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Invisibility, a fascinating ability of hiding objects within environments, has attracted broad interest for a long time. However, current invisibility technologies are still restricted to stationary environments and narrow band. Here, we experimentally demonstrate a Chimera metasurface for multiterrain invisibility by synthesizing the natural camouflage traits of various poikilotherms. The metasurface achieves chameleon-like broadband in situ tunable microwave reflection mimicry of realistic water surface, shoal, beach/desert, grassland, and frozen ground from 8 to 12 GHz freely via the circuit-topology-transited mode evolution, while remaining optically transparent as an invisible glass frog. Additionally, the mechanic-driven Chimera metasurface without active electrothermal effect, owning a bearded dragon-like thermal acclimation, can decrease the maximum thermal imaging difference to 3.1 °C in tested realistic terrains, which cannot be recognized by human eyes. Our work transitions camouflage technologies from the constrained scenario to ever-changing terrains and constitutes a big advance toward the new-generation reconfigurable electromagnetics with circuit-topology dynamics.
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BACKGROUND: To summarize the clinical and genetic characteristics of patients with pyridox(am)ine-5'-phosphate oxidase (PNPO) deficiency. METHODS: Clinical and genetic data of the patients were collected and analyzed. RESULTS: Eighteen patients from 17 families with variants in PNPO were collected, and 15 cases survived to date. The age of onset ranged from 1 day to 5 months (median age 6.5 days) and seven of them presented with seizures <24 h. About 7/18 (39%) of patients showed seizure-free with pyridoxine (PN) or pyridoxal-5'-phosphate treatment. Two patients showed surprised therapeutic responses to antiseizure medications therapy: one could be controlled for up to 1 year and 5 months, and the other showed seizure-free for >8 years. The neurodevelopment was normal in one patient, mild delay in four, in whom responded well to PN. Severe delay could be seen in the remaining 10 surviving patients. Genetic analysis revealed 14 variants of PNPO, seven of which were novel. Five pairs of unrelated patients were observed to carry the same variants, respectively, and had similar developmental status and onset age of seizures in some degree in each pair, whereas also had differences. CONCLUSIONS: The clinical characteristics, including age of onset, treatment response and prognosis, were variable and difficult to classify into different types clearly. Patients with PNPO deficiency who used PN as their main treatment and being able to control seizures seemed to be associated with better outcomes. Patients with the same genotype tended to show the correlation of phenotype-genotype.
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Encefalopatias Metabólicas , Hipóxia-Isquemia Encefálica , Doenças Metabólicas , Piridoxaminafosfato Oxidase , Humanos , Encefalopatias Metabólicas/genética , Hipóxia-Isquemia Encefálica/genética , Oxirredutases , Fosfatos/uso terapêutico , Fosfato de Piridoxal/uso terapêutico , Piridoxaminafosfato Oxidase/deficiência , Piridoxaminafosfato Oxidase/genética , Piridoxina , Convulsões/tratamento farmacológico , Convulsões/genéticaRESUMO
Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease with high case mortality rates, which is caused by Dabie bandavirus (DBV), a novel pathogen also termed as SFTS virus (SFTSV). Currently, no specific therapeutic drugs or vaccines are available for SFTS. Myxovirus resistance protein A (MxA) has been shown to inhibit multiple viral pathogens; however, the role of MxA in DBV infection is unknown. Here, we demonstrated that DBV stimulates MxA expression which, in turn, restricts DBV infection. Mechanistic target analysis revealed that MxA specifically interacts with the viral nucleocapsid protein (NP) in a manner independent of RNA. Minigenome reporter assay showed that in agreement with its targeting of NP, MxA inhibits DBV ribonucleoprotein (RNP) activity. In detail, MxA interacts with the NP N-terminal and disrupts the interaction of NP with the viral RNA-dependent RNA polymerase (RdRp) but not NP multimerization, the critical activities of NP for RNP formation and function. Furthermore, MxA N-terminal domain was identified as the functional domain inhibiting DBV infection, and, consistently, then was shown to interact with NP and obstruct the NP-RdRp interaction. Additionally, threonine 103 within the N-terminal domain is important for MxA inhibition to DBV, and its mutation (T103A) attenuates MxA binding to NP and obstruction of the NP-RdRp interaction. This study uncovers MxA inhibition of DBV with a series of functional and mechanistical analyses, providing insights into the virus-host interactions and probably helping inform the development of antiviral agents in the future.IMPORTANCEDBV/SFTSV is an emerging high-pathogenic virus. Since its first identification in China in 2009, cases of DBV infection have been reported in many other countries, posing a significant threat to public health. Uncovering the mechanisms of DBV-host interactions is necessary to understand the viral pathogenesis and host response and may advance the development of antiviral therapeutics. Here, we found that host factor MxA whose expression is induced by DBV restricts the virus infection. Mechanistically, MxA specifically interacts with the viral NP and blocks the NP-RdRp interaction, inhibiting the viral RNP activity. Further studies identified the key domain and amino acid residue required for MxA inhibition to DBV. Consistently, they were then shown to be important for MxA targeting of NP and obstruction of the NP-RdRp association. These findings unravel the restrictive role of MxA in DBV infection and the underlying mechanism, expanding our knowledge of the virus-host interactions.
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Phlebovirus , Febre Grave com Síndrome de Trombocitopenia , Humanos , Proteínas do Nucleocapsídeo , Ribonucleoproteínas/metabolismo , RNA Polimerase Dependente de RNA , Febre Grave com Síndrome de Trombocitopenia/metabolismo , Febre Grave com Síndrome de Trombocitopenia/virologia , Phlebovirus/fisiologia , Interações Hospedeiro-PatógenoRESUMO
We report the generation and comparative analysis of genome-wide chromatin state maps, PPARγ and CTCF localization maps, and gene expression profiles from murine and human models of adipogenesis. The data provide high-resolution views of chromatin remodeling during cellular differentiation and allow identification of thousands of putative preadipocyte- and adipocyte-specific cis-regulatory elements based on dynamic chromatin signatures. We find that the specific locations of most such elements differ between the two models, including at orthologous loci with similar expression patterns. Based on sequence analysis and reporter assays, we show that these differences are determined, in part, by evolutionary turnover of transcription factor motifs in the genome sequences and that this turnover may be facilitated by the presence of multiple distal regulatory elements at adipogenesis-dependent loci. We also utilize the close relationship between open chromatin marks and transcription factor motifs to identify and validate PLZF and SRF as regulators of adipogenesis.
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Adipogenia , Estudo de Associação Genômica Ampla , Adipócitos/citologia , Adipócitos/metabolismo , Adulto , Animais , Fator de Ligação a CCCTC , Antígenos CD36/genética , Montagem e Desmontagem da Cromatina , Feminino , Genômica , Histonas/metabolismo , Humanos , Camundongos , PPAR gama/metabolismo , Elementos Reguladores de Transcrição , Proteínas Repressoras/genética , Fator de Resposta Sérica/metabolismo , Fatores de Transcrição/metabolismoRESUMO
BACKGROUND: PHACTR1 (phosphatase and actin regulators) plays a key role in cortical migration and synaptic activity by binding and regulating G-actin and PPP1CA. This study aimed to expand the genotype and phenotype of patients with de novo variants in PHACTR1 and analyse the impact of variants on protein-protein interaction. METHODS: We identified seven patients with PHACTR1 variants by trio-based whole-exome sequencing. Additional two subjects were ascertained from two centres through GeneMatcher. The genotype-phenotype correlation was determined, and AlphaFold-Multimer was used to predict protein-protein interactions and interfaces. RESULTS: Eight individuals carried missense variants and one had CNV in the PHACTR1. Infantile epileptic spasms syndrome (IESS) was the unifying phenotype in eight patients with missense variants of PHACTR1. They could present with other types of seizures and often exhibit drug-resistant epilepsy with a poor prognosis. One patient with CNV displayed a developmental encephalopathy phenotype. Using AlphaFold-Multimer, our findings indicate that PHACTR1 and G-actin-binding sequences overlap with PPP1CA at the RPEL3 domain, which suggests possible competition between PPP1CA and G-actin for binding to PHACTR1 through a similar polymerisation interface. In addition, patients carrying missense variants located at the PHACTR1-PPP1CA or PHACTR1-G-actin interfaces consistently exhibit the IESS phenotype. These missense variants are mostly concentrated in the overlapping sequence (RPEL3 domain). CONCLUSIONS: Patients with variants in PHACTR1 can have a phenotype of developmental encephalopathy in addition to IESS. Moreover, our study confirmed that the variants affect the binding of PHACTR1 to G-actin or PPP1CA, resulting in neurological disorders in patients.
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Sequenciamento do Exoma , Estudos de Associação Genética , Proteínas dos Microfilamentos , Mutação de Sentido Incorreto , Fenótipo , Espasmos Infantis , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Actinas/genética , Predisposição Genética para Doença , Genótipo , Proteínas dos Microfilamentos/genética , Mutação de Sentido Incorreto/genética , Doenças do Sistema Nervoso/genética , Proteína Fosfatase 1/genética , Espasmos Infantis/genéticaRESUMO
Primary angle-closure glaucoma (PACG) is the leading cause of irreversible blindness in the world. Angle closure induced by pupil block and secondary iris synechia is the fundamental pathology of the PACG. The molecular mechanisms of angle closure have not yet been clearly illustrated. This study was designed to investigate the protein difference in the aqueous humour and explore new biomarker of the PACG. Aqueous humour (AH) was collected from patients with acute primary angle closure (APAC) and cataract (n = 10 in APAC group) and patients with cataract only (n = 10 in control group). Samples were pooled and measured using label-free proteome technology. Then, the differentially expressed proteins (DEPs) were verified by ELISA using independent AH samples (n = 20 each group). More than 400 proteins were revealed in both groups through proteomics. Comparing the two groups, there were 91DEPs. These proteins participate in biological activities such as inflammation, fibrosis, nerve growth and degeneration and metabolism. We found that the expression of transforming growth factor-ß2 and matrilin2 was downregulated in the APAC group. The two proteins are related to inflammation and extracellular matrix formation, which might be involved in angle closure. This study characterized DEPs in AH of the APAC and found a downregulated protein matrilin2.
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Humor Aquoso , Catarata , Humanos , Doença Aguda , Humor Aquoso/metabolismo , Catarata/metabolismo , Ensaio de Imunoadsorção Enzimática , Inflamação/metabolismo , Fator de Crescimento Transformador beta2/metabolismo , Proteínas Matrilinas/metabolismoRESUMO
Sterols have long been associated with diverse fields, such as cancer treatment, drug development, and plant growth; however, their underlying mechanisms and functions remain enigmatic. Here, we unveil a critical role played by a GmNF-YC9-mediated CCAAT-box transcription complex in modulating the steroid metabolism pathway within soybeans. Specifically, this complex directly activates squalene monooxygenase (GmSQE1), which is a rate-limiting enzyme in steroid synthesis. Our findings demonstrate that overexpression of either GmNF-YC9 or GmSQE1 significantly enhances soybean stress tolerance, while the inhibition of SQE weakens this tolerance. Field experiments conducted over two seasons further reveal increased yields per plant in both GmNF-YC9 and GmSQE1 overexpressing plants under drought stress conditions. This enhanced stress tolerance is attributed to the reduction of abiotic stress-induced cell oxidative damage. Transcriptome and metabolome analyses shed light on the upregulation of multiple sterol compounds, including fucosterol and soyasaponin II, in GmNF-YC9 and GmSQE1 overexpressing soybean plants under stress conditions. Intriguingly, the application of soybean steroids, including fucosterol and soyasaponin II, significantly improves drought tolerance in soybean, wheat, foxtail millet, and maize. These findings underscore the pivotal role of soybean steroids in countering oxidative stress in plants and offer a new research strategy for enhancing crop stress tolerance and quality from gene regulation to chemical intervention.
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Glycine max , Estresse Fisiológico , Glycine max/genética , Glycine max/fisiologia , Glycine max/metabolismo , Estresse Fisiológico/genética , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Plantas Geneticamente Modificadas , Esteroides/metabolismo , Secas , Produtos Agrícolas/genética , Produtos Agrícolas/metabolismo , Proteínas de Plantas/metabolismo , Proteínas de Plantas/genéticaRESUMO
Cancer remains a leading cause of mortality and poses a substantial threat to public health. Studies have revealed that Long noncoding RNA DANCR is a cytoplasmic lncRNA whose aberrant expression plays a pivotal role in various cancer types. Within tumour biology, DANCR exerts regulatory control over crucial processes such as proliferation, invasion, metastasis, angiogenesis, inflammatory responses, cellular energy metabolism reprogramming, and apoptosis. By acting as a competitive endogenous RNA for miRNAs and by interacting with proteins and mRNAs at the molecular level, DANCR contributes significantly to cancer progression. Elevated DANCR levels have also been linked to heightened resistance to anticancer drugs. Moreover, the detection of circulating DANCR holds promise as a valuable biomarker for aiding in the clinical differentiation of different cancer types. This article offers a comprehensive review and elucidation of the primary functions and molecular mechanisms through which DANCR influences tumours.
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Regulação Neoplásica da Expressão Gênica , Neoplasias , RNA Longo não Codificante , Humanos , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Neoplasias/genética , Neoplasias/patologia , Neoplasias/metabolismo , AnimaisRESUMO
Pseudoexfoliation syndrome (PEX) is characterized by the deposition of fibrous pseudoexfoliation material (PEXM) in the eye, and secondary glaucoma associated with this syndrome has a faster and more severe clinical course. The incidence of PEX and pseudoexfoliative glaucoma (PEXG) exhibits ethnic clustering; however, few proteomic studies related to PEX and PEXG have been conducted in Asian populations. Therefore, we aimed to conduct proteomic analysis on the aqueous humor (AH) obtained from Uyghur patients with cataracts, those with PEX and cataracts, and those with PEXG and cataracts to better understand the molecular mechanisms of the disease and identify its potential biomarkers. To this end, AH was collected from patients with cataracts (n = 10, control group), PEX with cataracts (n = 10, PEX group), and PEXG with cataracts (n = 10, PEXG group) during phacoemulsification. Label-free quantitative proteomic techniques combined with bioinformatics were used to identify and analyze differentially expressed proteins (DEPs) in the AH of PEX and PEXG groups. Then, independent AH samples (n = 12, each group) were collected to validate DEPs by enzyme-linked immunosorbent assay (ELISA). The PEX group exhibited 25 DEPs, while the PEXG group showed 44 DEPs, both compared to the control group. Subsequently, we found three newly identified proteins in both PEX and PEXG groups, wherein FRAS1-related extracellular matrix protein 2 (FREM2) and osteoclast-associated receptor (OSCAR) exhibited downregulation, whereas coagulation Factor IX (F9) displayed upregulation. Bioinformatics analysis suggested that extracellular matrix interactions, abnormal blood-derived proteins, and lysosomes were mainly involved in the process of PEX and PEXG, and the PPI network further revealed F9 may serve as a potential biomarker for both PEX and PEXG. In conclusion, this study provides new information for understanding the proteomics of AH in PEX and PEXG.
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Humor Aquoso , Síndrome de Exfoliação , Proteínas do Olho , Proteômica , Humanos , Síndrome de Exfoliação/metabolismo , Humor Aquoso/metabolismo , Proteômica/métodos , Masculino , Feminino , Idoso , Proteínas do Olho/metabolismo , China/epidemiologia , Glaucoma de Ângulo Aberto/metabolismo , Pessoa de Meia-Idade , Biomarcadores/metabolismo , Ensaio de Imunoadsorção Enzimática , Catarata/metabolismo , Pressão Intraocular/fisiologiaRESUMO
PROPOSE: The propose is to investigate the reasons for the insolubility of Form III in water and to explore the mechanism of the hydration process of Form III. METHODS: The conformational and cohesive energies of Form III and Form H1 were calculated using Gaussian 16 and Crystal Explorer 17. Gaussian 16 and Multiwfn 3.8 was used to calculate the molecular surface electrostatic potential of Form III and Form H1 and to calculate the energies of the stronger intermolecular interactions in the crystal structure. The behaviors of Form III in water were simulated using Gromacs 2020.6. Finally, the hydration process from Form III to Form H1 was monitored in situ using Raman spectroscopy. RESULTS: The conformational energies of Form III and H1 are almost the same. The cohesion energy of Form H1 is much larger than that of Form III because both number of hydrogen bonds and van der Waals interactions are higher in the Form H1. During the simulation, the supercell of APZ form a supramolecular cluster. Several molecules manually dismantled from the cluster spontaneously combine to form new molecular clusters. Both increases in temperature and external energy input accelerate the hydration process. CONCLUSIONS: More hydrogen bonds and strong van der Waals interactions in Form H1 lead to a greater stability. The overall decrease in polarity and the strong binding effect on APZ molecule clusters due to intermolecular interactions lead to the water insolubility of Form III. The hydration process from Form III to Form H1 follows a novel, dandelion sowing-like hydration mechanism.
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Água , Aripiprazol , Solubilidade , Temperatura , Água/química , Simulação por ComputadorRESUMO
In this work, we propose elastic metamaterials with phase discontinuities to steer the propagation of near-source bulk waves in a semi-infinite elastic medium. Our design exploits an array of embedded subwavelength resonators with tailored masses to attain a complete phase shift spanning [Formula: see text]. This phase control allows for diverse wave functionalities, such as directional refraction and energy focusing. Through the use of dispersion diagrams and the generalized Snell's law, along with a multiple scattering formulation, we analytically demonstrate the effectiveness of our design in achieving the desired wavefront manipulation. The proposed design has the potential to advance the field of guiding elastic waves using metamaterials and find practical applications in areas such as isolating ground-borne vibrations in densely urbanized regions and energy harvesting. This article is part of the theme issue 'Current developments in elastic and acoustic metamaterials science (Part 1)'.
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To identify the role of enterotoxin-related genes in colorectal cancer (CRC) development and progression. Upregulated differentially expressed genes shared by three out of five Gene Expression Omnibus (GEO) data sets were included to screen the key enterotoxin-induced oncogenes (EIOGs) according to criteria oncogene definition, enrichment, and protein-protein interaction (PPI) network analysis, followed by prognosis survival, immune infiltration, and protential drugs analyses was performed via integration of RNA-sequencing data and The Cancer Genome Atlas-derived clinical profiles. We screened nine common key EIOGs from at least three GEO data sets. A Cox proportional hazards regression models verified that more alive cases, decreased overall survival, and highest 4-year survival prediction in CRC patients with high-risk score. Protein tyrosine phosphatase receptor type F polypeptide-interacting protein alpha-4 (PPFIA4), STY11, SCN3B, and SPTBN5 were shared in the same PPI network. Immune infiltration results showed that SCN3B and synaptotagmin 11 expression were obviously associated with B cell, macrophage, myeloid dendritic cell, neutrophils, and T cell CD4+ and CD8+ in both colon adenocarcinoma and rectal adenocarcinoma. CHIR-99021, MLN4924, and YK4-279 were identified as the potential drugs for treatment. Finally, upregulated EIOGs genes PPFIA4 and SCN3B were found in colon adenocarcinoma and PPFIA4 and SCN3B were proved to promote cell proliferation and migration in vitro. We demonstrated here that EIOGs promoting a malignancy phenotype was related with poor survival and prognosis in CRC, which might be served as novel therapeutic targets in CRC management.
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Neoplasias Colorretais , Enterotoxinas , Humanos , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Mapas de Interação de ProteínasRESUMO
Omics, bioinformatics, molecular docking, and experimental validation were used to elucidate the hepatoprotective effects, mechanisms, and active compounds of Shandougen (SDG) based on the biolabel-led research pattern. Integrated omics were used to explore the biolabels of SDG intervention in liver tissue. Subsequently, bioinformatics and molecular docking were applied to topologically analyze its therapeutic effects, mechanisms, and active compounds based on biolabels. Finally, an animal model was used to verify the biolabel analysis results. Omics, bioinformatics, and molecular docking revealed that SDG may exert therapeutic effects on liver diseases in the multicompound and multitarget synergistic modes, especially liver cirrhosis. In the validation experiment, SDG and its active compounds (betulinic acid and gallic acid) significantly improved the liver histopathological damage in the CCl4-induced liver cirrhosis model. Meanwhile, they also produced significant inhibitory effects on the focal adhesion pathway (integrin alpha-1, myosin regulatory light chain 2, laminin subunit gamma-1, etc.) and alleviated the associated pathological processes: focal adhesion (focal adhesion kinase 1)-extracellular matrix (collagen alpha-1(IV) chain, collagen alpha-1(VI) chain, and collagen alpha-2(VI) chain) dysfunction, carcinogenesis (alpha-fetoprotein, NH3, and acetylcholinesterase), inflammation (tumor necrosis factor alpha, interleukin-1 [IL-1], IL-6, and IL-10), and oxidative stress (reactive oxygen species, malonaldehyde, and superoxide dismutase). This study provides new evidence and insights for the hepatoprotective effects, mechanisms, and active compounds of SDG.
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Biologia Computacional , Simulação de Acoplamento Molecular , Animais , Fígado/efeitos dos fármacos , Fígado/metabolismo , Substâncias Protetoras/farmacologia , Substâncias Protetoras/química , Masculino , Ratos , Tetracloreto de Carbono , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/metabolismo , Ácido Gálico/química , Ácido Gálico/farmacologia , Triterpenos/química , Triterpenos/farmacologia , Proteômica/métodos , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/químicaRESUMO
BACKGROUND: Investigating the molecular biology underpinning the early-stage of traumatic temporomandibular joint (TMJ) ankylosis is crucial for discovering new ways to prevent the disease. This study aimed to explore the dynamic changes of transcriptome from the intra-articular hematoma or the newly generated ankylosed callus during the onset and early progression of TMJ ankylosis. METHODS: Based on a well-established sheep model of TMJ bony ankylosis, the genome-wide microarray data were obtained from samples at postoperative Days 1, 4, 7, 9, 11, 14 and 28, with intra-articular hematoma at Day 1 serving as controls. Fold changes in gene expression values were measured, and genes were identified via clustering based on time series analysis and further categorised into three major temporal classes: increased, variable and decreased expression groups. The genes in these three temporal groups were further analysed to reveal pathways and establish their biological significance. RESULTS: Osteoblastic and angiogenetic genes were found to be significantly expressed in the increased expression group. Genes linked to inflammation and osteoclasts were found in the decreased expression group. The various biological processes and pathways related to each temporal expression group were identified, and the increased expression group comprised genes exclusively involved in the following pathways: Hippo signaling pathway, Wnt signaling pathway and Rap 1 signaling pathway. The decreased expression group comprised genes exclusively involved in immune-related pathways and osteoclast differentiation. The variable expression group consisted of genes associated with DNA replication, DNA repair and DNA recombination. Significant biological pathways and transcription factors expressed at each time point postoperatively were also identified. CONCLUSIONS: These data, for the first time, presented the temporal gene expression profiling and reveal the important process of molecular biology in the early-stage of traumatic TMJ bony ankylosis. The findings might contributed to identifying potential targets for the treatment of TMJ ankylosis.
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Anquilose , Transtornos da Articulação Temporomandibular , Articulação Temporomandibular , Animais , Ovinos/genética , Côndilo Mandibular , Anquilose/genética , Perfilação da Expressão Gênica , HematomaRESUMO
Objective: To create a novel chitosan antibacterial hemostatic sponge (NCAHS) and to evaluate its material and biological properties. Methods: Chitosan, a polysaccharide, was used as the sponge substrate and different proportions of sodium tripolyphosphate (STPP), glycerol, and phenol sulfonyl ethylamine were added to prepare the sponges through the freeze-drying method. The whole-blood coagulation index (BCI) was used as the screening criterion to determine the optimal concentrations of chitosan and the other additives and the hemostatic sponges were prepared accordingly. Zein/calcium carbonate (Zein/CaCO3) composite microspheres loaded with ciprofloxacin hydrochloride were prepared and added to the hemostatic sponges to obtain NCAHS. Scanning electron microscope was used to observe the microscopic morphology and porosity of the NCAHS. The water absorption rate, in vitro antibacterial susceptibility rate against Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli), in vitro coagulation performance, and hemocompatibility of NCAHS were examined. The coagulation performance of NCAHS was evaluated by using rabbit liver injury and rabbit auricular artery hemorrhageear models and commercial hemostatic sponge (CHS) was used as a control. The in vivo biocompatibility, including such aspects as cytotoxicity, skin irritation in animals, and acute in vivo toxicity, of the NCAHS extracts was examined by using as a reference the national standards for biological evaluation of medical devices. Results: The NCAHS prepared with 1.5% chitosan (W/V), 0.01% STPP (W/V), 0% glycerol (V/V), 0.15% phenol-sulfonyl-ethylamine (V/V), Zein and CaCO3 at the mixing ratio of 5â¶1 (W/W), Zein at the final mass concentration of 2.5 g/L, and ethanol at the final concentration of 17.5% (V/V) were fine and homogeneous, possessing a honeycomb-like porous structure with a pore size of about 200 µm. The NCAHS thus prepared had the lowest BCI value. The water absorption ([2362.16±201.15] % vs. [1102.56±91.79]%) and in vitro coagulation performance (31.338% vs. 1.591%) of NCAHS were significantly better than those of CHS (P<0.01). Tests with the in vivo auricular artery hemorrhage model ([36.00±13.42] s vs. [80.00±17.32] s) and rabbit liver bleeding model ([30.00±0] s vs. [70.00±17.32] s) showed that the hemostasis time of NCAHS was significantly shorter than that of CHS (P<0.01). NCAHS had significant inhibitory ability against S. aureus and E. coli. In addition, NCAHS showed good in vitro and in vivo biocompatibility. Conclusion: NCAHS is a composite sponge that shows excellent antimicrobial properties, hemostatic effect, and biocompatibility. Therefore, its extensive application in clinical settings is warranted.
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Quitosana , Hemostáticos , Zeína , Animais , Coelhos , Quitosana/química , Hemostáticos/farmacologia , Escherichia coli , Glicerol/farmacologia , Staphylococcus aureus , Zeína/farmacologia , Hemostasia , Antibacterianos/farmacologia , Hemorragia , Água/farmacologia , Etilaminas/farmacologia , Fenóis/farmacologiaRESUMO
The 4-coumarate: CoA ligase(4CL) is a key enzyme in the upstream pathway of phenylpropanoids such as flavonoids, soluble phenolic esters, lignans, and lignins in plants. In this study, 13 4CL family members of Arabidopsis thaliana were used as reference sequences to identify the 4CL gene family candidate members of Isatis indigotica from the reported I. indigotica genome. Further bioinformatics analysis and analysis of the expression pattern of 4CL genes and the accumulation pattern of flavonoids were carried out. Thirteen 4CL genes were obtained, named Ii4CL1-Ii4CL13, which were distributed on chromosomes 1, 2, 3, 4, and 6. The analysis of the gene structure and conserved structural domains revealed the intron number of I. indigotica 4CL genes was between 1 and 12 and the protein structural domains were highly conserved. Cis-acting element analysis showed that there were multiple response elements in the promoter sequence of I. indigotica 4CL gene family, and jasmonic acid had the largest number of reaction elements. The collinearity analysis showed that there was a close relationship between the 4CL gene family members of I. indigotica and A. thaliana. As revealed by qPCR results, the expression analysis of the 4CL gene family showed that 10 4CL genes had higher expression levels in the aboveground part of I. indigotica. The content assay of flavonoids in different parts of I. indigotica showed that flavonoids were mainly accumulated in the aboveground part of plants. This study provides a basis for further investigating the roles of the 4CL gene family involved in the biosynthesis of flavonoids in I. indigotica.
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Isatis , Ligases , Ligases/genética , Isatis/genética , Regiões Promotoras Genéticas , Plantas/metabolismo , Flavonoides , Coenzima A Ligases/genética , Coenzima A Ligases/química , Coenzima A Ligases/metabolismoRESUMO
Anaerobes dominate the microbiota of the gastrointestinal (GI) tract, where a significant portion of small molecules can be degraded or modified. However, the enormous metabolic capacity of gut anaerobes remains largely elusive in contrast to aerobic bacteria, mainly due to the requirement of sophisticated laboratory settings. In this study, we employed an in silico machine learning platform, MoleculeX, to predict the metabolic capacity of a gut anaerobe, Clostridium sporogenes, against small molecules. Experiments revealed that among the top seven candidates predicted as unstable, six indeed exhibited instability in C. sporogenes culture. We further identified several metabolites resulting from the supplementation of everolimus in the bacterial culture for the first time. By utilizing bioinformatics and in vitro biochemical assays, we successfully identified an enzyme encoded in the genome of C. sporogenes responsible for everolimus transformation. Our framework thus can potentially facilitate future understanding of small molecules metabolism in the gut, further improve patient care through personalized medicine, and guide the development of new small molecule drugs and therapeutic approaches.
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Clostridium , Everolimo , Humanos , Everolimo/metabolismo , Clostridium/metabolismo , Bactérias AnaeróbiasRESUMO
MOTIVATION: Properties of molecules are indicative of their functions and thus are useful in many applications. With the advances of deep-learning methods, computational approaches for predicting molecular properties are gaining increasing momentum. However, there lacks customized and advanced methods and comprehensive tools for this task currently. RESULTS: Here, we develop a suite of comprehensive machine-learning methods and tools spanning different computational models, molecular representations and loss functions for molecular property prediction and drug discovery. Specifically, we represent molecules as both graphs and sequences. Built on these representations, we develop novel deep models for learning from molecular graphs and sequences. In order to learn effectively from highly imbalanced datasets, we develop advanced loss functions that optimize areas under precision-recall curves (PRCs) and receiver operating characteristic (ROC) curves. Altogether, our work not only serves as a comprehensive tool, but also contributes toward developing novel and advanced graph and sequence-learning methodologies. Results on both online and offline antibiotics discovery and molecular property prediction tasks show that our methods achieve consistent improvements over prior methods. In particular, our methods achieve #1 ranking in terms of both ROC-AUC (area under curve) and PRC-AUC on the AI Cures open challenge for drug discovery related to COVID-19. AVAILABILITY AND IMPLEMENTATION: Our source code is released as part of the MoleculeX library (https://github.com/divelab/MoleculeX) under AdvProp. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
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Tratamento Farmacológico da COVID-19 , Humanos , Redes Neurais de Computação , Software , Descoberta de Drogas , Aprendizado de MáquinaRESUMO
It is particularly meaningful to therapeutic drug monitoring (TDM) of mycophenolic acid (MPA) for transplant patients to maximize the drug efficacy and minimize the adverse effect. In this study, a novel fluorescence and colorimetric dual-readout probe was put forward to fast and reliable detect MPA. The blue fluorescence of MPA was largely enhanced in the presence of poly (ethylenimine) (PEI), while the red fluorescence of CdTe@SiO2 (silica-coated CdTe quantum dots) provided a reliable reference signal. Hence, combining PEI70,000 and CdTe@SiO2, a fluorescence and colorimetric dual-readout probe could be constructed. For fluorescence measurement of MPA, the linearity was obtained in the MPA concentration range of 0.5-50 µg/mL, with a limit of detection (LOD) of 33 ng/mL. For the visual detection, the fluorescent colorimetric card was established in the MPA concentration from 0.5 to 50 µg/mL corresponding to the fluorescence color from red to violet and then to blue, which could be used for semi-quantification. Furthermore, in the light of the ColorCollect APP by the smartphone, the ratio of blue and red brightness values was linear with the MPA concentration from 1 to 50 µg/mL; thus, quantification of MPA could be realized by APP with the LOD of 83 ng/mL. The developed method was successfully applied to the analysis of MPA in the plasma samples of three patients after oral administration of mycophenolate mofetil, which was the prodrug of MPA. The result was comparable to those obtained by the clinically widely-used enzyme multiplied immunoassay technique. The developed probe was fast, cost-effective and operational convenience, and possessed high potential for TDM of MPA.
Assuntos
Compostos de Cádmio , Pontos Quânticos , Humanos , Ácido Micofenólico , Dióxido de Silício , Polietilenoimina , Colorimetria , Telúrio , Corantes FluorescentesRESUMO
Epilepsy is a chronic brain disease and often occurs suddenly for no reason. Eucommiae folium (EF), an edible herb, can be used in the treatment of various kinds of brain diseases in clinic. From the perspective of safety and efficacy, EF is especially suitable for the treatment of chronic brain diseases. With the help of biolabels, this study was aimed to explore the value and feasibility of EF in the treatment of epilepsy. Proteomics and metabolomics were used to explore the biolabels of EF intervention in brain tissues. Bioinformatics was then applied to topologically analyze its neuroprotective effects and mechanisms and material basis based on biolabels, which were validated in an animal model. The biolabel-led research revealed that EF may exert the therapeutic potential to treat brain diseases through the interaction between multiple compounds and multiple targets, among which its therapeutic potential for epilepsy is particularly prominent. In the pentylenetetrazole-induction model, EF and four active compounds (oleamide, catechol, chlorogenic acid, and kaempferol) protected epileptic hippocampal neurons (Nissl and FJB staining) against mitochondrial dysfunction (MYH6, MYL3, and MYBPC3, etc.) and calcium overload (TNNI3, TNNC1, and TNNT2, etc.) through the hypertrophic cardiomyopathy pathway. This study provides new evidence and insights for the neuroprotective effects of EF, in which four active compounds may be potential drug candidates for the treatment of epilepsy.