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BRCA1 expression is highly regulated to prevent genomic instability and tumorigenesis. Dysregulation of BRCA1 expression correlates closely with sporadic basal-like breast cancer and ovarian cancer. The most significant characteristic of BRCA1 regulation is periodic expression fluctuation throughout the cell cycle, which is important for the orderly progression of different DNA repair pathways throughout the various cell cycle phases and for further genomic stability. However, the underlying mechanism driving this phenomenon is poorly understood. Here, we demonstrate that RBM10-mediated RNA alternative splicing coupled to nonsense-mediated mRNA decay (AS-NMD), rather than transcription, determines the periodic fluctuations in G1/S-phase BRCA1 expression. Furthermore, AS-NMD broadly regulates the expression of period genes, such as DNA replication-related genes, in an uneconomical but more rapid manner. In summary, we identified an unexpected posttranscriptional mechanism distinct from canonical processes that mediates the rapid regulation of BRCA1 as well as other period gene expression during the G1/S-phase transition and provided insights into potential targets for cancer therapy.
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Neoplasias da Mama , Degradação do RNAm Mediada por Códon sem Sentido , Humanos , Feminino , Processamento Alternativo , Splicing de RNA , Neoplasias da Mama/genética , Instabilidade Genômica , Proteína BRCA1/genética , Proteínas de Ligação a RNA/genéticaRESUMO
Although tyrosine kinase inhibitor (TKI) therapy has markedly improved the survival of people with chronic-phase chronic myeloid leukemia (CML), 20-30% of people still experienced therapy failure. Data from 1,955 consecutive subjects with chronic-phase CML diagnosed by the European LeukemiaNet (ELN) recommendations from 1 center receiving initial TKI imatinib or a second-generation (2G-) TKI therapy were interrogated to develop a clinical prediction model for TKI therapy failure. This model was subsequently validated in 3,454 subjects from 76 other centers. Using the predictive clinical co-variates associated with TKI therapy failure, we developed a model that stratified subjects into low-, intermediate- and high-risk subgroups with significantly different cumulative incidences of therapy failure (p < 0.001). There was good discrimination and calibration in the external validation dataset, and the performance was consistent with that of the training dataset. Our model had the better prediction discrimination than the Sokal and ELTS scores did, with the greater time-dependent area under the receiver-operator characteristic curve (AUROC) values and a better ability to re-defined the risk of therapy failure. Our model could help physicians estimate the likelihood of initial imatinib or 2G-TKI therapy failure in people with chronic-phase CML.
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BACKGROUND: CD19-targeted chimeric antigen receptor T (CAR-T) cell therapy stands out as a revolutionary intervention, exhibiting remarkable remission rates in patients with refractory/relapsed (R/R) B-cell malignancies. However, the potential side effects of therapy, particularly cytokine release syndrome (CRS) and infections, pose significant challenges due to their overlapping clinical features. Promptly distinguishing between CRS and infection post CD19 target CAR-T cell infusion (CTI) remains a clinical dilemma. Our study aimed to analyze the incidence of infections and identify key indicators for early infection detection in febrile patients within 30 days post-CTI for B-cell malignancies. METHODS: In this retrospective cohort study, a cohort of 104 consecutive patients with R/R B-cell malignancies who underwent CAR-T therapy was reviewed. Clinical data including age, gender, CRS, ICANS, treatment history, infection incidence, and treatment responses were collected. Serum biomarkers procalcitonin (PCT), interleukin-6 (IL-6), and C-reactive protein (CRP) levels were analyzed using chemiluminescent assays. Statistical analyses employed Pearson's Chi-square test, t-test, Mann-Whitney U-test, Kaplan-Meier survival analysis, Cox proportional hazards regression model, Spearman rank correlation, and receiver operating characteristic (ROC) curve analysis to evaluate diagnostic accuracy and develop predictive models through multivariate logistic regression. RESULTS: In this study, 38 patients (36.5%) experienced infections (30 bacterial, 5 fungal, and 3 viral) within the first 30 days of CAR T-cell infusion. In general, bacterial, fungal, and viral infections were detected at a median of 7, 8, and 9 days, respectively, after CAR T-cell infusion. Prior allogeneic hematopoietic cell transplantation (HCT) was an independent risk factor for infection (Hazard Ratio [HR]: 4.432 [1.262-15.565], P = 0.020). Furthermore, CRS was an independent risk factor for both infection ((HR: 2.903 [1.577-5.345], P < 0.001) and severe infection (9.040 [2.256-36.232], P < 0.001). Serum PCT, IL-6, and CRP were valuable in early infection prediction post-CAR-T therapy, particularly PCT with the highest area under the ROC curve (AUC) of 0.897. A diagnostic model incorporating PCT and CRP demonstrated an AUC of 0.903 with sensitivity and specificity above 83%. For severe infections, a model including CRS severity and PCT showed an exceptional AUC of 0.991 with perfect sensitivity and high specificity. Based on the aforementioned analysis, we proposed a workflow for the rapid identification of early infection during CAR-T cell therapy. CONCLUSIONS: CRS and prior allogeneic HCT are independent infection risk factors post-CTI in febrile B-cell malignancy patients. Our identification of novel models using PCT and CRP for predicting infection, and PCT and CRS for predicting severe infection, offers potential to guide therapeutic decisions and enhance the efficacy of CAR-T cell therapy in the future.
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Antígenos CD19 , Febre , Imunoterapia Adotiva , Humanos , Feminino , Masculino , Pessoa de Meia-Idade , Imunoterapia Adotiva/métodos , Adulto , Antígenos CD19/metabolismo , Infecções/sangue , Idoso , Curva ROC , Adulto Jovem , Estudos RetrospectivosRESUMO
The bispecific T-cell engager (BiTE) blinatumomab against CD19 and CD3 has emerged as the most successful bispecific antibody (bsAb) to date; however, a significant proportion of patients do not respond to the treatments or eventually experience relapse after an initial response, and the recurrence rate increases significantly due to escape or downregulation of the CD19 antigen. To enhance antitumor efficacy and overcome potential immune escape, we developed a novel approach to design a CD19/CD22/CD3 trispecific antibody (tsAb) by site-specifically fusing anti-CD19 scFv (FMC63) and anti-CD22 nanobody (Nb25) to the defined sites of the CD3 antigen-binding fragment (Fab, SP34). This strategy allows for the optimal formation of immune synapses mediated by CD19/CD22/CD3 between target cells and T cells. Optimized tsAb can be superior for inducing T-cell-specific cytotoxicity and cytokine production against CD19+ and/or CD22+ tumor cells compared to other tsAb formats, and demonstrated significantly enhanced antitumor efficacy and the ability to overcome immune escape compared with the corresponding bsAbs alone or in combination, as well as with blinatumomab. In addition, tsAb treatment can lead to the long-term elimination of primary B-ALL patient samples in the PDX model and significantly prolong survival. This novel approach provides unique insight into the structural optimization of T-cell-redirected multispecific antibodies using site-specific recombination, and may be broadly applicable to heterogeneous and resistant tumor populations as well as solid tumors.
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Anticorpos Biespecíficos , Linfoma de Burkitt , Linfoma de Células B , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Antígenos CD19 , Complexo CD3 , Recidiva Local de Neoplasia/tratamento farmacológico , Anticorpos Biespecíficos/farmacologia , Anticorpos Biespecíficos/uso terapêutico , Linfoma de Células B/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Linfoma de Burkitt/tratamento farmacológico , Citocinas , Lectina 2 Semelhante a Ig de Ligação ao Ácido SiálicoRESUMO
SnTe is an environmentally friendly medium-temperature thermoelectric material, but its inherent low power factor (PF) and high lattice thermal conductivity severely limit its application. In this study, based on the fact that Mn doping can induce band convergence, the high-pressure and high-temperature (HPHT) synthesis method was used to optimize the sample preparation and shorten the synthesis cycle to 30 min. The results show that the Sn0.93Mn0.10Te sample achieves the maximum PF value of 34.00 µW cm-1 K-2 at 775 K and PFave value of 21.36 µW cm-1 K-2 between 300-875 K. Microstructure analysis shows that the high-pressure synthesis method introduces abundant grain boundaries, various grain sizes, multiple defects, and pore structures into the sample. These microscopic crystal structures can effectively scatter phonons and lower the lattice thermal conductivity. The modification of these micromorphologies results in the Sn0.92Mn0.11Te sample attaining a minimum lattice thermal conductivity of 0.45 W m-1 K-1 at 625 K. The thermoelectric figure of merit (zT) of sample Sn0.92Mn0.11Te reaches a maximum value of 1.1 at 775 K, and the zTave reaches 0.63 in the range of 300-875 K. This study indicates that the synergistic effect of Mn element doping and microstructure modification can effectively optimize the thermoelectric transport performance of SnTe materials.
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BACKGROUND: Prostate cancer (PCa) is one of the most deadly and metastatic cancers of the urinary tract. Latest studies have confirmed that long non-coding RNAs (lncRNAs) play a crucial role in a variety of cancers. Some of these lncRNAs code for small nucleolar RNAs (snoRNAs), called small nucleolar RNA host genes (SNHGs), which exert some value in predicting the prognosis of certain cancer patients, but little is known regarding the function of SNHGs within the PCa. AIM OF THE STUDY: To explore the expression distribution and differential analysis of SNHGs in different tumors using RNA-seq and survival data from TCGA and GTEx, and to assess the potential impacts of the lncRNA SNHG25 on human PCa. To validate the expression of SNHG25 using experimental data and to investigate in detail its particular molecular biological function on PCa both in vivo and in vitro. METHODS: LncRNA SNHG25 expression was analyzed by bioinformatic prediction and qPCR. CCK-8, EdU, transwell, wound healing, and western blotting assays were conducted to investigate the main role of lncRNA SNHG25 in PCa. Xenograft tumour growth model in nude mice was surveyed by in vivo imaging and Ki-67 staining. AKT pathway activator (SC79) was used to verify the interaction among SNHG25 and PI3K/AKT signaling pathway. RESULTS: Bioinformatics analysis and experimental research illuminated that the expression of lncRNA SNHG25 was observably up-regulated in PCa tissues and cells. Moreover, SNHG25 knockdown restrained PCa cell proliferation, invasion and migration, while promoting apoptosis. Xenografts model confirmed that the si-SNHG25 group had a significant inhibitory effect on PCa tumour growth in vivo. Additionally, a series of gain-of-function analyses suggested that SNHG25 could activate the PI3K/AKT pathway to accelerate PCa progression. CONCLUSIONS: These in vitro and in vivo findings demonstrate that SNHG25 is highly expressed in PCa and facilitates PCa development through regulation of PI3K/AKT signaling pathway. SNHG25 acts as an oncogene to predict tumour malignancy and survival in PCa patients and may therefore become a promising potential molecular target for early detection and therapy of lethal PCa.
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Neoplasias da Próstata , RNA Longo não Codificante , Masculino , Animais , Camundongos , Humanos , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , RNA Nucleolar Pequeno/genética , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Camundongos Nus , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Proliferação de Células/genética , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/genética , Movimento Celular/genéticaRESUMO
Social mobility beliefs play a significant role in shaping adolescents' adaptive developmental outcomes, including well-being and academic functioning. Nevertheless, existing research may not cast light on the distinct trajectories and potential protective factors of social mobility beliefs. The present study aims to identify heterogeneity in trajectory patterns of social mobility beliefs among Chinese adolescents (Mage = 12.45, SDage = 2.60; 55.1% boys; 40.0% rural adolescents) in a four-wave (i.e., fall 2017, fall 2018, spring 2019, and fall 2019) longitudinal design, and examines the protective roles of parental academic involvement and adolescent future orientation. Three distinct trajectories of social mobility beliefs were identified: high-increasing (35.1%; a positive trajectory with the best developmental outcomes, including the lowest problem behaviors and depression symptoms, and the highest life satisfaction and academic competence), moderate-stable (49.8%), and low-decreasing (15.1%; a negative trajectory with the worst developmental outcomes, including the highest problem behaviors and depression symptoms, and the lowest life satisfaction and academic competence). Apart from the main effects of parental academic involvement and future orientation, a significant interaction effect of these two protective factors and adolescent group was detected, and only rural adolescents who reported both high levels of parental academic involvement and future orientation have a greater chance of being placed in the high-increasing trajectory than the low-decreasing trajectory. These findings highlight the significance of clarifying individual differences in the dynamic process of social mobility beliefs during adolescence, and elucidate rural-urban disparities in the influences of protective factors on social mobility beliefs trajectories, and inform individualized intervention strategies.
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Comportamento do Adolescente , Mobilidade Social , Humanos , Adolescente , Masculino , Feminino , Estudos Longitudinais , China , Comportamento do Adolescente/psicologia , Relações Pais-Filho , Satisfação Pessoal , População Rural/estatística & dados numéricos , Criança , População do Leste AsiáticoRESUMO
Japanese encephalitis virus (JEV) infection can cause brain tissue lesions characterized by neuronal death, and apoptosis is involved in JEV-induced neuronopathy. In the present study, mouse microglia were infected with JEV, and pyknosis with dark-staining nuclei of infected cells was detected using Hoechst 33342 staining. TUNEL staining showed that JEV infection promoted the apoptosis of BV2 cells, and the apoptosis rate was significantly increased at 24-60 hours postinfection (hpi) (P < 0.01) and was the highest at 36 h (P < 0.0001). Western blot results showed that the expression of the Bcl-2 protein in JEV-infected cells was downregulated significantly at 60 hpi (P < 0.001), whereas that of the Bax protein was observably upregulated at 60 hpi (P < 0.001). At the same time, the level of cytochrome c (Cyt c) was significantly increased (P < 0.001), and the expression levels of two apoptosis-related proteins, namely, cleaved caspase-3 (P < 0.01) and caspase-9 (P < 0.001), were elevated significantly. Immunofluorescence staining showed that the amount of Cyt c increased with time after infection. After BV2 cells were infected with JEV, the expression of RIG-1 increased significantly from 24 hpi to 60 h (P < 0.001). The expression of MAVS increased significantly at 24 h (P < 0.001) and decreased gradually from 24 h to 60 hpi. The expression of TBK1 and NF-κB (p65) was not significantly changed. The expression of p-TBK1 and p-NF-κB (p-p65) increased significantly within 24 h (P < 0.001) and decreased from 24 to 60 hpi. The expression levels of IRF3 and p-IRF3 peaked at 24 hpi (P < 0.001) and decreased gradually from 24 to 60 hpi. However, the expression levels of JEV proteins showed no significant change at 24 and 36 hpi but were markedly elevated at 48 and 60 hpi. Interference with the expression of the RIG-1 protein in BV2 cells resulted in a dramatic increase in the expression of the anti-apoptotic protein Bcl-2 (P < 0.05), whereas the pro-apoptotic protein Bax, cleaved caspase-9, and especially cleaved caspase-3 were downregulated (P < 0.05), and viral protein expression was notably reduced (P < 0.05). These results indicate that JEV induces apoptosis through mitochondrial-dependent apoptosis pathways, interfering with the expression of RIG-1 in BV2 cells can inhibit viral replication and inhibit apoptosis.
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Vírus da Encefalite Japonesa (Espécie) , Encefalite Japonesa , Animais , Camundongos , Vírus da Encefalite Japonesa (Espécie)/fisiologia , Caspase 3/metabolismo , Caspase 9/genética , Caspase 9/metabolismo , NF-kappa B/metabolismo , Linhagem Celular , Apoptose , Transdução de Sinais , Proteínas Proto-Oncogênicas c-bcl-2/metabolismoRESUMO
Comparing with the effect of the average climate change on vegetation phenology, the impacts of extreme climate events remain unclear, especially considering their characteristic cumulative and time-lag effects. Using solar-induced chlorophyll fluorescence (SIF) satellite records, we investigated the cumulative and time-lag effects of drought and heat events on photosynthesis, particularly for the end date of autumn photosynthesis (EOP), in subtropical vegetation in China. Our results showed a negative effect of drought on the delay of EOP, with the cumulative effect on 30.12% (maximum continuous dry days, CDD), 34.82% (dry days, DRD), and 26.14% (dry period, DSDI) of the study area and the general time-lag effect on 50.73% (maximum continuous dry days), 56.61% (dry days), and 47.55% (dry period) of the study area. The cumulative and lagged time were 1-3 months and 2-3 months, respectively. In contrast, the cumulative effect of heat on EOP was observed in 16.27% (warm nights, TN90P), 23.66% (moderate heat days, TX50P), and 19.19% (heavy heat days, TX90P) of the study area, with cumulative time of 1-3 months. The lagged time was 3-4 months, detected in 31.02% (warm nights), 45.86% (moderate heat days), and 36.52% (heavy heat days) of the study area. At the vegetation community level, drought and heat had relatively rapid impacts on EOP in the deciduous broadleaved forest, whereas evergreen forests and bushes responded to heat slowly and took a longer time. Our results revealed that drought and heat have short-term cumulative and time-lag effects on the EOP of subtropical vegetation in China, with varying effects among different vegetation types. These findings provide new insights into the effect of drought and heat on subtropical vegetation and confirm the need to consider these effects in the development of prediction models of autumn phenology for subtropical vegetation.
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Secas , Temperatura Alta , Fotossíntese , Florestas , Luz Solar , Estações do Ano , China , Ecossistema , Mudança ClimáticaRESUMO
The objective of this study was to investigate the expression pattern of Wilms tumor 1 (WT1) gene at diagnosis, complete remission (CR) and relapse status in non-acute promyelocytic leukemia (non-APL) acute myeloid leukemia (AML) patients, and further explore the prognostic value of measurable residual disease (MRD) assessment by WT1 gene and multiparameter flow cytometry (MFC). Our results showed that the average expression level of WT1 was 4026 ± 616.1 copies/104 ABL at diagnosis, 155.3 ± 36.03 copies/104 ABL at CR, and 1766 ± 238.8 copies/104 ABL at relapse, with statistically significant differences (p = .000). ROC analysis showed that WT1 expression levels were 118.1 copies/104 ABL and MFC-MRD was 0.155%, which had good predictive efficacy for relapse of patients during consolidation therapy. Both WT1-MRD and MFC-MRD had a significant impact on relapse-free survival (RFS) and overall survival (OS). Patients with WT1-MRD positive or MFC-MRD positive were associated with worse RFS (HR 3.840, 95% CI 1.582-9.320, p = .003), (HR 4.464, 95% CI 1.841-10.984, p = .001) and worse OS (HR 2.963, 95% CI 1.058-8.295, p = .039), (HR 3.590, 95% CI 1.254-10.280, p = .017). Besides, compared with patients who were negative for both WT1-MRD and MFC-MRD, patients who were positive both WT1-MRD and MFC-MRD were associated with worse RFS (HR 6.200, 95% CI 2.206-17.430, p = .001) and worse OS (HR 4.886, 95% CI 1.388-17.197, p = .013). This study demonstrates that combined assessment of MRD by WT1 and MFC improves relapse and prognosis prediction in non-APL AML patients, and may help guide interventions for disease relapse.
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Leucemia Mieloide Aguda , Leucemia Promielocítica Aguda , Humanos , Prognóstico , Citometria de Fluxo/métodos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Indução de Remissão , Neoplasia Residual/diagnóstico , Neoplasia Residual/genética , Proteínas WT1/genética , Proteínas WT1/metabolismoRESUMO
Heat shock protein family A (HSP70) member 5 (HSPA5) is aberrantly expressed in various tumors and closely associated with the progression and prognosis of cancer. Nevertheless, its role in bladder cancer (BCa) remains elusive. The results of our study demonstrated that HSPA5 was upregulated in BCa and correlated with patient prognosis. Cell lines with low expression level of HSPA5 were constructed to explore the role of this protein in BCa. HSPA5 knockdown promoted apoptosis and retarded the proliferation, migration and invasion of BCa cells by regulating the VEGFA/VEGFR2 signaling pathway. In addition, overexpression of VEGFA alleviated the negative effect of HSPA5 downregulation. Moreover, we found that HSPA5 could inhibit the process of ferroptosis through the P53/SLC7A11/GPX4 pathway. Hence, HSPA5 can facilitate the progression of BCa and may be used as a novel biomarker and latent therapeutic target in the clinic.
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Ferroptose , Neoplasias da Bexiga Urinária , Humanos , Apoptose/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Ferroptose/genética , Neoplasias da Bexiga Urinária/metabolismoRESUMO
BACKGROUND: Prostate cancer (PCa) is the second leading cause of cancer-related male deaths worldwide. The purpose of this study was to investigate the effects of homo sapiens solute carrier family 4 member 4 (SLC4A4), which encodes the electrogenic Na+/HCO3- cotransporter isoform 1 (NBCe1), in the development and progression of PCa. METHODS: The expression levels of SLC4A4 in PCa and normal prostate tissues were evaluated by immunohistochemistry. The SLC4A4 knockdown cell model was structured by lentiviral infection, and the knockdown efficiency was validated by RT-qPCR and Western blotting. The effects of SLC4A4 knockdown on cell proliferation, apoptosis and cycle, migration, and invasion were detected by Celigo cell counting assay and CCK-8 assay, flow cytometry analysis, wound-healing, and Transwell assay, respectively. Tumor growth in nude mice was surveyed by in vivo imaging and Ki-67 staining. Furthermore, underlying mechanism of SLC4A4 silence induced inhibition of PCa progression was explored by human phospho-kinase array. RESULTS: Our results revealed that SLC4A4 expression was up-regulated in PCa tissues and human PCa cell lines. High expression of SLC4A4 in tumor specimens was significantly correlated with disease progression. SLC4A4 knockdown inhibited cell proliferation, migration and invasion, while facilitated apoptosis, which was also confirmed in vivo. Moreover, SLC4A4 promoted PCa progression through the AKT-mediated signalling pathway. CONCLUSION: The results of this study indicated that SLC4A4 overexpression was closely associated with the progression of PCa; SLC4A4 knockdown suppressed PCa development in vitro and in vivo. SLC4A4 acts as a tumor promotor in PCa by regulating key components of the AKT pathway and may therefore act as a potential therapeutic target for PCa treatment.
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Schizophrenia is a complex genetic disorder, the non-Mendelian features of which are likely complicated by epigenetic factors yet to be elucidated. Here, we performed RNA sequencing of peripheral blood RNA from monozygotic twins discordant for schizophrenia, and identified a schizophrenia-associated upregulated long noncoding RNA (lncRNA, AC006129.1) that participates in the inflammatory response by enhancing SOCS3 and CASP1 expression in schizophrenia patients and further validated this finding in AC006129.1-overexpressing mice showing schizophrenia-related abnormal behaviors. We find that AC006129.1 binds to the promoter region of the transcriptional repressor Capicua (CIC), facilitates the interactions of DNA methyltransferases with the CIC promoter, and promotes DNA methylation-mediated CIC downregulation, thereby ameliorating CIC-induced SOCS3 and CASP1 repression. Derepression of SOCS3 enhances the anti-inflammatory response by inhibiting JAK/STAT-signaling activation. Our findings reveal an epigenetic mechanism with etiological and therapeutic implications for schizophrenia.
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Metilação de DNA , RNA Longo não Codificante , Esquizofrenia , Proteína 3 Supressora da Sinalização de Citocinas , Animais , Regulação para Baixo , Humanos , Inflamação , Camundongos , RNA Longo não Codificante/genética , Esquizofrenia/genética , Proteína 3 Supressora da Sinalização de Citocinas/genética , Proteína 3 Supressora da Sinalização de Citocinas/metabolismoRESUMO
In this paper, an effective method is proposed for improving the energy of the shock waves that are generated by plasma expanding outward and colliding with another gas. Silicon targets are used as the response medium with roughness of 2.3 nm, 457.8 nm, 1.1 µm, and 37.1 µm, respectively. A 532-nm-laser with a pulse duration of 8 ns and a repetition rate of 10 Hz is used as the irradiation source. An intensified charge-coupled device (ICCD) is used to photograph the morphology of the shock waves. The time-resolved emission images of silicon plasma plumes are observed between 20-200 ns. As the surface roughness of the target increases, the intensity of the shock wave gradually increases, and the energy of the shock wave reaches up to 39.45 mJ at a roughness of 37.1 µm.
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In recent decades, researchers have paid more attention to the indirect tensile test than to the direct tensile test (DTT) of rocks, mainly due to difficulties in the alignment and the stress concentration at the end of an intact cylindrical specimen. In this paper, a new flattened cylinder specimen and a clamp device were designed to obtain the true tensile strength of the rock in DTT. Stress distributions of the specimen with different lengths (l) and cutting thicknesses (t) were analyzed, and damage processes of the specimen were monitored by the Digital Image Correlation (DIC), the fractured sections were also scanned. Different mechanical parameters were also obtained by the DTT of the flattened cylinder specimens and the intact cylinder specimens, as well as the Brazilian disc. Research results show that the tensile strength obtained by DTT is smaller than the Brazilian disc and is slightly greater than the intact cylindrical specimen. The flattened cylinder specimen with 0.20 ≤ 2t/D < 0.68 and 0.10 ≤ l/D ≤ 0.20 is recommended to measure the true tensile strength of rock material in DTT. This new shape of the specimen is promising to be extended in the uniaxial or triaxial direct tension test.
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The interactive effects of multiple global change drivers on terrestrial carbon (C) storage remain poorly understood. Here, we synthesise data from 633 published studies to show how the interactive effects of multiple drivers are generally additive (i.e. not differing from the sum of their individual effects) rather than synergistic or antagonistic. We further show that (1) elevated CO2 , warming, N addition, P addition and increased rainfall, all exerted positive individual effects on plant C pools at both single-plant and plant-community levels; (2) plant C pool responses to individual or combined effects of multiple drivers are seldom scale-dependent (i.e. not differing from single-plant to plant-community levels) and (3) soil and microbial biomass C pools are significantly less sensitive than plant C pools to individual or combined effects. We provide a quantitative basis for integrating additive effects of multiple global change drivers into future assessments of the C storage ability of terrestrial ecosystems.
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Sequestro de Carbono , Mudança Climática , Fenômenos Fisiológicos Vegetais , Microbiologia do Solo , Solo/química , Biomassa , Ecossistema , Modelos TeóricosRESUMO
Graves' disease (GD) is a common polygenic multifactorial autoimmune disease. Toll-like receptors (TLRs) play critical roles in the activation of innate and adaptive immune responses. This study investigated the association of TLR7 and TLR8 gene polymorphisms with susceptibility of GD. Five single nucleotide polymorphisms (SNPs), namely, rs179019, rs179010 and rs3853839 in TLR7 and rs3764880 and rs5744088 in TLR8, were evaluated in 332 GD patients and 351 controls using High-Resolution Melting analysis. After adjusting for age, SNP rs179010 was found to decrease the risk of GD in females (OR(T vs C) = 0.64, P = 0.004). In the additive model, the risk of GD decreased significantly as the number of T alleles increased in females [odds ratio (OR) = 0.67 (0.50-0.90), P = 0.007]. The multivariate logistic regression analysis confirmed the independent contribution of rs179010 to the protective effect against GD. This study indicates that rs179010 in TLR7 may be associated with the decreased susceptibility to GD in Chinese Cantonese.
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Doença de Graves/genética , Polimorfismo de Nucleotídeo Único , Receptor 7 Toll-Like/genética , Receptor 8 Toll-Like/genética , Adulto , Povo Asiático , Estudos de Casos e Controles , Análise Mutacional de DNA , Suscetibilidade a Doenças , Feminino , Doença de Graves/etnologia , Doença de Graves/imunologia , Doença de Graves/patologia , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Modelos Genéticos , Desnaturação de Ácido Nucleico , Razão de Chances , Receptor 7 Toll-Like/imunologia , Receptor 8 Toll-Like/imunologiaRESUMO
OBJECTIVE: The present study used the latent profile analysis (LPA) approach to explore the symptom patterns of depression and anxiety among Chinese teachers during COVID-19 and its relationship with fear of COVID-19 and suicidal ideation. METHOD: A sample of 6,121 teachers from primary and secondary schools in a district-level administrative unit in southern China was used. The LPA was employed to identify different symptom patterns of depression and anxiety. We subsequently used logistic regression to analyze the effects of demographic variables on the different profiles. The Bolck-Croon-Hagenaars method assessed the relationships between each profile and fear of COVID-19 and suicidal ideation. RESULTS: The study identified five significant latent profiles and two subtypes in the moderate psychological disorder group. We also found that gender, professional title, and age significantly influenced the distribution of the profiles. The risk for both fear of COVID-19 and suicidal ideation was highest in the severe psychological disorder group. The high anxiety subtype had a significantly greater fear of the new coronavirus epidemic than the high depression subtype, which had a significantly higher level of suicidal ideation than the high anxiety subtype. CONCLUSION: The profiles we identified have distinct features that confirm their unique patterns of symptom endorsement. Our study may have important implications for early warning and intervention in teacher mental health. (PsycInfo Database Record (c) 2024 APA, all rights reserved).
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Benzylamines belong to an important class of building blocks in the synthesis of biologically active natural products and drugs. Encumbered by amide-directed ortho-C-H activation, remote para-selective C-H functionalization of benzylamines has hitherto not been realized to date. Here, we report a palladium-catalyzed para-selective C-H olefination and acetoxylation of benzylamines using a functionalized benzoyl template. Enhancing the coordination strength of the directing group in the template significantly improved the site selectivity of C-H functionalization.