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1.
Arch Gerontol Geriatr ; 98: 104545, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34700136

RESUMO

OBJECTIVES: This study aimed to explore the gender and residence (rural/urban) differences in the associations between the specific dimensions of social support and subjective well-being (SWB) among the Chinese oldest-old. METHODS: This study included 12,989 individuals aged ≥ 80 from 2011, 2014, and 2018 waves of the Chinese Longitudinal Healthy Longevity Survey. SWB was measured by ten items covering self-rated life satisfaction, positive emotions (optimism, happiness, personal control, and conscientiousness), and negative emotions (loneliness, anxiety, uselessness, depression, and boring feelings). Social support included the variables of marriage quality, living arrangements, contacts with others, children's and siblings' frequent visits and telecommunications, children and siblings living nearby, the main source of financial support, adequate financial support, social security and commercialized insurances, community social services, the caregiver when sick, and main medical expenses payer. Generalized estimating equation models were used to determine the effects of social support on the SWB. RESULTS: Gender differences were found in the associations of living arrangements, contacts with others, children's frequent visits and telecommunications, community social services, caregiver when sick, and main medical expenses payer with SWB. Residence differences were found in the associations of living arrangements, contacts with others, children's frequent visits and telecommunications, siblings' frequent visits, community social services, and main medical expenses payer with SWB. CONCLUSIONS: There are gender and residence differences in the relationships between many dimensions of social support and SWB. Gender and residence-tailored interventions for social support are necessary to promote the well-being of the oldest old.


Assuntos
Felicidade , Apoio Social , Idoso de 80 Anos ou mais , China , Nível de Saúde , Humanos , Estudos Longitudinais
3.
Natl Sci Rev ; 8(3): nwaa180, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34691592

RESUMO

High throughput single-cell RNA-seq has been successfully implemented to dissect the cellular and molecular features underlying hematopoiesis. However, an elaborate and comprehensive transcriptome reference of the whole blood system is lacking. Here, we profiled the transcriptomes of 7551 human blood cells representing 32 immunophenotypic cell types, including hematopoietic stem cells, progenitors and mature blood cells derived from 21 healthy donors. With high sequencing depth and coverage, we constructed a single-cell transcriptional atlas of blood cells (ABC) on the basis of both protein-coding genes and long noncoding RNAs (lncRNAs), and showed a high consistence between them. Notably, putative lncRNAs and transcription factors regulating hematopoietic cell differentiation were identified. While common transcription factor regulatory networks were activated in neutrophils and monocytes, lymphoid cells dramatically changed their regulatory networks during differentiation. Furthermore, we showed a subset of nucleated erythrocytes actively expressing immune signals, suggesting the existence of erythroid precursors with immune functions. Finally, a web portal offering transcriptome browsing and blood cell type prediction has been established. Thus, our work provides a transcriptional map of human blood cells at single-cell resolution, thereby offering a comprehensive reference for the exploration of physiological and pathological hematopoiesis.

4.
Cell Discov ; 7(1): 60, 2021 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-34349096

RESUMO

Severe coronavirus disease 2019 (COVID-19) is often indicated by lymphopenia and increased myelopoiesis; however, the underlying mechanism is still unclear, especially the alteration of hematopoiesis. It is important to explore to what extent and how hematopoietic stem cells contribute to the impairment of peripheral lymphoid and myeloid compartments in COVID-19 patients. In this study, we used single-cell RNA sequencing to assess bone marrow mononuclear cells from COVID-19 patients with peripheral blood mononuclear cells as control. The results showed that the hematopoietic stem cells in these patients were mainly in the G1 phase and prone to apoptosis, with immune activation and anti-viral responses. Importantly, a significant accumulation of immature myeloid progenitors and a dramatic reduction of lymphoid progenitors in severe cases were identified, along with the up-regulation of transcription factors (such as SPI1, LMO4, ETS2, FLI1, and GATA2) that are important for the hematopoietic stem cell or multipotent progenitor to differentiate into downstream progenitors. Our results indicate a dysregulated hematopoiesis in patients with severe COVID-19.

5.
Sci Data ; 8(1): 203, 2021 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-34354089

RESUMO

Lithium-ion batteries (LIBs) represent the state of the art in high-density energy storage. To further advance LIB technology, a fundamental understanding of the underlying chemical processes is required. In particular, the decomposition of electrolyte species and associated formation of the solid electrolyte interphase (SEI) is critical for LIB performance. However, SEI formation is poorly understood, in part due to insufficient exploration of the vast reactive space. The Lithium-Ion Battery Electrolyte (LIBE) dataset reported here aims to provide accurate first-principles data to improve the understanding of SEI species and associated reactions. The dataset was generated by fragmenting a set of principal molecules, including solvents, salts, and SEI products, and then selectively recombining a subset of the fragments. All candidate molecules were analyzed at the ωB97X-V/def2-TZVPPD/SMD level of theory at various charges and spin multiplicities. In total, LIBE contains structural, thermodynamic, and vibrational information on over 17,000 unique species. In addition to studies of reactivity in LIBs, this dataset may prove useful for machine learning of molecular and reaction properties.

6.
J Nanobiotechnology ; 19(1): 235, 2021 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-34362394

RESUMO

BACKGROUND: Based on the concept of "multimodal analgesia", a novel dual drug delivery system was designed to achieve synergistic analgesia between najanajaatra venom protein (αCT) and resveratrol (Res). In order to meet the joint loading of two drugs with different physicochemical properties without affecting each other, an oral Janus nanoparticle (JNP) with a unique cavity structure and synergistic drug delivery was constructed using an improved double emulsion solvent evaporation method, and combined with low-molecular-weight chitosan/sodium alginate and PLGA to achieve its pH-responsive. RESULTS: The synthesized αCT/Res-JNPs are homogeneous in shape, with a two-compartment structure, approximately 230 nm in size, and zeta potential of 23.6 mV. Drug release assayed in vitro show that JNP was stable in simulated gastric juice (pH = 1.2) but was released in phosphate buffer saline (pH = 7.4). After intragastric administration in rats, PK evaluation showed that αCT/Res-JNPs could significantly improve the oral bioavailability, and the simultaneous encapsulation of the two drugs had no significant interaction on PK parameters. An obvious synergistic analgesic effects of αCT/Res-JNPs was confirmed in a spinal cord injury and acute pain model. Confocal laser scanning microscopy and single-pass intestinal perfusion model provided strong evidence that αCT/Res-JNPs could pass through intestinal epithelial cells, and the endocytosis pathway was mainly involved in the mediation and pinocytosis of reticulin. The concentrations of αCT and Res from αCT/Res-JNP in lymphatic transport were only about 8.72% and 6.08% of their blood concentrations at 1 h, respectively, which indicated that lymphatic transport in the form of JNP has limited advantages in improving the oral bioavailability of Res and αCT. Cellular uptake efficiency at 4 h was about 10-15% in Caco-2 cell lines for αCT/Res-JNP, but was reduced to 7% in Caco-2/HT29-MTX co-culture models due to the hindrance by the mucus layers. Approximately 12-17% of αCT/Res-JNP were transported across Caco-2/HT29-MTX/Raji monolayers. The cumulative absorption of JNP in three cell models was higher than that of free drug. CONCLUSIONS: This study investigated the contribution of Janus nanoparticles in oral absorption, and provide a new perspective for oral administration and analgesic treatment of dual drug delivery system containing peptide drugs.

7.
Bioengineered ; 12(1): 4924-4935, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34369264

RESUMO

Non-small cell lung cancer (NSCLC) is one of the fatal tumors and is associated with a poor prognosis. Cell-type identification by estimating relative subsets of RNA transcripts (CIBERSORT) was used to quantify the proportions of 22 types of immune cells. Weighted gene co-expression network analysis (WGCNA) was established from the GSE37745 data, and key modules correlating most with CD8+ T cell infiltration were determined. Genes that manifested a high module connectivity in the key module were identified as hub genes. Three bioinformatics online databases were used to evaluate hub gene expression levels in tumor and normal tissues. Finally, survival analysis was conducted for these hub genes. In this study, we chose four hub genes (AURKB, CDC20, TPX2 and KIF2C) based on the comprehensive bioinformatics analyses. All hub genes were overexpressed in tumor tissue, and high expression of AURKB, CDC20, TPX2, and KIF2C correlated with the poor prognosis of these patients. In vitro experiments confirmed that CDC20 knockdown inhibited cell proliferation and growth. The above results indicated that AURKB, CDC20, TPX2, and KIF2C are potential CD8+ T cell infiltration-related biomarkers and therapeutic targets.

8.
J Am Chem Soc ; 143(33): 13245-13258, 2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34379977

RESUMO

Interfacial reactions are notoriously difficult to characterize, and robust prediction of the chemical evolution and associated functionality of the resulting surface film is one of the grand challenges of materials chemistry. The solid-electrolyte interphase (SEI), critical to Li-ion batteries (LIBs), exemplifies such a surface film, and despite decades of work, considerable controversy remains regarding the major components of the SEI as well as their formation mechanisms. Here we use a reaction network to investigate whether lithium ethylene monocarbonate (LEMC) or lithium ethylene dicarbonate (LEDC) is the major organic component of the LIB SEI. Our data-driven, automated methodology is based on a systematic generation of relevant species using a general fragmentation/recombination procedure which provides the basis for a vast thermodynamic reaction landscape, calculated with density functional theory. The shortest pathfinding algorithms are employed to explore the reaction landscape and obtain previously proposed formation mechanisms of LEMC as well as several new reaction pathways and intermediates. For example, we identify two novel LEMC formation mechanisms: one which involves LiH generation and another that involves breaking the (CH2)O-C(═O)OLi bond in LEDC. Most importantly, we find that all identified paths, which are also kinetically favorable under the explored conditions, require water as a reactant. This condition severely limits the amount of LEMC that can form, as compared with LEDC, a conclusion that has direct impact on the SEI formation in Li-ion energy storage systems. Finally, the data-driven framework presented here is generally applicable to any electrochemical system and expected to improve our understanding of surface passivation.

9.
Aging (Albany NY) ; 13(13): 17380-17406, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34198262

RESUMO

The present study aimed to investigate the associations between the trajectory of blood pressure (BP) change and the risk of subsequent dementia and to explore the differences in age, gender, and hypertension subgroups. We included 10,660 participants aged ≥ 60 years from 1998 to 2018 waves of the Chinese Longitudinal Healthy Longevity Survey. Latent growth mixture models were used to estimate BP trajectories. Cox-proportional hazard models were used to analyze the effects of BP trajectories on the risk of dementia. According to the results, stabilized systolic BP (SBP) was found to be associated with a higher risk of dementia compared with normal SBP [adjusted hazard ratio (aHR): 1.62; 95% confidence interval (CI): 1.27-2.07] and elevated SBP (aHR: 2.22; 95% CI: 1.51-3.28) in and only in the subgroups of the oldest-old, women, and subjects without hypertension at baseline. Similarly, stabilized pulse pressure (PP) was associated with a higher risk of dementia compared with normal PP (aHR: 1.52; 95% CI: 1.24-1.88) and elevated PP (aHR: 2.12; 95% CI: 1.48-3.04) in and only in the subgroups of the oldest-old, women, and subjects with hypertension at baseline. These findings suggest that stabilized SBP and PP have predictive significance for the occurrence of dementia in late life, and the factors of age, gender, and late-life hypertension should be considered when estimating the risk of BP decline on dementia.


Assuntos
Pressão Sanguínea , Demência/epidemiologia , Demência/fisiopatologia , Idoso , Idoso de 80 Anos ou mais , Envelhecimento , China/epidemiologia , Estudos de Coortes , Feminino , Humanos , Hipertensão/complicações , Hipertensão/epidemiologia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Modelos de Riscos Proporcionais , Medição de Risco , Fatores Sexuais
10.
J Immunol Res ; 2021: 6629531, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34212053

RESUMO

Baicalin (BA) magnesium salt (BA-Mg) is a good water-soluble ingredient extracted from Scutellaria baicalensis Georgi, a commonly used traditional Chinese medicine. This study is aimed at investigating whether BA-Mg could exert a better protective effect on lipopolysaccharide- (LPS-) induced acute lung injury (ALI) in mice and illuminate the underlying mechanisms in vivo and in vitro. Mice were intraperitoneally administrated with equimolar BA-Mg, BA, and MgSO4 before LPS inducing ALI. Lung tissues and bronchoalveolar lavage fluid were collected for lung wet/dry ratio, histological examinations, cell counts, and biochemical analyses at 48 h post-LPS exposure. Meanwhile, the protein expressions of TLR4/NF-κB signaling pathway and proinflammatory cytokines in lung tissues and lung bronchial epithelial cells (BEAS-2B) were detected. The results showed BA-Mg pronouncedly ameliorated LPS-induced inflammatory response and histopathological damages, elevated antioxidant enzyme activity (SOD), and downregulated myeloperoxidase (MPO) and malonaldehyde (MDA) levels through the inhibition of TLR4/NF-κB signaling pathway activation. Moreover, the effect of BA-Mg was significantly better than that of BA and MgSO4 in ameliorating symptoms. Overall, BA-Mg can effectively relieve inflammatory response and oxidative stress triggered by LPS, indicating it may be a potential therapeutic candidate for treating ALI.

11.
Front Psychol ; 12: 675848, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34093371

RESUMO

In the contextual cueing task, visual search is faster for targets embedded in invariant displays compared to targets found in variant displays. However, it has been repeatedly shown that participants do not learn repeated contexts when these are irrelevant to the task. One potential explanation lays in the idea of associative blocking, where salient cues (task-relevant old items) block the learning of invariant associations in the task-irrelevant subset of items. An alternative explanation is that the associative blocking rather hinders the allocation of attention to task-irrelevant subsets, but not the learning per se. The current work examined these two explanations. In two experiments, participants performed a visual search task under a rapid presentation condition (300 ms) in Experiment 1, or under a longer presentation condition (2,500 ms) in Experiment 2. In both experiments, the search items within both old and new displays were presented in two colors which defined the irrelevant and task-relevant items within each display. The participants were asked to search for the target in the relevant subset in the learning phase. In the transfer phase, the instructions were reversed and task-irrelevant items became task-relevant (and vice versa). In line with previous studies, the search of task-irrelevant subsets resulted in no cueing effect post-transfer in the longer presentation condition; however, a reliable cueing effect was generated by task-irrelevant subsets learned under the rapid presentation. These results demonstrate that under rapid display presentation, global attentional selection leads to global context learning. However, under a longer display presentation, global attention is blocked, leading to the exclusive learning of invariant relevant items in the learning session.

12.
Chem Sci ; 12(13): 4931-4939, 2021 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-34163740

RESUMO

Modeling reactivity with chemical reaction networks could yield fundamental mechanistic understanding that would expedite the development of processes and technologies for energy storage, medicine, catalysis, and more. Thus far, reaction networks have been limited in size by chemically inconsistent graph representations of multi-reactant reactions (e.g. A + B → C) that cannot enforce stoichiometric constraints, precluding the use of optimized shortest-path algorithms. Here, we report a chemically consistent graph architecture that overcomes these limitations using a novel multi-reactant representation and iterative cost-solving procedure. Our approach enables the identification of all low-cost pathways to desired products in massive reaction networks containing reactions of any stoichiometry, allowing for the investigation of vastly more complex systems than previously possible. Leveraging our architecture, we construct the first ever electrochemical reaction network from first-principles thermodynamic calculations to describe the formation of the Li-ion solid electrolyte interphase (SEI), which is critical for passivation of the negative electrode. Using this network comprised of nearly 6000 species and 4.5 million reactions, we interrogate the formation of a key SEI component, lithium ethylene dicarbonate. We automatically identify previously proposed mechanisms as well as multiple novel pathways containing counter-intuitive reactions that have not, to our knowledge, been reported in the literature. We envision that our framework and data-driven methodology will facilitate efforts to engineer the composition-related properties of the SEI - or of any complex chemical process - through selective control of reactivity.

13.
Blood ; 137(24): 3339-3350, 2021 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-33881475

RESUMO

Total body irradiation (TBI) is commonly used in host conditioning regimens for human hematopoietic stem cell (HSC) transplantation to treat various hematological disorders. Exposure to TBI not only induces acute myelosuppression and immunosuppression, but also injures the various components of the HSC niche in recipients. Our previous study demonstrated that radiation-induced bystander effects (RIBE) of irradiated recipients decreased the long-term repopulating ability of transplanted mouse HSCs. However, RIBE on transplanted human HSCs have not been studied. Here, we report that RIBE impaired the long-term hematopoietic reconstitution of human HSCs as well as the colony-forming ability of human hematopoietic progenitor cells (HPCs). Our further analyses revealed that the RIBE-affected human hematopoietic cells showed enhanced DNA damage responses, cell-cycle arrest, and p53-dependent apoptosis, mainly because of oxidative stress. Moreover, multiple antioxidants could mitigate these bystander effects, though at different efficacies in vitro and in vivo. Taken together, these findings suggest that RIBE impair human HSCs and HPCs by oxidative DNA damage. This study provides definitive evidence for RIBE on transplanted human HSCs and further justifies the necessity of conducting clinical trials to evaluate different antioxidants to improve the efficacy of HSC transplantation for the patients with hematological or nonhematological disorders.

14.
Cell ; 184(7): 1895-1913.e19, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33657410

RESUMO

A dysfunctional immune response in coronavirus disease 2019 (COVID-19) patients is a recurrent theme impacting symptoms and mortality, yet a detailed understanding of pertinent immune cells is not complete. We applied single-cell RNA sequencing to 284 samples from 196 COVID-19 patients and controls and created a comprehensive immune landscape with 1.46 million cells. The large dataset enabled us to identify that different peripheral immune subtype changes are associated with distinct clinical features, including age, sex, severity, and disease stages of COVID-19. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA was found in diverse epithelial and immune cell types, accompanied by dramatic transcriptomic changes within virus-positive cells. Systemic upregulation of S100A8/A9, mainly by megakaryocytes and monocytes in the peripheral blood, may contribute to the cytokine storms frequently observed in severe patients. Our data provide a rich resource for understanding the pathogenesis of and developing effective therapeutic strategies for COVID-19.


Assuntos
COVID-19/imunologia , Megacariócitos/imunologia , Monócitos/imunologia , RNA Viral , SARS-CoV-2/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , China , Estudos de Coortes , Citocinas/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , RNA Viral/sangue , RNA Viral/isolamento & purificação , Análise de Célula Única , Transcriptoma/imunologia , Adulto Jovem
15.
Sci China Life Sci ; 64(10): 1634-1644, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-33564978

RESUMO

The blood and immune system of coronavirus disease 2019 (COVID-19) infected patients are dysfunctional, and numerous studies have been conducted to resolve their characteristics and pathogenic mechanisms. Nevertheless, the variations of immune responses along with disease severity have not been comprehensively documented. Here, we profiled the single-cell transcriptomes of 96,313 peripheral blood mononuclear cells (PBMCs) derived from 12 COVID-19 patients (including four moderate, four severe and four critical cases) and three healthy donors. We showed that proliferative CD8 effector T cells with declined immune functions and cytotoxicity accumulated in the critical stage. By contrast, the quantity of natural killer (NK) cells was significantly reduced, while they exhibited enhanced immune activities. Notably, a gradually attenuated responseto COVID-19 along with disease severity was observed in monocytes, in terms of cellular composition, transcriptional discrepancy and transcription factor regulatory network. Furthermore, we identified immune cell-type dependent cytokine signatures distinguishing the severity of COVID-19 patients. In addition, cell interactions between CD8 effector T/NK cells and monocytes mediated by inflammatory cytokines were enhanced in moderate and severe stages, but weakened in critical cases. Collectively, our work uncovers the cellular and molecular players underlying the disordered and heterogeneous immune responses associated with COVID-19 severity, which could provide valuable insights for the treatment of critical COVID-19 patients.


Assuntos
COVID-19/fisiopatologia , Leucócitos Mononucleares/metabolismo , Índice de Gravidade de Doença , Análise de Célula Única , Transcriptoma , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , COVID-19/sangue , COVID-19/genética , COVID-19/virologia , Estudos de Casos e Controles , Humanos , Células Matadoras Naturais/imunologia , SARS-CoV-2/isolamento & purificação
16.
J Appl Toxicol ; 41(5): 765-774, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33222186

RESUMO

Zirconia nanoparticles (NPs) have been widely used in biomedicine, which will likely lead to their interactions with endothelial cells (ECs). However, the toxicity of zirconia NPs to ECs is less investigated and the toxicological data are not consistent. Furthermore, no previous study, to the best of our knowledge, investigated the influence of zirconia NPs on lipid metabolism. This study investigated lipid profiles in human umbilical vein ECs (HUVECs) exposed to zirconia NPs with or without the presence of free fatty acids (FFAs). Incubation with FFA changed the hydrodynamic size, zeta potential, and surface profiles of zirconia NPs, indicating the surface coating effects. Exposure of HUVECs to various concentrations of zirconia NPs with or without the presence of FFA did not significantly decrease cellular viability, but FFA decreased zirconium elemental levels in NP-exposed cells. Oil Red O staining showed that FFA or zirconia NPs and FFA, but not zirconia NPs alone, significantly increased lipid accumulation in HUVECs. Consistently, lipidomic data suggested that exposure to FFA or zirconia NPs and FFA up-regulated most lipid classes in HUVECs. As the mechanisms for increased lipid accumulation, exposure to FFA or zirconia NPs and FFA up-regulated endoplasmic reticulum (ER) stress axis IRE1α-XBP-1, leading to increased FASN and ACSL3, proteins involved in lipid metabolism. Combined, our results demonstrated that zirconia NPs were noncytotoxic and showed minimal impact on ER stress-mediated lipid metabolism in HUVECs under both normal and FFA-challenged conditions, which indicated the relatively high biocompatibility of zirconia NPs to ECs.

17.
J Infect ; 82(1): 159-198, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32730998

RESUMO

China empowers mobile health technologies to fight against COVID-19 pandemic. The success of mobile health here may be a useful reference for other parts of the world. We explore China's application of mobile health technologies to replenishing traditional public-health and social approaches for mitigating and suppressing COVID-19, and found that Internet hospitals alleviate the unavailability, inaccessibility, and inequity of health services during the outbreak; the fact-check and information-release platforms reduce the spread of misinformation; and the infection risk scoring systems facilitate restoring the order of production and life.


Assuntos
COVID-19 , Telemedicina , Tecnologia Biomédica , China/epidemiologia , Hospitais , Humanos , Internet , Pandemias , SARS-CoV-2
18.
FASEB J ; 34(11): 15364-15378, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32978839

RESUMO

Ulcerative colitis (UC) is a widespread inflammatory bowel disease that causes long-lasting inflammation and ulcers in the colon and rectum. In the inflamed tissue of patients with UC, the tight junctions are disrupted and large amounts of pro-inflammatory cytokines are produced, resulting in immune dysregulation. The expression of Nur77 is significantly reduced in the colon of inflammatory bowel disease, while Nur77 deficiency increases the susceptibility to DSS-induced colitis. Here, we report that Gly-Pro-Ala (GPA) peptide isolated from fish skin gelatin hydrolysate can significantly alleviate intestinal inflammation and damage caused by DSS-induced mice colitis. Besides maintaining the intestinal epithelial barrier, GPA alleviates intestinal inflammation and oxidative stress by inhibiting NF-κB activation. Interestingly, GPA binds to the ligand-binding domain of Nur77 and stimulates its autotranscriptional activity to enhance its expression in intestinal epithelial cells. Furthermore, GPA activates the promoter of IκBα to increase its expression, resulting in the abolishment of the NF-κB pathway. In contrast, the inhibitory effects of GPA on colitis are abolished in Nur77-/- mice. Our results suggest that as a Nur77 modulator, GPA may be applied to the prevention of intestinal inflammation.


Assuntos
Colite/tratamento farmacológico , Sulfato de Dextrana/toxicidade , Células Epiteliais/efeitos dos fármacos , Inflamação/tratamento farmacológico , Mucosa Intestinal/efeitos dos fármacos , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , Fragmentos de Peptídeos/farmacologia , Animais , Colite/induzido quimicamente , Colite/metabolismo , Colite/patologia , Citocinas/metabolismo , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Regulação da Expressão Gênica , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/patologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/genética , Estresse Oxidativo
19.
J Chem Theory Comput ; 16(7): 4256-4270, 2020 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-32502350

RESUMO

Machine learning (ML) approximations to density functional theory (DFT) potential energy surfaces (PESs) are showing great promise for reducing the computational cost of accurate molecular simulations, but at present, they are not applicable to varying electronic states, and in particular, they are not well suited for molecular systems in which the local electronic structure is sensitive to the medium to long-range electronic environment. With this issue as the focal point, we present a new machine learning approach called "BpopNN" for obtaining efficient approximations to DFT PESs. Conceptually, the methodology is based on approaching the true DFT energy as a function of electron populations on atoms; in practice, this is realized with available density functionals and constrained DFT (CDFT). The new approach creates approximations to this function with neural networks. These approximations thereby incorporate electronic information naturally into a ML approach, and optimizing the model energy with respect to populations allows the electronic terms to self-consistently adapt to the environment, as in DFT. We confirm the effectiveness of this approach with a variety of calculations on LinHn clusters.

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