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Breast cancer is a complex and heterogeneous disease with varying cellular, genetic, epigenetic, and molecular expressions. The detection of intratumor heterogeneity in breast cancer poses significant challenges due to its complex multifaceted characteristics, yet its identification is crucial for guiding effective treatment decisions and understanding the disease progression. Currently, there exists no method capable of capturing the full extent of breast tumor heterogeneity. In this study, the aim is to identify and characterize metabolic heterogeneity in breast tumors using immune cells and an ultrafast laser-fabricated Immuno Nano Sensor. Combining spectral markers from both Natural Killer (NK) and T cells, a machine-learning approach is implemented to distinguish cancer from healthy samples, identify primary versus metastatic tumors, and determine estrogen receptor (ER)/progesterone receptor (PR) status at the single-cell level. The platform successfully distinguished heterogeneous breast cancer samples from healthy individuals, achieving 97.8% sensitivity and 92.2% specificity, and accurately identified primary tumors from metastatic tumors. Characteristic spectral signatures allow for discrimination between ER/PR-positive and negative tumors with 97.5% sensitivity. This study demonstrates the potential of immune cell-based metabolic profiling in providing a comprehensive assessment of breast tumor heterogeneity and paving the way for minimally invasive liquid biopsy approaches in breast cancer diagnosis and management.
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Diabetic gastroparesis (DGP) is characterized by delayed gastric emptying of solid food. Nitrergic neuron-mediated fundus relaxation and intragastric peristalsis are pivotal for gastric emptying and are impaired in DGP. Transient receptor potential vanilloid 1 (TRPV1) ion channels are expressed in gastrointestinal vagal afferent nerves and have a potential role in relevant gastrointestinal disorders. In this study, mice with high-fat diet (HFD)-induced type 2 diabetes mellitus (T2DM), associated with gastroparesis, were used to determine the role of TRPV1 in DGP. After feeding with HFD, mice exhibited obesity, hyperglycemia, insulin resistance, and delayed gastric emptying. Cholinergic- and nitrergic neuron-mediated neuromuscular contractions and relaxation were impaired. The antral tone of the DGP mice was attenuated. Interestingly, activating or suppressing TRPV1 facilitated or inhibited gastric fundus relaxation in normal mice. These effects were neutralized by using a nitric oxide synthase (NOS) inhibitor. Activation or suppression of TRPV1 also increased or reduced NO release. TRPV1 was specifically localized with neuronal NOS in the gastric fundus. These data suggest that TRPV1 activation facilitates gastric fundus relaxation by regulating neuronal NOS and promoting NO release. However, these effects and mechanisms disappeared in mice with DGP induced by HFD diet. TRPV1 expression was only marginally decreased in the fundus of DGP mice. TRPV1 dysfunction may be a potential mechanism underlying the dysfunction of DGP gastric nitrergic neuromuscular relaxation.
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Diabetes Mellitus Tipo 2 , Gastroparesia , Camundongos , Animais , Gastroparesia/etiologia , Gastroparesia/metabolismo , Diabetes Mellitus Tipo 2/complicações , Dieta Hiperlipídica/efeitos adversos , Obesidade/metabolismo , Esvaziamento Gástrico , Canais de Cátion TRPV/metabolismoRESUMO
F-box protein 11 (FBXO11) is a member of F-Box protein family, which has recently been proved to be associated with intellectual developmental disorder with dysmorphic facies and behavioral abnormalities (IDDFBA, OMIM: 618089). In this study, 12 intellectual disability individuals from 5 Chinese ID families were collected, and whole exome sequencing (WES), sanger sequencing, and RNA sequencing (RNA-seq) were conducted. Almost all the affected individuals presented with mild to severe intellectual disability (12/12), global developmental delay (10/12), speech and language development delay (8/12) associated with a range of alternate features including increased body weight (7/12), short stature (6/12), seizures (3/12), reduced visual acuity (4/12), hypotonia (1/12), and auditory hallucinations and hallucinations (1/12). Distinguishingly, malformation was not observed in all the affected individuals. WES analysis showed 5 novel FBXO11 variants, which include an inframe deletion variant, a missense variant, two frameshift variants, and a partial deletion of FBXO11 (exon 22-23). RNA-seq indicated that exon 22-23 deletion of FBXO11 results in a new mRNA structure. Conservation and protein structure prediction demonstrated deleterious effect of these variants. The DEGs analysis revealed 148 differentially expressed genes shared among 6 affected individuals, which were mainly associated with genes of muscle and immune system. Our research is the first report of FBXO11-associated IDDFBA in Chinese individuals, which expands the genetic and clinical spectrum of this newly identified NDD/ID syndrome.
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Sequenciamento do Exoma , Proteínas F-Box , Deficiência Intelectual , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Masculino , China , População do Leste Asiático/genética , Proteínas F-Box/genética , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Mutação , Linhagem , Fenótipo , Proteína-Arginina N-MetiltransferasesRESUMO
One of the key goals of ecology is to understand how communities are assembled. The species co-existence theory suggests that community ß-diversity is influenced by species pool and community assembly processes, such as environmental filtering, dispersal events, ecological drift and biotic interactions. However, it remains unclear whether there are similar ß-diversity patterns among different soil microbial groups and whether all these mechanisms play significant roles in mediating ß-diversity patterns. By conducting a broad survey across Chinese deserts, we aimed to address these questions by investing biological soil crusts (biocrusts). Through amplicon-sequencing, we acquired ß-diversity data for multiple microbial groups, that is, soil total bacteria, diazotrophs, phoD-harbouring taxa, and fungi. Our results have shown varying distance decay rates of ß-diversity across microbial groups, with soil total bacteria showing a weaker distance-decay relationship than other groups. The impact of the species pool on community ß-diversity varied across microbial groups, with soil total bacteria and diazotrophs being significantly influenced. While the contributions of specific assembly processes to community ß-diversity patterns varied among different microbial groups, significant effects of local community assembly processes on ß-diversity patterns were consistently observed across all groups. Homogenous selection and dispersal limitation emerged as crucial processes for all groups. Precipitation and soil C:P were the key factors mediating ß-diversity for all groups. This study has substantially advanced our understanding of how the communities of multiple microbial groups are structured in desert biocrust systems.
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Bactérias , Biodiversidade , Clima Desértico , Microbiologia do Solo , Bactérias/genética , Bactérias/classificação , Fungos/genética , Fungos/classificação , China , Microbiota/genética , Solo/químicaRESUMO
BACKGROUND: Definitive concurrent chemoradiotherapy (dCCRT) is the gold standard for the treatment of locally advanced esophageal squamous cell carcinoma (ESCC). However, the potential benefits of consolidation chemotherapy after dCCRT in patients with esophageal cancer remain debatable. Prospective randomized controlled trials comparing the outcomes of dCCRT with or without consolidation chemotherapy in patients with ESCC are lacking. In this study, we aim to generate evidence regarding consolidation chemotherapy efficacy in patients with locally advanced, inoperable ESCC. METHODS: This is a multicenter, prospective, open-label, phase-III randomized controlled trial comparing non-inferiority of dCCRT alone to consolidation chemotherapy following dCCRT. In total, 600 patients will be enrolled and randomly assigned in a 1:1 ratio to receive either consolidation chemotherapy after dCCRT (Arm A) or dCCRT alone (Arm B). Overall survival will be the primary endpoint, whereas progression-free survival, locoregional progression-free survival, distant metastasis-free survival, and treatment-related toxicity will be the secondary endpoints. DISCUSSION: This study aid in further understanding the effects of consolidation chemotherapy after dCCRT in patients with locally advanced, inoperable ESCC. TRIAL REGISTRATION: ChiCTR1800017646.
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Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Quimiorradioterapia , Quimioterapia de Consolidação , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/radioterapia , Carcinoma de Células Escamosas do Esôfago/terapia , Carcinoma de Células Escamosas do Esôfago/patologia , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Multicêntricos como Assunto , Ensaios Clínicos Fase III como Assunto , Estudos de Equivalência como AsuntoRESUMO
Hallucinogenic 5-HT2A receptor (5-HT2AR) agonists-induced head-twitch response (HTR) is regulated by Gs signaling pathway. Formation of heterodimers between 5-HT2AR and metabotropic glutamate mGlu2 receptor (mGluR2) is essential for the hallucinogenic 5-HT2AR agonist-induced HTR. In order to investigate the effects of mGluR2 agonists and inverse agonists on hallucinogenic 5-HT2AR agonists DOM-induced HTR, C57BL/6 mice were pretreated with mGluR2 agonists (LY379268, LY354740, LY404039) or the inverse agonist LY341495, and the HTR was manually counted after administering DOM immediately. IP-One (IP1) HTRF assay and cAMP assay were performed to evaluate the effect of LY341495 or LY354740 on DOM-induced Gq and Gs activation in Human Embryonic Kidney-293 (HEK-293) T-type cells co-expressing 5-HT2AR and mGluR2. The results showed that DOM-induced HTR in mice was dose-dependently inhibited by LY379268, LY354740, and LY404039, while it was dose-dependently enhanced by LY341495. Moreover, LY341495 reversed the inhibitory effect of LY354740 on DOM-induced HTR. In HEK-293T cells co-expressing 5-HT2AR and mGluR2, DOM-induced cAMP level was decreased by LY354740 and increased by LY341495, but DOM-induced IP1 level was not regulated by LY354740 or LY341495. The regulation of DOM-induced HTR by mGluR2 agonists and inverse agonists is closely related to 5-HT2AR-mediated Gs signaling pathway. In HEK-293T cells co-expressing 5-HT2AR and mGluR2 A677S/A681P/A685G mutant (mGluR2 3 A mutant), DOM-induced cAMP level was not regulated by LY354740, but was significantly enhanced by LY341495. The 5-HT2AR/mGluR2 heterodimers is critical for DOM-induced HTR and cAMP level, both of which are inhibited by mGluR2 agonists and enhanced by mGluR2 inverse agonists.
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Compostos Bicíclicos Heterocíclicos com Pontes , Compostos Bicíclicos com Pontes , Óxidos S-Cíclicos , Agonismo Inverso de Drogas , Receptores de Glutamato Metabotrópico , Serotonina , Camundongos , Humanos , Animais , Células HEK293 , Camundongos Endogâmicos C57BL , Transdução de SinaisRESUMO
This study used a self-administered questionnaire to investigate the relationship between HIV/AIDS knowledge, social discrimination, HIV self-efficacy, sexual behavioral characteristics and HIV testing behavior among young students with a history of sexual activity in Chongqing. Propensity score matching was used to construct a control group with similar demographic characteristics to the HIV testing group, only without HIV testing behaviors. Structural equation modeling was used to conduct chain-mediated effect analysis. The HIV testing rate among young students with a history of sexual behavior was 17.16%. Young students with HIV testing behavior had higher levels of HIV/AIDS knowledge, lower social discrimination, better self-efficacy, and no difference in sexual behavior characteristic scores between the two groups (P = 0.062). The mediated effect values of social discrimination and self-efficacy were 0.022 and 0.063, respectively, while their chain mediated effect value was 0.007. There was no mediated effect of sexual behavior characteristics. The level of young students' HIV/AIDS knowledge does not directly influence their HIV testing behavior but plays a complete chain mediating effect on HIV testing behavior through social discrimination and self-efficacy. HIV testing behavior should be promoted through the perspectives of enhancing HIV/AIDS knowledge level, reducing social discrimination, and improving self-efficacy.
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Síndrome da Imunodeficiência Adquirida , Infecções por HIV , Humanos , Infecções por HIV/diagnóstico , Autoeficácia , Análise de Mediação , Conhecimentos, Atitudes e Prática em Saúde , Comportamento Sexual , Inquéritos e Questionários , Estudantes , Teste de HIV , Discriminação SocialRESUMO
BACKGROUND: Brucellosis poses a significant public health concern. This study explores the spatial and temporal dynamic evolution of human brucellosis in China and analyses the spatial heterogeneity of the influencing factors related to the incidence of human brucellosis at the provincial level. METHODS: The Join-point model, centre of gravity migration model and spatial autocorrelation analysis were employed to evaluate potential changes in the spatial and temporal distribution of human brucellosis in mainland China from 2005 to 2021. Ordinary Least Squares (OLS), Geographically Weighted Regression (GWR), and Multi-scale Geographically Weighted Regression (MGWR) models were constructed to analyze the spatial and temporal correlation between the incidence rate of human brucellosis and meteorological and social factors. RESULTS: From 2005 to 2021, human brucellosis in China showed a consistent upward trend. The incidence rate rose more rapidly in South, Central, and Southwest China, leading to a shift in the center of gravity from the North to the Southwest, as illustrated in the migration trajectory diagram. Strong spatial aggregation was observed. The MGWR model outperformed others. Spatio-temporal plots indicated that lower mean annual temperatures and increased beef, mutton, and milk production significantly correlated with higher brucellosis incidence. Cities like Guangxi and Guangdong were more affected by low temperatures, while Xinjiang and Tibet were influenced more by beef and milk production. Inner Mongolia and Heilongjiang were more affected by mutton production. Importantly, an increase in regional GDP and health expenditure exerted a notable protective effect against human brucellosis incidence. CONCLUSIONS: Human brucellosis remains a pervasive challenge. Meteorological and social factors significantly influence its incidence in a spatiotemporally specific manner. Tailored prevention strategies should be region-specific, providing valuable insights for effective brucellosis control measures.
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Brucelose , Animais , Bovinos , Humanos , China/epidemiologia , Análise Espacial , Brucelose/epidemiologia , Regressão Espacial , Cidades , Incidência , Análise Espaço-TemporalRESUMO
PURPOSE: Aging contributes significantly to cardiovascular diseases and cardiac dysfunction, leading to the upregulation of matrix metalloproteinase-9 (MMP-9) in the heart and a significant decrease in hydrogen sulfide (H2S) content, coupled with impaired cardiac diastolic function. This study explores whether supplementing exogenous hydrogen sulfide during aging ameliorates the decline in H2S concentration in the heart, suppresses MMP-9 expression, and improves the age-associated impairment in cardiac morphology and function. METHODS: We collected plasma from healthy individuals of different ages to determine the relationship between aging and H2S and MMP-9 levels through Elisa detection and liquid chromatography-tandem mass spectrometry (LC/MC) detection of plasma H2S content. Three-month-old mice were selected as the young group, while 18-month-old mice were selected as the old group, and sodium hydrosulfide (NaHS) was injected intraperitoneally from 15 months old until 18 months old as the old + NaHS group. Plasma MMP-9 content was detected using Elisa, plasma H2S content, cardiac H2S content, and cystathionine gamma-lyase (CSE) activity were detected using LC/MC, and cardiac function was detected using echocardiography. Heart structure was assessed using hematoxylin and eosin staining, Masone staining was used to detect the degree of cardiac fibrosis, while western blot was used to detect the expression of MMP-9, CSE, and aging marker proteins. Knockdown of MMP-9 and CSE in H9c2 cells using small interfering RNA was carried out to determine the upstream-downstream relationship between MMP-9 and CSE. RESULTS: H2S content in the plasma of healthy individuals decreases with escalating age, whereas MMP-9 level rises with age progression. Aging leads to a decrease in H2S levels in the heart and plasma of mice, severe impairment of cardiac diastolic function, interstitial relaxation, and fibrosis of the heart. Supplementing with exogenous H2S can improve these phenomena. CONCLUSION: H2S maintains the structure and function of the heart by inhibiting the expression of MMP-9 during the aging process.
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Alzheimer's disease (AD) is traditionally considered as a brain disorder featured by amyloid-ß (Aß) deposition. The current study on whether pathological changes of AD extend to the enteric nervous system (ENS) is still in its infancy. In this study, we found enteric Aß deposition, intestinal dysfunction, and colonic inflammation in the young APP/PS1 mice. Moreover, these mice exhibited cholinergic and nitrergic signaling pathways damages and enteric neuronal loss. Our data show that Aß42 treatment remarkably affected the gene expression of cultured myenteric neurons and the spontaneous contraction of intestinal smooth muscles. The intra-colon administration of Aß42 induced ENS dysfunction, brain gliosis, and ß-amyloidosis-like changes in the wild-type mice. Our results suggest that ENS mirrors the neuropathology observed in AD brains, and intestinal pathological changes may represent the prodromal events, which contribute to brain pathology in AD. In summary, our findings provide new opportunities for AD early diagnosis and prevention.
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Doença de Alzheimer , Gastroenteropatias , Camundongos , Animais , Doença de Alzheimer/genética , Camundongos Transgênicos , Peptídeos beta-Amiloides/genética , NeurôniosRESUMO
BACKGROUND: This study reviews the research status of Diagnosis-related groups (DRGs) payment system in China and globally by analyzing topical issues in this field and exploring the evolutionary trends of DRGs in different developmental stages. METHODS: Abstracts of relevant literature in the field of DRGs were extracted from the China National Knowledge Infrastructure (CNKI) database and the Web of Science (WoS) core database and used as text data. A probabilistic distribution-based Latent Dirichlet Allocation (LDA) topic model was applied to mine the text topics. Topical issues were determined by topic intensity, and the cosine similarity of the topics in adjacent stages was calculated to analyze the topic evolution trend. RESULTS: A total of 6,758 English articles and 3,321 Chinese articles were included. Foreign research on DRGs focuses on grouping optimization, implementation effects, and influencing factors, whereas research topics in China focus on grouping and payment mechanism establishment, medical cost change evaluation, medical quality control, and performance management reform exploration. CONCLUSIONS: Currently, the field of DRGs in China is developing rapidly and attracting deepening research. However, the implementation depth of research in China remains insufficient compared with the in-depth research conducted abroad.
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Grupos Diagnósticos Relacionados , ChinaRESUMO
BACKGROUND: Colleges and universities face an increased risk of public health emergencies. Among them, medical colleges and universities deserve more attention as they serve as the play a fundamental role in providing public health emergency services and in cultivating medical professionals. Effectively managing infectious disease prevention and control, as well as responding to public health emergencies in medical colleges and universities, is of great importance for enhancing the capacity of social emergency governance and improving the completeness of the public health system. This study aims to understand the management of public health emergencies in medical colleges in a city in southwest China, explore the factors associated with medical college students' evaluations, and provide recommendations for emergency management mechanisms in colleges and universities. METHODS: In total, 781 medical college students were selected through stratified random sampling and surveyed using a questionnaire. The main factors affecting students' evaluation of emergency management were analyzed using multiple linear regression and structural equation modeling. RESULTS: The overall emergency management situation in medical colleges was relatively complete, with satisfactory results. Medical college students' satisfaction with the timeliness of prevention measures was the highest, while the publicity and education were the lowest. Multiple linear regression analysis showed that grades, emergency education, -simulation training, -information reporting, and dynamic adjustment measures were associated with the evaluation of emergency management by medical students. CONCLUSIONS: Although the evaluation of emergency management in medical colleges was generally positive, certain limitations still existed. To improve the development of the public health system, colleges and universities should constantly reform and innovate emergency management mechanisms according to the important links in the prevention and control processes.
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Estudantes de Medicina , Humanos , Saúde Pública , Estudos Transversais , Emergências , Universidades , ChinaRESUMO
This paper investigates the feasibility of cross-domain recognition for human activities captured using low-resolution 8 × 8 infrared sensors in indoor environments. To achieve this, a novel prototype recurrent convolutional network (PRCN) was evaluated using a few-shot learning strategy, classifying up to eleven activity classes in scenarios where one or two individuals engaged in daily tasks. The model was tested on two independent datasets, with real-world measurements. Initially, three different networks were compared as feature extractors within the prototype network. Following this, a cross-domain evaluation was conducted between the real datasets. The results demonstrated the model's effectiveness, showing that it performed well regardless of the diversity of samples in the training dataset.
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Atividades Humanas , Humanos , Atividades Humanas/classificação , Raios Infravermelhos , Redes Neurais de Computação , AlgoritmosRESUMO
Natural killer (NK) cells undergo multiple DNA genomic alterations, especially methylation-based modifications that affect activation and function. Several epigenetic modifier markers have been targeted for immunotherapy to date, but the possibility of cancer diagnosis using NK cell's DNA has been overlooked. Here, we investigated the potential use of NK cell DNA genome modifications as markers for the diagnosis of colorectal cancer (CRC) and validated their efficacy in CRC patients. Using Raman spectroscopy as the detection methodology, we identified CRC-specific methylation signatures by comparing CRC-interacted NK cells to healthy circulating NK cells. Subsequently, we identified methylation-dependent alterations in these NK cell populations. These markers were then utilized by a machine learning algorithm to develop a diagnostic model with predictive capabilities. The diagnostic prediction model accurately differentiated CRC patients from normal controls. Our findings demonstrated the utility of NK DNA markers in the diagnosis of CRC.
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Neoplasias Colorretais , Metilação de DNA , Humanos , Neoplasias Colorretais/genética , Células Matadoras Naturais , DNA/genética , Biomarcadores Tumorais/genéticaRESUMO
Recently, radioresistant cancer cells surviving radiotherapy have been suggested to show more aggressive phenotypes than parental cells, and the underlying mechanisms may be associated with cancer stem cells. This study provided novel mechanistic insights for E3 ubiquitin ligase CHIP in stem cell properties and radioresistance of non-small cell lung cancer (NSCLC). After bioinformatic prediction for key genes involved, NSCLC tissues and cells were collected to measure the expression of CHIP and PBK. E3 ubiquitin ligase CHIP was poorly expressed, while PBK was highly expressed in NSCLC tissues and cells. CHIP reduced the protein stability of PBK through the ubiquitin-protease pathway to repress the activation of ERK pathway. Based on the gain- or loss-of-function experiments, it was noted that restoration of CHIP curtailed stem cell properties and radioresistance in NSCLC, as manifested by inhibited sphere formation and cell proliferation, decreased number of CD133+CD44+ cells and expression of OCT4, SOX2, and NANOG, as well as facilitated apoptosis of NSCLC cells. Besides, in vivo animal experiments further confirmed that CHIP restrained tumorigenic ability and improved radiosensitivity of NSCLC cells by inhibiting PBK/ERK axis. Collectively, CHIP suppressed stem cell properties and radioresistance of NSCLC cells by inhibiting PBK/ERK axis, therefore offering a potential therapeutic target for enhancing efficacy of radiotherapy.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Animais , Apoptose/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/radioterapia , Neoplasias Pulmonares/metabolismo , Tolerância a Radiação/genética , Células-Tronco/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismoRESUMO
Glioblastoma (GBM) is the most prevalent and fatal form of brain tumor, which is associated with a poor prognosis. ATP-binding cassette subfamily F member 1 (ABCF1) is an E2 ubiquitin-conjugating enzyme, which is implicated in regulating immune responses and tumorigenesis. Aberrant E3 ubiquitylation has been evidenced in GBM. However, the role of ABCF1 in GBM needs to be further explored. The expression of ABCF1, CXC chemokine ligand 12 (CXCL12), and CXC chemokine receptor 4 (CXCR4) in GBM tissues was examined by the GEPIA tool, real-time PCR and Western blotting. HMC3, U251MG, and LN-229 cells were cultured and transfected with shRNA targeting ABCF1 and ABCF1 plasmids. The proliferative, migrative, and invasive ability of cells was detected. Western blotting was used to detect the levels of phosphorylated phosphatidylinositol 3-kinase (PI3K) and phosphorylated protein kinase B (AKT). We observed that GBM tissues had higher ABCF1, CXCL12, and CXCR4 expression levels. The expression levels of CXCL12 and CXCR4 were enhanced by ABCF1 overexpression, which were significantly reversed by silence of ABCF1 in GBM cells. Silencing ABCF1 or CXCR4 inhibition weakened the capacity of GBM cell growth, migration, and invasion, while ectopic ABCF1 expression or CXCL12 treatment enhanced the cellular function of GBM cells. Furthermore, p-PI3K and p-AKT protein levels were downregulated by ABCF1 knockdown or CXCR4 blockade, which were prompted by ABCF1 overexpression or CXCL12 supplement. The ABCF1-CXCL12-CXCR4 axis was identified as a key player in GBM cell survival and metastasis by activating the PI3K/AKT signaling pathway in GBM cells.
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BACKGROUND: Renal tubulointerstitial fibrosis is the hallmark of various chronic kidney diseases. Symmetric dimethylarginine (SDMA) is an independent cardiovascular risk factor in patients with chronic kidney diseases, which is mostly excreted through renal tubules. However, the effect of SDMA on kidneys in a pathological condition is currently unknown. In this study, we investigated the role of SDMA in renal tubulointerstitial fibrosis and explored its underlying mechanisms. METHODS: Mouse unilateral ureteral obstruction (UUO) and unilateral ischemia-reperfusion injury (UIRI) models were established to study renal tubulointerstitial fibrosis. SDMA was injected into kidneys through ureter retrogradely. TGF-ß stimulated human renal epithelial (HK2) cells were used as an in vitro model and treated with SDMA. Signal transducer and activator of transcription-4 (STAT4) was inhibited by berbamine dihydrochloride or siRNA or overexpressed by plasmids in vitro. Masson staining and Western blotting were performed to evaluate renal fibrosis. Quantitative PCR was performed to validate findings derived from RNA sequencing analysis. RESULTS: We observed that SDMA (from 0.01 to 10 µM) dose-dependently inhibited the expression of pro-fibrotic markers in TGF-ß stimulated HK2 cells. Intrarenal administration of SDMA (2.5 µmol/kg or 25 µmol/kg) dose-dependently attenuated renal fibrosis in UUO kidneys. A significant increase in SDMA concentration (from 19.5 to 117.7 nmol/g, p < 0.001) in mouse kidneys was observed after renal injection which was assessed by LC-MS/MS. We further showed that intrarenal administration of SDMA attenuated renal fibrosis in UIRI induced mouse fibrotic kidneys. Through RNA sequencing analysis, we found that the expression of STAT4 was reduced by SDMA in UUO kidneys, which was further confirmed by quantitative PCR and Western blotting analysis in mouse fibrotic kidneys and renal cells. Inhibition of STAT4 by berbamine dihydrochloride (0.3 mg/ml or 3.3 mg/ml) or siRNA reduced the expression of pro-fibrotic markers in TGF-ß stimulated HK2 cells. Furthermore, blockage of STAT4 attenuated the anti-fibrotic effect of SDMA in TGF-ß stimulated HK2 cells. Conversely, overexpression of STAT4 reversed the anti-fibrotic effect of SDMA in TGF-ß stimulated HK2 cells. CONCLUSION: Taken together, our study indicates that renal SDMA ameliorates renal tubulointerstitial fibrosis through inhibition of STAT4.
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Nefropatias , Insuficiência Renal Crônica , Obstrução Ureteral , Humanos , Camundongos , Animais , Cromatografia Líquida , Espectrometria de Massas em Tandem , Nefropatias/complicações , Rim/patologia , Obstrução Ureteral/complicações , Obstrução Ureteral/genética , Obstrução Ureteral/patologia , Insuficiência Renal Crônica/patologia , Fator de Crescimento Transformador beta/metabolismo , Fibrose , RNA Interferente Pequeno , Fator de Crescimento Transformador beta1/metabolismo , Fator de Transcrição STAT4/metabolismoRESUMO
Despite the vital role in carbon (C) sequestration and nutrient retention, variations and patterns in root C and nitrogen (N) stoichiometry of the first five root orders across woody plant species remains unclear. We compiled a dataset to explore variations and patterns of root C and N stoichiometry in the first five orders of 218 woody plant species. Across the five orders, root N concentrations were greater in deciduous, broadleaf, and arbuscular mycorrhizal species than in evergreen, coniferous species, and ectomycorrhizal association species, respectively. Contrasting trends were found for root C : N ratios. Most root branch orders showed clear latitudinal and altitudinal trends in root C and N stoichiometry. There were opposite patterns in N concentrations between latitude and altitude. Such variations were mainly driven by plant species, and climatic factors together. Our results indicate divergent C and N use strategies among plant types and convergence and divergence in the patterns of C and N stoichiometry between latitude and altitude across the first five root orders. These findings provide important data on the root economics spectrum and biogeochemical models to improve understanding and prediction of climate change effects on C and nutrient dynamics in terrestrial ecosystems.
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Micorrizas , Traqueófitas , Ecossistema , Madeira , Plantas , Nitrogênio , Raízes de PlantasRESUMO
The human SET nuclear proto-oncogene (SET) gene is a protein-coding gene that encodes proteins that affects chromatin remodeling and gene transcription. Mutations in the SET gene have been reported to cause intellectual disability (ID) and epilepsy. In this study, we collected and analyzed clinical, genetic, and transcript features of two unrelated Chinese patients with ID. Both patients were characterized by moderate intellectual disability. Whole-exome sequencing identified two novel heterozygous mutations in the SET gene: NM_001122821.1:c.532-3 T > A and NM_001122821.1:c.3 G > C (p.0?). Additionally, RNA sequencing revealed widespread dysregulation of genes involved in NF-kB signaling and neuronal system in these two patients. To our knowledge, this is the first report of SET mutations causing ID in the Chinese population, broadening the genetic and ethnic spectrum of SET-related disorders and highlighting the importance of screening for SET gene variants.
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Epilepsia , Deficiência Intelectual , Humanos , Deficiência Intelectual/genética , Sequenciamento do Exoma , Mutação , Epilepsia/genética , Perfilação da Expressão Gênica , LinhagemRESUMO
As agroecology deteriorates, agricultural production is threatened by the combined stressors of exposure to environmental pollutants and pathogenic microbes. Proper agronomic practices for crop growth management and fertilization require understanding plant tolerance strategies. Both rice blast and heavy metals substantially impair rice crops, while silicon (Si) is an effective amendment to alleviate the combined stressors. Herein, this study was conducted to investigate the rice physiology and pathology perspective on the mechanism of Si alleviation against both lead (Pb) toxicity and Magnaporthe oryzae infection, utilizing pot experiments with inoculation of the virulent Magnaporthe oryzae strain. Exogenous Si reduced the phyto-availability and plant absorption of Pb, resulting in a 73.5% reduction in exchangeable Pb concentration in soil and a 40.23% reduction in rice plants. Furthermore, Si addition boosted the plant antioxidant system by increasing the activities of related enzymes, as the activities of catalase, superoxide dismutase, and polyphenol oxidase were significantly improved while the activity of peroxidase in rice panicles decreased. As a result, an improvement in dry matter quantity by 19.19% was observed compared to treatments without Si application, and the panicle blast severity (PBS) was reduced by 0.4-37.52%. Notwithstanding the interaction between the combined stressors, this study revealed that the speciation of Pb formation in the rhizosphere was the primary contributor to the alleviation of abiotic stresses, whereas the regulation of oxidative stress by enzymatic antioxidants played a dominant role in alleviating Magnaporthe oryzae colonization and impairments. The regulation process may reveal the mechanism of siliceous fertilizer functioning in the paddy system. Thereby the role of exogenous Si in anti-fungal, heavy metal toxicology, and plant physiology needs further study to fully elucidate the role of Si amendment, which is proposed to be considered from the perspective of soil chemistry and plant physiology.