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Circadian gene transcription is fundamental to metabolic physiology. Here we report that the nuclear receptor REV-ERBα, a repressive component of the molecular clock, forms circadian condensates in the nuclei of mouse liver. These condensates are dictated by an intrinsically disordered region (IDR) located in the protein's hinge region which specifically concentrates nuclear receptor corepressor 1 (NCOR1) at the genome. IDR deletion diminishes the recruitment of NCOR1 and disrupts rhythmic gene transcription in vivo. REV-ERBα condensates are located at high-order transcriptional repressive hubs in the liver genome that are highly correlated with circadian gene repression. Deletion of the IDR disrupts transcriptional repressive hubs and diminishes silencing of target genes by REV-ERBα. This work demonstrates physiological circadian protein condensates containing REV-ERBα whose IDR is required for hub formation and the control of rhythmic gene expression.
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Relógios Circadianos , Camundongos , Animais , Relógios Circadianos/genética , Ritmo Circadiano/genética , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/genética , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/metabolismo , Fígado/metabolismo , Expressão GênicaRESUMO
Peroxisome proliferator-activated receptor γ (PPARγ) is a nuclear receptor that is a vital regulator of adipogenesis, insulin sensitivity, and lipid metabolism. Activation of PPARγ by antidiabetic thiazolidinediones (TZD) reverses insulin resistance but also leads to weight gain that limits the use of these drugs. There are two main PPARγ isoforms, but the specific functions of each are not established. Here we generated mouse lines in which endogenous PPARγ1 and PPARγ2 were epitope-tagged to interrogate isoform-specific genomic binding, and mice deficient in either PPARγ1 or PPARγ2 to assess isoform-specific gene regulation. Strikingly, although PPARγ1 and PPARγ2 contain identical DNA binding domains, we uncovered isoform-specific genomic binding sites in addition to shared sites. Moreover, PPARγ1 and PPARγ2 regulated a different set of genes in adipose tissue depots, suggesting distinct roles in adipocyte biology. Indeed, mice with selective deficiency of PPARγ1 maintained body temperature better than wild-type or PPARγ2-deficient mice. Most remarkably, although TZD treatment improved glucose tolerance in mice lacking either PPARγ1 or PPARγ2, the PPARγ1-deficient mice were protected from TZD-induced body weight gain compared with PPARγ2-deficient mice. Thus, PPARγ isoforms have specific and separable metabolic functions that may be targeted to improve therapy for insulin resistance and diabetes.
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Resistência à Insulina , Tiazolidinedionas , Adipócitos/metabolismo , Animais , Regulação da Expressão Gênica , Resistência à Insulina/genética , Camundongos , PPAR gama/genética , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismoRESUMO
MOTIVATION: Pediatric kidney disease is a widespread, progressive condition that severely impacts growth and development of children. Chronic kidney disease is often more insidious in children than in adults, usually requiring a renal biopsy for diagnosis. Biopsy evaluation requires copious examination by trained pathologists, which can be tedious and prone to human error. In this study, we propose an artificial intelligence (AI) method to assist pathologists in accurate segmentation and classification of pediatric kidney structures, named as AI-based Pediatric Kidney Diagnosis (APKD). RESULTS: We collected 2935 pediatric patients diagnosed with kidney disease for the development of APKD. The dataset comprised 93 932 histological structures annotated manually by three skilled nephropathologists. APKD scored an average accuracy of 94% for each kidney structure category, including 99% in the glomerulus. We found strong correlation between the model and manual detection in detected glomeruli (Spearman correlation coefficient r = 0.98, P < .001; intraclass correlation coefficient ICC = 0.98, 95% CI = 0.96-0.98). Compared to manual detection, APKD was approximately 5.5 times faster in segmenting glomeruli. Finally, we show how the pathological features extracted by APKD can identify focal abnormalities of the glomerular capillary wall to aid in the early diagnosis of pediatric kidney disease. AVAILABILITY AND IMPLEMENTATION: https://github.com/ChunyueFeng/Kidney-DataSet.
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Inteligência Artificial , Insuficiência Renal Crônica , Adulto , Humanos , Criança , Rim/diagnóstico por imagem , Rim/patologia , Insuficiência Renal Crônica/patologiaRESUMO
KDM4C is implicated in the regulation of cell proliferation, differentiation, and maintenance in various stem cell types. However, its function in neural stem cells (NSCs) remains poorly understood. Therefore, this study aims to investigate the role and regulatory mechanism of KDM4C in NSCs. Primary hippocampal NSCs were isolated from neonatal mice, and both in vivo and in vitro lentivirus-mediated overexpression of KDM4C were induced in these hippocampal NSCs. Staining results revealed a significant increase in BrdU- and Ki-67-positive cells, along with an elevated number of cells in S phases due to KDM4C overexpression. Subsequently, RNA-seq was employed to analyze gene expression changes following KDM4C upregulation. GO enrichment analysis, KEGG analysis, and GSEA highlighted KDM4C-regulated genes associated with development, cell cycle, and neurogenesis. Protein-protein interaction analysis uncovered that ApoE protein interacts with several genes (top 10 upregulated and downregulated) regulated by KDM4C. Notably, knocking down ApoE mitigated the proliferative effect induced by KDM4C overexpression in NSCs. Our study demonstrates that KDM4C overexpression significantly upregulates ApoE expression, ultimately promoting proliferation in mouse hippocampal NSCs. These findings provide valuable insights into the molecular mechanisms governing neurodevelopment, with potential implications for therapeutic strategies in neurological disorders.
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Apolipoproteínas E , Células-Tronco Neurais , Animais , Camundongos , Ciclo Celular , Proliferação de Células , HipocampoRESUMO
BACKGROUND: Abdominal aortic calcification (AAC), a marker of vascular disease, is associated with disease in other vascular beds including gastrointestinal arteries. We investigated whether AAC is related to rapid weight loss over 5 years and whether rapid weight loss is associated with 9.5-year all-cause mortality in community-dwelling older women. METHODS: Lateral spine images from dual-energy x-ray absorptiometry (1998/1999) were used to assess AAC (24-point AAC scoring method) in 929 older women. Over 5 years, body weight was assessed at 12-month intervals. Rapid weight loss was defined as >5% decrease in body weight within any 12-month interval. Multivariable-adjusted logistic regression was used to assess AAC and rapid weight loss and Cox regression to assess the relationship between rapid weight loss and 9.5-year all-cause mortality. RESULTS: Mean±SD age of women was 75.0±2.6 years. During the initial 5 years, 366 (39%) women presented with rapid weight loss. Compared with women with low AAC (24-point AAC score 0-1), those with moderate (24-point AAC score 2-5: odds ratio, 1.36 [95% CI, 1.00-1.85]) and extensive (24-point AAC score 6+: odds ratio, 1.59 [95% CI, 1.10-2.31]) AAC had higher odds for presenting with rapid weight loss. Results remained similar after further adjustment for dietary factors (alcohol, protein, fat, and carbohydrates), diet quality, blood pressure, and cholesterol measures. The estimates were similar in subgroups of women who met protein intake (n=599) and physical activity (n=735) recommendations (extensive AAC: odds ratios, 1.81 [95% CI, 1.12-2.92] and 1.58 [95% CI, 1.02-2.44], respectively). Rapid weight loss was associated with all-cause mortality over the next 9.5 years (hazard ratio, 1.49 [95% CI, 1.17-1.89]; P=0.001). CONCLUSIONS: AAC extent was associated with greater risk for rapid weight loss over 5 years in older women, a risk for all-cause mortality. Since the association was unchanged after taking nutritional intakes into account, these data support the possibility that vascular disease may play a role in the maintenance of body weight.
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Doenças da Aorta , Calcificação Vascular , Doenças Vasculares , Humanos , Feminino , Idoso , Masculino , Fatores de Risco , Estudos Longitudinais , Calcificação Vascular/etiologia , Envelhecimento , Peso Corporal , Redução de Peso , Aorta Abdominal/diagnóstico por imagem , Doenças da Aorta/etiologiaRESUMO
The prolonged duration of chronic low back pain (cLBP) inevitably leads to changes in the cognitive, attentional, sensory and emotional processing brain regions. Currently, it remains unclear how these alterations are manifested in the interplay between brain functional and structural networks. This study aimed to predict the Oswestry Disability Index (ODI) in cLBP patients using multimodal brain magnetic resonance imaging (MRI) data and identified the most significant features within the multimodal networks to aid in distinguishing patients from healthy controls (HCs). We constructed dynamic functional connectivity (dFC) and structural connectivity (SC) networks for all participants (n = 112) and employed the Connectome-based Predictive Modeling (CPM) approach to predict ODI scores, utilizing various feature selection thresholds to identify the most significant network change features in dFC and SC outcomes. Subsequently, we utilized these significant features for optimal classifier selection and the integration of multimodal features. The results revealed enhanced connectivity among the frontoparietal network (FPN), somatomotor network (SMN) and thalamus in cLBP patients compared to HCs. The thalamus transmits pain-related sensations and emotions to the cortical areas through the dorsolateral prefrontal cortex (dlPFC) and primary somatosensory cortex (SI), leading to alterations in whole-brain network functionality and structure. Regarding the model selection for the classifier, we found that Support Vector Machine (SVM) best fit these significant network features. The combined model based on dFC and SC features significantly improved classification performance between cLBP patients and HCs (AUC=0.9772). Finally, the results from an external validation set support our hypotheses and provide insights into the potential applicability of the model in real-world scenarios. Our discovery of enhanced connectivity between the thalamus and both the dlPFC (FPN) and SI (SMN) provides a valuable supplement to prior research on cLBP.
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Conectoma , Dor Lombar , Humanos , Dor Lombar/diagnóstico por imagem , Encéfalo , Tálamo , Imageamento por Ressonância Magnética/métodosRESUMO
Low vitamin D status is linked with poorer cognition in adults while findings in relation to high levels are mixed.We performed a systematic review and meta-analyses to examine dose-response associations between 25-hydroxyvitamin D (25OHD) levelsand cognitive performance in community-dwelling adults. Thirty-eight observational studies were included in dose-response meta-analyses. Positive, nonlinear associations were identified between baseline25OHD levels and global cognition incross-sectional and longitudinal analyses, and for performance in memory and executive function in longitudinal analyses. When restricted to studies involving older adults, thepattern emerged forspecific domains in cross-sectional analyses. Poorer performance was associated with low 25OHD levels, while a sharp improvement was associated withlevels up to 60-70 nM/L. Further improvement was observed only for longitudinal global cognition. Our findings support the association between low vitamin D and poorer cognition and suggest levels of at least 60 nM/L are associated with better cognition during ageing.
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Vida Independente , Vitamina D , Estudos Transversais , Cognição , Função ExecutivaRESUMO
Accurate prediction of open reading frames (ORFs) is important for studying and using genome sequences. Ribosomes move along mRNA strands with a step of three nucleotides and datasets carrying this information can be used to predict ORFs. The ribosome-protected footprints (RPFs) feature a significant 3-nt periodicity on mRNAs and are powerful in predicting translating ORFs, including small ORFs (sORFs), but the application of RPFs is limited because they are too short to be accurately mapped in complex genomes. In this study, we found a significant 3-nt periodicity in the datasets of populational genomic variants in coding sequences, in which the nucleotide diversity increases every three nucleotides. We suggest that this feature can be used to predict ORFs and develop the Python package 'OrfPP', which recovers ~83% of the annotated ORFs in the tested genomes on average, independent of the population sizes and the complexity of the genomes. The novel ORFs, including sORFs, identified from single-nucleotide polymorphisms are supported by protein mass spectrometry evidence comparable to that of the annotated ORFs. The application of OrfPP to tetraploid cotton and hexaploid wheat genomes successfully identified 76.17% and 87.43% of the annotated ORFs in the genomes, respectively, as well as 4704 sORFs, including 1182 upstream and 2110 downstream ORFs in cotton and 5025 sORFs, including 232 upstream and 234 downstream ORFs in wheat. Overall, we propose an alternative and supplementary approach for ORF prediction that can extend the studies of sORFs to more complex genomes.
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Ribossomos , Genoma , Fases de Leitura Aberta , Ribossomos/genética , Ribossomos/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Polimorfismo de Nucleotídeo ÚnicoRESUMO
MOTIVATION: It is fundamental to cut multi-domain proteins into individual domains, for precise domain-based structural and functional studies. In the past, sequence-based and structure-based domain parsing was carried out independently with different methodologies. The recent progress in deep learning-based protein structure prediction provides the opportunity to unify sequence-based and structure-based domain parsing. RESULTS: Based on the inter-residue distance matrix, which can be either derived from the input structure or predicted by trRosettaX, we can decode the domain boundaries under a unified framework. We name the proposed method UniDoc. The principle of UniDoc is based on the well-accepted physical concept of maximizing intra-domain interaction while minimizing inter-domain interaction. Comprehensive tests on five benchmark datasets indicate that UniDoc outperforms other state-of-the-art methods in terms of both accuracy and speed, for both sequence-based and structure-based domain parsing. The major contribution of UniDoc is providing a unified framework for structure-based and sequence-based domain parsing. We hope that UniDoc would be a convenient tool for protein domain analysis. AVAILABILITY AND IMPLEMENTATION: https://yanglab.nankai.edu.cn/UniDoc/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
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Algoritmos , Biologia Computacional , Domínios Proteicos , Biologia Computacional/métodos , Proteínas/químicaRESUMO
BACKGROUND: Omicron variant impacts populations with its rapid contagiousness, and part of patients suffered from persistent symptoms termed as long COVID. The molecular and immune mechanisms of this currently dominant global variant leading to long COVID remain unclear, due to long COVID heterogeneity across populations. METHODS: We recruited 66 participants in total, 22 out of 66 were healthy control without COVID-19 infection history, and 22 complaining about long COVID symptoms 6 months after first infection of Omicron, referred as long COVID (LC) Group. The left ones were defined as non-long COVID (NLC) Group. We profiled them via plasma neutralizing antibody titer, SARS-CoV-2 viral load, transcriptomic and proteomics screening, and machine learning. RESULTS: No serum residual SARS-CoV-2 was observed in the participants 6 months post COVID-19 infection. No significant difference in neutralizing antibody titers was found between the long COVID (LC) Group and the non-long COVID (NLC) Group. Transcriptomic and proteomic profiling allow the stratification of long COVID into neutrophil function upregulated (NU-LC) and downregulated types (ND-LC). The NU-LC, identifiable through a refined set of 5 blood gene markers (ABCA13, CEACAM6, CRISP3, CTSG and BPI), displays evidence of relatively higher neutrophil counts and function of degranulation than the ND-LC at 6 months after infection, while recovered at 12 months post COVID-19. CONCLUSION: The transcriptomic and proteomic profiling revealed heterogeneity among long COVID patients. We discovered a subgroup of long COVID population characterized by neutrophil activation, which might associate with the development of psychiatric symptoms and indicate a higher inflammatory state. Meanwhile, a cluster of 5 genes was manually curated as the most potent discriminators of NU-LC from long COVID population. This study can serve as a foundational exploration of the heterogeneity in the pathogenesis of long COVID and assist in therapeutic targeting and detailed epidemiological investigation of long COVID.
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COVID-19 , Neutrófilos , Proteômica , SARS-CoV-2 , Humanos , COVID-19/imunologia , COVID-19/virologia , COVID-19/sangue , Neutrófilos/imunologia , Masculino , Feminino , Pessoa de Meia-Idade , Transcriptoma/genética , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Adulto , Síndrome de COVID-19 Pós-Aguda , Carga Viral , Idoso , Perfilação da Expressão Gênica , Ativação de Neutrófilo , MultiômicaRESUMO
PURPOSE: Dietary nitrate intake is inversely related to numerous contributors towards frailty, including cardiovascular disease and poor physical function. Whether these findings extend to frailty remain unknown. We investigated if habitual nitrate intake, derived from plants or animal-based foods, was cross-sectionally associated with frailty in women. METHODS: Community-dwelling older Australian women (n = 1390, mean age 75.1 ± 2.7 years) completed a validated semi-quantitative food frequency questionnaire (FFQ). Nitrate concentrations in food were obtained from international nitrate databases. We adopted the Rockwood frailty index (FI) of cumulative deficits comprising 33 variables across multiple health domains (scored 0 to 1), which predicts increased hospitalisation and mortality risk. A FI ≥ 0.25 indicated frailty. Cross-sectional associations between nitrate intake (total plant and animal nitrate, separately) and frailty were analysed using multivariable-adjusted logistic regression models (including lifestyle factors), as part of restricted cubic splines. RESULTS: A non-linear inverse relationship was observed between total plant nitrate intake and frailty. Compared to women with the lowest plant nitrate intake (Quartile [Q]1), women with greater intakes in Q2 (OR 0.69 95%CI 0.56-0.84), Q3 (OR 0.67 95%CI 0.50-0.90) and Q4 (OR 0.66 95%CI 0.45-0.98) had lower odds for frailty. A nadir in the inverse association was observed once intakes reached ~ 64 mg/d (median Q2). No relationship was observed between total animal nitrate and frailty. CONCLUSION: Community-dwelling older women consuming low amounts of plant-derived nitrate were more likely to present with frailty. Consuming at least one daily serving (~ 75 g) of nitrate-rich green leafy vegetables may be beneficial in preventing frailty.
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Four undescribed compounds including one aromatic glucoside derivative, cordyceglycoside A (1), one new isoleucine derivative inner salt, cordycepisosalt A (2), a rare four-membered lactam, cinerealactam B (3), and one sesquiterpene derivative, cordycepsetp A (4), together with six known compounds were isolated from Cordyceps militaris. The structures including absolute configurations of these new compounds, were unambiguously elucidated by spectroscopic data analysis and single crystal X-ray diffraction. Biological evaluation of compounds 1-4 showed that 3 displays anti-renal fibrotic activities in TGF-ß1 induced NRK-52e cells. Furthermore, DARTS coupled with LC-MS/MS analysis was used to identify candidate target proteins for 3. Subsequently, C1qbp knockdown using siRNA allowed us to validate the target protein of 3.
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Cordyceps , Cordyceps/química , Cordyceps/metabolismo , Cromatografia Líquida , Espectrometria de Massas em Tandem , Análise Espectral , FibroseRESUMO
BACKGROUND AND AIMS: DXA-measured visceral adipose tissue (VATDXA) is associated with adverse cardiometabolic risk profiles in cross-sectional studies, but longitudinal associations have not been investigated. We examined the longitudinal associations of baseline and change in VATDXA with future cardiometabolic risk in Australian participants of the Busselton Healthy Ageing study. METHODS AND RESULTS: We studied 3569 participants (54.7% female, aged 46-70 years) with data on VATDXA (GE Lunar Prodigy) and cardiometabolic risk factors at baseline and 6 years follow-up. The associations were examined using logistic and linear regression models, adjusting for baseline age and lifestyle factors. Mean baseline VATDXA mass was 1653 ± 880 g and 855 ± 580 g, and mean change in VATDXA +99 ± 500 g and +58 ± 312 g in males and females, respectively. Among all participants, 182 males (11.3%) and 197 females (10.1%) developed incident metabolic syndrome (MetS). Baseline VATDXA was associated with incident MetS with an adjusted odds ratio of 2.53 (95% CI: 2.03, 3.15) in males and 2.78 (2.30, 3.36) in females per SD increment. There was a graded positive association between longitudinal change in VATDXA and MetS severity z score in both sexes adjusted for baseline VAT (P < 0.001). All the above associations remained significant after further adjustment for baseline or change in BMI, waist circumference or waist-to-hip ratio in respective models (all P < 0.001). CONCLUSIONS: Higher baseline and greater longitudinal increase in VATDXA are independently associated with raised cardiometabolic risk over time, and may serve as useful markers for identifying middle-aged individuals at increased cardiometabolic risk.
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BACKGROUND AND AIMS: Assessing the relationship between vitamin K1 intakes, using region-specific food databases, with both all-cause, and cardiovascular disease (CVD) mortality warrants further investigation to inform future preventative strategies. Consequently, we examined the aforementioned associations in the Perth Longitudinal Study of Ageing Women (PLSAW). METHODS AND RESULTS: 1436 community-dwelling older Australian women (mean ± SD age 75.2 ± 2.7 years) completed a validated food frequency questionnaire at baseline (1998). Vitamin K1 intake was calculated based on an Australian vitamin K food database, supplemented with published data. All-cause and CVD mortality data was obtained from linked health records. Associations were examined using restricted cubic splines within Cox-proportional hazard models, adjusted for a range of cardiovascular and lifestyle related risk factors. Over 15 years of follow-up, 601 (41.9%) women died, with 236 deaths (16.4%) due to CVD. Compared to women with the lowest vitamin K1 intakes (Quartile 1, median 49.1 µg/day), those with the highest intakes (Quartile 4, median 119.3 µg/day) had lower relative hazards for all-cause mortality (HR 0.66 95%CI 0.51-0.86) and CVD mortality (HR 0.61 95%CI 0.41-0.92). A plateau in the inverse association was observed from vitamin K1 intakes of approximately ≥80 µg/day. CONCLUSION: Higher vitamin K1 intakes were associated with lower risk for both all-cause and CVD mortality in community-dwelling older women, independent of CVD related risk factors. A higher intake of vitamin K1 rich foods, such as leafy green vegetables, may support cardiovascular health.
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Doenças Cardiovasculares , Humanos , Feminino , Idoso , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/prevenção & controle , Vitamina K 1 , Estudos Longitudinais , Vida Independente , Estudos Prospectivos , Austrália/epidemiologia , Fatores de RiscoRESUMO
OBJECTIVE: Hoffmann's sign testing is a commonly used physical examination in clinical practice for patients with cervical spondylotic myelopathy (CSM). However, the pathophysiological mechanisms underlying its occurrence and development have not been thoroughly investigated. Therefore, the present study aimed to explore whether a positive Hoffmann's sign (PHS) in CSM patients is associated with spinal cord and brain remodeling and to identify potential neuroimaging biomarkers with diagnostic value. METHODS: Seventy-six patients with CSM and 40 sex- and age-matched healthy controls (HCs) underwent multimodal MRI. Based on the results of the Hoffmann's sign examination, patients were divided into two groups: those with a PHS (n = 38) and those with a negative Hoffmann's sign (NHS; n = 38). Quantification of spinal cord and brain structural and functional parameters of the participants was performed using various methods, including functional connectivity analysis, voxel-based morphometry, and atlas-based analysis based on functional MRI and structural MRI data. Furthermore, this study conducted a correlation analysis between neuroimaging metrics and neurological function and utilized a support vector machine (SVM) algorithm for the classification of PHS and NHS. RESULTS: In comparison with the NHS and HC groups, PHS patients exhibited significant reductions in the cross-sectional area and fractional anisotropy (FA) of the lateral corticospinal tract (CST), reticulospinal tract (RST), and fasciculus cuneatus, concomitant with bilateral reductions in the volume of the lateral pallidum. The functional connectivity analysis indicated a reduction in functional connectivity between the left lateral pallidum and the right angular gyrus in the PHS group. The correlation analysis indicated a significant positive association between the CST and RST FA and the volume of the left lateral pallidum in PHS patients. Furthermore, all three variables exhibited a positive correlation with the patients' motor function. Finally, using multimodal neuroimaging metrics in conjunction with the SVM algorithm, PHS and NHS were classified with an accuracy rate of 85.53%. CONCLUSIONS: This research revealed a correlation between structural damage to the pallidum and RST and the presence of Hoffmann's sign as well as the motor function in patients with CSM. Features based on neuroimaging indicators have the potential to serve as biomarkers for assessing the extent of neuronal damage in CSM patients.
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Imageamento por Ressonância Magnética , Neuroimagem , Doenças da Medula Espinal , Espondilose , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Espondilose/diagnóstico por imagem , Neuroimagem/métodos , Doenças da Medula Espinal/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Idoso , Adulto , Vértebras Cervicais/diagnóstico por imagemRESUMO
OBJECTIVE: Deltamethrin (DLM) is a commonly used insecticide, which is harmful to many organs. Here, we explored the effects of chronic low-dose DLM residues on colon tissue and its potential mechanism. METHODS: The mice were given long-term low-dose DLM by intragastric administration, and the body weights and disease activity index (DAI) scores of the mice were regularly recorded. The colon tissues were then collected for hematoxylin-eosin, immunofluorescence and immunohistochemistry staining. Besides, the RNA sequencing was performed to explore the potential mechanism. RESULTS: Our results showed that long-term exposure to low-dose DLM could cause inflammation in mice colon tissue, manifested as weight loss, increased DAI score, increased apoptosis of colonic epithelial cells, and increased infiltration of inflammatory cells. However, we observed that after long-term exposure to DLM and withdrawal for a period of time, although apoptosis was restored, the recovery of colon inflammation was not ideal. Subsequently, we performed RNA sequencing and found that long-term DLM exposure could lead to the senescence of some cells in mice colon tissue. The results of staining of cellular senescence markers in colon tissue showed that the level of cellular senescence in the DLM group was significantly increased, and the p53 signalling related to senescence was also significantly activated, indicating that cellular senescence played a key role in DLM-induced colitis. We further treated mice with quercetin (QUE) after long-term DLM exposure, and found that QUE could indeed alleviate DLM-induced colitis. In addition, we observed that long-term accumulation of DLM could aggravate DSS-induced colitis in mice, and QUE treatment could reverse this scenario. CONCLUSION: Continuous intake of DLM caused chronic colitis in mice, and the inflammation persisted even after discontinuation of DLM intake. This was attributed to the induction of cellular senescence in colon tissue. Treatment with QUE alleviated DLM-induced colitis by reducing cellular senescence. Long-term DLM exposure also aggravated DSS-induced colitis, which could be mitigated by QUE treatment.
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Colite , Nitrilas , Piretrinas , Camundongos , Animais , Colite/induzido quimicamente , Colite/tratamento farmacológico , Inflamação/induzido quimicamente , Senescência Celular , Camundongos Endogâmicos C57BLRESUMO
This study aimed to compare and rank the effectiveness of optimal exercise intensity in improving executive function in patients with ADHD (Attention deficit hyperactivity disorder, ADHD) through a comprehensive comparison of direct and indirect evidence. A systematic search was performed in five electronic databases to explore the optimal exercise intensity for improving executive function in patients with ADHD by directly and indirectly comparing a variety of exercise intervention intensities. In addition, the isolated effects of exercise on improving executive function in patients with ADHD were explored through classical meta-analysis of paired direct comparisons. Twenty-nine studies were retrieved and included in this study. Classical paired meta-analysis showed that for the patients with ADHD in the age group of 7-17 years, statistical difference was observed for all the parameters of exercise interventions (intensity, frequency, period, and training method), the three dimensions of executive function, the use of medication or not, the high and low quality of the methodological approach. Network meta-analysis showed that high-intensity exercise training was optimal for improving working memory (97.4%) and inhibitory function (85.7%) in patients with ADHD. Meanwhile, moderate-intensity exercise training was optimal for improving cognitive flexibility (77.3%) in patients with ADHD. Moderate to high intensity exercise training shows potential for improving executive function in these patients. Therefore, we recommend applying high-intensity exercise intervention to improve executive function in patients with ADHD to achieve substantial improvement.
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The brown planthopper (Nilaparvata lugens) is a major destructive rice pest in Asia. High levels of insecticide resistance have been frequently reported, and the G932C mutation in the chitin synthase 1 (CHS1) gene has been found to mediate buprofezin resistance. However, there has been no direct evidence to confirm the functional significance of the single G932C substitution mutation leading to buprofezin resistance in N. lugens. Here, we successfully constructed a knock-in homozygous strain (Nl-G932C) of N. lugens using CRISPR/Cas9 coupled with homology-directed repair (HDR). Compared with the background strain susceptible to buprofezin (Nl-SS), the knock-in strain (Nl-G932C) showed a 94.9-fold resistance to buprofezin. Furthermore, resistant strains (Nl-932C) isolated from the field exhibited a 2078.8-fold resistance to buprofezin, indicating that there are other mechanisms contributing to buprofezin resistance in the field. Inheritance analysis showed that the resistance trait is incomplete dominance. In addition, the Nl-G932C strain had a relative fitness of 0.33 with a substantially decreased survival rate, emergence rate, and fecundity. This study provided in vivo functional evidence for the causality of G932C substitution mutation of CHS1 with buprofezin resistance and valuable information for facilitating the development of resistance management strategies in N. lugens. This is the first example of using CRISPR/Cas9 gene-editing technology in a hemipteran insect to directly confirm the role of a candidate target site mutation in insecticide resistance.
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Sistemas CRISPR-Cas , Quitina Sintase , Hemípteros , Resistência a Inseticidas , Inseticidas , Tiadiazinas , Animais , Hemípteros/genética , Resistência a Inseticidas/genética , Tiadiazinas/farmacologia , Quitina Sintase/genética , Inseticidas/farmacologia , Mutação , Proteínas de Insetos/genética , Proteínas de Insetos/metabolismo , Técnicas de Introdução de Genes , Feminino , MasculinoRESUMO
MXene usually exhibits weak pseudo-capacitance behavior in aqueous zinc-ion batteries, which cannot provide sufficient reversible capacity, resulting in the decline of overall capacity when used as the cathode materials. Taking inspiration from polymer electrolyte engineering, we have conceptualized an in situ induced growth strategy based on MXene materials. Herein, 5.25 % MXene was introduced into the nucleation and growth process of vanadium oxide (HVO), providing the heterogeneous nucleation site and serving as an initiator to regulate the morphology and structural of vanadium oxide (T-HVO). The resulted materials can significantly improve the capacity and rate performance of zinc-ion batteries. The growth mechanism of T-HVO was demonstrated by both characterizations and DFT simulations, and the improved performance was systematically investigated through a series of in situ experiments related to dynamic analysis steps. Finally, the evaluation and comparison of various defect introduction strategies revealed the efficient, safety, and high production output characteristics of the in situ induced growth strategy. This work proposes the concept of in situ induced growth strategy and discloses the induced chemical mechanism of MXene materials, which will aid the understanding, development, and application of cathode in aqueous zinc-ion batteries.
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The aim of this study is to investigate the clinical potential of immune microenvironment in peripheral blood for the severity and therapeutic efficacy of Langerhans cell histiocytosis (LCH). A total of 200 newly diagnosed children with LCH during 10 years was enrolled for analysis in this study. Peripheral blood samples were acquired from patients before treatment in our hospital and immune indicators were detected by a four-color flow cytometer. The levels of CD3 + CD8 + T cell, CD3 + CD4 + HLA-DR + T cell, CD3 + CD8 + HLA-DR + T cell, IL-4, IL-6, IL-10 and IFN-γ in peripheral blood were markedly elevated in LCH patients vs. healthy controls. Patients with multiple system with risk organ involvement (MS-RO + ) exhibited higher levels in IL-6, IL-10 and IFN-γ, CD3 + CD4 + HLA-DR + T cell and CD3 + CD8 + HLA-DR + T cell, compared to those in patients without risk organ involvement (RO-). Patients who responded effectively to initial chemotherapy showed significantly lower levels of IL-4, IL-10, IFN-γ, CD3 + CD4 + HLA-DR + T cell and CD3 + CD8 + HLA-DR + T cell in peripheral blood, compared to those in patients who did not respond to initial chemotherapy. Furthermore, univariate analyses were performed that the higher levels of CD3 + CD4 + HLA-DR + T cells, CD3 + CD8 + HLA-DR + T cells and IL-10 in peripheral blood were related to non-response in LCH after initial chemotherapy. Immune microenvironment in peripheral blood may be associated with the severity and treatment response of LCH. The levels of CD3 + CD4 + HLA-DR + T cells, CD3 + CD8 + HLA-DR + T cells and IL-10 may be biomarkers to predict treatment response of LCH patients.