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RNA binding protein RBM10 participates in various RNA metabolism, and its decreased expression or loss of function by mutation has been identified in many human cancers. However, how its dysregulation contributes to human cancer pathogenesis remains to be determined. Here, we found that RBM10 expression was decreased in breast tumors, and breast cancer patients with low RBM10 expression presented poorer survival rates. RBM10 depletion in breast cancer cells significantly promotes the cellular proliferation and migration. We further demonstrated that RBM10 forms a triple complex with YBX1 and phosphatase 1B (PPM1B), in which PPM1B serves as the phosphatase of YBX1. RBM10 knock-down markedly attenuated association between YBX1 and PPM1B, leading to elevated levels of YBX1 phosphorylation and its nuclear translocation. Furthermore, cancer cells with RBM10 depletion had a significantly accelerated tumor growth in nude mice. Importantly, these enhanced tumorigenic phenotypes can be reversed by overexpression of PPM1B. Our findings provide the mechanistic bases for functional loss of RBM10 in promoting tumorigenicity, and are potentially useful in the development of combined therapeutic strategies for cancer patients with defective RBM10.
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Neoplasias da Mama , Carcinogênese , Animais , Camundongos , Humanos , Feminino , Camundongos Nus , Carcinogênese/genética , Fosforilação , Proliferação de Células/genética , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Monoéster Fosfórico Hidrolases/genética , Regulação Neoplásica da Expressão Gênica , Linhagem Celular Tumoral , Proteína 1 de Ligação a Y-Box/genética , Proteína 1 de Ligação a Y-Box/metabolismo , Proteínas de Ligação a RNA/metabolismo , Proteína Fosfatase 2C/genética , Proteína Fosfatase 2C/metabolismoRESUMO
BACKGROUND: Theaceae, comprising 300 + species, holds significance in biodiversity, economics, and culture, notably including the globally consumed tea plant. Stewartia gemmata, a species of the earliest diverging tribe Stewartieae, is critical to offer insights into Theaceae's origin and evolutionary history. RESULT: We sequenced the complete organelle genomes of Stewartia gemmata using short/long reads sequencing technologies. The chloroplast genome (158,406 bp) exhibited a quadripartite structure including the large single-copy region (LSC), a small single-copy region (SSC), and a pair of inverted repeat regions (IRs); 114 genes encoded 80 proteins, 30 tRNAs, and four rRNAs. The mitochondrial genome (681,203 bp) exhibited alternative conformations alongside a monocyclic structure: 61 genes encoding 38 proteins, 20 tRNAs, three rRNAs, and RNA editing-impacting genes, including ATP6, RPL16, COX2, NAD4L, NAD5, NAD7, and RPS1. Comparative analyses revealed frequent recombination events and apparent rRNA gene gains and losses in the mitochondrial genome of Theaceae. In organelle genomes, the protein-coding genes exhibited a strong A/U bias at codon endings; ENC-GC3 analysis implies selection-driven codon bias. Transposable elements might facilitate interorganelle sequence transfer. Phylogenetic analysis confirmed Stewartieae's early divergence within Theaceae, shedding light on organelle genome characteristics and evolution in Theaceae. CONCLUSIONS: We studied the detailed characterization of organelle genomes, including genome structure, composition, and repeated sequences, along with the identification of lateral gene transfer (LGT) events and complexities. The discovery of a large number of repetitive sequences and simple sequence repeats (SSRs) has led to new insights into molecular phylogenetic markers. Decoding the Stewartia gemmata organellar genome provides valuable genomic resources for further studies in tea plant phylogenomics and evolutionary biology.
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Genoma de Cloroplastos , Theaceae , Filogenia , Theaceae/genética , Genômica , Códon/genética , Cloroplastos/genética , RNA de Transferência/genética , CháRESUMO
Depolymerization of the cellulose part in lignocellulose to glucose is a significant step for lignocellulose valorization. As one of the main by-products of agricultural biomass in crop-producing filed, valorization of corn straw has attracted considerable attention. In this study, a two-step depolymerizing strategy of high-pressure CO2-H2O pretreatment and oxidation-hydrolysis was applied for selective depolymerization of the cellulose component of corn straw to glucose production. Most part of the hemicellulose component could be removed through high-pressure CO2-H2O pretreatment in the presence of low concentration of acetic acid, and then as high as 32.2 % yield of glucose was achieved in water at 170 °C for 6â h without additional catalyst. The active acid sites generated during the partial oxidation of hydroxymethyl groups to carboxyl groups on glucose units of cellulose was shown to be crucial for the efficient valorization of corn straw for glucose production.
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Biomassa , Celulose , Glucose , Lignina , Polimerização , Zea mays , Zea mays/química , Glucose/química , Glucose/metabolismo , Celulose/química , Lignina/química , Hidrólise , Oxirredução , Dióxido de Carbono/química , Água/química , Ácido Acético/química , Catálise , Polissacarídeos/químicaRESUMO
Fifteen poplar varieties were used in a field trial to investigate the phytoremediation efficiency, stress resistance, and wood property of poplar hybrid varieties with diverse genetic backgrounds under the composite pollution of heavy metals. The coefficient of variation and clone repeatability for growth traits and Cd concentration were large. The Cd accumulation of poplar varieties 107 and QHQ reached 1.9 and 1.7â¯mg, respectively, followed by QHB, Ti, 69, and Pa, in which Cd accumulation reached 1.3â¯mg. Most of the intra-specific hybrid varieties (69, QH1, SL4, T3, and ZL46) had low Cd concentrations and small biomass, resulting in weak Cd accumulation and low phytoremediation efficiency for Cd-polluted soil. By contrast, the inter-sectional and inter-specific hybrid varieties exhibited better growth performance and accumulated higher concentrations of heavy metals than the intra-specific hybrids. The bioconcentration factor and translocation factor of Hg, As, and Pb were less than 1, indicating that poplars have low phytoremediation efficiency for these heavy metals. The hybrids between section Aigeiros and Tacamahaca (QHQ and QHB) and the inter-specific hybrid 107 within section Aigeiros were more resistant to composite heavy metal stress than the other poplar varieties were partially because of their high levels of free proline that exceeded 93⯵g·g-1 FW. According to the correlation analysis of the concentrations of the different heavy metals, the poplar roots absorbed different heavy metals in a cooperative manner, indicating that elite poplar varieties with superior capacity for accumulating diverse heavy metals can be bred feasibly. Compared with the intra-specific hybrid varieties, the inter-sectional (QHQ and QHB) and inter-specific (107) hybrid varieties had higher pollution remediation efficiency, larger biomass, higher cellulose content, and lower lignin content, which is beneficial for pulpwood. Therefore, breeding and extending inter-sectional (QHQ and QHB) and inter-specific hybrid varieties can improve the phytoremediation of composite pollution.
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PURPOSE: To report genetic characteristics and associated risk of chromosomal breaks due to chromosomal rearrangements in large samples. METHODS: MicroSeq, a technique that combines chromosome microdissection and next-generation sequencing, was used to identify chromosomal breakpoints. Long-range PCR and Sanger sequencing were used to precisely characterize 100 breakpoints in 50 ABCR carriers. RESULTS: In addition to the recurrent regions of balanced rearrangement breaks in 8q24.13, 11q11.23, and 22q11.21 that had been documented, we have discovered a 10-Mb region of 12q24.13-q24.3 that could potentially be a sparse region of balanced rearrangement breaks. We found that 898 breakpoints caused gene disruption and a total of 188 breakpoints interrupted genes recorded in OMIM. The percentage of breakpoints that disrupted autosomal dominant genes recorded in OMIM was 25.53% (48/188). Fifty-four of the precisely characterized breakpoints had 1-8-bp microhomologous sequences. CONCLUSION: Our findings provide a reference for the evaluation of the pathogenicity of mutations in related genes that cause protein truncation in clinical practice. According to the characteristics of breakpoints, non-homologous end joining and microhomology-mediated break-induced replication may be the main mechanism for ABCRs formation.
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Aberrações Cromossômicas , Translocação Genética , Humanos , Translocação Genética/genética , Pontos de Quebra do Cromossomo , Mutação , Rearranjo Gênico/genéticaRESUMO
Manipulation of the carrier density of layered transition-metal dichalcogenides (TMDs) is of fundamental significance for a wide range of electronic and optoelectronic applications. Herein, we applied the ionic-liquid-gating (ILG) method to inject the smallest ions, H+, into layered MoS2 to manipulate its carrier concentration. The measurements demonstrate that the injection of H+ realizes a nonvolatile n-type doping and metallic state in multilayer-MoS2 with a concentration of injection electron of â¼1.08 × 1013 cm-2 but has no effect on monolayer-MoS2, which clearly reveals that the H+ is injected into the interlayer of MoS2, not in the crystal lattice. The H+-injected multilayer-MoS2 was then used as the contact electrodes of a monolayer-MoS2 field effect transistor to improve the contact quality, and its performance has been enhanced. Our work deepens the understanding of the ILG technology and extends its application in TMDs.
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Microwaves are electromagnetic waves of specific frequencies (300 MHz-3000 GHz), whereas ultrasonic is mechanical waves of specific frequencies. Microwave and ultrasonic technology as a new processing method has been widely used in food processing fields. Combined ultrasonic and microwave technology is exploited by researchers as an improvement technique and has been successfully applied in food processing such as thawing, drying, frying, extraction, and sterilization. This paper overviews the principle and characteristics of ultrasonic- and microwave-assisted food processing techniques, particularly their combinations, design of equipment, and their applications in the processing of agricultural products such as thawing, drying, frying, extraction, and sterilization. The combination of ultrasonic and microwave is applied in food processing, where microwave enhances the heating rate, and ultrasonic improves the efficiency of heat and mass transfer. The synergy of the heating effect of microwave and the cavitation effect of ultrasonic improves processing efficiency and damages the cell structure of the material. The degradation of nutrient composition and energy consumption due to the short processing time of combined ultrasonic and microwave technology is decreased. Ultrasonic technology, as an auxiliary means of efficient microwave heating, is pollution-free, highly efficient, and has a wide range of applications in food processing.
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Micro-Ondas , Ultrassom , Manipulação de Alimentos/métodos , Tecnologia de Alimentos , TecnologiaRESUMO
Microwave is a form of electromagnetic radiation that has high penetration and heating efficiency in food processing. Uneven heating is the main problem of microwave processing, especially in solid foods. Fluid and semifluid media, which are good carriers in microwave processing, have uniform dielectric properties and good material fluidity. Herein, we review the development, application prospects, and limitations of microwave in fluid and semifluid food processing and the research progress in microwave heating with steam as carrier. The mixture of generated steam and tiny micro droplets from food material under the action of microwave can absorb microwave and transfer heat evenly, which effectively improves the uniformity of microwave heating. Due to the relatively uniform dielectric properties and consistent texture of fluid and semifluid food materials, uneven heating phenomenon during their microwave processing can be significantly inhibited. Based on the development of microwave heating technology and equipment design, the microbial inactivation and enzyme inhibition in fluid and semifluid food were improved and food product with better retention of nutrients and sensory profile were produced. Also, microwave radiation can be used to prepare the printing material or process the printed product for 3D food printing, which enhances the added value of 3D printed products and the personalization of food manufacturing. In future research, intelligent control technology can be applied in the microwave processing of fluid and semifluid food materials for various applications. Therefore, the processing conditions can be adjusted automatically.
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Calefação , Micro-Ondas , Manipulação de Alimentos , Vapor , TecnologiaRESUMO
Effects of dietary niacin on the growth performance, intestinal histomorphology, body composition, and antioxidant capacity were investigated in the present study to determine the optimum requirement of niacin for juvenile Eriocheir sinensis. All 360 crabs (initial average weight 1.14 ± 0.04 g) were randomly divided into 6 groups with 3 replicates in each group and 20 crabs in each replicate. Crabs were fed with the control diet (0.89 mg/kg) or niacin-supplemented diets (170.54 mg/kg, 347.05 mg/kg, 587.59 mg/kg, 784.85 mg/kg, and 1248.86 mg/kg) for 12 weeks (named as G1, G2, G3, G4, G5, and G6, respectively). The results showed that appropriate dietary niacin (above 347.05 mg/kg) significantly increased the weight gain rate (WGR) and specific growth rate (SGR) (p < 0.05), but did not affect the survival rate (SR), feed conversion ratio (FCR), daily feeding rate (DFR), and molting frequency (MF) of crabs (p > 0.05). The niacin content in the hepatopancreas of crabs in G1 and G2 was significantly lower than that of the other four groups (p < 0.05). Moreover, dietary niacin significantly affected the intestinal histomorphology of crabs, including the number of folds (NF), height of folds (HF), height of microvillus (HMV), and thickness of muscularis (TM) (p < 0.05). Additionally, moderate dietary niacin levels significantly affected the nonspecific immune responses of crabs, by improving the activity of catalase (CAT), glutathione s-transferase (GST), glutathione peroxidase (GSH-Px), and total superoxide dismutase (T-SOD) (p < 0.05). Based on the broken-line model analysis of SGR against dietary niacin level, the dietary niacin requirement of juvenile crabs was suggested to be 419.4 mg/kg.
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Grounded in family systems theory and the internal working model of attachment, the present study tested the effects of paternal adult attachment, paternal psychological flexibility and father-adolescent attachment on adolescent anxiety. In total, 906 pairs of fathers and their adolescents completed a set of questionnaires, including the Experiences in Close Relationships Scale, Parental Psychological Flexibility Questionnaire, Inventory of Parent and Peer Attachment, and Trait Anxiety Inventory. The results revealed that paternal adult attachment avoidance had a positive impact on adolescent anxiety. The relationship between paternal adult attachment and adolescent anxiety was chain mediated by paternal psychological flexibility and father-adolescent attachment. The mediation effects contained two paths: the separate mediation effect of paternal psychological flexibility, and the chain mediation effect of paternal psychological flexibility and father-adolescent attachment. The results of the study show that the father's adult attachment can not only directly affect adolescent anxiety, but also indirectly affect adolescent anxiety through the paternal psychological flexibility and the quality of father-adolescent attachment. Fathers have an important effect on adolescent anxiety.
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Ansiedade , Pai , Adolescente , Adulto , Transtornos de Ansiedade , Relações Pai-Filho , Pai/psicologia , Humanos , Masculino , Apego ao Objeto , Pais , Grupo AssociadoRESUMO
Heterojunction integrated by two-dimensional/three-dimensional materials has shown great potential applications in optoelectronic devices because of its fast response speed, high specific detectivity and broad spectral response. In this work, the vertical n-Si/p-GaTe heterojunction has been designed and fabricated, which shows a high responsivity up to 5.73 A W-1and a fast response time of 20µs at zero bias benifitting from the high efficiency of light absorption, internal photocurrent gain and strong built-in electrical field. A specific detectivity of 1012Jones and a broad spectral response ranging from 300 to 1100 nm can also be achieved. This work provides an alternative strategy for high-performance self-powered optoelectronic devices.
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AIM: Hepatitis B virus (HBV) integration is one of the mechanisms contributing to hepatocellular carcinoma (HCC) development. However, the status of HBV integration in intrahepatic cholangiocarcinoma (ICC) is poorly understood. This study aims to characterize the viral integration in HBV-related ICC. METHODS: The presence of HBV S and C gene in ICCs and the paratumor tissue was determined by polymerase chain reaction direct sequencing. Hepatitis B virus integration was detected by a high-throughput capture sequencing method. The expression analysis of the genes targeted by HBV in ICC was undertaken in The Cancer Genome Atlas dataset. RESULTS: Hepatitis B virus S and/or C gene fragments were detected in 71.43% (10/14) ICCs and 57.14% (8/14) paratumor tissues. Using the high-throughput capture sequencing approach, 139 and 183 HBV integration breakpoints were identified from seven ICC and seven paired paratumor tissues, respectively. Seven genes (TERT, CEACAM20, SPATA18, TRERF1, ZNF23, LINC01449, and LINC00486) were recurrently targeted by HBV-DNA in different ICC tissues or different cell populations of the same tissue. TERT, which is the most preferential HBV target gene in HCC, was found to be repeatedly interrupted by HBV-DNA in three different ICC tissues. Based on The Cancer Genome Atlas dataset, TERT, as well as three other HBV recurrently targeted genes (SPATA18, TRERF1, and ZNF23), showed differential expression levels between ICC and para-ICC tissues. CONCLUSIONS: Taken together, HBV integration is a common event in HBV-related ICC. The HBV recurrent integration genes identified from this study, such as TERT, provide new clues for further research on the causative link between HBV infection and ICC.
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Juglans regia is a world-famous woody oil plant, whose yield and quality are affected by drought stress. Ethylene-responsive factors (ERFs) play vital role in plant stress response. In current study, to comprehend the walnut molecular mechanism of drought stress response, an ERF transcription factor was clarified from J. regia (JrERF2-2) and its potential function mechanism to drought was clarified. The results showed that JrERF2-2 could be induced significantly by drought. The transgenic Arabidopsis over-expression of JrERF2-2 displayed enhanced growth, antioxidant enzyme vitalities, reactive oxygen species scavenging and proline produce under drought stress. Especial the glutathione-S-transferase (GST) activity and most GST genes' transcription were elevated obviously. Yeast one-hybrid (Y1H) and co-transient expression (CTE) methods revealed that JrERF2-2 could recognize JrGST4, JrGST6, JrGST7, JrGST8, and JrGSTF8 by binding to GCC-box, and recognize JrGST11, JrGST12, and JrGSTN2 by binding to DRE motif. Meanwhile, the binding activity was strengthened by drought stress. Moreover, JrERF2-2 could interact with JrWRKY7 to promote plant drought tolerance; JrWRKY7 could also distinguish JrGST4, JrGST7, JrGST8, JrGST11, JrGST12, and JrGSTF8 via binding to W-Box motif. These results suggested that JrERF2-2 could effectively improve plant drought tolerance through interacting with JrWRKY7 to control the expression of GSTs. JrERF2-2 is a useful plant representative gene for drought response in molecular breeding.
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Hepatitis B virus (HBV) infection has been reported to be associated with non-Hodgkin lymphoma (NHL). However, the evidence is limited to the seroepidemiological study. There is a lack of evidence showing the HBV infection and integration in NHL cells. Here, we reported that in the Shanghai area, the positive rates of serum HBsAg (OR: 3.11; 95% CI: 2.20-4.41) and HBeAg (OR: 3.99; 95% CI: 1.73-9.91) were significantly higher in patients with NHL. HBsAg, HBcAg and HBV DNA were detected in 34.4%, 45.2% and 47.0% of the NHL tissues, respectively. Furthermore, by using a high-throughput viral integration detection approach (HIVID), integrated HBV DNA was identified from 50% (6/12) HBV-related NHL tissues. There were a total of 313 HBV integration sites isolated from the NHL tissues, among which four protein-coding genes (FAT2, SETX, ITGA10 and CD63) were interrupted by HBV DNA in their exons. Seven HBV preferential target genes (ANKS1B, HDAC4, EGFLAM, MAN1C1, XKR6, ZBTB38 and CCDC91) showed significantly altered expression levels in NHL, suggesting a potential role of these genes in NHL development. Taken together, HBV integration is a common phenomenon in NHL. This finding opens up a new direction of research into the mechanistic link between HBV infection and NHL.
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DNA Viral/genética , Vírus da Hepatite B/genética , Hepatite B/virologia , Linfoma não Hodgkin/virologia , Integração Viral/genética , China , Éxons/genética , Feminino , Antígenos de Superfície da Hepatite B/genética , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Black phosphorus has many potential applications in optoelectronic devices because of its unique properties. Adjusting its performance by doping is an important issue of research. In this paper, we synthesized high-quality Te-doped crystals by the chemical vapor transport method. Tellurium doping with an atomic ratio of 0.1% was confirmed by X-ray photoelectron spectroscopy, X-ray diffraction, and energy dispersive X-ray analysis. The performance of field effect transistors devices shows that the hole mobility of Te-doped black phosphorous (BP) is significantly improved compared with that of undoped-BP. The highest hole mobility at room temperature is 719 cm2 V-1 s-1, and the electron mobility is 63 cm2 V-1 s-1. Te-doped BP field effect transistors show an obvious bipolar behavior.
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Resistive random access memory (RRAM) is considered to be one of the important candidates for the next generation of memory devices. Zinc oxide resistive memory has also been studied for many years, but there are still some controversial topics and problems. Herein, an unusual resistance state has been observed in devices following the measurement and analysis of ZnO resistive memories with different thicknesses, a middle resistance state was speculated to explain the instability of ZnO RRAM. According to this speculation, a two-layer structure ZnO RRAM has been designed to significantly increase the device performance with the introduction of an HfO2 layer and the enhancement has also been explained based on the results of first-principles calculations.
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Leaves are essential organs for plants. We previously identified a functional gene possibly encoding a component of the SWI/SNF complex named Leaf and Flower Related (LFR) in Arabidopsis thaliana. Loss-of-function mutants of LFR displayed obvious defects in leaf morphogenesis, indicating its vital role in leaf development. Here an allelic null mutant of ASYMMETRIC LEAVES2 (AS2), as2-6, was isolated as an enhancer of lfr-1 in petiole length, vasculature pattern and leaf margin development. The lfr as2 double-mutants showed enhanced ectopic expression of BREVIPEDICELLUS (BP) compared with each of the single-mutants, which is consistent with their synergistic genetic enhancement in multiple BP-dependent development processes. Moreover, LFR and several putative subunits of the SWI/SNF complex interacted physically with AS2. LFR associated with BP chromatin in an AS1-AS2-dependent manner to promote the nucleosome occupancy for appropriate BP repression in leaves. Taken together, our findings reveal that LFR and the SWI/SNF complex play roles in leaf development at least partly by repressing BP transcription as interacting factors of AS2, which expounds our understanding of BP repression at the chromatin structure level in leaf development.
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Chloride channel-3 (ClC-3), a member of the ClC family of voltage-gated Cl- channels, is involved in the resistance of tumor cells to chemotherapeutic drugs. Here, we report a new mechanism for ClC-3 in mediating multidrug resistance (MDR). ClC-3 was highly expressed in the P-glycoprotein (P-gp)-dependent human lung adenocarcinoma cell line (A549)/paclitaxel (PTX) and the human breast carcinoma cell line (MCF-7)/doxorubicin (DOX) resistant cells. Changes in the ClC-3 expression resulted in the development of drug resistance in formerly drug-sensitive A549 or MCF-7 cells, and drug sensitivity in formerly drug-resistant A549/Taxol and MCF-7/DOX cells. Double transgenic MMTV-PyMT/CLCN3 mice with spontaneous mammary cancer and ClC-3 overexpression demonstrated drug resistance to PTX and DOX. ClC-3 expression upregulated the expression of MDR1 messenger RNA and P-gp by activating the nuclear factor-κB (NF-κB)-signaling pathway. These data suggest that ClC-3 expression in cancer cells induces MDR by upregulating NF-κB-signaling-dependent P-gp expression involving another new mechanism for ClC-3 in the development of drug resistance of cancers.
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Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Neoplasias da Mama/metabolismo , Canais de Cloreto/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Células MCF-7 , NF-kappa B/metabolismo , Ativação Transcricional/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/fisiologiaRESUMO
Polyelectrolytes play an important role in both natural biological systems and human society, and their synthesis, functional exploration, and profound application are thus essential for biomimicry and creating new materials. In this study, we developed an efficient synthetic methodology for in situ generation of azonia-containing polyelectrolytes in a one-pot manner by using readily accessible nonionic reactant in the presence of commercially available cheap ionic species. The resulting polyelectrolytes are emissive in the solid state and can readily form luminescent photopatterns with different colors. The azonia-containing polyelectrolytes possess extraordinary potency of reactive oxygen species (ROS) generation, enabling them to impressively kill methicillin-resistant Staphylococcus aureus (MRSA), a drug resistant superbug, both in vitro and in vivo.
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Amidas/farmacologia , Antibacterianos/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Polieletrólitos/farmacologia , Amidas/química , Antibacterianos/síntese química , Antibacterianos/química , Luminescência , Staphylococcus aureus Resistente à Meticilina/metabolismo , Testes de Sensibilidade Microbiana , Estrutura Molecular , Processos Fotoquímicos , Polieletrólitos/síntese química , Polieletrólitos/química , Espécies Reativas de Oxigênio/metabolismoRESUMO
Hepatitis B virus-associated hepatocellular carcinoma (HBV-HCC) is usually considered an inflammation-related cancer associated with chronic inflammation triggered by exposure to HBV and tumor antigens. T-cell exhaustion is implicated in immunosuppression of chronic infections and tumors. Although immunotherapies that enhance immune responses by targeting programmed cell death-1(PD-1)/PD-L1 are being applied to malignancies, these treatments have shown limited response rates, suggesting that additional inhibitory receptors are also involved in T-cell exhaustion and tumor outcome. Here, we analyzed peripheral blood samples and found that coexpression of PD-1 and T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain (TIGIT) was significantly upregulated on CD4+ and CD8+ T cells from patients with HBV-HCC compared with those from patients with chronic HBV or HBV-liver cirrhosis. Additionally, PD-1+ TIGIT+ CD8+ T-cell populations were elevated in patients with advanced stage and progressed HBV-HCC. Importantly, PD-1+ TIGIT+ CD8+ T-cell populations were negatively correlated with overall survival rate and progression-free survival rates. Moreover, we showed that PD-1+ TIGIT+ CD8+ T cells exhibit features of exhausted T cells, as manifested by excessive activation, high expression of other inhibitory receptors, high susceptibility to apoptosis, decreased capacity for cytokine secretion, and patterns of transcription factor expression consistent with exhaustion. In conclusion, PD-1+ TIGIT+ CD8+ T-cell populations are associated with accelerated disease progression and poor outcomes in HBV-HCC, which might not only have important clinical implications for prognosis but also provide a rationale for new targets in immunotherapy.