We studied how intratumoral genetic heterogeneity shapes tumor growth and therapy response for isocitrate dehydrogenase (IDH)-wild-type glioblastoma, a rapidly regrowing tumor. We inferred the ...evolutionary trajectories of matched pairs of primary and relapsed tumors based on deep whole-genome-sequencing data. This analysis suggests both a distant origin of de novo glioblastoma, up to 7 years before diagnosis, and a common path of early tumorigenesis, with one or more of chromosome 7 gain, 9p loss, or 10 loss, at tumor initiation. TERT promoter mutations often occurred later as a prerequisite for rapid growth. In contrast to this common early path, relapsed tumors acquired no stereotypical pattern of mutations and typically regrew from oligoclonal origins, suggesting sparse selective pressure by therapeutic measures.
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•We inferred evolutionary trajectories of pairs of primary/relapsed glioblastomas•Chromosome 7 gain, 9p loss, or 10 loss commonly occurred at tumor initiation•TERT promoter mutations often occurred later as a prerequisite for rapid growth•Relapsed tumors typically regrew from oligoclonal origins
By analyzing 21 paired primary and locally relapsed IDH-wild-type glioblastomas (GBM), Körber et al. show that most GBM initiate by gains and losses of specific chromosomes; TERT promoter mutations often occur later as a prerequisite for rapid growth, and relapsed GBM acquire few stereotypical mutations.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
With the rapid development of the Chinese economy, the demand for resources has increased significantly, putting the environment under increasing pressure. Effectively using various resources has ...become crucial. This study employs the Super-Efficiency Data Envelopment Analysis to assess ecological efficiency during the same period and conducts a residual analysis on cities with high efficiency but not efficiently analyzed by Data Envelopment Analysis. The primary objective of this approach is to investigate the potential ecological development of these regions. The dynamic assessment of ecological efficiency is done using the Malmquist index, which takes into account changes in the total factor output growth rate. To investigate factors that affect ecological efficiency and their magnitudes, a Tobit model is being established using panel data. From 2017 to 2022, there were changes in ecological benefits among cities in Zhejiang Province due to intense competition between high-efficiency cities and frequent position changes, as evidenced by the results. The gap between cities with middle to low efficiency is narrowing, which suggests that ecological benefits are being balanced in the province despite a decreasing trend. Both the degree of openness and the proportion of asset investment have a significant and positive impact on ecological efficiency. Enhancing interregional communication, optimizing resource allocation, increasing openness, and adjusting industrial layout is essential to sustain technological innovation and progress.
Adverse early life events can induce long-lasting changes in physiology and behavior. We found that early-life stress (ELS) in mice caused enduring hypersecretion of corticosterone and alterations in ...passive stress coping and memory. This phenotype was accompanied by a persistent increase in arginine vasopressin (AVP) expression in neurons of the hypothalamic paraventricular nucleus and was reversed by an AVP receptor antagonist. Altered Avp expression was associated with sustained DNA hypomethylation of an important regulatory region that resisted age-related drifts in methylation and centered on those CpG residues that serve as DNA-binding sites for the methyl CpG-binding protein 2 (MeCP2). We found that neuronal activity controlled the ability of MeCP2 to regulate activity-dependent transcription of the Avp gene and induced epigenetic marking. Thus, ELS can dynamically control DNA methylation in postmitotic neurons to generate stable changes in Avp expression that trigger neuroendocrine and behavioral alterations that are frequent features in depression.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Early-life stress (ELS) increases the vulnerability thresholds for stress-related diseases such as major depression and anxiety by inducing alterations in the structure and function of neural ...circuits and endocrine pathways. We previously demonstrated the contribution of epigenetic mechanisms to the long-term programming of the hypothalamo-pituitary-adrenal axis activity following ELS exposure in male mice. Here, ELS comprising daily separation of pups from their dams on postnatal days 1–10 was observed to up-regulate the expression of the pituitary proopiomelanocortin (Pomc) gene; POMC serves as a prohormone for ACTH, a key mediator of the adrenocortical response to stress. Detailed analysis revealed that the increase in Pomc mRNA levels results from a reduction in DNA methylation at a critical regulatory region of the Pomc gene; interestingly, this change occurs with some delay after ELS and persists for up to 1 year. Using a Pomc-expressing pituitary cell line (AtT20), we confirmed a role for DNA methylation in restraining Pomc expression under resting conditions: specifically, we show that CpG site-specific methylation of the Pomc promoter represses Pomc mRNA transcription. Further, we show high-affinity binding of methyl-CpG binding protein-2 to the distal promoter of Pomc, suggesting that methyl-CpG binding protein-2 acts in association with the chromatin modifiers histone deacetylase 2 and DNA methyltransferase 1 to repress Pomc gene expression. Collectively, these experiments contribute to our understanding of the mechanisms through which environmental cues are translated into stable changes (“cellular memory”) in neuroendocrine cells.
Glioblastoma frequently exhibits therapy-associated subtype transitions to mesenchymal phenotypes with adverse prognosis. Here, we perform multi-omic profiling of 60 glioblastoma primary tumours and ...use orthogonal analysis of chromatin and RNA-derived gene regulatory networks to identify 38 subtype master regulators, whose cell population-specific activities we further map in published single-cell RNA sequencing data. These analyses identify the oligodendrocyte precursor marker and chromatin modifier SOX10 as a master regulator in RTK I-subtype tumours. In vitro functional studies demonstrate that SOX10 loss causes a subtype switch analogous to the proneural-mesenchymal transition observed in patients at the transcriptomic, epigenetic and phenotypic levels. SOX10 repression in an in vivo syngeneic graft glioblastoma mouse model results in increased tumour invasion, immune cell infiltration and significantly reduced survival, reminiscent of progressive human glioblastoma. These results identify SOX10 as a bona fide master regulator of the RTK I subtype, with both tumour cell-intrinsic and microenvironmental effects.
Three-dimensional (3D) design can improve students' spatial ability, but the research on the differences of spatial ability development after 3D design training for students with different initial ...spatial ability is not unified. The ability-as-enhancer hypothesis and the ability-as-compensator hypothesis explain the performance differences of students with different initial spatial abilities in different situations. However, the existing research has not formed a consistent conclusion, which makes students lack of fine guidance, and it is difficult to achieve good spatial ability training effect. This study first explored the differences of students' performance under different educational interventions, and verified the value of process data in the cultivation of spatial ability. Then, we collected more students' data, discussed the improvement of students' spatial ability by 3D design with different initial spatial ability, and tried to explain the difference of students' performance by students' 3D design behavior. We found that different educational interventions can affect students' task participation, and then the effect of spatial ability training. Students with different initial spatial abilities still have significant differences in spatial ability after 3D design, but there is no significant difference in the improvement of spatial ability, and no difference in the data of 3D design operation process. Through cluster analysis, this study also found five types of students in the process of 3D design. There are significant differences in the pre-test, post-test only among some types of students. This study provides a reference for the training effect evaluation of students with different initial spatial abilities.
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BFBNIB, DOBA, IZUM, KILJ, NMLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Juglone has been extensively reported as a natural antitumor pigment. However, it is easy to be oxidized due to active hydroxy in the quinone. Here, we designed some new juglone derivatives, as the ...hydroxy was replaced by methyl (D1), allyl (D2), butyl (D3), and benzyl (D4) groups. Nuclear magnetic resonance spectra and mass spectrometry were applied to confirm the derivatives and oxidative products of juglone. U87 and U251 cell lines were used for tests
in vitro
, and primary human glioblastoma cells were applied for
in vivo
experiments. The CCK8 and EdU assay demonstrated the anti-tumor effect of the four derivatives, and IC50 for U87 was 3.99, 3.28, 7.60, and 11.84 μM, respectively. In U251, IC50 was 7.00, 5.43, 8.64, and 18.05 μM, respectively. D2 and D3 were further selected, and flow cytometry showed that apoptosis rates were increased after D2 or D3 treatment via ROS generation. Potential targets were predicted by network pharmacology analysis, most of which were associated with apoptosis, cell cycle, and metabolism pathway. CDC25B and DUSP1 were two of the most likely candidates for targets. The orthotopic glioblastoma model was established to evaluate the anti-glioma effect and side-effect of juglone derivatives, and the
in vivo
experiments confirmed the anti-glioma effects of juglone derivatives. In conclusion, new derivatives of juglone were created via chemical group substitution and could inhibit glioma cell viability and proliferation and induce apoptosis rate
via
ROS generation.
Regulation of gene expression through multiple epigenetic components is a highly combinatorial process. Alterations in any of these layers, as is commonly found in cancer diseases, can lead to a ...cascade of downstream effects on tumor suppressor or oncogenes. Hence, deciphering the effects of epigenetic alterations on regulatory elements requires innovative computational approaches that can benefit from the huge amounts of epigenomic datasets that are available from multiple consortia, such as Roadmap or BluePrint. We developed a software tool named IRENE (Integrative Ranking of Epigenetic Network of Enhancers), which performs quantitative analyses on differential epigenetic modifications through an integrated, network-based approach. The method takes into account the additive effect of alterations on multiple regulatory elements of a gene. Applying this tool to well-characterized test cases, it successfully found many known cancer genes from publicly available cancer epigenome datasets.
Early-life stress induces persistent memory traces on our genes and programs the life-long risk for depression. Epigenetic marking of the arginine vasopressin (AVP) gene by early-life stress in mice ...underpins sustained expression and increased hypothalamic-pituitary-adrenal axis activity, triggering endocrine and behavioral alterations that are frequent features in depression. This epigenetic memory evolves in two steps coordinated by the epigenetic reader and writer MeCP2. While early derepression of AVP is driven by neuronal activity causing Ca2+/calmodulin kinase-dependent phosphorylation and dissociation of MeCP2, subsequent hypomethylation at the AVP enhancer gradually develops to sustain derepression. In a vicious circle MeCP2 occupancy uncouples from the initial stimulus and leads to the hard-coding of early-life experience at the level of DNA methylation. The sequential order of these events demarcates the transition from a preliminary to a persistent, possibly irreversible, epigenetic memory and thus defines a critical time window for the timely therapy of severe trauma.
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BFBNIB, GIS, IJS, KISLJ, NUK, PNG, UL, UM, UPUK
In this work, a promising dual-gated thin film transistor (TFT) structure has been proposed and introduced in the shift register (SR)-integrated circuits to reduce the rising time. The threshold ...voltage can be simultaneously changed by the top gate and the bottom gate in the proposed dual-gated TFTs. When the SR circuits start to export the scan signals in the displays, the driving currents in the SR circuits are increased by switching the working station of driving TFTs from the enhancement characterization to the depletion characterization. Subsequently, the detailed smart spice simulation has been used to study the function of the proposed SR circuits. In the next step, the proposed SR circuits have been fabricated in a G4.5 active-matrix organic light-emitting diode manufacture factory. The simulated and experimental results indicate that the shift register pulses with the full swing amplitude can be obtained in the SR circuits. Moreover, in contrast to the conventional SR circuits employing with the single-gated TFTs, it has been found that the rising time of the output signals can be reduced from 3.75 μs to 1.23 μs in the proposed SR circuits with the dual-gated TFTs, thus exhibiting the significant improvement of the driving force in the proposed SR circuits. Finally, we demonstrated a 31-inch 4K AMOLED display with the proposed SR circuits.
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