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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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Aprendizaje Automático , Sitios de Unión , Ingeniería de Proteínas/métodos , Proteínas Bacterianas/química , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Fosfatasa Ácida/química , Fosfatasa Ácida/genética , Fosfatasa Ácida/metabolismo , Especificidad por Sustrato , Bacillus anthracis/genética , Bacillus anthracis/enzimología , Klebsiella/genética , Klebsiella/enzimología , Ligandos , Unión Proteica , Modelos Moleculares , Redes Neurales de la ComputaciónRESUMEN
Although considerable progress toward gender equality in science has been made in recent decades, female researchers continue to face significant barriers in the academic labor market. International mobility has been increasingly recognized as a strategy for scientists to expand their professional networks, and that could help narrow the gender gap in academic careers. Using bibliometric data on over 33 million Scopus publications, we provide a global and dynamic view of gendered patterns of transnational scholarly mobility, as measured by volume, distance, diversity, and distribution, from 1998 to 2017. We find that, while female researchers continued to be underrepresented among internationally mobile researchers and migrate over shorter distances, this gender gap was narrowing at a faster rate than the gender gap in the population of general active researchers. Globally, the origin and destination countries of both female and male mobile researchers became increasingly diversified, which suggests that scholarly migration has become less skewed and more globalized. However, the range of origin and destination countries continued to be narrower for women than for men. While the United States remained the leading academic destination worldwide, the shares of both female and male scholarly inflows to that country declined from around 25% to 20% over the study period, partially due to the growing relevance of China. This study offers a cross-national measurement of gender inequality in global scholarly migration that is essential for promoting gender-equitable science policies and for monitoring the impact of such interventions.
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Bibliometría , Médicos , Humanos , Femenino , Masculino , China , Equidad de Género , InvestigadoresRESUMEN
Transcranial low-intensity ultrasound is a promising neuromodulation modality, with the advantages of noninvasiveness, deep penetration, and high spatiotemporal accuracy. However, the underlying biological mechanism of ultrasonic neuromodulation remains unclear, hindering the development of efficacious treatments. Here, the well-known Piezo1 was studied through a conditional knockout mouse model as a major mediator for ultrasound neuromodulation ex vivo and in vivo. We showed that Piezo1 knockout (P1KO) in the right motor cortex of mice significantly reduced ultrasound-induced neuronal calcium responses, limb movement, and muscle electromyogram (EMG) responses. We also detected higher Piezo1 expression in the central amygdala (CEA), which was found to be more sensitive to ultrasound stimulation than the cortex was. Knocking out the Piezo1 in CEA neurons showed a significant reduction of response under ultrasound stimulation, while knocking out astrocytic Piezo1 showed no-obvious changes in neuronal responses. Additionally, we excluded an auditory confound by monitoring auditory cortical activation and using smooth waveform ultrasound with randomized parameters to stimulate P1KO ipsilateral and contralateral regions of the same brain and recording evoked movement in the corresponding limb. Thus, we demonstrate that Piezo1 is functionally expressed in different brain regions and that it is an important mediator of ultrasound neuromodulation in the brain, laying the ground for further mechanistic studies of ultrasound.
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Corteza Auditiva , Encéfalo , Ratones , Animales , Encéfalo/fisiología , Corteza Auditiva/metabolismo , Ultrasonografía , Neuronas/metabolismo , Ratones Noqueados , Canales Iónicos/genética , Canales Iónicos/metabolismoRESUMEN
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 , Metilación de ADN , Embrión de Mamíferos , Desarrollo Embrionario , Regulación del Desarrollo de la Expresión Génica , Análisis de Expresión Génica de una Sola Célula , Sulfitos , Animales , Bovinos , Femenino , Embarazo , Blastocisto/metabolismo , Desarrollo Embrionario/genética , Epigénesis Genética , Perfilación de la Expresión Génica , Histona Desacetilasa 1/metabolismo , Histona Desacetilasa 2/metabolismo , Sulfitos/metabolismo , Peptidasa Específica de Ubiquitina 7/metabolismo , Embrión de Mamíferos/embriología , Embrión de Mamíferos/enzimologíaRESUMEN
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 , Triazoles , Ciclopropanos/química , Ciclopropanos/síntesis química , Triazoles/química , Triazoles/síntesis química , Estereoisomerismo , Piridinas/química , Piridinas/síntesis química , Estructura Molecular , BiocatálisisRESUMEN
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 , Diferenciación Celular , Peptidasa Específica de Ubiquitina 7 , Animales , Ratones , Blastocisto/metabolismo , Blastocisto/efectos de los fármacos , Peptidasa Específica de Ubiquitina 7/metabolismo , Peptidasa Específica de Ubiquitina 7/genética , Diferenciación Celular/efectos de los fármacos , Femenino , Desarrollo Embrionario/efectos de los fármacos , Desarrollo Embrionario/fisiología , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Linaje de la CélulaRESUMEN
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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Lesiones Encefálicas , Trampas Extracelulares , Proteína HMGB1 , Accidente Cerebrovascular Isquémico , Trombosis , Animales , Ratones , Humanos , Trampas Extracelulares/metabolismo , Proteína HMGB1/metabolismo , Trombosis/metabolismo , Neutrófilos , Lesiones Encefálicas/metabolismoRESUMEN
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 , Fermentación , Ingeniería Metabólica , Amycolatopsis/metabolismo , Amycolatopsis/genética , Ingeniería Metabólica/métodos , Sistemas CRISPR-Cas , Antibacterianos/biosíntesis , Vías Biosintéticas , Glicopéptidos/biosíntesisRESUMEN
BACKGROUND: S1P (sphingosine-1-phosphate) has been reported to possess vasodilatory properties, but the underlying pathways are largely unknown. METHODS: Isolated mouse mesenteric artery and endothelial cell models were used to determine S1P-induced vasodilation, intracellular calcium, membrane potentials, and calcium-activated potassium channels (KCa2.3 and KCa3.1 [endothelial small- and intermediate-conductance calcium-activated potassium channels]). Effect of deletion of endothelial S1PR1 (type 1 S1P receptor) on vasodilation and blood pressure was evaluated. RESULTS: Mesenteric arteries subjected to acute S1P stimulation displayed a dose-dependent vasodilation response, which was attenuated by blocking endothelial KCa2.3 or KCa3.1 channels. In cultured human umbilical vein endothelial cells, S1P stimulated immediate membrane potential hyperpolarization following activation of KCa2.3/KCa3.1 with elevated cytosolic Ca2+. Further, chronic S1P stimulation enhanced expression of KCa2.3 and KCa3.1 in human umbilical vein endothelial cells in dose- and time-dependent manners, which was abolished by disrupting either S1PR1-Ca2+ signaling or downstream Ca2+-activated calcineurin/NFAT (nuclear factor of activated T-cells) signaling. By combination of bioinformatics-based binding site prediction and chromatin immunoprecipitation assay, we revealed in human umbilical vein endothelial cells that chronic activation of S1P/S1PR1 promoted NFATc2 nuclear translocation and binding to promoter regions of KCa2.3 and KCa3.1 genes thus to upregulate transcription of these channels. Deletion of endothelial S1PR1 reduced expression of KCa2.3 and KCa3.1 in mesenteric arteries and exacerbated hypertension in mice with angiotensin II infusion. CONCLUSIONS: This study provides evidence for the mechanistic role of KCa2.3/KCa3.1-activated endothelium-dependent hyperpolarization in vasodilation and blood pressure homeostasis in response to S1P. This mechanistic demonstration would facilitate the development of new therapies for cardiovascular diseases associated with hypertension.
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Hipertensión , Vasodilatación , Ratones , Humanos , Animales , Presión Sanguínea , Endotelio/metabolismo , Canales de Potasio de Conductancia Intermedia Activados por el Calcio/genética , Canales de Potasio de Conductancia Intermedia Activados por el Calcio/metabolismo , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Homeostasis , Canales de Potasio de Pequeña Conductancia Activados por el Calcio/genética , Canales de Potasio de Pequeña Conductancia Activados por el Calcio/metabolismoRESUMEN
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 , Antivirales/farmacología , COVID-19/prevención & control , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Inhibidores de Proteasas/farmacología , SARS-CoV-2/efectos de los fármacos , Proteínas no Estructurales Virales , Pirazinas/química , Pirazinas/farmacología , Tratamiento Farmacológico de COVID-19RESUMEN
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 , Estructura Molecular , Fenalenos/farmacología , Fenalenos/química , Fenalenos/aislamiento & purificación , Animales , Ratones , Linfocitos T/efectos de los fármacos , Linfocitos B/efectos de los fármacos , Proliferación Celular/efectos de los fármacosRESUMEN
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 , Neumonía , Transducción de Señal , Triterpenos , Animales , Masculino , Ratones , Antiinflamatorios/farmacología , Líquido del Lavado Bronquioalveolar/citología , Líquido del Lavado Bronquioalveolar/química , Citocinas/metabolismo , Pulmón/efectos de los fármacos , Pulmón/patología , Pulmón/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Nanotubos de Carbono/toxicidad , FN-kappa B/metabolismo , Triterpenos Pentacíclicos/farmacología , Neumonía/inducido químicamente , Neumonía/tratamiento farmacológico , Neumonía/prevención & control , Neumonía/metabolismo , Transducción de Señal/efectos de los fármacos , Triterpenos/farmacologíaRESUMEN
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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Artritis , Enfermedades Cardiovasculares , Personas con Discapacidad , Humanos , Persona de Mediana Edad , Anciano , Actividades Cotidianas , Estudios Longitudinales , China/epidemiologíaRESUMEN
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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Insuficiencia Cardíaca , Calidad de Vida , Humanos , Ansiedad , Insuficiencia Cardíaca/terapia , HospitalizaciónRESUMEN
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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Enfermedad de Alzheimer , Diabetes Mellitus Tipo 2 , Microbioma Gastrointestinal , Morus , Humanos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Quempferoles , Simulación de Dinámica Molecular , Farmacología en Red , Enfermedad de Alzheimer/tratamiento farmacológico , Simulación del Acoplamiento Molecular , Frutas , FlavonoidesRESUMEN
BACKGROUND: Bronchopulmonary dysplasia (BPD) is the most common and serious chronic lung disease in preterm infants with pathological characteristics of arrested lung development. DNA double-strand breaks (DSBs) are a serious manifestation of oxidative stress damage, but little is known about the role of DSBs in BPD. The current study set out to detect DSB accumulation and cell cycle arrest in BPD and study the expression of genes related to DNA damage and repair in BPD through DNA damage signaling pathway-based PCR array to determine a suitable target to improve arrested lung development associated with BPD. METHODS: DSB accumulation and cell cycle arrest were detected in a BPD animal model and primary cells, then a DNA damage signaling pathway-based PCR array was used to identify the target of DSB repair in BPD. RESULTS: DSB accumulation and cell cycle arrest were shown in BPD animal model, primary type II alveolar epithelial cells (AECII) and cultured cells after exposure to hyperoxia. Of the 84 genes in the DNA damage-signaling pathway PCR array, eight genes were overexpressed and 11 genes were repressed. Rad1, an important protein for DSB repair, was repressed in the model group. Real-time PCR and western blots were used to verify the microarray results. Next, we confirmed that silencing Rad1 expression aggravated the accumulation of DSBs and cell cycle arrest in AECII cells, whereas its overexpression alleviated DSB accumulation and cell cycle arrest. CONCLUSIONS: The accumulation of DSBs in AECII might be an important cause of alveolar growth arrest associated with BPD. Rad1 could be an effective target for intervention to improve this arrest in lung development associated with BPD.
Asunto(s)
Displasia Broncopulmonar , Exonucleasas , Paro Cardíaco , Animales , Ratas , Células Epiteliales Alveolares , Displasia Broncopulmonar/genética , Puntos de Control del Ciclo Celular/genética , ADN , Roturas del ADN de Doble CadenaRESUMEN
Carbon nanodots (CNDs) synthesized from citric acid and formyl derivatives, that is, formamide, urea, or N-methylformamide, stand out through their broad-range visible-light absorbance and extraordinary photostability. Despite their potential, their use has thus far been limited to imaging research. This work has now investigated the link between CNDs' photochemical properties and their chemical structure. Electron-rich, yellow carbon nanodots (yCNDs) are obtained with in situ addition of NaOH during the synthesis, whereas otherwise electron-poor, red carbon nanodots (rCNDs) are obtained. These properties originate from the reduced and oxidized dimer of citrazinic acid within the matrix of yCNDs and rCNDs, respectively. Remarkably, yCNDs deposited on TiO2 give a 30% higher photocurrent density of 0.7 mA cm-2 at +0.3 V versus Ag/AgCl under Xe-lamp irradiation (450 nm long-pass filter, 100 mW cm-2 ) than rCNDs. The difference in overall photoelectric performance is due to fundamentally different charge-transfer mechanisms. These depend on either the electron-accepting or the electron-donating nature of the CNDs, as is evident from photoelectrochemical tests with TiO2 and NiO and time-resolved spectroscopic measurements.