RESUMO
BACKGROUND: Costaceae, commonly known as the spiral ginger family, consists of approximately 120 species distributed in the tropical regions of South America, Africa, and Southeast Asia, of which some species have important ornamental, medicinal and ecological values. Previous studies on the phylogenetic and taxonomic of Costaceae by using nuclear internal transcribed spacer (ITS) and chloroplast genome fragments data had low resolutions. Additionally, the structures, variations and molecular evolution of complete chloroplast genomes in Costaceae still remain unclear. Herein, a total of 13 complete chloroplast genomes of Costaceae including 8 newly sequenced and 5 from the NCBI GenBank database, representing all three distribution regions of this family, were comprehensively analyzed for comparative genomics and phylogenetic relationships. RESULT: The 13 complete chloroplast genomes of Costaceae possessed typical quadripartite structures with lengths from 166,360 to 168,966 bp, comprising a large single copy (LSC, 90,802 - 92,189 bp), a small single copy (SSC, 18,363 - 20,124 bp) and a pair of inverted repeats (IRs, 27,982 - 29,203 bp). These genomes coded 111 - 113 different genes, including 79 protein-coding genes, 4 rRNA genes and 28 - 30 tRNAs genes. The gene orders, gene contents, amino acid frequencies and codon usage within Costaceae were highly conservative, but several variations in intron loss, long repeats, simple sequence repeats (SSRs) and gene expansion on the IR/SC boundaries were also found among these 13 genomes. Comparative genomics within Costaceae identified five highly divergent regions including ndhF, ycf1-D2, ccsA-ndhD, rps15-ycf1-D2 and rpl16-exon2-rpl16-exon1. Five combined DNA regions (ycf1-D2 + ndhF, ccsA-ndhD + rps15-ycf1-D2, rps15-ycf1-D2 + rpl16-exon2-rpl16-exon1, ccsA-ndhD + rpl16-exon2-rpl16-exon1, and ccsA-ndhD + rps15-ycf1-D2 + rpl16-exon2-rpl16-exon1) could be used as potential markers for future phylogenetic analyses and species identification in Costaceae. Positive selection was found in eight protein-coding genes, including cemA, clpP, ndhA, ndhF, petB, psbD, rps12 and ycf1. Maximum likelihood and Bayesian phylogenetic trees using chloroplast genome sequences consistently revealed identical tree topologies with high supports between species of Costaceae. Three clades were divided within Costaceae, including the Asian clade, Costus clade and South American clade. Tapeinochilos was a sister of Hellenia, and Parahellenia was a sister to the cluster of Tapeinochilos + Hellenia with strong support in the Asian clade. The results of molecular dating showed that the crown age of Costaceae was about 30.5 Mya (95% HPD: 14.9 - 49.3 Mya), and then started to diverge into the Costus clade and Asian clade around 23.8 Mya (95% HPD: 10.1 - 41.5 Mya). The Asian clade diverged into Hellenia and Parahellenia at approximately 10.7 Mya (95% HPD: 3.5 - 25.1 Mya). CONCLUSION: The complete chloroplast genomes can resolve the phylogenetic relationships of Costaceae and provide new insights into genome structures, variations and evolution. The identified DNA divergent regions would be useful for species identification and phylogenetic inference in Costaceae.
Assuntos
Genoma de Cloroplastos , Filogenia , Teorema de Bayes , Genômica/métodos , DNARESUMO
To verify the inhibitory mechanism of ß-catenin-designed peptides in colorectal cancer(CRC) tumors, the following experiments were performed. In vitro colony formation, Transwell assays, and flow cytometry were performed to assess the biological effects of designed peptides (F18KD, F20A4-7k, F20A4-10k, and F20A3-9k + F20A4-10k + F20A5-9k) in HT-29 cells. In vivo xenograft experiments were performed and treated with peptides. Next, tumors were subjected to Hematoxylin and eosin staining (HE), immunohistochemical, and terminal deoxynucleotidyl transferase dUTP nick end labeling staining assays to evaluate the inhibitory effect of peptides on tumors. ß-Catenin levels were quantified via western blotting (WB) and quantitative real-time polymerase chain reaction, and ß-catenin was located using confocal laser scanning microscopy. T-cell factor-4 (TCF-4), C-myc, and CCND1 levels were quantified via WB. Results were obtained as following. First, the peptides reduced viability, migration, and invasion; promoted apoptosis; and stabilized the S phase of HT-29 cells. Second, peptides suppressed tumor growth and downregulated the expression of CD34, vascular endothelial growth factor, and ß-catenin in tumors. Furthermore, we found that peptides downregulated ß-catenin expression in both the cytoplasm and nucleus; TCF-4, C-myc, and CCND1 expression was also downregulated. Notably, ß-catenin-targeting peptides had a better inhibitory effect on CRC than non-ß-catenin-target peptides, and a combination of peptides exerted a more potent inhibitory effect on CRC than single peptides. It suggested that ß-Catenin-targeting peptides promote apoptosis in CRC tumors by inhibiting activation of the Wnt/ß-catenin pathway.
Assuntos
Neoplasias Colorretais , Fator A de Crescimento do Endotélio Vascular , Humanos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Via de Sinalização Wnt , Apoptose , Peptídeos/farmacologia , Peptídeos/metabolismo , Proliferação de Células , Linhagem Celular Tumoral , Movimento Celular , Regulação Neoplásica da Expressão GênicaRESUMO
Zingiberales includes eight families and more than 2600 species, with many species having important economic and ecological value. However, the backbone phylogenetic relationships of Zingiberales still remain controversial, as demonstrated in previous studies, and molecular dating based on chloroplast genomes has not been comprehensively studied for the whole order. Herein, 22 complete chloroplast genomes from 21 species in Zingiberales were sequenced, assembled, and analyzed. These 22 genomes displayed typical quadripartite structures, which ranged from 161,303 bp to 163,979 bp in length and contained 111-112 different genes. The genome structures, gene contents, simple sequence repeats, long repeats, and codon usage were highly conserved, with slight differences among these genomes. Further comparative analysis of the 111 complete chloroplast genomes of Zingiberales, including 22 newly sequenced ones and the remaining ones from the national center for biotechnology information (NCBI) database, identified three highly divergent regions comprising ccsA, psaC, and psaC-ndhE. Maximum likelihood and Bayesian inference phylogenetic analyses based on chloroplast genome sequences found identical topological structures and identified a strongly supported backbone of phylogenetic relationships. Cannaceae was sister to Marantaceae, forming a clade that was collectively sister to the clade of (Costaceae, Zingiberaceae) with strong support (bootstrap (BS) = 100%, and posterior probability (PP) = 0.99-1.0); Heliconiaceae was sister to the clade of (Lowiaceae, Strelitziaceae), then collectively sister to Musaceae with strong support (BS = 94-100%, and PP = 0.93-1.0); the clade of ((Cannaceae, Marantaceae), (Costaceae, Zingiberaceae)) was sister to the clade of (Musaceae, (Heliconiaceae, (Lowiaceae, Strelitziaceae))) with robust support (BS = 100%, and PP = 1.0). The results of divergence time estimation of Zingiberales indicated that the crown node of Zingiberales occurred approximately 85.0 Mya (95% highest posterior density (HPD) = 81.6-89.3 million years ago (Mya)), with major family-level lineages becoming from 46.8 to 80.5 Mya. These findings proved that chloroplast genomes could contribute to the study of phylogenetic relationships and molecular dating in Zingiberales, as well as provide potential molecular markers for further taxonomic and phylogenetic studies of Zingiberales.
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Genoma de Cloroplastos , Zingiberales , Humanos , Filogenia , Zingiberales/genética , Teorema de Bayes , Genômica , Cloroplastos/genéticaRESUMO
BACKGROUND: Long non-coding RNAs (lncRNAs) are critical regulators in lung adenocarcinoma (LUAD). M2-type tumor-associated macrophages (TAMs) also play oncogenic roles in LUAD. However, the involvement of lncRNAs in TAM activation is still largely unknown. METHODS: The expressions of LARRPM, LINC00240 and CSF1 were determined by RT-qPCR. The regulation of LINC00240 and CSF1 by LARRPM was investigated by RNA-protein pull-down, RNA immunoprecipitation, chromatin immunoprecipitation and bisulfite DNA sequencing. In vitro and in vivo gain- and loss-of-function assays were performed to investigate the roles of LARRPM. RESULTS: The lncRNA LARRPM was expressed at low levels in LUAD tissues and cells. The low expression of LARRPM was correlated with advanced stage and poor survival of patients with LUAD. Functional experiments revealed that LARRPM suppressed LUAD cell proliferation, migration and invasion, and promoted apoptosis. LARRPM also repressed macrophage M2 polarization and infiltration. Taken together, LARRPM significantly restricted LUAD progression in vivo. Mechanistically, LARRPM bound and recruited DNA demethylase TET1 to the promoter of its anti-sense strand gene LINC00240, leading to a decrease in DNA methylation level of the LINC00240 promoter and transcriptional activation of LINC00240. Functional rescue assays suggested that the lncRNA LINC00240 was responsible for the roles of LARRPM in the malignant behavior of LUAD cells. LARRPM decreased the binding of TET1 to the CSF1 promoter, resulting in increased DNA methylation of the CSF1 promoter and transcriptional repression of CSF1, which is responsible for the roles of LARRPM in macrophage M2 polarization and infiltration. The TAMs educated by LUAD cells exerted oncogenic roles, which was negatively regulated by LARRPM expressed in LUAD cells. CONCLUSIONS: LARRPM restricts LUAD progression through repressing both LUAD cell and macrophages. These data shed new insights into the regulation of LUAD progression by lncRNAs and provide data on the potential utility of LARRPM as a target for LUAD treatment.
Assuntos
Adenocarcinoma , Neoplasias Pulmonares , RNA Longo não Codificante , Adenocarcinoma/genética , Linhagem Celular Tumoral , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Humanos , Pulmão/metabolismo , Neoplasias Pulmonares/patologia , Fator Estimulador de Colônias de Macrófagos , Macrófagos/metabolismo , Oxigenases de Função Mista/genética , Proteínas Proto-Oncogênicas/genética , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismoRESUMO
Reliable and noninvasive biomarkers for the early diagnosis of non-small-cell lung cancer (NSCLC) are an unmet need. This study aimed to screen and validate potential urinary biomarkers for the early diagnosis of NSCLC. Using protein mass spectrometry, urinary MDH2 was found to be abundant both in patients with lung cancer and lung cancer model mice compared with controls. Urine samples obtained as retrospective and prospective cohorts including 1091 NSCLC patients and 736 healthy controls were measured using ELISA. Patients with stage I NSCLC had higher urinary MDH2 compared with healthy controls. The area under the receiver-operating characteristic curve (AUC) for the urinary MDH2 was 0.7679 and 0.7234 in retrospective and prospective cohorts to distinguish stage I cases from controls. Urinary MDH2 levels correlated with gender and smoking history. MDH2 expression levels were elevated in lung cancer tissues. MDH2 knockdown using shRNA inhibited the proliferation of lung cancer cells. Our study demonstrated that urinary MDH2 concentration was higher in early-stage NSCLC patients compared with that in controls and that MDH2 could serve as a potential biomarker for early detection of NSCLC.
Assuntos
Biomarcadores Tumorais/urina , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Neoplasias Pulmonares/diagnóstico , Malato Desidrogenase/urina , Regulação para Cima , Células A549 , Animais , Área Sob a Curva , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/urina , Estudos de Casos e Controles , Linhagem Celular Tumoral , Detecção Precoce de Câncer , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Espectrometria de Massas , Camundongos , Estadiamento de Neoplasias , Transplante de Neoplasias , Estudos Prospectivos , Estudos RetrospectivosRESUMO
An objective normalization strategy is essential in any evolutionary multiobjective or many-objective optimization (EMO or EMaO) algorithm, due to the distance calculations between objective vectors required to compute diversity and convergence of population members. For the decomposition-based EMO/EMaO algorithms involving the Penalty Boundary Intersection (PBI) metric, normalization is an important matter due to the computation of two distance metrics. In this article, we make a theoretical analysis of the effect of instabilities in the normalization process on the performance of PBI-based MOEA/D and a proposed PBI-based NSGA-III procedure. Although the effect is well recognized in the literature, few theoretical studies have been done so far to understand its true nature and the choice of a suitable penalty parameter value for an arbitrary problem. The developed theoretical results have been corroborated with extensive experimental results on three to 15-objective convex and non-convex instances of DTLZ and WFG problems. The article, makes important theoretical conclusions on PBI-based decomposition algorithms derived from the study.
Assuntos
Algoritmos , Evolução Biológica , Modelos TeóricosRESUMO
The aim of this study was to investigate in vitro magnetic resonance imaging (MRI) of PDAC using ENO1-targeted superparamagnetic iron oxide nanoparticles and xenograft models. Expression level and location of ENO1 protein in pancreatic cancer cell lines of CFPAC-1 and MiaPaCa-2 were detected by Western blotting, flow cytometry and confocal microscopy. Dex-g-PCL/SPIO nanoparticles targeting ENO1 were constructed with ENO1 antibody and characterized by MRI. In addition, ENO1-Dex-g-PCL/SPIO nanoparticles were tested to assess their efficacy on the detection of PDAC using in vitro and in vivo MRI. The results showed that ENO1 was expressed in both human PDAC cell lines of CFPAC-1 and MiaPaCa-2, demonstrating that the localization of cytoplasm and membrane was dominant. It was confirmed that ENO1 antibody was connected to the SPIO surface in ENO1-Dex-g-PCL/SPIO nanoparticles. The nanoparticles had satisfactory superparamagnetism and significantly enhance the detection of PDAC by in vivo and in vitro MRI. In conclusion, ENO1 can serve as a membrane protein expressed on human PDAC cell lines. ENO1-targeted SPIO nanoparticles using ENO1 antibody can increase the efficiency of detection of PDAC by in vitro and in vivo MRI.
Assuntos
Biomarcadores Tumorais/metabolismo , Proteínas de Ligação a DNA/metabolismo , Nanopartículas Magnéticas de Óxido de Ferro/química , Imageamento por Ressonância Magnética , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/diagnóstico , Fosfopiruvato Hidratase/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Animais , Linhagem Celular Tumoral , Dextranos/química , Humanos , Nanopartículas Magnéticas de Óxido de Ferro/ultraestrutura , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Pancreáticas/patologia , Poliésteres/químicaRESUMO
Dimerization is a promising strategy to develop novel drug candidates that could extend the biological spectrum, enhance the activity, overcome drug resistance, as well as improve pharmacological, pharmacokinetic, and physicochemical profiles. Isatin dimers possess a broad spectrum of biological properties and the isatin dimer indirubin has already been used in the clinic, revealing the potential of isatin dimers as putative drugs. This review covers the recent advances of isatin dimers as pharmacologically significant scaffolds and the structure-activity relationship to set up the direction for the design and development of isatin dimers with higher efficiency and lower toxicity.
Assuntos
Antibacterianos/farmacologia , Anti-Infecciosos/farmacologia , Antineoplásicos/farmacologia , Antituberculosos/farmacologia , Isatina/farmacologia , Animais , Antibacterianos/química , Anti-Infecciosos/química , Antineoplásicos/química , Antituberculosos/química , Dimerização , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Isatina/química , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Noncoding RNAs, including long non-coding RNAs (lncRNAs) and microRNAs, are involved in the development of neuropathic pain. Currently, we investigated that lncRNA X inactive-specific transcript (XIST) and toll-like receptor 5 (TLR5) were greatly upregulated in chronic constriction injury rat models, whereas miR-154-5p (microRNA-154-5p) was significantly downregulated. Bioinformatics analysis was used to predict miR-154-5p as a target gene of XIST, and dual-luciferase reporter tests proved the correlation between them. We observed that miR-154-5p was negatively modulated by XIST in vitro. XIST overexpression markedly induced neuropathic pain development in rats with chronic constriction injury, whereas the upregulation of miR-154-5p could reverse this phenomenon. Furthermore, TLR5 was demonstrated to be a target gene of miR-154-5p by using bioinformatics predictions. miR-154-5p negatively regulated TLR5 expression in vitro, and TLR5 was able to promote neuropathic pain development. In addition, overexpressing miR-154-5p can reverse the role of TLR5 neuropathic pain in vivo. Taken these together, we indicated that XIST could increase TLR5 expression by acting as a sponge of miR-154-5p in neuropathic pain development. This study revealed that XIST can contribute to neuropathic pain progression in rats through decreasing miR-154-5p and increasing TLR5. The XIST/miR-154-5p/ TLR5 axis can be provided as a novel therapeutic target in treating neuropathic pain.
RESUMO
Neuropathic pain, resulting from somatosensory nervous system dysfunction, remains a serious public health problem worldwide. microRNAs are involved in the physiological processes of neuropathic pain. However, the biological roles of miR-98 in neuropathic pain development have not been investigated. Therefore, in our current study, we focused on the effects of miR-98 in neuropathic pain. It was shown that miR-98 was significantly downregulated in chronic sciatic nerve injury (CCI) rat models. In addition, high mobility group A2 (HMGA2) was obviously upregulated in CCI rats. Overexpression of miR-98 inhibited neuropathic pain progression, including mechanical and thermal hyperalgesia. By a bioinformatics analysis, HMGA2 was predicted as a direct target of miR-98. The negative correlation between miR-98 and HMGA2 was validated in our present study. Furthermore, overexpression of miR-98 dramatically repressed HMGA2 protein and messenger RNA (mRNA) expression. Neuroinflammation participates in neural-immune interactions, which can contribute to the neuropathic pain development. Meanwhile, we found that inflammatory cytokine (interleukin [IL]-6, IL-1ß, and COX-2) protein expression in rats infected with LV-miR-98 was greatly suppressed. Taking these results together, we concluded that miR-98 might depress neuropathic pain development through modulating HMGA2.
Assuntos
Constrição Patológica/complicações , Proteína HMGA2/antagonistas & inibidores , Inflamação/prevenção & controle , MicroRNAs/genética , Neuralgia/prevenção & controle , Traumatismos dos Nervos Periféricos/complicações , Nervo Isquiático/lesões , Animais , Citocinas/metabolismo , Regulação da Expressão Gênica , Proteína HMGA2/genética , Proteína HMGA2/metabolismo , Hiperalgesia/complicações , Inflamação/etiologia , Inflamação/patologia , Masculino , Neuralgia/etiologia , Neuralgia/patologia , Ratos , Ratos Sprague-DawleyRESUMO
Emerging evidence has suggested that microRNAs play a critical role in neuropathic pain development. However, the biological role of miRNAs in regulating neuropathic pain remains barely known. In our present study, we found that miR-124-3p was significantly downregulated in rats after chronic sciatic nerve injury (CCI). In addition, it was showed that overexpression of miR-124-3p obviously repressed mechanical allodynia and heat hyperalgesia. Meanwhile, it has been reported that neuroinflammation can contribute a lot to neuropathic pain progression. Here, we found that inflammatory cytokine (IL-6, IL-1ß, and TNF-âº) protein expression in rats after CCI greatly increased and miR-124-3p mimics depressed inflammation cytokine levels. Consistently, miR-124-3p alleviated inflammation production in lipopolysaccharide-incubated spinal microglial cells. Bioinformatics analysis revealed that EZH2 acted as a direct target of miR-124-3p, which participated in the miR-124-3p-modulated effects on neuropathic pain development and neuroinflammation. We observed that miR-124-3p was able to promote neuroinflammation and neuropathic pain through targeting EZH2. The direct correlation between them was validated in our current study using dual-luciferase reporter assays. Subsequently, it was manifested that EZH2 abrogated the inhibitory role of miR-124-3p on neuropathic pain progression in CCI rats. Taken these together, our findings highlighted a novel contribution of miR-124-3p to neuropathic pain and indicated the possibilities for developing novel therapeutic options for neuropathic pain.
Assuntos
Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Hiperalgesia/prevenção & controle , Inflamação/prevenção & controle , MicroRNAs/genética , Neuralgia/prevenção & controle , Traumatismos dos Nervos Periféricos/complicações , Nervo Isquiático/lesões , Animais , Comportamento Animal , Modelos Animais de Doenças , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Feminino , Hiperalgesia/etiologia , Hiperalgesia/metabolismo , Hiperalgesia/patologia , Inflamação/etiologia , Inflamação/metabolismo , Inflamação/patologia , Neuralgia/etiologia , Neuralgia/metabolismo , Neuralgia/patologia , Ratos , Ratos Sprague-DawleyRESUMO
For a many-objective optimization problem with redundant objectives, we propose two novel objective reduction algorithms for linearly and, nonlinearly degenerate Pareto fronts. They are called LHA and NLHA respectively. The main idea of the proposed algorithms is to use a hyperplane with non-negative sparse coefficients to roughly approximate the structure of the PF. This approach is quite different from the previous objective reduction algorithms that are based on correlation or dominance structure. Especially in NLHA, in order to reduce the approximation error, we transform a nonlinearly degenerate Pareto front into a nearly linearly degenerate Pareto front via a power transformation. In addition, an objective reduction framework integrating a magnitude adjustment mechanism and a performance metric σ* are also proposed here. Finally, to demonstrate the performance of the proposed algorithms, comparative experiments are done with two correlation-based algorithms, LPCA and NLMVUPCA, and with two dominance-structure-based algorithms, PCSEA and greedy δ- MOSS, on three benchmark problems: DTLZ5(I,M), MAOP(I,M), and WFG3(I,M). Experimental results show that the proposed algorithms are more effective.
Assuntos
Algoritmos , Simulação por Computador , Modelos Teóricos , Inteligência Artificial , Benchmarking , HumanosRESUMO
BACKGROUND: Emergence agitation (EA) is a common phenomenon in preschool children during emergence from general anesthesia. This study evaluated the safety and efficacy of dezocine for emergence agitation in preschool children anesthetized with sevoflurane-remifentanil. METHODS: A total of 100 preschool children, scheduled for elective laparoscopic repair of an inguinal hernia by high ligation of the hernia sac under sevoflurane-remifentanil anesthesia were randomized into two groups: Group C (n = 50) received Ringer's lactate 10 mL and Group D received Ringer's lactate 10 mL containing dezocine 0.1 mg/kg, postoperatively. RESULTS: Incidence of EA, defined as a score ≥ 3 on Aono's four point scale or Pediatric Anesthesia Emergence Delirium (PAED) score ≥ 10 in the PACU (10% vs. 76%) and the percentage of patients with severe EA (PAED score ≥ 13) (12% vs. 76%) were significantly lower in Group D compared to Group C (P < 0.05). Mean Children and Infants Postoperative Pain Scale (CHIPPS) score was significantly lower in Group D compared to Group C (1.2 ± 0.5 vs. 5.2 ± 0.6; P < 0.05). Patients need for fentanyl (18% vs. 4%) or propofol rescue (20% vs. 0) was significantly greater in Group C compared to Group D. No significant differences in other relative aspects after surgery between groups. CONCLUSION: Administration of dezocine 0.1 mg/kg decreased the incidence and severity of EA in preschool children that had undergone laparoscopic repair of an inguinal hernia by high ligation of the hernia sac under sevoflurane-remifentanil anesthesia. TRIAL REGISTRATION: A single dose of dezocine suppresses emergence agitation in preschool children anesthetized with sevoflurane-remifentanil effectively: A double-blind, prospective, randomized, controlled study, Chinese Clinical Trial Registry (ID: ChiCTR-IOR-16010033), retrospectively registered on November 21, 2016.
Assuntos
Período de Recuperação da Anestesia , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Éteres Metílicos/administração & dosagem , Piperidinas/administração & dosagem , Complicações Pós-Operatórias/tratamento farmacológico , Agitação Psicomotora/tratamento farmacológico , Tetra-Hidronaftalenos/administração & dosagem , Analgésicos Opioides/administração & dosagem , Anestésicos Inalatórios/administração & dosagem , Anestésicos Inalatórios/efeitos adversos , Pré-Escolar , Método Duplo-Cego , Feminino , Humanos , Masculino , Éteres Metílicos/efeitos adversos , Piperidinas/efeitos adversos , Complicações Pós-Operatórias/induzido quimicamente , Complicações Pós-Operatórias/diagnóstico , Estudos Prospectivos , Agitação Psicomotora/etiologia , Remifentanil , SevofluranoRESUMO
Lymphangiogenesis is essential in embryonic development but is rare in adults. It occurs, however, in many disease conditions including cancers. Vascular endothelial growth factor-C/D (VEGF-C/D) and VEGF receptor-3 (Vegfr3) play a critical role in the regulation of lymphangiogenesis. We investigated how the VEGF-C/Vegfr3 signalling system is regulated by tumour necrosis factor superfamily member 15 (Tnfsf15), an endothelium-derived cytokine. We report here that Tnfsf15, which is known to induce apoptosis in vascular endothelial cells, can promote lymphatic endothelial cell (LEC) growth and migration, stimulate lymphangiogenesis, and facilitate lymphatic circulation. Treatment of mouse LECs with Tnfsf15 results in up-regulation of Vegfr3 expression; this can be inhibited by gene silencing of death domain-containing receptor-3 (DR3; Tnfrsf25), a cell surface receptor for Tnfsf15, with siRNA, or by blocking Tnfsf15-DR3 interaction with a Tnfsf15 neutralizing antibody, 4-3H. Additionally, Tnfsf15/DR3 signalling pathways in LECs include activation of NF-κB. Tnfsf15-overexpressing transgenic mice exhibit a marked enhancement of lymph drainage; this is confirmed by treatment of wild-type mice with intraperitoneal injection of recombinant Tnfsf15. Moreover, systemic treatment of pregnant Tnfsf15 transgenic mice with 4-3H leads to inhibition of embryonic lymphangiogenesis. Our data indicate that Tnfsf15, a cytokine produced largely by endothelial cells, facilitates lymphangiogenesis by up-regulating Vegfr3 gene expression in LECs, contributing to the maintenance of the homeostasis of the circulatory system. This finding also suggests that Tnfsf15 may be of potential value as a therapeutic tool for the treatment of lymphoedema.
Assuntos
Células Endoteliais/metabolismo , Linfangiogênese , Vasos Linfáticos/metabolismo , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/metabolismo , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Animais , Movimento Celular , Proliferação de Células , Células Cultivadas , Relação Dose-Resposta a Droga , Células Endoteliais/efeitos dos fármacos , Injeções Intraperitoneais , Linfa/metabolismo , Linfangiogênese/efeitos dos fármacos , Vasos Linfáticos/citologia , Vasos Linfáticos/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , NF-kappa B/metabolismo , Interferência de RNA , Membro 25 de Receptores de Fatores de Necrose Tumoral/genética , Membro 25 de Receptores de Fatores de Necrose Tumoral/metabolismo , Proteínas Recombinantes/administração & dosagem , Transdução de Sinais , Fatores de Tempo , Transfecção , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/administração & dosagem , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/genética , Regulação para Cima , Fator C de Crescimento do Endotélio Vascular/metabolismoRESUMO
Hepatitis B virus (HBV) infection is a major etiology of chronic liver disease worldwide. In the past decade, nonalcoholic fatty liver disease (NAFLD) has emerged as a common liver disorder in general population. Accordingly, the patient number of chronic hepatitis B (CHB) concomitant with NAFLD grows rapidly. The present article reviewed the recent studies aiming to explore the relationship between CHB and NAFLD from different aspects, including the relevant pathogenesis of CHB and NAFLD, the intracellular molecular mechanisms overlaying HBV infection and hepatic steatosis, and the observational studies with animal models and clinical cohorts for analyzing the coincidence of the two diseases. It is concluded that although numerous cross-links have been suggested between the molecular pathways in HBV infection and NAFLD pathogenesis, regarding whether HBV infection can substantially interfere with the occurrence of NAFLD or vice versa in the patients, there is still far from a conclusive agreement.
Assuntos
Hepatite B Crônica/complicações , Hepatopatia Gordurosa não Alcoólica/complicações , Animais , Vírus da Hepatite B , Hepatite B Crônica/virologia , Hepatite Viral Animal/complicações , Humanos , Hepatopatia Gordurosa não Alcoólica/etiologiaRESUMO
BACKGROUND: Gastritis cystica profunda (GCP) is an uncommon disease characterized by multiple cystic gastric glands within the submucosa of the stomach. CASE DESCRIPTION: Here, we present a case of a 63-year-old man with intermittent epigastric discomfort in whom gastroscopy revealed multiple irregular elevated nodular lesions with smooth surfaces at the anterior of the antrum. Surgical resection of the nodular lesions was performed, and the diagnosis of gastritis cystica profunda (GCP) was confirmed by histological examination. Another elevated nodular lesion approximately 10 mm in diameter with an ulcer was found on the gastric side of the remnant stomach near the resection side from 6 to 24 months after the surgical resection. Endoscopic ultrasonography (EUS) and repeated biopsies of the new elevated lesion were performed. Homogeneous, anechoic masses originating from the submucosa without gastric adenocarcinoma in histological examination showed GCP recurrence may occur. CONCLUSIONS: We report a case of GCP recurrence within 6 months after surgical resection. GCP should be considered in the differential diagnosis of elevated lesions in the stomach.
Assuntos
Gastrite/patologia , Complicações Pós-Operatórias , Seguimentos , Fundo Gástrico , Gastrite/cirurgia , Gastroscopia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , RecidivaRESUMO
Few-shot Event Detection (FSED) aims to identify novel event types in new domains with very limited annotated data. Previous PN-based (Prototypical Network) joint methods suffer from insufficient learning of token-wise label dependency and inaccurate prototypes. To solve these problems, we propose a span-based FSED model, called SpanFSED, which decomposes FSED into two subprocesses, including span extractor and event classifier. In span extraction, we convert sequential labels into a global boundary matrix that enables the span extractor to acquire precise boundary information irrespective of label dependency. In event classification, we align event types with an outside knowledge base like FrameNet and construct an enhanced support set, which injects more trigger information into the prototypical network of event prototypes. The superior performance of SpanFSED is demonstrated through extensive experiments on four event detection datasets, i.e., ACE2005, ERE, MAVEN and FewEvent. Access to our code and data is facilitated through the following link: .
Assuntos
Redes Neurais de Computação , Algoritmos , Humanos , Bases de Conhecimento , Aprendizado de MáquinaRESUMO
We investigated the effects of inhibiting heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNP A2/B1) expression on apoptosis, invasion, migration, and the chemotherapy sensitivity of pancreatic cancer cells to gemcitabine, 5-FU, and oxaliplatin chemotherapy using small interfering RNA (siRNA). Chemically synthesized siRNA hnRNP A2/B1 was transfected into the human pancreatic cancer cell lines SW1990 and BxPC-3. The IC(50) of gemcitabine, 5-FU, and oxaliplatin was determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. Cell apoptosis and cycle were detected using flow cytometry. The expressions of apoptosis-related genes, p53, Bax, Bcl-2, TRAIL, Survivin, multidrug resistance 1 (MDR1), E-cadherin, and matrix metalloproteinases-2 (MMP-2) were detected using real-time PCR and western blot. Plate colony formation assay, wound scratch assay, invasion, and migration were also examined. Gemcitabine, 5-FU, and oxaliplatin inhibit the proliferation of SW1990 and BxPC-3 cells in a concentration-dependent manner. Inhibition of hnRNP A2/B1 expression significantly reduced the IC(50) of gemcitabine, 5-FU, and oxaliplatin (P<0.01). hnRNP A2/B1 siRNA combined with gemcitabine, 5-FU and oxaliplatin significantly increased (P<0.01) apoptosis of pancreatic cancer cell lines SW1990 and BxPC-3, increased the expression level of Bax mRNA, decreased Bcl-2 mRNA and MDR1 mRNA expression (P<0.01), and induced no change in p53, TRAIL, and Survivin mRNA expression in SW1990. In the western blot analysis, the expression level of Bax protein increased (P<0.01); the expression of both P-glycoprotein (Pg-p) protein and Bcl-2 protein decreased (P<0.01). Silencing hnRNP A2/B1 decreased invasion and migration in the cell line SW1990. Silencing hnRNP A2/B1 in SW1990 also correlated with an increase in E-cadherin expression and a decrease in MMP-2 expression at the same time. Inhibition of hnRNP A2/B1 expression can induce apoptosis in pancreatic cancer cells and improve chemosensitivity to gemcitabine, 5-FU, and oxaliplatin. hnRNP A2/B1 may play a role in invasion and migration in the pancreatic cancer cell line SW1990 through the regulation of E-cadherin and expression of MMP-2.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose/efeitos dos fármacos , Fluoruracila/farmacologia , Ribonucleoproteínas Nucleares Heterogêneas Grupo A-B/antagonistas & inibidores , Neoplasias Pancreáticas/tratamento farmacológico , RNA Interferente Pequeno/farmacologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Genes Neoplásicos/efeitos dos fármacos , Humanos , Compostos Organoplatínicos/farmacologia , RNA Mensageiro/metabolismo , TransfecçãoRESUMO
The radial basis function (RBF) model and the Kriging model have been widely used in the surrogate-assisted evolutionary algorithms (SAEAs). Based on their characteristics, a global and local surrogate-assisted differential evolution algorithm (GL-SADE) for high-dimensional expensive problems is proposed in this article, in which a global RBF model is trained with all samples to estimate a global trend, and then its optima is used to significantly accelerate the convergence process. A local Kriging model prefers to select points with good predicted fitness and great uncertainty, which can effectively prevent the search from getting trapped into local optima. When the local Kriging model finds the best solution so far, a reward search strategy is executed to further exploit the local Kriging model. The experiments on a set of benchmark functions with dimensions varying from 30 to 200 are conducted to evaluate the performance of the proposed algorithm. The experimental results of the proposed algorithm are compared to four state-of-the-art algorithms to show its effectiveness and efficiency in solving high-dimensional expensive problems. Besides, GL-SADE is applied to an airfoil optimization problem to show its effectiveness.
RESUMO
With weight-sharing and continuous relaxation strategies, the differentiable architecture search (DARTS) proposes a fast and effective solution to perform neural network architecture search in various deep learning tasks. However, unresolved issues, such as the inefficient memory utilization, and the poor stability of the search architecture due to channels randomly selected, which has even caused performance collapses, are still perplexing researchers and practitioners. In this paper, a novel efficient channel attention mechanism based on partial channel connection for differentiable neural architecture search, termed EPC-DARTS, is proposed to address these two issues. Specifically, we design an efficient channel attention module, which is applied to capture cross-channel interactions and assign weight based on channel importance, to dramatically improve search efficiency and reduce memory occupation. Moreover, only partial channels with higher weights in the mixed calculation of operation are used through the efficient channel attention mechanism, and thus unstable network architectures obtained by the random selection operation can also be avoided in the proposed EPC-DARTS. Experimental results show that the proposed EPC-DARTS achieves remarkably competitive performance (CIFAR-10/CIFAR-100: a test accuracy rate of 97.60%/84.02%), compared to other state-of-the-art NAS methods using only 0.2 GPU-Days.