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AIMS: Succinate, a metabolite in the tricarboxylic acid cycle, is increasingly recognized to play essential roles in inflammation by functioning either as an intracellular or extracellular signaling molecule. However, the role and mechanisms of succinate in inflammation remain elusive. Here, we investigated the mechanism underlying the effects of succinate on neuroinflammation in intracerebral hemorrhage (ICH) models. RESULTS: We unexpectedly found that succinate robustly inhibited neuroinflammation and conferred protection following ICH. Mechanistically, oxidation of succinate by succinate dehydrogenase (SDH) drove reverse electron transport (RET) at mitochondrial complex I, leading to mitochondrial superoxide production in microglia. Complex I-derived superoxide, in turn, activated uncoupling protein 2 (UCP2). By using mice with specific deletion of UCP2 in microglia/macrophage, we showed that UCP2 was needed for succinate to inhibit neuroinflammation, confer protection, and activate downstream AMP-activated protein kinase (AMPK) following ICH. Moreover, knockdown of SDH, complex I or AMPK abolished the therapeutic effects of succinate following ICH. INNOVATION AND CONCLUSION: We provide evidence that driving complex I RET to activate UCP2 is a novel mechanism of succinate intracellular signaling and a mechanism underlying the inhibition of neuroinflammation by succinate. KEY WORDS: succinate; uncoupling protein 2; microglia; neuroinflammation; intracerebral hemorrhage.
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The abnormal aggregation of Aß has been considered one of the primary causative factors for Alzheimer's disease. Diverse molecular entities have been developed to mitigate the formation of toxic Aß aggregates within the brain by inhibiting Aß aggregation. Recognizing that many FDA-approved drugs are derived from natural products, we present a summary of recent discoveries involving natural product molecules with inhibitory effects on Aß aggregation. By consolidating these findings, our review offers researchers a concise overview of the latest advancements in natural product-based interventions for Alzheimer's disease.
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Doença de Alzheimer , Peptídeos beta-Amiloides , Produtos Biológicos , Agregados Proteicos , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Produtos Biológicos/síntese química , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Humanos , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Agregados Proteicos/efeitos dos fármacos , Estrutura MolecularRESUMO
The development of high-temperature nondestructive testing (NDT) requires ultrasonic transducers with good temperature resistance and high sensitivity for improved detection efficiency. Piezoelectric composite can improve the performance of transducers because of its high electromechanical coupling coefficient and adjustable acoustic impedance. In this study, 1-3-2 composites and 1-3-2 high-temperature composite ultrasonic transducers (HTCUTs) based on 0.36BiScO3-0.64PbTiO3 (BSPT), which is preferred piezoelectric materials at 200 ° C- 300 ° C, and high-temperature epoxy with a center frequency of 6 MHz were designed and fabricated. From 25 ° C to 250 ° C, 1-3-2 composites show a higher electromechanical coupling coefficient kt especially at high temperatures (~0.53 at 25 ° C and ~0.64 at 250 ° C) than monolithic BSPT (~0.5). The signal of the pulse-echo response of 1-3-2 HTCUTs is distinguishable up to 250 ° C and remains stable ( [Formula: see text] mV) below 150 ° C, exhibiting higher sensitivity (improved by 7 dB) than that of monolithic BSPT high-temperature ultrasonic transducers (HTUTs). Bandwidth has been greatly enhanced especially at high temperatures (~103% at 250 ° C) compared with that of monolithic BSPT HTUTs (~30% at 250 ° C). To verify the excellent performance, B-mode scanning imaging measurement of a stepped steel block and defect location detection of a steel block was performed, showing the potential for high-temperature NDT applications.
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Sunscreens play a crucial role in protecting the skin from ultraviolet (UV) damage. However, present commercial sunscreens have a tendency to generate free radicals in the UV window, resulting in serious inflammatory responses and health problems. In this study, we demonstrate that silk fibroin microspheres (SFMPs) assembled from regenerated silk fibroin (SF) could scavenge free radicals while preventing UV irradiation and thus present a promising sunscreen. The SFMP reflected more UV light than SF and presented a higher stability than that of organic commercial sunscreens. In vitro analysis proved that SFMP could more efficiently scavenge the hydroxy radical and reduce the intracellular reactive oxygen than titanium dioxide (TiO2). In vivo experiments exhibited that SFMP provided stronger skin protection against UV irradiation than commercial sunscreens and TiO2. Furthermore, SFMP treatment significantly inhibited the skin inflammatory response. This work suggests that the SFMP has great potential to be developed into a biosafe sunscreen.
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Bombyx , Fibroínas , Animais , Fibroínas/farmacologia , Protetores Solares/farmacologia , Microesferas , Radicais Livres , SedaRESUMO
Nucleophilic substitutions are fundamentally important transformations in synthetic organic chemistry. Despite the substantial advances in bimolecular nucleophilic substitutions (SN2) at saturated carbon centers, analogous SN2 reaction at the amide nitrogen atom remains extremely limited. Here we report an SN2 substitution method at the amide nitrogen atom with amine nucleophiles for nitrogen-nitrogen (N-N) bond formation that leads to a novel strategy toward biologically and medicinally important hydrazide derivatives. We found the use of sulfonate-leaving groups at the amide nitrogen atom played a pivotal role in the reaction. This new N-N coupling reaction allows the use of O-tosyl hydroxamates as electrophiles and readily available amines, including acyclic aliphatic amines and saturated N-heterocycles as nucleophiles. The reaction features mild conditions, broad substrate scope (>80 examples), excellent functional group tolerability, and scalability. The method is applicable to late-stage modification of various approved drug molecules, thus enabling complex hydrazide scaffold synthesis.
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Peptides and proteins undergo crucial modifications to alter their physicochemical properties to expand their applications in diverse fields. Various techniques, such as unnatural amino acid incorporation, enzyme catalysis, and chemoselective methods, have been employed for site-selective peptide and protein modification. While traditional methods remain valuable, advancement in host-guest chemistry introduces innovative and promising approaches for the selective modification of peptides and proteins. Macrocycles exhibit robust binding affinities, particularly with natural amino acids, which facilitates their use in selectively binding to specific sequences. This distinctive property endows macrocycles with the potential for modification of target peptides and proteins. This review provides a comprehensive overview of strategies utilizing macrocycles for the selective modification of peptides and proteins. These strategies unlock new possibilities for constructing antibody-drug conjugates and stabilizing volatile medications.
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Peptídeos , Proteínas , Peptídeos/química , Proteínas/química , Aminoácidos/química , Processamento de Proteína Pós-TraducionalRESUMO
Ultra-high frequency (>100 MHz) acoustic waves feature biocompatibility and high sensitivity and allow biomedical imaging and acoustic tweezers. Primarily, excellent spatial resolution and broad bandwidth at ultra-high frequency is the goal for pathological research and cell selection at the cellular level. Here, we propose an efficient approach to visualize mouse brain atrophy by self-focused ultrasonic sensors at ultra-high frequency with ultra-broad bandwidth. The numerical models of geometry and theoretically predicted acoustic parameters for half-concave piezoelectric elements are calculated by the differential method, which agrees with measured results (lateral resolution: 24 µm, and bandwidth: 115% at -6 dB). Compared with the brain slices of 2-month-old mouse, the atrophy visualization of the 6-month-old mouse brain was realized by C-mode imaging with an acoustic microscopy system, which is a potential prospect for diagnosis and treatment of Alzheimer's disease (AD) combined with neuroscience. Meanwhile, the acoustic properties of the brain slices were quantitatively measured by the acoustic microscopy. These encouraging results demonstrate the promising application for high-resolution imaging in vitro biological tissue with ultra-high frequency self-focusing ultrasonic sensors.
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Diagnóstico por Imagem , Ultrassom , Camundongos , Animais , Acústica , Encéfalo/diagnóstico por imagem , AtrofiaRESUMO
Viruses are ubiquitous in the oceans, exhibiting high abundance and diversity. Here, we systematically analyze existing genomic sequences of marine prokaryotes to compile a Marine Prokaryotic Genome Dataset (MPGD, consisting of over 12,000 bacterial and archaeal genomes) and a Marine Temperate Viral Genome Dataset (MTVGD). At least 40% of the MPGD genomes contain one or more proviral sequences, indicating that they are lysogens. The MTVGD includes over 12,900 viral contigs or putative proviruses, clustered into 10,897 viral genera. We show that lysogens and proviruses are abundant in marine ecosystems, particularly in the deep sea, and marine lysogens differ from non-lysogens in multiple genomic features and growth properties. We reveal several virus-host interaction networks of potential ecological relevance, and identify proviruses that appear to be able to infect (or to be transferred between) different bacterial classes and phyla. Auxiliary metabolic genes in the MTVGD are enriched in functions related to carbohydrate metabolism. Finally, we experimentally demonstrate the impact of a prophage on the transcriptome of a representative marine Shewanella bacterium. Our work contributes to a better understanding of the ecology of marine prokaryotes and their viruses.
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Provírus , Vírus , Provírus/genética , Ecossistema , Oceanos e Mares , Genoma Viral , Bactérias/genética , Vírus/genética , FilogeniaRESUMO
Herein, we report the total syntheses of phleghenrines A and C from commercially available starting materials in 7 and 8 steps, respectively. Notable steps include an inverse electron-demand Diels-Alder reaction between a masked o-benzoquinone and a N-protected enamine to prepare one key intermediate with a bicyclo[2.2.2]octenone core, a Büchner-Curtius-Schlotterbeck one-carbon insertion to expand the bicyclo[2.2.2]octenone to a bicyclo[3.2.2]nonenone, and Trauner's modified 2-pyridone synthesis to install the 2-pyridone moiety.
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Cardiac tissue engineering is a promising strategy for the treatment of myocardial damage. Mesenchymal stem cells (MSCs) are extensively used in tissue engineering. However, transformation of MSCs into cardiac myocytes is still a challenge. Furthermore, weak adhesion of MSCs to substrates often results in poor cell viability. Here, we designed a composite matrix based on silk fibroin (SF) and graphene oxide (GO) for improving the cell adhesion and directing the differentiation of MSCs into cardiac myocytes. Specifically, patterned SF films were first produced by soft lithographic. After being treated by air plasma, GO nanosheets could be successfully coated on the patterned SF films to construct the desired matrix (P-GSF). The resultant P-GSF films presented a nano-topographic surface characterized by linear grooves interlaced with GO ridges. The P-GSF films exhibited high protein absorption and suitable mechanical strength. Furthermore, the P-GSF films accelerated the early cell adhesion and directed the growth orientation of MSCs. RT-PCR results and immunofluorescence imaging demonstrated that the P-GSF films significantly improved the cardiomyogenic differentiation of MSCs. This work indicates that patterned SF films coated with GO are promising matrix in the field of myocardial repair tissue engineering.
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Fibroínas , Células-Tronco Mesenquimais , Humanos , Fibroínas/química , Adesão Celular , Engenharia Tecidual/métodos , Diferenciação Celular , Proliferação de CélulasRESUMO
Weeding is very critical for agriculture due to its importance for reducing crop yield loss. Accurate recognition of weed species is one of the major challenges for achieving automatic and precise weeding. To improve the recognition performance of weeds and crops with similar visual characteristics, a fine-grained weed recognition method based on Swin Transformer and two-stage transfer learning is proposed in this study. First, the Swin Transformer network is introduced to learn the discriminative features that can distinguish subtle differences between visually similar weeds and crops. Second, a contrastive loss is applied to further enlarge the feature differences between different categories of weeds and crops. Finally, a two-stage transfer learning strategy is proposed to address the problem of insufficient training data and improve the accuracy of weed recognition. To evaluate the effectiveness of the proposed method, we constructed a private weed dataset (MWFI) with maize seedling and seven species of associated weeds that are collected in the farmland environment. The experimental results on this dataset show that the proposed method achieved the recognition accuracy, precision, recall, and F1 score of 99.18%, 99.33%, 99.11%, and 99.22%, respectively, which are superior to the performance of the state-of-the-art convolutional neural network (CNN)-based architectures including VGG-16, ResNet-50, DenseNet-121, SE-ResNet-50, and EfficientNetV2. Additionally, evaluation results on the public DeepWeeds dataset further demonstrate the effectiveness of the proposed method. This study can provide a reference for the design of automatic weed recognition systems.
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Vicinal diamines are privileged scaffolds in medicine, agrochemicals, catalysis, and other fields. While significant advancements have been made in diamination of olefins, diamination of allenes is only sporadically explored. Furthermore, direct incorporation of acyclic and cyclic alkyl amines onto unsaturated π systems is highly desirable and important, but problematic for many previously reported amination reactions including the diamination of olefins. Herein, we report a modular and practical diamination of allenes, which offers efficient syntheses of ß,γ-diamino carboxylates and sulfones. This reaction features broad substrate scope, excellent functional group tolerability, and scalability. Experimental and computational studies support an ionic reaction pathway initiated with a nucleophilic addition of the in situ formed iodoamine to the electron deficient allene substrate. An iodoamine activation mode via a halogen bond with a chloride ion was revealed to substantially increase the nucleophilicity of the iodoamine and lower the activation energy barrier for the nucleophilic addition step.
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Acoustic microscopes and acoustic tweezers have great value in the application of microparticle manipulation, biomedical research and non-destructive testing. Ultrahigh frequency (UHF) ultrasonic transducers act as the key component in acoustic microscopes, and acoustic tweezers and acoustic lenses are essential parts of UHF ultrasonic transducers. Therefore, the preparation of acoustic lenses is crucial. Silicon is a suitable material for preparing acoustic lenses because of its high acoustic velocity, low acoustic attenuation and excellent machinability. In previous research, silicon lenses were mainly prepared by etching. However, etching has some drawbacks. The etching of large sizes is complex, time-consuming and expensive. Furthermore, vertical etching is preferred to spherical etching. Thus, a new method of ultra-precision machining was introduced to prepare silicon lenses. In this paper, silicon lenses with an aperture of 892 µm and a depth of 252 µm were prepared. Then, UHF ultrasonic transducers with a center frequency of 157 MHz and a -6-dB bandwidth of 52% were successfully prepared based on silicon lenses. The focal distance of the transducers was 736 µm and the F-number was about 0.82. The transducers had a lateral resolution of 11 µm and could distinguish the 13 µm slots on silicon wafers clearly.
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Resources and environmental carrying capacity (RECC) describes the ability of a system to achieve healthy and sustainable development. Various marine ranching enterprises have emerged in China in recent years, which have aroused concern and debate about the RECC of marine ranching systems. By taking the environmental impact calculated by life cycle assessment (LCA) into consideration in emergy analysis (EA), this study evaluated the comprehensive RECC performance of the whole system and each stage of a marine ranching system in China. The resource use efficiency (RUE) and system carrying ratio (SCR) of the system were reasonably good. However, its environmental loading ratio (ELR), emergy yield ratio (EYR), and emergy sustainability index (ESI) were unsatisfactory. First, the nonrenewable resources dominated the emergy input. Second, the emergy input from the purchased resources was much greater than that of local resources. Third, the potential environmental impact mainly came from the construction stage. Fourth, serious overload of RECC was observed in the maintenance stage. The results indicate that the system is efficient, and its RECC is in a safe state, but the system has deficiencies in environmental protection and the exploitation and utilization of local resources. The proposed analysis framework helps us comprehensively understand the marine ranching RECC performance and provides a research paradigm reference for the sustainability analysis of other complex eco-economic systems.
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Agricultura , Conservação dos Recursos Naturais , Animais , Conservação dos Recursos Naturais/métodos , Agricultura/métodos , China , Estágios do Ciclo de Vida , EcossistemaRESUMO
Gibberellins (GAs) are important plant hormones, but some of their family members are in extremely limited natural supply including GA18. Herein, we report a concise synthesis of (-)-GA18 methyl ester, a member of the C20 gibberellins, from commercially available and cheap andrographolide. Our synthesis features an intramolecular ene reaction to form the C ring, an oxidative cleavage followed by aldol condensation to realize a ring contraction and form the challenging trans-hydrindane (AB ring), and a photochemical [2+2] cycloaddition accompanied by a subsequent SmI2-mediated skeletal rearrangement to construct the methylenebicyclo[3.2.1]octanol moiety (CD ring).
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Ésteres , Giberelinas , Estereoisomerismo , Ciclização , Reguladores de Crescimento de PlantasRESUMO
Ensuring nutrient adequacy for all is a common goal of the international community, but spatial difference is one of the barriers to its development. Exploring nutrient adequacy in coastal areas of China can help regions where food production systems and economic development systems are under mutual stress to reduce nutritional disparities and improve nutrition levels. This paper used the transformation food-to-nutrient model to calculate nutrient production and nutrient consumption in 11 coastal provinces of China and analyzed their spatial patterns, after which spatial differences in nutrient adequacy (including energy, protein and fat) were analyzed. The results showed that nutrient production and nutrient consumption in coastal areas of China showed significant spatial differences, in which nutrient production was mainly concentrated in land food, and the three provinces of Shandong, Jiangsu and Hebei contributed more. Guangdong had the highest nutrient consumption; in contrast, Shanghai, Tianjin, and Hainan had the lowest consumption. Nutrient adequacy was not optimistic, with fat being particularly significant, and nutrient surplus quantity was mainly concentrated in Shandong and Jiangsu and nutrient deficiency quantity was mainly concentrated in Guangdong. Overall, the study area had adequate levels of protein and was deficient in energy and fat levels, with surplus or shortage of 2.41 million tonnes, 2620 billion kcal and 9.97 million tonnes, respectively.
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Nutrientes , ChinaRESUMO
Sensing technology is under intense development to enable the Internet of everything and everyone in new and useful ways. Here we demonstrate a method of stretchable and self-powered temperature sensing. The basic sensing element consists of three layers: an electrolyte, a dielectric, and an electrode. The electrolyte/dielectric interface accumulates ions, and the dielectric/electrode interface accumulates electrons (in either excess or deficiency). The ions and electrons at the two interfaces are usually not charge-neutral, and this charge imbalance sets up an ionic cloud in the electrolyte. The design functions as a charged temperature-sensitive capacitor. When temperature changes, the ionic cloud changes thickness, and the electrode changes open-circuit voltage. We demonstrate high sensitivity (â¼1 mV/K) and fast response (â¼10 ms). Such temperature sensors can be made small, stable, and transparent. Depending on the arrangement of the electrolyte, dielectric, and electrode, we develop four designs for the temperature sensor. In addition, the temperature sensor has good linearity in the range of tens of Kelvin. We further show that the temperature sensors can be integrated into stretchable electronics and soft robots.
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A time-varying magnetic field generates an electric field in an electrolyte, in which ions move. This magnetoionic transduction is studied here in several arrangements. The electrolyte is a hydrogel containing mobile ions, and is in contact with two metallic electrodes. An alternating electric current applied to a metal coil generates a time-varying magnetic field. In response, ions in the hydrogel move. The two hydrogel/electrode interfaces are non-faradaic and accumulate excess ions of opposite signs, which attract and repel electrons in the two electrodes. When the two electrodes are connected to a voltmeter of internal resistance much larger than that of the hydrogel, an open-circuit voltage is measured, linear in the alternating current applied to the metal coil. A metal coil and a hydrogel coil form an ionotronic transformer, in which an alternating electric current in the metal coil induces an alternating ionic current in the hydrogel coil. Such a transformer can be used for noncontact power transmission, with a voltage high enough to turn on many light-emitting diodes in series. The hydrogel is soft, and readily conforms to a curved surface, such as a glove on a human hand. Motion of the hand can be detected by noncontact magnetoionic transduction.
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Eletrólitos , Imãs , Fontes de Energia Elétrica , Eletrodos , Humanos , ÍonsRESUMO
BACKGROUND: Liver cancer is a common malignant tumor in China, with high mortality. Its occurrence and development were thoroughly studied by high-throughput expression microarray, which produced abundant data on gene expression, mRNA quantification and the clinical data of liver cancer. However, the hub genes, which can be served as biomarkers for diagnosis and treatment of early liver cancer, are not well screened. RESULTS: Here we present a new method for getting 6 key genes, aiming to diagnose and treat the early liver cancer. We firstly analyzed the different expression microarrays based on TCGA database, and a total of 1564 differentially expressed genes were obtained, of which 1400 were up-regulated and 164 were down-regulated. Furthermore, these differentially expressed genes were studied by using GO and KEGG enrichment analysis, a PPI network was constructed based on the STRING database, and 15 hub genes were obtained. Finally, 15 hub genes were verified by applying the survival analysis method on Oncomine database, and 6 key genes were ultimately identified, including PLK1, CDC20, CCNB2, BUB1, MAD2L1 and CCNA2. The robustness analysis of four independent data sets verifies the accuracy of the key gene's classification of the data set. CONCLUSIONS: Although there are complicated differences between cancer and normal cells in gene functions, cancer cells could be differentiated in case that a group of special genes expresses abnormally. Here we presented a new method to identify the 6 key genes for diagnosis and treatment of early liver cancer, and these key genes can help us understand the pathogenesis of liver cancer more deeply.
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Biologia Computacional , Neoplasias Hepáticas , Biomarcadores Tumorais/genética , Detecção Precoce de Câncer , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Neoplasias Hepáticas/genética , Mapas de Interação de ProteínasRESUMO
Massarinolinâ A and purpurolides are bioactive bergamotane sesquiterpenes condensed with a variety of synthetically challenging ring systems: a bicyclo[3.1.1]heptane, an oxaspiro[3.4]octane, and a dioxaspiro[4.4]nonane (oxaspirolactone). Herein, we report the first enantioselective total syntheses of massarinolinâ A, purpurolidesâ B, D, E, and 2,3-deoxypurpurolide C. Our synthesis and computational analysis also led to a structural revision of massarinolinâ A. The divergent approach features an enantioselective organocatalyzed Diels-Alder reaction to install the first stereogenic center in high ee, a scalable flow photochemical Wolff rearrangement to build the key bicyclo[3.1.1]heptane, a furan oxidative cyclization to form the oxaspirolactone, a late-stage allylic C-H oxidation, and a Myers' NBSH-promoted sigmatropic elimination to install the exo methylene group of massarinolinâ A.