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Engineering enzyme-substrate binding pockets is the most efficient approach for modifying catalytic activity, but is limited if the substrate binding sites are indistinct. Here, we developed a 3D convolutional neural network for predicting protein-ligand binding sites. The network was integrated by DenseNet, UNet, and self-attention for extracting features and recovering sample size. We attempted to enlarge the dataset by data augmentation, and the model achieved success rates of 48.4%, 35.5%, and 43.6% at a precision of ≥50% and 52%, 47.6%, and 58.1%. The distance of predicted and real center is ≤4 Å, which is based on SC6K, COACH420, and BU48 validation datasets. The substrate binding sites of Klebsiella variicola acid phosphatase (KvAP) and Bacillus anthracis proline 4-hydroxylase (BaP4H) were predicted using DUnet, showing high competitive performance of 53.8% and 56% of the predicted binding sites that critically affected the catalysis of KvAP and BaP4H. Virtual saturation mutagenesis was applied based on the predicted binding sites of KvAP, and the top-ranked 10 single mutations contributed to stronger enzyme-substrate binding varied while the predicted sites were different. The advantage of DUnet for predicting key residues responsible for enzyme activity further promoted the success rate of virtual mutagenesis. This study highlighted the significance of correctly predicting key binding sites for enzyme engineering.
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Aprendizado de Máquina , Sítios de Ligação , Engenharia de Proteínas/métodos , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Fosfatase Ácida/química , Fosfatase Ácida/genética , Fosfatase Ácida/metabolismo , Especificidade por Substrato , Bacillus anthracis/genética , Bacillus anthracis/enzimologia , Klebsiella/genética , Klebsiella/enzimologia , Ligantes , Ligação Proteica , Modelos Moleculares , Redes Neurais de ComputaçãoRESUMO
Extensive epigenetic reprogramming occurs during preimplantation embryonic development. However, the impact of DNA methylation in plateau yak preimplantation embryos and how epigenetic reprogramming contributes to transcriptional regulatory networks are unclear. In this study, we quantified gene expression and DNA methylation in oocytes and a series of yak embryos at different developmental stages and at single-cell resolution using single-cell bisulfite-sequencing and RNA-seq. We characterized embryonic genome activation and maternal transcript degradation and mapped epigenetic reprogramming events critical for embryonic development. Through cross-species transcriptome analysis, we identified 31 conserved maternal hub genes and 39 conserved zygotic hub genes, including SIN3A, PRC1, HDAC1/2, and HSPD1. Notably, by combining single-cell DNA methylation and transcriptome analysis, we identified 43 candidate methylation driver genes, such as AURKA, NUSAP1, CENPF, and PLK1, that may be associated with embryonic development. Finally, using functional approaches, we further determined that the epigenetic modifications associated with the histone deacetylases HDAC1/2 are essential for embryonic development and that the deubiquitinating enzyme USP7 may affect embryonic development by regulating DNA methylation. Our data represent an extensive resource on the transcriptional dynamics of yak embryonic development and DNA methylation remodeling, and provide new insights into strategies for the conservation of germplasm resources, as well as a better understanding of mammalian early embryonic development that can be applied to investigate the causes of early developmental disorders.
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Blastocisto , Metilação de DNA , Embrião de Mamíferos , Desenvolvimento Embrionário , Regulação da Expressão Gênica no Desenvolvimento , Análise da Expressão Gênica de Célula Única , Sulfitos , Animais , Bovinos , Feminino , Gravidez , Blastocisto/metabolismo , Desenvolvimento Embrionário/genética , Epigênese Genética , Perfilação da Expressão Gênica , Histona Desacetilase 1/metabolismo , Histona Desacetilase 2/metabolismo , Sulfitos/metabolismo , Peptidase 7 Específica de Ubiquitina/metabolismo , Embrião de Mamíferos/embriologia , Embrião de Mamíferos/enzimologiaRESUMO
Hemoproteins have recently emerged as powerful biocatalysts for new-to-nature carbene transfer reactions. Despite this progress, these strategies have remained largely limited to diazo-based carbene precursor reagents. Here, we report the development of a biocatalytic strategy for the stereoselective construction of pyridine-functionalized cyclopropanes via the hemoprotein-mediated activation of pyridotriazoles (PyTz) as stable and readily accessible carbene sources. This method enables the asymmetric cyclopropanation of a variety of olefins, including electron-rich and electrodeficient ones, with high activity, high stereoselectivity, and enantiodivergent selectivity, providing access to mono- and diarylcyclopropanes that incorporate a pyridine moiety and thus two structural motifs of high value in medicinal chemistry. Mechanistic studies reveal a multifaceted role of 7-halogen substitution in the pyridotriazole reagent toward favoring multiple catalytic steps in the transformation. This work provides the first example of asymmetric olefin cyclopropanation with pyridotriazoles, paving the way to the exploitation of these attractive and versatile reagents for enzyme-catalyzed carbene-mediated reactions.
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Ciclopropanos , Triazóis , Ciclopropanos/química , Ciclopropanos/síntese química , Triazóis/química , Triazóis/síntese química , Estereoisomerismo , Piridinas/química , Piridinas/síntese química , Estrutura Molecular , BiocatáliseRESUMO
Preimplantation embryos undergo a series of important biological events, including epigenetic reprogramming and lineage differentiation, and the key genes and specific mechanisms that regulate these events are critical to reproductive success. Ubiquitin-specific protease 7 (USP7) is a deubiquitinase involved in the regulation of a variety of cellular functions, yet its precise function and mechanism in preimplantation embryonic development remain unknown. Our results showed that RNAi-mediated silencing of USP7 in mouse embryos or treatment with P5091, a small molecule inhibitor of USP7, significantly reduced blastocyst rate and blastocyst quality, and decreased total and trophectoderm cell numbers per blastocyst, as well as destroyed normal lineage differentiation. The results of single-cell RNA-seq, reverse transcription-quantitative polymerase chain reaction, western blot, and immunofluorescence staining indicated that interference with USP7 caused failure of the morula-to-blastocyst transition and was accompanied by abnormal expression of key genes (Cdx2, Oct4, Nanog, Sox2) for lineage differentiation, decreased transcript levels, increased global DNA methylation, elevated repressive histone marks (H3K27me3), and decreased active histone marks (H3K4me3 and H3K27ac). Notably, USP7 may regulate the transition from the morula to blastocyst by stabilizing the target protein YAP through the ubiquitin-proteasome pathway. In conclusion, our results suggest that USP7 may play a crucial role in preimplantation embryonic development by regulating lineage differentiation and key epigenetic modifications.
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Blastocisto , Diferenciação Celular , Peptidase 7 Específica de Ubiquitina , Animais , Camundongos , Blastocisto/metabolismo , Blastocisto/efeitos dos fármacos , Peptidase 7 Específica de Ubiquitina/metabolismo , Peptidase 7 Específica de Ubiquitina/genética , Diferenciação Celular/efeitos dos fármacos , Feminino , Desenvolvimento Embrionário/efeitos dos fármacos , Desenvolvimento Embrionário/fisiologia , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Linhagem da CélulaRESUMO
AIMS: Neutrophil extracellular traps (NETs) have been implicated in thrombotic diseases. There is no definitive explanation for how NETs form during acute ischemic strokes (AIS). The purpose of our study was to investigate the potential mechanism and role of NETs formation in the AIS process. METHODS: As well as 45 healthy subjects, 45 patients with AIS had ELISA tests performed to detect NET markers. Expression of high-mobility group box 1 (HMGB1) on platelet microvesicles (PMVs) was analyzed by flow cytometry in healthy subjects and AIS patients' blood samples. We established middle cerebral artery occlusion (MCAO) mice model to elucidate the interaction between PMPs and NETs. RESULTS: A significant elevation in NET markers was found in patient plasma in AIS patients, and neutrophils generated more NETs from patients' neutrophils. HMGB1 expression was upregulated on PMVs from AIS patients and induced NET formation. NETs enhanced Procoagulant activity (PCA) through tissue factor and via platelet activation. Targeting lactadherin in genetical and in pharmacology could regulate the formation of NETs in MCAO model. CONCLUSIONS: NETs mediated by PMVs derived HMGB1 exacerbate thrombosis and brain injury in AIS. Video Abstract.
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Lesões Encefálicas , Armadilhas Extracelulares , Proteína HMGB1 , AVC Isquêmico , Trombose , Animais , Camundongos , Humanos , Armadilhas Extracelulares/metabolismo , Proteína HMGB1/metabolismo , Trombose/metabolismo , Neutrófilos , Lesões Encefálicas/metabolismoRESUMO
Carbon dioxide (CO2) has been widely used to enhance the recovery of adsorbed hydrocarbons from the organic matter (OM) in shale formations. To reveal the driving force of replacing adsorbed hydrocarbons from OM by CO2, we performed molecular dynamics (MD) simulations of the replacement process and calculated the interaction forces between CO2 and hydrocarbons. In addition, based on the umbrella sampling method, steered MD simulations were performed, and the free energy profiles of hydrocarbons were obtained using the weighted histogram analysis method. Results show that the condition of the hydrocarbon replacement by CO2 requires the hydrocarbon to have sufficient kinetic energy or to have a sufficiently large attractive force exerted to ensure that the hydrocarbon escapes the potential well of the OM. The attractive forces exerted on hydrocarbon molecules by CO2 can significantly decrease the energy barrier associated with hydrocarbon movement away from the OM surface. Furthermore, both CO2 and supercritical CO2 can effectively displace adsorbed hydrocarbon gas (methane) on the OM, while supercritical CO2 is required to enhance the recovery of adsorbed hydrocarbon oil (n-dodecane). The results obtained in this study provide guidance for enhancing the recovery of adsorbed hydrocarbons by CO2 in shale formations.
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BACKGROUND: Oritavancin is a new generation of semi-synthetic glycopeptide antibiotics against Gram-positive bacteria, which served as the first and only antibiotic with a single-dose therapeutic regimen to treat ABSSSI. A naturally occurring glycopeptide A82846B is the direct precursor of oritavancin. However, its application has been hampered by low yields and homologous impurities. This study established a multi-step combinatorial strategy to rationally construct a high-quality and high-efficiency biosynthesis system for A82846B and systematically optimize its fermentation process to break through the bottleneck of microbial fermentation production. RESULTS: Firstly, based on the genome sequencing and analysis, we deleted putative competitive pathways and constructed a better A82846B-producing strain with a cleaner metabolic background, increasing A82846B production from 92 to 174 mg/L. Subsequently, the PhiC31 integrase system was introduced based on the CRISPR-Cas12a system. Then, the fermentation level of A82846B was improved to 226 mg/L by over-expressing the pathway-specific regulator StrR via the constructed PhiC31 system. Furthermore, overexpressing glycosyl-synthesis gene evaE enhanced the production to 332 mg/L due to the great conversion of the intermediate to target product. Finally, the scale-up production of A82846B reached 725 mg/L in a 15 L fermenter under fermentation optimization, which is the highest reported yield of A82846B without the generation of homologous impurities. CONCLUSION: Under approaches including blocking competitive pathways, inserting site-specific recombination system, overexpressing regulator, overexpressing glycosyl-synthesis gene and optimizing fermentation process, a multi-step combinatorial strategy for the high-level production of A82846B was developed, constructing a high-producing strain AO-6. The combinatorial strategies employed here can be widely applied to improve the fermentation level of other microbial secondary metabolites, providing a reference for constructing an efficient microbial cell factory for high-value natural products.
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Amycolatopsis , Fermentação , Engenharia Metabólica , Amycolatopsis/metabolismo , Amycolatopsis/genética , Engenharia Metabólica/métodos , Sistemas CRISPR-Cas , Antibacterianos/biossíntese , Vias Biossintéticas , Glicopeptídeos/biossínteseRESUMO
The COVID-19 caused by SARS-CoV-2 has led to a global pandemic that continues to impact societies and economies worldwide. The main protease (Mpro) plays a crucial role in SARS-CoV-2 replication and is an attractive target for anti-SARS-CoV-2 drug discovery. Herein, we report a series of 3-oxo-1,2,3,4-tetrahydropyrido[1,2-a]pyrazin derivatives as non-peptidomimetic inhibitors targeting SARS-CoV-2 Mpro through structure-based virtual screening and biological evaluation. Further similarity search and structure-activity relationship study led to the identification of compound M56-S2 with the enzymatic IC50 value of 4.0 µM. Moreover, the molecular simulation and predicted ADMET properties, indicated that non-peptidomimetic inhibitor M56-S2 might serve as a useful starting point for the further discovery of highly potent inhibitors targeting SARS-CoV-2 Mpro.
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COVID-19 , Pirazinas , SARS-CoV-2 , Humanos , Antivirais/farmacologia , COVID-19/prevenção & controle , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Inibidores de Proteases/farmacologia , SARS-CoV-2/efeitos dos fármacos , Proteínas não Estruturais Virais , Pirazinas/química , Pirazinas/farmacologia , Tratamento Farmacológico da COVID-19RESUMO
Nine new oligophenalenone dimers, adpressins A-G (1-9), together with nine known compounds (10-18), were isolated from the fungus Talaromyces adpressus. Their chemical structures were determined on the basis of spectroscopic and mass spectral analyses. Their relative and absolute configurations were identified by 1H and 13C NMR calculations followed by DP4+ analyses, electronic circular dichroism (ECD) calculations, and ECD spectra comparison with related compounds. Compound 1 is the first example of a duclauxin derivative featuring an unusual 6/6/6/5/6/6/6 ring system, while compounds 6 and 7 contained a novel pyrrolidine ring. Compounds 5, 9, and 18 exhibited moderate inhibition against LPS-induced B lymphocyte proliferation with IC50 values ranging from 1.6 to 8.6 µM. Additionally, compounds 9 and 18 exhibited moderate inhibition against Con A-induced T lymphocyte proliferation with IC50 values of 9.3 and 2.6 µM, respectively.
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Talaromyces , Talaromyces/química , Estrutura Molecular , Fenalenos/farmacologia , Fenalenos/química , Fenalenos/isolamento & purificação , Animais , Camundongos , Linfócitos T/efeitos dos fármacos , Linfócitos B/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacosRESUMO
BACKGROUND: Sugammadex is a neuromuscular blockade (NMB) reversal agent introduced in the United States in 2016, which allows the reversal of deep NMB, not possible with neostigmine. Few data describe associated practice changes, if any, in NMB medication use that may have resulted from its availability. We hypothesized that after institutional introduction, use of NMB agents increased. Furthermore, as NMB medication is typically used when the airway has been secured with an endotracheal tube (ETT), we speculated that ETT use may have also increased over the same time period as a result of sugammadex availability. METHODS: This was a single-center cross-sectional study of patients ages 2 to 17 years undergoing general anesthesia for surgical cases where anesthesia providers often have discretion over NMB medication use or whether to use an ETT versus a laryngeal mask airway (LMA), comparing the time periods 2014 to 2016 (presugammadex) to 2017 to 2019 (early sugammadex) and 2020 to 2022 (established sugammadex). Outcomes included use of (1) any nondepolarizing NMB medication during the case and (2) an ETT versus LMA. We used generalized linear mixed models to examine changes in practice patterns over time. We also examined whether patient age group and in-room provider (resident versus certified registered nurse anesthetist [CRNA]) were associated with increased NMB medication or ETT use. RESULTS: There were 25,638 eligible anesthetics. Patient and surgical characteristics were similar across time periods. In adjusted analyses, the odds of NMB medication use increased from 2017 to 2019 (odds ratio [OR], 1.55, 95% confidence interval [CI], 1.38-1.75) and 2020 to 2022 (OR, 5.62, 95% CI, 4.96-6.37) relative to 2014 to 2016, and were higher in older children (age 6-11 years vs 2-5 years OR, 1.81, 95% CI, 1.63-2.01; age 12-17 years vs 2-5 years OR, 7.01, 95% CI, 6.19-7.92) and when the primary in-room provider was a resident rather than a CRNA (OR, 1.24, 95% CI, 1.12-1.37). The odds of ETT use declined 2017 to 2019 (OR, 0.69, 95% CI, 0.63-0.75) and 2020 to 2022 (OR, 0.71, 95% CI, 0.65-0.78), more so in older children (age 6-11 years vs 2-5 years OR, 0.45, 95% CI, 0.42-0.49; age 12-17 years vs 2-5 years OR, 0.28, 95% CI, 0.25-0.31). Resident presence at induction was associated with increased odds of ETT use (OR, 1.50, 95% CI, 1.38-1.62). CONCLUSIONS: The decision to use NMB medication as part of an anesthetic plan increased substantially after sugammadex became available, particularly in older children and cases staffed by residents. ETT use declined over the study period.
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Multiwalled carbon nanotubes (MWCNTs) have numerous applications in the field of carbon nanomaterials. However, the associated toxicity concerns have increased significantly because of their widespread use. The inhalation of MWCNTs can lead to nanoparticle deposition in the lung tissue, causing inflammation and health risks. In this study, celastrol, a natural plant medicine with potent anti-inflammatory properties, effectively reduced the number of inflammatory cells, including white blood cells, neutrophils, and lymphocytes, and levels of inflammatory cytokines, such as IL-1ß, IL-6, and TNF-α, in mice lungs exposed to MWCNTs. Moreover, celastrol inhibited the activation of the NF-κB-signaling pathway. This study confirmed these findings by demonstrating comparable reductions in inflammation upon exposure to MWCNTs in mice with the deletion of NF-κB (P50-/-). These results indicate the utility of celastrol as a promising pharmacological agent for preventing MWCNT-induced lung tissue inflammation.
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Nanotubos de Carbono , Triterpenos Pentacíclicos , Pneumonia , Transdução de Sinais , Triterpenos , Animais , Masculino , Camundongos , Anti-Inflamatórios/farmacologia , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/química , Citocinas/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Nanotubos de Carbono/toxicidade , NF-kappa B/metabolismo , Triterpenos Pentacíclicos/farmacologia , Pneumonia/induzido quimicamente , Pneumonia/tratamento farmacológico , Pneumonia/prevenção & controle , Pneumonia/metabolismo , Transdução de Sinais/efeitos dos fármacos , Triterpenos/farmacologiaRESUMO
AIM: This study aimed to assess the trends in disabilities in activities of daily living (ADL) and instrumental activities of daily living (IADL) among older Chinese adults and explore the influence of multimorbidity and unhealthy behaviors on ADL/IADL disability over time. METHODS: Data were obtained from four waves (2011-2018) of the China Health and Retirement Longitudinal Study. Disability in ADL/IADL was defined as inability to perform any ADL/IADL task. Latent class analysis was used to identify multimorbidity patterns. The generalized estimating equation was used to test disability trends. Logistic regression was used to investigate the factors influencing disability. RESULTS: The prevalence of IADL and ADL disability showed significant increasing trends among older Chinese adults from 2011 to 2018 (ptrend < 0.001). The negative association between alcohol intake more than once per month and IADL disability strengthened over time (ptrend < 0.05). The influence of the "arthritis/digestive diseases" pattern, "cardiometabolic disease" pattern and "high multimorbidity" pattern on ADL disability weakened over time (ptrend < 0.05). CONCLUSIONS: The prevalence of IADL and ADL disability among Chinese older adults increased over time. The "arthritis/digestive diseases" pattern, "cardiometabolic disease" pattern and "high multimorbidity" pattern appeared to be less disabling in ADL over time. Improving the prevention and treatment of multimorbidity and developing age-friendly living conditions could be helpful to reduce the risks of disability.
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Artrite , Doenças Cardiovasculares , Pessoas com Deficiência , Humanos , Pessoa de Meia-Idade , Idoso , Atividades Cotidianas , Estudos Longitudinais , China/epidemiologiaRESUMO
Fixed-wing UAVs have shown great potential in both military and civilian applications. However, achieving safe and collision-free flight in complex obstacle environments is still a challenging problem. This paper proposed a hierarchical two-layer fixed-wing UAV motion planning algorithm based on a global planner and a local reinforcement learning (RL) planner in the presence of static obstacles and other UAVs. Considering the kinematic constraints, a global planner is designed to provide reference guidance for ego-UAV with respect to static obstacles. On this basis, a local RL planner is designed to accomplish kino-dynamic feasible and collision-free motion planning that incorporates dynamic obstacles within the sensing range. Finally, in the simulation training phase, a multi-stage, multi-scenario training strategy is adopted, and the simulation experimental results show that the performance of the proposed algorithm is significantly better than that of the baseline method.
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AIMS: The aim of this study is to evaluate the relative merits of various heart failure models of care with regard to a variety of outcomes. DESIGN: Systematic review. DATA SOURCES: Five databases including PubMed, Web of Science, Medline, Embase and Science Direct were searched from the inception date of databases to August 20, 2022. REVIEW METHODS: This review used the Cochrane Collaboration's 'Risk of Bias' tool to assess quality. Only randomised controlled trails were included in this review that assessed all care models in the management of adults with heart failure. A categorical summary of the pattern of the papers was found, followed by extraction of outcome indicators. RESULTS: Twenty articles (19 studies) were included. Seven examined nurse-led care, two examined multidisciplinary specialist care, nine (10 articles) examined patient self-management, and one examined nurse and physiotherapist co-led care. Regarding outcomes, this review examined how well the four models performed with regard to quality of life, health services use, HF self-care, and anxiety and depression for heart failure patients. The model of patient self-management showed more beneficial results than nurse-led care, multidisciplinary specialist care, and nurse and physiotherapist co-led care in reducing hospital days, improving symptoms, promoting self-care behaviours of HF patients, enhancing the quality of life, and strengthening self-care ability. CONCLUSIONS: This systematic review synthesises the different care models and their relative effectiveness. Four different models of care were summarised. Of these models, the self-management model demonstrated better outcomes. IMPACT: The self-management model is more effective in increasing self-management behaviours and self-management abilities, lowering the risk of hospitalisation and death, improving quality of life, and relieving anxiety and depression than other models. NO PATIENT OR PUBLIC CONTRIBUTION: There was no funding to remunerate a patient/member of the public for this review.
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Insuficiência Cardíaca , Qualidade de Vida , Humanos , Ansiedade , Insuficiência Cardíaca/terapia , HospitalizaçãoRESUMO
Recently, studies have reported a correlation that individuals with diabetes show an increased risk of developing Alzheimer's disease (AD). Mulberry leaves, serving as both a traditional medicinal herb and a food source, exhibit significant hypoglycemic and antioxidative properties. The flavonoid compounds in mulberry leaf offer therapeutic effects for relieving diabetic symptoms and providing neuroprotection. However, the mechanisms of this effect have not been fully elucidated. This investigation aimed to investigate the combined effects of specific mulberry leaf flavonoids (kaempferol, quercetin, rhamnocitrin, tetramethoxyluteolin, and norartocarpetin) on both type 2 diabetes mellitus (T2DM) and AD. Additionally, the role of the gut microbiota in these two diseases' treatment was studied. Using network pharmacology, we investigated the potential mechanisms of flavonoids in mulberry leaves, combined with gut microbiota, in combating AD and T2DM. In addition, we identified protein tyrosine phosphatase 1B (PTP1B) as a key target for kaempferol in these two diseases. Molecular docking and molecular dynamics simulations showed that kaempferol has the potential to inhibit PTP1B for indirect treatment of AD, which was proven by measuring the IC50 of kaempferol (279.23 µM). The cell experiment also confirmed the dose-dependent effect of kaempferol on the phosphorylation of total cellular protein in HepG2 cells. This research supports the concept of food-medicine homology and broadens the range of medical treatments for diabetes and AD, highlighting the prospect of integrating traditional herbal remedies with modern medical research.
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Doença de Alzheimer , Diabetes Mellitus Tipo 2 , Microbioma Gastrointestinal , Morus , Humanos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Quempferóis , Simulação de Dinâmica Molecular , Farmacologia em Rede , Doença de Alzheimer/tratamento farmacológico , Simulação de Acoplamento Molecular , Frutas , FlavonoidesRESUMO
Mitochondria-associated endoplasmic reticulum membranes (MAMs) are the physical connection sites between mitochondria and endoplasmic reticulum (ER). As the compartments controlling substance and information communications between ER and mitochondria, MAMs were involved in the regulation of various pathophysiological processes, such as calcium homeostasis, mitochondrial morphology and function, lipid metabolism and autophagy. In the past decades, accumulating lines of evidence have revealed the pivotal role of MAMs in diverse cardiovascular diseases (CVD). Aging is one of the major independent risk factors for CVD, which causes progressive degeneration of the cardiovascular system, leading to increased morbidity and mortality of CVD. This review aims to summarize the research progress of MAMs in age-related CVD, and explore new targets for its prevention and treatment.
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Doenças Cardiovasculares , Membranas Mitocondriais , Humanos , Doenças Cardiovasculares/metabolismo , Sinalização do Cálcio/fisiologia , Mitocôndrias/fisiologia , Retículo Endoplasmático/metabolismoRESUMO
Semantic segmentation of 3D point clouds is important for many applications, such as autonomous driving. To train semantic segmentation models, labeled point cloud segmentation datasets are essential. Meanwhile, point cloud labeling is time-consuming for annotators, which typically involves tuning the camera viewpoint and selecting points with a lasso tool. To reduce the time cost of point cloud labeling, we propose a viewpoint recommendation approach to reduce annotators' labeling time costs. We adapt Fitts' law to model the time cost of lasso selection in point clouds. Using the modeled time cost, the viewpoint that minimizes the lasso selection time cost is recommended to the annotator. We build a data labeling system for semantic segmentation of 3D point clouds that integrates our viewpoint recommendation approach. The system enables users to navigate to recommended viewpoints for efficient annotation. Through a user study, we observed that our approach effectively reduced the data labeling time cost. We also qualitatively compare our approach with previous viewpoint selection approaches on different datasets.
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OBJECTIVES: This study aimed to identify long-term distinct trajectories of multimorbidity with ageing from 50 to 85 years among Chinese older adults and examine the relationship between exposure to early-life adversity (ELA; including specific types of adversity and accumulation of different adversities) and these long-term multimorbidity trajectories. DESIGN: The group-based trajectory models identified long-term multimorbidity trajectories. Multinomial logistic regression models were used to examine the relationship between ELA and the identified multimorbidity trajectories. SETTING: This study used data from the China Health and Retirement Longitudinal Study (CHARLS, 2011-2018) and the 2014 Life History Survey. PARTICIPANTS: We used data from 9112 respondents (aged 60 and above) of the 2018 wave of CHARLS. OUTCOME MEASURES: Each respondent's history of chronic conditions and experiences of ELA were collected from the 2011-2018 waves of CHARLS and the 2014 Life History Survey. RESULTS: Four heterogeneous long-term trajectories of multimorbidity development were identified: 'maintaining-low' (19.1%), 'low onset-rapidly increasing' (23.3%), 'middle onset-moderately increasing' (41.5%) and 'chronically-high' (16.2%). Our findings indicated that the heterogeneity can be explained by ELA experiences. Across various types of different ELA experiences, exposure to food insufficiency (relative risk ratios from 1.372 (95% CI 1.190 to 1.582) to 1.780 (95% CI 1.472 to 2.152)) and parental quarrel/divorce (relative risk ratios from 1.181 (95% CI 1.000 to 1.394) to 1.262 (95% CI 1.038 to 1.536)) had the most prominent associations with health deterioration. The accumulation of more different ELA experiences was associated with a higher relative risk of developing more severe multimorbidity trajectories (relative risk ratio for five to seven ELAs and chronically high trajectory: 7.555, 95% CI 4.993 to 11.431). CONCLUSIONS: There are heterogeneous long-term trajectories of multimorbidity in Chinese older adults, and the risk of multimorbidity associated with ELA accumulates over the lifespan. Our findings highlight the role of a supportive early-life family environment in promoting health development across the lifespan, advocating for the integration of life-course approaches to implementing health disparity interventions.
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Experiências Adversas da Infância , Aposentadoria , Humanos , Idoso , Estudos Longitudinais , Multimorbidade , China/epidemiologiaRESUMO
Based on the whole virus or spike protein of pigs, δ coronavirus (PDCoV) as an immunogen may have unrelated antigenic epitope interference. Therefore, it is essential for screening and identifying advantageous protective antigen epitopes. In addition, immunoinformatic tools are described as an important aid in determining protective antigenic epitopes. In this study, the primary, secondary, and tertiary structures of vaccines were measured using ExPASy, PSIPRED 4.0, and trRosetta servers. Meanwhile, the molecular docking analysis and vector of the candidate nanovaccine were constructed. The immune response of the candidate vaccine was simulated and predicted using the C-ImmSim server. This experiment screened B cell epitopes with strong immunogenicity and high conservation, CTL epitopes, and Th epitopes with IFN-γ and IL-4 positive spike proteins. Ferritin is used as a self-assembled nanoparticle element for designing candidate nanovaccine. After analysis, it has been found to be soluble, stable, non-allergenic, and has a high affinity for its target receptor, TLR-3. The preliminary simulation analysis results show that the candidate nanovaccine has the ability to induce a humoral and cellular immune response. Therefore, it may provide a new theoretical basis for research on coronavirus self-assembled nanovaccines. It may be an effective candidate vaccine for controlling and preventing PDCoV.
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Synthetic chemistry plays an indispensable role in drug discovery, contributing to hit compounds identification, lead compounds optimization, candidate drugs preparation, and so on. As Nobel Prize laureate James Black emphasized, "the most fruitful basis for the discovery of a new drug is to start with an old drug"1. Late-stage modification or functionalization of drugs, natural products and bioactive compounds have garnered significant interest due to its ability to introduce diverse elements into bioactive compounds promptly. Such modifications alter the chemical space and physiochemical properties of these compounds, ultimately influencing their potency and druggability. To enrich a toolbox of chemical modification methods for drug discovery, this review focuses on the incorporation of halogen, oxygen, and nitrogen-the ubiquitous elements in pharmacophore components of the marketed drugs-through late-stage modification in recent two decades, and discusses the state and challenges faced in these fields. We also emphasize that increasing cooperation between chemists and pharmacists may be conducive to the rapid discovery of new activities of the functionalized molecules. Ultimately, we hope this review would serve as a valuable resource, facilitating the application of late-stage modification in the construction of novel molecules and inspiring innovative concepts for designing and building new drugs.