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The follicle is the basic structural and functional unit of the ovary in female mammals. The excessive depletion of follicles will lead to diminished ovarian reserve or even premature ovarian failure, resulting in diminished ovarian oogenesis and endocrine function. Excessive follicular depletion is mainly due to loss of primordial follicles. Our analysis of published human ovarian single-cell sequencing results by others revealed a significant increase in rho-associated protein kinase 1 (ROCK1) expression during primordial follicle development. However, the role of ROCK1 in primordial follicle development and maintenance is not clear. This study revealed a gradual increase in ROCK1 expression during primordial follicle activation. Inhibition of ROCK1 resulted in reduced primordial follicle activation, decreased follicular reserve, and delayed development of growing follicles. This effect may be achieved through the HIPPO pathway. The present study indicates that ROCK1 is a key molecule for primordial follicular reserve and follicular development.NEW & NOTEWORTHY ROCK1, one of the Rho GTPases, plays an important role in primordial follicle reserve and follicular development. ROCK1 was primarily expressed in the cytoplasm of oocytes and granulosa cell in mice. Inhibition of ROCK1 significantly reduced the primordial follicle reserve and delayed growing follicle development. ROCK1 regulates primordial follicular reserve and follicle development through the HIPPO signaling pathway. These findings shed new lights on the physiology of sustaining female reproduction.
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Oocitos , Folículo Ovárico , Animales , Femenino , Humanos , Ratones , Células de la Granulosa/metabolismo , Mamíferos , Oogénesis , Folículo Ovárico/metabolismo , Ovario/metabolismo , Quinasas Asociadas a rho/genética , Quinasas Asociadas a rho/metabolismoRESUMEN
Parcellation of human cerebellar pathways is essential for advancing our understanding of the human brain. Existing diffusion magnetic resonance imaging tractography parcellation methods have been successful in defining major cerebellar fibre tracts, while relying solely on fibre tract structure. However, each fibre tract may relay information related to multiple cognitive and motor functions of the cerebellum. Hence, it may be beneficial for parcellation to consider the potential importance of the fibre tracts for individual motor and cognitive functional performance measures. In this work, we propose a multimodal data-driven method for cerebellar pathway parcellation, which incorporates both measures of microstructure and connectivity, and measures of individual functional performance. Our method involves first training a multitask deep network to predict various cognitive and motor measures from a set of fibre tract structural features. The importance of each structural feature for predicting each functional measure is then computed, resulting in a set of structure-function saliency values that are clustered to parcellate cerebellar pathways. We refer to our method as Deep Multimodal Saliency Parcellation (DeepMSP), as it computes the saliency of structural measures for predicting cognitive and motor functional performance, with these saliencies being applied to the task of parcellation. Applying DeepMSP to a large-scale dataset from the Human Connectome Project Young Adult study (n = 1065), we found that it was feasible to identify multiple cerebellar pathway parcels with unique structure-function saliency patterns that were stable across training folds. We thoroughly experimented with all stages of the DeepMSP pipeline, including network selection, structure-function saliency representation, clustering algorithm, and cluster count. We found that a 1D convolutional neural network architecture and a transformer network architecture both performed comparably for the multitask prediction of endurance, strength, reading decoding, and vocabulary comprehension, with both architectures outperforming a fully connected network architecture. Quantitative experiments demonstrated that a proposed low-dimensional saliency representation with an explicit measure of motor versus cognitive category bias achieved the best parcellation results, while a parcel count of four was most successful according to standard cluster quality metrics. Our results suggested that motor and cognitive saliencies are distributed across the cerebellar white matter pathways. Inspection of the final k = 4 parcellation revealed that the highest-saliency parcel was most salient for the prediction of both motor and cognitive performance scores and included parts of the middle and superior cerebellar peduncles. Our proposed saliency-based parcellation framework, DeepMSP, enables multimodal, data-driven tractography parcellation. Through utilising both structural features and functional performance measures, this parcellation strategy may have the potential to enhance the study of structure-function relationships of the cerebellar pathways.
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Cerebelo , Aprendizaje Profundo , Imagen de Difusión Tensora , Humanos , Cerebelo/fisiología , Cerebelo/diagnóstico por imagen , Cerebelo/anatomía & histología , Imagen de Difusión Tensora/métodos , Adulto , Vías Nerviosas/fisiología , Vías Nerviosas/diagnóstico por imagen , Vías Nerviosas/anatomía & histología , Conectoma/métodos , Masculino , Femenino , Adulto Joven , Procesamiento de Imagen Asistido por Computador/métodos , Actividad Motora/fisiologíaRESUMEN
The superficial white matter (SWM) consists of numerous short-range association fibers connecting adjacent and nearby gyri and plays an important role in brain function, development, aging, and various neurological disorders. Diffusion MRI (dMRI) tractography is an advanced imaging technique that enables in vivo mapping of the SWM. However, detailed imaging of the small, highly-curved fibers of the SWM is a challenge for current clinical and research dMRI acquisitions. This work investigates the efficacy of mapping the SWM using in vivo ultra-high-resolution dMRI data. We compare the SWM mapping performance from two dMRI acquisitions: a high-resolution 0.76-mm isotropic acquisition using the generalized slice-dithered enhanced resolution (gSlider) protocol and a lower resolution 1.25-mm isotropic acquisition obtained from the Human Connectome Project Young Adult (HCP-YA) database. Our results demonstrate significant differences in the cortico-cortical anatomical connectivity that is depicted by these two acquisitions. We perform a detailed assessment of the anatomical plausibility of these results with respect to the nonhuman primate (macaque) tract-tracing literature. We find that the high-resolution gSlider dataset is more successful at depicting a large number of true positive anatomical connections in the SWM. An additional cortical coverage analysis demonstrates significantly higher cortical coverage in the gSlider dataset for SWM streamlines under 40 mm in length. Overall, we conclude that the spatial resolution of the dMRI data is one important factor that can significantly affect the mapping of SWM. Considering the relatively long acquisition time, the application of dMRI tractography for SWM mapping in future work should consider the balance of data acquisition efforts and the efficacy of SWM depiction.
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Sustancia Blanca , Humanos , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/anatomía & histología , Adulto , Adulto Joven , Conectoma/métodos , Masculino , Imagen de Difusión Tensora/métodos , Imagen de Difusión por Resonancia Magnética/métodos , Imagen de Difusión por Resonancia Magnética/normas , Femenino , Procesamiento de Imagen Asistido por Computador/métodos , Procesamiento de Imagen Asistido por Computador/normas , Animales , Encéfalo/diagnóstico por imagen , Encéfalo/anatomía & histologíaRESUMEN
Control over the self-assembly of small molecules at specific areas is of great interest for many high-tech applications, yet remains a formidable challenge. Here, how the self-assembly of hydrazone-based molecular hydrogelators can be specifically triggered at water-water interfaces for the continuous fabrication of supramolecular microcapsules by virtue of the microfluidic technique is demonstrated. The non-assembling hydrazide- and aldehyde-based hydrogelator precursors are distributed in two immiscible aqueous polymer solutions, respectively, through spontaneous phase separation. In the presence of catalysts, hydrazone-based hydrogelators rapidly form and self-assemble into hydrogel networks at the generated water-water interfaces. Relying on the microfluidic technique, microcapsules bearing a shell of supramolecular hydrogel are continuously produced. The obtained microcapsules can effectively load enzymes, enabling localized enzymatic growth of supramolecular fibrous supramolecular structures, reminiscent of the self-assembly of biological filaments within living cells. This work may contribute to the development of biomimetic supramolecular carriers for applications in biomedicine and fundamental research, for instance, the construction of protocells.
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BACKGROUND: Accurate diagnosis of breast lesions and discrimination of axillary lymph node (ALN) metastases largely depend on radiologist experience. PURPOSE: To develop a deep learning-based whole-process system (DLWPS) for segmentation and diagnosis of breast lesions and discrimination of ALN metastasis. STUDY TYPE: Retrospective. POPULATION: 1760 breast patients, who were divided into training and validation sets (1110 patients), internal (476 patients), and external (174 patients) test sets. FIELD STRENGTH/SEQUENCE: 3.0T/dynamic contrast-enhanced (DCE)-MRI sequence. ASSESSMENT: DLWPS was developed using segmentation and classification models. The DLWPS-based segmentation model was developed by the U-Net framework, which combined the attention module and the edge feature extraction module. The average score of the output scores of three networks was used as the result of the DLWPS-based classification model. Moreover, the radiologists' diagnosis without and with the DLWPS-assistance was explored. To reveal the underlying biological basis of DLWPS, genetic analysis was performed based on RNA-sequencing data. STATISTICAL TESTS: Dice similarity coefficient (DI), area under receiver operating characteristic curve (AUC), accuracy, sensitivity, specificity, and kappa value. RESULTS: The segmentation model reached a DI of 0.828 and 0.813 in the internal and external test sets, respectively. Within the breast lesions diagnosis, the DLWPS achieved AUCs of 0.973 in internal test set and 0.936 in external test set. For ALN metastasis discrimination, the DLWPS achieved AUCs of 0.927 in internal test set and 0.917 in external test set. The agreement of radiologists improved with the DLWPS-assistance from 0.547 to 0.794, and from 0.848 to 0.892 in breast lesions diagnosis and ALN metastasis discrimination, respectively. Additionally, 10 breast cancers with ALN metastasis were associated with pathways of aerobic electron transport chain and cytoplasmic translation. DATA CONCLUSION: The performance of DLWPS indicates that it can promote radiologists in the judgment of breast lesions and ALN metastasis and nonmetastasis. LEVEL OF EVIDENCE: 4 TECHNICAL EFFICACY STAGE: 3.
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Neoplasias de la Mama , Aprendizaje Profundo , Humanos , Femenino , Metástasis Linfática/diagnóstico por imagen , Metástasis Linfática/patología , Estudios Retrospectivos , Ganglios Linfáticos/diagnóstico por imagen , Ganglios Linfáticos/patología , Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/patología , Imagen por Resonancia MagnéticaRESUMEN
PURPOSE: High fasting plasma glucose (HFPG) has been identified as a risk factor for drug-resistant tuberculosis incidence and mortality. However, the epidemic characteristics of HFPG-attributable multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) remain unclear. We aimed to analyze the global spatial patterns and temporal trends of HFPG-attributable MDR-TB and XDR-TB from 1990 to 2019. METHODS: Utilizing data from the Global Burden of Disease 2019 project, annual deaths and disability-adjusted life years (DALYs) of HFPG-attributable MDR-TB and XDR-TB were conducted from 1990 to 2019. Joinpoint regression was employed to quantify trends over time. RESULTS: From 1990 to 2019, the deaths and DALYs due to HFPG-attributable MDR-TB and XDR-TB globally showed an overall increasing trend, with a significant increase until 2003 to 2004, followed by a gradual decline or stability thereafter. The low sociodemographic index (SDI) region experienced the most significant increase over the past 30 years. Regionally, Sub-Saharan Africa, Central Asia and Oceania remained the highest burden. Furthermore, there was a sex and age disparity in the burden of HFPG-attributable MDR-TB and XDR-TB, with young males in the 25-34 age group experiencing higher mortality, DALYs burden and a faster increasing trend than females. Interestingly, an increasing trend followed by a stable or decreasing pattern was observed in the ASMR and ASDR of HFPG-attributable MDR-TB and XDR-TB with SDI increasing. CONCLUSION: The burden of HFPG-attributable MDR-TB and XDR-TB rose worldwide from 1990 to 2019. These findings emphasize the importance of routine bi-directional screening and integrated management for drug-resistant TB and diabetes.
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Tuberculosis Extensivamente Resistente a Drogas , Tuberculosis Resistente a Múltiples Medicamentos , Masculino , Femenino , Humanos , Glucemia , Estudios Retrospectivos , Carga Global de Enfermedades , Tuberculosis Resistente a Múltiples Medicamentos/epidemiología , Tuberculosis Resistente a Múltiples Medicamentos/diagnóstico , AyunoRESUMEN
The tumor microenvironment (TME) can aid tumor cells in evading surveillance and clearance by immune cells, creating an internal environment conducive to tumor cell growth. Consequently, there is a growing focus on researching anti-tumor immunity through the regulation of immune cells within the TME. Various bioactive compounds in traditional Chinese medicine (TCM) are known to alter the immune balance by modulating the activity of immune cells in the TME. In turn, this enhances the body's immune response, thus promoting the effective elimination of tumor cells. This study aims to consolidate recent findings on the regulatory effects of bioactive compounds from TCM on immune cells within the TME. The bioactive compounds of TCM regulate the TME by modulating macrophages, dendritic cells, natural killer cells and T lymphocytes and their immune checkpoints. TCM has a long history of having been used in clinical practice in China. Chinese medicine contains various chemical constituents, including alkaloids, polysaccharides, saponins and flavonoids. These components activate various immune cells, thereby improving systemic functions and maintaining overall health. In this review, recent progress in relation to bioactive compounds derived from TCM will be covered, including TCM alkaloids, polysaccharides, saponins and flavonoids. This study provides a basis for further in-depth research and development in the field of anti-tumor immunomodulation using bioactive compounds from TCM.
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Medicamentos Herbarios Chinos , Medicina Tradicional China , Neoplasias , Microambiente Tumoral , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunología , Humanos , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/uso terapéutico , Neoplasias/inmunología , Neoplasias/tratamiento farmacológico , Animales , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/efectos de los fármacos , Inmunomodulación/efectos de los fármacos , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Macrófagos/metabolismoRESUMEN
White matter fiber clustering is an important strategy for white matter parcellation, which enables quantitative analysis of brain connections in health and disease. In combination with expert neuroanatomical labeling, data-driven white matter fiber clustering is a powerful tool for creating atlases that can model white matter anatomy across individuals. While widely used fiber clustering approaches have shown good performance using classical unsupervised machine learning techniques, recent advances in deep learning reveal a promising direction toward fast and effective fiber clustering. In this work, we propose a novel deep learning framework for white matter fiber clustering, Deep Fiber Clustering (DFC), which solves the unsupervised clustering problem as a self-supervised learning task with a domain-specific pretext task to predict pairwise fiber distances. This process learns a high-dimensional embedding feature representation for each fiber, regardless of the order of fiber points reconstructed during tractography. We design a novel network architecture that represents input fibers as point clouds and allows the incorporation of additional sources of input information from gray matter parcellation. Thus, DFC makes use of combined information about white matter fiber geometry and gray matter anatomy to improve the anatomical coherence of fiber clusters. In addition, DFC conducts outlier removal naturally by rejecting fibers with low cluster assignment probability. We evaluate DFC on three independently acquired cohorts, including data from 220 individuals across genders, ages (young and elderly adults), and different health conditions (healthy control and multiple neuropsychiatric disorders). We compare DFC to several state-of-the-art white matter fiber clustering algorithms. Experimental results demonstrate superior performance of DFC in terms of cluster compactness, generalization ability, anatomical coherence, and computational efficiency.
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Aprendizaje Profundo , Sustancia Blanca , Adulto , Humanos , Masculino , Femenino , Anciano , Imagen de Difusión Tensora/métodos , Encéfalo/diagnóstico por imagen , Encéfalo/anatomía & histología , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/anatomía & histología , Análisis por Conglomerados , Algoritmos , Procesamiento de Imagen Asistido por Computador/métodosRESUMEN
BACKGROUND: Macrophage migration inhibitory factor (MIF) and GTPase dynamin-related protein 1 (Drp1)-dependent aberrant mitochondrial fission are closely linked to the pathogenesis of asthma. However, it is unclear whether Drp1-mediated mitochondrial fission and its downstream targets mediate MIF-induced proliferation of airway smooth muscle cells (ASMCs) in vitro and airway remodeling in chronic asthma models. The present study aims to clarify these issues. METHODS: In this study, primary cultured ASMCs and ovalbumin (OVA)-induced asthmatic rats were applied. Cell proliferation was detected by CCK-8 and EdU assays. Western blotting was used to detect extracellular signal-regulated kinase (ERK) 1/2, Drp1, autophagy-related markers and E-cadherin protein phosphorylation and expression. Inflammatory cytokines production, airway reactivity test, histological staining and immunohistochemical staining were conducted to evaluate the development of asthma. Transmission electron microscopy was used to observe the mitochondrial ultrastructure. RESULTS: In primary cultured ASMCs, MIF increased the phosphorylation level of Drp1 at the Ser616 site through activation of the ERK1/2 signaling pathway, which further activated autophagy and reduced E-cadherin expression, ultimately leading to ASMCs proliferation. In OVA-induced asthmatic rats, MIF inhibitor 4-iodo-6-phenylpyrimidine (4-IPP) treatment, suppression of mitochondrial fission by Mdivi-1 or inhibiting autophagy with chloroquine phosphate (CQ) all attenuated the development of airway remodeling. CONCLUSIONS: The present study provides novel insights that MIF promotes airway remodeling in asthma by activating autophagy and degradation of E-cadherin via ERK/Drp1 signaling pathway, suggesting that targeting MIF/ERK/Drp1 might have potential therapeutic value for the prevention and treatment of asthma.
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Asma , Factores Inhibidores de la Migración de Macrófagos , Animales , Ratas , Remodelación de las Vías Aéreas (Respiratorias) , Dinaminas , Asma/inducido químicamente , Autofagia , CadherinasRESUMEN
BACKGROUND: HMGB1 and ER stress have been considered to participate in the progression of pulmonary artery hypertension (PAH). However, the molecular mechanism underlying HMGB1 and ER stress in PAH remains unclear. This study aims to explore whether HMGB1 induces pulmonary artery smooth muscle cells (PASMCs) functions and pulmonary artery remodeling through ER stress activation. METHODS: Primary cultured PASMCs and monocrotaline (MCT)-induced PAH rats were applied in this study. Cell proliferation and migration were determined by CCK-8, EdU and transwell assay. Western blotting was conducted to detect the protein levels of protein kinase RNA-like endoplasmic reticulum kinase (PERK), activating transcription factor-4 (ATF4), seven in absentia homolog 2 (SIAH2) and homeodomain interacting protein kinase 2 (HIPK2). Hemodynamic measurements, immunohistochemistry staining, hematoxylin and eosin staining were used to evaluate the development of PAH. The ultrastructure of ER was observed by transmission electron microscopy. RESULTS: In primary cultured PASMCs, HMGB1 reduced HIPK2 expression through upregulation of ER stress-related proteins (PERK and ATF4) and subsequently increased SIAH2 expression, which ultimately led to PASMC proliferation and migration. In MCT-induced PAH rats, interfering with HMGB1 by glycyrrhizin, suppression of ER stress by 4-phenylbutyric acid or targeting SIAH2 by vitamin K3 attenuated the development of PAH. Additionally, tetramethylpyrazine (TMP), as a component of traditional Chinese herbal medicine, reversed hemodynamic deterioration and vascular remodeling by targeting PERK/ATF4/SIAH2/HIPK2 axis. CONCLUSIONS: The present study provides a novel insight to understand the pathogenesis of PAH and suggests that targeting HMGB1/PERK/ATF4/SIAH2/HIPK2 cascade might have potential therapeutic value for the prevention and treatment of PAH.
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Proteína HMGB1 , Hipertensión Pulmonar , Hipertensión Arterial Pulmonar , Ratas , Animales , Arteria Pulmonar/metabolismo , Ratas Sprague-Dawley , Proteína HMGB1/metabolismo , Hipertensión Arterial Pulmonar/metabolismo , Hipertensión Pulmonar/patología , Proliferación Celular , Miocitos del Músculo Liso/metabolismo , Células Cultivadas , Monocrotalina , Proteínas Serina-Treonina QuinasasRESUMEN
KEY MESSAGE: Overexpression of JcGAST1 promotes plant growth but inhibits pistil development. The pyrimidine box and CGTCA motif of the JcGAST1 promoter were responsible for the GA and MeJA responses. Members of the gibberellic acid-stimulated Arabidopsis (GASA) gene family play roles in plant growth and development, particularly in flower induction and seed development. However, there is still relatively limited knowledge of GASA genes in Jatropha curcas. Herein, we identified a GASA family gene from Jatropha curcas, namely, JcGAST1, which encodes a protein containing a conserved GASA domain. Sequence alignment showed that the JcGAST1 protein shares 76% sequence identity and 80% sequence similarity with SlGAST1. JcGAST1 had higher expression and protein levels in the female flowers than in the male flowers. Overexpression of JcGAST1 in tobacco promotes plant growth but inhibits pistil development. JcGAST1 expression was upregulated by GA and downregulated by MeJA. Promoter analysis indicated that the pyrimidine box and CGTCA motif were the GA- and MeJA-responsive elements of the JcGAST1 promoter. Using a Y1H screen, six transcription factors were found to interact with the pyrimidine box, and three transcription factors were found to interact with the CGTCA motif. Overall, the results of this study improve our understanding of the JcGAST1 gene and provide useful information for further studies.
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Arabidopsis , Jatropha , Jatropha/genética , Jatropha/metabolismo , Regulación de la Expresión Génica de las Plantas/genética , Regiones Promotoras Genéticas/genética , Arabidopsis/genética , Arabidopsis/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismoRESUMEN
Objective: Accurate detection and classification of breast lesions in early stage is crucial to timely formulate effective treatments for patients. We aim to develop a fully automatic system to detect and classify breast lesions using multiple contrast-enhanced mammography (CEM) images. Methods: In this study, a total of 1,903 females who underwent CEM examination from three hospitals were enrolled as the training set, internal testing set, pooled external testing set and prospective testing set. Here we developed a CEM-based multiprocess detection and classification system (MDCS) to perform the task of detection and classification of breast lesions. In this system, we introduced an innovative auxiliary feature fusion (AFF) algorithm that could intelligently incorporates multiple types of information from CEM images. The average free-response receiver operating characteristic score (AFROC-Score) was presented to validate system's detection performance, and the performance of classification was evaluated by area under the receiver operating characteristic curve (AUC). Furthermore, we assessed the diagnostic value of MDCS through visual analysis of disputed cases, comparing its performance and efficiency with that of radiologists and exploring whether it could augment radiologists' performance. Results: On the pooled external and prospective testing sets, MDCS always maintained a high standalone performance, with AFROC-Scores of 0.953 and 0.963 for detection task, and AUCs for classification were 0.909 [95% confidence interval (95% CI): 0.822-0.996] and 0.912 (95% CI: 0.840-0.985), respectively. It also achieved higher sensitivity than all senior radiologists and higher specificity than all junior radiologists on pooled external and prospective testing sets. Moreover, MDCS performed superior diagnostic efficiency with an average reading time of 5 seconds, compared to the radiologists' average reading time of 3.2 min. The average performance of all radiologists was also improved to varying degrees with MDCS assistance. Conclusions: MDCS demonstrated excellent performance in the detection and classification of breast lesions, and greatly enhanced the overall performance of radiologists.
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Glioma-associated oncogene homolog 1 (GLI1), a zinc-finger transcription factor, is upregulated in tumors and promotes cancer cell proliferation and migration. However, whether GLI1 involves in pulmonary artery smooth muscle cells (PASMCs) proliferation and migration and the detailed molecular mechanisms underlying GLI1 in pulmonary arterial hypertension (PAH) are not yet clear. Primary cultured rat PASMCs and monocrotaline (MCT)-induced PAH rats model were applied to address these issues in the present study. We found that the expression of GLI1 was significantly increased in endothelin-1 (ET-1) treated PASMCs, accompanied with the activation of microRNA (miR)-27b-3p/F-box and WD repeat domain containing 7 (FBXW7)/kruppel-like factor 5 (KLF5)/GLI1 pathway through endothelin-1 receptor type A (ETAR). Elevated miR-27b-3p suppressed FBXW7 expression, which led to KLF5 accumulation by decreasing its ubiquitinated degradation, KLF5 further induced GLI1 upregulation leading to PASMCs proliferation and migration. In addition, in MCT-induced PAH rats, targeting ETAR/miR-27b-3p/FBXW7/KLF5/GLI1 pathway effectively prevented the pulmonary vascular remodeling and the development of PAH in rats. Our study indicates that interfering ETAR/miR-27b-3p/FBXW7/KLF5/GLI1 signaling axis might have a potential value in the prevention and treatment of PAH.
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MicroARNs , Hipertensión Arterial Pulmonar , Proteína con Dedos de Zinc GLI1 , Animales , Proliferación Celular , Endotelina-1/metabolismo , Proteína 7 que Contiene Repeticiones F-Box-WD/metabolismo , Factores de Transcripción de Tipo Kruppel/genética , Factores de Transcripción de Tipo Kruppel/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Monocrotalina , Miocitos del Músculo Liso/metabolismo , Hipertensión Arterial Pulmonar/genética , Arteria Pulmonar/patología , Ratas , Receptor de Endotelina A/metabolismo , Proteína con Dedos de Zinc GLI1/metabolismoRESUMEN
Sphingosine-1-phosphate (S1P), a natural multifunctional phospholipid, is highly increased in plasma from patients with pulmonary arterial hypertension and mediates proliferation of pulmonary artery smooth muscle cells (PASMCs) by activating the Notch3 signaling pathway. However, the mechanisms underpinning S1P-mediated induction of PASMCs proliferation remain unclear. In this study, using biochemical and molecular biology approaches, RNA interference and gene expression analyses, 5'-ethynyl-2'-deoxyuridine incorporation assay, and 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay, we demonstrated that S1P promoted the activation of signal transducers and activators of transcription 3 (STAT3) through sphingosine-1-phosphate receptor 2 (S1PR2), and subsequently upregulated the expression of the microRNA miR-135b, which further reduced the expression of E3 ubiquitin ligase ß-transduction repeat-containing protein and led to a reduction in yes-associated protein (YAP) ubiquitinated degradation in PASMCs. YAP is the core effector of the Hippo pathway and mediates the expression of particular genes. The accumulation of YAP further increased the expression and activation of Notch3 and ultimately promoted the proliferation of PASMCs. In addition, we showed that preblocking S1PR2, prior silencing of STAT3, miR-135b, or YAP, and prior inhibition of Notch3 all attenuated S1P-induced PASMCs proliferation. Taken together, our study indicates that S1P stimulates PASMCs proliferation by activation of the S1PR2/STAT3/miR-135b/ß-transduction repeat-containing protein/YAP/Notch3 pathway, and our data suggest that targeting this cascade might have potential value in ameliorating PASMCs hyperproliferation and benefit pulmonary arterial hypertension.
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Regulación de la Expresión Génica/efectos de los fármacos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Lisofosfolípidos/farmacología , Miocitos del Músculo Liso/citología , Miocitos del Músculo Liso/efectos de los fármacos , Arteria Pulmonar/citología , Receptor Notch3/metabolismo , Esfingosina/análogos & derivados , Animales , Proliferación Celular/efectos de los fármacos , Masculino , Miocitos del Músculo Liso/metabolismo , Ratas , Ratas Sprague-Dawley , Esfingosina/farmacología , Proteínas Señalizadoras YAPRESUMEN
Language and theory of mind (ToM) are the cognitive capacities that allow for the successful interpretation and expression of meaning. While functional MRI investigations are able to consistently localize language and ToM to specific cortical regions, diffusion MRI investigations point to an inconsistent and sometimes overlapping set of white matter tracts associated with these two cognitive domains. To further examine the white matter tracts that may underlie these domains, we use a two-tensor tractography method to investigate the white matter microstructure of 809 participants from the Human Connectome Project. 20 association white matter tracts (10 in each hemisphere) are uniquely identified by leveraging a neuroanatomist-curated automated white matter tract atlas. The fractional anisotropy (FA), mean diffusivity (MD), and number of streamlines (NoS) are measured for each white matter tract. Performance on neuropsychological assessments of semantic memory (NIH Toolbox Picture Vocabulary Test, TPVT) and emotion perception (Penn Emotion Recognition Test, PERT) are used to measure critical subcomponents of the language and ToM networks, respectively. Regression models are constructed to examine how structural measurements of left and right white matter tracts influence performance across these two assessments. We find that semantic memory performance is influenced by the number of streamlines of the left superior longitudinal fasciculus III (SLF-III), and emotion perception performance is influenced by the number of streamlines of the right SLF-III. Additionally, we find that performance on both semantic memory & emotion perception is influenced by the FA of the left arcuate fasciculus (AF). The results point to multiple, overlapping white matter tracts that underlie the cognitive domains of language and ToM. Results are discussed in terms of hemispheric dominance and concordance with prior investigations.
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Asociación , Imagen de Difusión Tensora , Red Nerviosa/anatomía & histología , Red Nerviosa/diagnóstico por imagen , Psicolingüística , Teoría de la Mente/fisiología , Sustancia Blanca/diagnóstico por imagen , Adulto , Conectoma , Femenino , Humanos , Masculino , Vías Nerviosas/anatomía & histología , Vías Nerviosas/diagnóstico por imagen , Adulto JovenRESUMEN
BACKGROUND: High body mass index (BMI) plays a key role in the progression of asthma and asthma related to high BMI resulted in a high burden of disease globally. OBJECTIVE: To explore the geographic and temporal trends in the global burden of asthma associated with high BMI from 1990 to 2019. METHODS: This is a retrospective analysis with data based on the Global Burden of Disease Study 2019 database. Deaths, disability-adjusted life-years (DALYs), age-standardized mortality rate (ASMR), and age-standardized DALY rate (ASDR) were estimated according to sex, age, and sociodemographic index levels. The estimated annual percentage change was used to evaluate the variation trends of ASMR and ASDR from 1990 to 2019. RESULTS: In 2019, the number of global asthma deaths and DALYs related to high BMI increased by 69.69% and 63.91%, respectively, compared with 1990, among which more deaths and DALYs occurred in women. The corresponding ASMR and ASDR exhibited a slightly decreasing tendency globally. South Asia accounted for the highest number of deaths and DALYs, with India ranking first worldwide in 2019. The number of deaths and DALYs were mainly seen in individuals 60 to 79 years old and 55 to 69 years old, respectively, from 1990 to 2019. The heaviest burden existed in the low-middle sociodemographic index region. CONCLUSION: The global asthma burden associated with obesity increased in absolute value but the standardized burden decreased slightly. Large variations existed in the high BMI-related asthma burdens among sexes, ages, and regions.
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Asma , Carga Global de Enfermedades , Humanos , Femenino , Persona de Mediana Edad , Anciano , Índice de Masa Corporal , Años de Vida Ajustados por Calidad de Vida , Estudios Retrospectivos , Salud Global , Asma/epidemiologíaRESUMEN
Two Zn-MOFs, namely, {[Zn(L)0.5(bpea)]·0.5H2O·0.5DMF}n [LCU-113 (for Liaocheng University)] and {[Zn(L)0.5(ibpt)]·H2O·DMF}n (LCU-114), were synthesized based on flexible tetracarboxylic acid 1,3-bis(3,5-dicarboxyphenoxy)benzene (H4L) and different N-ligands [bpea = 1,2-dipyridyl ethane; ibpt = 3-(4'-imidazolobenzene)-5-(pyridine-4'-yl)-1,2,4-triazole]. LCU-113 and LCU-114 possess twofold interpenetrating three-dimensional pillared layer structures, in which a two-dimensional layer formed by carboxylic acid and Zn2+ ions was pillared by bpea and ibpt, respectively. The two complexes show high water stability and high luminescence sensing performance toward organic solvents, ions, and antibiotics, as well as chemicals, in simulated urine. The investigation showed that (1) LCU-113 and LCU-114 could detect uric acid (UA, 2,6,8-trihydroxypurine, metabolite of purine) and p-aminophenol (PAP, biomarker of phenamine) in simulated urine by luminescence quenching, respectively, and (2) luminescence quenching of LCU-113 and LCU-114 occurred in aqueous solutions of nitrofurazone (NZF), Fe3+, and CrO42-/Cr2O72-. All the above detections have excellent anti-interference ability and recyclability. The luminescence mechanism analysis indicates that weak interactions between the framework structures and the target analytes as well as the energy competition (inner filter effect) play an important role in sensing the above analytes. The practical application for monitoring NZF/Fe3+ in water samples was also tested.
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Antibacterianos , Luminiscencia , Aniones , Antibacterianos/análisis , Cationes , Humanos , Agua/química , Zinc/químicaRESUMEN
Traditional methods of tumor treatment such as surgical resection, chemotherapy, and radiation therapy have certain limitations, and their treatment effects are not always satisfactory. As a new tumor treatment method, photothermal therapy based on nanostructures has attracted the attention of researchers due to its characteristics of minimally invasive, low side effects, and inhibition of cancer metastasis. In recent years, there has been a variety of inorganic or organic nanostructures used in the field of photothermal tumor treatment, and they have shown great application prospects. In this paper, the advantages and disadvantages of a variety of nanomaterials/nanostructures as photothermal agents (PTAs) for photothermal therapy as well as their research progress are reviewed. For the sake of clarity, the recently reported nanomaterials/nanostructures for photothermal therapy of tumor are classified into five main categories, i.e., carbon nanostructures, noble metal nanostructures, transition metal sulfides, organic polymer, and other nanostructures. In addition, future perspectives or challenges in the related field are discussed.
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Hipertermia Inducida , Nanoestructuras , Neoplasias , Elementos de Transición , Humanos , Neoplasias/terapia , Fototerapia , Nanoestructuras/uso terapéutico , Nanoestructuras/químicaRESUMEN
OBJECTIVES: Stroke is the main cause of death in Chinese residents, bringing a heavy economic burden to patients. This study aims to explore the characteristics and the factors influencing the hospitalization cost for stroke, and to provide scientific evidence for reducing the economic burden on stroke patients. METHODS: The data were mainly obtained from the Shanghai Statistics Center for Health. Using the coding system of International Classification of Diseases (ICD)-10, we retrospectively collected the stroke-related first hospitalization records of stroke patients in J district, Shanghai during January 1, 2016 to December 31, 2019 whose main diagnostic disease codes were I61-I63. After cleaning and arranging the data, we counted the first hospitalization cost and length of hospital stay (LOS) of the patients. Univariate analysis was performed using non-parametric tests, and the factors influencing stroke hospitalization cost were further analyzed by multiple linear regression fitting path model. RESULTS: A total of 3 901 stroke patients were included. Ischemic and hemorrhagic stroke patients accounted for 92.59% and 7.41%, respectively, of which the mean hospitalization cost per patient were 12 397.35 yuan and 28 814.72 yuan, respectively, and the mean LOS per patient were 13 days and 19 days, respectively. Hospitalization cost for ischemic stroke mainly consisted of medicine fees, diagnosis fees, and service fees, accounting for 44.70%, 29.92%, and 15.42%, respectively, and hospitalization cost for hemorrhagic stroke mainly consisted of medicine fees, diagnosis fees, consumables fees, and service fees, accounting for 38.76%, 18.33%, 17.59%, and 15.38%, respectively. From 2016 to 2019, the proportion of medicine fees for ischemic stroke was decreased by 19.38 percentage points, and the diagnosis fees and service fees were increased by 8.43 percentage points and 9.04 percentage points, respectively; the proportions of medicine fees and consumables fees for hemorrhagic stroke were decreased by 7.54 percentage points and 13.43 percentage points, respectively, and the proportions of diagnostic fees and service fees were increased by 6.87 percentage points and 10.15 percentage points, respectively. Path analysis results showed that the main direct factors influencing hospitalization cost were the LOS, hospital level, operation, and year, and the main indirect factors were age and hospital level (all P<0.05). CONCLUSIONS: The cost burden of stroke patients in Shanghai is relatively heavy, and we should continue to promote the medical reform policy and consolidate the achievements of medical reform. Hospitals should strengthen clinical pathway management and patient health education to improve medical efficiency and reduce invalid hospitalization days. Government departments should continue to improve the medical insurance system, enhance the supervision to medical insurance, and promote health equity.
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Accidente Cerebrovascular Hemorrágico , Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , China/epidemiología , Promoción de la Salud , Hospitalización , Humanos , Tiempo de Internación , Estudios Retrospectivos , Accidente Cerebrovascular/terapiaRESUMEN
OBJECTIVES: After cardiac surgery involving the aortic arch, the incidence of neurological complications remains high, therefore it is very important to take measures to protect brain. This study is to investigate the safety and effectiveness of deep hypothermic circulatory arrest and retrograde cerebral perfusion for aortic root combined with right half aortic arch replacement. METHODS: Clinical data of 31 patients, who underwent aortic root and right half aortic arch replacement with deep hypothermic circulatory arrest and retrograde cerebral perfusion in Xiangya Hospital, Central South University, were retrospectively analyzed. This cohort included 23 aortic aneurysms and 8 aortic dissections. Aortic root replacement was conducted in 26 patients by Bentall procedures, and 5 patients by David procedures. Time of deep hypothermic circulatory arrest and retrograde cerebral perfusion in surgery was (21.9±5.2) min. The in-hospital mortality, postoperative neurological dysfunction and other major adverse complications were observed and recorded. RESULTS: No in-hospital death and permanent neurological dysfunction occurred. Two patients had transient neurological dysfunction and 2 patients with aortic dissection requiring long-time ventilation due to hypoxemia, 1 patient underwent resternotomy. During 6-36 months of follow-up, all patients recovered satisfactorily. CONCLUSIONS: Deep hypothermic circulatory arrest and retrograde cerebral perfusion can be safely and effectively applied in aortic root and right half aortic arch replacement, and which can simplify the surgical procedures and be worth of clinical promotion.