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1.
J Org Chem ; 88(6): 3981-3986, 2023 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-36862134

RESUMO

The total synthesis of levesquamide, a natural product with an unprecedented pentasubstituted pyridine-isothiazolinone skeleton, has been accomplished from kojic acid for the first time. The key features of the synthesis include a Suzuki coupling reaction between bromopyranone and oxazolyl borate fragments, a copper-mediated introduction of a thioether, a mild hydrolysis of a pyridine 2-N-methoxyamide, and a Pummerer-type cyclization of a tert-butyl sulfoxide to form the key pyridine-isothiazolinone unit of the natural product.

2.
Org Biomol Chem ; 20(10): 2102-2108, 2022 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-35195145

RESUMO

(±) Commiphorane C, (±) commiphorane D, and their two isomers were synthesized through a linear synthesis strategy in 14 steps. Key features of the strategy include the construction of the relative configurations of C-5 and C-6 via aldehyde crotylation followed by the Mitsunobu reaction and ring A via an intramolecular Aldol reaction. The biological evaluation revealed that (±) commiphorane C and (±) isomer-1 significantly attenuated the overproduction of fibronectin, collagen I, and α-SMA in TGF-ß1-induced rat renal proximal tubular cells. Intermediate (±) 11 significantly decrease the overexpression of collagen I. Cytotoxicity studies showed that 1a-1d and (±) 11 were not toxic to NRK-52E cells.

3.
Small ; 17(19): e2005248, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33734598

RESUMO

Tremendous efforts have been dedicated to the development of high-performance electrochemical energy storage devices. The development of lithium- and sodium-ion batteries (LIBs and SIBs) with high energy densities is urgently needed to meet the growing demands for portable electronic devices, electric vehicles, and large-scale smart grids. Anode materials with high theoretical capacities that are based on alloying storage mechanisms are at the forefront of research geared towards high-energy-density LIBs or SIBs. However, they often suffer from severe pulverization and rapid capacity decay due to their huge volume change upon cycling. So far, a wide variety of advanced materials and electrode structures are developed to improve the long-term cyclability of alloying-type materials. This review provides fundamentals of anti-pulverization and cutting-edge concepts that aim to achieve high-performance alloying anodes for LIBs/SIBs from the viewpoint of architectural engineering. The recent progress on the effective strategies of nanostructuring, incorporation of carbon, intermetallics design, and binder engineering is systematically summarized. After that, the relationship between architectural design and electrochemical performance as well as the related charge-storage mechanisms is discussed. Finally, challenges and perspectives of alloying-type anode materials for further development in LIB/SIB applications are proposed.

4.
Bioorg Chem ; 107: 104536, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33342565

RESUMO

Caffeic acid phenethyl ester (CAPE), a bioactive component extracted from propolis of honeybee hives, can inhibit hepatocellular carcinoma (HCC). In order to explore more stable CAPE derivatives, 25 compounds were designed, synthesized, and pharmacologically assessed in vitro and in vivo as anti-tumor agents in HCC. Compounds 8d, 8f, 8l, 8j, and 8k showed favorable antiproliferative activity than other compounds including CAPE in the HCC cell lines. Based on the result of QTRP (Quantitative Thiol Reactivity Profiling), epidermal growth factor receptor (EGFR) and C-terminal Src kinase (CSK) were supposed to the targets of 8f, which was confirmed by binding mode analysis. Furthermore, compounds 8f, 8l, 8j, 8k, 8g, and 8h showed potent inhibitory effects against both CSK and EGFR than other derivatives in an ADP-Glo™ kinase assay. The representative compound, 8f, potently inhibited various tumor growth in murine model including murine hepatocellular carcinoma H22, meanwhile downregulating the EGFR/AKT pathway and enhancing T cell proliferation through inhibition of CSK. Metabolic stability in vitro suggested 8f and 8k were more stable in mouse plasma than CAPE and susceptible to metabolism in liver microsomes. The overall excellent profile of compound 8f makes it a potential candidate for further preclinical investigation.


Assuntos
Ácidos Cafeicos/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Receptores ErbB/antagonistas & inibidores , Neoplasias Hepáticas/tratamento farmacológico , Álcool Feniletílico/análogos & derivados , Quinases da Família src/antagonistas & inibidores , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Sítios de Ligação , Ácidos Cafeicos/química , Ácidos Cafeicos/farmacologia , Carcinoma Hepatocelular/patologia , Domínio Catalítico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Regulação para Baixo/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/metabolismo , Feminino , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Simulação de Acoplamento Molecular , Álcool Feniletílico/química , Álcool Feniletílico/farmacologia , Álcool Feniletílico/uso terapêutico , Relação Estrutura-Atividade , Quinases da Família src/metabolismo
5.
Mol Cell ; 49(5): 997-1009, 2013 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-23333308

RESUMO

The DNA remodeling enzyme FANCM and its DNA-binding partner, FAAP24, constitute a complex involved in the activation of Fanconi anemia (FA) DNA damage response mechanism, but neither gene has distinct patient mutants. In this study, we created isogenic models for both FANCM and FAAP24 and investigated their integrated functions in DNA damage response. We found that FANCM and FAAP24 coordinately facilitate FA pathway activation and suppress sister chromatid exchange. Importantly, we show that FANCM and FAAP24 possess nonoverlapping functions such that FAAP24 promotes ATR-mediated checkpoint activation particularly in response to DNA crosslinking agents, whereas FANCM participates in recombination-independent interstrand crosslink repair by facilitating recruitment of lesion incision activities, which requires its translocase activity. Our data suggest that FANCM and FAAP24 play multiple, while not fully epistatic, roles in maintaining genomic integrity.


Assuntos
DNA Helicases/genética , Proteínas de Ligação a DNA/genética , Genoma Humano , Instabilidade Genômica , DNA/metabolismo , DNA Helicases/metabolismo , Reparo do DNA , Proteínas de Ligação a DNA/metabolismo , Anemia de Fanconi/genética , Anemia de Fanconi/metabolismo , Proteínas de Grupos de Complementação da Anemia de Fanconi , Células HCT116 , Células HEK293 , Humanos
6.
J Sci Food Agric ; 100(12): 4364-4377, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32378212

RESUMO

BACKGROUND: Storage is an essential part of brown rice circulation. During the storage process, the metabolic activity of brown rice is still ongoing, and long-term storage leads to the deterioration of brown rice. Metabolomics analysis was performed using gas chromatography-mass spectrometry to investigate the changes in metabolites of brown rice after storage at 18 °C for 12 months. RESULTS: In terms of quantity, sugar, fatty acids, and other metabolites in brown rice decreased after storage, and alcohols, aldehydes, phenols, and amines increased. A total of 34 differential metabolites were screened. In terms of contents, carbohydrates, amino acids, and fatty acids of brown rice decreased after storage, while those of sugar alcohol, amines, and aldehydes increased after storage. Cluster analysis of the samples at zero storage time revealed that the metabolites expressed least became highly expressed after storage and those expressed highly became low after storage. Metabolic pathway analysis showed that storage significantly influenced the lipid metabolism in brown rice. Palmitoleic acid, cholesterol, linoleic acid, and lauric acid are four key metabolites in lipid metabolism during storage of brown rice. CONCLUSION: Significant changes occurred in quantity and type of brown rice metabolites after storage. Storage has the greatest effect on lipids. Storage caused a 'reverse change' in the metabolites content of brown rice. The results obtained may help in understanding the changes in metabolites profile and delaying of the quality deterioration of brown rice during storage.


Assuntos
Armazenamento de Alimentos/métodos , Oryza/química , Álcoois/análise , Álcoois/metabolismo , Aldeídos/análise , Aldeídos/metabolismo , Aminoácidos/análise , Aminoácidos/metabolismo , Ácidos Graxos/análise , Ácidos Graxos/metabolismo , Cromatografia Gasosa-Espectrometria de Massas , Metabolômica , Oryza/metabolismo , Sementes/química , Sementes/metabolismo
7.
Blood ; 117(1): 156-64, 2011 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-20971952

RESUMO

Homoharringtonine (HHT) is a plant alkaloid that inhibits the elongation phase of translation that is currently in clinical trials. Because the intrinsically short-lived antiapoptotic protein myeloid cell leukemia-1 (Mcl-1) has been reported to support the survival of chronic lymphocytic leukemia (CLL) cells, we hypothesized that inhibition of protein synthesis by HHT would decrease Mcl-1 expression and induce apoptosis in CLL. In primary CLL cells, HHT induced significant apoptosis independent of the prognostic characteristics of the patients. This was associated with inhibition of translation and decreased Mcl-1 levels in CLL cells. Mcl-1 reduction was evident as early as 2 hours and continued to decrease in the next 6-8 hours, whereas cell death started in 2 hours and continued to increase for 24 hours. Reduction of the Mcl-1 level was due to translation inhibition and proteasome degradation rather than to transcription inhibition or caspase cleavage. HHT and the transcription inhibitor SNS-032 induced synergistic cell killing. Although stromal cells induced Mcl-1 expression and protected CLL cells from the toxicity of fludarabine, this induction was reversed by HHT, which overcame stromal cell-mediated protection. Thus, these results provide a rationale for clinical development of HHT in CLL as single agent or in combinations.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Harringtoninas/farmacologia , Leucemia Linfocítica Crônica de Células B/patologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Western Blotting , Proliferação de Células/efeitos dos fármacos , Sinergismo Farmacológico , Quimioterapia Combinada , Mepesuccinato de Omacetaxina , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/metabolismo , Linfócitos/efeitos dos fármacos , Pessoa de Meia-Idade , Membranas Mitocondriais/efeitos dos fármacos , Proteína de Sequência 1 de Leucemia de Células Mieloides , Oxazóis/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/genética , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Estromais/efeitos dos fármacos , Tiazóis/farmacologia , Células Tumorais Cultivadas
8.
Proc Natl Acad Sci U S A ; 107(40): 17274-9, 2010 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-20855601

RESUMO

The creation of accessible DNA in the context of chromatin is a key step in many DNA functions. To reveal how ATP-dependent chromatin remodeling activities impact DNA repair, we constructed mammalian genetic models for the INO80 chromatin remodeling complex and investigated the impact of loss of INO80 function on the repair of UV-induced photo lesions. We showed that deletion of two core components of the INO80 complex, INO80 and ARP5, significantly hampered cellular removal of UV-induced photo lesions but had no significant impact on the transcription of nucleotide excision repair (NER) factors. Loss of INO80 abolished the assembly of NER factors, suggesting that prior chromatin relaxation is important for the NER incision process. Ino80 and Arp5 are enriched to UV-damaged DNA in an NER-incision-independent fashion, suggesting that recruitment of the remodeling activity likely takes place during the initial stage of damage recognition. These results demonstrate a critical role of INO80 in creating DNA accessibility for the NER pathway and provide direct evidence that repair of UV lesions and perhaps most bulky adduct lesions requires chromatin reconfiguration.


Assuntos
Montagem e Desmontagem da Cromatina , Dano ao DNA , Reparo do DNA , DNA , Proteínas de Saccharomyces cerevisiae/metabolismo , DNA/genética , DNA/metabolismo , DNA/efeitos da radiação , Técnicas de Silenciamento de Genes , Subunidades Proteicas/genética , Subunidades Proteicas/metabolismo , Saccharomyces cerevisiae/efeitos dos fármacos , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Raios Ultravioleta
9.
Sci Rep ; 13(1): 3759, 2023 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-36882567

RESUMO

This study aimed to develop a nomogram for predicting the progression-free survival (PFS) of testicular germ cell tumors (TGCT) patients based on DNA methylation signature and clinicopathological characteristics. The DNA methylation profiles, transcriptome data, and clinical information of TGCT patients were obtained from the Cancer Genome Atlas (TCGA) database. Univariate Cox, lasso Cox, and stepwise multivariate Cox regression were applied to identify a prognostic CpG sites-derived risk signature. Differential expression analysis, functional enrichment analysis, immunoinfiltration analysis, chemotherapy sensitivity analysis, and clinical feature correlation analysis were performed to elucidate the differences among risk groups. A prognostic nomogram integrating CpG sites-derived risk signature and clinicopathological features was further established and evaluated likewise. A risk score model based on 7 CpG sites was developed and found to exhibit significant differences among different survival, staging, radiotherapy, and chemotherapy subgroups. There were 1452 differentially expressed genes between the high- and low-risk groups, with 666 being higher expressed and 786 being lower expressed. Genes highly expressed were significantly enriched in immune-related biological processes and related to T-cell differentiation pathways; meanwhile, down-regulated genes were significantly enriched in extracellular matrix tissue organization-related biological processes and involved in multiple signaling pathways such as PI3K-AKT. As compared with the low-risk group, patients in the high-risk group had decreased lymphocyte infiltration (including T-cell and B-cell) and increased macrophage infiltration (M2 macrophages). They also showed decreased sensitivity to etoposide and bleomycin chemotherapy. Three clusters were obtained by consensus clustering analysis based on the 7 CpG sites and showed distinct prognostic features, and the risk scores in each cluster were significantly different. Multivariate Cox regression analysis found that the risk scores, age, chemotherapy, and staging were independent prognostic factors of PFS of TGCT, and the results were used to formulate a nomogram model that was validated to have a C-index of 0.812. Decision curve analysis showed that the nomogram model was superior to other strategies in the prediction of PFS of TGCT. In this study, we successfully established CpG sites-derived risk signature, which might serve as a useful tool in the prediction of PFS, immunoinfiltration, and chemotherapy sensitivity for TGCT patients.


Assuntos
Metilação de DNA , Neoplasias Embrionárias de Células Germinativas , Humanos , Metilação de DNA/genética , Intervalo Livre de Progressão , Fosfatidilinositol 3-Quinases/genética , Neoplasias Embrionárias de Células Germinativas/genética
10.
Trials ; 24(1): 349, 2023 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-37221541

RESUMO

BACKGROUND: Night shift work-related disturbed biological rhythm and insufficient sleep affect the functioning of brain activity and thus impair cognitive performance and mood state, which potentially leads to negative and even devastating results for both individuals and patients. A virtual reality (VR)-based restorative environment has shown to be an effective new technique to reduce stress and improve cognitive performance, but little is known about its mechanism of improving neuronal activity and connectivity. METHODS: This is a randomized, controlled, single-center clinical trial. A total of 140 medical staff will be enrolled and randomized in a 1:1 allocation to either the VR immersion group (intervention group) or the control group. In the morning after the night shift, the participants in the intervention group will watch 360° panoramic videos of immersive VR natural restorative environments for 10 min, while the participants in the control group will just rest for 10 min. Assessments of abbreviated Profile of Mood States Questionnaire (POMS) and verbal fluency task (VFT) performances, as well as oxygenated hemoglobin (oxy-Hb) and deoxygenated hemoglobin (deoxy-Hb) and total hemoglobin concentration acquired by functional near-infrared spectroscopy (fNIRS) will be performed at baseline (day work), the morning after night shift but before the intervention (previous) and after intervention (post). Data collected after a night shift will be compared to baseline performance as well as between the two groups. DISCUSSION: This trial will investigate the effects of the night shift and VR-based restorative environment intervention on mood, cognitive performance, and neuronal activity and connectivity. A positive result in this trial could encourage hospitals to apply VR technology to reduce physical and mental dysfunction during of night shifts among medical staff in every department. Furthermore, the findings from this study will contribute to understanding the underlying neuromodulation mechanisms of how restorative environments influence mood and cognition. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2200064769 . Registered on 17 October 2022.


Assuntos
Afeto , Corpo Clínico , Humanos , China , Oxiemoglobinas , Córtex Pré-Frontal , Ensaios Clínicos Controlados Aleatórios como Assunto
11.
Am J Mens Health ; 17(3): 15579883231183770, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37381630

RESUMO

To evaluate the clinical efficacy of pelvic floor low-frequency electrical stimulation combined with anus lifting training in the treatment of urinary incontinence after radical prostatectomy in a Chinese cohort. Fifty-five patients with urinary incontinence after radical prostatectomy were randomly divided into treatment group and control group. Patients in control group received only anus lifting training therapy, while treatment group combined with pelvic floor low-frequency electrical stimulation. The urinary control including urinary incontinence questionnaire (ICI-Q-SF), urinary incontinence quality of life (I-QOL), visual analogue scale (VAS), and pelvic floor muscle strength assessment (Glazer) of the two groups of patients before treatment and every week was recorded for statistical analysis. There was a statistically significant difference between treatment group and control group in the urinary control curve. The scores of ICI-Q-SF, I-QOL, VAS, and Glazer in the treatment group after 2 weeks were statistically different from those before treatment, and effects were accumulating with the extension of treatment time. Compared with the control group, the scores of treatment group in the 2 to 10 weeks improved more significantly. Especially, in the sixth week, total effective rate of treatment group was significantly better than that of control group (74.07% [20/27], 35.71% [10/28], p < .05). The difference between two groups gradually narrowed after 10 weeks and no significant difference after 10 weeks of treatment between two groups. Pelvic floor low-frequency electrical stimulation combined with anus lifting training after radical prostatectomy can significantly shorten the recovery time of urinary incontinence in patients after radical prostatectomy.


Assuntos
Qualidade de Vida , Incontinência Urinária , Masculino , Humanos , Canal Anal , População do Leste Asiático , Remoção , Prostatectomia/efeitos adversos , Incontinência Urinária/etiologia , Incontinência Urinária/terapia , Estimulação Elétrica
12.
Adv Mater ; 34(52): e2200945, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35362162

RESUMO

Alkali (lithium, sodium)-based second batteries are considered one of the brightest candidates for energy-storage applications in order to utilize the random and intermittent renewable energy to achieve carbon neutrality. Conventional lithium/sodium batteries containing liquid organic electrolytes are vulnerable to electrolytes leakage and even combustion, which hinders their large-scale and reliable application. All-solid-state electrolytes which are considered to have better safety have been developed in recent years. However, most of them suffer from low ionic conductivity and large interfacial resistance with the electrode. Ionogel-electrolyte membranes composed of ionic liquids and solid matrices, have attracted much attention because of their nonvolatility, nonflammability, and superior chemical and electrochemical properties. This review focuses on the most recent advances of ionogel electrolytes that sprang up with the emerging demand and progress of safe lithium/sodium batteries. The ionogel-electrolyte membranes are discussed based on the framework components and preparation methods. Their structure and properties, including ionic conductivity, mechanical strength, electrochemical stabilities, and so on, are demonstrated in combination with their applications. The current challenges and insights on the future development of ionogel electrolytes for advanced safe lithium/sodium batteries are also proposed.

13.
PLoS One ; 17(3): e0265097, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35259197

RESUMO

The influence of compaction methods such as the Marshall compaction method (MCM), vibration compaction method (VCM) and gyration compaction method (GCM), on the performance of stone mastic asphalt (SMA-13) mixture has yet to be explored. Therefore, to compare the influences of compaction methods and work on the physical and mechanical properties of SMA-13 mixture, the volume parameters, mechanical properties, and gradation changes of SMA-13 mixture specimens prepared under different vibration compaction times, Marshall double-compaction numbers, and gyration compaction numbers were studied. The compaction method for SMA-13 mixture design was also proposed under the principle of optimum properties. Results demonstrate that the asphalt aggregate ratio and compaction work directly affect the volumetric properties (VV, VFA, and VMA) of asphalt mixture specimens while the raw material and mineral aggregate gradation were fixed. The influence of compaction work on physical properties is greater than that of asphalt aggregate ratio. The mechanical strength of VCM and GCM specimens is higher than that of MCM specimens under the same compaction work and the optimum asphalt aggregate ratio. With the increase in compaction work, the mechanical properties of SMA-13 mixture are improved at the same compaction method and the optimum asphalt aggregate ratio. The aggregate gradation of the SMA-13 mixture before and after compacted using VCM and GCM changes minimally compared with that of the SMA-13 mixture compacted by MCM. Thus, the compaction methods of VCM65 and GCM130 were recommended for SMA-13 mixture design.


Assuntos
Minerais
14.
Front Nutr ; 9: 893270, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35571892

RESUMO

This study aimed to elucidate the potential regulatory mechanism of mung bean peptides (MBPs) on glucolipid metabolism in insulin-resistant mice induced by high-fat diet (HFD) using untargeted serum metabolomics, enzyme linked immunosorbent assay (ELISA), intraperitoneal injection glucose tolerance test (IPGTT), insulin tolerance test (IPITT), and hematoxylin-eosin staining (H&E). The regulatory effect of MBPs for alleviating insulin resistance was studied by measuring body weight, fasting blood glucose (FBG) and serum insulin levels, C-Peptide levels, inflammatory and antioxidant factors, and histopathological observation of C57BL/6 mice. The experimental results showed that dietary intervention with MBPs (245 mg/kg/d) for 5 weeks significantly relieved insulin resistance in HFD mice. The body weight, insulin resistance index, and the levels of FBG, C-Peptide, IL-6, TNF-α, and MDA in the serum of HFD mice significantly decreased (P < 0.05). Conversely, SOD content and pancreatic ß cell function index significantly increased (P < 0.05), and the damaged pancreatic tissue was repaired. One biomarker associated with insulin resistance was glycine. In addition, there were four important differential metabolites: pyroglutamate, D-glutamine, aminoadipic acid, and nicotinamide, involved in 12 metabolic pathway changes. It was found that MBPs may regulate amino acid, glycerol phospholipid, fatty acid, alkaloid, and nicotinamide metabolism to regulate the metabolic profile of HFD mice in a beneficial direction.

15.
Materials (Basel) ; 15(6)2022 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-35329588

RESUMO

To study the mechanical properties of cement-graded crushed stone for use in the transition sections of intercity railways, the growth laws governing unconfined compressive strength, splitting strength and resilience modulus of cement-graded crushed stone and their influencing factors were studied by the vertical vibration compaction method (VVCM). The strength growth equations of cement-graded crushed stone are proposed, and strength prediction equations are established. The research shows the unconfined compressive strength, splitting strength and resilience modulus of cement-graded crushed stone with a strong interlocked skeleton density type (VGM-30) are significantly enhanced to 20, 20 and 17% higher, respectively, than those of standard cement-graded crushed stone. The growth law of mechanical properties of cement-graded crushed stone is similar, with the fastest growth occurring before 14 days, and the rate decreasing after 28 days. The strength growth tended to be stable after 90 days, increasing with the increase in curing time, compaction coefficient and cement dosage. The correlation coefficients (R2) of the strength growth prediction models were found to be 0.99, 0.97, and 0.99, respectively. These values can be used to accurately predict the strength growth curve. This paper verifies the superiority of VGM-30 gradation through laboratory tests, providing a reference for gradation selection in the construction of intercity railway transition sections.

16.
Mol Pharmacol ; 80(2): 321-7, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21546556

RESUMO

4-Hydroxy-5-methoxy-2,3-dihydro-1H-[1,3]benzodioxolo[5,6-c]pyrrolo[1,2-f]-phenanthridium chloride (NK314) is a benzo[c] phenanthridine alkaloid that inhibits topoisomerase IIα, leading to the generation of DNA double-strand breaks (DSBs) and activating the G(2) checkpoint pathway. The purpose of the present studies was to investigate the DNA intercalating properties of NK314, to evaluate the DNA repair mechanisms activated in cells that may lead to resistance to NK314, and to develop mechanism-based combination strategies to maximize the antitumor effect of the compound. A DNA unwinding assay indicated that NK314 intercalates in DNA, a property that likely cooperates with its ability to trap topoisomerase IIα in its cleavage complex form. The consequence of this is the formation of DNA DSBs, as demonstrated by pulsed-field gel electrophoresis and H2AX phosphorylation. Clonogenic assays demonstrated a significant sensitization in NK314-treated cells deficient in DNA-dependent protein kinase (DNA-PK) catalytic subunit, Ku80, ataxia telangiectasia mutated (ATM), BRCA2, or XRCC3 compared with wild-type cells, indicating that both nonhomologous end-joining and homologous recombination DNA repair pathways contribute to cell survival. Furthermore, both the DNA-PK inhibitor 8-(4-dibenzothienyl)-2-(4-morpholinyl)-4H-1-benzopyran-4-one (NU7441) and the ATM inhibitor 2-(4-morpholinyl)-6-(1-thianthrenyl)-4H-pyran-4-one (KU55933) significantly sensitized cells to NK314. We conclude that DNA-PK and ATM contribute to cell survival in response to NK314 and could be potential targets for abrogating resistance and maximizing the antitumor effect of NK314.


Assuntos
Antígenos de Neoplasias/metabolismo , Ataxia Telangiectasia/enzimologia , Ataxia Telangiectasia/patologia , Proteínas de Ciclo Celular/fisiologia , DNA Topoisomerases Tipo II/metabolismo , Proteína Quinase Ativada por DNA/fisiologia , Proteínas de Ligação a DNA/antagonistas & inibidores , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/fisiologia , Fenantrenos/farmacologia , Proteínas Serina-Treonina Quinases/fisiologia , Inibidores da Topoisomerase/farmacologia , Proteínas Supressoras de Tumor/fisiologia , Antineoplásicos/farmacologia , Ataxia Telangiectasia/tratamento farmacológico , Proteínas Mutadas de Ataxia Telangiectasia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Humanos
17.
PLoS One ; 16(9): e0258113, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34591939

RESUMO

A numerical model of the dynamic triaxial test of graded crushed stone was established based on DEM (Discrete Element Method) to study its dynamic characteristics. The influence of test conditions on simulation results was analysed through numerical simulation. A method for determining the test conditions was proposed, and the reliability of the simulation was verified. We studied the accumulation rule and failure standard of permanent deformation. We then determined the critical failure stress level. The prediction model of permanent deformation cumulative failure was then established. When the calculation time step is greater than 1E-4 s per step, the stability of the dynamic triaxial numerical test of graded crushed stone is good. The plastic deformation of the simulated specimen tends to be stable under 10,000 dynamic loading cycles. When the specimen height and diameter are greater than 20 and 10 cm, respectively, the specimen size has little influence on the simulated axial strain. The recommended specimen size is 10 cm (Ф) × 20 cm (h). The action time curve results are consistent with indoor measurement results, which proves the simulation's reliability. The critical failure stress is approximately linearly correlated with the confining pressure, and the cumulative failure equation of plastic deformation is established.


Assuntos
Simulação por Computador , Modelos Teóricos , Estresse Mecânico , Humanos , Reprodutibilidade dos Testes
18.
Materials (Basel) ; 14(13)2021 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-34203216

RESUMO

Herein, the effects of the contents of emulsified asphalt, waterborne epoxy resin emulsion, and curing agent on the permeability, bond shear strength, water stability, and aging resistance of epoxy-emulsified asphalt were studied. A formulation of epoxy-emulsified asphalt as a fog-sealing adhesive material was recommended, and a comparison between the fabricated adhesive material and a traditional Chinese fog-sealing adhesive material was conducted to verify the technical performance of the new material. In addition, the strength formation mechanism of the epoxy-emulsified asphalt was revealed via microcosmic analysis. Results show that the curing agent content mainly affects the permeability of epoxy-emulsified asphalt, and the emulsified asphalt content significantly affects the bond shear strength, water stability, and aging resistance. Moreover, the ratio of waterborne epoxy resin emulsion to the curing agent (epoxy ratio) has a certain effect on the bond shear strength. In the recommended formulation (a high-permeability and high-bonding fog-sealing adhesive material, which can be referred to simply as HPBFA), emulsified asphalt accounts for 80% of the total mass of the mixture, and the epoxy ratio is 2:1-3:1. It can improve air permeability, bond shear strength, water stability and aging resistance. The HPBFA-cured material exhibits a continuous three-dimensional network structure, hydrophobic surface, and large contact angle. Furthermore, the initial thermal weight loss temperature of the HPBFA-cured material is significantly higher than the environmental aging temperature. Additionally, the maximum temperature decomposition range is 0-160 °C, indicating improved strength, wear resistance, permeability, and aging resistance of the material.

19.
ACS Appl Mater Interfaces ; 13(14): 16445-16453, 2021 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-33793195

RESUMO

The demand for fast-charging of lithium-ion batteries (LIBs) in modern electric transportation and wearable electronics is rapidly growing. However, commercially available graphite anodes still suffer from slow kinetics of lithium-ion diffusion and severe safety concerns of lithium plating when achieving the fast-charging goal. Here, it is demonstrated that the Li-ion diffusion kinetics of orthorhombic Nb2O5 nanotubes (T-Nb2O5 NTs) is enhanced by atomically precise manufacturing of nanoarchitectures. The controlled fabrication of T-Nb2O5 NTs with wall thicknesses from 24 to 43 nm is realized via atomic layer deposition (ALD) using electrospun polyacrylonitrile nanofibers as a sacrificing template. The wall thickness of T-Nb2O5 NTs can be precisely tuned by adjusting the number of ALD cycles. The relationship between the wall thicknesses and electrochemical performances is investigated in detail. The electrochemical kinetic analysis suggests that the lithium storage in T-Nb2O5 NTs is dominated by surface and intercalation pseudocapacitance. The morphology of T-Nb2O5 crystallites is found to have significant effects on the Li-ion insertion/extraction kinetics and the performance of the electrodes in LIBs. The resulting T-Nb2O5 NTs exhibit fast charge-storage kinetics and enable highly reversible insertion/extraction of Li ions without a phase change. This work may open up a new avenue for further development of intercalation-pseudocapacitive nanostructured materials for high-rate and ultrastable energy-storage devices.

20.
PLoS One ; 16(7): e0253199, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34197469

RESUMO

The effects of cement dosage, compaction coefficient, molding method (vertical vibration method and static pressure method), and dry-wet and freeze-thaw cycles on the mechanical strength of cement-improved loess (CIL) were studied to reveal its strength degradation law under dry-wet and freeze-thaw cycles. Results show that when using the vertical vibration molding method, the strength degradation effect of CIL can be improved by increasing the cement dosage and compaction coefficient; however, it is not obvious. Under the action of dry-wet cycle, damages, such as voids and cracks of CIL, develop continuously. Further, the strength deteriorates continuously and does not decrease after more than 15 dry-wet cycles. Therefore, the dry-wet cycle degradation system is selected by considering the most unfavorable conditions. In the process of freeze-thaw alternation, the pores and fissures of CIL develop and evolve continuously and the strength deteriorates continuously under the joint influence of water and low temperature. The strength tends to become stable after more than 12 freeze-thaw cycles. According to the safety principle, the deterioration coefficient of the freeze-thaw cycles is 0.3.


Assuntos
Cinza de Carvão/química , Materiais de Construção/análise , Congelamento , Sedimentos Geológicos/química , Vibração , Resistência ao Cisalhamento , Solo
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