal cancers. This study firstly presents a rapid and accurate ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method for analyzing the levels of fuzuloparib and its major metabolite (SHR165202), and to investigate drug-drug interaction between fuzuloparib and curcumin in vitro and in vivo studies. After protein precipitation with acetonitrile, mobile phase consisted of acetonitrile and 0.1 % formic acid with a gradient elution was used to successfully separate fuzuloparib, SHR165202 and talazoparib (internal standard, IS). The results indicated that fuzuloparib and SHR165202 had good linearity over the calibration range of 2-50 ng/mL and 1-20 ng/mL, respectively. The precision, accuracy, stability, matrix effect, and extraction recovery required for methodological validation all complied with the requirements of the Bioanalytical Method Validation Guidelines. In vitro microsome incubation experiments, curcumin exhibited inhibitory effect on fuzuloparib in both rat liver microsomes (RLM) and human liver microsomes (HLM) with half-maximal inhibitory concentration (IC50) value of 10.54 µM and 47.64 µM, respectively, and the corresponding mechanism was non-competitive. Furthermore, the inhibitory mechanism of curcumin on fuzuloparib was validated through molecular docking. In pharmacokinetic experiments in rats, curcumin significantly altered the plasma exposure of fuzuloparib, resulting in significant increases in AUC(0-t) and Cmax of fuzuloparib and a significant decrease in CLz/F. Moreover, the metabolite SHR165202 showed significant increases in AUC(0-t), AUC(0-∞), Tmax and Cmax and a significant decrease in CLz/F. This further supports the notion that curcumin could inhibit the metabolism of fuzuloparib. Therefore, when co-administering fuzuloparib and curcumin in clinic, it is recommended to monitor plasma levels of fuzuloparib and pay close attention to adverse effects. If necessary, the dose of fuzuloparib needs to be reduced.

Diagnostic value of CEUS combined with C-TIRADS for indeterminate FNA cytological thyroid nodules.

OBJECTIVES: To investigate the diagnostic value of CEUS combined with C-TIRADS for indeterminate FNA cytological thyroid nodules. METHODS: The clinical data, ultrasonic images, C-TIRADS categories and CEUS images of 192 patients with indeterminate FNA cytological thyroid nodules confirmed by the surgical pathology were analyzed retrospectively. The diagnostic efficacy of CEUS, C-TIRADS and CEUS-TIRADS were calculated. RESULTS: The AUCs of CEUS, C-TIRADS and CEUS-TIRADS were 0.905 (95% CI: 0.862∼0.949), 0.881 (95% CI: 0.825∼0.938) and 0.954 (95% CI: 0.922∼0.986), respectively. The sensitivity, specificity, PPV, NPV, accuracy, LR- and LR+ were 84.7% (116/137), 85.5% (47/55), 93.5% (116/124), 69.1% (47/68), 84.9% (163/192), 0.179, 5.82 and 84.7% (116/137), 83.6% (46/55), 92.8% (116/125), 68.7% (46/67), 84.4% (162/192), 0.183, 5.17, 92.7% (127/137), 89.1% (49/55), 95.5% (127/133), 83.1% (49/59), 91.7% (176/192), 0.082, and 8.50, respectively. Compared with CEUS and C-TIRADS, CEUS-TIRADS had improved the AUC, sensitivity and accuracy (all P < 0.05). CONCLUSIONS: CEUS and C-TIRADS had high diagnostic values in indeterminate FNA cytological thyroid nodules. CEUS-TIRADS improved AUC, diagnostic sensitivity and accuracy, and helped to distinguish indeterminate FNA cytological nodules.

Schnurri-3 inhibition rescues skeletal fragility and vascular skeletal stem cell niche pathology in the OIM model of osteogenesis imperfecta.

Osteogenesis imperfecta (OI) is a disorder of low bone mass and increased fracture risk due to a range of genetic variants that prominently include mutations in genes encoding type I collagen. While it is well known that OI reflects defects in the activity of bone-forming osteoblasts, it is currently unclear whether OI also reflects defects in the many other cell types comprising bone, including defects in skeletal vascular endothelium or the skeletal stem cell populations that give rise to osteoblasts and whether correcting these broader defects could have therapeutic utility. Here, we find that numbers of skeletal stem cells (SSCs) and skeletal arterial endothelial cells (AECs) are augmented in Col1a2oim/oim mice, a well-studied animal model of moderate to severe OI, suggesting that disruption of a vascular SSC niche is a feature of OI pathogenesis. Moreover, crossing Col1a2oim/oim mice to mice lacking a negative regulator of skeletal angiogenesis and bone formation, Schnurri 3 (SHN3), not only corrected the SSC and AEC phenotypes but moreover robustly corrected the bone mass and spontaneous fracture phenotypes. As this finding suggested a strong therapeutic utility of SHN3 inhibition for the treatment of OI, a bone-targeting AAV was used to mediate Shn3 knockdown, rescuing the Col1a2oim/oim phenotype and providing therapeutic proof-of-concept for targeting SHN3 for the treatment of OI. Overall, this work both provides proof-of-concept for inhibition of the SHN3 pathway and more broadly addressing defects in the stem/osteoprogenitor niche as is a strategy to treat OI.

Inhibitory effect of imperatorin on dabrafenib metabolism in vitro and in vivo.

Dabrafenib is a BRAF inhibitor that has been demonstrated to be efficacious in the treatment of melanoma and non-small-cell lung cancer patients with BRAF V600E mutations. The objective of this study was to investigate the effects of 51 traditional Chinese medicines on the metabolism of dabrafenib and to further investigate the inhibitory effect of imperatorin. The quantification of dabrafenib and its metabolite hydroxy-dabrafenib was carried out using a sensitive, rapid, and accurate assay method based on ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). The results of in vitro experiments showed that 20 drugs inhibited the metabolism of dabrafenib by more than 80 %. In a further study of imperatorin on dabrafenib, the half-maximal inhibitory concentration (IC50) values of imperatorin on dabrafenib were 0.22 µM and 3.68 µM in rat liver microsomes (RLM) and human liver microsomes (HLM), respectively, while the inhibition mechanisms were non-competitive and mixed type inhibition, respectively. The results of in vivo experiments demonstrated that in the presence of imperatorin, the AUC(0-t), AUC(0-∞), Cmax, and Tmax of dabrafenib were increased by 2.38-, 2.26-, 1.05-, and 6.10-fold, respectively, while CLz/F was decreased by 67.9 %. In addition, Tmax of hydroxy-dabrafenib was increased by 1.4-fold. The results of the research showed that imperatorin had a consistent inhibitory effect on dabrafenib in vitro and in vivo. When the concurrent use of dabrafenib and imperatorin is unavoidable, clinicians should closely monitor for potential adverse events and make timely adjustments to the administered dosage.

Effects of the antitumor drugs adagrasib and asciminib on apixaban metabolism in vitro and in vivo.

Apixaban is an oral anticoagulant that directly inhibits the target Factor Xa (FXa). In this study, we focused on the in vivo and in vitro effects of adagrasib and asciminib on apixaban metabolism, to discover potential drug-drug interactions (DDI) and explore their inhibitory mechanisms. The levels of apixaban and its metabolite, O-desmethyl-apixaban (M2), were determined by ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). In vitro evaluation, the maximum half inhibitory concentration (IC50) of adagrasib in rat liver microsomes (RLM) and human liver microsomes (HLM) against apixaban was 7.99 µM and 117.40 µM, respectively. The IC50 value of asciminib against apixaban in RLM and HLM was 4.28 µM and 18.42 µM, respectively. The results of the analysis on inhibition mechanisms showed that adagrasib inhibited the metabolism of apixaban through a non-competitive mechanism, while asciminib inhibited the metabolism of apixaban through a mixed mechanism. Moreover, the interaction of apixaban with adagrasib and asciminib in Sprague-Dawley (SD) rats was also investigated. It was found that the pharmacokinetic characteristics of apixaban were significantly changed when combined with these two antitumor drugs, where AUC(0-t), AUC(0-∞), t1/2, Tmax, and Cmax were increased, while CLz/F was significantly decreased. But both drugs did not appear to affect the metabolism of M2 in a significant way. Consistent results from in vitro and in vivo demonstrated that both adagrasib and asciminib inhibited the metabolism of apixaban. It provided reference data for the future clinical individualization of apixaban.

Differential immobilization of cadmium and changes in soil surface charge in acidic Ultisol by chitosan and citric acid: effect of their functional groups.

Soil organic matter plays an important role in cadmium adsorption and immobilization. Since different organic matter components affect cadmium adsorption processes differently, selecting the right organic substrate and knowing how to apply it could improve cadmium remediation. This study compares the effects of two contrasting organic molecules; chitosan and citric acid, on cadmium adsorption and speciation in acidic Ultisol. The adsorption of chitosan to Ultisol significantly increased the soil positive charge while adsorption of citric acid increased the soil negative charge. At pH 5.0, the maximum amount of cadmium adsorbed in excess chitosan was 341% greater than that in excess citric acid. About 73-89% and 60-62% of adsorbed cadmium were bound to Fe/Mn oxides and organic matter/sulfide at pH 4.0 while this fraction was 77-100% and 57-58% for citric acid and chitosan at pH 5.0, respectively. This decrease in the complexing ability of chitosan was related to the destabilizing effect of high pH on chitosan's structure. Also, the sequence through which chitosan, citric acid, and cadmium were added into the adsorption system influenced the adsorption profile and this was different along a pH gradient. Specifically, adding chitosan and cadmium together increased adsorption compared to when chitosan was pre-adsorbed within pH 3.0-6.5. However, for citric acid, the addition sequence had no significant effect on cadmium adsorption between pH 3.0-4.0 compared to pH 6.5 and 7.5, with excess citric acid generally inhibiting adsorption. Given that the action of citric acid is short-lived in soil, chitosan could be a good soil amendment material for immobilizing cadmium.

The top 100 most cited articles on axon regeneration from 2003 to 2023: a bibliometric analysis.

Objective: In this study, we used a bibliometric and visual analysis to evaluate the characteristics of the 100 most cited articles on axon regeneration. Methods: The 100 most cited papers on axon regeneration published between 2003 and 2023 were identified by searching the Web of Science Core Collection database. The extracted data included the title, author, keywords, journal, publication year, country, and institution. A bibliometric analysis was subsequently undertaken. Results: The examined set of 100 papers collectively accumulated a total of 39,548 citations. The number of citations for each of the top 100 articles ranged from 215 to 1,604, with a median value of 326. The author with the most contributions to this collection was He, Zhigang, having authored eight papers. Most articles originated in the United States (n = 72), while Harvard University was the institution with the most cited manuscripts (n = 19). Keyword analysis unveiled several research hotspots, such as chondroitin sulfate proteoglycan, alternative activation, exosome, Schwann cells, axonal protein synthesis, electrical stimulation, therapeutic factors, and remyelination. Examination of keywords in the articles indicated that the most recent prominent keyword was "local delivery." Conclusion: This study offers bibliometric insights into axon regeneration, underscoring that the United States is a prominent leader in this field. Our analysis highlights the growing relevance of local delivery systems in axon regeneration. Although these systems have shown promise in preclinical models, challenges associated with long-term optimization, agent selection, and clinical translation remain. Nevertheless, the continued development of local delivery technologies represents a promising pathway for achieving axon regeneration; however, additional research is essential to fully realize their potential and thereby enhance patient outcomes.

Functional assessment of CYP3A4 and CYP2C19 genetic polymorphisms on the metabolism of clothianidin invitro.

Clothianidin, classified as a second-generation neonicotinoid, has achieved extensive application due to its high efficacy against insect pests. This broad-spectrum usage has resulted in its frequent detection in environmental surveys. CYP2C19 and CYP3A4 are crucial for converting clothianidin to desmethyl-clothianidin (dm-clothianidin). The expression of these CYP450s can be significantly influenced by genetic polymorphisms. The objective of our research was to examine the catalytic effects of 27 CYP3A4 variants and 31 CYP2C19 variants on the metabolism of clothianidin within recombinant insect microsomes. These variants were assessed through a well-established incubation procedure. In addition, the concentration of its metabolite dm-clothianidin was quantified by employing an ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). Lastly, the kinetic parameters of these CYP3A4 and CYP2C19 variants were calculated by applying Michaelis-Menten kinetic analysis to fit the data. The observed changes in enzyme activity were related to the metabolic transformation of clothianidin to dm-clothianidin. In the CYP2C19 metabolic pathway, one variant (CYP2C19.23) showed no notable change in intrinsic clearance (CLint), four variants (CYP2C19.29, .30, .31 and L16F) demonstrated a marked increase in CLint (110.86-183.46 %), and the remaining 25 variants exhibited a considerable decrease in CLint (26.38-89.79 %), with a maximum decrease of 73.62 % (CYP2C19.6). In the CYP3A4 metabolic pathway, 26 variants demonstrated significantly reduced CLint (10.54-52.52 %), with a maximum decrease of 89.46 % (CYP3A4.20). Our results suggested that most variants of CYP3A4 and CYP2C19 significantly altered the enzymatic activities associated with clothianidin metabolism to various degrees. This study provides new insights into assessing the metabolic behavior of pesticides and delivers crucial data that can guide clinical detoxification strategies.

A cross-dataset adaptive domain selection transfer learning framework for motor imagery-based brain-computer interfaces.

Objective. In brain-computer interfaces (BCIs) that utilize motor imagery (MI), minimizing calibration time has become increasingly critical for real-world applications. Recently, transfer learning (TL) has been shown to effectively reduce the calibration time in MI-BCIs. However, variations in data distribution among subjects can significantly influence the performance of TL in MI-BCIs.Approach.We propose a cross-dataset adaptive domain selection transfer learning framework that integrates domain selection, data alignment, and an enhanced common spatial pattern (CSP) algorithm. Our approach uses a huge dataset of 109 subjects as the source domain. We begin by identifying non-BCI illiterate subjects from this huge dataset, then determine the source domain subjects most closely aligned with the target subjects using maximum mean discrepancy. After undergoing Euclidean alignment processing, features are extracted by multiple composite CSP. The final classification is carried out using the support vector machine.Main results.Our findings indicate that the proposed technique outperforms existing methods, achieving classification accuracies of 75.05% and 76.82% in two cross-dataset experiments, respectively.Significance.By reducing the need for extensive training data, yet maintaining high accuracy, our method optimizes the practical implementation of MI-BCIs.

Simultaneous measurement of COVID-19 treatment drugs (nirmatrelvir and ritonavir) in rat plasma by UPLC-MS/MS and its application to a pharmacokinetic study.

PAXLOVID™ (Co-packaging of Nirmatrelvir with Ritonavir) has been approved for the treatment of Coronavirus Disease 2019 (COVID-19). The goal of the experiment was to create an accurate and straightforward analytical method using ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) to simultaneously quantify nirmatrelvir and ritonavir in rat plasma, and to investigate the pharmacokinetic profiles of these drugs in rats. After protein precipitation using acetonitrile, nirmatrelvir, ritonavir, and the internal standard (IS) lopinavir were separated using ultra performance liquid chromatography (UPLC). This separation was achieved with a mobile phase composed of acetonitrile and an aqueous solution of 0.1% formic acid, using a reversed-phase column with a binary gradient elution. Using multiple reaction monitoring (MRM) technology, the analytes were detected in the positive electrospray ionization mode. Favorable linearity was observed in the calibration range of 2.0-10000 ng/mL for nirmatrelvir and 1.0-5000 ng/mL for ritonavir, respectively, within plasma samples. The lower limits of quantification (LLOQ) attained were 2.0 ng/mL for nirmatrelvir and 1.0 ng/mL for ritonavir, respectively. Both drugs demonstrated inter-day and intra-day precision below 15%, with accuracies ranging from -7.6% to 13.2%. Analytes were extracted with recoveries higher than 90.7% and without significant matrix effects. Likewise, the stability was found to meet the requirements of the analytical method under different conditions. This UPLC-MS/MS method, characterized by enabling accurate and precise quantification of nirmatrelvir and ritonavir in plasma, was effectively utilized for in vivo pharmacokinetic studies in rats.