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Purpose: Sinomenine (SIN) is commonly used in Traditional Chinese Medicine (TCM) as a respected remedy for rheumatoid arthritis (RA). Nevertheless, the therapeutic mechanism of SIN in RA remains incompletely understood. This study aimed to delve into the molecular mechanism of SIN in the treatment of RA. Methods: The potential targets of SIN were predicted using the TCMSP server, STITCH database, and SwissTarget Prediction. Differentially expressed genes (DEGs) in RA were obtained from the GEO database. Enrichment analyses and molecular docking were conducted to explore the potential mechanism of SIN in the treatment of RA. In vitro and in vivo studies were conducted to validate the intervention effects of SIN on rheumatoid arthritis, as determined through network pharmacology analyses. Results: A total of 39 potential targets associated with the therapeutic effects of SIN in RA were identified. Enrichment analysis revealed that these potential targets are primarily enriched in PI3K-Akt signaling pathway, and the molecular docking suggests that SIN may act on specific proteins in the pathway. Experimental results have shown that exposure to SIN inhibits cytokine secretion, promotes apoptosis, reduces metastasis and invasion, and blocks the activation of the PI3K-Akt signaling pathway in RA fibroblast-like synoviocytes (RA-FLS). Moreover, SIN treatment alleviated arthritis-related symptoms and regulated the differentiation of CD4+ T cells in the spleen of collagen-induced arthritis (CIA) mice. Conclusion: By utilizing network pharmacology, molecular modeling, and in vitro/in vivo validation, this study demonstrates that SIN can alleviate RA by inhibiting the PI3K-Akt signaling pathway. These findings enhance the understanding of the therapeutic mechanisms of SIN in RA, offering a stronger theoretical foundation for its future clinical application.
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Artrite Reumatoide , Simulação de Acoplamento Molecular , Morfinanos , Farmacologia em Rede , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Morfinanos/farmacologia , Morfinanos/química , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Camundongos , Animais , Transdução de Sinais/efeitos dos fármacos , Humanos , Fosfatidilinositol 3-Quinases/metabolismo , Masculino , Antirreumáticos/farmacologia , Antirreumáticos/química , Células Cultivadas , Artrite Experimental/tratamento farmacológico , Artrite Experimental/patologia , Artrite Experimental/metabolismo , Camundongos Endogâmicos DBARESUMO
The United Nations proposed the Sustainable Development Goals with the aim to make human settlements in cities resilient and sustainable. The excessive discharge of urban waste including sludge and garden waste can pollute groundwater and lead to the emission of greenhouse gases (e.g., CH4). The proper recycling of urban waste is essential for responsible consumption and production, reducing environmental pollution and addressing climate change issues. This study aimed to prepare biochar with high adsorption amounts of iodine using urban sludge and peach wood from garden waste. The study was conducted to examine the variations in the mass ratio between urban sludge and peach wood (2/1, 1/1, and 1/2) as well as pyrolysis temperatures (300 °C, 500 °C, and 700 °C) on the carbon yield and adsorption capacities of biochar. Scanning electron microscopy, Brunauer-Emmett-Teller analysis, Fourier transform infrared spectrometry, powder X-ray diffraction, and elemental analysis were used to characterize the biochar produced at different pyrolysis temperatures and mass ratios. The results indicate that the carbon yield of biochar was found to be the highest (>60%) at a pyrolysis temperature of 300 °C across different pyrolysis temperatures. The absorbed amounts of iodine in the aqueous solution ranged from 86 to 223 mg g-1 at a mass ratio of 1:1 between urban sludge and peach wood, which were comparably higher than those observed in other mass ratios. This study advances water treatment by offering a cost-effective method by using biochar derived from the processing of urban sludge and garden waste.
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Carvão Vegetal , Iodo , Pirólise , Esgotos , Carvão Vegetal/química , Iodo/química , Esgotos/química , Adsorção , Temperatura , Jardins , Espectroscopia de Infravermelho com Transformada de Fourier , CidadesRESUMO
Background: Traditional dose selection for oncology registration trials typically employs a one- or two-step single maximum tolerated dose (MTD) approach. However, this approach may not be appropriate for molecularly targeted therapy, which tends to have toxicity profiles that are markedly different than cytotoxic agents. The US Food and Drug Administration launched Project Optimus to reform dose optimization in oncology drug development and has recently released a related guidance for industry. Methods: We propose a "three steps toward dose optimization" procedure, in response to these initiatives, and discuss the details in dose-optimization designs and analyses. The first step is dose escalation to identify the MTD or maximum administered dose with an efficient hybrid design, which can offer good overdose control and increases the likelihood of the recommended MTD being close to the true MTD. The second step is the selection of appropriate recommended doses for expansion (RDEs), based on all available data, including emerging safety, pharmacokinetics, pharmacodynamics, and other biomarker information. The third step is dose optimization, which uses data from a randomized fractional factorial design with multiple RDEs explored in multiple tumor cohorts during the expansion phase to ensure a feasible dose is selected for registration trials, and that the tumor type most sensitive to the investigative treatment is identified. Conclusion: We believe using this three-step approach can increase the likelihood of selecting an optimal dose for a registration trial that demonstrates a balanced safety profile while retaining much of the efficacy observed at the MTD.
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Thrombospondin-1 (TSP1) is a matricellular protein associated with the regulation of cell migration through direct binding interactions with integrin proteins and by associating with other receptors known to regulate integrin function, including CD47 and CD36. We previously demonstrated that deletion of an epithelial TSP1 receptor CD47 attenuates epithelial wound repair following intestinal mucosal injury. However, the mechanisms by which TSP1 contributes to intestinal mucosal repair remains poorly understood. Our results show upregulated TSP1 expression in colonic mucosal wounds and impaired intestinal mucosal wound healing in vivo upon intestinal epithelial specific loss of TSP1 (VillinCre/+Thbs1f/f or Thbs1ΔIEC). We report that exposure to exogenous TSP1 enhanced migration of IECs in a CD47- and TGFß1-dependent manner, and that deficiency of TSP1 in primary murine colonic epithelial cells resulted in impaired wound healing. Mechanistically, TSP1 modulated epithelial actin cytoskeletal dynamics by suppression of RhoA activity, activation of Rac1, and changes in F-actin bundling. Overall, TSP1 was found to regulate intestinal mucosal wound healing via CD47 and TGFß1, coordinate integrin-containing cell-matrix adhesion dynamics and remodel the actin cytoskeleton in migrating epithelial cells to enhance cell motility and promote wound repair.
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Bacterial RNAP needs to form holoenzyme with σ factors to initiate transcription. While Staphylococcus aureus σA controls housekeeping functions, S. aureus σB regulates virulence, biofilm formation, persistence, cell internalization, membrane transport, and antimicrobial resistance. Besides the sequence difference, the spacers between the -35 element and -10 element of σB regulated promoters are shorter than those of σA regulated promoters. Therefore, how σB recognizes and initiates transcription from target promoters can not be inferred from that of the well studied σ. Here, we report the cryo-EM structures of S. aureus RNAP-promoter open complexes comprising σA and σB, respectively. Structural analyses, in combination with biochemical experiments, reveal the structural basis for the promoter specificity of S. aureus transcription. Although the -10 element of σA regulated promoters is recognized by domain σA2 as single-stranded DNA, the -10 element of σB regulated promoters is co-recognized by domains σB2 and σB3 as double-stranded DNA, accounting for the short spacers of σB regulated promoters. S. aureus RNAP is a validated target of antibiotics, and our structures pave the way for rational drug design targeting S. aureus RNAP.
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Proteínas de Bactérias , Microscopia Crioeletrônica , RNA Polimerases Dirigidas por DNA , Regiões Promotoras Genéticas , Fator sigma , Staphylococcus aureus , Staphylococcus aureus/genética , Staphylococcus aureus/enzimologia , RNA Polimerases Dirigidas por DNA/metabolismo , RNA Polimerases Dirigidas por DNA/genética , RNA Polimerases Dirigidas por DNA/química , Fator sigma/metabolismo , Fator sigma/genética , Fator sigma/química , Proteínas de Bactérias/metabolismo , Proteínas de Bactérias/genética , Proteínas de Bactérias/química , Regulação Bacteriana da Expressão Gênica , Modelos Moleculares , Transcrição Gênica , Ligação ProteicaRESUMO
Innate lymphoid cells (ILCs), strategically positioned throughout the body, undergo population declines over time. A solution to counteract this problem is timely mobilization of multipotential progenitors from the bone marrow. It remains unknown what triggers the mobilization of bone marrow ILC progenitors (ILCPs). We report that ILCPs are regulated by the circadian clock to emigrate and generate mature ILCs in the periphery. We found that circadian-clock-defective ILCPs fail to normally emigrate and generate ILCs. We identified circadian-clock-controlled endocrine and cytokine cues that, respectively, regulate the retention and emigration of ILCPs at distinct times of each day. Activation of the stress-hormone-sensing glucocorticoid receptor upregulates CXCR4 on ILCPs for their retention in the bone marrow, while the interleukin-18 (IL-18) and RORα signals upregulate S1PR1 on ILCPs for their mobilization to the periphery. Our findings establish important roles of circadian signals for the homeostatic efflux of bone marrow ILCPs.
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Relógios Circadianos , Animais , Camundongos , Citocinas/metabolismo , Camundongos Endogâmicos C57BL , Medula Óssea/metabolismo , Transdução de Sinais , Receptores CXCR4/metabolismo , Células da Medula Óssea/metabolismo , Células da Medula Óssea/citologia , Células Progenitoras Linfoides/metabolismo , Células Progenitoras Linfoides/citologia , Imunidade Inata , Movimento Celular , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Receptores de Glucocorticoides/metabolismo , Linfócitos/metabolismo , Linfócitos/imunologiaRESUMO
BACKGROUND: Anemia is prevalent among patients with T2DM with DFU. However, there is limited research on the relationship between Hb level and DFU. OBJECTIVE: To investigate the characteristics and relationship between Hb level and prognosis in patients with DFU. MATERIALS AND METHODS: A total of 212 patients with T2DM were included and grouped according to the presence (n = 105) or absence (n = 107) of DFU. The independent t test and multiple logistic regression analysis were used to analyze the effect of different factors on the occurrence of anemia in patients with DFU and whether Hb level could be used to predict prognosis. RESULTS: There were significant differences in clinical indicators that directly or indirectly contributed to anemia in patients with DFU (P < .05). Hb level was independently associated with DFU (OR, 0.899; P < .05). Hb levels were significantly decreased in patients aged 65 years or older (P < .05). Mild anemia was prevalent among most patients with DFU (59.62%). Hb level decreased with the severity of foot ulcer (P < .05) and was correlated with the duration of diabetes (R2 = 0.653; P < .05). The AUC value was 0.82, with a cutoff value of 122.5 g/L to identify patients with DFU at high risk of adverse outcomes. CONCLUSION: Anemia is common in patients with DFU. Anemia is a marker of DFU severity, and Hb level can predict poor prognosis in patients with DFU.
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Anemia , Diabetes Mellitus Tipo 2 , Pé Diabético , Hemoglobinas , Humanos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/sangue , Pé Diabético/sangue , Masculino , Feminino , Estudos Transversais , Anemia/sangue , Pessoa de Meia-Idade , Hemoglobinas/metabolismo , Hemoglobinas/análise , Idoso , Prognóstico , Prevalência , Fatores de Risco , Índice de Gravidade de DoençaRESUMO
Obesity has significant repercussions for female reproductive health, including adverse effects on oocyte quality, fertility, embryo development and offspring health. Here, we showed that intermittent fasting (IF) has several notable effects on follicular development, oocyte development and maturation and offspring health in obese mice. IF treatment prevents obesity-associated germline-soma communication defects, mitochondrial dysfunction, oxidative damage, apoptosis, and spindle/chromosomal disruption. RNA-sequencing analysis of oocytes from normal diet (ND), high-fat diet (HFD), and HFD + IF mice indicated that IF treatment improved mitochondrial oxidative phosphorylation function and mRNA storage and translation, which was potentially mediated by the Smith-like family member 14 B (LSM14B). Knockdown of LSM14B by siRNA injection in oocytes from ND mice recapitulates all the translation, mitochondrial dysfunction and meiotic defect phenotypes of oocytes from HFD mice. Remarkably, the injection of Lsm14b mRNA into oocytes from HFD mice rescued the translation, mitochondrial dysfunction and meiotic defect phenotypes. These results demonstrated that dysfunction in the oocyte translation program is associated with obesity-induced meiotic defects, while IF treatment increased LSM14B expression and maternal mRNA translation and restored oocyte quality. This research has important implications for understanding the effects of obesity on female reproductive health and offers a potential nonpharmacological intervention to improve oocyte quality and fertility in obese individuals.
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Jejum Intermitente , RNA Mensageiro Estocado , Animais , Feminino , Camundongos , Meiose , Camundongos Obesos , Doenças Mitocondriais/metabolismo , Obesidade/metabolismo , Oócitos/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Mensageiro Estocado/metabolismoRESUMO
BACKGROUND: Adverse childhood experiences (ACEs) profoundly disrupt preschoolers' attentional regulation development. Different patterns of ACEs may be associated with different attentional regulation outcomes. OBJECTIVE: Drawing from developmental systems theory and attachment theory, this study aimed to identify distinct patterns of early ACEs at age three and examined the associations of these patterns with preschoolers' attentional regulation at age five. PARTICIPANTS AND SETTING: This study used the two waves of longitudinal data from the Future of Families and Child Wellbeing Study (N = 4457). METHODS: First, this study applied latent class analysis (LCA) across nine indicators of ACEs at age three. Second, class membership was examined for associations with preschoolers' attentional regulation at age five. RESULTS: LCA identified four latent classes of ACEs: separation (41.2 %), parental incarceration (33 %), family dysfunction (20.8 %), and child abuse (5 %). Children in the child abuse class exhibited lower levels of attentional regulation than those in the family dysfunction class (0.33 standard deviation difference, p < .01) or separation class (0.48 standard deviation difference, p < .001). Children in the parental incarceration class demonstrated lower levels of attentional regulation than those in the separation class (0.63 standard deviation difference, p < .001). CONCLUSIONS: Findings provide implications for the need to prevent early child abuse and incorporate trauma-informed intervention programs to support preschoolers' attentional regulation during school-entry age.
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Experiências Adversas da Infância , Maus-Tratos Infantis , Criança , Humanos , Análise de Classes Latentes , Saúde da Criança , PaisRESUMO
Microwaves have the advantage of penetrating vegetation and exhibit sensitivity to properties such as vegetation water content (VWC); yet, their potential utility in the fire domain is infrequently investigated. This study elucidates the different impacts of the microwave VWC index EDVI on fire radiative energy (FRE) across various biome types and the significant predictive power for high-severity fires (defined based on FRE) in mainland Southeast Asia. While EDVI exhibits lower predictive power for high severe fires compared to the commonly used fire weather indices (e.g., FWI), an enhancement is observed when these predictors are used in combination. Either by employing EDVI or fire weather indices, the predictability of fires is found to be highest over forests and lowest over croplands. Factors such as increasing human influence and fuel limitation in croplands are likely reducing the roles of VWC and weather on fires, contributing to the lower prediction skill of EDVI and fire weather. These results indicate the usefulness of microwave VWC index in fire studies. Although fire weather presents more considerable impacts on fires, the microwave VWC index seem to still provide some complementary information in fire danger assessment.
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Micro-Ondas , Tempo (Meteorologia) , Humanos , Ecossistema , Florestas , Água , Sudeste AsiáticoRESUMO
PURPOSE: Lung cancer has a high morbidity and mortality rate of all cancers worldwide. Therefore, there is an urgent need for reliable cancer markers for diagnosis and prognosis of patients with lung cancer. METHODS: In this study, we used the bioinformatics database to compare the expression of the TBX2 subfamily at the transcriptional and protein levels in non-small cell lung cancer. Then, to confirm our bioinformatics analysis above, we used western bloting to determine the expression of TBX2, TBX3, TBX4 and TBX5 in human lung squamous carcinoma cell lines. Besides, low expression of TBX2 subfamily predicted a poor prognosis of patients with lung cancer. Finally, The methylation database was used to explore the relationship between the low expression of TBX2 subfamily and methylation of gene promoter region. RESULTS: Our data showed a significant decrease of TBX2 subfamily expression in lung cancer tissues of several histological subtypes. Finally, the methylation of TBX2 subfamily members in the promoter region of NSCLC was significantly higher than that in normal tissues. CONCLUSION: Our research provided sufficient evidence that TBX2 subfamily might play an inhibitory role in malignancy progression of lung cancer, which is promising to shed light on discovering a novel reliable cancer marker for prognosis of lung cancer patients.
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An inference procedure is proposed to provide consistent estimators of parameters in a modal regression model with a covariate prone to measurement error. A score-based diagnostic tool exploiting parametric bootstrap is developed to assess adequacy of parametric assumptions imposed on the regression model. The proposed estimation method and diagnostic tool are applied to synthetic data generated from simulation experiments and data from real-world applications to demonstrate their implementation and performance. These empirical examples illustrate the importance of adequately accounting for measurement error in the error-prone covariate when inferring the association between a response and covariates based on a modal regression model that is especially suitable for skewed and heavy-tailed response data.
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Simulação por ComputadorRESUMO
The New York State Office for People With Developmental Disabilities seeks to better understand the direct support professional (DSP) workforce and offer data-informed strategies for DSP retention. We used the 2018 NCI-IDD Staff Stability Survey (now called State of the Workforce Survey) to investigate agency-level factors influencing DSP tenure. A total 303 provider agencies completed the survey in New York State, representing 72,252 DSPs. Multiple linear regression analysis revealed that selected agency-level variables explained 12.6% of the variance in DSP tenure, R2 = .16, Radj2 = .126, F (11, 260) = 4.54, p < .05. This study yielded strong empirical evidence consistent with existing national reports and research on the role that wages, benefits, and supervisory support play on DSP tenure.
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Pessoal de Saúde , Deficiência Intelectual , Humanos , Criança , New York , Deficiências do Desenvolvimento , Recursos HumanosRESUMO
Recently, biomass has been regarded as a promising option for solid energy in China, which is promoted in the residential sector and firing power plants. We collected 200 PM2.5 samples (particulate matter with a aerodynamic diameter smaller than 2.5 µm) at multi-sites across Beijing from three individual sampling cases from 2015 to 2017. The levels of OC, OC fractions, EC, EC fractions, as well as K+ were measured. Then, we adopted the Positive Matrix Factorization 5.0 to apportion the sources of carbonaceous aerosols. The source apportionment results were compared with the estimates of source contribution using the bottom-up technical method with the latest emission inventories after the Action Plan was put into effect in 2013. Our results demonstrate that high pollution of carbonaceous aerosols originated from wood smoking based on the receptor modeling and bottom-up technical method in Beijing from 2015 to 2017. Future energy transition policy should focus on the technologies and regulations for reducing emissions from renewable biomass fuel combustion. This study highlights the importance of regulations that address emissions controls on fuels replacing coal combustion to meet the needs to mitigate air pollution from primary energy use.
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Poluentes Atmosféricos , Pequim , Poluentes Atmosféricos/análise , Fumaça , Madeira/química , Estações do Ano , Monitoramento Ambiental/métodos , Material Particulado/análise , China , Atmosfera , Aerossóis/análise , Políticas , Carbono/análiseRESUMO
Objective: To promote the development and therapeutic application of new medications, it is crucial to conduct a thorough investigation into the mechanism by which the traditional Chinese herb pair of Haizao-Kunbu (HK) treats Graves' disease (GD). Materials and methods: Chemical ingredients of HK, putative target genes, and GD-associated genes were retrieved from online public databases. Using Cytoscape 3.9.1, a compound-gene target network was established to explore the association between prosperous ingredients and targets. STRING, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes pathway analyses visualized core targets and disease pathways. Additionally, we conducted a refined analysis of the binding interactions between active ingredients and their respective targets. To visualize these findings, we employed precise molecular docking techniques. Furthermore, we carried out molecular dynamics simulations to gain insights into the formation of more tightly bound complexes. Results: We found that there were nine key active ingredients in HK, which mainly acted on 21 targets. These targets primarily regulated several biological processes such as cell population proliferation, protein phosphorylation, and regulation of kinase activity, and acted on PI3K-AKT and MAPK pathways to treat GD. Analysis of the molecular interaction simulation under computer technology revealed that the key targets exhibited strong binding activity to active ingredients, and Fucosterol-AKT1 and Isofucosterol-AKT1 complexes were highly stable in humans. Conclusion: This study demonstrates that HK exerts therapeutic effects on GD in a multi-component, multi-target, and multi-pathway manner by regulating cell proliferation, differentiation, inflammation, and immunomodulatory-related targets. This study provides a theoretical foundation for further investigation into GD.
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Doença de Graves , Simulação de Dinâmica Molecular , Humanos , Simulação de Acoplamento Molecular , Farmacologia em Rede , Fosfatidilinositol 3-Quinases , Doença de Graves/tratamento farmacológico , Doença de Graves/genéticaRESUMO
Hemorrhagic shock (HS) is the leading cause of death in trauma patients. Inflammation following HS can lead to cardiac damage. Pachymic acid (PA), a triterpenoid extracted from Poria cocos, has been found to possess various biological activities, including anti-inflammatory and anti-apoptotic properties. Our research aims to investigate the protective effects of PA against HS-induced heart damage and the underlying mechanisms involved. Male Sprague-Dawley rats were intraperitoneally injected with PA (7.5 or 15[Formula: see text]mg/kg) daily for three days. Subsequently, we created a rat model of HS by drawing blood through a catheter inserted into the femoral artery followed by resuscitation. The results revealed that HS led to abnormalities in hemodynamics, serum cardiac enzyme levels, and cardiac structure, as well as induced cardiac apoptosis. However, pretreatment with PA effectively alleviated these effects. PA-pretreatment also suppressed mRNA and protein levels of interleukin (IL)-1[Formula: see text], IL-6, and tumor necrosis factor [Formula: see text] (TNF-[Formula: see text]) in the heart tissues of HS rats. Additionally, PA-pretreatment reduced inflammatory cell infiltration and M1 macrophage polarization while exaggerating M2 polarization in HS rat hearts. The study observed a decreased proportion of the expression of of M1 macrophages (CD86[Formula: see text]) and their marker (iNOS), along with an increased proportion of the expression of M2 macrophages (CD206[Formula: see text]) and their marker (Arg-1). Notably, PA-pretreatment suppressed NF-[Formula: see text]B pathway activation via inhibiting NF-[Formula: see text]B p65 phosphorylation and its nuclear translocation. In conclusion, PA-pretreatment ameliorates HS-induced cardiac injury, potentially through its inhibition of the NF-[Formula: see text]B pathway. Therefore, PA treatment holds promise as a strategy for mitigating cardiac damage in HS.
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Traumatismos Cardíacos , Choque Hemorrágico , Triterpenos , Humanos , Masculino , Ratos , Animais , NF-kappa B/metabolismo , Choque Hemorrágico/complicações , Choque Hemorrágico/metabolismo , Ratos Sprague-Dawley , Transdução de Sinais , Macrófagos/metabolismo , Triterpenos/farmacologia , Triterpenos/uso terapêutico , Interleucina-1/metabolismo , Traumatismos Cardíacos/metabolismoRESUMO
BACKGROUND: Intimate partner violence (IPV) often co-occurs with childhood maltreatment and negatively impacts children's development. While previous research has shown a direct link between these experiences and children's self-regulation, less is known about the potential unique effect and bidirectional associations between them. OBJECTIVE: The present study aims to investigate the bidirectional effects among maternal IPV experiences, child maltreatment, and children's behavioral self-regulation. PARTICIPANTS AND SETTING: 4,402 participants from three waves of the longitudinal study of the Future of Families and Child Wellbeing Study (FFCWS) were included in the study. METHODS: Cross-lagged path analyses were conducted to examine the longitudinal reciprocal relationships among IPV, child maltreatment, and children's behavioral regulation when children were 3, 5, and 9 years old. RESULTS: IPV exposure at ages 3 and 5 was negatively associated with levels of behavioral self-regulation at ages 5 and 9, even after accounting for physical maltreatment, psychological maltreatment, or neglect. Neglect at ages 3 and 5 was found to be associated with lower levels of behavioral self-regulation at later ages, when IPV exposure was considered in the models. Lower levels of behavioral self-regulation at age 3 were found to be linked with higher levels of psychological maltreatment, physical maltreatment, neglect, and IPV exposure at age 5. CONCLUSION: This study revealed bidirectional effects between maternal IPV experiences, child maltreatment, and children's behavioral self-regulation. Furthermore, the study demonstrated that exposure to IPV during early childhood significantly predicts long-term behavioral self-regulation difficulties, even after controlling for the effects of child maltreatment.
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Maus-Tratos Infantis , Exposição à Violência , Violência por Parceiro Íntimo , Autocontrole , Criança , Humanos , Pré-Escolar , Estudos Longitudinais , Maus-Tratos Infantis/psicologia , Violência por Parceiro Íntimo/psicologia , Abuso Físico/psicologia , Exposição à Violência/psicologiaRESUMO
The overall oocyte quality declines with aging, and this effect is strongly associated with a higher reactive oxygen species (ROS) level and the resultant oxidative damage. C-type natriuretic peptide (CNP) is a well-characterized physiological meiotic inhibitor that has been successfully used to improve immature oocyte quality during in vitro maturation. However, the underlying roles of CNP in maternally aged oocytes have not been reported. Here, we found that the age-related reduction in the serum CNP concentration was highly correlated with decreased oocyte quality. Treatment with exogenous CNP promoted follicle growth and ovulation in aged mice and enhanced meiotic competency and fertilization ability. Interestingly, the cytoplasmic maturation of aged oocytes was thoroughly improved by CNP treatment, as assessed by spindle/chromosome morphology and redistribution of organelles (mitochondria, the endoplasmic reticulum, cortical granules, and the Golgi apparatus). CNP treatment also ameliorated DNA damage and apoptosis caused by ROS accumulation in aged oocytes. Importantly, oocyte RNA-seq revealed that the beneficial effect of CNP on aged oocytes was mediated by restoration of mitochondrial oxidative phosphorylation, eliminating excessive mitophagy. CNP reversed the defective phenotypes in aged oocytes by alleviating oxidative damage and suppressing excessive PINK1/Parkin-mediated mitophagy. Mechanistically, CNP functioned as a cAMP/PKA pathway modulator to decrease PINK1 stability and inhibit Parkin recruitment. In summary, our results demonstrated that CNP supplementation constitutes an alternative therapeutic approach for advanced maternal age-related oocyte deterioration and may improve the overall success rates of clinically assisted reproduction in older women.
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Técnicas de Maturação in Vitro de Oócitos , Peptídeo Natriurético Tipo C , Animais , Feminino , Camundongos , Células do Cúmulo/metabolismo , Técnicas de Maturação in Vitro de Oócitos/métodos , Meiose , Mitofagia , Peptídeo Natriurético Tipo C/farmacologia , Peptídeo Natriurético Tipo C/genética , Peptídeo Natriurético Tipo C/metabolismo , Oócitos/metabolismo , Proteínas Quinases/metabolismo , Espécies Reativas de Oxigênio/metabolismoRESUMO
This study investigates the effect of porosity and pore shape on the biological and mechanical behavior of additively manufactured scaffolds for bone tissue engineering (BTE). Polylactic acid scaffolds with varying porosity levels (15-78%) and pore shapes, including regular (rectangular pores), gyroid, and diamond (triply periodic minimal surfaces) structures, are fabricated by fused filament fabrication. Murine-derived macrophages and human bone marrow-derived mesenchymal stromal cells (hBMSCs) are seeded onto the scaffolds. The compressive behavior and surface morphology of the scaffolds are characterized. The results show that scaffolds with 15%, 30%, and 45% porosity display the highest rate of macrophage and hBMSC growth. Gyroid and diamond scaffolds exhibit a higher rate of macrophage proliferation, while diamond scaffolds exhibit a higher rate of hBMSC proliferation. Additionally, gyroid and diamond scaffolds exhibit better compressive behavior compared to regular scaffolds. Of particular note, diamond scaffolds have the highest compressive modulus and strength. Surface morphology characterization indicates that the surface roughness of diamond and gyroid scaffolds is greater than that of regular scaffolds at the same porosity level, which is beneficial for cell attachment and proliferation. This study provides valuable insights into porosity and pore shape selection for additively manufactured scaffolds in BTE.
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Engenharia Tecidual , Alicerces Teciduais , Humanos , Animais , Camundongos , Alicerces Teciduais/química , Porosidade , Teste de Materiais , Força Compressiva , Engenharia Tecidual/métodos , DiamanteRESUMO
PURPOSE: Early adverse childhood experiences (ACEs) predict early onset of sexual intercourse. However, patterns of ACEs identified using latent class analysis (LCA) and their links to early sexual intercourse have been less examined. In this study, we apply LCA to identify ACEs profiles at age five and to examine whether these profiles differentially predict adolescents' sexual initiation. METHODS: We analyzed data obtained from the Future of Families and Child Wellbeing Study for 3,185 participants (male = 1,638; female = 1,547). This included parental/caregivers' reports of 10 types of ACEs when participants were on average at age five and youth self-report data on sexual intercourse before or at age 15. We used LCA to classify the participants into subgroups and multinomial logistic regressions to examine differences in early sexual initiation among the ACEs subgroups. RESULTS: LCA showed evidence of four classes for both genders: low adversity (51.8%), socioeconomic adversity (32.0%), family dysfunction (12.0%), and abuse (4.2%). We found class membership differences in early sexual intercourse in all three adversity classes compared to the low adversity group. Pairwise comparison tests further revealed that adolescents in the family dysfunction class had lesser odds of engaging in early sexual intercourse than their counterparts in the socioeconomic adversity and abuse classes. DISCUSSION: Our findings suggest that LCA could help identify meaningful and distinctive child adversity patterns while accounting for the co-occurrence of ACEs. This is particularly helpful in evaluating who might be at greatest health risk which can further inform more effective and targeted interventions.