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Pueraria lobata (Willd.) Ohwi, known as kudzu and used as a "longevity powder" in China, is an edible plant which is rich in flavonoids and believed to be useful for regulating blood sugar and treating diabetes, although the modes of action are unknown. Here, a total of 53 flavonoids including 6 novel compounds were isolated from kudzu using multidimensional preparative liquid chromatography. The flavonoid components were found to lower blood sugar levels, promote urine sugar levels in mice, and reduce the urine volume. Molecular docking and in vitro assays suggested that the antidiabetic effect of kudzu was attributed to at least three targets: sodium-dependent glucose transporter 2 (SGLT2), protein tyrosine phosphatase-1B (PTP1B), and alpha-glucosidase (AG). This study suggests a possible mechanism for the antidiabetic effect that may involve the synergistic action of multiple active compounds from kudzu.
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Flavonoides , Hipoglicemiantes , Extratos Vegetais , Proteína Tirosina Fosfatase não Receptora Tipo 1 , Pueraria , Pueraria/química , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Flavonoides/química , Animais , Camundongos , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Humanos , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Simulação de Acoplamento Molecular , Masculino , alfa-Glucosidases/metabolismo , alfa-Glucosidases/química , Glicemia/metabolismo , Plantas Comestíveis/químicaRESUMO
Histamine 4 receptor (H4R), the most recently identified subtype of histamine receptor, primarily induces inflammatory reactions upon activation. Several H4R antagonists have been developed for the treatment of inflammatory bowel disease (IBD) and atopic dermatitis (AD), but their use has been limited by adverse side effects, such as a short half-life and toxicity. Natural products, as an important source of anti-inflammatory agents, offer minimal side effects and reduced toxicity. This work aimed to identify novel H4R antagonists from natural products. An H4R target-pathway model deconvoluted downstream Gi and MAPK signaling pathways was established utilizing cellular label-free integrative pharmacology (CLIP), on which 148 natural products were screened. Cryptotanshinone was identified as selective H4R antagonist, with an IC50 value of 11.68 ± 1.30 µM, which was verified with Fluorescence Imaging Plate Reader (FLIPR) and Cellular Thermal Shift (CTS) assays. The kinetic binding profile revealed the noncompetitive antagonistic property of cryptotanshinone. Two allosteric binding sites of H4R were predicted using SiteMap, Fpocket and CavityPlus. Subsequent molecular docking and dynamics simulation indicated that cryptotanshinone interacts with H4R at a pocket formed by the outward interfaces between TM3/4/5, potentially representing a new allosteric binding site for H4R. Overall, this study introduced cryptotanshinone as a novel H4R antagonist, offering promise as a new hit for drug design of H4R antagonist. Additionally, this study provided a novel screening model for the discovery of H4R antagonists.
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Produtos Biológicos , Relação Dose-Resposta a Droga , Descoberta de Drogas , Receptores Histamínicos H4 , Humanos , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Receptores Histamínicos H4/antagonistas & inibidores , Receptores Histamínicos H4/metabolismo , Relação Estrutura-Atividade , Estrutura Molecular , Fenantrenos/farmacologia , Fenantrenos/química , Antagonistas dos Receptores Histamínicos/farmacologia , Antagonistas dos Receptores Histamínicos/química , Simulação de Acoplamento Molecular , FenótipoRESUMO
The water oxidation reaction, a crucial process for solar energy conversion, has garnered significant research attention. Achieving efficient energy conversion requires the development of cost-effective and durable water oxidation catalysts. To design effective catalysts, it is essential to have a fundamental understanding of the reaction mechanisms. This review presents a comprehensive overview of recent advancements in the understanding of the mechanisms of water oxidation using transition metal-based heterogeneous electrocatalysts, including Mn, Fe, Co, Ni, and Cu-based catalysts. It highlights the catalytic mechanisms of different transition metals and emphasizes the importance of monitoring of key intermediates to explore the reaction pathway. In addition, advanced techniques for physical characterization of water oxidation intermediates are also introduced, for the purpose of providing information for establishing reliable methodologies in water oxidation research. The study of transition metal-based water oxidation electrocatalysts is instrumental in providing novel insights into understanding both natural and artificial energy conversion processes.
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ETHNOPHARMACOLOGICAL RELEVANCE: Prostatitis and benign prostatic hyperplasia (BPH) are inflammations of the prostate gland, which surrounds the urethra in males. Jinqiancao granules are a traditional Chinese medicine used to treat kidney stones and this medicine consists of four herbs: Desmodium styracifolium (Osbeck) Merr., Pyrrosia calvata (Baker) Ching, Plantago asiatica L. and stigma of Zea mays L. AIM OF THE STUDY: We hypothesized that Jinqiancao granules could be a potential therapy for prostatitis and BPH, and this work aimed to elucidate active compounds in Jinqiancao granules and their target mechanisms for the potential treatment of the two diseases. MATERIALS AND METHODS: Jinqiancao granules were commercially available and purchased. Database-driven data mining and networking were utilized to establish a general correlation between Jinqiancao granules and the two diseases above. Ultra-performance liquid chromatography-mass spectrometry was used for compound separation and characterization. The characterized compounds were evaluated on four G-protein coupled receptors (GPCRs: GPR35, muscarinic acetylcholine receptor M3, alpha-1A adrenergic receptor α1A and cannabinoid receptor CB2). A dynamic mass redistribution technique was applied to evaluate compounds on four GPCRs. Nitric acid (NO) inhibition was tested on the macrophage cell line RAW264.7. Molecular docking was conducted on GPR35-active compounds and GPR35 crystal structure. Statistical analysis using GEO datasets was conducted. RESULTS: Seventy compounds were isolated and twelve showed GPCR activity. Three compounds showed potent GPR35 agonistic activity (EC50 < 10 µM) and the GPR35 agonism action of PAL-21 (Scutellarein) was reported for the first time. Docking results revealed that the GPR35-targeting compounds interacted at the key residues for the agonist-initiated activation of GPR35. Five compounds showed weak antagonistic activity on M3, which was confirmed to be a disease target by statistical analysis. Seventeen compounds showed NO inhibitory activity. Several compounds showed multi-target properties. An experiment-based network reflected a pharmacological relationship between Jinqiancao granules and the two diseases. CONCLUSIONS: This study identified active compounds in Jinqiancao granules that have synergistic mechanisms, contributing to anti-inflammatory effects. The findings provide scientific evidence for the potential use of Jinqiancao granules as a treatment for prostatitis and BPH.
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Hiperplasia Prostática , Prostatite , Masculino , Humanos , Prostatite/tratamento farmacológico , Prostatite/metabolismo , Hiperplasia Prostática/tratamento farmacológico , Hiperplasia Prostática/metabolismo , Simulação de Acoplamento Molecular , Próstata , Receptores Acoplados a Proteínas G/metabolismoRESUMO
Myocardial dysfunction is a prevalent complication of sepsis (septic cardiomyopathy) with a high mortality rate and limited therapeutic options. Naringenin, a natural flavonoid compound with anti-inflammatory and antioxidant properties, holds promise as a potential treatment for sepsis-induced myocardial dysfunction. This study investigated the pharmacological effects of naringenin on septic cardiomyopathy. In vivo and in vitro experiments demonstrated that naringenin improved cardiomyocyte damage. Network pharmacology and database analysis revealed that HIF-1α is a key target protein of naringenin. Elevated expression of HIF-1α was observed in damaged cardiomyocytes, and the HIF-1α inhibitor effectively protected against LPS-induced cardiomyocyte damage. Molecular docking studies confirmed the direct binding between naringenin and HIF-1α protein. Importantly, our findings demonstrated that naringenin did not provide additional attenuation of cardiomyocyte injury on the biases of HIF-1α inhibitor treatment. In conclusion, this study proves that naringenin protects against septic cardiomyopathy through HIF-1α signaling. Naringenin is a promising therapeutic candidate for treating septic cardiomyopathy.
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Cardiomiopatias , Flavanonas , Sepse , Animais , Camundongos , Cardiomiopatias/tratamento farmacológico , Cardiomiopatias/etiologia , Cardiomiopatias/prevenção & controle , Lipopolissacarídeos/farmacologia , Simulação de Acoplamento Molecular , Miócitos Cardíacos/metabolismo , Sepse/complicações , Sepse/tratamento farmacológico , Sepse/metabolismo , Subunidade alfa do Fator 1 Induzível por HipóxiaRESUMO
This work explores potential high-temperature superconductor materials in hydrogen-rich systems. Here, the crystal structure stabilities of ternary Ca-Sc-H systems under high-pressure (P = 100-250 GPa) and their superconductivities are investigated using the particle swarm optimization methodology combined with first-principles calculations. For the predicted candidate structures of Ca-Sc-H systems, the pressure-dependent phase diagram and thermodynamic convex hull were investigated across a wide range of compositions; the electronic properties of all the predicted phases were analyzed in detail to study the bonding behavior of these stable phases. We identified the crystal structures of four thermodynamically stable compounds: R3Ìm-CaScH6, Immm-CaSc2H9,C2/m-Ca2ScH10, and R3Ìm-CaScH12. Among them, R3Ìm-CaScH12 was predicted to have the highest Tc value (i.e., 173 K) at 200 GPa. The discovery of this previously unreported pressure-induced decomposition of Ca-Sc-H systems will pave the way for investigations on the nature of hydrogen-metal interactions.
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Modeling correlations between multimodal physiological signals [e.g., canonical correlation analysis (CCA)] for emotion recognition has attracted much attention. However, existing studies rarely consider the neural nature of emotional responses within physiological signals. Furthermore, during fusion space construction, the CCA method maximizes only the correlations between different modalities and neglects the discriminative information of different emotional states. Most importantly, temporal mismatches between different neural activities are often ignored; therefore, the theoretical assumptions that multimodal data should be aligned in time and space before fusion are not fulfilled. To address these issues, we propose a discriminative correlation fusion method coupled with a temporal alignment mechanism for multimodal physiological signals. We first use neural signal analysis techniques to construct neural representations of the central nervous system (CNS) and autonomic nervous system (ANS). respectively. Then, emotion class labels are introduced in CCA to obtain more discriminative fusion representations from multimodal neural responses, and the temporal alignment between the CNS and ANS is jointly optimized with a fusion procedure that applies the Bayesian algorithm. The experimental results demonstrate that our method significantly improves the emotion recognition performance. Additionally, we show that this fusion method can model the underlying mechanisms in human nervous systems during emotional responses, and our results are consistent with prior findings. This study may guide a new approach for exploring human cognitive function based on physiological signals at different time scales and promote the development of computational intelligence and harmonious human-computer interactions.
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Algoritmos , Emoções , Humanos , Teorema de Bayes , Inteligência Artificial , CogniçãoRESUMO
OBJECTIVES: Chronic hepatitis B (CHB) caused by HBV infection greatly increases the risk of liver cirrhosis and hepatocellular carcinoma. Hepatitis B surface antigen (HBsAg) plays critical roles in the pathogenesis of CHB. HBsAg loss is the key indicator for cure of CHB, but is rarely achieved by current approved anti-HBV drugs. Therefore, novel anti-HBV strategies are urgently needed to achieve sustained HBsAg loss. DESIGN: We developed multiple chimeric antigen receptors (CARs) based on single-chain variable fragments (scFvs, namely MA18/7-scFv and G12-scFv), respectively, targeting HBV large and small envelope proteins. Their impacts on HBsAg secretion and HBV infection, and the underlying mechanisms, were extensively investigated using various cell culture models and HBV mouse models. RESULTS: After secretory signal peptide mediated translocation into endoplasmic reticulum (ER) and secretory pathway, MA18/7-scFv and CARs blocked HBV infection and virion secretion. G12-scFv preferentially inhibited virion secretion, while both its CAR formats and crystallisable fragment (Fc)-attached versions blocked HBsAg secretion. G12-scFv and G12-CAR arrested HBV envelope proteins mainly in ER and potently inhibited HBV budding. Furthermore, G12-scFv-Fc and G12-CAR-Fc strongly suppressed serum HBsAg up to 130-fold in HBV mouse models. The inhibitory effect lasted for at least 8 weeks when delivered by an adeno-associated virus vector. CONCLUSION: CARs possess direct antiviral activity, besides the well-known application in T-cell therapy. Fc attached G12-scFv and G12-CARs could provide a novel approach for reducing circulating HBsAg.
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Hepatite B Crônica , Hepatite B , Neoplasias Hepáticas , Receptores de Antígenos Quiméricos , Camundongos , Animais , Antígenos de Superfície da Hepatite B , Vírus da Hepatite B/genética , Retículo Endoplasmático/metabolismoRESUMO
This study investigated the effects of estrogen and estrogen receptor alpha (ERα) on the pathogenesis of primary biliary cholangitis (PBC) in human intrahepatic bile duct epithelial cells (HiBECs). The researchers measured serum levels of ERα, oxidative stress indicators, and cytokines in PBC patients and healthy controls. They examined the expression of ERα, pyruvate dehydrogenase complex E2-component (PDC-E2), and apoptosis-related proteins in the small bile ducts. In vitro experiments with HiBECs showed that estrogen had a dual effect on cell viability, increasing it at low concentrations but reducing it at higher concentrations. ERα activation led to mitochondrial damage, apoptosis, and upregulation of ERα and PDC-E2 expression. These findings suggest that the high expression of ERα in the bile ducts contributes to mitochondrial damage, inflammation, and apoptosis in PBC. The study highlights ERα as a potential target for understanding and treating estrogen-mediated PBC pathogenesis.
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Células Epiteliais , Receptor alfa de Estrogênio , Cirrose Hepática Biliar , Mitocôndrias , Humanos , Cirrose Hepática Biliar/patologia , Ductos Biliares Intra-Hepáticos/citologia , Células Epiteliais/patologia , Mitocôndrias/patologia , Estresse Oxidativo , Estudos de Casos e Controles , Receptor alfa de Estrogênio/metabolismo , Estrogênios/metabolismo , Apoptose , Feminino , Pessoa de Meia-Idade , Sobrevivência Celular , Estradiol/farmacologia , Proteínas Reguladoras de Apoptose/metabolismoRESUMO
The surface properties exhibited by chemically cross-linked polydimethylsiloxanes (CPDMS) such as morphology, stiffness, and wettability have garnered great interest in the study of bacteria-material interactions. Nevertheless, the hidden factor of uncross-linked free PDMS chains that dissociate in CPDMS has often been overlooked when studying the biofilm formation on these polymeric elastomer surfaces. Here, we undertake a comparative characterization of the effects of free chains in CPDMS on bacterial adhesion to both flat and textured Sharklet CPDMS surfaces. Surprisingly, compared to unextracted surfaces, removing free chains from flat and textured CPDMS through solvent extraction results in a tremendous increase in bacterial colony-forming units for both Gram-negative and Gram-positive bacteria up to 2-3 orders in the initial adhesion stage of 2 h. These findings demonstrate that the solvent extraction of free chains from CPDMS is essential in studying the interactions between bacteria and silicone elastomer materials when focusing on a single variable.
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Aderência Bacteriana , Dimetilpolisiloxanos , Molhabilidade , Propriedades de Superfície , Dimetilpolisiloxanos/química , Solventes , BiofilmesRESUMO
How to use the characteristics of EEG signals to obtain more complementary and discriminative data representation is an issue in EEG-based emotion recognition. Many studies have tried spatio-temporal or spatio-spectral feature fusion to obtain higher-level representations of EEG data. However, these studies ignored the complementarity between spatial, temporal and spectral domains of EEG signals, thus limiting the classification ability of models. This study proposed an end-to-end network based on ManifoldNet and BiLSTM networks, named STSNet. The STSNet first constructed a 4-D spatio-temporal-spectral data representation and a spatio-temporal data representation based on EEG signals in manifold space. After that, they were fed into the ManifoldNet network and the BiLSTM network respectively to calculate higher-level features and achieve spatio-temporal-spectral feature fusion. Finally, extensive comparative experiments were performed on two public datasets, DEAP and DREAMER, using the subject-independent leave-one-subject-out cross-validation strategy. On the DEAP dataset, the average accuracy of the valence and arousal are 69.38% and 71.88%, respectively; on the DREAMER dataset, the average accuracy of the valence and arousal are 78.26% and 82.37%, respectively. Experimental results show that the STSNet model has good emotion recognition performance.
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L-Alanyl-L-Glutamine (Ala-Gln) is a common parenteral nutritional supplement. In our previous study, the recombinant whole-cell catalyst Escherichia coli BL21(DE3) overexpressing α-amino acid ester acyltransferase (BPA) to produce Ala-Gln has high activity and has been applied to large-scale production experiments. However, the degradation of Ala-Gln is detected under prolonged incubation, and endogenous broad-spectrum dipeptidase may be the primary cause. In this study, a CRISPR-Cas9 method was used to target pepA, pepB, pepD, pepN, dpp, and dtp to knock out one or more target genes. The deletion combination was optimized, and a triple knockout strain BL21(DE3)-ΔpepADN was constructed. The degradation performance of the knockout chassis was measured, and the results showed that the degradation rate of Ala-Gln was alleviated by 48% compared with the control. On this basis, BpADNPA (BPA-ΔpepADN) was built, and the production of Ala-Gln was 129% of the BPA's accumulation, proving that the ΔpepADN knockout conducive to the accumulation of dipeptide. This study will push forward the industrialization process of Ala-Gln production by whole-cell catalyst Escherichia coli expressing α-amino acid ester acyltransferase. KEY POINTS: ⢠Endogenous dipeptidase knockout alleviates the degradation of Ala-Gln by the chassis ⢠The balanced gene knockout combination is pepA, pepD, and pepN ⢠The accumulation of Ala-Gln with BpADNPA was 129% of the control.
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Aminoácidos , Dipeptidases , Aminoácidos/metabolismo , Escherichia coli/genética , Escherichia coli/metabolismo , Dipeptidases/metabolismo , Aciltransferases/genética , Aciltransferases/metabolismo , Técnicas de Inativação de Genes , Dipeptídeos/metabolismo , Glutamina/metabolismoRESUMO
l-Alanyl-l-glutamine (Ala-Gln) is a widely used value-added dipeptide whose production relies heavily upon an efficient biocatalyst. The currently available yeast biocatalysts that express α-amino acid ester acyltransferase (SsAet) possess relatively low activity, which may be attributed to glycosylation. Here, to promote SsAet activity in yeast, we identified the N-glycosylation site as the Asn residue at position 442 and subsequently eliminated the negative effect of N-glycosylation on SsAet by removing artificial and native signal peptides to obtain K3A1, a novel yeast biocatalyst with significantly improved activity. Additionally, the optimal reaction conditions of strain K3A1 were determined (25 °C, pH 8.5, AlaOMe/Gln = 1:2), resulting in a maximum molar yield and productivity of approximately 80% and 1.74 g·(L·min)-1, respectively. Therefore, we developed a promising system to cleanly produce Ala-Gln in a safe, efficient, and sustainable manner, which may contribute to the future industrial production of Ala-Gln.
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Aciltransferases , Glutamina , Aminoácidos , Dipeptídeos/química , Glutamina/metabolismo , Glicosilação , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , BiocatáliseRESUMO
Lung adenocarcinoma (LADC) is a prevalent type of lung cancer that is associated with lung and gut microbiota. However, the interactions between these microbiota and cancer development remain unclear. In this study, a microbiome study was performed on paired fecal and bronchoalveolar lavage fluid (BALF) samples from 42 patients with LADC and 64 healthy controls using 16S rRNA gene amplicon and shotgun metagenome sequencing, aiming to correlate the lung and gut microbiota with LADC. Patients with LADC had reduced α-diversity in the gut microbiome and altered ß-diversity compared with healthy controls, and the abundances of Flavonifractor, Eggerthella, and Clostridium were higher in the gut microbiome of LADC patients. The increased abundance of microbial species, such as Flavonifractor plautii, was associated with advanced-stage LADC and a higher metastasis rate. Phylogenetically, Haemophilus parainfluenzae was the most frequently shared taxon in the lung and gut microbiota of LADC patients. Gut microbiome functional pathways involving leucine, propanoate, and fatty acids were associated with LADC progression. In conclusion, the low diversity of the gut microbiota and the presence of H. parainfluenzae in gut and lung microbiota were linked to LADC development, while an increased abundance of F. plautii and the enriched metabolic pathways could be associated with the progression of LADC.
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To achieve the goal of "dual-carbon", induction furnaces with high efficiency and energy-saving advantages are paid more attention in the foundry and metallurgy industries. The service life and safety of induction furnaces strongly depended on the lining because expansion and forward sintering could result in the erosion and slag resistance of the lining. Focusing on the tailoring properties of alumina-magnesia-based dry ramming mixes, calcined magnesia particles were replaced with the novel multi-component materials of calcium magnesium aluminate (CaO-MgO-Al2O3, CMA) with a size of 200 mesh. Properties such as the bulk density, apparent porosity, strength, and slag corrosion resistance of alumina-magnesia-based dry ramming mix containing CMA were evaluated contrastively. The results demonstrate that the penetration index of manganese-bearing slag in dry ramming mixes first decreased and then slightly increased with the addition of CMA. Meanwhile, the permanent linear change in dry ramming mixes was gradually reduced. When the addition of CMA reached 4 wt%, the strength of the dry ramming mixes was slightly greater than the reference, and the slag penetration index was just 75% of the latter.
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Soybean (Glycine max) is a major source of protein and edible oil world-wide and is cultivated in a wide range of latitudes. However, it is extremely sensitive to photoperiod, which influences flowering time, maturity, and yield, and severely limits soybean latitude adaptation. In this study, a genome-wide association study (GWAS) identified a novel locus in accessions harboring the E1 allele, called Time of flowering 8 (Tof8), which promotes flowering and enhances adaptation to high latitude in cultivated soybean. Gene functional analyses showed that Tof8 is an ortholog of Arabidopsis FKF1. We identified two FKF1 homologs in the soybean genome. Both FKF1 homologs are genetically dependent on E1 by binding to E1 promoter to activate E1 transcription, thus repressing FLOWERING LOCUS T 2a (FT2a) and FT5a transcription, which modulate flowering and maturity through the E1 pathway. We also demonstrate that the natural allele FKF1bH3 facilitated adaptation of soybean to high-latitude environments and was selected during domestication and improvement, leading to its rapid expansion in cultivated soybean. These findings provide novel insights into the roles of FKF1 in controlling flowering time and maturity in soybean and offer new means to fine-tune adaptation to high latitudes and increase grain yield.
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Glycine max , Proteínas de Plantas , Aclimatação , Adaptação Fisiológica , Flores/fisiologia , Regulação da Expressão Gênica de Plantas , Estudo de Associação Genômica Ampla , Fotoperíodo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Glycine max/metabolismoRESUMO
KEY MESSAGE: Five loci related to soybean protein and amino acid contents were colocated by performing linkage mapping and GWAS. The haplotype analysis showed that Glyma.08G109100 may be useful to improve the soybean seed composition. Soybean (Glycine max (L.) Merr.) seeds are good protein sources. Although genetic variation is abundant, natural variation in seed amino acids and their derived traits is lacking across soybean accessions. Here, we determined the contents of protein and 17 amino acids, obtained 36 derived traits based on the protein and total amino acid contents, and derived 34 traits based on seven amino acid family groups. Furthermore, we performed a linkage analysis of the contents of 17 amino acids and 73 amino acid-derived traits based on the recombinant inbred line (RIL)-derived Kefeng No. 1 × Nannong 1138-2. Six hundred thirty-nine quantitative trait loci (QTLs) were identified, explaining 6.07-39.00% of the phenotypic variation. Among these loci, five were detected in diverse soybean accessions using a genome-wide association study. A network analysis revealed that some loci that were significantly associated with multiple amino acids were tightly linked on chromosome 8 based on linkage disequilibrium values, which also further confirmed the results of the correlation analysis among amino acid traits. Through a combination of a genome-wide association study, linkage analysis, qRT-PCR, and genomic polymorphism comparison, Glyma.08G109100 on chromosome 8, which may affect amino acid contents, was selected. The haplotype analysis showed that Hap-T of Glyma.08G109100 may be useful to improve the contents of protein and 16 amino acids in soybean. This study provides new insights into the genetic basis of the amino acid composition in soybean seeds and may facilitate marker-based breeding of soybean with improved nutritional value.
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Estudo de Associação Genômica Ampla , Glycine max , Glycine max/metabolismo , Aminoácidos/metabolismo , Melhoramento Vegetal , Fenótipo , Sementes/química , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Background: Vitamin D3 [VitD3, 1,25 (OH)2D3] is known to have immunomodulatory and anti-microbial properties; however, its activity against Helicobacter pylori is unclear. In this study, we established H. pylori infection models in wild-type and VitD3 receptor (VDR) knockdown mice and analyzed the effects of VitD3 and their underlying mechanisms. Methods: VDR+/+ and VDR+/- mice were intragastrically infected with the H. pylori SS1 strain. After confirmation of H. pylori infection, mice were treated with different doses of VitD3. The infection levels in stomach tissues were quantified using the colony-forming assay, and the expression levels of the VDR and cathelicidin antimicrobial peptide (CAMP) in the gastric mucosa were analyzed by immunohistochemistry and western blotting. Results: The gastric mucosa of VDR+/- mice was more susceptible to H. pylori colonization and had lower levels of VDR and CAMP expression than that of VDR+/+ mice. H. pylori infection upregulated VDR and CAMP expression in the stomach of both wild-type and mutant mice, and VitD3 treatment resulted in further increase of VDR and CAMP levels, while significantly and dose-dependently decreasing the H. pylori colonization rate in both mouse groups, without affecting blood calcium or phosphorus levels. Conclusion: Our data indicate that oral administration of VitD3 reduces the H. pylori colonization rate and upregulates VDR and CAMP expression in the gastric mucosa, suggesting a role for VitD3/VDR/CAMP signaling in the eradication of H. pylori in the stomach. These findings provide important insights into the mechanism underlying the anti-H. pylori activity of VitD3 and should be useful in the development of measures to eradicate H. pylori.
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Single-chain variable fragments (scFvs), composed of variable domains of heavy and light chains of an antibody joined by a linker, share antigen binding capacity with their parental antibody. Due to intrinsically low solubility and stability, only two Escherichia coli-produced scFvs have been approved for therapy. Here we report that a 33-residue peptide, termed P17 tag, increases the solubility of multiple scFvs produced in Escherichia coli SHuffle strain by up to 11.6 fold. Hydrophilic sequence, especially charged residues, but not the predicted α-helical secondary structure of P17 tag, contribute to the solubility enhancement. Notably, the P17 tag elevates the thermostability of scFv as efficiently as intra-domain disulfide bonds. Moreover, a P17-tagged scFv targeting hepatitis B virus surface proteins shows over two-fold higher antigen-binding affinity and virus-neutralizing activity than the untagged version. These data strongly suggest a type I intramolecular chaperone-like activity of the P17 tag. Hence, the P17 tag could benefit the research, production, and application of scFv.
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Escherichia coli , Anticorpos de Cadeia Única , Escherichia coli/metabolismo , Chaperonas Moleculares/metabolismo , SolubilidadeRESUMO
Polymers are widely used in our daily life; however, most of them are highly flammable. Once modified with flame retardants (FRs), polymers always have deteriorative properties in mechanical strength aspects. As a countermeasure, a novel unified phosphorus and nitrogen-containing organic nano-layered flame retardant (BA-MA) was synthesized by the assembly of biphenyl-4,4'-diphosphonic acid (BA) and melamine (MA), which was used as an additive flame retardant for polystyrene (PS) resin. The chemical structure and morphology of BA-MA were characterized, and a possible growth mechanism of the nanolayered structure was presented in detail. The resulting BA-MA with a thickness of about 60 nm can be uniformly dispersed in the PS resin, thus maintaining the mechanical properties of the material. Remarkably, under only 1 wt% loading of BA-MA, the flammability of PS can be largely reduced with a 68% reduction in the peak heat release rate. Additionally, the smoke release was also significantly inhibited. The research on flame retardant mechanisms shows that BA-MA mainly produces incombustible gas to dilute the concentration of combustibles and promote the formation of aromatic carbon layers to isolate oxygen transmission and heat transfer.