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The mesenchymal-epithelial transition factor (c-Met) is a tyrosine kinase receptor protein, and excessive cell transformation can lead to cancer. Therefore, there is an urgent need to develop novel receptor tyrosine kinase inhibitors by inhibiting the activity of c-Met protein. In this study, 41 compounds are selected from the reported literature, and the interactions between phenoxy pyridine derivatives and tumor-associated proteins are systematically investigated using a series of computer-assisted drug design (CADD) methods, aiming to predict potential c-Met inhibitors with high activity. The Topomer CoMFA (q2=0.620, R2=0.837) and HQSAR (q2=0.684, R2=0.877) models demonstrate a high level of robustness. Further internal and external validation assessments show high applicability and accuracy. Based on the results of the Topomer CoMFA model, structural fragments with higher contribution values are identified and randomly combined using a fragment splice technique, result in a total of 20 compounds with predicted activities higher than the template molecules. Molecular docking results show that these compounds have good interactions and van der Waals forces with the target proteins. The results of molecular dynamics and ADMET predictions indicate that compounds Y4, Y5, and Y14 have potential as c-Met inhibitors. Among them, compound Y14 exhibits superior stability with a binding free energy of -165.18â KJ/mol. These studies provide a reference for the future design and development of novel compounds with c-Met inhibitory activity.
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BACKGROUND: With the requirements of environmental, cost and economic sustainability, new sources of alternative proteins in the livestock industry are receiving increasing attention. Mulberry (Morus alba L.) leaves are a unique feed resource because of their high protein content and large availability. Therefore, mining sustainable protein suitable for the animal husbandry industry in sericulture resources could achieve a win-win situation. RESULTS: The protein content in mulberry leaves is 232.10-386.16 g kg-1 , and the mean value of crude fat content is 43.76 ± 8.48 g kg-1 , which has the advantages of protein content and energy. In addition, the average content of phytic acid in mulberry leaves is only 1.88 ± 0.56 g kg-1 , which means that it is not inhibited in terms of nutrient absorption. Meanwhile, the digestibility of protein was Bean pulp > Sample 8 ≈ Alfalfa ≈ Sample 13 ≈ Cottonseed meal > Fish meal, and the ß-turn and particle size of mulberry leaf protein are more conducive to digestion in vitro. Furthermore, the protein of Sample 13 had the richest essential amino acids (252.00 g kg-1 ) and the highest essential amino acid index (EAAI), which was superior to conventional feed protein. In addition, the partial substitution of mulberry leaf protein (15%) significantly increased the EAAI value of conventional feed protein. However, to balance nutrition, it is necessary to combine mulberry leaf protein with other proteins to further broaden its application field. CONCLUSION: Mulberry leaves are a new source of feed protein, which helps to alleviate the two major problems of mulberry resource surplus and feed protein resource shortage. © 2023 Society of Chemical Industry.
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Morus , Animais , Morus/química , Folhas de Planta/químicaRESUMO
Rare earth elements (REEs) are critical for numerous modern technologies, and demand is increasing globally; however, production steps are resource-intensive and environmentally damaging. Some plant species are able to hyperaccumulate REEs, and understanding the biology behind this phenomenon could play a pivotal role in developing more environmentally friendly REE recovery technologies. Here, we identified a REE transporter NRAMP REE Transporter 1 (NREET1) from the REE hyperaccumulator fern Dicranopteris linearis. Although NREET1 belongs to the natural resistance-associated macrophage protein (NRAMP) family, it shares a low similarity with other NRAMP members. When expressed in yeast, NREET1 exhibited REE transport capacity, but it could not transport divalent metals, such as zinc, nickel, manganese, or iron. NREET1 is mainly expressed in D. linearis roots and predominantly localized in the plasma membrane. Expression studies in Arabidopsis thaliana revealed that NREET1 functions as a transporter mediating REE uptake and transfer from root cell walls into the cytoplasm. Moreover, NREET1 has a higher affinity for transporting light REEs compared to heavy REEs, which is consistent to the preferential enrichment of light REEs in field-grown D. linearis. We therefore conclude that NREET1 may play an important role in the uptake and consequently hyperaccumulation of REEs in D. linearis. These findings lay the foundation for the use of synthetic biology techniques to design and produce sustainable, plant-based REE recovery systems.
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Gleiquênias , Proteínas de Membrana Transportadoras , Metais Terras Raras , Membrana Celular , Gleiquênias/metabolismo , Zinco/metabolismoRESUMO
The high cell density, immobilization and stability of biofilms are ideal characteristics for bacteria in resisting antibiotic therapy. CsgD is a transcription activating factor that regulates the synthesis of curly fimbriae and cellulose in Escherichia coli, thereby enhancing bacterial adhesion and promoting biofilm formation. To investigate the role of CsgD in biofilm formation and stress resistance in bacteria, the csgD deletion mutant ΔcsgD was successfully constructed from the engineered strain E. coli BL21(DE3) using the CRISPR/Cas9 gene-editing system. The results demonstrated that the biofilm of ΔcsgD decreased by 70.07% (p < 0.05). Additionally, the mobility and adhesion of ΔcsgD were inhibited due to the decrease in curly fimbriae and extracellular polymeric substances. Furthermore, ΔcsgD exhibited a significantly decreased resistance to acid, alkali and osmotic stress conditions (p < 0.05). RNA-Seq results revealed 491 differentially expressed genes between the parent strain and ΔcsgD, with enrichment primarily observed in metabolism-related processes as well as cell membrane structure and catalytic activity categories. Moreover, CsgD influenced the expression of biofilm and stress response genes pgaA, motB, fimA, fimC, iraP, ompA, osmC, sufE and elaB, indicating that the CsgD participated in the resistance of E. coli by regulating the expression of biofilm and stress response. In brief, the transcription factor CsgD plays a key role in the stress resistance of E. coli, and is a potential target for treating and controlling biofilm.
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Proteínas de Escherichia coli , Escherichia coli , Escherichia coli/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , Proteínas de Bactérias/metabolismo , Transativadores/metabolismo , Regulação Bacteriana da Expressão Gênica , Biofilmes , Proteínas da Membrana Bacteriana Externa/genéticaRESUMO
Mineral-based bulk structural materials (MBSMs) are known for their long history and extensive range of usage. The inherent brittleness of minerals poses a major problem to the performance of MBSMs. To overcome this problem, design principles have been extracted from natural biominerals, in which the extraordinary mechanical performance is achieved via the hierarchical organization of minerals and organics. Nevertheless, precise and efficient fabrication of MBSMs with bioinspired hierarchical structures under mild conditions has long been a big challenge. This Perspective provides a panoramic view of an emerging fabrication strategy, matrix-directed mineralization, which imitates the in vivo growth of some biominerals. The advantages of the strategy are revealed by comparatively analyzing the conventional fabrication techniques of artificial hierarchically structured MBSMs and the biomineral growth processes. By introducing recent advances, we demonstrate that this strategy can be used to fabricate artificial MBSMs with hierarchical structures. Particular attention is paid to the mass transport and the precursors that are involved in the mineralization process. We hope this Perspective can provide some inspiring viewpoints on the importance of biomimetic mineralization in material fabrication and thereby spur the biomimetic fabrication of high-performance MBSMs.
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Materiais Biomiméticos , Biomimética , Materiais Biomiméticos/química , Biomimética/métodos , Minerais/químicaRESUMO
Dicranopteris linearis is the best-known hyperaccumulator species of rare earth elements (REEs) and silicon (Si), capable of dealing with toxic level of REEs. Hence, this study aimed to clarify how D. linearis leaves cope with excessive REE stress, and whether Si plays a role in REE detoxification. The results show that lanthanum (La - as a representative of the REEs) stress led to decreased biomass and an increase of metabolism related to leaf cell wall synthesis and modification. However, the La stress-induced responses, especially the increase of pectin-related gene expression level, pectin polysaccharides concentration, and methylesterase activity, could be mitigated by Si supply. Approximately 70% of the Si in D. linearis leaves interacted with the cell walls to form organosilicon Si-O-C linkages. The Si-modified cell walls contained more hydroxyl groups, leading to a more efficient REE retention compared to the Si-free ones. Moreover, this [Si-cell wall] matrix increased the pectin-La accumulation capacity by 64%, with no effect on hemicellulose-La and cellulose-La accumulation capacity. These results suggest that [Si-pectin] matrix fixation is key in REE detoxification in D. linearis, laying the foundation for the development of phytotechnological applications (e.g., REE phytomining) using this species in REE-contaminated sites.
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Metais Terras Raras , Traqueófitas , Silício , Pectinas , LantânioRESUMO
The high fracture toughness of mollusk nacre is predominantly attributed to the structure-associated extrinsic mechanisms such as platelet sliding and crack deflection. While the nacre-mimetic structures are widely adopted in artificial ceramics, the extrinsic mechanisms are often weakened by the relatively low tensile strength of the platelets with a large aspect ratio, which makes the fracture toughness of these materials much lower than expected. Here, it is demonstrated that the fracture toughness of artificial nacre materials with high inorganic contents can be improved by residual stress-induced platelet strengthening, which can catalyze more effective extrinsic toughening mechanisms that are specific to the nacre-mimetic structures. Thereby, while the absolute fracture toughness of the materials is not comparable with advanced ceramic-based composites, the toughness amplification factor of the material reaches 16.1 ± 1.1, outperforming the state-of-the-art biomimetic ceramics. The results reveal that, with the merit of nacre-mimetic structural designs, the overall fracture toughness of the artificial nacre can be improved by the platelet strengthening through extrinsic toughening mechanisms, although the intrinsic fracture toughness may decrease at platelet level due to the strengthening. It is anticipated that advanced structural ceramics with exceeding performance can be fabricated through these unconventional strategies.
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LAY ABSTRACT: Autism spectrum disorder has long been conceptualized as a disorder of "atypical development of functional brain connectivity (which refers to correlations in activity levels of distant brain regions)." However, most of the research has focused on the connectivity between cortical regions, and much remains unknown about the developmental changes of functional connectivity between subcortical and cortical areas in autism spectrum disorder. We used the technique of resting-state functional magnetic resonance imaging to explore the developmental characteristics of intrinsic functional connectivity (functional brain connectivity when people are asked not to do anything) between subcortical and cortical regions in individuals with and without autism spectrum disorder aged 6-30 years. We focused on one important subcortical structure called striatum, which has roles in motor, cognitive, and affective processes. We found that cortico-striatal intrinsic functional connectivities showed opposite developmental trajectories in autism spectrum disorder and typically developing individuals, with connectivity increasing with age in autism spectrum disorder and decreasing or constant in typically developing individuals. We also found significant negative behavioral correlations between those atypical cortico-striatal intrinsic functional connectivities and autistic symptoms, such as social-communication deficits, and restricted/repetitive behaviors and interests. Taken together, this work highlights that the atypical development of cortico-subcortical functional connectivity might be largely involved in the neuropathological mechanisms of autism spectrum disorder.
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Transtorno do Espectro Autista , Transtorno do Espectro Autista/diagnóstico por imagem , Encéfalo , Mapeamento Encefálico/métodos , Cognição , Humanos , Imageamento por Ressonância Magnética/métodos , Vias Neurais/diagnóstico por imagemRESUMO
Background: Autism spectrum disorder is characterized by atypical developmental changes during brain maturation, but regional brain functional changes that occur with age and across different frequency bands are unknown. Therefore, the current study aimed to explore potential age and frequency band-related changes in the regional brain activities in autism. Methods: A total of 65 participants who met the DSM-IV criteria for autistic disorder and 55 typically developed (TD) participants (both age 6-30 years) were recruited in the current study. The two groups were matched in age (t=-1.314, P=0.191) and gender (χ2=2.760, P=0.097). The amplitude of low-frequency fluctuations (ALFF) was employed to explore the effect of development on spontaneous brain activity in individuals with autism and in TD participants across slow-5 (0.01-0.027 Hz), slow-4 (0.027-0.073 Hz), and slow-3 (0.073-0.1 Hz) frequency bands. The diagnosis-by-age interaction effect in the whole brain voxels in autism and TD groups was investigated. Results: Autism individuals showed significantly higher ALFF in the dorsal striatum in childhood (Caudate cluster: t=3.626, P=0.001; Putamen cluster: t=2.839, P=0.007) and remarkably lower ALFF in the dorsal striatum in adulthood (Caudate cluster: t=-2.198, P=0.038; Putamen cluster: t=-2.314, P=0.030) relative to TD, while no significant differences were observed in adolescence (all P>0.05). In addition, abnormal ALFF amplitudes were specific to the slow-4 (0.027-0.073 Hz) frequency band in the clusters above. Conclusions: The current study indicated abnormal development patterns in the spontaneous activity of the dorsal striatum in autism and highlighted the potential role of the slow-4 frequency band in the pathology of autism. Also, the potential brain mechanism of autism was revealed, suggesting that autism-related variations should be investigated in a specific frequency.
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BACKGROUND: Health-related risky behaviors generally refer to behaviors that have a negative impact on health and quality of life. Health-related risky behaviors in adolescents with high-functioning autism (HFA) have not been well understood so far. Adolescents with HFA may have more health-related risky behaviors than neurotypical adolescents. AIM: To investigate health-related risky behaviors and their risk factors with HFA. METHODS: This is an observational study. Our study enrolled 110 adolescents aged 12-19-years-old meeting Diagnostic and Statistical Manual of Mental Disorders 4th edition criteria for HFA. They were recruited from Peking University Sixth Hospital. There were also 110 age, sex and nationality matched controls enrolled who came from a public school in Beijing, China. Both groups completed the Adolescents Health-related Risky Behavior Inventory. Nonparametric tests were carried out for comparison of the Adolescents Health-related Risky Behavior Inventory scores between the two groups. Expression recognition, the Inventory of Subjective Life Quality for Child and Adolescent, Chinese Wechsler Intelligence Scale for Children, Wechsler Intelligence Scale for Adult-Chinese Revised, Theory of Mind test and Autism Spectrum Screening Questionnaire were assessed in the autism group to explore factors associated with health-related risky behaviors. Multivariate regression analysis was conducted to explore the risk factors of health-related risky behaviors in the HFA group. RESULTS: The results showed that the total score of the Adolescents Health-related Risky Behavior Inventory and scores of "aggression and violence," "suicide and self-injury," "health compromising behavior" and "unprotected sex" subscales in the HFA group were significantly higher than those in the control group (Z range -4.197 to -2.213, P < 0.05). Among the associated factors, poor emotional experience (B = -0.268, P < 0.001), depression (B = -0.321, P < 0.001), low score of intelligence (B = -0.032, P = 0.042), low score of Theory of Mind test (B = -1.321, P = 0.003) and poor adaptation to school life (B = -0.152, P = 0.006) were risk factors. These risky behaviors may promote the occurrence of health-related risky behaviors in adolescents with HFA. CONCLUSION: This study showed that adolescents with HFA were more likely to be involved in health-related risky behaviors. Different health-related risky behaviors have different reasons.