Long-read transcriptome landscapes of primary and metastatic liver cancers at transcript resolution.

BACKGROUND: The liver ranks as the sixth most prevalent site of primary cancer in humans, and it frequently experiences metastases from cancers originating in other organs. To facilitate the development of effective treatments and improve survival rates, it is crucial to comprehend the intricate and diverse transcriptome landscape of primary and metastatic liver cancers. METHODS: We conducted long-read isoform sequencing and short-read RNA sequencing using a cohort of 95 patients with primary and secondary liver cancer who underwent hepatic resection. We compared the transcriptome landscapes of primary and metastatic liver cancers and systematically investigated hepatocellular carcinoma (HCC), paired primary tumours and liver metastases, and matched nontumour liver tissues. RESULTS: We elucidated the full-length isoform-level transcriptome of primary and metastatic liver cancers in humans. Our analysis revealed isoform-level diversity in HCC and identified transcriptome variations associated with liver metastatis. Specific RNA transcripts and isoform switching events with clinical implications were profound in liver cancer. Moreover, we defined metastasis-specific transcripts that may serve as predictors of risk of metastasis. Additionally, we observed abnormalities in adjacent paracancerous liver tissues and characterized the immunological and metabolic alterations occurring in the liver. CONCLUSIONS: Our findings underscore the power of full-length transcriptome profiling in providing novel biological insights into the molecular mechanisms underlying tumourigenesis. These insights will further contribute to improving treatment strategies for primary and metastatic liver cancers.

MicroRNA-148a-3p suppresses the glycolysis and Cell proliferation by targeting transmembrane protein 54 in liver cancer.

Liver cancer is the fourth most lethal cancer, but the treatment options for liver cancer are usually limited. Metabolic reprogramming is a hallmark of malignancy, ensuring activated cell glycolysis and increased macromolecular precursors required for the proliferation and migration of exuberant cancer cells. MicroRNAs (miRNAs) have been reported to participate in cancer metabolic shifts mainly by directly silencing the expression of specific genes. Here, we identified miR-148a-3p as a negative regulator for glycometabolism and cell proliferation in liver cancer. miR-148a-3p directly targets the 3'UTR of transmembrane protein 54 (TMEM54), leading to the significant inhibition of lactate production, glucose consumption, intracellular ATP level and extracellular acidification rate (ECAR), as well as the repression of the proliferation and colony formation ability of liver cancer cells. miR-148a-3p expression is often down-regulated in liver cancer tissues. In addition, there was a negative correlation between the expression levels of miR-148a-3p and TMEM54 in liver cancer tissues. Moreover, the low miR-148a-3p expression levels or high TMEM54 expression levels were associated with poorer prognosis in hepatocellular carcinoma (HCC) patients. Together, these findings support that the miR-148a-3p/TMEM54 regulatory pathway regulates the glycometabolism and cell proliferation in liver cancer, which is a possible target for the diagnosis and treatment of liver cancer.

FLIBase: a comprehensive repository of full-length isoforms across human cancers and tissues.

Regulatory processes at the RNA transcript level play a crucial role in generating transcriptome diversity and proteome composition in human cells, impacting both physiological and pathological states. This study introduces FLIBase (www.FLIBase.org), a specialized database that focuses on annotating full-length isoforms using long-read sequencing techniques. We collected and integrated long-read (351 samples) and short-read (12 469 samples) RNA sequencing data from diverse normal and cancerous human tissues and cells. The current version of FLIBase comprises a total of 983 789 full-length spliced isoforms, identified through long-read sequences and verified using short-read exon-exon splice junctions. Of these, 188 248 isoforms have been annotated, while 795 541 isoforms remain unannotated. By overcoming the limitations of short-read RNA sequencing methods, FLIBase provides an accurate and comprehensive representation of full-length transcripts. These comprehensive annotations empower researchers to undertake various downstream analyses and investigations. Importantly, FLIBase exhibits a significant advantage in identifying a substantial number of previously unannotated isoforms and tumor-specific RNA transcripts. These tumor-specific RNA transcripts have the potential to serve as a source of immunogenic recurrent neoantigens. This remarkable discovery holds tremendous promise for advancing the development of tailored RNA-based diagnostic and therapeutic strategies for various types of human cancer.

Metagenomic analyses reveal microbial communities and functional differences between Daqu from seven provinces.

Microbial communities perform the brewing function in Daqu. Macrogenomics and PICRUST II analyses revealed the differences in microbes and metabolic functions among Daqu from the seven Baijiu-producing provinces. Jiang-flavored Daqu (Guizhou, Shandong, and Hubei provinces) generally forms an aroma-producing functional microbiota with Kroppenstedtia, Bacillus, Thermoascus, Virgibacillus, and Thermomyces as the core, which promotes the metabolism of various amino acids and aroma compounds. Light-flavored Daqu (Shanxi Province) enriched the Saccharomycopsis, Saccharomyces, and lactic acid bacteria (LAB) microbiota through low-temperature fermentation. These microbes can synthesize alcohol and lactic acid but inhibit amino acid metabolism within the Light-flavored Daqu. Bifidobacterium and Saccharomycopsis were dominant in the Tao-flavored Daqu (Henan province). This unique microbial structure is beneficial for pyruvate fermentation to lactate. Research also found that Strong-flavored Daqu from Jiangsu and Sichuan provinces differed significantly. The microbial communities and metabolic pathways within Jiangsu Daqu were similar to those within Jiang-flavored Daqu, but Sichuan Daqu was dominated by Thermoascus, LAB, and Thermoactinomyces. In addition, Spearman correlation analysis indicated that Kroppenstedtia, Bacillus, and Thermomyces were not only positively related to flavor metabolism but also negatively correlated with Saccharomycopsis. This research will help establish a systematic understanding of the microbial community and functional characteristics in Daqu.

Aldolase A Accelerates Cancer Progression by Modulating mRNA Translation and Protein Biosynthesis via Noncanonical Mechanisms.

Aldolase A (ALDOA), a crucial glycolytic enzyme, is often aberrantly expressed in various types of cancer. Although ALDOA has been reported to play additional roles beyond its conventional enzymatic role, its nonmetabolic function and underlying mechanism in cancer progression remain elusive. Here, it is shown that ALDOA promotes liver cancer growth and metastasis by accelerating mRNA translation independent of its catalytic activity. Mechanistically, ALDOA interacted with insulin- like growth factor 2 mRNA-binding protein 1 (IGF2BP1) to facilitate its binding to m6 A-modified eIF4G mRNA, thereby increasing eIF4G protein levels and subsequently enhancing overall protein biosynthesis in cells. Importantly, administration of GalNAc-conjugated siRNA targeting ALDOA effectively slows the tumor growth of orthotopic xenografts. Collectively, these findings uncover a previously unappreciated nonmetabolic function of ALDOA in modulating mRNA translation and highlight the potential of specifically targeting ALDOA as a prospective therapeutic strategy in liver cancer.

An ultrasensitive label-free electrochemical aptasensing platform for thiamethoxam detection based on ZIF-67 derived Co-N doped porous carbon.

Herein, a new electrochemical aptasensor was developed for the highly selective and sensitive detection of thiamethoxam (TMX). Co-N doped porous carbon (CoNC) was first modified on the glassy carbon electrode (GCE) as a conductive substrate. Then, nickel hexacyanoferrate nanoparticles (NiHCFNPs) were drop-coated on CoNC as signal probes to generate measurable redox peaks. Benefiting from the superior structural features and catalytic activity, CoNC not only facilitated the immobilization of NiHCFNPs, but also exhibited good catalytic activity for the redox of NiHCFNPs, thus clearly amplifying the sensing signal. Subsequently, gold nanoparticles (AuNPs) were deposited on NiHCFNPs/CoNC/GCE to anchor the aptamer of TMX. When TMX was captured onto the sensor via specific affinity of the aptamer, the formed TMX-Apt complex impeded electron transfer, resulting in a decrease in the peak current. Thus, TMX can be easily detected by measuring the change in peak current. The label-free aptasensor displays high sensitivity to TMX with a quite low LOD of 3.65 × 10-3 µg/L. The acceptable recoveries of environmental water and potato samples varied from 94.05 % to 105.20 %, demonstrating the proposed aptasensor will be a promising tool for the highly sensitive, specific and reliable detection of TMX in both environmental and food matrices.

Brain region-specific synaptic function of FUS underlies the FTLD-linked behavioural disinhibition.

Synaptic dysfunction is one of the earliest pathological processes that contribute to the development of many neurological disorders, including Alzheimer's disease and frontotemporal lobar degeneration. However, the synaptic function of many disease-causative genes and their contribution to the pathogenesis of the related diseases remain unclear. In this study, we investigated the synaptic role of fused in sarcoma, an RNA-binding protein linked to frontotemporal lobar degeneration and amyotrophic lateral sclerosis, and its potential pathological role in frontotemporal lobar degeneration using pyramidal neuron-specific conditional knockout mice (FuscKO). We found that FUS regulates the expression of many genes associated with synaptic function in a hippocampal subregion-specific manner, concomitant with the frontotemporal lobar degeneration-linked behavioural disinhibition. Electrophysiological study and molecular pathway analyses further reveal that fused in sarcoma differentially regulates synaptic and neuronal properties in the ventral hippocampus and medial prefrontal cortex, respectively. Moreover, fused in sarcoma selectively modulates the ventral hippocampus-prefrontal cortex projection, which is known to mediate the anxiety-like behaviour. Our findings unveil the brain region- and synapse-specific role of fused in sarcoma, whose impairment might lead to the emotional symptoms associated with frontotemporal lobar degeneration.

Systematic characterization of cancer transcriptome at transcript resolution.

Transcribed RNAs undergo various regulation and modification to become functional transcripts. Notably, cancer transcriptome has not been fully characterized at transcript resolution. Herein, we carry out a reference-based transcript assembly across >1000 cancer cell lines. We identify 498,255 transcripts, approximately half of which are unannotated. Unannotated transcripts are closely associated with cancer-related hallmarks and show clinical significance. We build a high-confidence RNA binding protein (RBP)-transcript regulatory network, wherein most RBPs tend to regulate transcripts involved in cell proliferation. We identify numerous transcripts that are highly associated with anti-cancer drug sensitivity. Furthermore, we establish RBP-transcript-drug axes, wherein PTBP1 is experimentally validated to affect the sensitivity to decitabine by regulating KIAA1522-a6 transcript. Finally, we establish a user-friendly data portal to serve as a valuable resource for understanding cancer transcriptome diversity and its potential clinical utility at transcript level. Our study substantially extends cancer RNA repository and will facilitate anti-cancer drug discovery.

A Label-Free Electrochemical Aptasensor Based on Zn/Fe Bimetallic MOF Derived Nanoporous Carbon for Ultra-Sensitive and Selective Determination of Paraquat in Vegetables.

Paraquat (PQ) has high acute toxicity, even at low concentrations. For most people, the main pathway of exposure to PQ is through the diet. Therefore, the development of simple and efficient methods for PQ testing is critical for ensuring food safety. In this study, a new electrochemical detection strategy for paraquat is proposed based on the specific binding of PQ to its nucleic acid aptamer. Firstly, the Zn/Fe bimetallic ZIF derived nanoporous carbon (Zn/Fe-ZIF-NPC) and nickel hexacyanoferrate nanoparticles (NiHCF-NPs) were sequentially modified onto the glassy carbon electrode (GCE). NiHCF-NPs served as the signal probes, while Zn/Fe-ZIF-NPC facilitated electron transfer and effectively enhanced the sensing signal of NiHCF-NPs. Au nanoparticles (AuNPs) were then electrodeposited on the NiHCF-NPs/Zn/Fe-ZIF-NPC/GCE and then the thiolated aptamer was assembled on the AuNPs/NiHCF-NPs/Zn/Fe-ZIF-NPC/GCE via Au-S bonding. When incubated with PQ, the formation of PQ-aptamer complexes delayed the interfacial electron transport reaction of NiHCF-NPs, which caused a decrease in the current signals. As a result, simple and highly sensitive detection of PQ can be readily achieved by detecting the signal changes. A linear range was obtained from 0.001 to 100 mg/L with a detection limit as low as 0.34 µg/L. Due to the recognition specificity of the aptamer to its target molecule, the proposed method has excellent anti-interference ability. The prepared electrochemical aptasensor was successfully used for PQ assay in lettuce, cabbage and agriculture irrigation water samples with recoveries ranging from 96.20% to 104.02%, demonstrating the validity and practicality of the proposed method for PQ detection in real samples.

RNA binding protein RALY activates the cholesterol synthesis pathway through an MTA1 splicing switch in hepatocellular carcinoma.

Alternative splicing is an important RNA processing event that contributes to RNA complexity and protein diversity in cancer. Accumulating evidence demonstrates the essential roles of some alternatively spliced genes in carcinogenesis. However, the potential roles of alternatively spliced genes in hepatocellular carcinoma (HCC) are still largely unknown. Here we showed that the HnRNP Associated with Lethal Yellow Protein Homolog (RALY) gene is upregulated and associated with poor outcomes in HCC patients. RALY acts as a tumor-promoting factor by cooperating with splicing factor 3b subunit 3 (SF3B3) and modulating the splicing switch of Metastasis Associated 1 (MTA1) from MTA-S to MTA1-L. Normally, MTA1-S inhibits cell proliferation by reducing the transcription of cholesterol synthesis genes. In HCC, RALY and SF3B3 cooperate to regulate the MTA1 splicing switch, leading to a reduction in the MTA1-S level, and alleviating the inhibitory effect of MTA1-S on cholesterol synthesis genes, thus promoting HCC cell proliferation. In conclusion, our results revealed that the RALY-SF3B3/MTA1/cholesterol synthesis pathway contributes essentially to hepatic carcinogenesis and could serve as a promising therapeutic target for HCC.

SRTdb: an omnibus for human tissue and cancer-specific RNA transcripts.

The production of functional mature RNA transcripts from genes undergoes various pre-transcriptional regulation and post-transcriptional modifications. Accumulating studies demonstrated that gene transcription carries out in tissue and cancer type-dependent ways. However, RNA transcript-level specificity analysis in large-scale transcriptomics data across different normal tissue and cancer types is lacking. We applied reference-based de novo transcript assembly and quantification of 27,741 samples across 33 cancer types, 29 tissue types, and 25 cancer cell line types. We totally identified 231,836 specific RNA transcripts (SRTs) across various tissue and cancer types, most of which are found independent of specific genes. Almost half of tumor SRTs are also tissue-specific but in different tissues. Furthermore, we found that 10 ~ 20% of tumor SRTs in most tumor types were testis-specific. The SRT database (SRTdb) was constructed based on these resources. Taking liver cancer as an example, we showed how SRTdb resource is utilized to optimize the identification of RNA transcripts for more precision diagnosis of particular cancers. Our results provide a useful resource for exploring transcript specificity across various cancer and tissue types, and boost the precision medicine for tumor patients.

A novel electrochemical sensing platform based on the esterase extracted from kidney bean for high-sensitivity determination of organophosphorus pesticides.

Similar to acetylcholinesterase, the activity of plant-derived esterase can also be inhibited by organophosphorus pesticides. Therefore, an electrochemical sensing platform using kidney bean esterase as a new detection enzyme was proposed for the highly sensitive determination of organophosphorus pesticides. Purified kidney bean esterase was obtained by an efficient and economical aqueous two-phase extraction method. Carboxylated graphene/carbon nanotube composites (cCNTs-cGR) and Au nanoparticles were used to provide a biocompatible environment to immobilize kidney bean esterase and also accelerate electron transport between the analyte and the electrode surface. Due to the good synergistic electrocatalytic effects of these nanomaterials, the biosensor exhibited an amplified electrocatalytic response to the oxidation of α-naphthalenol, which makes the sensor more sensitive. Based on the inhibitory effect of trichlorfon on kidney bean esterase activity, high sensitivity and low-cost detection of trichlorfon was achieved. Under optimum conditions, the inhibition of trichlorfon is proportional to its concentration in the range of 5 to 150 ng L-1 and 150 ng L-1 to 700 ng L-1 with an ultra-low detection limit of 3 ng L-1. Moreover, the validity of the prepared biosensor was verified by analyzing several actual agricultural products (cabbage and rice) with satisfactory recoveries ranging from 94.05% to 106.76%, indicating that kidney bean esterase is a promising enzyme source for the analysis of organophosphorus pesticides in food samples.

A pathway-guided strategy identifies a metabolic signature for prognosis prediction and precision therapy for hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a highly lethal and heterogeneous disease with a poor prognosis and no effective treatments. Herein, we presented a pathway-guided computational framework to establish a metabolic signature with the capacity for HCC prognosis prediction. By using the TCGA dataset as a training cohort (n = 365), we built an eight-gene (ACADS, ALDH1A2, FTCD, GOT2, GPX7, HADHA, LDHA and UGT2A1) risk score called the MGP score from the 20 metabolic pathways downregulated in HCC. The robustness of the MGP model was successfully validated in seven other independent cohorts (LIRI-JP, n = 231; Chinese, n = 159; GSE148355, n = 33; GSE14520, n = 225; GSE54236, n = 81; E-TABM-36, n = 41; and qPCR, n = 126). Moreover, three subtypes, L, H1 and H2, with distinct clinical outcomes were further stratified by using 761 HCC patients in the combined RNA-Seq cohort. Further analysis identified strong negative associations between metabolic pathways and other molecular features, including immune infiltration, expression of immune checkpoint genes, and hypoxic conditions, among the three subtypes. In 81 liver cancer cell lines, the MGP score indicated sensitivity to three preclinical agents (erastin, piperlongumine and PI-103), which may have potential therapeutic implications for the high-MGP score subtypes H1 and H2. Overall, our analysis highlights the potential of applying the MGP score for prognosis prediction and precision therapy for HCC.

A simple sensing platform based on a 1T@2H-MoS2/cMWCNTs composite modified electrode for ultrasensitive detection of illegal Sudan I dye in food samples.

The work presented here describes a highly sensitive and simple electrochemical sensor for the detection of Sudan I dye based on a nanocomposite made of MoS2 heterogeneous nanosheets (1T@2H-MoS2) and carboxylated carbon nanotubes (cMWCNTs) (1T@2H-MoS2/cMWCNTs). XPS results indicate that the content of 1T phase MoS2 was estimated to be 72% in 1T@2H-MoS2. Electron microscopy results show that the tubular cMWCNTs are uniformly interwoven in MoS2 nanosheets to form a three-dimensional network structure. Due to the synergistic electrocatalytic ability and high electroactive surface area, the 1T@2H-MoS2/cMWCNTs modified electrode demonstrated excellent analytical performance for Sudan I, including simple operation, good stability and a wide linear range from 5.00 × 10-9 to 2.00 × 10-6 mol L-1 and 2.00 × 10-6 to 1.00 × 10-4 mol L-1 with an ultra-low detection limit of 1.56 × 10-9 mol L-1. The recoveries of Sudan I from spiked real samples (chilli powder and ketchup) were in the range of 95.60% to 106.10% with low RSD (<5%), indicating that the 1T@2H-MoS2/cMWCNTs modified electrode is a promising tool for the analysis of illegal Sudan I in food samples.

Long noncoding RNA BS-DRL1 modulates the DNA damage response and genome stability by interacting with HMGB1 in neurons.

Long noncoding RNAs (lncRNAs) are known to regulate DNA damage response (DDR) and genome stability in proliferative cells. However, it remains unknown whether lncRNAs are involved in these vital biological processes in post-mitotic neurons. Here, we report and characterize a lncRNA, termed Brain Specific DNA-damage Related lncRNA1 (BS-DRL1), in the central nervous system. BS-DRL1 is a brain-specific lncRNA and depletion of BS-DRL1 in neurons leads to impaired DDR upon etoposide treatment in vitro. Mechanistically, BS-DRL1 interacts with HMGB1, a chromatin protein that is important for genome stability, and is essential for the assembly of HMGB1 on chromatin. BS-DRL1 mediated DDR exhibits cell-type specificity in the cortex and cerebellum in gamma-irradiated mice and BS-DRL1 knockout mice show impaired motor function and concomitant purkinje cell degeneration. Our study extends the understanding of lncRNAs in DDR and genome stability and implies a protective role of lncRNA against neurodegeneration.

Comprehensive Analysis of APA Events and Their Association With Tumor Microenvironment in Lung Adenocarcinoma.

BACKGROUND: Alternative polyadenylation (APA) is a pervasive posttranscriptional mechanism regulating gene expression. However, the specific dysregulation of APA events and its potential biological or clinical significance in lung adenocarcinoma (LUAD) remain unclear. METHODS: Here, we collected RNA-Seq data from two independent datasets: GSE40419 (n = 146) and The Cancer Genome Atlas (TCGA) LUAD (n = 542). The DaPars algorithm was employed to characterize the APA profiles in tumor and normal samples. Spearman correlation was used to assess the effects of APA regulators on 3' UTR changes in tumors. The Cox proportional hazard model was used to identify clinically relevant APA events and regulators. We stratified 512 patients with LUAD in the TCGA cohort through consensus clustering based on the expression of APA factors. FINDINGS: We identified remarkably consistent alternative 3' UTR isoforms between the two cohorts, most of which were shortened in LUAD. Our analyses further suggested that aberrant usage of proximal polyA sites resulted in escape from miRNA binding, thus increasing gene expression. Notably, we found that the 3' UTR lengths of the mRNA transcriptome were correlated with the expression levels of APA factors. We further identified that CPSF2 and CPEB3 may serve as key regulators in both datasets. Finally, four LUAD subtypes according to different APA factor expression patterns displayed distinct clinical results and oncogenic features related to tumor microenvironment including immune, metabolic, and hypoxic status. INTERPRETATION: Our analyses characterize the APA profiles among patients with LUAD and identify two key regulators for APA events in LUAD, CPSF2 and CPEB3, which could serve as the potential prognostic genes in LUAD.

Environmental exposure to cooking oil fumes and fatty liver disease.

BACKGROUND: Evidence on the effect of cooking oil fumes exposure on fatty liver disease (FLD) is limited. Our study aimed to investigate the association between exposure to the fumes of cooking oil and the risk of FLD. METHODS: A total of 55,959 participants aged 40-75 years old participated in a community-based survey in Ningbo, China. Information on exposure to cooking oil fumes and FLD were collected by face-to-face interviews. Stratified analysis was performed, and participants were divided into 2 groups according to gender. Multiple logistic regression analyses were conducted to investigate the association between exposure to cooking oil fumes and the risk of FDL. Furthermore, ordered logistic regression analysis was conducted to investigate the association between cooking oil fume exposure and the severity of FLD. RESULTS: The prevalence of FLD was 8.79% in the no oil fume exposure group, 10.52% in the light oil fume exposure group, 23.47% in the moderate oil fume exposure group, and 41.45% in the heavy oil fume exposure group. After adjusting for confounding factors, participants in the light, moderate, and heavy cooking oil fume exposure groups all had significantly higher odds ratios (ORs) as compared with participants in the no oil fume exposure group. In addition, an interaction effect between cooking oil fume exposure and gender on the prevalence and severity of FLD was observed. Females with heavy oil fume exposure had the highest ORs of FLD and extent of disease severity. In the stratified analysis, compared to participants in the fumeless group, males and females in the light, moderate, and heavy cooking oil fume exposure groups all had significantly higher risks of FLD and more severe extent of disease, while participants with heavier cooking oil fume exposure tended to have higher risk of FLD and more severe extent of disease. CONCLUSIONS: Exposure to the fumes of cooking oil is associated with the incidence and severity of FLD in 40-75 year old Chinese people. The associations might be dose-responsive. In addition, heavy exposure to oil fumes and the female gender might have a synergistic effect on the incidence and severity of FLD.

The Neuronal Activation of Deep Cerebellar Nuclei Is Essential for Environmental Enrichment-Induced Post-Stroke Motor Recovery.

The level of cerebellar activity in stroke patients has been shown to correlate with the extent of functional recovery. We reasoned that the cerebellum may be an important player in post-stroke rehabilitation. Because the neurons in the deep cerebellar nuclei (DCN) represent virtually all of the output from the cerebellum, in this study, using environmental enrichment (EE) to promote rehabilitation, we investigated the influence of the optogenetic neuronal modulation of DCN on EE-induced rehabilitation. We found that neuronal inhibition of the DCN almost completely blocked motor recovery in EE treated mice, but the stroke mice with neuronal activation of the DCN achieved a similar recovery level as those in the EE treated group. No difference was observed in anxiety-like behavior. Moreover, Htr2a in the DCN, the gene encoding 5-HT2A receptor, was shown to be a hub gene in the protein-protein interaction network identified using RNA-seq. This indicated that 5-HT2A receptor-mediated signaling may be responsible for DCN-dependent functional improvement in EE. We further verified this using the 5-HT2A receptor antagonist, MDL100907, to inhibit the function of 5-HT2A receptor in the DCN. This treatment resulted in impaired recovery in EE treated mice, who performed at a level as poor as the stroke-only group. Thus, this work contributes to an understanding of the importance of the DCN activation in EE-induced post-stroke rehabilitation. Attempts to clarify the mechanism of 5-HT2A receptor-mediated signaling in the DCN may also lead to the creation of a pharmacological mimetic of the benefits of EE-induced rehabilitation.

The prognostic signature of the somatic mutations in Ewing sarcoma: from a network view.

BACKGROUND: Ewing sarcoma is a malignant bone tumor mainly affecting teenagers and young adults. Its main driver mutation, the EWS-FLI1 fusion gene, has been identified more than 20 years ago, whereas its other somatic mutations have been just recently reported. METHODS: In this study, we organized the somatic mutations from 216 Ewing sarcoma cases into 216 individual protein-protein interaction networks by using interactome information. These mutation networks were then classified into five different clusters based on their structural similarities. The prognostic effect of mutation genes was evaluated according to their network features. RESULTS: The cases in cluster two exhibited remarkably high metastasis and mortality rates, and STAG2, TP53 and TTN were the three most significantly mutated genes in this cluster. Microarray data demonstrate that the expression of STAG2, TP53 and TTN are down-regulated in the EWS-FLI1-knockdown Ewing sarcoma cells. However, the mutation effect analysis shows that the somatic mutations in TTN are less damaging than those in STAG2 and TP53. The analyses of functional network modules further revealed that STAG2, TP53 and their interacting gene partners participate in the oncogenic-related biological modules such as cell cycle and regulation of transcription from RNA polymerase II promoter while TTN, TP53 and their interacting gene partners constitute the modules less relevant to oncogenesis. The results of Gene Ontology analyses demonstrated that the uniquely mutated genes associated with poor prognosis in Clusters 1, 4 and 5 were distinctively enriched in epidermal growth factor-related functions and phosphoproteins. CONCLUSIONS: Our study identified the highly lethal mutation combination cases and characterized the possible prognostic genes in Ewing sarcoma from a network perceptive.

Integrative analysis identifies DNMTs against immune-infiltrating neutrophils and dendritic cells in colorectal cancer.

Molecular characterizations, including microsatellite instability (MSI) and the CpG island methylator phenotype (CIMP) showed strong associations in colorectal carcinoma (CRC) and provided a deeper understanding of the etiology of disease. However, the global relationship between epigenetic alternations and changes in mRNA expression in CRC remains largely undefined, especially regarding the roles of DNA methyltransferases (DNMTs). Here, we conducted a systematic network comparison to explore the global conservation between co-expressed and co-methylated modules. We successfully identified immune-related modules that were regulated by DNMTs and had strong associations with immune-infiltrating neutrophils and dendritic cells in CRC. Moreover, we found that genes in those modules were prognostic for CRC, with 97.1% (168/173) being significantly influenced by DNMTs. Thus, this study resolved an interaction between DNA methylation and mRNA expression through DNMTs. Additionally, we provided evidence that DNMTs control the global hypomethylation of oncogenes, including ALOX5AP and CSF3R that otherwise have high methylation in normal colons. Such genes were also more sensitive to DNMT changes, such as in CRC. Collectively, our analyzes provided a systems biology approach to investigate the association among different molecular phenotypes in diseases.