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Alzheimer's disease (AD) is a complex neurodegenerative condition characterized by metabolic imbalances and neuroinflammation, posing a formidable challenge in medicine due to the lack of effective treatments. Despite considerable research efforts, a cure for AD remains elusive, with current therapies primarily focused on symptom management rather than addressing the disease's underlying causes. This study initially discerned, through Mendelian randomization analysis that elevating pantothenate levels significantly contributes to the prophylaxis of Alzheimer's disease. We explore the therapeutic potential of pantothenate encapsulated in liposomes (Pan@TRF@Liposome NPs), targeting the modulation of CRM1-mediated PKM2 nuclear translocation, a critical mechanism in AD pathology. Additionally, we investigate the synergistic effects of exercise, proposing a combined approach to AD treatment. Exercise-induced metabolic alterations share significant similarities with those associated with dementia, suggesting a potential complementary effect. The Pan@TRF@Liposome NPs exhibit notable biocompatibility, showing no liver or kidney toxicity in vivo, while demonstrating stability and effectiveness in modulating CRM1-mediated PKM2 nuclear translocation, thereby reducing neuroinflammation and neuronal apoptosis. The combined treatment of exercise and Pan@TRF@Liposome NP administration in an AD animal model leads to improved neurofunctional outcomes and cognitive performance. These findings highlight the nanoparticles' role as effective modulators of CRM1-mediated PKM2 nuclear translocation, with significant implications for mitigating neuroinflammation and neuronal apoptosis. Together with exercise, this dual-modality approach could offer new avenues for enhancing cognitive performance and neurofunctional outcomes in AD, marking a promising step forward in developing treatment strategies for this challenging disorder.
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AIMS: Although there are various model-based approaches to individualized vancomycin (VCM) administration, few have been reported for adult patients with periprosthetic joint infection (PJI). This work attempted to develop a machine learning (ML)-based model for predicting VCM trough concentration in adult PJI patients. METHODS: The dataset of 287 VCM trough concentrations from 130 adult PJI patients was split into a training set (229) and a testing set (58) at a ratio of 8:2, and an independent external 32 concentrations were collected as a validation set. A total of 13 covariates and the target variable (VCM trough concentration) were included in the dataset. A covariate model was respectively constructed by support vector regression, random forest regression and gradient boosted regression trees and interpreted by SHapley Additive exPlanation (SHAP). RESULTS: The SHAP plots visualized the weight of the covariates in the models, with estimated glomerular filtration rate and VCM daily dose as the 2 most important factors, which were adopted for the model construction. Random forest regression was the optimal ML algorithm with a relative accuracy of 82.8% and absolute accuracy of 67.2% (R2 =.61, mean absolute error = 2.4, mean square error = 10.1), and its prediction performance was verified in the validation set. CONCLUSION: The proposed ML-based model can satisfactorily predict the VCM trough concentration in adult PJI patients. Its construction can be facilitated with only 2 clinical parameters (estimated glomerular filtration rate and VCM daily dose), and prediction accuracy can be rationalized by SHAP values, which highlights a profound practical value for clinical dosing guidance and timely treatment.
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OBJECTIVE: This study aimed to develop an ultrasomics model for predicting lymph node metastasis preoperative in patients with gastric cancer (GC). METHODS: This study enrolled GC patients who underwent preoperative ultrasound examination. Manual segmentation of the region of interest (ROI) was performed by an experienced radiologist to extract radiomics features using the Pyradiomics software. The Z-score algorithm was used for feature normalization, followed by the Wilcoxon test to identify the most informative features. Linear prediction models were constructed using the least absolute shrinkage and selection operator (LASSO). The performance of the ultrasomics model was evaluated using the area under curve (AUC), sensitivity, specificity, and the corresponding 95% confidence intervals (CIs). RESULTS: A total of 464 GC patients (mean age: 60.4 years ±11.3 [SD]; 328 men [70.7%]) were analyzed, of whom 291 had lymph node metastasis. The patients were randomly assigned to either the training (n=324) or test (n=140) sets, using a 7:3 ratio. An ultrasomics model that consisted of 19 radiomics features was developed using Wilcoxon and LASSO algorithms in the training set. Our ultrasomics model showed moderate performance for lymph node metastasis prediction in both the training (AUC: 0.802, 95%CI: 0.752-0.851, P<0.001) and test sets (AUC: 0.802, 95%CI: 0.724-0.879, P<0.001). The calibration curve analysis indicated good agreement between the predicted probabilities of ultrasomics and actual lymph node metastasis status. CONCLUSION: Our study highlights the potential of a machine learning-based ultrasomics model in predicting lymph node metastasis in GC patients, offering implications for personalized therapy approaches.
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Diabetic peripheral neuropathic pain (DPNP) and postherpetic neuralgia (PHN) are challenging and often intractable complex medical conditions, with a substantial impact on the quality of life. Mirogabalin, a novel voltage-gated Ca2+ channel α2δ ligand, was approved for the indication of DPNP and PHN. However, the time course of effects has not yet been clarified.We aimed to establish pharmacodynamic and placebo effect models of mirogabalin and pregabalin in DPNP and PHN, and to quantitatively compare the efficacy characteristics (maximum efficacy, onset time, and other pharmacodynamic parameters) and safety of mirogabalin and pregabalin. Public databases were comprehensively searched for randomized placebo-controlled clinical trials. A model-based meta-analysis (MBMA) was developed to describe the time course of drug efficacy and placebo effects. Adverse events were compared using a fixed-effects meta-analysis. Sixteen studies including 5,147 participants were eligible for this study. The placebo effect was relatively high and gradually increased with time, and it required at least eight weeks to reach a plateau. The pharmacodynamic model revealed that the maximum pure efficacy for mirogabalin and pregabalin was approximately -7.85 % and -8.86 %, respectively; the efficacy of mirogabalin to relieve DPNP and PHN was not superior to that of pregabalin, and both drugs had similar safety. While the rate constant of the onset rate of pregabalin was approximately thrice as high as that of mirogabalin. In addition, the baseline level of pain was an important factor affecting pregabalin efficacy. These findings are helpful in evaluating the clinical extension value of mirogabalin. They suggest that the high placebo effect and the baseline level of pain should be considered when grouping patients in future research and development of voltage-gated Ca2+ channel neuroanalgesic.
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Analgésicos , Compuestos Bicíclicos con Puentes , Neuropatías Diabéticas , Neuralgia Posherpética , Pregabalina , Humanos , Neuralgia Posherpética/tratamiento farmacológico , Neuropatías Diabéticas/tratamiento farmacológico , Analgésicos/uso terapéutico , Pregabalina/uso terapéutico , Compuestos Bicíclicos con Puentes/uso terapéutico , Compuestos Bicíclicos con Puentes/farmacología , Ensayos Clínicos Controlados Aleatorios como Asunto , Resultado del Tratamiento , Modelos BiológicosRESUMEN
BACKGROUND AND OBJECTIVES: Delayed or missed antiseizure medications (ASMs) doses are common during long-term or lifelong antiepilepsy treatment. This study aims to explore optimal individualized remedial dosing regimens for delayed or missed doses of 11 commonly used ASMs. METHODS: To explore remedial dosing regimens, Monte Carlo simulation was used based on previously identified and published population pharmacokinetic models. Six remedial strategies for delayed or missed doses were investigated. The deviation time outside the individual therapeutic range was used to evaluate each remedial regimen. The influences of patients' demographics, concomitant medication, and scheduled dosing intervals on remedial regimens were assessed. RxODE and Shiny in R were used to perform Monte Carlo simulation and recommend individual remedial regimens. RESULTS: The recommended remedial regimens were highly correlated with delayed time, scheduled dosing interval, and half-life of the ASM. Moreover, the optimal remedial regimens for pediatric and adult patients were different. The renal function, along with concomitant medication that affects the clearance of the ASM, may also influence the remedial regimens. A web-based dashboard was developed to provide individualized remedial regimens for the delayed or missed dose, and a user-defined module with all parameters that could be defined flexibly by the user was also built. DISCUSSION: Monte Carlo simulation based on population pharmacokinetic models may provide a rational approach to propose remedial regimens for delayed or missed doses of ASMs in pediatric and adult patients with epilepsy.
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Epilepsia , Adulto , Humanos , Niño , Epilepsia/tratamiento farmacológico , Método de Montecarlo , Simulación por Computador , Modelos Biológicos , Esquema de MedicaciónRESUMEN
The development of electrode materials with a high specific capacitance, power density, and long-term stability is essential and remains a challenge for developing supercapacitors. Cobalt sulfides (CoS2) are considered one of the most promising and widely studied electrode materials for supercapacitors. Herein, CoS2 and hierarchical porous carbon derived from Pien Tze Huang waste are assembled into a cobalt sulfide/carbon (CoS2/PZH) matrix composite using a one-step hydrothermal method to resolve the challenges of supercapacitors. The resulting CoS2/PZH composite material exhibits a hierarchical porous structure with hollow CoS2 embedded in a PZH framework. The uniform dispersion of the hierarchical porous structure CoS2/PZH is achieved due to the PZH framework, while the uniform decoration of the porous PZH with the hollow CoS2 prevents the PZH from stacking easily. Moreover, the excellent synergistic effect of the hierarchical porous and hollow structure of CoS2/PZH can shorten the electron/ion diffusion channels, expose additional active sites, and provide stable structures for subsequent reactions. As a result, the CoS2/PZH composite material displays a high initial specific capacity of 447.5 F g-1 at 0.5 A g-1, a high energy density of 22.38 W h kg-1, and long-term cycling stability (a retention rate of 92.3% over 10 000 cycles at 5 A g-1).
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Recent studies have shown that physical activities can prevent aging-related neurodegeneration. Exercise improves the metabolic landscape of the body. However, the role of these differential metabolites in preventing neurovascular unit degeneration (NVU) is still unclear. Here, we performed single-cell analysis of brain tissue from young and old mice. Normalized mutual information (NMI) was used to measure heterogeneity between each pair of cells using the non-negative Matrix Factorization (NMF) method. Astrocytes and choroid plexus epithelial cells (CPC), two types of CNS glial cells, differed significantly in heterogeneity depending on their aging status and intercellular interactions. The MetaboAnalyst 5.0 database and the scMetabolism package were used to analyze and calculate the differential metabolic pathways associated with aging in the CPC. These mRNAs and corresponding proteins were involved in the metabolites (R)-3-Hydroxybutyric acid, 2-Hydroxyglutarate, 2-Ketobutyric acid, 3-Hydroxyanthranilic acid, Fumaric acid, L-Leucine, and Oxidized glutathione pathways in CPC. Our results showed that CPC age heterogeneity-associated proteins (ECHS1, GSTT1, HSD17B10, LDHA, and LDHB) might be directly targeted by the metabolite of oxidized glutathione (GSSG). Further molecular dynamics and free-energy simulations confirmed the insight into GSSG's targeting function and free-energy barrier on these CPC age heterogeneity-associated proteins. By inhibiting these proteins in CPC, GSSG inhibits brain energy metabolism, whereas exercise improves the metabolic pathway activity of CPC in NVU by regulating GSSG homeostasis. In order to develop drugs targeting neurodegenerative diseases, further studies are needed to understand how physical exercise enhances NVU function and metabolism by modulating CPC-glial cell interactions.
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Background: Currently, only a few studies have examined the link between dental health, cognitive impairment, and physical activity. The current study examined the relationship between denture use and physical activity in elderly patients with different cognitive abilities. Methods: The study data was sourced from the 2018 China Health and Retirement Longitudinal Study (CHARLS) database, which included information on denture use and amount of daily physical activity undertaken by older persons. Physical activity was categorized into three levels using the International Physical Activity General Questionnaire and the International Physical Activity Scale (IPAQ) rubric. The relationship between denture use and physical activity in middle-aged and older persons with varying degrees of cognitive functioning was studied using logistic regression models. Results: A total of 5,892 older people with varying cognitive abilities were included. Denture use was linked to physical activity in the cognitively healthy 60 + age group (p = 0.004). Denture use was positively related with moderate physical activity in the population (odds ratio, OR: 1.336, 95% confidence interval: 1.173-1.520, p < 0.001), according to a multivariate logistic regression analysis, a finding that was supported by the calibration curve. Furthermore, the moderate physical activity group was more likely to wear dentures than the mild physical activity group among age-adjusted cognitively unimpaired middle-aged and older persons (OR: 1.213, 95% CI: 1.053-1.397, p < 0.01). In a fully adjusted logistic regression model, moderate physical activity population had increased ORs of 1.163 (95% CI: 1.008-1.341, p < 0.05) of dentures and vigorous physical activity population had not increased ORs of 1.016 (95% CI: 0.853-1.210, p > 0.05), compared with mild physical activity population. Conclusion: This findings revealed that wearing dentures affects physical activity differently in older persons with different cognitive conditions. In cognitively unimpaired older adults, wearing dentures was associated with an active and appropriate physical activity status.
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PURPOSE: To explore the law of development and existing problems in prosthodontics teaching in the new era, through flipped classroom teaching based on WeChat public platform. METHODS: WeChat public number was applied and WeChat groups were set up among the students of grade 2013, and 93 students were divided into 20 WeChat groups, with 4 to 5 students in each group. The main platform on reform of prosthodontics teaching was WeChat app, supplemented by platforms of Lediaocha and Youkaoshi. Teachers published courseware and learning resources with WeChat public number and WeChat groups. Two-dimensional codes on questionnaires and tests which were generated by Lediaocha and Youkaoshi could be published with WeChat and the final learning effectiveness was compared using SPSS 19.0 software package for t test. RESULTS: The results showed that 59.1% students admitted WeChat teaching effective, only 5.4% students believed ineffective. Based upon partial chapters of prosthodontics, the score of classroom test (91.35±4.45) was significantly higher than that of pre-class test(90.14±5.03, Pï¼0.05). CONCLUSIONS: The reform of flipped classroom based on WeChat platform in prosthodontics have some advantages, such as more flexibility in teaching form and time arrangement, promoting students' learner autonomy, and increasing students' motivation and effects of learning prosthodontics.
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Aprendizaje , Prostodoncia , Humanos , Estudiantes , Encuestas y CuestionariosRESUMEN
Research shows that redox complementarity and synergism among the ingredients of heterogeneous catalysts can enhance the performance of the catalyst. In this research, a porous CuMoO4@Co3O4 nanosheet electrocatalyst is prepared, which is uniformly decorated on nickel foam (NF) by hydrothermal reactions and the impregnation method. The CuMoO4@Co3O4 is an efficient bifunctional catalyst with prominent electrocatalytic activity and durability. It requires overpotentials of only 54 and 251 mV to obtain current densities of 10 and 50 mA cm-2 for the cathodic hydrogen evolution reaction (HER) and the anodic oxygen evolution reaction (OER) in 1.0 mol L-1 KOH, corresponding to Tafel slope values of 98.8 and 87.4 mV dec-1, respectively. Furthermore, the CuMoO4@Co3O4 shows excellent stability of 120 h chronopotentiometry at a current density of 100 mA cm-2 for the HER/OER. Notably, an alkaline electrolyzer (with CuMoO4@Co3O4 as the HER and OER electrodes) can deliver a current density of 10 mA cm-2 at a low voltage of 1.51 V. The catalytic activity of CuMoO4@Co3O4 can be attributed to the structure of the porous nanosheets and the synergistic effect between CuMoO4 and Co3O4.
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Phenol and its chemical derivatives serve as essential chemical materials are indispensable for the synthesis of many kinds of polymers. However, they are highly toxic, carcinogenic, difficult to be degraded biologically, and often found in aqueous effluents. Recovery of hazardous phenol from wastewater remains a daunting challenge. Herein, we prepared a hybrid membrane containing polyether block amide (PEBA) matrix and HZIF-8 fillers. To improve the compatibility between ZIF-8 and PEBA, ZIF-8 was modified by using polystyrene (PS) as a template to prepare porous HZIF-8. ZIF-8, composed of zinc nodes linked by the imidazole ring skeleton, is a kind of inorganic material with high hydrothermal stability, ordered pores, and hydrophobic microporous surfaces, which has a wide range of applications in membrane separation. The separation performance of the PEBA/HZIF-8 based membranes for phenol/water is improved due to the presence of PS on the surface of HZIF-8 and the imidazole ring skeleton in ZIF-8, which enhance the π-π interaction between HZIF-8 and phenol molecules. The effects of HZIF-8 content, feed phenol concentration, and feed temperature on the pervaporation performance of PEBA/HZIF-8 membranes were further investigated. The results showed that the pervaporation performance of the PEBA/HZIF-8-10 membrane was promising with a separation factor of 80.89 and permeate flux of 247.70 g/m2·h under the feed phenol concentration of 0.2 wt % at 80 °C. In addition, the PEBA/HZIF-8-10 membrane presented excellent stability, which has great prospect for practical application in phenol recovery from waste water.
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Monocytes have been reported to be important mediators of the protective effect of exercise against the development of Alzheimer's disease (AD). This study aims explored the mechanism by which monocytes achieve this. Using single cell transcriptome analysis, results showed that CD14 + and CD16 + monocytes interacted with other cells in the circulating blood. TNF, CCR1, APP, and AREG, the key ligand-receptor-related genes, were found to be differentially expressed between exercise-treated and AD patients. The SCENIC analysis was performed to identify individual clusters of the key transcription factors (TFs). Nine clusters (M1-M9) were obtained from the co-expression network. Among the identified TFs, MAFB, HES4, and FOSL1 were found to be differentially expressed in AD. Moreover, the M4 cluster to which MAFB, HES4, and FOSL1 belonged was defined as the signature cluster for AD phenotype. Differential analysis by bulkRNA-seq revealed that the expression of TNF, CCR1, and APP were all upregulated after exercise (p < 0.05). And ATF3, MAFB, HES4, and KLF4 that were identified in M4 clusters may be the TFs that regulate TNF, CCR1, and APP in exercise prescription. After that, APP, CCR1, TNF, ATF3, KLF4, HES4, and MAFB formed a regulatory network in the ERADMT gene set, and all of them were mechanistically linked. The ERADMT gene set has been found to be a potential risk marker for the development of AD and can be used as an indicator of compliance to exercise therapy in AD patients. Using single-cell integration analysis, a network of exercise-regulating TFs in monocytes was constructed for AD disease. The constructed network reveals the mechanism by which exercise regulated monocytes to confer therapeutic benefits against AD and its complications. However, this study, as a bioinformatic research, requires further experimental validation.
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PURPOSE: This study aimed to evaluate the diagnostic performance of convolutional neural network (CNN) models in Chiari malformation type I (CMI) and to verify whether CNNs can identify the morphological features of the craniocervical junction region between patients with CMI and healthy controls (HCs). To date, numerous indicators based on manual measurements are used for the diagnosis of CMI. However, the corresponding postoperative efficacy and prognostic evaluations have remained inconsistent. From a diagnostic perspective, CNN models may be used to explore the relationship between the clinical features and image morphological parameters. METHODS: This study included a total of 148 patients diagnosed with CMI at our institution and 205 HCs were included. T1-weighted sagittal magnetic resonance imaging (MRI) images were used for the analysis. A total of 220 and 355 slices were acquired from 98 patients with CMI and 155 HCs, respectively, to train and validate the CNN models. In addition, median sagittal images obtained from 50 patients with CMI and 50 HCs were selected to test the models. We applied original cervical MRI images (CI) and images of posterior cranial fossa and craniocervical junction area (CVI) to train the CI- and CVI-based CNN models. Transfer learning and data augmentation were used for model construction and each model was retrained 10 times. RESULTS: Both the CI- and CVI-based CNN models achieved high diagnostic accuracy. In the validation dataset, the models had diagnostic accuracy of 100% and 97% (p = 0.005), sensitivity of 100% and 98% (p = 0.016), and specificity of 100% (p = 0.929), respectively. In the test dataset, the accuracy was 97% and 96% (p = 0.25), sensitivity was 97% and 92% (p = 0.109), and specificity was 100% (p = 0.123), respectively. For patients with cerebellar subungual herniation less than 5 mm, three out of the 10 CVI-based retrained models reached 100% sensitivity. CONCLUSIONS: Our results revealed that the CNN models demonstrated excellent diagnostic performance for CMI. The models had higher sensitivity than the application of cerebellar tonsillar herniation alone and could identify features in the posterior cranial fossa and craniocervical junction area of patients. Our preliminary experiments provided a feasible method for the diagnosis and study of CMI using CNN models. However, further studies are needed to identify the morphologic characteristics of patients with different clinical outcomes, as well as patients who may benefit from surgery.
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Malformación de Arnold-Chiari , Adulto , Malformación de Arnold-Chiari/diagnóstico por imagen , Malformación de Arnold-Chiari/patología , Fosa Craneal Posterior/patología , Encefalocele/patología , Humanos , Imagen por Resonancia Magnética/métodos , Redes Neurales de la ComputaciónRESUMEN
BACKGROUND: Several studies have shown that members of the tumor necrosis factor (TNF) family play an important role in cancer immunoregulation, and trials targeting these molecules are already underway. Our study aimed to integrate and analyze the expression patterns and clinical significance of TNF family-related genes in gliomas. METHODS: A total of 1749 gliomas from 4 datasets were enrolled in our study, including the Cancer Genome Atlas (TCGA) dataset as the training cohort and the other three datasets (CGGA, GSE16011, and Rembrandt) as validation cohorts. Clinical information, RNA expression data, and genomic profile were collected for analysis. We screened the signature gene set by Cox proportional hazards modelling. We evaluated the prognostic value of the signature by Kaplan-Meier analysis and timeROC curve. Gene Ontology (GO) and Gene set enrichment analysis (GSEA) analysis were performed for functional annotation. CIBERSORT algorithm and inflammatory metagenes were used to reveal immune characteristics. RESULTS: In gliomas, the expression of most TNF family members was positively correlated. Univariate analysis showed that most TNF family members were related to the overall survival of patients. Then through the LASSO regression model, we developed a TNF family-based signature, which was related to clinical, molecular, and genetic characteristics of patients with glioma. Moreover, the signature was found to be an independent prognostic marker through survival curve analysis and Cox regression analysis. Furthermore, a nomogram prognostic model was constructed to predict individual survival rates at 1, 3 and 5 years. Functional annotation analysis revealed that the immune and inflammatory response pathways were enriched in the high-risk group. Immunological analysis showed the immunosuppressive status in the high-risk group. CONCLUSIONS: We developed a TNF family-based signature to predict the prognosis of patients with glioma. Video abstract.
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Neoplasias Encefálicas , Glioma , Biomarcadores de Tumor/genética , Neoplasias Encefálicas/metabolismo , Regulación Neoplásica de la Expresión Génica , Glioma/patología , Humanos , Factores de Necrosis Tumoral/genética , Factores de Necrosis Tumoral/metabolismoRESUMEN
INTRODUCTION: Regeneration of fibrochondrocytes is essential for the healing of the tendon-bone interface (TBI), which is similar to the formation of neurogenic heterotopic ossification (HO). Through single-cell integrative analysis, this study explored the homogeneity of HO cells and fibrochondrocytes. METHODS: This study integrated six datasets, namely, GSE94683, GSE144306, GSE168153, GSE138515, GSE102929, and GSE110993. The differentiation trajectory and key transcription factors (TFs) for HO occurrence were systematically analyzed by integrating single-cell RNA (scRNA) sequencing, bulk RNA sequencing, and assay of transposase accessible chromatin seq. The differential expression and enrichment pathways of TFs in heterotopically ossified tissues were identified. RESULTS: HO that mimicked pathological cells was classified into HO1 and HO2 cell subsets. Results of the pseudo-temporal sequence analysis suggested that HO2 is a differentiated precursor cell of HO1. The analysis of integrated scRNA data revealed that ectopically ossified cells have similar transcriptional characteristics to cells in the fibrocartilaginous zone of tendons. The modified SCENIC method was used to identify specific transcriptional regulators associated with ectopic ossification. Xbp1 was defined as a common key transcriptional regulator of ectopically ossified tissues and the fibrocartilaginous zone of tendons. Subsequently, the CellPhoneDB database was completed for the cellular ligand-receptor analysis. With further pathway screening, this study is the first to propose that Xbp1 may upregulate the Notch signaling pathway through Jag1 transcription. Twenty-four microRNAs were screened and were found to be potentially associated with upregulation of XBP1 expression after acute ischemic stroke. CONCLUSION: A systematic analysis of the differentiation landscape and cellular homogeneity facilitated a molecular understanding of the phenotypic similarities between cells in the fibrocartilaginous region of tendon and HO cells. Furthermore, by identifying Xbp1 as a hub regulator and by conducting a ligand-receptor analysis, we propose a potential Xbp1/Jag1/Notch signaling pathway.
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Huesos/patología , Estrés del Retículo Endoplásmico , Fibrocartílago/patología , Osificación Heterotópica/patología , Receptores Notch/metabolismo , Análisis de la Célula Individual/métodos , Proteína 1 de Unión a la X-Box/metabolismo , Animales , Huesos/metabolismo , Diferenciación Celular , Linaje de la Célula , Fibrocartílago/metabolismo , Perfilación de la Expresión Génica , Humanos , Masculino , Ratones Endogámicos C57BL , Osificación Heterotópica/genética , Osificación Heterotópica/metabolismo , Osteogénesis , Receptores Notch/genética , Proteína 1 de Unión a la X-Box/genéticaRESUMEN
BACKGROUND: The critical role of vascular health on brain function has received much attention in recent years. At the single-cell level, studies on the developmental processes of cerebral vascular growth are still relatively few. Techniques for constructing gene regulatory networks (GRNs) based on single-cell transcriptome expression data have made significant progress in recent years. Herein, we constructed a single-cell transcriptional regulatory network of mouse cerebrovascular cells. METHODS: The single-cell RNA-seq dataset of mouse brain vessels was downloaded from GEO (GSE98816). This cell clustering was annotated separately using singleR and CellMarker. We then used a modified version of the SCENIC method to construct GRNs. Next, we used a mouse version of SEEK to assess whether genes in the regulon were coexpressed. Finally, regulatory module analysis was performed to complete the cell type relationship quantification. RESULTS: Single-cell RNA-seq data were used to analyze the heterogeneity of mouse cerebrovascular cells, whereby four cell types including endothelial cells, fibroblasts, microglia, and oligodendrocytes were defined. These subpopulations of cells and marker genes together characterize the molecular profile of mouse cerebrovascular cells. Through these signatures, key transcriptional regulators that maintain cell identity were identified. Our findings identified genes like Lmo2, which play an important role in endothelial cells. The same cell type, for instance, fibroblasts, was found to have different regulatory networks, which may influence the functional characteristics of local tissues. CONCLUSIONS: In this study, a transcriptional regulatory network based on single-cell analysis was constructed. Additionally, the study identified and profiled mouse cerebrovascular cells using single-cell transcriptome data as well as defined TFs that affect the regulatory network of the mouse brain vasculature.
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Encéfalo/irrigación sanguínea , Encéfalo/metabolismo , Regulación de la Expresión Génica , Análisis de la Célula Individual , Transcriptoma/genética , Animales , Biomarcadores/metabolismo , Encéfalo/citología , Células Endoteliales/metabolismo , Fibroblastos/metabolismo , Redes Reguladoras de Genes , Ratones , Análisis de Secuencia de ARNRESUMEN
INTRODUCTION: Oxcarbazepine is commonly used as first-line treatment for partial and generalized tonic-clonic seizures. Owing to the high pharmacokinetic variability, several population pharmacokinetic models have been developed for oxcarbazepine to explore potential covariates that affect its pharmacokinetic variation. AREAS COVERED: This review summarizes the published population pharmacokinetic studies of oxcarbazepine in children and adults available in PubMed and Embase databases. The quality of the retrieved studies was evaluated, and significant covariates that may have an impact on the dosage regimen of oxcarbazepine were explored. EXPERT OPINION: The pharmacokinetics of oxcarbazepine was founded to be affected by body weight and co-administration with enzyme inducers. Pediatric patients require a higher dose per kilogram than adults because children generally have a higher clearance than adults. Moreover, to maintain the target concentration, patients co-administrate with enzyme inducers need a higher dose than monotherapy due to higher clearance in those patients. Because limited information is available for exposure-response relationship, additional pharmacokinetic/pharmacodynamics investigations of oxcarbazepine need to be conducted to optimize the dosage regimen in clinical practice.
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Anticonvulsivantes/administración & dosificación , Epilepsia/tratamiento farmacológico , Oxcarbazepina/administración & dosificación , Adulto , Factores de Edad , Anticonvulsivantes/farmacocinética , Niño , Relación Dosis-Respuesta a Droga , Epilepsia/fisiopatología , Humanos , Modelos Biológicos , Oxcarbazepina/farmacocinéticaRESUMEN
A two-dimensional molybdenum disulfide (MoS2) nanosheet, as a new type of inorganic material with high hydrophobicity and excellent physicochemical stability, holds great application potential in the preparation of a high separation performance organic-inorganic hybrid membrane. In this work, high hydrophobic MoS2 was embedded in hydrophobic polyether copolymer block amide (PEBA) to prepare PEBA/MoS2 organic-inorganic hybrid membranes. The structure, morphology, and hydrophobicity of the hybrid membrane were characterized by scanning electron microscopy, thermogravimetric analysis, contact angle goniometry, X-ray diffraction, infrared spectroscopy analysis, and atomic force microscopy. The effect of embedding of MoS2 on the swelling degree and pervaporation separation performance of the PEBA/MoS2 hybrid membrane was studied with a 1.0 wt % pyridine dilute solution. The results indicated that with increasing the MoS2 content, the separation factor of PEBA/MoS2 increased first and then decreased, while it showed a downward trend in the permeation flux. When the MoS2 content in the PEBA/MoS2 hybrid membrane was 10.0 wt %, the permeation flux was 83.4 g m-2 h-1 (decreased by 21.5% compared with the pure PEBA membrane), and the separation factor reached a maximum value of 11.11 (increased by 37.6% compared with the pure PEBA membrane). Meanwhile, the effects of feed temperature on the pervaporation separation performance of PEBA/MoS2 hybrid membranes were also studied. In addition, as the PEBA/MoS2 hybrid membrane has excellent thermal stability, it is expected to be a promising material for recovering pyridine from wastewater.
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Cation/H+ -exchanger (CHX) perform diverse functions in plants, including being a part of the protective mechanisms to cope with salt stress. GmCHX1 has been previously identified as the causal gene in a major salt-tolerance quantitative trait locus (QTL) in soybean, but little is known about another close paralog, GmCHX20a, found in the same QTL. In this study, GmCHX20a was characterized along with GmCHX1. The expression patterns of the two genes and the direction of Na+ flux directed by overexpression of these two transporters are different, suggesting that they are functionally distinct. The ectopic expression of GmCHX20a led to an increase in salt sensitivity and osmotic tolerance, which was consistent with its role in increasing Na+ uptake into the root. Although this seems counter-intuitive, it may in fact be part of the mechanism by which soybean could counter act the effects of osmotic stress, which is commonly manifested in the initial stage of salinity stress. On the other hand, GmCHX1 from salt-tolerant soybean was shown to protect plants via Na+ exclusion under salt stress. Taken together these results suggest that GmCHX20a and GmCHX1 might work complementally through a concerted effort to address both osmotic stress and ionic stress as a result of elevated salinity.
Asunto(s)
Glycine max , Tolerancia a la Sal , Cationes , Membrana Celular , Proteínas de Plantas/genética , Salinidad , Estrés Salino , Tolerancia a la Sal/genética , Glycine max/genéticaRESUMEN
The transformation of CO2 into polymeric materials is an important and hot research topic from the viewpoint of renewable resources and environmental effects. Herein, a series of polyureas have been synthesized by polycondensation from CO2 with diamines of 1,12-diaminododecane (DAD) and/or 4,7,10-trioxa-1,13-tridecanediamine (TTD). The properties of polyureas synthesized were characterized by FTIR, 1H NMR, 13C NMR, XRD, DSC, TGA, and DMA. The polyureas synthesized from CO2 with a mixture of diamines presented high performances compared to those of polyureas synthesized from CO2 with a single diamine. The thermal and mechanical properties were improved largely by the variation in the crystallization and the chain flexibility depending on the changes in the density and/or intensity of hydrogen bonds. With increasing amounts of TTD from 0 to 100% in weight, the melting (Tm), crystallization (Tc), and glass transition (Tg) temperatures decreased from 207 to 116 °C, from 181 to 54 °C, and from 66 to -34 °C, respectively. When the TTD content was increased from 0 to 50 wt %, the Young's modulus decreased from 1170 to 406 MPa, and the tensile strength decreased from 53.3 to 42.9 MPa. However, the elongation at break increased from 13 to 330%. Furthermore, the chain length of aliphatic diamines and polyetheramines had a significant effect on the mechanical properties. The initial decomposition temperature (Td,5%) is >295 °C, about 110 °C higher than the Tm (116-207 °C), which is advantageous for the postprocessing. The mechanical properties of the polyureas synthesized herein are superior to those of polycarbonate and polyamide 6. Thus, polyureas synthesized from the renewable and cheap resources, CO2 and diamines, will find wide potential applications in the field of polymeric materials.