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Proton-coupled monocarboxylate transporters MCT1-4 catalyze the transmembrane movement of metabolically essential monocarboxylates and have been targeted for cancer treatment because of their enhanced expression in various tumors. Here, we report five cryo-EM structures, at resolutions of 3.0-3.3 Å, of human MCT1 bound to lactate or inhibitors in the presence of Basigin-2, a single transmembrane segment (TM)-containing chaperon. MCT1 exhibits similar outward-open conformations when complexed with lactate or the inhibitors BAY-8002 and AZD3965. In the presence of the inhibitor 7ACC2 or with the neutralization of the proton-coupling residue Asp309 by Asn, similar inward-open structures were captured. Complemented by structural-guided biochemical analyses, our studies reveal the substrate binding and transport mechanism of MCTs, elucidate the mode of action of three anti-cancer drug candidates, and identify the determinants for subtype-specific sensitivities to AZD3965 by MCT1 and MCT4. These findings lay out an important framework for structure-guided drug discovery targeting MCTs.
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Antineoplásicos/farmacologia , Transportadores de Ácidos Monocarboxílicos/antagonistas & inibidores , Transportadores de Ácidos Monocarboxílicos/química , Simportadores/antagonistas & inibidores , Simportadores/química , Sequência de Aminoácidos , Animais , Basigina/química , Sítios de Ligação , Microscopia Crioeletrônica , Humanos , Ligantes , Modelos Moleculares , Transportadores de Ácidos Monocarboxílicos/ultraestrutura , Proteínas Mutantes/química , Proteínas Mutantes/metabolismo , Prótons , Pirimidinonas/química , Pirimidinonas/farmacologia , Ratos , Homologia Estrutural de Proteína , Especificidade por Substrato , Simportadores/ultraestrutura , Tiofenos/química , Tiofenos/farmacologiaRESUMO
Plasmodium species, the causative agent of malaria, rely on glucose for energy supply during blood stage. Inhibition of glucose uptake thus represents a potential strategy for the development of antimalarial drugs. Here, we present the crystal structures of PfHT1, the sole hexose transporter in the genome of Plasmodium species, at resolutions of 2.6 Å in complex with D-glucose and 3.7 Å with a moderately selective inhibitor, C3361. Although both structures exhibit occluded conformations, binding of C3361 induces marked rearrangements that result in an additional pocket. This inhibitor-binding-induced pocket presents an opportunity for the rational design of PfHT1-specific inhibitors. Among our designed C3361 derivatives, several exhibited improved inhibition of PfHT1 and cellular potency against P. falciparum, with excellent selectivity to human GLUT1. These findings serve as a proof of concept for the development of the next-generation antimalarial chemotherapeutics by simultaneously targeting the orthosteric and allosteric sites of PfHT1.
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Proteínas de Transporte de Monossacarídeos/ultraestrutura , Plasmodium falciparum/metabolismo , Plasmodium falciparum/ultraestrutura , Proteínas de Protozoários/ultraestrutura , Sequência de Aminoácidos , Animais , Antimaláricos , Transporte Biológico , Glucose/metabolismo , Humanos , Malária , Malária Falciparum/parasitologia , Proteínas de Transporte de Monossacarídeos/química , Proteínas de Transporte de Monossacarídeos/metabolismo , Parasitos , Plasmodium falciparum/genética , Proteínas de Protozoários/química , Proteínas de Protozoários/metabolismo , Açúcares/metabolismoRESUMO
Noradrenaline, also known as norepinephrine, has a wide range of activities and effects on most brain cell types1. Its reuptake from the synaptic cleft heavily relies on the noradrenaline transporter (NET) located in the presynaptic membrane2. Here we report the cryo-electron microscopy (cryo-EM) structures of the human NET in both its apo state and when bound to substrates or antidepressant drugs, with resolutions ranging from 2.5 Å to 3.5 Å. The two substrates, noradrenaline and dopamine, display a similar binding mode within the central substrate binding site (S1) and within a newly identified extracellular allosteric site (S2). Four distinct antidepressants, namely, atomoxetine, desipramine, bupropion and escitalopram, occupy the S1 site to obstruct substrate transport in distinct conformations. Moreover, a potassium ion was observed within sodium-binding site 1 in the structure of the NET bound to desipramine under the KCl condition. Complemented by structural-guided biochemical analyses, our studies reveal the mechanism of substrate recognition, the alternating access of NET, and elucidate the mode of action of the four antidepressants.
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Understanding the polymer solubility in ionic liquids (ILs) is important for polymer processing or polymeric material preparation. Previously, two-parameter H-bonding analysis has been proposed to clarify that polymer solubility in ILs is dominated by H-bonding interactions (Y. F. Yuan et al., Phys. Chem. Chem. Phys., 2021, 23, 21893-21900). In the present work, 1H-NMR spectra are adopted to characterize the H-bonding interactions between polymers and ILs, which provide a microscopic relation between polymer solubility and two-parameter H-bonding analysis.
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Artemisinin-resistant malaria parasites have emerged and have been spreading, posing a significant public health challenge. Antimalarial drugs with novel mechanisms of action are therefore urgently needed. In this report, we exploit a "selective starvation" strategy by inhibiting Plasmodium falciparum hexose transporter 1 (PfHT1), the sole hexose transporter in P. falciparum, over human glucose transporter 1 (hGLUT1), providing an alternative approach to fight against multidrug-resistant malaria parasites. The crystal structure of hGLUT3, which shares 80% sequence similarity with hGLUT1, was resolved in complex with C3361, a moderate PfHT1-specific inhibitor, at 2.3-Å resolution. Structural comparison between the present hGLUT3-C3361 and our previously reported PfHT1-C3361 confirmed the unique inhibitor binding-induced pocket in PfHT1. We then designed small molecules to simultaneously block the orthosteric and allosteric pockets of PfHT1. Through extensive structure-activity relationship studies, the TH-PF series was identified to selectively inhibit PfHT1 over hGLUT1 and potent against multiple strains of the blood-stage P. falciparum Our findings shed light on the next-generation chemotherapeutics with a paradigm-shifting structure-based design strategy to simultaneously target the orthosteric and allosteric sites of a transporter.
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Antimaláricos/química , Transportador de Glucose Tipo 1/genética , Transportador de Glucose Tipo 3/ultraestrutura , Malária Falciparum/tratamento farmacológico , Proteínas de Transporte de Monossacarídeos/ultraestrutura , Proteínas de Protozoários/ultraestrutura , Sítio Alostérico , Sequência de Aminoácidos/genética , Animais , Cristalografia por Raios X , Glucose/metabolismo , Transportador de Glucose Tipo 1/antagonistas & inibidores , Transportador de Glucose Tipo 1/química , Transportador de Glucose Tipo 3/química , Malária Falciparum/genética , Malária Falciparum/parasitologia , Proteínas de Transporte de Monossacarídeos/antagonistas & inibidores , Proteínas de Transporte de Monossacarídeos/genética , Plasmodium falciparum/química , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/genética , Plasmodium falciparum/patogenicidade , Conformação Proteica/efeitos dos fármacos , Proteínas de Protozoários/antagonistas & inibidores , Proteínas de Protozoários/genética , Relação Estrutura-AtividadeRESUMO
BACKGROUND: Idiopathic pulmonary fibrosis is a chronic progressive, lethal disease in which ectopic lung fibroblast (LF) activation plays a vital part. We have previously shown that alamandine (ALA) exerts anti-fibrosis effects via the MAS-related G-protein coupled receptor D (MrgD). Here, we further investigate how it moderates transforming growth factor ß1 (TGF-ß1)-induced LF activation by regulating glucose metabolism and mitochondria autophagy (mitophagy). METHODS: In vitro, we examined glycolysis-related protein hexokinase 2 (HK2), 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), and lactic acid in cells treated with TGF-ß1. The oxygen consumption rate and the extracellular acidification rate were detected using Seahorse assays. Then, mitophagy was evaluated using transmission electron microscopy, mt-Keima, and the co-localization of Parkin and COX IV with LC3 and LAMP1, respectively. The autophagic degradation of HK2 and PFKFB3 was detected by 3MA and bafilomycin A1 and assessed by their co-localization with LC3 and LAMP1, respectively. The effects of ALA on LF activation markers collagen I and α-SMA were detected. The effects of ALA on glucose metabolism, mitophagy, and the activation of LF were also investigated in vivo. RESULTS: We found that the ALA/MrgD axis improved TGF-ß1-mediated LF activation by repressing glycolysis by downregulating HK2 and PFKFB3 expression. Lactic acid sustained positive feedback between glycolysis and LF activation by maintaining the expression of HK2 and PFKFB3. We also showed that glycolysis enhancement resulted from blocking the autophagic degradation of HK2 and PFKFB3 while upregulated mRNA levels by TGF-ß1, while all of those improved by ALA adding. Importantly, we determined that moderation of Parkin/LC3-mediated mitophagy by TGF-ß1 also promotes glycolysis but is reversed by ALA. Furthermore, we proved that ALA counteracts the effects of bleomycin on HK2, PFKFB3, LC3, Parkin, and LF activation in vivo. CONCLUSION: In this study, we show that the ALA/MrgD axis prevents TGF-ß1-mediated fibroblast activation via regulation of aerobic glycolysis and mitophagy.
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Mitofagia , Fator de Crescimento Transformador beta1 , Fator de Crescimento Transformador beta1/metabolismo , Fibroblastos/metabolismo , Glicólise , Ubiquitina-Proteína Ligases/metabolismo , Glucose/metabolismoRESUMO
Ecological restoration projects (ERPs) are an indispensable component of natural climate solutions and have proven to be very important for reversing environmental degradation in vulnerable regions and enhancing ecosystem services. However, the level of enhancement would be inevitably influenced by global drought and rising CO2 , which remain less investigated. In this study, we took the Beijing-Tianjin sand source region (which has experienced long-term ERPs), China, as an example and combined the process-based Biome-BGCMuSo model to set multiple scenarios to address this issue. We found ERP-induced carbon sequestration (CS), water retention (WR), soil retention (SR), and sandstorm prevention (SP) increased by 22.21%, 2.87%, 2.35%, and 28.77%, respectively. Moreover, the ecosystem services promotion from afforestation was greater than that from grassland planting. Approximately 91.41%, 98.13%, and 64.51% of the increased CS, SR, and SP were contributed by afforestation. However, afforestation also caused the WR to decline. Although rising CO2 amplified ecosystem services contributed by ERPs, it was almost totally offset by drought. The contribution of ERPs to CS, WR, SR, and SP was reduced by 5.74%, 32.62%, 11.74%, and 14.86%, respectively, under combined drought and rising CO2 . Our results confirmed the importance of ERPs in strengthening ecosystem services provision. Furthermore, we provide a quantitative way to understand the influence rate of drought and rising CO2 on ERP-induced ecosystem service dynamics. In addition, the considerable negative climate change impact implied that restoration strategies should be optimized to improve ecosystem resilience to better combat negative climate change impacts.
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Dióxido de Carbono , Ecossistema , Secas , China , Pequim , Solo , Mudança ClimáticaRESUMO
BACKGROUND: Cigarette smoking (CS) is a strong risk factor for idiopathic pulmonary fibrosis (IPF). It can activate lung fibroblasts (LF) by inducing redox imbalance. We previously showed that clearing mitochondrial reactive oxygen species (mtROS) protects against CS-induced pulmonary fibrosis. However, the precise mechanisms of mtROS in LF need further investigation. Here we focused on mtROS to elucidate how it was regulated by CS in LF and how it contributed to LF activation. METHODS: We treated cells with 1% cigarette smoking extract (CSE) and examined mtROS level by MitoSOX™ indicator. And the effect of CSE on expression of SIRT1, SOD2, mitochondrial NOX4 (mtNOX4), fatty acid oxidation (FAO)-related protein PPARα and CPT1a and LF activation marker Collagen I and α-SMA were detected. Nile Red staining was performed to show cellular lipid content. Then, lipid droplets, autophagosome and lysosome were marked by Bodipy 493/503, LC3 and LAMP1, respectively. And lipophagy was evaluated by the colocalization of lipid droplets with LC3 and LAMP1. The role of autophagy on lipid metabolism and LF activation were explored. Additionally, the effect of mitochondria-targeted ROS scavenger mitoquinone and SIRT1 activator SRT1720 on mitochondrial oxidative stress, autophagy flux, lipid metabolism and LF activation were investigated in vitro and in vivo. RESULTS: We found that CS promoted mtROS production by increasing mtNOX4 and decreasing SOD2. Next, we proved mtROS inhibited the expression of PPARα and CPT1a. It also reduced lipophagy and upregulated cellular lipid content, suggesting lipid metabolism was disturbed by CS. In addition, we showed both insufficient FAO and lipophagy resulted from blocked autophagy flux caused by mtROS. Moreover, we uncovered decreased SIRT1 was responsible for mitochondrial redox imbalance. Furthermore, we proved that both SRT1720 and mitoquinone counteracted the effect of CS on NOX4, SOD2, PPARα and CPT1a in vivo. CONCLUSIONS: We demonstrated that CS decreased SIRT1 to activate LF through dysregulating lipid metabolism, which was due to increased mtROS and impaired autophagy flux. These events may serve as therapeutic targets for IPF patients.
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Fumar Cigarros , Fibrose Pulmonar Idiopática , Metabolismo dos Lipídeos , Estresse Oxidativo , Sirtuína 1 , Autofagia , Fumar Cigarros/efeitos adversos , Fibroblastos/metabolismo , Humanos , Fibrose Pulmonar Idiopática/metabolismo , Lipídeos , Pulmão/metabolismo , PPAR alfa/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Sirtuína 1/metabolismoRESUMO
BACKGROUND: Exposure to toluene diisocyanate (TDI) is a significant pathogenic factor for asthma. We previously reported that the receptor for advanced glycation end products (RAGE) plays a key role in TDI-induced asthma. Histone deacetylase (HDAC) has been reported to be important in asthmatic pathogenesis. However, its effect on TDI-induced asthma is not known. The aim of this study was to determine the role of RAGE and HDAC in regulating airway inflammation using a TDI-induced murine asthma model. METHODS: BALB/c mice were sensitized and challenged with TDI to establish an asthma model. FPS-ZM1 (RAGE inhibitor), JNJ-26482585 and romidepsin (HDAC inhibitors) were administered intraperitoneally before each challenge. In vitro, the human bronchial epithelial cell line 16HBE was stimulated with TDI-human serum albumin (TDI-HSA). RAGE knockdown cells were constructed and evaluated, and MK2006 (AKT inhibitor) was also used in the experiments. RESULTS: In TDI-induced asthmatic mice, the expression of RAGE, HDAC1, and p-AKT/t-AKT was upregulated, and these expressions were attenuated by FPS-ZM1. Airway reactivity, Th2 cytokine levels in lymph supernatant, IgE, airway inflammation, and goblet cell metaplasia were significantly increased in the TDI-induced asthmatic mice. These increases were suppressed by JNJ-26482585 and romidepsin. In addition, JNJ-26482585 and romidepsin ameliorated the redistribution of E-cadherin and ß-catenin in TDI-induced asthma. In TDI-HSA-stimulated 16HBE cells, knockdown of RAGE attenuated the upregulation of HDAC1 and phospho-AKT (p-AKT). Treatment with the AKT inhibitor MK2006 suppressed TDI-induced HDAC1 expression. CONCLUSIONS: These findings indicate that RAGE modulates HDAC1 expression via the PI3K/AKT pathway, and that inhibition of HDAC prevents TDI-induced airway inflammation.
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Asma/prevenção & controle , Histona Desacetilase 1/metabolismo , Inflamação/prevenção & controle , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Asma/induzido quimicamente , Benzamidas/farmacologia , Linhagem Celular , Citocinas/metabolismo , Depsipeptídeos/farmacologia , Modelos Animais de Doenças , Histona Desacetilase 1/antagonistas & inibidores , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Fosfatidilinositol 3-Quinases/metabolismo , Receptor para Produtos Finais de Glicação Avançada/antagonistas & inibidores , Tolueno 2,4-Di-Isocianato/toxicidadeRESUMO
Polymer solubility in ionic liquids (ILs) cannot be predicted by the solubility parameter approach based on the "like dissolves like" principle. According to the Kamlet-Abraham-Taft (KAT) multi-parameter polarity scale, ILs can be categorized on the basis of hydrogen-bond acidity or basicity ones. The experimental observations, that acidic ILs easily dissolve basic polymers and basic ILs dissolve acidic polymers, reflect the complementary nature of hydrogen-bonding interactions. A quantitative hydrogen-bonding analysis is proposed for predicting the solubility by taking the product of ΔαΔß as an indicator of the competition between cross-association and self-association hydrogen bonding (H-bonding), where Δα is the difference of acidity parameters between the polymer and IL, and Δß is the difference of basicity. This solubility criterion has been validated by the solubility data of 19 polymers (11 acidic and 8 basic) in 11 ILs (7 acidic and 4 basic). These principles based on KAT parameters can be applied to other systems dominated by hydrogen bonding.
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Adsorptive separation is an appealing technology for propylene and propane separation; however, the challenge lies in the design of efficient adsorbents which can distinguish the two molecules having very similar properties. Here we report a kinetically amplified separation by creating wiggling mesopores in structurally robust carbon monoliths. The wiggling mesopores with alternating wide and narrow segments afford a surface area of 413â m2 g-1 and a tri-modal pore size distribution centered at 1.5, 4.2 and 6.6â nm, respectively. The synergistically kinetic and equilibrium effects were observed and quantitatively assessed, which together ensured a remarkable propylene/propane selectivity up to 39. This selectivity outperformed not only the available carbon adsorbents but also highly competitive among the dominated crystalline porous adsorbents. In addition, the wiggling mesoporous carbon adsorbent showed excellent dynamical separation stability, which ensured its great potential in practical molecular separations.
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Both targeting and penetrating ability are the key characteristics for tissue probing and precise delivery. To construct an efficient nano probing and delivery system toward human epidermal growth factor receptor 2 (HER2) positive cancer, we established a nano liposomal system functionalized with a newly screened HER2 targeting peptide (HP2, YDLKEPEH) and the cell-penetrating peptide TAT simultaneously. Compared with the monofunctionalized liposomal probes, the dual-functional ones demonstrated a synergetic effect in cell uptake, drug delivery, and in vivo imaging. The improved efficacy of the synergetic system provides a prospective strategy for cancer diagnosis and therapy.
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Carbocianinas/química , Sistemas de Liberação de Medicamentos , Corantes Fluorescentes/química , Peptídeos/química , Animais , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Doxorrubicina/administração & dosagem , Doxorrubicina/uso terapêutico , Células HEK293 , Humanos , Ligantes , Lipossomos/química , Neoplasias Mamárias Experimentais/diagnóstico por imagem , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/metabolismo , Camundongos , Estrutura Molecular , Imagem Óptica , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/metabolismoRESUMO
Acting as a brain stimulant, coffee resulted in heightening alertness, keeping arousal, improving executive speed, maintaining vigilance, and promoting memory, which are associated with attention, mood, and cognitive function. Functional near-infrared spectroscopy (fNIRS) is a noninvasive optical method to monitor brain activity by measuring the absorption of the near-infrared light through the intact skull. This study is aimed at acquiring brain activation during executing task performance. The aim is to explore the effect of coffee on cognitive function by the fNIRS neuroimaging method, particularly on the prefrontal cortex regions. The behavioral experimental results on 31 healthy subjects with a Stroop task indicate that coffee can easily and effectively modulate the execute task performance by feedback information of the response time and accuracy rate. The findings of fNIRS showed that apparent hemodynamic changes were detected in the bilateral VLPFC regions and the brain activation regions varied with different coffee conditions.
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Atenção/efeitos dos fármacos , Cafeína/farmacologia , Cognição/efeitos dos fármacos , Função Executiva/efeitos dos fármacos , Adulto , Atenção/fisiologia , Mapeamento Encefálico/métodos , Função Executiva/fisiologia , Feminino , Neuroimagem Funcional/métodos , Humanos , Masculino , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/fisiologia , Espectroscopia de Luz Próxima ao Infravermelho/métodos , Teste de Stroop , Análise e Desempenho de Tarefas , Adulto JovemRESUMO
GLUT1 facilitates the down-gradient translocation of D-glucose across cell membrane in mammals. XylE, an Escherichia coli homolog of GLUT1, utilizes proton gradient as an energy source to drive uphill D-xylose transport. Previous studies of XylE and GLUT1 suggest that the variation between an acidic residue (Asp27 in XylE) and a neutral one (Asn29 in GLUT1) is a key element for their mechanistic divergence. In this work, we combined computational and biochemical approaches to investigate the mechanism of proton coupling by XylE and the functional divergence between GLUT1 and XylE. Using molecular dynamics simulations, we evaluated the free energy profiles of the transition between inward- and outward-facing conformations for the apo proteins. Our results revealed the correlation between the protonation state and conformational preference in XylE, which is supported by the crystal structures. In addition, our simulations suggested a thermodynamic difference between XylE and GLUT1 that cannot be explained by the single residue variation at the protonation site. To understand the molecular basis, we applied Bayesian network models to analyze the alteration in the architecture of the hydrogen bond networks during conformational transition. The models and subsequent experimental validation suggest that multiple residue substitutions are required to produce the thermodynamic and functional distinction between XylE and GLUT1. Despite the lack of simulation studies with substrates, these computational and biochemical characterizations provide unprecedented insight into the mechanistic difference between proton symporters and uniporters.
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Proteínas de Escherichia coli/química , Proteínas de Escherichia coli/ultraestrutura , Transportador de Glucose Tipo 1/química , Transportador de Glucose Tipo 1/ultraestrutura , Modelos Químicos , Simulação de Dinâmica Molecular , Simportadores/química , Simportadores/ultraestrutura , Transferência de Energia , Humanos , Ligação Proteica , Conformação Proteica , Relação Estrutura-Atividade , TermodinâmicaRESUMO
In this study, bipolar memristive behaviors were systematically characterized in Ag/Sb2Te3/Ag hetero-junctions. By using in situ Raman and photoluminescence spectroscopy, a direct observation of the bonding environment and band structure confirmed that resistive switches are strongly related to the electronic valence changes in Sb2Te3 and the formation of Schottky barriers at Ag/Sb2Te3 interfaces. Band movement of Sb2Te3 acquired by first-principles calculations also supports the electrostatic barrier charging as a memristive mechanism of Ag/Sb2Te3/Ag heterocells. Independent resistance-switching behaviors that can be utilized in both amorphous and crystalline Sb2Te3 lead to multiple resistance values with a large memory window (104-105) and low read voltage (â¼0.2 V), giving rise to a unique multi-level memory concept. This study based on Ag/Sb2Te3/Ag hetero-junctions offers a significant understanding to promote the use of Sb2Te3 and other chalcogenide memristors as promising candidates for compatible high-density memory applications.
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Over the past two decades, oil spills have been one of the most serious ecological disasters, causing massive damage to the aquatic and terrestrial ecosystems as well as the socio-economy. In view of this situation, several methods have been developed and utilized to analyze oil samples. Among these methods, laser-induced fluorescence (LIF) technology has been widely used in oil spill detection due to its classification method, which is based on the fluorescence characteristics of chemical material in oil. This review systematically summarized the LIF technology from the perspective of excitation wavelength selection and the application of traditional and novel machine learning algorithms to fluorescence spectrum processing, both of which are critical for qualitative and quantitative analysis of oil spills. It can be seen that an appropriate excitation wavelength is indispensable for spectral discrimination due to different kinds of polycyclic aromatic hydrocarbons' (PAHs) compounds in petroleum products. By summarizing some articles related to LIF technology, we discuss the influence of the excitation wavelength on the accuracy of the oil spill detection model and proposed several suggestions on the selection of excitation wavelength. In addition, we introduced some traditional and novel machine learning (ML) algorithms and discussed the strengths and weaknesses of these algorithms and their applicable scenarios. With an appropriate excitation wavelength and data processing algorithm, it is believed that laser-induced fluorescence technology will become an efficient technique for real-time detection and analysis of oil spills.
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Poluição por Petróleo , Petróleo , Hidrocarbonetos Policíclicos Aromáticos , Poluentes Químicos da Água , Poluição por Petróleo/análise , Fluorescência , Ecossistema , Poluentes Químicos da Água/análise , Petróleo/análise , Hidrocarbonetos Policíclicos Aromáticos/análise , Lasers , Monitoramento Ambiental/métodosRESUMO
The planned viaduct in Jining, Shandong is a priority project in the city. However, the 63 working faces of a mine in Jining is only 3 m away from the planned viaduct, posing a serious threat to the safety of the viaduct's construction. Consequently, it is essential to evaluate the stability of the planned viaduct's goaf area under the influence of the 63 working faces. However, the 63 working faces are short faces, and there is a lack of corresponding prediction of surface residual subsidence. To address this issue, this paper employs theoretical analysis and numerical simulation to uncover the foundation deformation mechanism and characteristics of fractured rock and soil mass in the short goaf. Subsequently, a residual subsidence prediction method for the short goaf was proposed for the viaduct mined-out area. This new approach was implemented for the planned viaduct in Jining, and its effectiveness was validated through InSAR and leveling monitoring results. The research findings offer technical support for viaduct construction in areas affected by underground mining.
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Mineração , Solo , Simulação por Computador , CidadesRESUMO
BACKGROUND: This study presents a case of rapidly developing respiratory failure due to antisynthetase syndrome (AS) following coronavirus disease 2019 (COVID-19) in a 33-year-old man diagnosed with Klinefelter syndrome (KS). CASE SUMMARY: A 33-year-old man with a diagnosis of KS was admitted to the Department of Pulmonary and Critical Care Medicine of a tertiary hospital in China for fever and shortness of breath 2 wk after the onset of COVID-19. Computed tomography of both lungs revealed diffuse multiple patchy heightened shadows in both lungs, accompanied by signs of partial bronchial inflation. Metagenomic next-generation sequencing of the bronchoalveolar lavage fluid suggested absence of pathogen. A biopsy specimen revealed organizing pneumonia with alveolar septal thickening. Additionally, extensive auto-antibody tests showed strong positivity for anti-SSA, anti-SSB, anti-Jo-1, and anti-Ro-52. Following multidisciplinary discussions, the patient received a final diagnosis of AS, leading to rapidly progressing respiratory failure. CONCLUSION: This study underscores the clinical progression of AS-associated interstitial lung disease subsequent to viral infections such as COVID-19 in patients diagnosed with KS.
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Peri-implantitis, a leading cause of implant failure, currently lacks effective therapeutic strategies. Given that bacterial infection and reactive oxygen species overabundance serve as primary pathogenic and triggering factors, respectively, an adhesive hydrogel has been created for in-situ injection. The hydrogel is a gallic acid-grafted chitosan (CS-GA) hydrogel containing tannic acid miniaturized particles (TAMP). This provides antibacterial and antioxidant properties. Therefore, this study aims to evaluate the potential role of this hydrogel in preventing and treating peri-implantitis via several experiments. It undergoes rapid formation within a span of over 20 s via an oxidative crosslinking reaction catalyzed by horseradish peroxidase and hydrogen peroxide, demonstrating robust adhesion, superior cell compatibility, and a sealing effect. Furthermore, the incorporation of TAMP offer photothermal properties to the hydrogel, enabling it to enhance the viability, migration, and antioxidant activity of co-cultured human gingival fibroblasts when subjected 0.5 W/cm2 808 nm near-infrared (NIR) irradiation. At higher irradiation power, the hydrogel exhibits progressive improvements in its antibacterial efficacy against Porphyromonas gingivalis and Fusobacterium nucleatum. It attains rates of 83.11 ± 5.42 % and 83.48 ± 6.855 %, respectively, under 1 W/cm2 NIR irradiation. In summary, the NIR-controlled CS-GA/TAMP hydrogel, exhibiting antibacterial and antioxidant properties, represents a promising approach for the prophylaxis and management of peri-implantitis.
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Quitosana , Peri-Implantite , Humanos , Peri-Implantite/tratamento farmacológico , Peri-Implantite/prevenção & controle , Ácido Gálico/farmacologia , Hidrogéis , Antioxidantes/farmacologia , Antibacterianos/farmacologiaRESUMO
γ-Aminobutyric acid (GABA), an important inhibitory neurotransmitter in the central nervous system, is recycled through specific GABA transporters (GATs). GAT1, which is mainly expressed in the presynaptic terminals of axons, is a potential drug target of neurological disorders due to its essential role in GABA transport. Here we report four cryogenic electron microscopy structures of human GAT1, at resolutions of 2.2-3.2 Å. GAT1 in substrate-free form or in complex with the antiepileptic drug tiagabine exhibits an inward-open conformation. In the presence of GABA or nipecotic acid, inward-occluded structures are captured. The GABA-bound structure reveals an interaction network bridged by hydrogen bonds and ion coordination for GABA recognition. The substrate-free structure unwinds the last helical turn of transmembrane helix TM1a to release sodium ions and substrate. Complemented by structure-guided biochemical analyses, our studies reveal detailed mechanism of GABA recognition and transport, and elucidate mode of action of the inhibitors, nipecotic acid and tiagabine.