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Recently, growing attention has been given to new classes of bioactive lipid mediators derived from ω-3 polyunsaturated fatty acids, such as docosahexaenoic acid (DHA), especially in the context of their role as endogenous signal modulators. One such molecule is 17-oxo-DHA, generated from DHA by the action of COX2 and a dehydrogenase. The redox-sensitive transcription factor, Nrf2 plays a key role in cellular stress responses. In the present study, the effects of 17-oxo-DHA on Nrf2-mediated expression of cytoprotective enzymes were examined in mouse skin in vivo and cultured murine epidermal JB6 cells. Topical application of 17-oxo-DHA markedly elevated the nuclear localization of Nrf2 and expression of heme oxygenase-1 (HO-1) and NAD(P)H:quinone oxidoreductase-1 in hairless mouse skin. In contrast to 17-oxo-DHA, the non-electrophilic metabolic precursor 17-hydroxy-DHA was a much weaker inducer of Nrf2 activation and its target protein expression. Likewise, 17-oxo-DHA significantly enhanced nuclear translocation and transcriptional activity of Nrf2 with concomitant upregulation of HO-1 expression in cultured JB6 cells. 17-Oxo-DHA was a much stronger inducer of Nrf2-mediated antioxidant response than its parent molecule, DHA. HO-1 expression was abolished in Nrf2 knockdown JB6 cells or embryo fibroblasts from Nrf2 knock out mice. 17-Oxo-DHA also markedly reduced the level of Keap1 protein by inducing ubiquitination. Mutation of Cys151 and Cys273 in Keap1 abrogated 17-oxo-DHA-induced ubiquitination and proteasome-mediated degradation of Keap1 as well as HO-1 expression, suggesting that these cysteine residues are putative sites for 17-oxo-DHA binding. Further, Keap1 degradation stimulated by 17-oxo-DHA coincided with accumulation of the autophagy substrate, p62/SQSTM1.
Assuntos
Ácidos Docosa-Hexaenoicos/farmacologia , Epiderme/metabolismo , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Heme Oxigenase-1/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Animais , Ácidos Docosa-Hexaenoicos/metabolismo , Epiderme/efeitos dos fármacos , Feminino , Células HEK293 , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/química , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Camundongos , Simulação de Acoplamento Molecular , Conformação ProteicaRESUMO
Semiconductor quantum well structures have been critical to the development of modern photonics and solid-state optoelectronics. Quantum level tunable structures have introduced new transformative device applications and afforded a myriad of groundbreaking studies of fundamental quantum phenomena. However, noncolloidal, III-V compound quantum well structures are limited to traditional semiconductor materials fabricated by stringent epitaxial growth processes. This report introduces artificial multiple quantum wells (MQWs) built from CsPbBr3 perovskite materials using commonly available thermal evaporator systems. These perovskite-based MQWs are spatially aligned on a large-area substrate with multiple stacking and systematic control over well/barrier thicknesses, resulting in tunable optical properties and a carrier confinement effect. The fabricated CsPbBr3 artificial MQWs can be designed to display a variety of photoluminescence (PL) characteristics, such as a PL peak shift commensurate with the well/barrier thickness, multiwavelength emissions from asymmetric quantum wells, the quantum tunneling effect, and long-lived hot-carrier states. These new artificial MQWs pave the way toward widely available semiconductor heterostructures for light-conversion applications that are not restricted by periodicity or a narrow set of dimensions.
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Carbonic anhydrase IX is overexpressed in many solid tumors including hypoxic tumors and is a potential target for cancer therapy and diagnosis. Reported imaging agents targeting CA-IX are successful mostly in clear cell renal carcinoma as SKRC-52 and no candidate was approved yet in clinical trials for imaging of CA-IX. To validate CA-IX as a valid target for imaging of hypoxic tumor, we designed and synthesized novel [18F]-PET tracer (1) based on acetazolamide which is one of the well-known CA-IX inhibitors and performed imaging study in CA-IX expressing hypoxic tumor model as 4T1 and HT-29 in vivo models other than SKRC-52. [18F]-acetazolamide (1) was found to be insufficient for the specific accumulation in CA-IX expressing tumor. This study might be useful to understand in vivo behavior of acetazolamide PET tracer and can contribute to the development of successful PET imaging agents targeting CA-IX in future. Additional study is needed to understand the mechanism of poor targeting of CA-IX, as if CA-IX is not reliable as a sole target for imaging of CA-IX expressing hypoxic solid tumors.
Assuntos
Acetazolamida/química , Anidrase Carbônica IX/análise , Inibidores da Anidrase Carbônica/química , Carcinoma de Células Renais/enzimologia , Neoplasias Renais/enzimologia , Tomografia por Emissão de Pósitrons , Acetazolamida/síntese química , Acetazolamida/farmacocinética , Animais , Anidrase Carbônica IX/biossíntese , Anidrase Carbônica IX/metabolismo , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/farmacocinética , Carcinoma de Células Renais/diagnóstico , Radioisótopos de Flúor , Humanos , Neoplasias Renais/diagnóstico , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias Experimentais/diagnóstico , Neoplasias Experimentais/enzimologia , Distribuição TecidualRESUMO
Understanding defect chemistry, particularly ion migration, and its significant effect on the surface's optical and electronic properties is one of the major challenges impeding the development of hybrid perovskite-based devices. Here, using both experimental and theoretical approaches, we demonstrated that the surface layers of the perovskite crystals may acquire a high concentration of positively charged vacancies with the complementary negatively charged halide ions pushed to the surface. This charge separation near the surface generates an electric field that can induce an increase of optical band gap in the surface layers relative to the bulk. We found that the charge separation, electric field, and the amplitude of shift in the bandgap strongly depend on the halides and organic moieties of perovskite crystals. Our findings reveal the peculiarity of surface effects that are currently limiting the applications of perovskite crystals and more importantly explain their origins, thus enabling viable surface passivation strategies to remediate them.
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α-Pinene is a major monoterpene of the pine tree essential oils. It has been reported that α-pinene shows anxiolytic and hypnotic effects upon inhaled administration. However, hypnotic effect by oral supplementation and the molecular mechanism of α-pinene have not been determined yet. By combining in vivo sleep behavior, ex vivo electrophysiological recording from brain slices, and in silico molecular modeling, we demonstrate that (-)-α-pinene shows sleep enhancing property through a direct binding to GABAA-benzodiazepine (BZD) receptors by acting as a partial modulator at the BZD binding site. The effect of (-)-α-pinene on sleep-wake profiles was evaluated by recording electroencephalogram and electromyogram. The molecular mechanism of (-)-α-pinene was investigated by electrophysiology and molecular docking study. (-)-α-pinene significantly increased the duration of non-rapid eye movement sleep (NREMS) and reduced the sleep latency by oral administration without affecting duration of rapid eye movement sleep and delta activity. (-)-α-pinene potentiated the GABAA receptor-mediated synaptic response by increasing the decay time constant of sIPSCs in hippocampal CA1 pyramidal neurons. These effects of (-)-α-pinene on sleep and inhibitory synaptic response were mimicked by zolpidem, acting as a modulator for GABAA-BZD receptors, and fully antagonized by flumazenil, an antagonist for GABAA-BZD receptor. (-)-α-pinene was found to bind to aromatic residues of α1- and -γ2 subunits of GABAA-BZD receptors in the molecular model. We conclude that (-)-α-pinene enhances the quantity of NREMS without affecting the intensity of NREMS by prolonging GABAergic synaptic transmission, acting as a partial modulator of GABAA-BZD receptors and directly binding to the BZD binding site of GABAA receptor.
Assuntos
Benzodiazepinas/metabolismo , Movimentos Oculares/efeitos dos fármacos , Monoterpenos/farmacologia , Pinus/química , Óleos de Plantas/farmacologia , Receptores de GABA-A/metabolismo , Sono/efeitos dos fármacos , Animais , Monoterpenos Bicíclicos , Sítios de Ligação , Flumazenil/química , Flumazenil/farmacologia , Potenciais Pós-Sinápticos Inibidores/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Modelos Moleculares , Monoterpenos/química , Pentobarbital , Piridinas/química , Piridinas/farmacologia , Sono REM/efeitos dos fármacos , Fatores de Tempo , Vigília/efeitos dos fármacos , ZolpidemRESUMO
A series of new 2-anilinoquinolines possessing 3-(morpholino or 4-methylpiperazin-1-yl)propoxy moiety at C5 of quinoline has been designed and synthesized as potential anticancer agents. Their antiproliferative activities were evaluated against a panel of 60 cancer cell lines at NCI and compared with gefitinib as a reference compound. Most of the tested compounds displayed potent and broad spectrum antiproliferative activities. Compounds 7d, 7f and 7g showed strong inhibitory and lethal effects at 10µM concentration. Moreover, they manifested superior potencies and efficacies than gefitinib across the most tested cell lines. Compound 7d, with 4-chloro-3-trifluoromethylphenyl group, proved to be the most potent and efficacious derivative in this series, with mean GI50 and TGI values of 1.62µM and 3.47µM, respectively. Kinase screening of 7d against a panel of 47 oncogenic kinases revealed its selective inhibitory effect (96% inhibition) towards TrkA kinase. Furthermore, the most potent compounds showed low cytotoxic effects against HFF-1 normal cell line.
Assuntos
Antineoplásicos/farmacologia , Morfolinos/farmacologia , Naftalenos/farmacologia , Fosfotransferases/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Quinolinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Morfolinos/química , Naftalenos/química , Fosfotransferases/metabolismo , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Quinolinas/química , Relação Estrutura-AtividadeRESUMO
Protease-activated receptor 2 (PAR2) is a G protein-coupled receptor, mediating inflammation and pain signaling in neurons, thus it is considered to be a potential therapeutic target for inflammatory diseases. In this study, we performed a ligand-based virtual screening of 1.6 million compounds by employing a common-feature pharmacophore model and two-dimensional similarity search to identify a new PAR2 antagonist. The common-feature pharmacophore model was established based on the biological screening results of our in-house library. The initial virtual screening yielded a total number of 47 hits, and additional biological activity tests including PAR2 antagonism and anti-inflammatory effects resulted in a promising candidate, compound 43, which demonstrated an IC50 value of 8.22 µM against PAR2. In next step, a PAR2 homology model was constructed using the crystal structure of the PAR1 as a template to explore the binding mode of the identified ligands. A molecular docking method was optimized by comparing the binding modes of a known PAR2 agonist GB110 and antagonist GB83, and applied to predict the binding mode of our hit compound 43. In-depth docking analyses revealed that the hydrophobic interaction with Phe243(5.39) is crucial for PAR2 ligands to exert antagonistic activity. MD simulation results supported the predicted docking poses that PAR2 antagonist blocked a conformational rearrangement of Na(+) allosteric site in contrast to PAR2 agonist that showed Na(+) relocation upon GPCR activation. In conclusion, we identified new a PAR2 antagonist together with its binding mode, which provides useful insights for the design and development of PAR2 ligands.
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Receptor PAR-2/antagonistas & inibidores , Receptor PAR-2/metabolismo , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Sequência de Aminoácidos , Animais , Células CHO , Cricetulus , Descoberta de Drogas , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Receptor PAR-2/química , Alinhamento de SequênciaRESUMO
Herein, we report compound KST9046, a new agent possessing quinazoline-urea scaffold. Preliminary biological evaluation done by the National Cancer Institute (NCI), USA, showed a great inhibitory effect of KST9046 over the 60 cell-line tumor panel. Accordingly, it was selected for a dose-response assay; a broad spectrum antiproliferative activity with GI(50) ranging from 1.3 to 3.9 µM was exerted. To explore a potential kinase inhibitory effect, KST9046 was applied at a single dose of 10 µM against a kinase panel of 347 different enzymes representing >50% of the predicted human protein kinome. Interestingly, selective inhibition of 76% was observed on DDR1 kinase. Further, KST9046 showed an IC(50) value of 4.38 µM for DDR1. A molecular docking model presented KST9046 as a potential type III inhibitor for DDR1 kinase with an allosteric mode of interaction, which may offer an explanation for its selectivity. As further investigation, CYP450 assay was carried out for KST9046, it showed a promising toxicity profile against four different isoforms. Based on these findings, KST9046 can be further evaluated as a promising safe new hit for the development of broad spectrum anticancer agents with a selectivity for DDR1 kinase.
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Antineoplásicos/farmacologia , Descoberta de Drogas , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/farmacologia , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Ureia/análogos & derivados , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Receptor com Domínio Discoidina 1 , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Quinazolinas/síntese química , Quinazolinas/química , Receptores Proteína Tirosina Quinases/metabolismo , Relação Estrutura-Atividade , Ureia/síntese química , Ureia/química , Ureia/farmacologiaRESUMO
A series of novel picolinamide based benzothiazoles (17 final compounds), targeting both wild-type and the most resistant T315I mutant of Bcr-Abl kinase, has been designed and synthesized. Moreover, a selected array (8 compounds) was evaluated for its antiproliferative activity over a panel of 60 cancer cell lines. Compound 5l was the most potent derivative against both native and T315I mutant ABL with IC50 values of 18.2 and 39.9nM, respectively, and showed highly selective inhibitory activity (89.8%) towards the Bcr-Abl dependent leukemia cell (K-562) at 10µM concentration. Significance of C6-oxypicolinamide moiety and SAR study for the C2 aliphatic side chain of benzothiazole are discussed in detail.
Assuntos
Antineoplásicos/farmacologia , Benzotiazóis/farmacologia , Proliferação de Células/efeitos dos fármacos , Proteínas Oncogênicas v-abl/antagonistas & inibidores , Ácidos Picolínicos/química , Amidas/química , Benzotiazóis/química , Linhagem Celular Tumoral , HumanosRESUMO
A series of azacyclic compounds substituted with isoxazole and 5-substituted isoxazolines were synthesized as acyclic modifications of the oxime class M1 mACh receptor agonist. Among them, 3-(tetrahydropyrin-3-yl)-5-(2-pyrrolodin-1-yl)isoxazoline compound 4f displayed potent and selective M1 mACh receptor agonist activity in the functional calcium mobilization assay (EC50=31 nM). Introduction of 2-pyrrolidinone and 3-tetrahydropyridine groups are pivotal to the high potency. Moreover, 4f was found to facilitate non-amyloidogenic amyloid precursor protein (APP) processing by significantly increasing ERK1/2 phosphorylation and sAPPα secretion, known disease-modifying effects related to M1 mAChR agonists in Alzheimer's disease (AD).
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Isoxazóis/farmacologia , Receptor Muscarínico M1/agonistas , Relação Dose-Resposta a Droga , Humanos , Isoxazóis/síntese química , Isoxazóis/química , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Protease-activated receptor 2 (PAR2) is a member of G protein-coupled receptor and its activation initiates diverse inflammatory responses. Recent studies suggest that antagonists of PAR2 may provide a novel therapeutic strategy for inflammatory diseases. In this study, we have developed a series of 2-aryloxy-4-amino-quinazoline derivatives as PAR2 antagonists and examined their effects against LPS-induced inflammatory responses in RAW 264.7 macrophages. Among these derivatives, compound 2f displayed the greatest antagonistic activity with the IC50 value of 2.8µM. Binding modes of the newly identified PAR2 antagonists were analyzed by molecular docking using IFD/MM-GBSA methods in the putative binding site of PAR2 homology model. Moreover, 2f demonstrated significant inhibitory effects on the LPS-activated pro-inflammatory mediators including nitric oxide (NO), prostaglandin E2 (PGE2), interleukin-1ß (IL-1ß), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) through the regulation of various intracellular signaling pathways involving nuclear factor-κB (NF-κB), activator protein 1 (AP-1) and the mitogen-activated protein kinases (MAPK). Furthermore, administration of 2f significantly reduced the mortality of LPS-induced sepsis in mice. These results provide useful insights into the development of novel PAR2 antagonists with anti-inflammatory activity in vitro and in vivo.
Assuntos
Anti-Inflamatórios/química , Anti-Inflamatórios/uso terapêutico , Quinazolinas/química , Quinazolinas/uso terapêutico , Receptor PAR-2/antagonistas & inibidores , Sepse/tratamento farmacológico , Aminação , Animais , Anti-Inflamatórios/farmacologia , Linhagem Celular , Dinoprostona/imunologia , Interleucina-1beta/imunologia , Lipopolissacarídeos/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , NF-kappa B/imunologia , Quinazolinas/farmacologia , Receptor PAR-2/imunologia , Sepse/imunologia , Fator de Necrose Tumoral alfaRESUMO
We have synthesized three categories of α,ß-unsaturated carbonyl derivatives and evaluated their MAO-A and MAO-B inhibitory activities. Among them, compound 10b including α,ß-unsaturated ketone group showed the most potent and selective MAO-B inhibitory activity (IC50 human MAO-B 16 nM, >6000-fold selective vs MAO-A) and compound 10b exhibited good reversibility compared with selegiline, a well-known irreversible MAO-B inhibitor. However, both α,ß-unsaturated amide and ester derivatives exhibited weaker MAO-B inhibition potencies. The docking studies provided insights into the possible binding modes and the key interaction sites of the synthesized MAO-B inhibitors.
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Cetonas/química , Inibidores da Monoaminoxidase/síntese química , Monoaminoxidase/química , Sítios de Ligação , Sequestradores de Radicais Livres/síntese química , Sequestradores de Radicais Livres/química , Humanos , Peróxido de Hidrogênio/química , Cetonas/síntese química , Cetonas/metabolismo , Cinética , Simulação de Acoplamento Molecular , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/química , Inibidores da Monoaminoxidase/metabolismo , Ligação Proteica , Estrutura Terciária de Proteína , Relação Estrutura-AtividadeRESUMO
The COVID-19 pandemic is an ongoing global public health threat. COVID-19 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and binding of the SARS-CoV-2 spike to its receptor, angiotensin-converting enzyme 2 (ACE2), on host cells is critical for viral infection. Here, we developed a luminescent biosensor that readily detects interactions of the spike receptor-binding domain (RBD) and ACE2 in cell culture medium ('SpACE-CCM'), which was based on bimolecular complementation of the split nanoluciferase-fused spike RBD and ectodomain of ACE2 and further engineered to be efficiently secreted from cells by adding a heterologous secretory signal peptide (SSP). Screening of various SSPs identified 'interferon-α+alanine-aspartate' as the SSP that induced the highest activity. The SpACE-CCM biosensor was validated by observing a marked reduction of the activity caused by interaction-defective mutations or in the presence of neutralizing antibodies, recombinant decoy proteins, or peptides. Importantly, the SpACE-CCM biosensor responded well in assay-validating conditions compared with conventional cell lysate-based NanoLuc Binary Technology, indicating its advantage. We further demonstrated the biosensor's versatility by quantitatively detecting neutralizing activity in blood samples from COVID-19 patients and vaccinated individuals, discovering a small molecule interfering with the spike RBD-ACE2 interaction through high-throughput screening, and assessing the cross-reactivity of neutralizing antibodies against SARS-CoV-2 variants. Because the SpACE-CCM is a facile and rapid one-step reaction biosensor that aptly recapitulates the native spike-ACE2 interaction, it would be advantageous in many experimental and clinical applications associated with this interaction.
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Técnicas Biossensoriais , COVID-19 , Humanos , SARS-CoV-2 , Enzima de Conversão de Angiotensina 2 , Pandemias , Ligação Proteica , Anticorpos Neutralizantes/metabolismo , Técnicas de Cultura de Células , Glicoproteína da Espícula de CoronavírusRESUMO
Licorice (Glycyrrhiza glabra, GG) is one of the most frequently used herbal medicines worldwide, and its various biological activities have been widely studied. GG is reported to have neurological properties such as antidepressant, anxiolytic, and anticonvulsant effects. However, its hypnotic effects and the mechanism of GG and its active compounds have not yet been demonstrated. In this study, GG ethanol extract (GGE) dose-dependently potentiated pentobarbital-induced sleep and increased the amount of non-rapid eye movement sleep in mice without decreasing delta activity. The hypnotic effect of GGE was completely inhibited by flumazenil, which is a well-known γ-aminobutyric acid type A-benzodiazepine (GABA(A)-BZD) receptor antagonist, similar to other GABA(A)-BZD receptor agonists (e.g., diazepam and zolpidem). The major flavonoid glabrol was isolated from the flavonoid-rich fraction of GGE; it inhibited [(3)H] flumazenil binding to the GABA(A)-BZD receptors in rat cerebral cortex membrane with a binding affinity (K(i)) of 1.63 µM. The molecular structure and pharmacophore model of glabrol and liquiritigenin indicate that the isoprenyl groups of glabrol may play a key role in binding to GABA(A)-BZD receptors. Glabrol increased sleep duration and decreased sleep latency in a dose-dependent manner (5, 10, 25, and 50mg/kg); its hypnotic effect was also blocked by flumazenil. The results imply that GGE and its flavonoid glabrol induce sleep via a positive allosteric modulation of GABA(A)-BZD receptors.
Assuntos
Flavonoides/farmacologia , Glycyrrhiza/química , Hipnóticos e Sedativos/farmacologia , Extratos Vegetais/farmacologia , Receptores de GABA-A/metabolismo , Animais , Relação Dose-Resposta a Droga , Etanol/química , Movimentos Oculares/efeitos dos fármacos , Flavanonas/química , Flavanonas/farmacologia , Flavonoides/química , Flavonoides/isolamento & purificação , Flumazenil/farmacologia , Antagonistas de Receptores de GABA-A/metabolismo , Antagonistas de Receptores de GABA-A/farmacologia , Hipnóticos e Sedativos/química , Ligantes , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Pentobarbital/farmacologia , Extratos Vegetais/química , Preparações de Plantas , Sono/efeitos dos fármacosRESUMO
The by-products of iron smelting and smithing include slag, flake hammer scale, and spheroidal hammer scale. The analysis of such iron-making by-products reveals critical information regarding the development of iron culture and the process characteristics. Using a metallographic microscope, SEM-EDS, and Raman micro-spectroscopy, we investigated the manufacturing process by examining the microstructure and determining the composition of the flake hammer scale and spheroidal hammer scale excavated from Korean Peninsula sites of iron manufacture during the Proto-Three Kingdoms Period, in the third and fourth centuries CE. Microstructure analysis confirmed that as the process progressed, the flake hammer scale's thickness decreased owing to forging, which flattened the structure. Additionally, three layers were observed, with the surface layer identified as hematite (Fe2O3), the middle layer identified as magnetite (Fe3O4), and the inner layer identified as wüstite (FeO). The analysis of hammer scales revealed that the forging process to create iron bars required repeated working, following a refining process to remove impurities, confirming the division of labor in the smithing process. Correspondingly, the smithing process stages can be deduced from the structural shape and thickness of the hammer scale produced during the iron manufacturing process. Thus, the findings of this study are expected to be invaluable in furthering our understanding of the smithing process in detail, through future research on hammer scale.
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The main advantages of the three-dimensional (3D) printing process are flexible design, rapid prototyping, multi-component structures, and minimal waste. For stereolithography (SLA) 3D printing, common photocurable polymers, such as bisphenol-A glycidyl methacrylate (Bis-EMA), trimethylolpropane triacrylate (TMPTMA), as well as urethane oligomers, have been widely used. For a successful 3D printing process, these photocurable polymers must satisfy several requirements, including transparency, a low viscosity, good mechanical strength, and low shrinkage post-ultraviolet curing process. Herein, we investigated SLA-type photocurable resins prepared using Bis-EMA, TMPTMA, and urethane oligomers. The flexural strength, hardness, conversion rate, output resolution, water absorption, and solubility of the printed materials were investigated. The degree of conversion of the printed specimens measured by infrared spectroscopy ranged from 30 to 60%. We also observed that 64-80 MPa of the flexural strength, 40-60 HV of the surface hardness, 15.6-29.1 MPa of the compression strength, and 3.3-14.5 MPa of the tensile strength. The output resolution was tested using three different structures comprising a series of columns (5-50 mm), circles (0.6-6 mm), and lines (0.2-5 mm). In addition, we used five different pigments to create colored resins and successfully printed complex models of the Eiffel Tower. The research on resins, according to the characteristics of these materials, will help in the design of new materials. These results suggests that acrylate-based resins have the potential for 3D printing.
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Recently, lead halide perovskite nanocrystals have been considered as potential light-emitting materials because of their narrow full width at half-maximum (FWHM) and high photoluminescence quantum yield (PLQY). In addition, they have various emission spectra because the bandgap can be easily tuned by changing the size of the nanocrystals and their chemical composition. However, these perovskite materials have poor long-term stability due to their sensitivity to moisture. Thus far, various approaches have been attempted to enhance the stability of the perovskite nanocrystals. However, the required level of stability in the mass production process of perovskite nanocrystals under ambient conditions has not been secured. In this work, we developed a facile two-step ball-milling and ethanol/water-induced phase transition method to synthesize stable CsPbBr3 perovskite materials. We obtained pure CsPbBr3 perovskite solutions with stability retention of 86% for 30 days under ambient conditions. Our materials show a high PLQY of 35% in solid films, and excellent thermal stability up to 80 °C. We believe that our new synthetic method could be applicable for the mass production of light-emitting perovskite materials.
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Cancer-associated fibroblasts (CAFs) represent a major component of the tumor microenvironment and interplay with cancer cells by secreting cytokines, growth factors and extracellular matrix proteins. When estrogen receptor-negative breast cancer MDA-MB-231 cells were treated with the CAF-conditioned medium (CAF-CM), Akt and STAT3 involved in cell proliferation and survival were activated through phosphorylation. CAFs secrete fibroblast growth factor 2 (FGF2), thereby stimulating breast cancer cell progression. Akt activation induced by CAF-CM in MDA-MB-231 cells was abolished when FGF2-neutralizing antibody was added. Treatment of MDA-MB-231 cells directly with FGF2 enhanced the phosphorylation of Akt and the FGF receptor (FGFR) substrate, FRS2α. These events were abrogated by siRNA-mediated silencing of FGFR1. In a xenograft mouse model, co-injection of MDA-MB-231 cells with activated fibroblasts expressing FGF2 dramatically enhanced activation of Akt. Stable knockdown of FGFR1 blunted Akt phosphorylation in xenograft tumors. MDA-MB-231 cells co-cultured with CAFs or directly stimulated with FGF2 exhibited enhanced nuclear localization of FGFR1. Notably, FGF2 stimulation produced reactive oxygen species (ROS) accumulation in MDA-MB-231 cells, and FGF2-induced nuclear accumulation of FGFR1 was abrogated by the ROS scavenging agent, N-acetylcysteine.
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We have functionalized core-shell CdSe/ZnS quantum dots (QDs) with a photosensitive monolayer, rendering them solution processable and photopatternable. Upon exposure to ultraviolet radiation, films composed of this material were found to polymerize, forming interconnected arrays of QDs. The photoluminescence properties of the nanocrystal films increased with photocuring. The material was found to be suitable for spin casting and was used as the active layer in a green electroluminescent device. The electroluminescence efficiency of devices containing a photocured active layer was found to be largely enhanced when compared to devices containing nonphotocured active layers. The material also showed excellent adhesion to both organic and inorganic substrates because of the unique combination of a siloxane and a photopatternable layer as ligands. The pristine functionalized nanocrystals could easily be used for two-dimensional patterning on organic and inorganic substrates. The photopatternable quantum dots were uniformly dispersed into a photopolymerizable resin to fabricate QD embedded three-dimensional microstructures.