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Lithium niobate (LiNbO3) is viewed as a promising material for optical communications and quantum photonic chips1,2. Recent breakthroughs in LiNbO3 nanophotonics have considerably boosted the development of high-speed electro-optic modulators3-5, frequency combs6,7 and broadband spectrometers8. However, the traditional method of electrical poling for ferroelectric domain engineering in optic9-13, acoustic14-17 and electronic applications18,19 is limited to two-dimensional space and micrometre-scale resolution. Here we demonstrate a non-reciprocal near-infrared laser-writing technique for reconfigurable three-dimensional ferroelectric domain engineering in LiNbO3 with nanoscale resolution. The proposed method is based on a laser-induced electric field that can either write or erase domain structures in the crystal, depending on the laser-writing direction. This approach offers a pathway for controllable nanoscale domain engineering in LiNbO3 and other transparent ferroelectric crystals, which has potential applications in high-efficiency frequency mixing20,21, high-frequency acoustic resonators14-17 and high-capacity non-volatile ferroelectric memory19,22.
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Haploinsufficiency for SOX9, the master chondrogenesis transcription factor, can underlie campomelic dysplasia (CD), an autosomal dominant skeletal malformation syndrome, because heterozygous Sox9 null mice recapitulate the bent limb (campomelia) and some other phenotypes associated with CD. However, in vitro cell assays suggest haploinsufficiency may not apply for certain mutations, notably those that truncate the protein, but in these cases in vivo evidence is lacking and underlying mechanisms are unknown. Here, using conditional mouse mutants, we compared the impact of a heterozygous Sox9 null mutation (Sox9+/-) with the Sox9+/Y440X CD mutation that truncates the C-terminal transactivation domain but spares the DNA-binding domain. While some Sox9+/Y440X mice survived, all Sox9+/- mice died perinatally. However, the skeletal defects were more severe and IHH signaling in developing limb cartilage was significantly enhanced in Sox9+/Y440X compared with Sox9+/-. Activating Sox9Y440X specifically in the chondrocyte-osteoblast lineage caused milder campomelia, and revealed cell- and noncell autonomous mechanisms acting on chondrocyte differentiation and osteogenesis in the perichondrium. Transcriptome analyses of developing Sox9+/Y440X limbs revealed dysregulated expression of genes for the extracellular matrix, as well as changes consistent with aberrant WNT and HH signaling. SOX9Y440X failed to interact with ß-catenin and was unable to suppress transactivation of Ihh in cell-based assays. We propose enhanced HH signaling in the adjacent perichondrium induces asymmetrically localized excessive perichondrial osteogenesis resulting in campomelia. Our study implicates combined haploinsufficiency/hypomorphic and dominant-negative actions of SOX9Y440X, cell-autonomous and noncell autonomous mechanisms, and dysregulated WNT and HH signaling, as the cause of human campomelia.
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Ouriços , Via de Sinalização Wnt , Humanos , Camundongos , Animais , Ouriços/metabolismo , Regulação da Expressão Gênica , Fatores de Transcrição SOX9/genética , Fatores de Transcrição SOX9/metabolismo , Diferenciação Celular/genética , Proteínas/metabolismo , Condrócitos/metabolismoRESUMO
SignificanceThin transparent semiconductors of two-dimensional materials are attractive for the practical applications in next-generation nanoelectronic and optoelectronic devices. Probing the electron states and electrical switching mechanisms of a molybdenum disulphide monolayer with atomic-scale thickness (6.5 Å) allows us to unlock the full technological potential of this nanomaterial. We introduced a plasmonic phase imaging method to uncover the underlying mechanism and detailed switching dynamics of an electrical-state switching event. This dramatic phase change can be attributed to the reversible switching of classical electromagnetic coupling and quantum coupling effects interplaying between a single metal nanoparticle and molybdenum disulphide monolayer, and the transient intermediate states during the switching event can be directly imaged by a plasmonic technique.
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Acute myeloid leukemia (AML) can manifest as de novo AML (dn-AML) or secondary AML (s-AML), with s-AML being associated with inferior survival and distinct genomic characteristics. The underlying reasons for this disparity remain to be elucidated. In this multicenter study, next-generation sequencing (NGS) was employed to investigate the mutational landscape of AML in 721 patients from June 2020 to May 2023.Genetic mutations were observed in 93.34% of the individuals, with complex variations (more than three gene mutations) present in 63.10% of them. TET2, ASXL1, DNMT3A, TP53 and SRSF2 mutations showed a higher prevalence among older individuals, whereas WT1 and KIT mutations were more commonly observed in younger patients. BCOR, BCORL1, ZRSR2, ASXL1 and SRSF2 exhibited higher mutation frequencies in males. Additionally, ASXL1, NRAS, PPMID, SRSF2, TP53 and U2AF1 mutations were more common in patients with s-AML, which PPM1D was more frequently associated with therapy-related AML (t-AML). Advanced age and hyperleukocytosis independently served as adverse prognostic factors for both types of AML; however, s-AML patients demonstrated a greater number of monogenic adverse prognostic factors compared to dn-AML cases (ASXL1, PPM1D, TP53 and U2AF1 in s-AML vs. FLT3, TP53 and U2AF1 in dn-AML). Age and sex-related gene mutations suggest epigenetic changes may be key in AML pathogenesis. The worse prognosis of s-AML compared to dn-AML could be due to the older age of s-AML patients and more poor-prognosis gene mutations. These findings could improve AML diagnosis and treatment by identifying potential therapeutic targets and risk stratification biomarkers.
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The safety, low cost, and high power density of aqueous Zn-based devices (AZDs) appeal to large-scale energy storage. Yet, the presence of hydrogen evolution reaction (HER) and chemical corrosion in the AZDs leads to local OH- concentration increasement and the formation of ZnxSOy(OH)zâ¢nH2O (ZHS) by-products at the Zn/electrolyte interface, causing instability and irreversibility of the Zn-anodes. Here, a strategy is proposed to regulate OH- by introducing a bio-sourced/renewable polypeptide (É-PL) as a pH regulator in electrolyte. The consumption of OH- species is evaluated through in vitro titration and cell in vivo in situ attenuated total reflection surface-enhanced infrared absorption spectroscopy at a macroscopic and molecular level. The introduction of É-PL is found to significantly suppress the formation of ZHS and associated side reactions, and reduce the local coordinated H2O of the Zn2+ solvation shell, widening electrochemical stable window and suppressing OH- generation during HER. As a result, the inclusion of É-PL improves the cycle time of Zn/Zn symmetrical cells from 15 to 225 h and enhances the cycle time of aqueous Zn- I2 cells to 1650 h compared to those with pristine electrolytes. This work highlights the potential of kinetical OH- regulation for by-product and dendrite-free AZDs.
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Potassium (K+) is one of the most abundant cations in the human body. Under normal conditions, the vast majority of K+ is found within cells, and the extracellular [K+] is tightly regulated to within 3.0 to 5.0 mM. However, it has recently been shown that high levels of localized necrosis can increase the extracellular concentration of K+ to above 50 mM. This raises the possibility that elevated extracellular K+ might influence a variety of biological processes that occur within regions of necrotic tissue. For example, K+ has been shown to play a central role in the replication cycles of numerous viral families, and in cases of lytic infection, localized regions containing large numbers of necrotic cells can be formed. Here, we show that the replication of the model poxvirus myxoma virus (MYXV) is delayed by elevated levels of extracellular K+. These increased K+ concentrations alter the cellular endocytic pathway, leading to increased phagocytosis but a loss of endosomal/lysosomal segregation. This slows the release of myxoma virus particles from the endosomes, resulting in delays in genome synthesis and infectious particle formation as well as reduced viral spread. Additionally, mathematical modeling predicts that the extracellular K+ concentrations required to impact myxoma virus replication can be reached in viral lesions under a variety of conditions. Taken together, these data suggest that the extracellular [K+] plays a role in determining the outcomes of myxoma infection and that this effect could be physiologically relevant during pathogenic infection. IMPORTANCE Intracellular K+ homeostasis has been shown to play a major role in the replication of numerous viral families. However, the potential impact of altered extracellular K+ concentrations is less well understood. Our work demonstrates that increased concentrations of extracellular K+ can delay the replication cycle of the model poxvirus MYXV by inhibiting virion release from the endosomes. Additionally, mathematical modeling predicts that the levels of extracellular K+ required to impact MYXV replication can likely be reached during pathogenic infection. These results suggest that localized viral infection can alter K+ homeostasis and that these alterations might directly affect viral pathogenesis.
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Myxoma virus , Humanos , Myxoma virus/genética , Potássio , Endossomos , Replicação Viral , VírionRESUMO
Aqueous zinc-ion batteries (AZIBs) are considered promising candidates for large-scale energy storage due to their high safety, low cost, and environmental friendliness. As a core component, separator plays a unique yet oftentimes overlooked role in providing electrochemical stability in AZIBs. This concept focuses on the exquisite structure-property relationship of separators, highlighting three forms of these components and their structural design requirements, i.e., traditional membranes, solid-state electrolytes, and electrode coatings. The mechanism by which separators influence the zinc anode and the cathode is discussed. The article also identifies the challenges and potential future directions for functional separators in the development of high-performance AZIBs.
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Glioblastoma multiforme (GBM) is the most malignant brain tumor with rapid angiogenesis. How to inhibit GBM angiogenesis is a key problem to be solved. To explore the targets of inhibiting GBM angiogenesis, this study confirmed that the expression of circMTA1 (hsa_circ_0033614) was significantly upregulated in human brain microvascular endothelial cells exposed to glioma cell-conditioned medium (GECs). The expression of circMTA1 in the cytoplasm was significantly higher than that in the nucleus. Upregulated circMTA1 in GECs can promote cell proliferation, migration, and tube formation. Further exploration of the circularization mechanism of circMTA1 confirmed that KHDRBS1 protein can bind to the upstream and downstream flanking sequences of circMTA1 and promote circMTA1 biogenesis by coordinating Alu element pairing. KHDRBS1 upregulated the proliferation, migration, and tube formation of GECs by promoting the biogenesis of circMTA1. CircMTA1 can encode the protein MTA1-134aa by internal ribosome entry site sequence-mediated translation mechanism, and promote the proliferation, migration, and tube formation of GECs through the encoded MTA1-134aa. This study provides a new target for inhibiting angiogenesis in brain GBM and a new strategy for improving the therapeutic efficacy of GBM.
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Neoplasias Encefálicas , Glioblastoma , Glioma , Humanos , Glioblastoma/genética , Células Endoteliais , Elementos Alu , Neoplasias Encefálicas/genética , Proteínas de Ciclo Celular , Proteínas de Ligação a DNA , Proteínas de Ligação a RNA , Proteínas Adaptadoras de Transdução de SinalRESUMO
Tryptophan (TRP) contributes to individual immune homeostasis and good condition via three complex metabolism pathways (5-hydroxytryptamine (5-HT), kynurenine (KP), and gut microbiota pathway). Indole propionic acid (IPA), one of the TRP derivatives of the microbiota pathway, has raised more attention because of its impact on metabolic disorders. Here, we retrospect increasing evidence that TRP metabolites/IPA derived from its proteolysis impact host health and disease. IPA can activate the immune system through aryl hydrocarbon receptor (AHR) and/or Pregnane X receptor (PXR) as a vital mediator among diet-caused host and microbe cross-talk. Different levels of IPA in systemic circulation can predict the risk of NAFLD, T2DM, and CVD. IPA is suggested to alleviate cognitive impairment from oxidative damage, reduce gut inflammation, inhibit lipid accumulation and attenuate the symptoms of NAFLD, putatively enhance the intestinal epithelial barrier, and maintain intestinal homeostasis. Now, we provide a general description of the relationships between IPA and various physiological and pathological processes, which support an opportunity for diet intervention for metabolic diseases.
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Nitrous oxide (N2O) has a detrimental impact on the greenhouse effect, and its efficient catalytic decomposition at low temperatures remains challenging. Herein, the cobalt-based high-entropy oxide with a spinel-type structure (Co-HEO) is successfully fabricated via a facile coprecipitation method for N2O catalytic decomposition. The obtained Co-HEO catalyst displays more remarkable catalytic performance and higher thermal stability compared with single and binary Co-based oxides, as the temperature of 90% N2O decomposition (T90) is 356 °C. A series of characterization results reveal that the synergistic effect of multiple elements enhances the reducibility and augments oxygen vacancy in the high-entropy system, thus boosting the activity of the Co-HEO catalyst. Moreover, density functional theory (DFT) calculations and the temperature-programmed surface reaction (TPSR) with isotope labeling demonstrate that N2O decomposition on the Co-HEO catalyst follows the Langmuir-Hinshelwood (L-H) mechanism with the promotion of abundant oxygen vacancies. This work provides a fundamental understanding of the synergistic catalytic effect in N2O decomposition and paves the way for the novel environmental catalytic applications of HEO.
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Cobalto , Óxidos , Entropia , Óxidos/química , Cobalto/química , OxigênioRESUMO
The adsorption and activation of pollutant molecules and oxygen play a critical role in the oxidation reaction of volatile organic compounds (VOCs). In this study, superior adsorption and activation ability was achieved by modulating the interaction between Pt nanoparticles (NPs) and UiO-66 (U6) through the spatial position effect. Pt@U6 exhibits excellent activity in toluene, acetone, propane, and aldehyde oxidation reactions. Spectroscopic studies, 16O2/18O2 kinetic isotopic experiments, and density functional theory (DFT) results jointly reveal that the encapsulated Pt NPs of Pt@U6 possess higher electron density and d-band center, which is conducive for the adsorption and dissociation of oxygen. The toluene oxidation reaction and DFT results indicate that Pt@U6 is more favorable to activate the C-H of toluene and the CâC of maleic anhydride, while Pt/U6 with lower electron density and d-band center exhibits a higher oxygen dissociation temperature and higher reactant activation energy barriers. This study provides a deep insight into the architecture-performance relation of Pt-based catalysts for the catalytic oxidation of VOCs.
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Estruturas Metalorgânicas , Nanopartículas , Ácidos Ftálicos , Compostos Orgânicos Voláteis , Compostos Orgânicos Voláteis/química , Tolueno/química , OxigênioRESUMO
BACKGROUND: Web-based health care has the potential to improve health care access and convenience for patients with limited mobility, but its success depends on active physician participation. The economic returns of internet-based health care initiatives are an important factor that can motivate physicians to continue their participation. Although several studies have examined the communication patterns and influences of web-based health consultations, the correlation between physicians' communication characteristics and their economic returns remains unexplored. OBJECTIVE: This study aims to investigate how the linguistic features of 2 modes of physician-patient communication, instrumental and affective, determine the physician's economic returns, measured by the honorarium their patients agree to pay per consultation. We also examined the moderating effects of communication media (web-based text messages and voice messages) and the compounding effects of different communication features on economic returns. METHODS: We collected 40,563 web-based consultations from 528 physicians across 4 disease specialties on a large, web-based health care platform in China. Communication features were extracted using linguistic inquiry and word count, and we used multivariable linear regression and K-means clustering to analyze the data. RESULTS: We found that the use of cognitive processing language (ie, words related to insight, causation, tentativeness, and certainty) in instrumental communication and positive emotion-related words in affective communication were positively associated with the economic returns of physicians. However, the extensive use of discrepancy-related words could generate adverse effects. We also found that the use of voice messages for service delivery magnified the effects of cognitive processing language but did not moderate the effects of affective processing language. The highest economic returns were associated with consultations in which the physicians used few expressions related to negative emotion; used more terms associated with positive emotions; and later, used instrumental communication language. CONCLUSIONS: Our study provides empirical evidence about the relationship between physicians' communication characteristics and their economic returns. It contributes to a better understanding of patient-physician interactions from a professional-client perspective and has practical implications for physicians and web-based health care platform executives.
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Médicos , Voz , Humanos , Comunicação , Linguística , IdiomaRESUMO
Surfactants play a crucial role in tertiary oil recovery by reducing the interfacial tension between immiscible phases, altering surface wettability, and improving foam film stability. Oil reservoirs have high temperatures and high pressures, making it difficult and hazardous to conduct lab experiments. In this context, molecular dynamics (MD) simulation is a valuable tool for complementing experiments. It can effectively study the microscopic behaviors (such as diffusion, adsorption, and aggregation) of the surfactant molecules in the pore fluids and predict the thermodynamics and kinetics of these systems with a high degree of accuracy. MD simulation also overcomes the limitations of traditional experiments, which often lack the necessary temporal-spatial resolution. Comparing simulated results with experimental data can provide a comprehensive explanation from a microscopic standpoint. This article reviews the state-of-the-art MD simulations of surfactant adsorption and resulting interfacial properties at gas/oil-water interfaces. Initially, the article discusses interfacial properties and methods for evaluating surfactant-formed monolayers, considering variations in interfacial concentration, molecular structure of the surfactants, and synergistic effect of surfactant mixtures. Then, it covers methods for characterizing microstructure at various interfaces and the evolution process of the monolayers' packing state as a function of interfacial concentration and the surfactants' molecular structure. Next, it examines the interactions between surfactants and the aqueous phase, focusing on headgroup solvation and counterion condensation. Finally, it analyzes the influence of hydrophobic phase molecular composition on interactions between surfactants and the hydrophobic phase. This review deepened our understanding of the micro-level mechanisms of oil displacement by surfactants and is beneficial for screening and designing surfactants for oil field applications.
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Aqueous zinc-metal batteries are prospective energy storge devices due to their intrinsically high safety and cost effectiveness. Yet, uneven deposition of zinc ions in electrochemical reduction and side reactions at the anode interface significantly hinder their development and application. Here, we propose a solvation-interface attenuation strategy enabled by a frustrated tertiary amine amphiphilic dipolymer electrolyte additive. The configuration of superhydrophilic segments with covalently bonded lipophilic spacers enables coupled steric hindrance/coordination, which establishes a balanced push-pull dynamic of dipolymer-H2O-Zn2+. Such interplay reconstructs the solvation structure of Zn2+ and allows the formation of a stable dipolymer-inorganic hybrid solid electrolyte interface (SEI) layer. This SEI layer effectively shields the zinc-metal anode from water and anions, significantly reducing side reactions. In addition, the dipolymer adsorbed at the zinc-metal anode interface regulates the interfacial electrochemical reduction kinetics and ensures uniform zinc deposition. As a result, the Zn-Zn symmetric cells with dipolymer-containing electrolyte exhibit remarkable cycling stability exceeding 5800â h (242â days). The Zn-NVO batteries and Zn-AC hybrid ion supercapacitors also deliver stable cycling for up to 1440â h (60â days) with high-capacity retention over 80 %. This research demonstrates the potential to facilitate the development and commercialization of zinc-based energy storage devices.
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We demonstrate an integrated optical-electrical calibration module for improving the nonlinearity of the optical source for frequency-modulated continuous-wave (FMCW) LiDAR applications. The linearity of the light source has a considerable influence on FMCW LiDAR range performance, and calibration is typically necessary. However, a majority of existing calibration techniques are based on separate devices, resulting in high cost and limited integration. Our module is made up of a silicon photonic chip with a long optical delay line, a tunable phase shifter, two balanced photodetectors, and some passive components. For this module, we also built the aided amplification and voltage bias circuits. After packaging this module, we used it with our nonlinearity calibration algorithm to analyze the laser's relative nonlinearity. After nonlinearity calibration, the laser relative nonlinearity 1-r2 could be improved to 10-6â¼10-7. In the future, the calibration result of nonlinearity could be enhanced further by increasing the length of the on-chip optical delay line.
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BACKGROUND: Glioblastoma (GBM) is the most aggressive malignant primary brain tumor. The transfer RNA-derived fragments (tRFs) are a new group of small noncoding RNAs, which are dysregulated in many cancers. Until now, the expression and function of tRFs in glioma remain unknown. METHODS: The expression profiles of tRF subtypes were analyzed using the Cancer Genome Atlas (TCGA)-low-grade gliomas (LGG)/GBM dataset. The target genes of tRFs were subjected to Gene Ontology, Kyoto Encyclopedia and Gene set enrichment analysis of Genes and Genomes pathway enrichment analysis. The protein-protein interaction enrichment analysis was performed by STRING. QRT-PCR was performed to detect the expressions of tRFs in human glioma cell lines U87, U373, U251, and human astrocyte cell line SVG p12. Western blot assay was used to detect to the expression of S100A11. The interaction between tRF-19-R118LOJX and S100A11 mRNA 3'UTR was detected by dual-luciferase reporter assay. The effects of tRF-19-R118LOJX, tRF-19-6SM83OJX and S100A11 on the glioma cell proliferation, migration and in vitro vasculogenic mimicry formation ability were examined by CCK-8 proliferation assay, EdU assay, HoloMonitor cell migration assay and tube formation assay, respectively. RESULTS: tRF-19-R118LOJX and tRF-19-6SM83OJX are the most differentially expressed tRFs between LGG and GBM groups. The functional enrichment analysis showed that the target genes of tRF-19-R118LOJX and tRF-19-6SM83OJX are enriched in regulating blood vessel development. The upregulated target genes are linked to adverse survival outcomes in glioma patients. tRF-19-R118LOJX and tRF-19-6SM83OJX were identified to suppress glioma cell proliferation, migration, and in vitro vasculogenic mimicry formation. The mechanism of tRF-19-R118LOJX might be related to its function as an RNA silencer by targeting the S100A11 mRNA 3'UTR. CONCLUSION: tRFs would become novel diagnostic biomarkers and therapeutic targets of glioma, and the mechanism might be related to its post-transcriptionally regulation of gene expression by targeting mRNA 3'UTR.
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Glioma , RNA de Transferência , Humanos , Regiões 3' não Traduzidas , RNA de Transferência/genética , RNA de Transferência/metabolismo , Linhagem Celular , Diferenciação Celular , Glioma/genéticaRESUMO
Zizania latifolia is an aquatic and medicinal plant with a long history of development in China and the East Asian region. The smut fungus "Ustilago esculenta" parasitizes Z. latifolia and induces culm expansion to form a vegetable named Jiaobai, which has a unique taste and nutritional attributes. However, the postharvest quality of water bamboo shoots is still a big challenge for farmers and merchants. This paper traced the origin, development process, and morphological characteristics of Z. latifolia. Subsequently, the compilation of the primary nutrients and bioactive substances are presented in context to their effects on ecology a postharvest storage and preservation methods. Furthermore, the industrial, environmental, and material science applications of Z. latifolia in the fields of industry were discussed. Finally, the primary objective of the review proposes future directions for research to support the development of Z. latifolia industry and aid in maximizing its value. To sum up, Z. latifolia, aside from its potential as material it can be utilized to make different productions and improve the existing applications. This paper provides an emerging strategy for researchers undertaking Z. latifolia.
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Znic-based metal-organic framework materials (ZIF-8) show great potential and excellent performance in the fields of sensing and catalysis. However, powdered metal-organic framework makes it easy to lose in the process of application. Herein, we use a simple blending electrostatic spinning method to combine ZIF-8 particles with polyacrylonitrile (PAN) nanofibers. ZIF-8/PAN composite nanofiber membrane. The ZIF-8/PAN nanofiber membrane is characterized by scanning electron microscope (SEM), x-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR) and N2adsorption-desorption. The results show that the ZIF-8/PAN nanofiber membrane has the characteristic peaks of XRD and FTIR, which are consistent with those of simulated ZIF-8. The specific surface area of ZIF-8/PAN nanofiber membrane increases from 13.5371 to 711.4171 m2g-1due to the introduction of ZIF-8 particles. The sensor using the nanofiber membrane as the gas sensing layer shows good response and linear correlation to different concentrations of acetone gas. The minimum detection limit of the sensor for acetone is 51.9 ppm. The blank control shows that the response of the sensor to acetone is mainly due to the introduction of ZIF-8 particles. In addition, the sensor also shows a good cyclic response to acetone.
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OBJECTIVES: Periodontitis is closely associated with kidney disease and reactive oxygen species (ROS) involvement. Mitochondria are the primary source of both endogenous ROS and renal energy. We investigated whether resveratrol (RSV) prevents renal injury and mitochondrial dysfunction in periodontitis rats. METHODS: Thirty male Wistar rats were divided into control, experimental periodontitis (Ep) and Ep-RSV groups. To induce periodontitis, a steel ligature was placed on the cervix of the bilateral first maxillary molars. RSV (50 mg/kg/day) to the Ep-RSV group and vehicle to the Ep and control groups were gavaged. After 8 weeks, alveolar bone loss, pocket depth, gingival blood index and tooth mobility were assessed. Oxidative stress parameters, mitochondrial structure, mitochondrial membrane potential (MMP), mitochondrial ROS, adenosine triphosphate (ATP), sirtuin 1 (SIRT1) and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) were analysed in renal. Renal function and histology were also evaluated. RESULTS: Compared with the control group, the Ep group showed renal structural destruction, elevated oxidative stress levels, mitochondrial structure destruction, MMP loss, mitochondrial ROS accumulation, ATP reduction, and decreased SIRT1 and PGC-1α levels. RSV prevented these destruction (p < 0.05). However, there was no significant impairment in renal function (p > 0.05). CONCLUSIONS: Periodontitis induces mitochondrial dysfunction in renal tissues. Resveratrol exerts a preventive effect on periodontitis-induced kidney injury by preventing mitochondrial dysfunction.
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Periodontite , Sirtuína 1 , Feminino , Ratos , Masculino , Animais , Resveratrol/farmacologia , Resveratrol/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Sirtuína 1/metabolismo , Sirtuína 1/farmacologia , Ratos Wistar , Estresse Oxidativo , Periodontite/complicações , Periodontite/prevenção & controle , Periodontite/metabolismo , Rim/metabolismo , Mitocôndrias , Trifosfato de Adenosina/metabolismo , Trifosfato de Adenosina/farmacologiaRESUMO
The small GTPase KRAS is localized at the plasma membrane where it functions as a molecular switch, coupling extracellular growth factor stimulation to intracellular signaling networks. In this process, KRAS recruits effectors, such as RAF kinase, to the plasma membrane where they are activated by a series of complex molecular steps. Defining the membrane-bound state of KRAS is fundamental to understanding the activation of RAF kinase and in evaluating novel therapeutic opportunities for the inhibition of oncogenic KRAS-mediated signaling. We combined multiple biophysical measurements and computational methodologies to generate a consensus model for authentically processed, membrane-anchored KRAS. In contrast to the two membrane-proximal conformations previously reported, we identify a third significantly populated state using a combination of neutron reflectivity, fast photochemical oxidation of proteins (FPOP), and NMR. In this highly populated state, which we refer to as "membrane-distal" and estimate to comprise â¼90% of the ensemble, the G-domain does not directly contact the membrane but is tethered via its C-terminal hypervariable region and carboxymethylated farnesyl moiety, as shown by FPOP. Subsequent interaction of the RAF1 RAS binding domain with KRAS does not significantly change G-domain configurations on the membrane but affects their relative populations. Overall, our results are consistent with a directional fly-casting mechanism for KRAS, in which the membrane-distal state of the G-domain can effectively recruit RAF kinase from the cytoplasm for activation at the membrane.