Glioblastoma evolution and heterogeneity from a 3D whole-tumor perspective.

Treatment failure for the lethal brain tumor glioblastoma (GBM) is attributed to intratumoral heterogeneity and tumor evolution. We utilized 3D neuronavigation during surgical resection to acquire samples representing the whole tumor mapped by 3D spatial coordinates. Integrative tissue and single-cell analysis revealed sources of genomic, epigenomic, and microenvironmental intratumoral heterogeneity and their spatial patterning. By distinguishing tumor-wide molecular features from those with regional specificity, we inferred GBM evolutionary trajectories from neurodevelopmental lineage origins and initiating events such as chromothripsis to emergence of genetic subclones and spatially restricted activation of differential tumor and microenvironmental programs in the core, periphery, and contrast-enhancing regions. Our work depicts GBM evolution and heterogeneity from a 3D whole-tumor perspective, highlights potential therapeutic targets that might circumvent heterogeneity-related failures, and establishes an interactive platform enabling 360° visualization and analysis of 3D spatial patterns for user-selected genes, programs, and other features across whole GBM tumors.

Subtype-specific 3D genome alteration in acute myeloid leukaemia.

Acute myeloid leukaemia (AML) represents a set of heterogeneous myeloid malignancies, and hallmarks include mutations in epigenetic modifiers, transcription factors and kinases1-5. The extent to which mutations in AML drive alterations in chromatin 3D structure and contribute to myeloid transformation is unclear. Here we use Hi-C and whole-genome sequencing to analyse 25 samples from patients with AML and 7 samples from healthy donors. Recurrent and subtype-specific alterations in A/B compartments, topologically associating domains and chromatin loops were identified. RNA sequencing, ATAC with sequencing and CUT&Tag for CTCF, H3K27ac and H3K27me3 in the same AML samples also revealed extensive and recurrent AML-specific promoter-enhancer and promoter-silencer loops. We validated the role of repressive loops on their target genes by CRISPR deletion and interference. Structural variation-induced enhancer-hijacking and silencer-hijacking events were further identified in AML samples. Hijacked enhancers play a part in AML cell growth, as demonstrated by CRISPR screening, whereas hijacked silencers have a downregulating role, as evidenced by CRISPR-interference-mediated de-repression. Finally, whole-genome bisulfite sequencing of 20 AML and normal samples revealed the delicate relationship between DNA methylation, CTCF binding and 3D genome structure. Treatment of AML cells with a DNA hypomethylating agent and triple knockdown of DNMT1, DNMT3A and DNMT3B enabled the manipulation of DNA methylation to revert 3D genome organization and gene expression. Overall, this study provides a resource for leukaemia studies and highlights the role of repressive loops and hijacked cis elements in human diseases.

Genome-wide detection of enhancer-hijacking events from chromatin interaction data in rearranged genomes.

Recent efforts have shown that structural variations (SVs) can disrupt three-dimensional genome organization and induce enhancer hijacking, yet no computational tools exist to identify such events from chromatin interaction data. Here, we develop NeoLoopFinder, a computational framework to identify the chromatin interactions induced by SVs, including interchromosomal translocations, large deletions and inversions. Our framework can automatically resolve complex SVs, reconstruct local Hi-C maps surrounding the breakpoints, normalize copy number variation and allele effects and predict chromatin loops induced by SVs. We applied NeoLoopFinder in Hi-C data from 50 cancer cell lines and primary tumors and identified tens of recurrent genes associated with enhancer hijacking. To experimentally validate NeoLoopFinder, we deleted the hijacked enhancers in prostate adenocarcinoma cells using CRISPR-Cas9, which significantly reduced expression of the target oncogene. In summary, NeoLoopFinder enables identification of critical oncogenic regulatory elements that can potentially reveal therapeutic targets.

Synthesis of Bio-Base Fluorescence Carbon Dots for Selective Detection of Tartrazine and Sunset Yellow in Food Samples.

A green, economical and simple method for the preparation of water-soluble, high-fluorescent carbon quantum dots (CQDs) has been developed via hydrothermal process using pomelo peels as carbon source. The synthesized CQDs were characterized by transmission electron microscopy (TEM), X-ray diffraction(XRD), Fourier transform infrared spectroscopy (FTIR), UV - vis absorption spectra and fluorescence spectrophotometer. The results reveal that the as-prepared C-dots were spherical shape with an average diameter of 2.64 nm and emit bright blue photoluminescence (PL) with a quantum yield of approximately 3.63%. The surface of the C-dots was rich in hydroxyl groups and presented various merits including excellent photostability, low toxicity, and satisfactory solubility. Additionally, we found that two widely used synthetic food colorants, tartrazine and sunset yellow, could result in a strong fluorescence quenching of the C-dots, The possible mechanisms are caused by different ratios of inner filter and static quenching effects. According to this property, This study attempts to establish an analytical method for the determination of tartrazine and sunset yellow using carbon quantum dots as fluorescent probe. A linear relationship was found in the range of 0-100 µM tartrazine and sunset yellow with the detection limit(3σ/k) of 0.65 nM and 1.7 nM. The relative standard deviation (RSD) was 3.5% (tartrazine) and 3.0% (sunset yellow).This observation was further successfully applied for the determination of tartrazine and sunset yellow in food samples collected from local markets, and the recovery rates of the two ranges from 79% to 117.8 and 81 -103.5%, respectively. suggesting its great potential toward food routine analysis.

Epigenomics analysis of miRNA cis-regulatory elements in pig muscle and fat tissues.

Although large-scale and accurate identification of cis-regulatory elements on pig protein-coding and long non-coding genes has been reported, similar study on pig miRNAs is still lacking. Here, we systematically characterized the cis-regulatory elements of pig miRNAs in muscle and fat by adopting miRNAomes, ChIP-seq, ATAC-seq, RNA-seq and Hi-C data. In total, the cis-regulatory elements of 257 (85.95%) expressed miRNAs including 226 known and 31 novel miRNAs were identified. Especially, the miRNAs associated with super-enhancers, active promoters, and "A" compartment were significantly higher than those associated by typical enhancers, prompters without H3K27ac, and "B" compartment, respectively. The tissue specific transcription factors were the primary determination of core miRNA expression pattern in muscle and fat. Moreover, the miRNA promoters are more evolutionarily conserved than miRNA enhancers, like other type genes. Our study adds additional important information to existing pig epigenetic data and provides essential resource for future in-depth investigation of pig epigenetics.

Myc-Miz1 signaling promotes self-renewal of leukemia stem cells by repressing Cebpα and Cebpδ.

c-Myc (Myc hereafter) is found to be deregulated and/or amplified in most acute myeloid leukemias (AMLs). Almost all AML cells are dependent upon Myc for their proliferation and survival. Thus, Myc has been proposed as a critical anti-AML target. Myc has Max-mediated transactivational and Myc-interacting zinc finger protein 1 (Miz1)-mediated transrepressional activities. The role of Myc-Max-mediated transactivation in the pathogenesis of AML has been well studied; however, the role of Myc-Miz1-mediated transrepression in AML is still somewhat obscure. Myc protein harboring a V394D mutation (MycV394D) is a mutant form of Myc that lacks transrepressional activity due to a defect in its ability to interact with Miz1. We found that, compared with Myc, the oncogenic function of MycV394D is significantly impaired. The AML/myeloproliferative disorder that develops in mice receiving MycV394D-transduced hematopoietic stem/progenitor cells (HSPCs) is significantly delayed compared with mice receiving Myc-transduced HSPCs. Using a murine MLL-AF9 AML model, we found that AML cells expressing MycV394D (intrinsic Myc deleted) are partially differentiated and show reductions in both colony-forming ability in vitro and leukemogenic capacity in vivo. The reduced frequency of leukemia stem cells (LSCs) among MycV394D-AML cells and their reduced leukemogenic capacity during serial transplantation suggest that Myc-Miz1 interaction is required for the self-renewal of LSCs. In addition, we found that MycV394D-AML cells are more sensitive to chemotherapy than are Myc-AML cells. Mechanistically, we found that Myc represses Miz1-mediated expression of CCAAT/enhancer-binding protein α (Cebpα) and Cebpδ, thus playing an important role in the pathogenesis of AML by maintaining the undifferentiated state and self-renewal capacity of LSCs.

Real scene acquisition and holographic near-eye display system based on a zoom industrial endoscope.

In this paper, we propose a real scene acquisition and holographic near-eye display system based on a zoom industrial endoscope. By controlling the driving current of the liquid lens, the working distance and focal length of the zoom industrial endoscope can be tuned accordingly. Thus, the object at different depths can be captured. Then, the sub-sampling algorithm is used to generate the hologram. By adjusting the hologram sampling rate of the objects with different depths, the holographic near-eye 3D display can be realized. Experimental results demonstrate that the working distance of the zoom industrial endoscope can be tuned from 20 mm to 200 mm with the driving current changing from 80 mA to 190 mA. With the proposed system, the human eye can intuitively see the depth relationships among the real objects. The proposed system is expected to be applied to 3D display and industrial inspection fields.

[Material basis and molecular mechanism of Angelicae Sinensis Radix in activating blood:based on computer-aided drug design].

Angelicae Sinensis Radix excels in activating blood, but the scientific mechanism has not been systematically analyzed, thus limiting the development of the medicinal. This study employed the computer-aided drug design methods, such as structural similarity-based target reverse prediction, complex network analysis, molecular docking, binding free energy calculation, cluster analysis, and ADMET(absorption, distribution, metabolism, excretion, toxicity) calculation, and enzyme activity assay in vitro, to explore the components and mechanism of Angelicae Sinensis Radix in activating blood. Target reverse prediction and complex network analysis yielded 40 potential anticoagulant targets of the medicinal. Gene Ontology(GO) term enrichment and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analysis indicated that the targets mainly acted on the complement and coagulation cascade signaling pathway to exert the anticoagulant function. Among them, the key enzymes thrombin(THR) and coagulation factor Xa(FXa) in coagulation cascade and thrombosis were the drug targets for thromboembolic diseases. At the same time, molecular docking and cluster analysis showed that the medicinal had high selectivity for FXa. According to binding free energy score, 8 potential active components were selected for enzyme activity assay in vitro. The results demonstrated that 8 components inhibited THR and FXa, and the inhibition was stronger on FXa than on THR. The pharmacophore model of 8 active compounds was constructed, which suggested that the components had the common pharmacophore AAHH. The ADMET calculation result indicated that they had good pharmacokinetic properties and were safe. Based on target reverse prediction, complex network analysis, molecular docking and binding free energy calculation, anticoagulant activity in vitro, spatial binding conformation of molecules and targets, pharmacophore model construction, and ADMET calculation, this study preliminarily clarified the material basis and molecular mechanism of Angelicae Sinensis Radix in activating blood from the perspective of big data, and calculated the pharmacology and toxicology parameters of the active components. Our study, for the first time, revealed that the medicinal had obvious selectivity and pertinence for different coagulation proteins, reflecting the unique effect of different Chinese medicinals and the biological basis. Therefore, this study can provide clues for precision application of Angelicae Sinensis Radix and the development of the blood-activating components with modern technology.

In Vitro and In Vivo Evaluation of SP94 Modified Liposomes Loaded with N-14NCTDA, a Norcantharimide Derivative for Hepatocellular Carcinoma-Targeting.

The purpose of this research is to develop a liposomal drug delivery system, which can selectively target hepatocellular carcinoma (HCC) to deliver the antitumor agent N-14NCTDA, a C14 alkyl chain norcantharimide derivative of norcantharidin. N-14NCTDA-loaded liposomes were successfully prepared by lipid membrane hydration and extrusion methods. SP94, a targeting peptide for HCC cells, was attached to the liposomes loaded with N-14NCTDA by the post-insertion method to obtain SP94 modified liposomes (SP94-LPs). SP94-LPs had a significant cytotoxicity against Hep G2 cells with the IC50 of 15.395 ± 0.89 µg/mL, which is lower than that of NCTD-S (IC50 = 20.863 ± 0.56 µg/mL) and GAL-LPs (IC50 = 24.589 ± 1.02 µg/mL). Compared with conventional liposomes (Con-LPs), SP94-LPs showed greater cellular uptake in Hep G2 cells. Likewise, significant tumor suppression was achieved in H22 tumor-bearing mice which were treated with SP94-LPs. The tumor inhibition rate (IRw) of SP94-LPs was 82 ± 0.98%, obviously higher than that of GAL-LPs (69 ± 1.39%), Con-LPs (60 ± 2.78%), and NCTD-S (51 ± 3.67%). SP94-LPs exhibited a significant hepatocellular carcinoma-targeting activity in vitro and in vivo, which will provide a new alternative for hepatocellular carcinoma treatment in future. Graphical Abstract.

Role of PGC-1α in Mitochondrial Quality Control in Neurodegenerative Diseases.

As one of the major cell organelles responsible for ATP production, it is important that neurons maintain mitochondria with structural and functional integrity; this is especially true for neurons with high metabolic requirements. When mitochondrial damage occurs, mitochondria are able to maintain a steady state of functioning through molecular and organellar quality control, thus ensuring neuronal function. And when mitochondrial quality control (MQC) fails, mitochondria mediate apoptosis. An apparently key molecule in MQC is the transcriptional coactivator peroxisome proliferator activated receptor γ coactivator-1α (PGC-1α). Recent findings have demonstrated that upregulation of PGC-1α expression in neurons can modulate MQC to prevent mitochondrial dysfunction in certain in vivo and in vitro aging or neurodegenerative encephalopathy models, such as Huntington's disease, Alzheimer's disease, and Parkinson's disease. Because mitochondrial function and quality control disorders are the basis of pathogenesis in almost all neurodegenerative diseases (NDDs), the role of PGC-1α may make it a viable entry point for the treatment of such diseases. This review focuses on multi-level MQC in neurons, as well as the regulation of MQC by PGC-1α in these major NDDs.

Climate change risk perception in global: Correlation with petroleum and liver disease: A meta-analysis.

BACKGROUND: Liver diseases have been bound to environmental factors, inclusive of air pollution. The exposure of workers to petrochemicals counts as a possible cause of Liver diseases, whereas results are inconsistent with the previous studies. In this study, a meta-analysis is conducted to assess the pooled risk. METHODS AND FINDING: A systematic search was performed by related researchers. Correlations are analyzed among petroleum and liver cirrhosis mortality, fatty liver, alanine amino transferase (abbreviated as ALT), aspartate amino transferase (abbreviated as AST). Pooled risk ratios (RR) with 95% confidence interval (CI) and effect size(ES) with 95% confidence interval are calculated. Sensitivity analysis and publication bias are also tested. Data are analyzed from 5 studies involving 296 participants. Results are incorporated through adopting a random effects meta-analysis. Working in a petrochemical plant shall not increase the death risk posed by cirrhosis (RR = 0.44, 95% CI [0.36; 0.54]). Yet the incidence of fatty liver increases (RR = 1.22, 95% CI [1.21; 1.23]). Abnormal incidence of ALT and AST also increases. CONCLUSIONS: Occupational exposure plays an important role in causing ALT abnormalities and fatty liver among oil workers, but not a risk factor of cirrhosis, AST abnormalities and liver cancer.

Comparative skin histological and transcriptomic analysis of Rana kukunoris with two different skin colors.

This study compares the skin structures of Rana kukunoris with two different skin colors living in the same area of Haibei in the Northeastern Qinghai-Tibet Plateau. The skin thickness of the khaki R. kukunoris was significantly greater than that of the brown R. kukunoris (P < 0.01), and significantly more mucous and granular glands were present on the dorsal skin of the khaki frog (P < 0.05). Meanwhile, the melanocytes on the dorsal skin of the brown frog were significantly larger than those on the khaki one (P < 0.05). Morphological changes in the expansion and aggregation of melanocytes seemed to deepen the skin color of R. kukunoris. Moreover, transcriptome sequencing identified tyrosine metabolism, melanogenesis, and riboflavin metabolism as the main pathways involved in melanin formation and metabolism in brown R. kukunoris. TYR, MC1R was upregulated as the skin color of R. kukunoris was deepened and contributed to melanin production and metabolism. In contrast, the khaki frog had significantly more upregulated genes and metabolic pathways related to autoimmunity. The khaki frog appeared to defend against ultraviolet (UV) radiation-induced damage by secreting mucus and small molecular peptides, whereas the brown frog protected itself by distributing a large amount of melanin. Hence, the different skin colors of R. kukunoris might represent different adaptation strategies for survival in the intense UV radiation environment of the Qinghai-Tibet Plateau.

Suicide attempt and suicidal ideation and their associations with demographic and clinical correlates and quality of life in Chinese schizophrenia patients.

OBJECTIVES: This study aimed to examine the prevalence and correlates of lifetime suicide attempts and current suicidal ideation in community-dwelling schizophrenia patients in China. METHOD: A sample of 540 schizophrenia patients was randomly selected in Beijing, China. All subjects were interviewed using standardized assessment instruments and their basic socio-demographic and clinical data including history of suicide attempts were collected. RESULTS: The prevalence of lifetime suicide attempts and the point prevalence of suicidal ideation were 12.0%, and 21.1%, respectively. In multiple logistic regression analyses, the presence of lifetime suicide attempt was independently associated with rural residence, having major medical conditions and better social functioning, while higher likelihood of current suicidal ideation was associated with past suicide attempt, the severity of overall psychopathology and depressive symptoms and lower psychological quality of life (QOL). CONCLUSION: Among Chinese outpatients with schizophrenia, increased current symptoms and poorer QOL were correlated with current suicidal ideation, while demographic factors and indicators of greater social support were mostly correlated with lifetime suicide attempts. This study may help to identify important subgroups of patients with schizophrenia at particularly high risk of suicidal behavior.

Targeting CHAF1B Enhances IFN Activity against Myeloproliferative Neoplasm Cells.

Interferons (IFNs) are cytokines with potent antineoplastic and antiviral properties. IFNα has significant clinical activity in the treatment of myeloproliferative neoplasms (MPN), but the precise mechanisms by which it acts are not well understood. Here, we demonstrate that chromatin assembly factor 1 subunit B (CHAF1B), an Unc-51-like kinase 1 (ULK1)-interactive protein in the nuclear compartment of malignant cells, is overexpressed in patients with MPN. Remarkably, targeted silencing of CHAF1B enhances transcription of IFNα-stimulated genes and promotes IFNα-dependent antineoplastic responses in primary MPN progenitor cells. Taken together, our findings indicate that CHAF1B is a promising newly identified therapeutic target in MPN and that CHAF1B inhibition in combination with IFNα therapy might offer a novel strategy for treating patients with MPN. Significance: Our findings raise the potential for clinical development of drugs targeting CHAF1B to enhance IFN antitumor responses in the treatment of patients with MPN and should have important clinical translational implications for the treatment of MPN and possibly in other malignancies.

Quality of life in community-dwelling patients with schizophrenia in China.

The aim of this study was to assess Chinese schizophrenia patients' quality of life (QOL) and identify its demographic and clinical correlates. A random sample of 540 community-dwelling schizophrenia patients was interviewed using standardized assessment instruments. The patients' basic sociodemographic and clinical data and QOL were collected. Compared with the general population, patients had significantly lower scores in the physical and psychological QOL domains. Multivariate analyses showed that better social support independently predicted higher QOL in all domains, whereas more severe positive symptoms predicted worse psychological and environmental domains. Overall psychopathology predicted both worse physical and psychological domains; depressive symptoms and being married predicted worse physical and social QOL, respectively. Our results suggest that therapeutic and psychosocial interventions alleviating positive and depressive symptoms and improving poor social support and marriage-related problems in Chinese patients with schizophrenia might be of considerable benefit in improving their QOL.

Chromatin reconstruction during mouse terminal erythropoiesis.

Mammalian terminal erythropoiesis involves chromatin and nuclear condensation followed by enucleation. Late-stage erythroblasts undergo caspase-mediated nuclear opening that is important for nuclear condensation through partial histone release. It remains unknown the dynamic changes of three-dimensional (3D) genomic organization during terminal erythropoiesis. Here, we used Hi-C to determine the chromatin structural change during primary mouse erythroblast terminal differentiation. We also performed RNA-sequencing and ATAC-sequencing under the same experimental setting to further reveal the genome accessibility and gene expression changes during this process. We found that late-stage terminal erythropoiesis involves global loss of topologically associating domains and establishment of inter-chromosomal interactions of the heterochromatin regions, which are associated with globally increased chromatin accessibility and upregulation of erythroid-related genes.

Design and synthesis of hierarchical MnO2 nanospheres/carbon nanotubes/conducting polymer ternary composite for high performance electrochemical electrodes.

For efficient use of metal oxides, such as MnO(2) and RuO(2), in pseudocapacitors and other electrochemical applications, the poor conductivity of the metal oxide is a major problem. To tackle the problem, we have designed a ternary nanocomposite film composed of metal oxide (MnO(2)), carbon nanotube (CNT), and conducting polymer (CP). Each component in the MnO(2)/CNT/CP film provides unique and critical function to achieve optimized electrochemical properties. The electrochemical performance of the film is evaluated by cyclic voltammetry, and constant-current charge/discharge cycling techniques. Specific capacitance (SC) of the ternary composite electrode can reach 427 F/g. Even at high mass loading and high concentration of MnO(2) (60%), the film still showed SC value as high as 200 F/g. The electrode also exhibited excellent charge/discharge rate and good cycling stability, retaining over 99% of its initial charge after 1000 cycles. The results demonstrated that MnO(2) is effectively utilized with assistance of other components (fFWNTs and poly(3,4-ethylenedioxythiophene)-poly(styrenesulfonate) in the electrode. Such ternary composite is very promising for the next generation high performance electrochemical supercapacitors.

Ru-catalysed C(sp2)-H vinylation/annulation of benzoic acids and alkynes: rapid access to medium-sized lactones.

An unprecedented ruthenium catalysed [4+4] annulation of readily available benzoic acids and alkynes is reported for the first time. The carboxylate group acts as both a directing group and an internal nucleophilic reagent to facilitate a C(sp2)-H vinylation/annulation cascade. This reaction avoids the classically oxidative [4+2] annulation, allowing the efficient synthesis of a wide array of eight-membered lactones under oxidant-free conditions. Moreover, this catalytic system can be successfully extended to [4+3] and [4+5] annulations for the assembly of seven- and nine-membered lactones.

Merging C-H Activation and Strain-Release in Ruthenium-Catalyzed Isoindolinone Synthesis.

The merger of strain-release of 1,2-oxazetidines with carboxylic acid directed C-H activation in catalytic synthesis of isoindolinones is reported for the first time. This reaction opens a new and sustainable avenue to prepare a range of structurally diverse isoindolinone skeletons from readily available benzoic acids. The success of late-stage functionalization of some bioactive acids, and concise synthesis of biologically important skeletons demonstrated its great synthetic potential in drug discovery. Mechanistic studies indicated a plausible C-H activation/ß-carbon elimination/intramolecular cyclization cascade pathway.

Epigenomic landscape and 3D genome structure in pediatric high-grade glioma.

Pediatric high-grade gliomas (pHGGs), including glioblastoma multiforme (GBM) and diffuse intrinsic pontine glioma (DIPG), are morbid brain tumors. Even with treatment survival is poor, making pHGG the number one cause of cancer death in children. Up to 80% of DIPGs harbor a somatic missense mutation in genes encoding histone H3. To investigate whether H3K27M is associated with distinct chromatin structure that alters transcription regulation, we generated the first high-resolution Hi-C maps of pHGG cell lines and tumor tissue. By integrating transcriptome (RNA-seq), enhancer landscape (ChIP-seq), genome structure (Hi-C), and chromatin accessibility (ATAC-seq) datasets from H3K27M and wild-type specimens, we identified tumor-specific enhancers and regulatory networks for known oncogenes. We identified genomic structural variations that lead to potential enhancer hijacking and gene coamplification, including A2M, JAG2, and FLRT1 Together, our results imply three-dimensional genome alterations may play a critical role in the pHGG epigenetic landscape and contribute to tumorigenesis.