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1.
Artigo em Inglês | MEDLINE | ID: mdl-38866533

RESUMO

Objectives Well-being serves as a crucial indicator of national governance and societal advancement. Consequently, the Better Life Index (BLI) developed by the Organisation for Economic Co-operation and Development (OECD) has emerged as a pivotal multidimensional measure of well-being, surpassing traditional indicators such as Gross Domestic Product (GDP). However, current well-being indicators predominantly focus on national measurements and do not effectively evaluate well-being in smaller regions such as states or prefectures. This study aimed to calculate a Regional Well-Being Index (RWI) tailored to localized areas in Japan.Methods Japanese official statistics, publicly available as open data, were analyzed, focusing on 11 domains similar to those in the BLI: "Income," "Jobs," "Housing," "Health," "Work-Life Balance," "Education," "Community," "Civic Engagement," "Environment," "Safety," and "Life Satisfaction." The RWI scores were calculated for each prefecture in 2010, 2013, 2016, and 2019 using standard normalization techniques. To represent the overall well-being of each prefecture in each year, scores were aggregated across all domains; this aggregate is referred to as the Integrated RWI. The reliability and validity of RWI were assessed by examining time-series changes and Pearson's correlation coefficients.Results Median Integrated RWI scores for Japanese prefectures remained relatively stable across the study period, with slight variations observed: median = 0.67 (Interquartile range [IQR]: -2.48-2.71) in 2010, median = 0.00 (IQR: -2.85-2.76) in 2013, median = 0.13 (IQR: -3.05-2.49) in 2016, and median = 0.19 (IQR: -2.75-3.06) in 2019. Geographical analysis showed lower scores in regions such as Western Kyushu and Shikoku, and higher scores in Chubu and Eastern Kinki. The RWI and the BLI demonstrated construct validity, with Pearson's correlation coefficients ranging from 0.58 to 0.99 across various domains.Conclusion The RWI, based on the OECD's BLI, proved to be a reliable and valid tool for assessing comprehensive well-being at the regional level in Japan. It offers foundational data for identifying challenges to regional well-being and shaping targeted policies, thereby contributing to evidence-based policymaking. Moreover, this methodology has potential applicability in evaluating comprehensive well-being beyond GDP at the regional level in other countries using official statistics.

2.
Nature ; 625(7996): 768-777, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38200313

RESUMO

Cerebrospinal fluid (CSF) in the subarachnoid space around the brain has long been known to drain through the lymphatics to cervical lymph nodes1-17, but the connections and regulation have been challenging to identify. Here, using fluorescent CSF tracers in Prox1-GFP lymphatic reporter mice18, we found that the nasopharyngeal lymphatic plexus is a major hub for CSF outflow to deep cervical lymph nodes. This plexus had unusual valves and short lymphangions but no smooth-muscle coverage, whereas downstream deep cervical lymphatics had typical semilunar valves, long lymphangions and smooth muscle coverage that transported CSF to the deep cervical lymph nodes. α-Adrenergic and nitric oxide signalling in the smooth muscle cells regulated CSF drainage through the transport properties of deep cervical lymphatics. During ageing, the nasopharyngeal lymphatic plexus atrophied, but deep cervical lymphatics were not similarly altered, and CSF outflow could still be increased by adrenergic or nitric oxide signalling. Single-cell analysis of gene expression in lymphatic endothelial cells of the nasopharyngeal plexus of aged mice revealed increased type I interferon signalling and other inflammatory cytokines. The importance of evidence for the nasopharyngeal lymphatic plexus functioning as a CSF outflow hub is highlighted by its regression during ageing. Yet, the ageing-resistant pharmacological activation of deep cervical lymphatic transport towards lymph nodes can still increase CSF outflow, offering an approach for augmenting CSF clearance in age-related neurological conditions in which greater efflux would be beneficial.


Assuntos
Líquido Cefalorraquidiano , Vértebras Cervicais , Drenagem , Vasos Linfáticos , Animais , Camundongos , Envelhecimento/metabolismo , Líquido Cefalorraquidiano/metabolismo , Vértebras Cervicais/metabolismo , Células Endoteliais/metabolismo , Fluorescência , Genes Reporter , Interferon Tipo I/imunologia , Interferon Tipo I/metabolismo , Vasos Linfáticos/fisiologia , Miócitos de Músculo Liso/metabolismo , Óxido Nítrico/metabolismo , Nariz/fisiologia , Faringe/metabolismo , Receptores Adrenérgicos alfa/metabolismo , Análise de Célula Única , Transdução de Sinais
3.
Sci Immunol ; 8(88): eadg6155, 2023 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-37801517

RESUMO

High neonatal susceptibility to meningitis has been attributed to the anatomical barriers that act to protect the central nervous system (CNS) from infection being immature and not fully developed. However, the mechanisms by which pathogens breach CNS barriers are poorly understood. Using the Armstrong strain of lymphocytic choriomeningitis virus (LCMV) to study virus propagation into the CNS during systemic infection, we demonstrate that mortality in neonatal, but not adult, mice is high after infection. Virus propagated extensively from the perivenous sinus region of the dura mater to the leptomeninges, choroid plexus, and cerebral cortex. Although the structural barrier of CNS border tissues is comparable between neonates and adults, immunofluorescence staining and single-cell RNA sequencing analyses revealed that the neonatal dural immune cells are immature and predominantly composed of CD206hi macrophages, with major histocompatibility complex class II (MHCII)hi macrophages being rare. In adults, however, perivenous sinus immune cells were enriched in MHCIIhi macrophages that are specialized for producing antiviral molecules and chemokines compared with CD206hi macrophages and protected the CNS against systemic virus invasion. Our findings clarify how systemic pathogens enter the CNS through its border tissues and how the immune barrier at the perivenous sinus region of the dura blocks pathogen access to the CNS.


Assuntos
Encefalite Viral , Coriomeningite Linfocítica , Meningite Viral , Meningoencefalite , Camundongos , Animais , Sistema Nervoso Central , Meninges , Vírus da Coriomeningite Linfocítica
4.
Nat Commun ; 14(1): 2754, 2023 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-37179330

RESUMO

Active thermogenesis in the brown adipose tissue (BAT) facilitating the utilization of lipids and glucose is critical for maintaining body temperature and reducing metabolic diseases, whereas inactive BAT accumulates lipids in brown adipocytes (BAs), leading to BAT whitening. Although cellular crosstalk between endothelial cells (ECs) and adipocytes is essential for the transport and utilization of fatty acid in BAs, the angiocrine roles of ECs mediating this crosstalk remain poorly understood. Using single-nucleus RNA sequencing and knock-out male mice, we demonstrate that stem cell factor (SCF) derived from ECs upregulates gene expressions and protein levels of the enzymes for de novo lipogenesis, and promotes lipid accumulation by activating c-Kit in BAs. In the early phase of lipid accumulation induced by denervation or thermoneutrality, transiently expressed c-Kit on BAs increases the protein levels of the lipogenic enzymes via PI3K and AKT signaling. EC-specific SCF deletion and BA-specific c-Kit deletion attenuate the induction of the lipogenic enzymes and suppress the enlargement of lipid droplets in BAs after denervation or thermoneutrality in male mice. These data provide insight into SCF/c-Kit signaling as a regulator that promotes lipid accumulation through the increase of lipogenic enzymes in BAT when thermogenesis is inhibited.


Assuntos
Adipócitos Marrons , Hipercolesterolemia , Animais , Masculino , Camundongos , Adipócitos Marrons/metabolismo , Tecido Adiposo Marrom/metabolismo , Células Endoteliais/metabolismo , Ácidos Graxos/metabolismo , Hipercolesterolemia/metabolismo , Lipogênese/genética , Camundongos Knockout , Receptores Proteína Tirosina Quinases/metabolismo , Fator de Células-Tronco/genética , Fator de Células-Tronco/metabolismo , Termogênese/genética , Proteínas Proto-Oncogênicas c-kit
5.
Knee Surg Sports Traumatol Arthrosc ; 31(4): 1388-1397, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-36006418

RESUMO

PURPOSE: Evaluating lower extremity alignment using full-leg plain radiographs is an essential step in diagnosis and treatment of patients with knee osteoarthritis. The study objective was to present a deep learning-based anatomical landmark recognition and angle measurement model, using full-leg radiographs, and validate its performance. METHODS: A total of 11,212 full-leg plain radiographs were used to create the model. To train the data, 15 anatomical landmarks were marked by two orthopaedic surgeons. Mechanical lateral distal femoral angle (mLDFA), medial proximal tibial angle (MPTA), joint line convergence angle (JLCA), and hip-knee-ankle angle (HKAA) were then measured. For inter-observer reliability, the inter-observer intraclass correlation coefficient (ICC) was evaluated by comparing measurements from the model, surgeons, and students, to ground truth measurements annotated by an orthopaedic specialist with 14 years of experience. To evaluate test-retest reliability, all measurements were made twice by each measurer. Intra-observer ICCs were then derived. Performance evaluation metrics used in previous studies were also derived for direct comparison of the model's performance. RESULTS: Inter-observer ICCs for all angles of the model were 0.98 or higher (p < 0.001). Intra-observer ICCs for all angles were 1.00, which was higher than that of the orthopaedic specialist (0.97-1.00). Measurements made by the model showed no significant systemic variation. Except for JLCA, angles were precisely measured with absolute error averages under 0.52 degrees and proportion of outliers under 4.26%. CONCLUSIONS: The deep learning model is capable of evaluating lower extremity alignment with performance as accurate as an orthopaedic specialist with 14 years of experience. LEVEL OF EVIDENCE: III, retrospective cohort study.


Assuntos
Aprendizado Profundo , Osteoartrite do Joelho , Humanos , Perna (Membro) , Estudos Retrospectivos , Reprodutibilidade dos Testes , Extremidade Inferior , Tíbia/diagnóstico por imagem , Tíbia/cirurgia , Articulação do Joelho/diagnóstico por imagem , Articulação do Joelho/cirurgia , Osteoartrite do Joelho/cirurgia
6.
Sci Adv ; 8(23): eabn2611, 2022 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-35687678

RESUMO

In sprouting angiogenesis, the precise mechanisms underlying how intracellular vascular endothelial growth factor receptor 2 (VEGFR2) signaling is higher in one endothelial cell (EC) compared with its neighbor and acquires the tip EC phenotype under a similar external cue are elusive. Here, we show that Merlin, encoded by the neurofibromatosis type 2 (NF2) gene, suppresses VEGFR2 internalization depending on VE-cadherin density and inhibits tip EC induction. Accordingly, endothelial Nf2 depletion promotes tip EC induction with excessive filopodia by enhancing VEGFR2 internalization in both the growing and matured vessels. Mechanistically, Merlin binds to the VEGFR2-VE-cadherin complex at cell-cell junctions and reduces VEGFR2 internalization-induced downstream signaling during tip EC induction. As a consequence, nonfunctional excessive sprouting occurs during tumor angiogenesis in EC-specific Nf2-deleted mice, leading to delayed tumor growth. Together, Nf2/Merlin is a crucial molecular gatekeeper for tip EC induction, capillary integrity, and proper tumor angiogenesis by suppressing VEGFR2 internalization.

7.
Nat Commun ; 12(1): 4405, 2021 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-34285232

RESUMO

Stimulator of interferon genes (STING) promotes anti-tumour immunity by linking innate and adaptive immunity, but it remains unclear how intratumoural treatment with STING agonists yields anti-tumour effects. Here we demonstrate that intratumoural injection of the STING agonist cGAMP induces strong, rapid, and selective apoptosis of tumour endothelial cells (ECs) in implanted LLC tumour, melanoma and breast tumour, but not in spontaneous breast cancer and melanoma. In both implanted and spontaneous tumours, cGAMP greatly increases TNFα from tumour-associated myeloid cells. However, compared to spontaneous tumour ECs, implanted tumour ECs are more vulnerable to TNFα-TNFR1 signalling-mediated apoptosis, which promotes effective anti-tumour activity. The spontaneous tumour's refractoriness to cGAMP is abolished by co-treatment with AKT 1/2 inhibitor (AKTi). Combined treatment with cGAMP and AKTi induces extensive tumour EC apoptosis, leading to extensive tumour apoptosis and marked growth suppression of the spontaneous tumour. These findings propose an advanced avenue for treating primary tumours that are refractory to single STING agonist therapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Proteínas de Membrana/agonistas , Neoplasias/tratamento farmacológico , Nucleotídeos Cíclicos/farmacologia , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos dos fármacos , Apoptose/imunologia , Linhagem Celular Tumoral/transplante , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Técnicas de Silenciamento de Genes , Células Endoteliais da Veia Umbilical Humana , Humanos , Imunidade Inata/efeitos dos fármacos , Injeções Intralesionais , Masculino , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Transgênicos , Neoplasias/irrigação sanguínea , Neoplasias/imunologia , Neoplasias/patologia , Nucleotídeos Cíclicos/uso terapêutico , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia , Fator de Necrose Tumoral alfa/metabolismo
8.
Int J Biol Macromol ; 182: 1713-1723, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34051260

RESUMO

The importance of developing more potent antimicrobials and robust infection prevention practices has been highlighted recently with the increase in reports of emerging bacterial resistance mechanisms and the development of antibiotic-resistant microbes. In this study, a quaternary ammonium chitosan derivative, N,N,N-trimethyl chitosan chloride (TMC) with inherent bactericidal property was synthesized and complexed with povidone­iodine (PVP-I) to create a potentially more potent antiseptic solution that could also significantly enhance the wound healing process. TMC, a positively charged, water-soluble derivative of chitosan, formed stable solutions with PVP-I at 5% w/v TMC concentration (TMC5/PVP-I). TMC5/PVP-I was significantly effective against multidrug-resistant bacteria S. aureus compared with PVP-I alone. TMC/PVP-I solutions also showed fungicidal property against C. albicans, with no cytotoxic effects when tested against human fibroblast cells cultured in vitro. Wound healing assessment in vivo revealed early collagen formation and re-epithelialization for TMC5/PVP-I treated wounds in rats relative to control and PVP-I only. Formulation of TMC/PVP-I solutions presented in the study can be easily adapted in the existing production of commercial PVP-I creating a new product with more potent bactericidal and enhanced wound healing properties for optimal wound care.


Assuntos
Anti-Infecciosos Locais/farmacologia , Quitosana/farmacologia , Povidona-Iodo/farmacologia , Compostos de Amônio Quaternário/farmacologia , Cicatrização/efeitos dos fármacos , Animais , Antibacterianos/farmacologia , Antifúngicos/farmacologia , Bactérias/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Quitosana/química , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Fungos/efeitos dos fármacos , Humanos , Masculino , Testes de Sensibilidade Microbiana , Nefelometria e Turbidimetria , Povidona-Iodo/química , Espectroscopia de Prótons por Ressonância Magnética , Compostos de Amônio Quaternário/química , Ratos Sprague-Dawley
9.
J Clin Invest ; 131(13)2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34003804

RESUMO

The upper respiratory tract is compromised in the early period of COVID-19, but SARS-CoV-2 tropism at the cellular level is not fully defined. Unlike recent single-cell RNA-Seq analyses indicating uniformly low mRNA expression of SARS-CoV-2 entry-related host molecules in all nasal epithelial cells, we show that the protein levels are relatively high and that their localizations are restricted to the apical side of multiciliated epithelial cells. In addition, we provide evidence in patients with COVID-19 that SARS-CoV-2 is massively detected and replicated within the multiciliated cells. We observed these findings during the early stage of COVID-19, when infected ciliated cells were rapidly replaced by differentiating precursor cells. Moreover, our analyses revealed that SARS-CoV-2 cellular tropism was restricted to the nasal ciliated versus oral squamous epithelium. These results imply that targeting ciliated cells of the nasal epithelium during the early stage of COVID-19 could be an ideal strategy to prevent SARS-CoV-2 propagation.


Assuntos
COVID-19/virologia , Interações entre Hospedeiro e Microrganismos , Mucosa Nasal/virologia , SARS-CoV-2 , Enzima de Conversão de Angiotensina 2/genética , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , COVID-19/patologia , COVID-19/fisiopatologia , Diferenciação Celular , Cílios/patologia , Cílios/fisiologia , Cílios/virologia , Furina/genética , Furina/metabolismo , Interações entre Hospedeiro e Microrganismos/genética , Interações entre Hospedeiro e Microrganismos/fisiologia , Humanos , Macaca , Modelos Biológicos , Mucosa Nasal/patologia , Mucosa Nasal/fisiopatologia , Pandemias , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA-Seq , SARS-CoV-2/genética , SARS-CoV-2/patogenicidade , SARS-CoV-2/fisiologia , Serina Endopeptidases/genética , Serina Endopeptidases/metabolismo , Células-Tronco/patologia , Células-Tronco/virologia , Internalização do Vírus , Replicação Viral/genética , Replicação Viral/fisiologia
10.
Abdom Radiol (NY) ; 46(9): 4266-4277, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33813624

RESUMO

OBJECTIVE: To predict the histologic grade and type of small papillary renal cell carcinomas (pRCCs) using texture analysis and machine learning algorithms. METHODS: This was a retrospective HIPAA-compliant study. 24 noncontrast (NC), 22 corticomedullary (CM) phase, and 24 nephrographic (NG) phase CTs of small (< 4 cm) surgically resected pRCCs were identified. Surgical pathology classified the tumors as low- or high-Fuhrman histologic grade and type 1 or 2. The axial image with the largest cross-sectional tumor area was exported and segmented. Six histogram and 31 texture (20 gray-level co-occurrences and 11 gray-level run-lengths) features were calculated for each tumor in each phase. Feature values in low- versus high-grade and type 1 versus 2 pRCCs were compared. Area under the receiver operating curve (AUC) was calculated for each feature to assess prediction of histologic grade and type of pRCCs in each phase. Histogram, texture, and combined histogram and texture feature sets were used to train and test three classification algorithms (support vector machine (SVM), random forest, and histogram-based gradient boosting decision tree (HGBDT)) with stratified shuffle splits and threefold cross-validation; AUCs were calculated for each algorithm in each phase to assess prediction of histologic grade and type of pRCCs. RESULTS: Individual histogram and texture features did not have statistically significant differences between low- and high-grade or type 1 and type 2 pRCCs across all phases. Individual features had low predictive power for tumor grade or type in all phases (AUC < 0.70). HGBDT was highly accurate at predicting pRCC histologic grade and type using histogram, texture or combined histogram and texture feature data from the CM phase (AUCs = 0.97-1.0). All algorithms had highest AUCs using CM phase feature data sets; AUCs decreased using feature sets from NC or NG phases. CONCLUSIONS: The histologic grade and type of small pRCCs can be predicted with classification algorithms using CM histogram and texture features, which outperform NC and NG phase image data. The accurate prediction of pRCC histologic grade and type may be able to further guide management of patients with small (< 4 cm) pRCCs being considered for active surveillance.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Carcinoma de Células Renais/diagnóstico por imagem , Estudos Transversais , Estudos de Viabilidade , Humanos , Neoplasias Renais/diagnóstico por imagem , Redes Neurais de Computação , Estudos Retrospectivos , Tomografia Computadorizada por Raios X
11.
Nat Commun ; 11(1): 4102, 2020 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-32796823

RESUMO

Emerging evidence suggests that intestinal stromal cells (IntSCs) play essential roles in maintaining intestinal homeostasis. However, the extent of heterogeneity within the villi stromal compartment and how IntSCs regulate the structure and function of specialized intestinal lymphatic capillary called lacteal remain elusive. Here we show that selective hyperactivation or depletion of YAP/TAZ in PDGFRß+ IntSCs leads to lacteal sprouting or regression with junctional disintegration and impaired dietary fat uptake. Indeed, mechanical or osmotic stress regulates IntSC secretion of VEGF-C mediated by YAP/TAZ. Single-cell RNA sequencing delineated novel subtypes of villi fibroblasts that upregulate Vegfc upon YAP/TAZ activation. These populations of fibroblasts were distributed in proximity to lacteal, suggesting that they constitute a peri-lacteal microenvironment. Our findings demonstrate the heterogeneity of IntSCs and reveal that distinct subsets of villi fibroblasts regulate lacteal integrity through YAP/TAZ-induced VEGF-C secretion, providing new insights into the dynamic regulatory mechanisms behind lymphangiogenesis and lymphatic remodeling.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas de Ciclo Celular/metabolismo , Fibroblastos/metabolismo , Mucosa Intestinal/metabolismo , Fatores de Transcrição/metabolismo , Fator C de Crescimento do Endotélio Vascular/metabolismo , Aciltransferases , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Proteínas de Ciclo Celular/genética , Células Cultivadas , Análise por Conglomerados , Ensaio de Imunoadsorção Enzimática , Fibroblastos/ultraestrutura , Citometria de Fluxo , Imunofluorescência , Hibridização in Situ Fluorescente , Mucosa Intestinal/ultraestrutura , Linfangiogênese/genética , Linfangiogênese/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Eletrônica , Neovascularização Fisiológica/genética , Neovascularização Fisiológica/fisiologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Transcrição/genética , Fator C de Crescimento do Endotélio Vascular/genética , Proteínas de Sinalização YAP
12.
Nat Commun ; 11(1): 3866, 2020 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-32737287

RESUMO

Upon severe head injury (HI), blood vessels of the meninges and brain parenchyma are inevitably damaged. While limited vascular regeneration of the injured brain has been studied extensively, our understanding of meningeal vascular regeneration following head injury is quite limited. Here, we identify key pathways governing meningeal vascular regeneration following HI. Rapid and complete vascular regeneration in the meninges is predominantly driven by VEGFR2 signaling. Substantial increase of VEGFR2 is observed in both human patients and mouse models of HI, and endothelial cell-specific deletion of Vegfr2 in the latter inhibits meningeal vascular regeneration. We further identify the facilitating, stabilizing and arresting roles of Tie2, PDGFRß and Dll4 signaling, respectively, in meningeal vascular regeneration. Prolonged inhibition of this angiogenic process following HI compromises immunological and stromal integrity of the injured meninges. These findings establish a molecular framework for meningeal vascular regeneration after HI, and may guide development of wound healing therapeutics.


Assuntos
Traumatismos Craniocerebrais/genética , Células Endoteliais/metabolismo , Neovascularização Fisiológica/genética , Regeneração/genética , Transdução de Sinais/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Vasos Sanguíneos/metabolismo , Vasos Sanguíneos/patologia , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/metabolismo , Circulação Cerebrovascular , Traumatismos Craniocerebrais/metabolismo , Traumatismos Craniocerebrais/patologia , Modelos Animais de Doenças , Células Endoteliais/patologia , Regulação da Expressão Gênica/genética , Humanos , Macrófagos/metabolismo , Macrófagos/patologia , Meninges/lesões , Meninges/metabolismo , Camundongos , Camundongos Knockout , Receptor beta de Fator de Crescimento Derivado de Plaquetas/genética , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo , Receptor TIE-2/genética , Receptor TIE-2/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Cicatrização/genética
13.
Nat Commun ; 11(1): 519, 2020 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-31980640

RESUMO

Fibroblastic reticular cells (FRCs) are immunologically specialized myofibroblasts of lymphoid organ, and FRC maturation is essential for structural and functional properties of lymph nodes (LNs). Here we show that YAP and TAZ (YAP/TAZ), the final effectors of Hippo signaling, regulate FRC commitment and maturation. Selective depletion of YAP/TAZ in FRCs impairs FRC growth and differentiation and compromises the structural organization of LNs, whereas hyperactivation of YAP/TAZ enhances myofibroblastic characteristics of FRCs and aggravates LN fibrosis. Mechanistically, the interaction between YAP/TAZ and p52 promotes chemokine expression that is required for commitment of FRC lineage prior to lymphotoxin-ß receptor (LTßR) engagement, whereas LTßR activation suppresses YAP/TAZ activity for FRC maturation. Our findings thus present YAP/TAZ as critical regulators of commitment and maturation of FRCs, and hold promise for better understanding of FRC-mediated pathophysiologic processes.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas de Ciclo Celular/metabolismo , Diferenciação Celular , Fibroblastos/metabolismo , Linfonodos/citologia , Transativadores/metabolismo , Adipócitos/metabolismo , Animais , Quimiocinas/metabolismo , Fibroblastos/ultraestrutura , Linfonodos/ultraestrutura , Receptor beta de Linfotoxina/metabolismo , Mesoderma/metabolismo , Camundongos Endogâmicos C57BL , Miofibroblastos/metabolismo , Proteínas de Sinalização YAP
14.
Nat Commun ; 10(1): 838, 2019 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-30783090

RESUMO

Hypoxia is a main driver of sprouting angiogenesis, but how tip endothelial cells are directed to hypoxic regions remains poorly understood. Here, we show that an endothelial MST1-FOXO1 cascade is essential for directional migration of tip cells towards hypoxic regions. In mice, endothelial-specific deletion of either MST1 or FOXO1 leads to the loss of tip cell polarity and subsequent impairment of sprouting angiogenesis. Mechanistically, MST1 is activated by reactive oxygen species (ROS) produced in mitochondria in response to hypoxia, and activated MST1 promotes the nuclear import of FOXO1, thus augmenting its transcriptional regulation of polarity and migration-associated genes. Furthermore, endothelial MST1-FOXO1 cascade is required for revascularization and neovascularization in the oxygen-induced retinopathy model. Together, the results of our study delineate a crucial coupling between extracellular hypoxia and an intracellular ROS-MST1-FOXO1 cascade in establishing endothelial tip cell polarity during sprouting angiogenesis.


Assuntos
Células Endoteliais/metabolismo , Proteína Forkhead Box O1/metabolismo , Fator de Crescimento de Hepatócito/metabolismo , Neovascularização Fisiológica/fisiologia , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Transporte Ativo do Núcleo Celular , Animais , Hipóxia Celular , Polaridade Celular , Células Cultivadas , Proteína Forkhead Box O1/genética , Regulação da Expressão Gênica , Fator de Crescimento de Hepatócito/genética , Células Endoteliais da Veia Umbilical Humana , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Neovascularização Patológica/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Espécies Reativas de Oxigênio/metabolismo , Retina/citologia , Retina/fisiologia
15.
Spine J ; 18(5): 797-810, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-28962913

RESUMO

BACKGROUND CONTEXT: Many studies tend to characterize cervical kyphosis as a significant clinical condition that needs to be treated. Moreover, opinions vary on whether cervical kyphosis should be considered a pathologic status or a natural occurrence in asymptomatic people. PURPOSE: This study aimed to determine the frequency of kyphotic posture of the cervical spine in currently asymptomatic individuals and to ascertain its relation with other spinopelvic parameters. STUDY DESIGN: A cross-sectional radiographic study was carried out. PATIENT SAMPLE: This study targeted 1,026 currently asymptomatic adult volunteers who agreed to participate in this study from January 2010 to March 2016. Only 958 were eligible for the study. OUTCOME MEASURES: Radiographic images, including the C-spine dynamic view and whole-spine lateral view, were measured. The sagittal parameters of the cervical spine and other parts of the spine and pelvis, such as the C2-C7 angle, C0-C2 range of motion (ROM), C2-C7 ROM, and C0-C7 ROM, thoracic kyphosis, lumbar lordosis, sacral slope, pelvic tilt, and pelvic incidence, were measured. METHODS: Based on the C-spine neutral lateral X-ray, a C2-C7 Cobb angle greater than 0 degree was defined as lordosis and an angle less than 0 degree was defined as kyphosis. Patients who showed kyphosis were further classified into the reducible or non-reducible group, depending on the ability of recovering neck motions (lordosis) in extension. The cervical and other global spine parameters between the two groups were analyzed, and the relation between the cervical alignment and other parts of the spine and pelvis were also examined. This study was not supported by any funding and had no conflicts of interest. RESULTS: Nearly one-fourth of the asymptomatic participants (26.3%) have kyphotic cervical posture, and almost one-sixth of the kyphotic individuals (16.7%) have non-reducible kyphosis. The prevalence increases with advanced age; non-reducible cases are mostly kyphotic, kyphosis stems from the C2-C7 region, and kyphosis is not correlated with any of the radiological parameters of the other parts of the spine except lumbar lordosis. CONCLUSIONS: Cervical kyphosis can be observed in normal healthy adults.


Assuntos
Vértebras Cervicais/diagnóstico por imagem , Cifose/diagnóstico por imagem , Adulto , Idoso , Doenças Assintomáticas/epidemiologia , Feminino , Humanos , Cifose/epidemiologia , Cifose/patologia , Masculino , Pessoa de Meia-Idade , Postura , Radiografia , Amplitude de Movimento Articular
16.
Osteoporos Sarcopenia ; 4(3): 79-85, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30775548

RESUMO

Dual energy X-ray absorptiometry (DXA) has become the most common method for measuring bone mineral density (BMD) of small animals in metabolic bone disease research, and errors should be minimized in all procedures involved in research studies in order to increase the accuracy of the study results. DXA is simpler and rapid compared to micro-computed tomography for quantitative analysis of change in trabecular bone of test subject. In human research, measuring BMD is widely used; postoperative evaluation on orthopedic surgery, evaluation of osteoporosis medication in menopause and many other areas of study. For the study, the inspector should be trained by the equipment manufacturer regarding the utilization and analysis of the equipment and regular phantom testing should be conducted to ensure the stability of the equipment, and precision tests should be conducted to analyze the positioning and data analysis. They should also be familiar with the clinical trials and conduct studies based on the approval of the Institutional Review Board. In the absolute BMD measurement of the human body, it is necessary to apply and compare the position and condition, rotation degree, region of interest, and area of the scan in the follow-up test. In the case of small animals, animal selection, measurement and equipment should be modeled to match the research. Therefore, we would like to provide information for researchers to minimize the errors, effective data management and accurate data presentation. This article reviews the process of DXA measurement for research purpose including plan for DXA examination, BMD measurement in a human body study and small animal studies.

17.
Korean J Food Sci Anim Resour ; 38(6): 1196-1202, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30675112

RESUMO

The objective of this study was to determine the antioxidant activity of gamma- irradiated Asparagus cochinchinensis (Asparagi radix) (Lour.) Merr. Extract (ARE) and its inhibition effect on food lipid oxidation using emulsion-type pork sausage as a model. ARE was prepared from dried Asparagi radix root and ARE solution (1.0 g/mL) was gamma-irradiated with designated doses at 5, 10, and 20 kGy. Antioxidant activity of ARE solution was determined by measuring 1,1-diphenyl-e-picrylhydrazyl (DPPH) and 2,2'-azino-bis (3-ethylbenzothiazoline-9-sulphonic acid) (ABTS) radicals. Activities of DPPH and ABTS radicals were decreased, whereas total phenolic contents increased after gamma irradiation with a dose dependence. Addition of gamma-irradiated ARE dose-dependently retarded lipid oxidation of emulsion-type pork sausage during storage at 4℃. These results indicated that gamma-irradiated ARE might have antioxidant activity more than non-irradiated ARE due to increase of the content of polyphenolic compounds by ionizing radiation.

18.
Korean J Fam Med ; 38(5): 311-312, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29026494

RESUMO

[This corrects the article on p. 173 in vol. 38, PMID: 28775806.].

19.
Korean J Fam Med ; 38(4): 173-180, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28775806

RESUMO

BACKGROUND: Hypertension is highly prevalent among patients who visit primary care clinics. Various factors and lifestyle behaviors are associated with effective blood pressure control. We aimed to identify factors and lifestyle modifications associated with blood pressure control among patients prescribed antihypertensive agents. METHODS: This survey was conducted at 15 hospital-based family practices in Korea from July 2008 to June 2010. We prospectively recruited and retrospectively assessed 1,453 patients prescribed candesartan. An initial evaluation of patients' lifestyles was performed using individual questions. Follow-up questionnaires were administered at 4, 8, and 12 weeks. We defined successful blood pressure control as blood pressure <140 mm Hg systolic and <90 mm Hg diastolic. RESULTS: Of the 1,453 patients, 1,139 patients with available data for initial and final blood pressures were included. In the univariate analysis of the change in performance index, weight gain (odds ratio [OR], 2.18; 95% confidence interval [CI], 1.52 to 3.11; P<0.001), physical inactivity (OR, 1.195; 95% CI, 1.175 to 3.387; P=0.011), and increased salt intake (OR, 1.461; 95% CI, 1.029 to 2.075; P=0.034) were related to inadequate blood pressure control. Salt intake also showed a significant association. Multivariate ORs were calculated for age, sex, body mass index, education, income, alcohol consumption, smoking status, salt intake, comorbidity, and family history of hypertension. In the multivariate analysis, sex (OR, 3.55; 95% CI, 2.02 to 6.26; P<0.001), salt intake (OR, 0.64; 95% CI 0.43 to 0.97; P=0.034), and comorbidity (OR, 1.82; 95% CI, 1.23 to 2.69; P=0.003) were associated with successful blood pressure control. CONCLUSION: Weight gain, physical inactivity, and high salt intake were associated with inadequate blood pressure control.

20.
Spine J ; 17(9): 1297-1309, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28495241

RESUMO

BACKGROUND CONTEXT: Prevertebral soft tissue swelling (PSTS) after anterior cervical spine surgery (ACSS) has been regarded as one of the critical complications that cause airway obstruction. Still, however, no research has dealt with how PSTS returns to presurgery status after ACSS; most recommendations are being performed without information about its natural course, focusing on acute-phase swelling after surgery. PURPOSE: The study aimed to examine how long postsurgery PSTS lasts and when it returns to its presurgery state, and to analyze the actual influence of a number of factors to observe the natural progress of postsurgery PSTS. STUDY DESIGN/SETTING: This is a prospective observational study. PATIENT SAMPLE: The sample included a total of 160 patients who underwent ACSS, including anterior cervical discectomy and fusion (ACDF) and cervical total disc replacement (TDR). OUTCOME MEASURES: The diameter of PSTS measured at each set time point after surgeries was compared with PSTS measurements before surgery, and analyzed with factors influencing PSTS. METHODS: Anterior and posterior diameters of the anterior soft tissue of C3 (pharyngeal airway) and C6 (laryngeal airway) were measured using simple lateral radiography before surgery, immediately after surgery, at 2 weeks, 1, 3, 6, and 12 months after surgery. The progress of postsurgery PSTS was analyzed according to patients' individual characteristics, such as age, gender, weight, body mass index (BMI), smoking status, use of antiplatelet therapy, hypertension and diabetes mellitus, complaints of dysphagia, along with surgical factors such as anesthesia time, operation time, numbers of involved operation segments, transfusion, estimated blood loss , and operation method. Multivariable analysis by generalized linear mixed model was used to perform additional univariable analysis on variables found to be related to PSTS. In addition, to find the postsurgery interval at which PSTS naturally stabilizes, repeated measures analysis of variance and Bonferroni method were used to perform post-hoc tests. There were no sources of funding and no conflicts of interest associated with this study. RESULTS: For ACDF, the mean values (95% confidence interval [CI]) of PSTS in C3 were 4.38 (4.04~4.71), 10.40 (9.64~11.17), 7.72 (7.10~8.35), 6.24 (5.74~6.69), 5.43 (5.03~5.82), 5.14 (4.77~5.50), and 4.96 (4.59~5.33) mm at each follow-up time, respectively. In C6, the average values (95% CI) of PSTS were 14.43 (13.96~14.91), 19.18 (18.59~19.77), 17.92 (17.37~18.47), 16.98 (16.45~17.51), 16.18 (15.67~16.69), 15.95 (15.50~16.40), and 15.49 (15.50~16.40) mm. For cervical TDR, the mean values (95% CI) of PSTS in C3 were 3.67 (3.45~3.89), 8.05 (7.17~8.93), 5.42 (4.92~5.91), 4.57 (4.21~4.92), 4.12 (3.99~4.36), 4.10 (3.87~4.34), and 3.90 (3.66~4.14) mm at each follow-up time, respectively. In C6, the average values (95% CI) of PSTS were 13.61 (12.96~14.25), 16.51 (15.80~17.21), 15.77 (15.13~16.42), 15.24 (14.61~15.87), 14.62 (14.01~15.22), 14.52 (13.88~15.17), and 13.94 (13.20~14.68) mm. It is discovered that PSTS after surgery returned to presurgery status within 1 to 3 months in the pharyngeal airway (C3) and within 3 to 6 months in the laryngeal airway (C6), and gender, BMI, and surgery method (ACDF) were determined to be the factors having influence on PSTS after surgery. CONCLUSIONS: It is necessary to pay attention to PSTS and patient conditions after ACSS for at least 1 to 6 months postsurgery, depending on surgical method and operation levels.


Assuntos
Vértebras Cervicais/cirurgia , Transtornos de Deglutição/etiologia , Discotomia/efeitos adversos , Edema/etiologia , Complicações Pós-Operatórias/etiologia , Fusão Vertebral/efeitos adversos , Substituição Total de Disco/efeitos adversos , Adulto , Idoso , Transtornos de Deglutição/diagnóstico , Transtornos de Deglutição/epidemiologia , Edema/diagnóstico , Edema/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/epidemiologia , Estudos Prospectivos
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