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Background: An increasing body of evidence suggests that neuroinflammation is one of the key drivers of late-onset Alzheimer's disease (LOAD) pathology. Due to the increased permeability of the blood-brain barrier (BBB) in older adults, peripheral plasma proteins can infiltrate the central nervous system (CNS) and drive neuroinflammation through interactions with neurons and glial cells. Because these inflammatory factors are heritable, a greater understanding of their genetic relationship with LOAD could identify new biomarkers that contribute to LOAD pathology or offer protection against it. Methods: We used a genome-wide association study (GWAS) of 90 different plasma proteins (n = 17,747) to create polygenic scores (PGSs) in an independent discovery (cases = 1,852 and controls = 1,990) and replication (cases = 799 and controls = 778) cohort. Multivariate logistic regression was used to associate the plasma protein PGSs with LOAD diagnosis while controlling for age, sex, principal components 1-2, and the number of APOE-e4 alleles as covariates. After meta-analyzing the PGS-LOAD associations between the two cohorts, we then performed a two-sample Mendelian randomization (MR) analysis using the summary statistics of significant plasma protein level PGSs in the meta-analysis as an exposure, and a GWAS of clinically diagnosed LOAD (cases = 21,982, controls = 41,944) as an outcome to explore possible causal relationships between the two. Results: We identified four plasma protein level PGSs that were significantly associated (FDR-adjusted p < 0.05) with LOAD in a meta-analysis of the discovery and replication cohorts: CX3CL1, hepatocyte growth factor (HGF), TIE2, and matrix metalloproteinase-3 (MMP-3). When these four plasma proteins were used as exposures in MR with LOAD liability as the outcome, plasma levels of HGF were inferred to have a negative causal relationship with the disease when single-nucleotide polymorphisms (SNPs) used as instrumental variables were not restricted to cis-variants (OR/95%CI = 0.945/0.906-0.984, p = 0.005). Conclusion: Our results show that plasma HGF has a negative causal relationship with LOAD liability that is driven by pleiotropic SNPs possibly involved in other pathways. These findings suggest a low transferability between PGS and MR approaches, and future research should explore ways in which LOAD and the plasma proteome may interact.
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Background: The co-occurrence of depression and anxiety among adolescents is typically associated with suicide ideation. Aims: The study aimed to investigate the symptom-level relationship between suicide ideation and the comorbidity of depression and anxiety. Methods: 1501 adolescents aged 12-19 years were assessed using the Patient Health Questionnaire (PHQ-9) and the Generalized Anxiety Disorder Scale, and 716 adolescents who scored ≥5 on both scales were selected as participants. Network analysis was used to identify the network structure of depressive symptoms and anxiety symptoms. Participants were categorised into either the suicide ideation or non-suicide ideation groups based on their scoring on the suicide-related item in PHQ-9. A comparison was made between the depression-anxiety symptom networks of the two groups. Results: 'Restlessness', 'sad mood' and 'trouble relaxing' were the most prominent central symptoms in the depression-anxiety symptom network, and 'restlessness', 'nervousness' and 'reduced movement' were the bridge symptoms in this network. 'Sad mood' was found to be directly related to 'suicide ideation' with the highest variance. The network structure was significantly different in properties between the suicide ideation group and the non-suicide ideation group, with 'restlessness' and 'sad mood' exhibiting significantly higher influence in the network of the suicide ideation group than that in the non-suicide ideation group. Conclusion: Restlessness and sad mood could be targeted for the intervention of depression-anxiety symptoms among adolescents with suicide ideation.
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BACKGROUND: Parenting styles and the associated proximal psychological factors are suggested to increase suicidal risks in adolescents. However, how the two factors interact and confer risks on the emergence of adolescent suicidal thoughts remains unclear. Herein, we used a network approach to investigate their interrelationship and explore whether the network properties predict adolescent suicidal thoughts. METHODS: Self-report questionnaires were completed by 1171 students aged 12-16. Network analyses were performed by Gaussian graphical models estimating the adolescent psychosocial network structure of parenting styles and psychological variables including depression, anxiety, affective lability, rumination, and resilience. Furthermore, we re-examined the network by adding a variable measuring active suicidal thoughts. Moreover, we conducted linear regressions to examine the predictive utility of bridge symptoms for adolescent suicidal thoughts. RESULTS: Resilience, Afraid, Rumination, Concentration, and affective lability (Anger) had the highest bridge strengths in the adolescent psychosocial network. Among the identified bridge symptoms, Resilience was negatively correlated with active suicidal thoughts (regularized edge weights = -0.181, bootstrapped 95% CIs: [-0.043, -0.155]), whereas affective lability (from Anxiety to Depression, Anger), Rumination, and Afraid were positively correlated with active suicidal thoughts, with edge weights (bootstrapped 95% CIs) ranging from 0.057 (0.001, 0.112) to 0.081(0.026, 0.136). Regression analysis showed that bridge strength was significantly correlated with active suicidal thoughts (R2 = 0.432, P = 0.001). CONCLUSION: Negative parenting styles may drive and maintain suicidal thoughts by modifying the key proximal psychological variables. Our findings highlight the important role of bridge symptoms, which may serve as vital targets for triggering adolescent suicide.
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Pancreatic ductal adenocarcinoma (PDAC), the most deadly solid malignancy, is typically detected late and at an inoperable stage. Early or incidental detection is associated with prolonged survival, but screening asymptomatic individuals for PDAC using a single test remains unfeasible due to the low prevalence and potential harms of false positives. Non-contrast computed tomography (CT), routinely performed for clinical indications, offers the potential for large-scale screening, however, identification of PDAC using non-contrast CT has long been considered impossible. Here, we develop a deep learning approach, pancreatic cancer detection with artificial intelligence (PANDA), that can detect and classify pancreatic lesions with high accuracy via non-contrast CT. PANDA is trained on a dataset of 3,208 patients from a single center. PANDA achieves an area under the receiver operating characteristic curve (AUC) of 0.986-0.996 for lesion detection in a multicenter validation involving 6,239 patients across 10 centers, outperforms the mean radiologist performance by 34.1% in sensitivity and 6.3% in specificity for PDAC identification, and achieves a sensitivity of 92.9% and specificity of 99.9% for lesion detection in a real-world multi-scenario validation consisting of 20,530 consecutive patients. Notably, PANDA utilized with non-contrast CT shows non-inferiority to radiology reports (using contrast-enhanced CT) in the differentiation of common pancreatic lesion subtypes. PANDA could potentially serve as a new tool for large-scale pancreatic cancer screening.
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Carcinoma Ductal Pancreático , Aprendizado Profundo , Neoplasias Pancreáticas , Humanos , Inteligência Artificial , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/patologia , Tomografia Computadorizada por Raios X , Pâncreas/diagnóstico por imagem , Pâncreas/patologia , Carcinoma Ductal Pancreático/diagnóstico por imagem , Carcinoma Ductal Pancreático/patologia , Estudos RetrospectivosRESUMO
BACKGROUND: Posttraumatic stress symptoms of healthcare workers have become a significant public concern in the healthcare system that have long COVID-19. It is less known how the pandemic impacts the HCWs' PTSS longitudinally and long-term risk factors for it. METHODS: Four consecutive surveys were conducted among healthcare workers in China from 2019 to 2023 COVID-19 outbreaks. Multilevel mixed-effect models were used to examine longitudinal changes and risk factors. Network analysis was utilized to explore network centrality changes in PTSS symptoms. RESULTS: HCWs' PTSS symptoms were increased over time during the COVID-19 pandemic. Being female, being nurse, working in the emergency department, working longer hours, less frequently going back home and having COVID-19 infection are risk factors of PTSS for HCWs; unmarried is the protective factor. Significant interaction between symptom changes and profession exists. PTSS networks showed that Avoidance of thoughts, Emotional-cue activity, Exaggerated startle response and Hypervigilance were the central symptoms during four waves. The global strength of the PTSS network grows over time, and nodal strength of Avoidance of thoughts, Loss of interest and Negative beliefs increased by COVID-19. CONCLUSION: The pandemic's impacts on healthcare workers vary by professions. PTSS symptoms exacerbate, reinforce each other, and persists with recurring waves.
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COVID-19 , Transtornos de Estresse Pós-Traumáticos , Humanos , Feminino , Masculino , Pandemias , Estudos Longitudinais , Síndrome de COVID-19 Pós-Aguda , Transtornos de Estresse Pós-Traumáticos/epidemiologia , Pessoal de SaúdeRESUMO
Background: Alzheimer's disease (AD) is a common neurodegenerative disease in the elderly population, with genetic factors playing an important role. A considerable proportion of elderly people carry a high genetic AD risk but evade AD. On the other hand, some individuals with a low risk for AD eventually develop AD. We hypothesized that unknown counterfactors might be involved in reversing the polygenic risk scores (PRS) prediction, which might provide insights into AD pathogenesis, prevention, and early clinical intervention. Methods: We built a novel computational framework to identify genetically-regulated pathways (GRPa) using PRS-based stratification for each cohort. We curated two AD cohorts with genotyping data; the discovery and the replication dataset include 2722 and 2492 individuals, respectively. First, we calculated the optimized PRS model based on the three latest AD GWAS summary statistics for each cohort. Then, we sub-grouped the individuals by their PRS and clinical diagnosis into groups such as cognitively normal (CN) with high PRS for AD (resilient group), AD cases with low PRS (susceptible group), and AD/CNs participants with similar PRS backgrounds. Lastly, we imputed the individual genetically-regulated expression (GReX) and identified the differential GRPas between subgroups with gene-set enrichment analysis and gene-set variational analysis in 2 models with and without the effect of APOE. Results: For each subgroup, we conducted the same procedures in both the discovery and replication datasets across three PRS models for comparison. In Model 1 with the APOE region, we identified well-known AD-related pathways, including amyloid-beta clearance, tau protein binding, and astrocytes response to oxidative stress. In Model 2 without the APOE region, synapse function, microglia function, histidine metabolism, and thiolester hydrolase activity were significant, suggesting that they are pathways independent of the effect of APOE. Finally, our GRPa-PRS method reduces the false discovery rate in detecting differential pathways compared to another variants-based pathway PRS method. Conclusions: We developed a framework, GRPa-PRS, to systematically explore the differential GRPas among individuals stratified by their estimated PRS. The GReX-level comparison among those groups unveiled new insights into the pathways associated with AD risk and resilience. Our framework can be extended to other polygenic complex diseases.
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RATIONALE AND OBJECTIVES: Pancreatic fibrosis is the hallmark of chronic pancreatitis (CP), which is associated with microcirculatory disturbance. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) can assess the perfusion and permeability of the pancreas by providing information about microcirculation. We hypothesize that DCE-MRI parameters can be utilized to assess pancreatic fibrosis and may furthermore provide an opportunity to evaluate response to antifibrotic treatment with curcumin. Our study was to evaluate the feasibility of quantitative DCE-MRI in assessing pancreatic fibrosis and the antifibrotic effect of curcumin in a rat model of CP. MATERIALS AND METHODS: Pancreatic fibrosis was induced by injecting dibutyltin dichloride (DBTC). Seventy rats were randomized to five groups: the control group (n = 10); DBTC for 2 weeks (n = 15); DBTC for 4 weeks (n = 15); DBTC + curcumin for 2 weeks (n = 15); DBTC + curcumin for 4 weeks (n = 15). DCE-MRI was performed at an 11.7 T MR scanner. DCE-MRI quantitative parameters (Ktrans, Ve, and Vp) were derived from an extended Tofts model. Fibrosis content and DCE-MRI parameters were compared among the above groups (one-way analysis of variance). The correlations between DCE-MRI parameters and pancreatic fibrosis content as well as the expression of α-SMA were computed by Spearman correlation coefficients. RESULTS: Fifty-three rats survived and underwent MR imaging. Ktrans in rats 4 weeks after DBTC injection was significantly lower than DBTC 2 weeks rats and control rats (0.30 ± 0.06 min vs 0.49 ± 0.09 vs 0.62 ± 0.09, respectively). Vp in DBTC 4 weeks rats was also significantly lower than control rats (0.048 ± 0.010 min-1 vs 0.065 ± 0.011 min-1, respectively). Ktrans and Vp significantly correlated with fibrosis content of pancreas (r = -0.619 and -0.450, all P < 0.001), and the expression of α-SMA (r = -0.688 and -0.402, all P < 0.01). Ktrans and Vp in rats with daily curcumin treatment for 4 weeks were significantly higher than DBTC 4 weeks rats (Ktrans, 0.51 ± 0.09 vs 0.30 ± 0.06; Vp, 0.064 ± 0.015 vs 0.048 ± 0.010). CONCLUSION: DCE-MRI parameters (Ktrans and Vp) have the potential to noninvasively assess pancreatic fibrosis and the antifibrotic treatment response of curcumin.
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Curcumina , Animais , Ratos , Meios de Contraste , Curcumina/farmacologia , Curcumina/uso terapêutico , Fibrose , Imageamento por Ressonância Magnética/métodos , MicrocirculaçãoRESUMO
OBJECTIVES: Firefighters are prone to suffer from psychological trauma and post-traumatic stress disorder (PTSD) in the workplace, and have a poor prognosis after PTSD. Reliable models for predicting PTSD allow for effective identification and intervention for patients with early PTSD. By collecting the psychological traits, psychological states and work situations of firefighters, this study aims to develop a machine learning algorithm with the aim of effectively and accurately identifying the onset of PTSD in firefighters, as well as detecting some important predictors of PTSD onset. METHODS: This study conducted a cross-sectional survey through convenient sampling of firefighters from 20 fire brigades in Changsha, which were evenly distributed across 6 districts and Changsha County, with a total of 628 firefighters. We used the synthetic minority oversampling technique (SMOTE) to process data sets and used grid search to finish the parameter tuning. The predictive capability of several commonly used machine learning models was compared by 5-fold cross-validation and using the area under the receiver operating characteristic curve (ROC-AUC), accuracy, precision, recall, and F1 score. RESULTS: The random forest model achieved good performance in predicting PTSD with an average AUC score at 0.790. The mean accuracy of the model was 90.1%, with an F1 score of 0.945. The three most important predictors were perseverance, forced thinking, and reflective deep thinking, with weights of 0.165, 0.158, and 0.152, respectively. The next most important predictors were employment time, psychological power, and optimism. CONCLUSIONS: PTSD onset prediction model for Changsha firefighters constructed by random forest has strong predictive ability, and both psychological characteristics and work situation can be used as predictors of PTSD onset risk for firefighters. In the next step of the study, validation using other large datasets is needed to ensure that the predictive models can be used in clinical setting.
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Bombeiros , Transtornos de Estresse Pós-Traumáticos , Humanos , Transtornos de Estresse Pós-Traumáticos/epidemiologia , Transtornos de Estresse Pós-Traumáticos/etiologia , Transtornos de Estresse Pós-Traumáticos/diagnóstico , Bombeiros/psicologia , Estudos Transversais , Algoritmos , Aprendizado de MáquinaRESUMO
A growing body of evidence suggests that dysbiosis of the human gut microbiota is associated with neurodegenerative diseases like Alzheimer's disease (AD) via neuroinflammatory processes across the microbiota-gut-brain axis. The gut microbiota affects brain health through the secretion of toxins and short-chain fatty acids, which modulates gut permeability and numerous immune functions. Observational studies indicate that AD patients have reduced microbiome diversity, which could contribute to the pathogenesis of the disease. Uncovering the genetic basis of microbial abundance and its effect on AD could suggest lifestyle changes that may reduce an individual's risk for the disease. Using the largest genome-wide association study of gut microbiota genera from the MiBioGen consortium, we used polygenic risk score (PRS) analyses with the "best-fit" model implemented in PRSice-2 and determined the genetic correlation between 119 genera and AD in a discovery sample (ADc12 case/control: 1278/1293). To confirm the results from the discovery sample, we next repeated the PRS analysis in a replication sample (GenADA case/control: 799/778) and then performed a meta-analysis with the PRS results from both samples. Finally, we conducted a linear regression analysis to assess the correlation between the PRSs for the significant genera and the APOE genotypes. In the discovery sample, 20 gut microbiota genera were initially identified as genetically associated with AD case/control status. Of these 20, three genera (Eubacterium fissicatena as a protective factor, Collinsella, and Veillonella as a risk factor) were independently significant in the replication sample. Meta-analysis with discovery and replication samples confirmed that ten genera had a significant correlation with AD, four of which were significantly associated with the APOE rs429358 risk allele in a direction consistent with their protective/risk designation in AD association. Notably, the proinflammatory genus Collinsella, identified as a risk factor for AD, was positively correlated with the APOE rs429358 risk allele in both samples. Overall, the host genetic factors influencing the abundance of ten genera are significantly associated with AD, suggesting that these genera may serve as biomarkers and targets for AD treatment and intervention. Our results highlight that proinflammatory gut microbiota might promote AD development through interaction with APOE. Larger datasets and functional studies are required to understand their causal relationships.
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Doença de Alzheimer , Microbioma Gastrointestinal , Microbiota , Humanos , Doença de Alzheimer/patologia , Microbioma Gastrointestinal/genética , Estudo de Associação Genômica Ampla , Apolipoproteínas E/genéticaRESUMO
Objective: Previous studies on the reliability and validity of the Affective Lability Scale short-form (ALS-SF) have only been evaluated in adults, which may not be able to generalize to the adolescent population. We aimed to examine the factor structure, the reliability and validity of ALS-SF among Chinese adolescents and construct an adolescent form of ALS (ALS-AF). Methods: A total of 1,439 middle school students were investigated with a broad survey including ALS-SF, Patient Health Questionnaire-9 (PHQ-9), Generalized Anxiety Disorder 7-item (GAD-7), Connor-Davidson Resilience Scale 10-item (CD-RISC-10) and non-suicidal self-injury (NSSI) behavior self-report. Exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) were conducted to investigate the structural validity of ALS-SF and construct ALS-AF. Cronbach's α was used to assess the internal consistency and reliability of the scale. Factor loading, Average Variance Extracted (AVE) and Composite Reliability (CR) were applied to measure the convergent validity and divergent validity. Besides, Correlation and regression analyses were used to explore the relationship between affective lability and depression, anxiety, NSSI and resilience. Results: Factor analysis failed to support the original three-factor model of 18-item ALS-SF and confirmed the three-factor model of 15-item ALS-AF. The ALS-AF showed good internal consistency as well as strong convergent and discriminative validity. Besides, ALS-AF was positively correlated with PHQ-9, GAD-7 and self-harm, and was negatively associated with resilience. Conclusion: Our study shows that the ALS-AF has good reliability and validity for testing affective lability in Chinese adolescents.
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Intracellular transport of fatty acids involves binding of ligands to their carrier fatty acid binding proteins (FABPs) and interactions of ligand-free and -bound FABPs with membranes. Previous studies focused on ligand-free FABPs. Here, our amide hydrogen exchange data showed that oleic acid binding to human intestinal FABP (hIFABP) stabilizes the protein, most likely through enhancing the hydrogen-bonding network, and induces rearrangement of sidechains even far away from the ligand binding site. Using NMR relaxation techniques, we found that the ligand binding affects not only conformational exchanges between major and minor states but also the affinity of hIFABP to nanodiscs. Analyses of the relaxation and amide exchange data suggested that two minor native-like states existing in both ligand-free and -bound hIFABPs originate from global "breathing" motions, while one minor native-like state comes from local motions. The amide hydrogen exchange data also indicated that helix αII undergoes local unfolding through which ligands can exit from the binding cavity.
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Proteínas de Ligação a Ácido Graxo , Ácidos Graxos , Humanos , Proteínas de Ligação a Ácido Graxo/química , Ácidos Graxos/metabolismo , Ligantes , Hidrogênio/metabolismo , Amidas , Ligação ProteicaRESUMO
Therapeutic hypothermia (TH) may attenuate myocardial ischaemia-reperfusion injury, thereby improving outcomes in acute myocardial infarction. However, the specific mechanism by which TH alleviates MIRI has not been elucidated so far. In this study, 120 healthy male Sprague-Dawley rats were randomly divided into five groups. Haemodynamic parameters, myocardial infarction area, histological changes and the levels of cardiac enzymes, caspase-1 and inflammatory cytokines were determined. In addition, the extent of myocardial fibrosis, the degree of cardiomyocyte apoptosis and the expression levels of SIRT3, GSDMD-N, fibrosis-related proteins and inflammation-related proteins were estimated.TH reduced myocardial infarct area and cardiac enzyme levels, improved cardiomyopathic damage and haemodynamic indexes, and attenuated myocardial fibrosis, the protein expression levels of collagen I and III, myocardial apoptosis, the levels of inflammatory cytokines and inflammation-related proteins. Notably, the immunofluorescence and protein expression levels of SIRT3 were upregulated in the 34H+DMSO group compared to the I/R group, but this protective effect was abolished by the SIRT3 inhibitor 3-TYP. After administration of Mcc950, the reversal effects of 3-TYP were significantly abolished, and TH could protect against MIRI in a rat isolated heart model by inhibiting inflammation and fibrosis. The SIRT3/NLRP3 signalling pathway is one of the most important signalling pathways in this regard.
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Hipotermia Induzida , Infarto do Miocárdio , Traumatismo por Reperfusão Miocárdica , Sirtuína 3 , Animais , Apoptose , Caspases , Colágeno/farmacologia , Citocinas/farmacologia , Dimetil Sulfóxido/farmacologia , Dimetil Sulfóxido/uso terapêutico , Fibrose , Inflamação , Masculino , Infarto do Miocárdio/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Proteína 3 que Contém Domínio de Pirina da Família NLR , Ratos , Ratos Sprague-Dawley , Sirtuína 3/genética , Sirtuína 3/metabolismoRESUMO
Background. Of all intestinal microbiome-derived metabolites, trimethylamine N-oxide (TMAO) has received increasing attention because of its potent role in colorectal cancer development. Accumulating evidence suggests that TMAO generated by the gut microbiota is a new and important player in the etiological process of colorectal cancer. Nevertheless, the carcinogenic mechanism of TMAO in colorectal cancer remains unclear. In this study, TMAO induced colorectal cancer cell proliferation and produced higher vascular endothelial growth factor A (VEGFA) levels in vitro. In vivo, after long-term choline feeding in tumor-bearing mice, circulating TMAO levels, tumor volume, new blood vessel formation, and VEGFA and CD31 amounts were increased significantly. This study revealed that TMAO exerts oncogenic effects by promoting cell proliferation and angiogenesis in colorectal cancer.
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Neoplasias Colorretais , Metilaminas , Fator A de Crescimento do Endotélio Vascular , Animais , Proliferação de Células , Neoplasias Colorretais/irrigação sanguínea , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Metilaminas/metabolismo , Camundongos , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
BACKGROUND: T1, T2, and T1ρ might be potential biomarkers for assessing liver fibrosis. However, few studies reported the value of them in different animal models. PURPOSE: To investigate and compare the performances of T1, T2, and T1ρ for noninvasively staging liver fibrosis in bile duct ligation (BDL) or carbon tetrachloride (CCl4 ) model. STUDY TYPE: Prospective animal model. SUBJECTS: Liver fibrosis was induced by BDL or injection of CCl4 in 120 rats. FIELD STRENGTH/SEQUENCE: 11.7 T, T1 mapping with 10 repetition times, T2 mapping with 32 echo times, and T1ρ with 10 spin-lock times. ASSESSMENT: T1, T2, and T1ρ were measured and correlated with liver fibrosis stages, as well as the degree of inflammation, steatosis, iron deposition, and the expression of cytokeratin 19. The discriminative performance of T1, T2, and T1ρ for staging liver fibrosis was compared. STATISTICAL TESTS: One-way analysis of variance (ANOVA), Spearman's correlation analysis, factorial design ANOVA, and receiver operating characteristic curves (P < 0.05 was considered statistically significant). RESULTS: T1, T2, and T1ρ (BDL: rho = 0.73, 0.85, 0.68; CCl4 : rho = 0.80, 0.29, 0.61) were significantly correlated with liver fibrosis stages, while there was no significant difference in T2 among stage F0-F4 in the CCl4 model (P = 0.204). The area under the curves (AUCs) range of T1, T2, and T1ρ for predicting ≥F1, ≥F2, ≥F3, and F4 were 0.76-0.95, 0.89-0.98, and 0.80-0.94 in the CCl4 model. For the CCl4 model, the AUCs range of T1, T2, and T1ρ for predicting ≥F1, ≥F2, ≥F3, and F4 were 0.83-0.95, 0.61-0.74, and 0.73-0.89, respectively. T2 had significantly higher AUC in the BDL model than CCl4 model for diagnosing liver fibrosis. DATA CONCLUSION: The most sensitive and accurate method for staging liver fibrosis appeared to be T1 in our animal models followed by T1ρ. T2 may not be suitable for evaluating liver fibrosis. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY STAGE: 2.
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Tetracloreto de Carbono , Cirrose Hepática , Animais , Ductos Biliares/diagnóstico por imagem , Fígado/patologia , Cirrose Hepática/diagnóstico por imagem , Cirrose Hepática/patologia , Imageamento por Ressonância Magnética , Estudos Prospectivos , RatosRESUMO
Fatty acid binding proteins (FABPs) can facilitate the transfer of long-chain fatty acids between intracellular membranes across considerable distances. The transfer process involves fatty acids, their donor membrane and acceptor membrane, and FABPs, implying that potential protein-membrane interactions exist. Despite intensive studies on FABP-membrane interactions, the interaction mode remains elusive, and the protein-membrane association and dissociation rates are inconsistent. In this study, we used nanodiscs (NDs) as mimetic membranes to investigate FABP-membrane interactions. Our NMR experiments showed that human intestinal FABP interacts weakly with both negatively charged and neutral membranes, but it prefers the negatively charged one. Through simultaneous analysis of NMR relaxation in the rotating-frame (R1ρ), relaxation dispersion, chemical exchange saturation transfer, and dark-state exchange saturation transfer data, we estimated the affinity of the protein to negatively charged NDs, the dissociation rate, and apparent association rate. We further showed that the protein in the ND-bound state adopts a conformation different from the native structure and the second helix is very likely involved in interactions with NDs. We also found a membrane-induced FABP conformational state that exists only in the presence of NDs. This state is native-like, different from other conformational states in structure, unbound to NDs, and in dynamic equilibrium with the ND-bound state.
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Proteínas de Ligação a Ácido Graxo , Proteínas do Tecido Nervoso , Proteína 7 de Ligação a Ácidos Graxos , Ácidos Graxos , Humanos , Proteínas de NeoplasiasRESUMO
The intracellular energy state will alter under the influence of physiological or pathological stimuli. In response to this change, cells usually mobilize various molecules and their mechanisms to promote the stability of the intracellular energy status. Mitochondria are the main source of ATP. Previous studies have found that the function of mitochondria is impaired in aging, neurodegenerative diseases, and metabolic diseases, and the damaged mitochondria bring lower ATP production, which further worsens the progression of the disease. Silent information regulator-1 (SIRT1) is a multipotent molecule that participates in the regulation of important biological processes in cells, including cellular metabolism, cell senescence, and inflammation. In this review, we mainly discuss that promoting the expression and activity of SIRT1 contributes to alleviating the energy stress produced by physiological and pathological conditions. The review also discusses the mechanism of precise regulation of SIRT1 expression and activity in various dimensions. Finally, according to the characteristics of this mechanism in promoting the recovery of mitochondrial function, the relationship between current pharmacological preparations and aging, neurodegenerative diseases, metabolic diseases, and other diseases was analyzed.
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Ligustilide exerts potential neuroprotective effects against various cerebral ischaemic insults and neurodegenerative disorders. However, the function and mechanisms of LIG-mediated hippocampal neural stem cells (H-NSCs) activation as well as cognitive recovery in the context of post-operative cognitive dysfunction (POCD) remain elusive and need to be explored. Mice were subjected to transient global cerebral ischaemia and reperfusion (tGCI/R) injury and treated with LIG (80 mg/kg) or vehicle for 1 month. Morris water maze test and western blot were employed to assess cognitive function. Nissl staining and immunofluorescence (IF) staining were used to detect H-NSCs proliferation and neurogenesis in hippocampus. Subsequently, primary H-NSCs were treated with LIG, and the level of H-NSCs proliferation and neuronal-differentiation was examined by IF staining for Edu and ß-Tubulin III. The protein levels of ERK1/2, ß-catenin, NICD, TLR4, Akt and FoxO1 were examined using western blotting. Finally, pretreatment with the ERK agonist SCH772984 was performed to observe the change in ERK expression. LIG treatment promoted H-NSCs proliferation and neurogenesis, increased the number of neurons in the hippocampal subfields, and ultimately reversed cognitive impairment in tGCI/R injury. Furthermore, LIG also promoted primary H-NSCs proliferation and neuronal-differentiation, as well as ERK1/2 phosphorylation. Pretreatment with SCH772984 effectively reversed the ability of LIG to induce ERK1/2 phosphorylation and promote H-NSCs proliferation and neuronal-differentiation. LIG can promote cognitive recovery after tGCI/R injury by activating ERK1/2 in H-NSCs to promote their proliferation and neurogenesis in the hippocampus. Therefore, LIG has potential for use in the prevention and/or treatment of POCD.
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Células-Tronco Neurais , Complicações Cognitivas Pós-Operatórias , 4-Butirolactona/análogos & derivados , Animais , Proliferação de Células , Cognição , Hipocampo , Camundongos , NeurogêneseRESUMO
Microglia are the primary resident immune cells of the central nervous system that maintain physiological homeostasis in the brain and contribute to the pathogenesis of many psychiatric disorders and neurodegenerative diseases. Due to the lack of appropriate human cellular models, it is difficult to study the basic pathophysiological processes linking microglia to brain diseases. In this study, we adopted a microglia-like cellular model derived from peripheral blood monocytes with granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-34 (IL-34). We characterized and validated this in vitro cellular model by morphology, immunocytochemistry, gene expression profiles, and functional study. Our results indicated that the iMG cells developed typical microglial ramified morphology, expressed microglial specific surface markers (P2RY12 and TMEM119), and possessed phagocytic activity. Principal component analyses and multidimensional scaling analyses of RNA-seq data showed that iMG cells were distinct from monocytes and induced macrophages (iMacs) but clustered closer to human microglia and hiPSC-induced microglia. Heatmap analyses also found that iMG cells, but not monocytes, were closely clustered with human primary microglia. Further pathway and relative expression analysis indicated that unique genes from iMG cells were involved in the regulation of the complement system, especially in the synapse and ion transport. Overall, our data demonstrated that the iMG model mimicked many features of the brain resident microglia, highlighting its utility in the study of microglial function in many brain diseases, such as schizophrenia and Alzheimer's disease (AD).
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This article has been retracted. Please see the Retraction Notice for more detail: https://doi.org/10.1038/s41398-020-00987-z.
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Schizophrenia (SCZ) is a severe psychiatric disorder with a strong genetic component. High heritability of SCZ suggests a major role for transmitted genetic variants. Furthermore, SCZ is also associated with a marked reduction in fecundity, leading to the hypothesis that alleles with large effects on risk might often occur de novo. In this study, we conducted whole-genome sequencing for 23 families from two cohorts with unaffected siblings and parents. Two nonsense de novo mutations (DNMs) in GJC1 and HIST1H2AD were identified in SCZ patients. Ten genes (DPYSL2, NBPF1, SDK1, ZNF595, ZNF718, GCNT2, SNX9, AACS, KCNQ1, and MSI2) were found to carry more DNMs in SCZ patients than their unaffected siblings by burden test. Expression analyses indicated that these DNM implicated genes showed significantly higher expression in prefrontal cortex in prenatal stage. The DNM in the GJC1 gene is highly likely a loss function mutation (pLI = 0.94), leading to the dysregulation of ion channel in the glutamatergic excitatory neurons. Analysis of rare variants in independent exome sequencing dataset indicates that GJC1 has significantly more rare variants in SCZ patients than in unaffected controls. Data from genome-wide association studies suggested that common variants in the GJC1 gene may be associated with SCZ and SCZ-related traits. Genes co-expressed with GJC1 are involved in SCZ, SCZ-associated pathways, and drug targets. These evidences suggest that GJC1 may be a risk gene for SCZ and its function may be involved in prenatal and early neurodevelopment, a vulnerable period for developmental disorders such as SCZ.