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BACKGROUND & AIMS: High expression of phosphatidylinositol 4-kinase III alpha (PI4KIIIα) correlates with poor survival rates in patients with hepatocellular carcinoma. In addition, hepatitis C virus (HCV) infections activate PI4KIIIα and contribute to hepatocellular carcinoma progression. We aimed at mechanistically understanding the impact of PI4KIIIα on the progression of liver cancer and the potential contribution of HCV in this process. METHODS: Several hepatic cell culture and mouse models were used to study the functional importance of PI4KIIIα on liver pathogenesis. Antibody arrays, gene silencing, and PI4KIIIα-specific inhibitor were applied to identify the involved signaling pathways. The contribution of HCV was examined by using HCV infection or overexpression of its nonstructural protein. RESULTS: High PI4KIIIα expression and/or activity induced cytoskeletal rearrangements via increased phosphorylation of paxillin and cofilin. This led to morphologic alterations and higher migratory and invasive properties of liver cancer cells. We further identified the liver-specific lipid kinase phosphatidylinositol 3-kinase C2 domain-containing subunit gamma (PIK3C2γ) working downstream of PI4KIIIα in regulation of the cytoskeleton. PIK3C2γ generates plasma membrane phosphatidylinositol 3,4-bisphosphate-enriched, invadopodia-like structures that regulate cytoskeletal reorganization by promoting Akt2 phosphorylation. CONCLUSIONS: PI4KIIIα regulates cytoskeleton organization via PIK3C2γ/Akt2/paxillin-cofilin to favor migration and invasion of liver cancer cells. These findings provide mechanistic insight into the contribution of PI4KIIIα and HCV to the progression of liver cancer and identify promising targets for therapeutic intervention.
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Fatores de Despolimerização de Actina , Carcinoma Hepatocelular , Movimento Celular , Citoesqueleto , Neoplasias Hepáticas , Invasividade Neoplásica , Paxilina , Transdução de Sinais , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/genética , Humanos , Animais , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/genética , Citoesqueleto/metabolismo , Citoesqueleto/patologia , Paxilina/metabolismo , Camundongos , Fatores de Despolimerização de Actina/metabolismo , Fatores de Despolimerização de Actina/genética , Fosforilação , Hepacivirus , Linhagem Celular Tumoral , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Células Hep G2 , Hepatite C/patologia , Hepatite C/metabolismo , Hepatite C/virologia , Interferência de RNARESUMO
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific neutralizing antibodies (NAbs) lack cross-reactivity between SARS-CoV species and variants and fail to mediate long-term protection against infection. The maintained protection against severe disease and death by vaccination suggests a role for cross-reactive T cells. We generated vaccines containing sequences from the spike or receptor binding domain, the membrane and/or nucleoprotein that induced only T cells, or T cells and NAbs, to understand their individual roles. In three models with homologous or heterologous challenge, high levels of vaccine-induced SARS-CoV-2 NAbs protected against neither infection nor mild histological disease but conferred rapid viral control limiting the histological damage. With no or low levels of NAbs, vaccine-primed T cells, in mice mainly CD8+ T cells, partially controlled viral replication and promoted NAb recall responses. T cells failed to protect against histological damage, presumably because of viral spread and subsequent T cell-mediated killing. Neither vaccine- nor infection-induced NAbs seem to provide long-lasting protective immunity against SARS-CoV-2. Thus, a more realistic approach for universal SARS-CoV-2 vaccines should be to aim for broadly cross-reactive NAbs in combination with long-lasting highly cross-reactive T cells. Long-lived cross-reactive T cells are likely key to prevent severe disease and fatalities during current and future pandemics.
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Anticorpos Neutralizantes , Vacinas contra COVID-19 , COVID-19 , Animais , Humanos , Camundongos , Anticorpos Antivirais , Linfócitos T CD8-Positivos , COVID-19/prevenção & controle , Vacinas contra COVID-19/efeitos adversos , SARS-CoV-2 , Vacinas ViraisRESUMO
Phosphorus (P) is a crucial macronutrient for plant growth, development, and reproduction. The effects of low P (LP) stress on leaf senescence and the role of PHR1 in LP-induced leaf senescence are still unknown. Here, we report that PHR1 plays a crucial role in LP-induced leaf senescence, showing delayed leaf senescence in phr1 mutant and accelerated leaf senescence in 35S:PHR1 transgenic Arabidopsis under LP stress. The transcriptional profiles indicate that 763 differentially expressed SAGs (DE-SAGs) were upregulated and 134 DE-SAGs were downregulated by LP stress. Of the 405 DE-SAGs regulated by PHR1, 27 DE-SAGs were involved in P metabolism and transport. PHR1 could bind to the promoters of six DE-SAGs (RNS1, PAP17, SAG113, NPC5, PLDζ2, and Pht1;5), and modulate them in LP-induced senescing leaves. The analysis of RNA content, phospholipase activity, acid phosphatase activity, total P and phosphate content also revealed that PHR1 promotes P liberation from senescing leaves and transport to young tissues under LP stress. Our results indicated that PHR1 is one of the crucial modulators for P recycling and redistribution under LP stress, and the drastic decline of P level is at least one of the causes of early senescence in P-deficient leaves.
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Proteínas de Arabidopsis , Arabidopsis , Arabidopsis/metabolismo , Fósforo/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Senescência Vegetal , Fatores de Transcrição/metabolismo , Fosfatos/metabolismo , Folhas de Planta/metabolismo , Homeostase , Regulação da Expressão Gênica de PlantasRESUMO
We aimed to evaluate the association between air pollutants and mortality risk in patients with acute aortic dissection (AAD) in a longitudinal cohort and to explore the potential mechanisms of adverse prognosis induced by fine particulate matter (PM2.5). Air pollutants data, including PM2.5, PM10.0, nitrogen dioxide (NO2), carbon monoxide (CO), sulfur dioxide (SO2), and ozone (O3), were collected from official monitoring stations, and multivariable Cox regression models were applied. Single-cell sequencing and proteomics of aortic tissue were conducted to explore the potential mechanisms. In total, 1,267 patients with AAD were included. Exposure to higher concentrations of air pollutants was independently associated with an increased mortality risk. The high-PM2.5 group carried approximately 2 times increased mortality risk. There were linear associations of PM10, NO2, CO, and SO2 exposures with long-term mortality risk. Single-cell sequencing revealed an increase in mast cells in aortic tissue in the high-PM2.5 exposure group. Enrichment analysis of the differentially expressed genes identified the inflammatory response as one of the main pathways, with IL-17 and TNF signaling pathways being among the top pathways. Analysis of proteomics also identified these pathways. This study suggests that exposure to higher PM2.5, PM10, NO2, CO, and SO2 are associated with increased mortality risk in patients with AAD. PM2.5-related activation and degranulation of mast cells may be involved in this process.
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Poluentes Atmosféricos , Poluição do Ar , Dissecção Aórtica , Ozônio , Humanos , Poluentes Atmosféricos/análise , Poluição do Ar/efeitos adversos , Poluição do Ar/análise , Dióxido de Nitrogênio/análise , Proteômica , Material Particulado/análise , Ozônio/análise , Dióxido de Enxofre , Exposição Ambiental/análise , ChinaRESUMO
OBJECTIVE: To understand the current status of protein, fat, carbohydrates, energy, vitamins, minerals and other contents in common dishes of large, small, and medium-sized restaurants in Shandong Province. METHODS: From July to October 2021, 90 Shandong cuisine dishes were collected from 9 large, medium, and small restaurants in Shandong Province. One dish was collected from each restaurant, and samples from different types of restaurants were mixed as one sample. The content of nutrients and their carbohydrate and energy levels were detected and calculated. RESULTS: The median fat and protein content detected in the 90 dishes collected were 7.7 and 6.8 g/100 g, respectively. The calculated median values of energy and carbohydrates were 528 kJ/100 g and 5.4 g/100 g, respectively. The energy supply ratio of carbohydrates per 100 g of dishes was 17.2%, fat was 55.3%, and protein was 21.4%. The content of vitamin A, vitamin B_1, vitamin B_2, vitamin C and vitamin E was trace(tr)-26 700 µg/100 g, tr-0.12 mg/100 g, tr-0.40 mg/100 g, tr-56.5 mg/100 g and tr-5.31 mg α-TE/100 g. The medium number of dishes and potassium content was 375 and 219 mg/100 g. The detection rate of trans fat acid was 81.1%, and the median content was 0.06 g/100 g. CONCLUSION: The energy supply ratio of protein and fat in dishes is relatively high, while the energy supply ratio of total carbohydrates is relatively low. The sodium content is high, showing the characteristics of high sodium and low potassium. Vitamin, especially vitamin B_1 and vitamin B_2, has a low content.
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Valor Nutritivo , Restaurantes , Vitaminas , China , Vitaminas/análise , Cidades , Carboidratos da Dieta/análise , Gorduras na Dieta/análise , Proteínas Alimentares/análise , Minerais/análise , Análise de Alimentos , Vitamina A/análise , Ingestão de Energia , Vitamina E/análise , Ácido Ascórbico/análise , Nutrientes/análise , Oligoelementos/análiseRESUMO
The aim of this study was to explore the role and mechanism of long non-coding RNA (lncRNA) HIF1A antisense RNA 2 (HIF1A-AS2) in regulating imatinib (IM) resistance in gastrointestinal stromal tumor (GIST) cells under hypoxia. The expression of HIF1A-AS2 was silenced by siRNA in GIST cells. Cytotoxicity, apoptosis, and autophagy were evaluated under normoxic and hypoxic conditions. The expression levels of HIF1A-AS2, HIF1A, apoptosis-associated genes, and autophagy-associated genes were determined by qRT-PCR analysis and western blot. We found that lncRNA HIF1A-AS2 was highly expressed in GIST tissues and cells. Knockdown of HIF1A-AS2 increased the sensitivity of GIST cells to IM and increased apoptosis. Moreover, a hypoxic environment decreased the sensitivity of GIST cells to IM, and the knockdown of HIF1A-AS2 reversed this effect. Mechanistically, the knockdown of HIF1A-AS2 inhibited IM-mediated autophagy. Finally, HIF1A was found to positively regulate HIF1A-AS2 under hypoxic conditions. Collectively, these data demonstrate that hypoxia-induced HIF1A-AS2 promotes IM resistance in GIST cells by regulating autophagy.
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Tumores do Estroma Gastrointestinal , RNA Longo não Codificante , Humanos , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/genética , Mesilato de Imatinib/farmacologia , Linhagem Celular Tumoral , Autofagia/genética , Hipóxia/genética , Proliferação de Células/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/genéticaRESUMO
OBJECTIVES: The value of adding radiotherapy (RT) is still unclear for patients with gastric cancer (GC) after D2 lymphadenectomy. The purpose of this study is to predict and compare the overall survival (OS) and disease-free survival (DFS) of GC patients treated by chemotherapy and chemoradiation based on contrast-enhanced CT (CECT) radiomics. METHODS: A total of 154 patients treated by chemotherapy and chemoradiation in authors' hospital were retrospectively reviewed and randomly divided into the training and testing cohorts (7:3). Radiomics features were extracted from contoured tumor volumes in CECT using the pyradiomics software. Radiomics score and nomogram with integrated clinical factors were developed to predict the OS and DFS and evaluated with Harrell's Consistency Index (C-index). RESULTS: Radiomics score achieved a C index of 0.721(95%CI: 0.681-0.761) and 0.774 (95%CI: 0.738-0.810) in the prediction of DFS and OS for GC patients treated by chemotherapy and chemoradiation, respectively. The benefits of additional RT only demonstrated in subgroup of GC patients with Lauren intestinal type and perineural invasion (PNI). Integrating clinical factors further improved the prediction ability of radiomics models with a C-index of 0.773 (95%CI: 0.736-0.810) and 0.802 (95%CI: 0.765-0.839) for DFS and OS, respectively. CONCLUSIONS: CECT based radiomics is feasible to predict the OS and DFS for GC patients underwent chemotherapy and chemoradiation after D2 resection. The benefits of additional RT only observed in GC patients with intestinal cancer and PNI.
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Neoplasias Gástricas , Humanos , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Neoplasias Gástricas/diagnóstico por imagem , Neoplasias Gástricas/radioterapia , Neoplasias Gástricas/cirurgia , Tomografia Computadorizada por Raios XRESUMO
Background: Prenatal alcohol exposure (PAE) has been related to poor consequences of mental health in offspring. However, it remains unknown whether maternal alcohol drinking during pregnancy is associated with depression in the offspring. Methods: A meta-analysis was performed accordingly. Relevant observational studies were identified from Medline, Embase, and Web of Science databases. A fixed-effect or a random-effect model was selected dependending on the between-study heterogeneity. Results: Eight cohort studies were included. The heterogeneity was not significant (I 2 = 14%). A meta-analysis with a fixed-effect model showed that PAE was associated with a higher risk of depression in offspring (odds ratio (OR): 2.28, 95% confidence interval (CI): 1.61 to 3.25, p < 0.001). Subgroup analysis showed that moderate (OR: 1.74, 95% CI: 1.22 to 2.49, p=0.002, I 2 = 0%) or heavy (OR: 2.41, 95% CI: 1.55 to 3.73, p < 0.001, I 2 = 0%) maternal alcohol drinking in pregnancy was associated with depression in offspring, but not for those with low maternal alcohol drinking (OR: 1.18, 95% CI: 0.97 to 1.44, p=0.10, I 2 = 0%). Further subgroup analyses according to study design, timing of PAE evaluation, age at depression diagnosis, and quality scores showed consistent results. Univariate metaregression showed a dose-response association between PAE and offspring depression (coefficient: 0.073, 95% CI: 0.019 to 0.127, p=0.014). Conclusions: Current evidence suggests that PAE may be a risk factor of depression in offspring.
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Efeitos Tardios da Exposição Pré-Natal , Consumo de Bebidas Alcoólicas/efeitos adversos , Depressão/epidemiologia , Feminino , Humanos , Razão de Chances , Gravidez , Fatores de RiscoRESUMO
PURPOSE: The applicability of laparoscopic-assisted radical gastrectomy for elderly patients with gastric cancer is still not well clarified. The aim of this double-center study was to explore the feasibility and effectiveness of laparoscopic-assisted radical gastrectomy on elderly patients with gastric cancer. METHODS: We prospectively collected data of patients who underwent gastrectomy for cancer in two centers from June 2016 to December 2019. Propensity score matching was performed at a ratio of 1:1 to compare the laparoscopic-assisted radical gastrectomy group and open radical gastrectomy group. Univariate analyses and multivariate logistic regression analyses evaluating the risk factors for total, surgical, and medical complications were performed. RESULTS: A total of 481 patients with gastric cancer met the inclusion criteria and were included in this study. After propensity score analysis, 258 patients were matched each other (laparoscopic-assisted radical gastrectomy (LAG) group, n = 129; open radical gastrectomy (OG) group, n = 129). LAG group had lower rate of surgical complications (P = 0.009), lower rate of severe complications (P = 0.046), shorter postoperative hospital stay (P = 0.001), and lower readmission rate (P = 0.039). Multivariate analyses revealed that anemia, Charlson comorbidity index, and combined resection were independent risk factors in the LAG group, whereas body mass index and American Society of Anesthesiology grade in the OG group. CONCLUSION: Laparoscopic-assisted radical gastrectomy was relative safe even effective in elderly gastric cancer patients. We should pay attention to the different risk factors when performing different surgical procedures for gastric cancer in elderly patients.
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Laparoscopia , Neoplasias Gástricas , Idoso , Gastrectomia , Humanos , Excisão de Linfonodo , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Pontuação de Propensão , Estudos Retrospectivos , Neoplasias Gástricas/cirurgia , Resultado do TratamentoRESUMO
This work reports a bioinspired anisotropic nanocomposite by polar solution assisted mechanical stretching method, consisting of polyvinyl alcohol (PVA) and silicon carbide nanowires (SiCNWs) with aligned morphology in one direction. Inspired by the structural mimicry of myofibers, in which the uniaxial mechanical property of materials can be improved evidently, highly-aligned SiCNWs and PVA chains that interact using intermolecular force can be obtained. Hysteresis is observed and reversible deformation occurs while tensile-relaxation cycles are applied to the 100% stretched SiCNWs/PVA nanocomposites. The nanocomposites exhibit excellent properties and the tensile strength of 100% stretched SiCNWs/PVA nanocomposites is 188.30 ± 4.2 MPa and elastic modulus is 6.95 GPa, which are increased by 421.90% and 581.37% compared with pure PVA. Finite element simulation of fracture mechanism shows good agreement with the experimental results. An improvement of thermal conductivity is also achieved in well-aligned SiCNWs/PVA. The work imitates the structure of mammal muscle and also has great potential for the macroscopic application of one-dimensional nanomaterials as super flexible heat dissipation materials.
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OBJECTIVE: To understand the sleep conditions of adults in Shandong Province. METHODS: From 2010 to 2012, 10 201 residents aged ≥6 years old were selected from 7 counties and cities in Shandong Province by multi-stage stratified cluster sampling method in proportion to the population. A face-to-face interview was conducted with a questionnaire uniformly formulated by "China National Nutrition and Health Surveillance"to investigate and analyze the sleep status of residents aged 18 years and above. RESULTS: A total of 6626 people over the age of 18 were investigated. The average daily sleep was(7. 84±1. 29) h. There was no significant difference between male((7. 80 ± 1. 07) h) and female((7. 86 ± 1. 18) h). However, there was significant difference between males((7. 87±1. 17) h) and females((8. 01±1. 27) h) in rural areas(t = 3. 08, P < 0. 01). There was significant difference in different regions(big cities(7. 62± 1. 17) h, small and medium-sized cities(7. 85 ± 0. 89) h, rural areas(7. 95 ±1. 23) h, F = 39. 733, P<0. 001) and in different age groups(18-44 years old(7. 97±0. 98) h, 45-49 years old(7. 80±1. 07) h, 60 years old and above(7. 74±1. 33) h, F =21. 642, P<0. 001), the average daily sleep time was decreased with increasing age. The insufficient sleep rate was 9. 8%, there was no significant different between male(9. 5%)and female(10. 1%). There was significant difference in different regions(big cities15. 3%, small and medium-sized cities 5. 2%, rural areas 9. 7%, χ~2= 105. 870, P <0. 001) and in different age groups(18-44 years old 5. 1%, 45-59 years old 9. 7%, 60 years old and above 15. 3%, χ~2= 114. 308, P < 0. 001). Big cities had the higher insufficient sleep rate than medium-sized cities and rural areas, The insufficient sleep rate showed an upward trend with the increase of age. The proportion of excessive sleep was9. 3%. The difference between male(8. 4%) and female(10. 0%) was statistically significant(t = 2. 11, P < 0. 05). There were statistically significant differences in different regions(7. 0% in large cities, 6. 0% in medium and small cities, 12. 8% in rural areas, χ~2= 77. 156, P< 0. 01) and different, age groups(6. 7% in 18-44 years old, 6. 1% in 45-59 years old, 16. 8% in 60 years old and above, χ~2= 175. 556, P <0. 01). The rate of excessive sleep in rural areas was higher than that in cities, and the rate of excessive sleep in the 45-59 age group was the highest. CONCLUSION: Insufficient sleep is common in adult residents in Shandong Province. The insufficient sleep is more significant among elderly population and residents of big cities. The problem of excessive sleep also exists.
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Estado Nutricional , População Rural , Adolescente , Adulto , Criança , China , Cidades , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inquéritos e Questionários , Adulto JovemRESUMO
OBJECTIVE: To understand the sleep conditions of children and adolescents aged 6-17 years old in Shandong Province. METHODS: The data of physical activity from " 2010-2012 China National Nutrition and Health Surveillance " in Shandong Province were used. A total of 1808 children aged 6 to 17 years old in urban and rural schools were investigated to analyze their sleep conditions by multi-stage stratified cluster random samplingand a unified questionnaire. RESULTS: the average sleeping time of children aged 6 to 17 years old in Shandong Province was 8. 62 h, and there was no significant difference between children of different genders( male 8. 66 h, n = 900, female 8. 59 h, n = 908) and children of different regions( urban 8. 64 h, n =982, rural 8. 61 h, n = 826). The lack of sleep rate among children aged 6-17 years old was 60. 1%( n = 1808), that of boys( 58. 3%) was lower than that of girls( 61. 8%), and that of urban( 59. 9%) and rural( 60. 3%) was close, with no statistically significant difference. However, there were statistically significant differences between urban and rural lack of sleep rates between the ages 6 to 11 years old( t = 3. 57, P <0. 01) and between the ages 15 to 17 years old( t = 8. 60, P < 0. 001). With the increase of age, the average sleep time decreased, the lack of sleep rate showed a downward trend. CONCLUSION: The average sleeping time of average daily sleep time, lack of sleep rate, children and adolescents children aged 6 to 17 years old is insufficient and the rate of sleep deficiency is high in shandong province.
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Estado Nutricional , Sono , Adolescente , Criança , China , Feminino , Inquéritos Epidemiológicos , Humanos , Masculino , População Rural , Instituições AcadêmicasRESUMO
Although potential neutralization epitopes on the fiber knob of adenovirus (AdV) serotype 2 (Ad2) and Ad5 have been revealed, few studies have been carried out to identify neutralization epitopes on the knob from a broader panel of AdV serotypes. In this study, based on sequence and structural analysis of knobs from Ad1, Ad2, Ad5 and Ad6 (all from species C), several trimeric chimeric knob proteins were expressed in Escherichia coli to identify the locations of neutralization epitopes on the knobs by analysing their reactivity with mouse and rabbit polyclonal sera raised against AdVs and human sera with natural AdV infection. The dominant neutralization epitopes were located mainly in the N-terminal part of knobs from Ad1, Ad2 and Ad5, but they seemed to be located in the C-terminal part of the Ad6 knob, with some individual differences in rabbit and human populations. Our study adds to our understanding of humoral immune responses to AdVs and will facilitate the construction of more desirable capsid-modified recombinant Ad5 vectors.
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Adenoviridae/química , Adenoviridae/imunologia , Epitopos/química , Adenoviridae/classificação , Adenoviridae/genética , Infecções por Adenoviridae/virologia , Sequência de Aminoácidos , Animais , Clonagem Molecular , Mapeamento de Epitopos , Epitopos/genética , Epitopos/imunologia , Escherichia coli/genética , Escherichia coli/metabolismo , Expressão Gênica , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/imunologia , Células HEK293 , Humanos , Soros Imunes/química , Camundongos , Dados de Sequência Molecular , Testes de Neutralização , Plasmídeos/química , Plasmídeos/metabolismo , Coelhos , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia , Alinhamento de Sequência , SorogrupoRESUMO
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), which is capable of selectively inducing apoptosis of cancer cells, is a potential targeted drug for cancer therapy. The TRAIL protein induces apoptosis only in trimeric form. However, the recombinant soluble TRAIL (sTRAIL) trimer has low stability and a short half-life, which is a major obstacle for its advancement into clinical trials. Moreover, a percentage of engineered sTRAIL proteins are produced as dimers which may be toxic to normal human hepatocytes. In this study, we inserted three copies of the same subunit fragment of sTRAIL with a His tag into a polycistronic expression vector (pST39) to explore whether it would increase the proportion of trimers. We also constructed a heterozygous vector containing three subunit fragments of sTRAIL each with a different tag (His, HA, and Cmyc). Hybrid sTRAIL proteins (P-dTags) mainly as heterologous trimers were obtained by elution with a low concentration of imidazole based on different binding affinities of His with a nickel column. Functional analysis demonstrated that heterotrimeric forms of sTRAIL showed more stable activity compared to the P-3H at 4°C but not at 37°C without alteration in the native killing capacity. In addition, the heterologous trimers showed decreased toxicity to hepatocytes. These results suggest that the polycistronic expression system may be useful for expression of recombinant sTRAIL and improving its potential in cancer therapeutic applications.
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Proteínas Recombinantes de Fusão/isolamento & purificação , Proteínas Recombinantes de Fusão/metabolismo , Ligante Indutor de Apoptose Relacionado a TNF/isolamento & purificação , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Apoptose , Linhagem Celular Tumoral , Sobrevivência Celular , Escherichia coli , Humanos , Plasmídeos/genética , Estabilidade Proteica , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/genética , Ligante Indutor de Apoptose Relacionado a TNF/química , Ligante Indutor de Apoptose Relacionado a TNF/genética , TemperaturaRESUMO
Background: Aortic dissection (AD) is a lethal aortic disease with limited effective therapeutic strategies. Aging increases the risk of AD, yet the underlying mechanisms remain unclear. This study aims to analyze the association of aging-related genes (Args) and AD using bioinformatic analysis. This helps provide novel insights into AD pathogenesis and contributes to developing novel therapeutic strategies. Methods: mRNA (GSE52093, GSE153434), miRNA (GSE98770) and single-cell RNA-sequencing (scRNA-seq, GSE213740) datasets of AD were downloaded from GEO database. Args were downloaded from Aging Atlas database. Differentially-expressed Args were determined by intersecting Args and differentially-expressed mRNAs of two mRNA datasets. Cytoscape was used to identify hub genes and construct hub gene regulatory networks related to miRNAs. Seurat and clusterProfiler R package were used for investigating expression patterns of hub genes at single-cell level, and functional analysis, respectively. To validate the cellular expression pattern of hub genes, the same analysis was applied to our own scRNA-seq data. Drugs targeting hub Args were determined using the DGIdb database. Results: HGF, CXCL8, SERPINE1, HIF1A, TIMP1, ESR1 and PLAUR were identified as aging-related hub genes in AD. miR-221-3p was predicted to interact with ESR1. A decreased ESR1 expression in smooth muscle cell subpopulation 4 (SMC4) was observed in AD versus normal aortic tissues, which was validated by sequencing 197,605 aortic cells from 13 AD patients. Additionally, upregulated genes of SMC4 in AD tissues were enriched in the "cellular senescence" pathway. These data indicated that decreased ESR1 might promote SMC4 aging during AD formation. Eleven existing drugs targeting hub genes were identified, including ruxolitinib and filgrastim, which are associated with AD. Conclusions: By sequencing transcriptomic data, this study revealed aging-related hub genes and regulatory network involved in AD formation. Additionally, this study proposed a noteworthy hypothesis that downregulated ESR1 may exacerbate AD by promoting SMC aging, which requires further investigation.
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Background: Thyroid hormones significantly influence cardiovascular pathophysiology, yet their prognostic role in acute aortic dissection (AAD) remains inadequately explored. This study assesses the prognostic value of thyroid hormone levels in AAD, focusing on the mediating roles of renal function and coagulation. Methods: We included 964 AAD patients in this retrospective cohort study. Utilizing logistic regression, restricted cubic splines, and causal mediation analysis, we investigated the association between thyroid hormones and in-hospital mortality and major adverse cardiovascular events (MACEs). Results: In AAD patients overall, an increase of one standard deviation in FT4 levels was associated with a 31.9% increased risk of MACEs (OR 1.319; 95% CI 1.098-1.584) and a 36.1% increase in in-hospital mortality (OR 1.361; 95% CI 1.095-1.690). Conversely, a higher FT3/FT4 ratio was correlated with a 20.2% reduction in risk of MACEs (OR 0.798; 95% CI 0.637-0.999). This correlation was statistically significant predominantly in Type A AAD, while it did not hold statistical significance in Type B AAD. Key renal and coagulation biomarkers, including blood urea nitrogen, creatinine, cystatin C, prothrombin time ratio, prothrombin time, and prothrombin time international normalized ratio, were identified as significant mediators in the interplay between thyroid hormones and MACEs. The FT3/FT4 ratio exerted its prognostic influence primarily through the mediation of renal functions and coagulation, while FT4 levels predominantly impacted outcomes via a partial mediation effect on coagulation. Conclusion: FT4 levels and the FT3/FT4 ratio are crucial prognostic biomarkers in AAD patients. Renal function and coagulation mediate the association between the thyroid hormones and MACEs.
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Dissecção Aórtica , Coagulação Sanguínea , Hormônios Tireóideos , Humanos , Masculino , Feminino , Prognóstico , Estudos Retrospectivos , Pessoa de Meia-Idade , Hormônios Tireóideos/sangue , Coagulação Sanguínea/fisiologia , Dissecção Aórtica/sangue , Dissecção Aórtica/fisiopatologia , Rim/fisiopatologia , Idoso , Biomarcadores/sangue , Mortalidade Hospitalar , Adulto , Doença AgudaRESUMO
Aims: In addition to reducing the respiratory function, crystalline silica (SiO2) disturbs the immune response by affecting immune cells during the progression of silicosis. Regulatory T cell (Treg) differentiation may play a key role in the abnormal polarization of T helper cell (Th)1 and Th2 cells in the development of silicosis-induced fibrosis. Alpha-lipoic acid (ALA) has immunomodulatory effects by promoting Tregs differentiation. Thus, ALA may have a therapeutic potential for treating autoimmune disorders in patients with silicosis. However, little is known regarding whether ALA regulates the immune system during silicosis development. Results: We found that the expression levels of collagen increased, and the antioxidant capacity was lower in the Lias-/-+SiO2 group than in the Lias+/++SiO2 group. The proportion of Tregs decreased in the peripheral blood and spleen tissue in mice exposed to SiO2. The proportion of Tregs in the Lias-/-+SiO2 group was significantly lower than that in the Lias+/++SiO2 group. Supplementary exogenous ALA attenuates the accumulation of inflammatory cells and extracellular matrix in lung tissues. ALA promotes the immunological balance between Th17 and Treg responses during the development of silicosis-induced fibrosis. Innovation and Conclusion: Our findings confirmed that low expression of lipoic acid synthase aggravates SiO2-induced silicosis, and that supplementary exogenous ALA has therapeutic potential by improving Tregs in silicosis fibrosis.
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The bulk photovoltaic effect (BPVE) in non-centrosymmetric materials has attracted significant attention in recent years due to its potential to surpass the Shockley-Queisser limit. Although these materials are strictly constrained by symmetry, progress has been made in artificially reducing symmetry to stimulate BPVE in wider systems. However, the complexity of these techniques has hindered their practical implementation. In this study, we demonstrate a large intrinsic photocurrent response in centrosymmetric topological insulator Ag2Te, attributed to the surface photogalvanic effect (SPGE), which is induced by symmetry reduction of the surface. Through diverse spatially-resolved measurements on specially designed devices, we directly observe that SPGE in Ag2Te arises from the difference between two opposite photocurrent flows generated from the top and bottom surfaces. Acting as an efficient SPGE material, Ag2Te demonstrates robust performance across a wide spectral range from visible to mid-infrared, making it promising for applications in solar cells and mid-infrared detectors. More importantly, SPGE generated on low-symmetric surfaces can potentially be found in various systems, thereby inspiring a broader range of choices for photovoltaic materials.
RESUMO
Hyperactivation of ribosome biosynthesis (RiBi) is a hallmark of cancer, and targeting ribosome biogenesis has emerged as a potential therapeutic strategy. The depletion of TAF1B, a major component of selectivity factor 1 (SL1), disrupts the pre-initiation complex, preventing RNA polymerase I from binding ribosomal DNA and inhibiting the hyperactivation of RiBi. Here, we investigate the role of TAF1B, in regulating RiBi and proliferation in stomach adenocarcinoma (STAD). We disclosed that the overexpression of TAF1B correlates with poor prognosis in STAD, and found that knocking down TAF1B effectively inhibits STAD cell proliferation and survival in vitro and in vivo. TAF1B knockdown may also induce nucleolar stress, and promote c-MYC degradation in STAD cells. Furthermore, we demonstrate that TAF1B depletion impairs rRNA gene transcription and processing, leading to reduced ribosome biogenesis. Collectively, our findings suggest that TAF1B may serve as a potential therapeutic target for STAD and highlight the importance of RiBi in cancer progression.
RESUMO
Three new benzothieno[3,2-b]thiophene (BTT; 1) derivatives, which were end-functionalized with phenyl (BTT-P; 2), benzothiophenyl (BTT-BT; 3), and benzothieno[3,2-b]thiophenyl groups (BBTT; 4; dimer of 1), were synthesized and characterized in organic thin-film transistors (OTFTs). A new and improved synthetic method for BTTs was developed, which enabled the efficient realization of new BTT-based semiconductors. The crystal structure of BBTT was determined by single-crystal X-ray diffraction. Within this family, BBTT, which had the largest conjugation of the BTT derivatives in this study, exhibited the highest p-channel characteristic, with a carrier mobility as high as 0.22â cm(2) V(-1) s(-1) and a current on/off ratio of 1×10(7) , as well as good ambient stability for bottom-contact/bottom-gate OTFT devices. The device characteristics were correlated with the film morphologies and microstructures of the corresponding compounds.