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Hutchinson-Gilford progeria syndrome (HGPS) is a lethal premature aging disorder without an effective therapeutic regimen. Because of their targetability and influence on gene expression, microRNAs (miRNAs) are attractive therapeutic tools to treat diseases. Here we identified that hsa-miR-59 (miR-59) was markedly upregulated in HGPS patient cells and in multiple tissues of an HGPS mouse model (LmnaG609G/G609G ), which disturbed the interaction between RNAPII and TFIIH, resulting in abnormal expression of cell cycle genes by targeting high-mobility group A family HMGA1 and HMGA2. Functional inhibition of miR-59 alleviated the cellular senescence phenotype of HGPS cells. Treatment with AAV9-mediated anti-miR-59 reduced fibrosis in the quadriceps muscle, heart, and aorta, suppressed epidermal thinning and dermal fat loss, and yielded a 25.5% increase in longevity of LmnaG609G/G609G mice. These results identify a new strategy for the treatment of HGPS and provide insight into the etiology of HGPS disease.
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MicroRNAs , Progéria , Camundongos , Animais , Progéria/genética , Antagomirs/uso terapêutico , Senescência Celular/genética , MicroRNAs/genética , FenótipoRESUMO
Colorectal cancer (CRC) is characterized by a complex tumor inflammatory microenvironment, while angiogenesis and immunosuppression frequently occur concomitantly. However, the exact mechanism that controls angiogenesis and immunosuppression in CRC microenvironment remains unclear. Herein, we found that expression levels of lipid raft protein STOML2 were increased in CRC and were associated with advanced disease stage and poor survival outcomes. Intriguingly, we revealed that STOML2 is essential for CRC tumor inflammatory microenvironment, which induces angiogenesis and facilitates tumor immune escape simultaneously both in vitro and in vivo. Moreover, tumors with STOML2 overexpression showed effective response to anti-angiogenesis treatment and immunotherapy in vivo. Mechanistically, STOML2 regulates CRC proliferation, angiogenesis, and immune escape through activated NF-κB signaling pathway via binding to TRADD protein, resulting in upregulation of CCND1, VEGF, and PD-L1. Furthermore, treatment with NF-κB inhibitor dramatically reversed the ability of proliferation and angiogenesis. Clinically, we also observed a strong positive correlation between STOML2 expression and Ki67, CD31, VEGFC and PD-1 of CD8+T cell expression. Taken together, our results provided novel insights into the role of STOML2 in CRC inflammatory microenvironment, which may present a therapeutic opportunity for CRC.
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Neoplasias Colorretais , Proteínas de Membrana , NF-kappa B , Microambiente Tumoral , Humanos , Linhagem Celular Tumoral , Neoplasias Colorretais/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais , Regulação para Cima , Microdomínios da Membrana , Proteínas de Membrana/genéticaRESUMO
The study of exciton polarons has offered profound insights into the many-body interactions between bosonic excitations and their immersed Fermi sea within layered heterostructures. However, little is known about the properties of exciton polarons with interlayer interactions. Here, through magneto-optical reflectance contrast measurements, we experimentally investigate interlayer Fermi polarons for 2s excitons in WSe2/graphene heterostructures, where the excited exciton states (2s) in the WSe2 layer are dressed by free charge carriers of the adjacent graphene layer in the Landau quantization regime. First, such a system enables an optical detection of integer and fractional quantum Hall states (e.g., ν = ±1/3, ±2/3) of monolayer graphene. Furthermore, we observe that the 2s state evolves into two distinct branches, denoted as attractive and repulsive polarons, when graphene is doped out of the incompressible quantum Hall gaps. Our work paves the way for the understanding of the excited composite quasiparticles and Bose-Fermi mixtures.
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BACKGROUND: The adolescent depression associated with childhood trauma has been confirmed, but the underlying mechanisms remain unclear. This study aims to explore the chain-mediated role of borderline personality traits and self-control in the relationship between childhood trauma and adolescent depression. METHODS: A cross-sectional study was conducted on 2,664 students from a senior high school through online questionnaires from October to December 2022 in Henan, China. Childhood Trauma Questionnaire-Short Form, Borderline Personality Dimension of Personality Diagnostic Questionnaire-4, Self-Control Scale, and Children's Depression Inventory were used to measure childhood trauma, borderline personality traits, and self-control. RESULTS: The prevalence of depression in adolescents was 21.17%, while the prevalence of borderline personality was 12.00%. childhood trauma (r = 0.50, p < 0.001) and borderline personality traits (r = 0.60, p < 0.001) were positively correlated with adolescent depressive symptoms, while self-control was negatively correlated with depressive symptoms (r = - 0.50, p < 0.001). Borderline personality traits and Self-control both play a mediating role in childhood trauma and depressive symptoms, and the mediating effect values are 0.116 (95%CI = [0.098, 0.137]), and 0.022 (95%CI = [0.012, 0.032]) respectively. The chain mediating effect of borderline personality traits and self-control on the relationship between childhood trauma and depressive symptoms was significant (effect value: 0.034, 95%CI = [0.028, 0.042]). CONCLUSIONS: Childhood trauma can predict depressive symptoms in adolescents due to the formation of borderline personality traits and the reduction of self-control. These findings are important for understanding the formation of personality traits, self-control abilities and coping strategies shaped by traumatic experiences in adolescents.
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Experiências Adversas da Infância , Transtorno da Personalidade Borderline , Depressão , Autocontrole , Humanos , Adolescente , Feminino , Masculino , Transtorno da Personalidade Borderline/psicologia , Transtorno da Personalidade Borderline/epidemiologia , Estudos Transversais , Depressão/psicologia , Depressão/epidemiologia , Experiências Adversas da Infância/psicologia , Autocontrole/psicologia , China/epidemiologia , Prevalência , Inquéritos e QuestionáriosRESUMO
PURPOSE: Postpartum depression (PPD) brings adverse and serious consequences to both new parents and newborns. Neuroticism affects PPD, which remains controversial for confounding factors and reverse causality in cross-sectional research. Therefore, mendelian randomization (MR) study has been adopted to investigate their causal relationship. METHODS: This study utilized large-scale genome-wide association study genetic pooled data from three major databases: the United Kingdom Biobank, the European Bioinformatics Institute, and the FinnGen databases. The causal analysis methods used inverse variance weighting (IVW). The weighted median, MR-Egger method, MR-PRESSO test, and the leave-one-out sensitivity test have been used to examine the results' robustness, heterogeneity, and horizontal pleiotropy. The fixed effect model yielded the results of meta-analysis. RESULTS: In the IVW model, a meta-analysis of the MR study showed that neuroticism increased the risk of PPD (OR, 1.17; 95% CI, 1.11-1.25, p < 0.01). Reverse analysis showed that PPD could not genetically predict neuroticism. There was no significant heterogeneity or horizontal pleiotropy bias in this result. CONCLUSION: Our study suggests neuroticism is the risk factor for PPD from a gene perspective and PPD is not the risk factor for neuroticism. This finding may provide new insights into prevention and intervention strategies for PPD according to early detection of neuroticism.
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The circadian rhythm plays a central role in immune function, and its disruption has been closely linked to the etiology of depression. However, the mechanisms underlying the association between depression and circadian rhythm remain unclear. We found that mice deficient of Per2, a central clock component of circadian output, were resilient to neuroinflammation-induced depressive behavior. After repeated central lipopolysaccharide (LPS) injections, MCP-1, MIP-1ß, and RANTES increased in wild type (WT) but not in Per2-deficient mice. In addition, intracerebroventricular injection of RANTES resulted in depression-like behavior, and Met-RANTES, a CCR5 antagonist, could reverse depression-like behavior induced by LPS treatments. These results indicated that the Per2 gene contributes to depression via chemokines, especially RANTES. Furthermore, BMAL1 expression decreased in LPS-treated Per2-deficient mice and BMAL1 could bind to the promoter of Rantes, indicating clock gene can act as a regulator for neuroinflammation. In conclusion, Rantes, a clock-controlled gene (CCG), is involved in clock-immunological mechanisms underlying the effects of Per2 on neuroinflammation-induced depression-like behavior.
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Proteínas CLOCK/metabolismo , Quimiocinas/metabolismo , Depressão/metabolismo , Inflamação/imunologia , Fatores de Transcrição ARNTL/metabolismo , Animais , Ritmo Circadiano/fisiologia , Lipopolissacarídeos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Circadianas Period/metabolismoRESUMO
The current protein interaction method is time consuming and cumbersome or the instrument is expensive. A new method that is convenient, fast, and high throughput needs to be studied urgently. The purpose of this study was to establish a homogeneous immunoassay to detect the interaction between insulin-like growth factor-1 receptor-ß (IGF1R-ß) and suppressor of cytokine signaling 1 (SOCS1). The recombinant vectors IGF1R-ß/pENTER and SOCS1/pENTER were constructed and transfected into 293T cells. Based on homogeneous immunoassay technology, we established a suitable method. The signal intensity in the 293T lysate that overexpressed IGF1R-ß and SOCS1, respectively, was compared with the signal intensity in the simultaneous expression of IGF1R-ß and SOCS1. The interaction between IGF1R-ß and SOCS1 was verified in vitro. The detection system for the interaction between IGF1R-ß and SOCS1 was established. Compared with other methods, homogeneous immunoassay has the advantages of being rapid and sensitive, having higher sensitivity, and easy to operate. The interaction between IGF1R-ß and SOCS1 was tested to verify the feasibility of this method and prove its practicability and sensitivity. This new method can be used as a high-throughput platform for protein-protein interaction, with the advantages of trace detection, short detective time, and high detective sensitivity.
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Biomarcadores Tumorais/metabolismo , Proteínas de Neoplasias/metabolismo , Receptor IGF Tipo 1/metabolismo , Proteína 1 Supressora da Sinalização de Citocina/metabolismo , Biomarcadores Tumorais/genética , Linhagem Celular , Humanos , Imunoensaio , Proteínas de Neoplasias/genética , Receptor IGF Tipo 1/genética , Proteína 1 Supressora da Sinalização de Citocina/genéticaRESUMO
Lactic acid, traditionally considered as a metabolic waste product arising from glycolysis, has undergone a resurgence in scientific interest since the discovery of the Warburg effect in tumor cells. Numerous studies have proved that lactic acid could promote angiogenesis and impair the function of immune cells within tumor microenvironments. Nevertheless, the precise molecular mechanisms governing these biological functions remain inadequately understood. Recently, lactic acid has been found to induce a posttranslational modification, lactylation, that may offer insight into lactic acid's non-metabolic functions. Notably, the posttranslational modification of proteins by lactylation has emerged as a crucial mechanism by which lactate regulates cellular processes. This article provides an overview of the discovery of lactate acidification, outlines the potential "writers" and "erasers" responsible for protein lactylation, presents an overview of protein lactylation patterns across different organisms, and discusses the diverse physiological roles of lactylation. Besides, the article highlights the latest research progress concerning the regulatory functions of protein lactylation in pathological processes and underscores its scientific significance for future investigations.
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Processamento de Proteína Pós-Traducional , Humanos , Ácido Láctico/metabolismo , Animais , Histonas/metabolismo , Histonas/genética , Código das Histonas/genética , Neoplasias/genética , Neoplasias/metabolismo , Epigênese Genética/genéticaRESUMO
Cyclic GMP-AMP synthase (cGAS), promotes non-small cell lung cancer (NSCLC) cell proliferation. However, the specific mechanisms of cGAS-mediated NSCLC cell proliferation are largely unknown. In this study, we found asymmetric dimethylation by protein arginine methyltransferase 1 (PRMT1) at R127 of cGAS. This facilitated the binding of deubiquitinase USP7 and contributed to deubiquitination and stabilization of cGAS. PRMT1-and USP7-dependent cGAS stability, which also played a pivotal role in accelerating NSCLC cell proliferation through activating AKT pathway. We validated that the expression of cGAS and PRMT1 were positive correlated in human non-small cell lung cancer samples. Our study demonstrates a unique mechanism for managing cGAS stability by arginine methylation and indicates that PRMT1-cGAS-USP7 axis is a potential therapeutic target for NSCLC.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Arginina , Carcinoma Pulmonar de Células não Pequenas/genética , Proliferação de Células , Neoplasias Pulmonares/genética , Metilação , Proteína-Arginina N-Metiltransferases/genética , Proteína-Arginina N-Metiltransferases/metabolismo , Proteínas Repressoras/metabolismo , Peptidase 7 Específica de Ubiquitina/metabolismoRESUMO
Despite business model innovation being the object of much interest, limited attention has paid on how and when knowledge management capabilities enhance business model innovation in the literature. Build upon institutional theory and knowledge-based view, we seek to investigate how knowledge management capabilities affect the business model innovation by exploring the dual role of different types of legitimation motivations in triggering knowledge management capabilities, and moderating the relationship between knowledge management capabilities, and business model innovation. The data collected from the 236 Chinese new ventures running their businesses across a variety of sectors. The results indicate the both political and market legitimation motivation positively affect knowledge management capabilities. The relationship between knowledge management capabilities and business model innovation are more strongly in high motivation to achieve market legitimacy. However, the positive effect of knowledge management capabilities stimulate business model innovation is more strongly in moderately motivation to achieve political legitimacy than in low or highly political legitimation motivation. The paper has significantly contributed to advancing the body of knowledge of institutional and business model innovation theory and providing deeper insights on the correlation between firm's motivation to achieve legitimacy and knowledge management capabilities for business model innovations.
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An accumulating body of evidence indicates an association between mitotic defects and the aging process in Hutchinson-Gilford progeria syndrome (HGPS), which is a premature aging disease caused by progerin accumulation. Here, we found that BUBR1, a core component of the spindle assembly checkpoint, was downregulated during HGPS cellular senescence. The remaining BUBR1 was anchored to the nuclear membrane by binding with the C terminus of progerin, thus further limiting the function of BUBR1. Based on this, we established a unique progerin C-terminal peptide (UPCP) that effectively blocked the binding of progerin and BUBR1 and enhanced the expression of BUBR1 by interfering with the interaction between PTBP1 and progerin. Finally, UPCP significantly inhibited HGPS cellular senescence and ameliorated progeroid phenotypes, extending the lifespan of LmnaG609G/G609G mice. Our findings reveal an essential role for the progerin-PTBP1-BUBR1 axis in HGPS. Therapeutics designed around UPCP may be a beneficial strategy for HGPS treatment.
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Senilidade Prematura , Progéria , Camundongos , Animais , Progéria/tratamento farmacológico , Senilidade Prematura/tratamento farmacológico , FenótipoRESUMO
PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant tumors. Endoplasmic reticulum stress (ERS) plays an essential role in PDAC progression. Here, we aim to identify the ERS-related genes in PDAC and build reliable risk models for diagnosis, prognosis and immunotherapy response of PDAC patients as well as investigate the potential mechanism. METHODS: We obtained PDAC cohorts with transcriptional profiles and clinical data from the ArrayExpress, The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases. Univariate Cox regression, LASSO regression and multivariate Cox regression analyses were used to construct an ERS-related prognostic signature. The CIBERSORT and ssGSEA algorithms were applied to explore the correlation between the prognostic signature and immune cell infiltration and immune-related pathways. The GDSC database and TIDE algorithm were used to predict responses to chemotherapy and immunotherapy, identifying potential drugs for treating patients with PDAC. RESULTS: We established and validated an ERS-related prognostic signature comprising eight genes (HMOX1, TGFB1, JSRP1, GAPDH, CAV1, CHRNE, CD74 and ERN2). Patients with higher risk scores displayed worse outcomes than those with lower risk scores. PDAC patients in low-risk groups might benefit from immunotherapy. Dasatinib and lapatinib might have potential therapeutic implications in high-risk PDAC patients. CONCLUSION: We established and validated an ERS-related prognostic signature comprising eight genes to predict the overall survival outcome of PDAC patients, which closely correlating with the response to immunotherapy and sensitivity to anti-tumor drugs, as well as could be beneficial for formulating clinical strategies and administering individualized treatments.
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Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/genética , Prognóstico , Imunoterapia , Endorribonucleases , Proteínas de Membrana , Proteínas Serina-Treonina Quinases , Neoplasias PancreáticasRESUMO
Rydberg excitons, the solid-state counterparts of Rydberg atoms, have sparked considerable interest with regard to the harnessing of their quantum application potentials, but realizing their spatial confinement and manipulation poses a major challenge. Lately, the rise of two-dimensional moiré superlattices with highly tunable periodic potentials provides a possible pathway. Here, we experimentally demonstrate this capability through the spectroscopic evidence of Rydberg moiré excitons (XRM), which are moiré-trapped Rydberg excitons in monolayer semiconductor tungsten diselenide adjacent to twisted bilayer graphene. In the strong coupling regime, the XRM manifest as multiple energy splittings, pronounced red shift, and narrowed linewidth in the reflectance spectra, highlighting their charge-transfer character wherein electron-hole separation is enforced by strongly asymmetric interlayer Coulomb interactions. Our findings establish the excitonic Rydberg states as candidates for exploitation in quantum technologies.
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BACKGROUND: Previous studies have explored the association between parenting style and offspring's psychological well-being, and the association between offspring's achievement attribution pattern and psychological well-being. However, little is known about the role of offspring's achievement attribution in the relationship between parenting and offspring's psychological well-being. We aimed to find the role of adolescents' achievement attribution pattern in the relationship between parent-child communication quality and adolescents' mental health. METHODS: A cross-sectional analysis was conducted on 2,725 adolescents aged from 9 to 18 years who are participating in the China Family Panel Studies. Participants supplied demographic information and completed a series of psychological scales including the Center for Epidemiologic Studies Depression scale, an adapted version of the Parental Bonding Instrument, an achievement attribution scale, and single-item measures of subjective well-being and subjective interpersonal popularity. RESULTS: Linear regression analysis revealed that after controlling for demographic factors good parent-child communication negatively correlated with depression symptoms, and positively associated with subjective well-being and subjective interpersonal popularity. Next, mediation analysis found that internal attribution of achievement partly mediated the effects of parent-child communication quality on adolescents' depression, subjective well-being, and subjective interpersonal popularity. The result was robust after controlling demographic variables. CONCLUSIONS: An internal attribution pattern of achievement partially accounted for the associations between parent-child communication quality and adolescents' psychological outcomes including depression, subjective well-being, and subjective interpersonal popularity. Future interventions for adolescents' mental health promotion can target parent-child communication and adolescents' positive achievement attribution pattern.
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Análise de Mediação , Relações Pais-Filho , Logro , Adolescente , Comunicação , Estudos Transversais , HumanosRESUMO
Senescence is accompanied with histones level alteration; however, the roles and the mechanisms of histone reduction in cellular senescence are largely unknown. Protein arginine methyltransferase 1 (PRMT1) is the major enzyme that generates monomethyl and asymmetrical dimethyl arginine. Here we showed that abrogation of PRMT1-mediated senescence was accompanied with decreasing histone H4 level. Consistently, under multiple classic senescence models, H4 decreasing was also been found prior to the other 3 core histones. Noticeably, asymmetric demethylation of histone H4 at arginine 3 (H4R3me2as), catalyzed by PRMT1, was decreased prior to histone H4. In addition, we showed that the PRMT1-mediated H4R3me2as maintained H4 stability. Reduction of H4R3me2as level increased the interaction between proteasome activator PA200 and histone H4, which catalyzes the poly-ubiquitin-independent degradation of H4. Moreover, H4 degradation promoted nucleosome decomposition, resulting in increased senescence-associated genes transcription. Significantly, H4 was restored by 3 well-informed anti-aging drugs (metformin, rapamycin, and resveratrol) much earlier than other senescence markers detected under H2O2-induced senescence. Thus, we uncovered a novel function of H4R3me2as in modulation of cellular senescence via regulating H4 stability. This finding also points to the value of histone H4 as a senescence indicator and a potential anti-aging drug screening marker.