NRC-interacting factor 1 interacts with p35 and regulates neuronal differentiation

Cdk5, a proline-directed serine/threonine kinase, plays a critical role during neuronal development. The activity of Cdk5 depends on its association with two regulatory partners, p35 or p39, which are prominently expressed in neural tissues. Recent emerging studies suggest an involvement of Cdk5 in nuclear functions. Several proteins that are involved in transcriptional regulation including p53, myocyte enhancer factor-2, signal transducer and activator of transcription-3 as well as mSds3 have been demonstrated to be the substrates for Cdk5. We have recently identified another nuclear protein, NRC-interacting factor 1 (NIF-1) as one of the interacting proteins of p35. NIF-1 is suggested to regulate the transcriptional activity through its interaction with nuclear hormone receptor coregulator (NRC). Interestingly, we found that p35 regulates the shuttling of NIF-1 between nucleus and cytoplasm. Furthermore, we found that the nuclear export of NIF-1 mediated by p35 is CRM1-dependent. NIF-1 protein is prominently expressed in neurons at early embryonic stages and declined during development. To explore the functions of NIF-1, we silenced the NIF-1 protein in neurons using siRNA approach and found that NIF-1 is required for the neuronal differentiation and neurite outgrowth, Taken together, the identification of NIF-1 as p35-interacting protein further supports an important role of Cdk5 in nuclear function and provides insights into understanding how Cdk5 regulates neuronal differentiation

Influence of andrographolide on the pharmacokinetics of warfarin in rats

Context: Andrographolide and warfarin are often used together in clinics in China. However, the herb-drug interaction between andrographolide and warfarin is still unknown. Objective: This study investigates the herb-drug interaction between andrographolide and warfarin in vivo and in vitro. Materials and methods: A sensitive and reliable LC-MS/MS method was developed for the determination of warfarin in male Sprague-Dawley rats plasma, and then the pharmacokinetics of orally administered warfarin (0.5 mg/kg) with or without andrographolide (30 mg/kg/day for 7 days) pretreatment was investigated. In addition, Sprague-Dawley rat liver microsomes incubation systems were used to support the in vivo pharmacokinetic data and investigate its potential mechanism. Results: The method validation results showed that a sensitive and reliable LC-MS/MS method was developed for the determination of warfarin in rat plasma samples. The pharmacokinetic results indicated that co-administration of andrographolide could increase the systemic exposure of warfarin significantly, including area under the curve (118.92 ± 18.08 vs. 60.58 ± 9.46 μg × h/mL), maximum plasma concentration (3.32 ± 0.41 vs. 2.35 ± 0.25 μg/mL) and t1/2 (22.73 ± 3.28 vs. 14.27 ± 2.67 h). Additionally, the metabolic stability of warfarin increased from 23.5 ± 4.7 to 38.7 ± 6.1 min with the pretreatment of andrographolide, and the difference was significant (p < 0.05). Discussion and conclusion: In conclusion, andrographolide could increase the systemic exposure of warfarin in rats when andrographolide and warfarin were co-administered, and possibly by slowing down the metabolism of warfarin in rat liver by inhibiting the activity of CYP3A4 or CYP2C9

Current assessment and management of measurable residual disease in patients with acute lymphoblastic leukemia in the setting of CAR-T-cell therapy

Abstract. Chimeric antigen receptor (CAR)-modified T-cell therapy has achieved remarkable success in the treatment of acute lymphoblastic leukemia (ALL). Measurable/minimal residual disease (MRD) monitoring plays a significant role in the prognostication and management of patients undergoing CAR-T-cell therapy. Common MRD detection methods include flow cytometry (FCM), polymerase chain reaction (PCR), and next-generation sequencing (NGS), and each method has advantages and limitations. It has been well documented that MRD positivity predicts a poor prognosis and even disease relapse. Thus, how to perform prognostic evaluations, stratify risk based on MRD status, and apply MRD monitoring to guide individual therapeutic decisions have important implications in clinical practice. This review assesses the common and novel MRD assessment methods. In addition, we emphasize the critical role of MRD as a prognostic biomarker and summarize the latest studies regarding MRD-directed combination therapy with CAR-T-cell therapy and allogeneic hematopoietic stem cell transplantation (allo-HSCT), as well as other therapeutic strategies to improve treatment effect. Furthermore, this review discusses current challenges and strategies for MRD detection in the setting of disease relapse after targeted therapy

Sound absorption performance of a micro perforated sandwich panel with honeycomb-hierarchical pore structure core

A new micro perforated sandwich panel with honeycomb-hierarchical pore structure core is designed and prepared in this study. Carbonized cotton with hierarchical pore structure is combined with a micro perforated honeycomb core sandwich panel, which enhances the sound-absorbing performance of the structure without significantly increasing its weight. The experiment showed that pure carbonized cotton filling can improve the average sound absorption coefficient (at 125, 250, 500, 1000, 2000, and 4000 Hz) of the structure from 0.220 to 0.558, and hierarchical pore structure can further improve the average sound absorption coefficient to 0.626. Meanwhile, appropriate theoretical and finite element models are established, with 16.8 % and 8.6 % error respectively based on the predicted average sound absorption coefficient relative to experimental results

Composition, Structure and Morphology Evolution of Octadecylamine (ODA)–Reduced Graphene Oxide and Its Dispersion Stability under Different Reaction Conditions

Octadecylamine (ODA) can solve the aggregation problem of graphene sheets in the chemical exfoliation method. However, no attempts have been made to investigate the evolution of ODA&ndash;reduced graphene oxide (ORGO) with reaction conditions and the modification mechanism, which is the core problem to realize the controllable production and practical application of graphene. In this study, we treated graphene oxide (GO) with ODA under different reaction conditions to prepare ORGO. Fourier transform infrared spectroscopy (FTIR), X-ray photoelectron spectroscopy, atomic force microscopy, Raman spectroscopy, thermogravimetric analysis (TGA), and UV&ndash;vis spectrophotometry were employed to analyze the composition, structure, morphology and characteristics of the as&ndash;prepared graphene sheets. The results showed that the reduction reaction could occur under mild conditions, but the edge grafting reaction could only be activated by a higher temperature. Moreover, the ORGO created at 80 &deg;C for 5 h and 120 &deg;C for 0.5 h exhibited the optimized properties, both excellent dispersing stability and high heat resisting property, since they had more edge grafting chains and a suitable reduction degree

Research on the Influences of Task Interdependence on Team Performance in the Context of the Leader–Member Exchange Differentiation in the Public–Private Partnership Projects

Task interdependence is essential in sustainable cooperation, conflict prevention, and performance improvement of public–private partnership (PPP) project teams and promotes the sustainable development of PPP projects. Based on the theoretical logic of Input–Process–Output (IPO), integrating Team Process Theory and Leader–Member Exchange (LMX) Theory, we constructed a mediated model of task interdependence, team reflection, team performance, and leader–member exchange differentiation in PPP projects. Based on this, we conducted questionnaire research and research analysis on 168 PPP project teams. The results of the study indicate that task interdependence in PPP projects has a significant positive effect on team performance, and there is a significant mediating role of team reflection in the relationship between task interdependence and team performance. The leader–member exchange differentiation in teams not only moderates the relationship between task interdependence and team reflection and team reflection and team performance but also further moderates the indirect effect of task interdependence in PPP projects on team performance through team reflection. The findings extend the impact effects of task interdependence in engineering projects, as well as the moderating mechanisms of leader–member exchange differentiation in Chinese organizational scenarios, providing lessons for PPP project team performance management and sustainable development of PPP projects

Effect of Gut Microbiota-Derived Metabolites on Immune Checkpoint Inhibitor Therapy: Enemy or Friend?

The human gut is inhabited by hundreds of billions of commensal microbiota that collectively produce thousands of small molecules and metabolites with local and systemic effects on the physiology of the host. Much evidence from preclinical to clinical studies has gradually confirmed that the gut microbiota can regulate anti-tumor immunity and affect the efficacy of cancer immune checkpoint inhibitors (ICIs) therapy. In particular, one of the main modes of gut microbiota regulating anti-tumor immunity is through metabolites, which are small molecules that can be transported in the body and act on local and systemic anti-tumor immune responses to promote ICIs immunotherapy efficacy. We discuss the functions of microbial metabolites in humans, focusing on the effects and mechanisms of microbial metabolites on immunotherapy, and analyze their potential applications as immune adjuvants and therapeutic targets to regulate immunity and enhance ICIs. In summary, this review provides the basis for the rational design of microbiota and microbial metabolite-based strategies of enhancing ICIs