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On the way to carbon neutrality, directly catalyzing atmospheric CO2 into high-value chemicals might be an effective approach to mitigate the negative impacts of rising airborne CO2 concentrations. Here, we pioneer the investigation of the influence of the H2/CO2 partial pressure ratio (PPR) on air-level CO2 methanation. Using Ni/CeO2 as a case catalyst, increasing H2/CO2 PPR significantly improves low-temperature CO2 conversion and high-temperature CH4 selectivity, i.e., from 10 of H2/CO2 PPR on, CO2 is completely methanized at 250 °C, and nearly 100% CH4 selectivity is achieved at 400 °C. 100-hour stability tests demonstrate the practical application potential of Ni/CeO2 at 250 °C and 400 °C. In-situ DRIFTS reveal that reinforced formate pathway by increasing H2/CO2 PPR is responsible for the high CH4 yield. In contrast, even though the CO pathway dominated CO2 conversion on Ni is enhanced by rising H2/CO2 PPR, but at a high reaction temperature, the promoted CO desorption still leads to lower CH4 selectivity. This work offers deep insights into the direct air-level CO2 resourceization, contributing to the achievement of airborne CO2 reductions.
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Small molecules targeting RNA can be valuable chemical probes and potential therapeutics. The interactions between small molecules, particularly fragments, and RNA, however, can be difficult to detect due to their modest affinities and short residence times. Here, we present a protocol for mapping the molecular fingerprints of small molecules in vitro and throughout the human transcriptome in live cells. We describe steps for compound treatment, cross-linking, RNA extraction, fragmentation, and pull-down. We then detail procedures for RNA sequencing and data analysis. For complete details on the use and execution of this protocol, please refer to Tong et al.1.
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Small molecules targeting RNA can be valuable chemical probes and potential therapeutics. The interactions between small molecules, particularly fragments, and RNA, however, can be difficult to detect due to their modest affinities and short residence times. Here, we describe the procedures for mapping the molecular fingerprints of small molecules in vitro and throughout the human transcriptome in live cells, identifying both the targets bound by the small molecule and the sites of binding therein. For complete details on the use and execution of this protocol, please refer to 1.
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α-Synuclein is an important drug target for the treatment of Parkinson's disease (PD), but it is an intrinsically disordered protein lacking typical small-molecule binding pockets. In contrast, the encoding SNCA mRNA has regions of ordered structure in its 5' untranslated region (UTR). Here, we present an integrated approach to identify small molecules that bind this structured region and inhibit α-synuclein translation. A drug-like, RNA-focused compound collection was studied for binding to the 5' UTR of SNCA mRNA, affording Synucleozid-2.0, a drug-like small molecule that decreases α-synuclein levels by inhibiting ribosomes from assembling onto SNCA mRNA. This RNA-binding small molecule was converted into a ribonuclease-targeting chimera (RiboTAC) to degrade cellular SNCA mRNA. RNA-seq and proteomics studies demonstrated that the RiboTAC (Syn-RiboTAC) selectively degraded SNCA mRNA to reduce its protein levels, affording a fivefold enhancement of cytoprotective effects as compared to Synucleozid-2.0. As observed in many diseases, transcriptome-wide changes in RNA expression are observed in PD. Syn-RiboTAC also rescued the expression of ~50% of genes that were abnormally expressed in dopaminergic neurons differentiated from PD patient-derived iPSCs. These studies demonstrate that the druggability of the proteome can be expanded greatly by targeting the encoding mRNAs with both small molecule binders and RiboTAC degraders.
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Proteínas Intrinsicamente Desordenadas , Doença de Parkinson , Humanos , alfa-Sinucleína/genética , RNA Mensageiro/genética , Proteínas Intrinsicamente Desordenadas/genética , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/genética , Regiões 5' não Traduzidas , RibonucleasesRESUMO
The formation of bone in a bone defect is accomplished by osteoblasts, while the over activation of fibroblasts promotes fibrosis. However, it is not clear how the extracellular matrix stiffness of the bone-regeneration microenvironment affects the function of osteoblasts and fibroblasts. This study aim to investigate the effect of bone-regeneration microenvironment stiffness on cell adhesion, cell proliferation, cell differentiation, synthesizing matrix ability and its potential mechanisms in mechanotransduction, in pre-osteoblasts and fibroblasts. Polyacrylamide substrates mimicking the matrix stiffness of different stages of the bone-healing process (15 kPa, mimic granulation tissue; 35 kPa, mimic osteoid; 150 kPa, mimic calcified bone matrix) were prepared. Mouse pre-osteoblasts MC3T3-E1 and mouse fibroblasts NIH3T3 were plated on three types of substrates, respectively. There were significant differences in the adhesion of pre-osteoblasts and fibroblasts on different polyacrylamide substrates. Runx2 expression increased with increasing substrate stiffness in pre-osteoblasts, while no statistical differences were found in the Acta2 expression in fibroblasts on three substrates. OPN expression in pre-osteoblasts, as well as Fn1 and Col1a1 expression in fibroblasts, decreased with increasing stiffness. The difference between the cell traction force generated by pre-osteoblasts and fibroblasts on substrates was also found. Our results indicated that substrate stiffness is a potent regulator of pre-osteoblasts and fibroblasts with the ability of promoting osteogenic differentiation of pre-osteoblasts, while having no effect on myofibroblast differentiation of fibroblasts.
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Despite the successful application of chimeric antigen receptor (CAR)-T cell therapy in hematological malignancies, the treatment efficacy in solid tumors remains unsatisfactory, largely due to the highly immunosuppressive tumor microenvironment and low density of specific tumor antigens. Natural killer group 2 member D (NKG2D) CAR-T cells have shown promising treatment effects on several cancers such as lymphoma and multiple myeloma. However, the application and efficacy of NKG2D-CAR-T cells in gastric cancer (GC) still needs further exploration. This study identified a novel combination immunotherapy strategy with Dickkopf-1 (DKK1) inhibition and NKG2D-CAR-T cells, exerting synergistic and superior antitumor effect in GC. We show that the baseline expression of NKG2D ligands (NKG2DLs) is at low levels in GC tissues from The Cancer Genome Atlas and multiple GC cell lines including NCI-N87, MGC803, HGC27, MKN45, SGC7901, NUGC4, and AGS. In addition, DKK1 inhibition by WAY-262611 reverses the suppressive tumor immune microenvironment (TIME) and upregulates NKG2DL expression levels in both GC cell lines and GC tissues from a xenograft NCG mouse model. DKK1 inhibition in GC cells markedly improves the immune-activating and tumor-killing ability of NKG2D-CAR-T cells as shown by cytotoxicity assays in vitro. Moreover, the combination therapy of NKG2D-CAR-T and WAY-262611 triggers superior antitumor effects in vivo in a xenograft NCG mouse model. In sum, our study reveals the role of DKK1 in remodeling GC TIME and regulating the expression levels of NKG2DLs in GC. We also provide a promising treatment strategy of combining DKK1 inhibition with NKG2D-CAR-T cell therapy, which could bring new breakthroughs for GC immunotherapy.
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Receptores de Antígenos Quiméricos , Neoplasias Gástricas , Humanos , Camundongos , Animais , Subfamília K de Receptores Semelhantes a Lectina de Células NK/genética , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , Neoplasias Gástricas/terapia , Neoplasias Gástricas/metabolismo , Linhagem Celular Tumoral , Imunoterapia Adotiva , Linfócitos T , Microambiente Tumoral , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismoRESUMO
The Chinese giant salamander (Andrias davidianus) has been increasingly popular in the aquaculture market in China in recent years. In the breeding process of Andrias davidianus, we found that some albino individuals were extremely rare and could not be inherited stably, which severely limits their commercialization in the aquaculture market. In this study, we performed transcriptome and small RNA (sRNA) sequencing analyses in the skin samples of wild-type (WT) and albino (AL) Andrias davidianus. In total, among 5517 differentially expressed genes (DEGs), 2911 DEGs were down-regulated in AL, including almost all the key genes involved in melanin formation. A total of 25 miRNAs were differentially expressed in AL compared to WT, of which 17 were up-regulated. Through the integrated analysis, no intersection was found between the target genes of the differentially expressed miRNAs and the key genes for melanin formation. Gene Ontology (GO) and KEGG pathway analyses on DEGs showed that these genes involved multiple processes relevant to melanin synthesis and the key signal pathway MAPK. Interestingly, the transcription factors SOX10 and PAX3 and the Wnt signaling pathway that play a key role in other species were not included, while the other two transcription factors in the SOX family, SOX21 and SOX7, were included. After analyzing the key genes for melanin formation, it was interesting to note an alternative splicing form of the MITF in WT and a critical mutation of the SLC24A5 gene in AL, which might be the main reason for the skin color change of Andrias davidianus. The results contributed to understanding the molecular mechanism of skin pigmentation in Andrias davidianus and accelerating the acquisition process of individuals with specific body colors by genetic means.
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Altay white-headed cattle have not received enough attention for several reasons. Due to irrational breeding and selection practices, the number of pure Altay white-headed cattle has decreased significantly and the breed is now on the eve of extinction. The genomic characterization will be a crucial step towards understanding the genetic basis of productivity and adaptability to survival under native Chinese agropastoral systems; nevertheless, no attempt has been made in Altay white-headed cattle. In the current study, we compared the genomes of 20 Altay white-headed cattle to the genomes of 144 individuals in representative breeds. Population genetic diversity revealed that the nucleotide diversity of Altay white-headed cattle was less than that of indicine breeds and comparable to that of Chinese taurus cattle. Using population structure analysis, we also found that Altay white-headed cattle carried the ancestry of the European and East Asian cattle lineage. In addition, we used three different methods (F ST, θπ ratio and XP-EHH) to investigate the adaptability and white-headed phenotype of Altay white-headed cattle and compared it with Bohai black cattle. We found EPB41L5, SCG5 and KIT genes on the list of the top one percent genes, these genes might have an association with environmental adaptability and the white-headed phenotype for this breed. Our research reveals the distinctive genomic features of Altay white-headed cattle at the genome-wide level.
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Polyurethane (PU) is a versatile plastic that boasts high environmental resistance. The biodegradation of PU has become a hot topic of research aimed at finding ways to potentially solve PU pollutants. Identifying microorganisms capable of efficiently degrading PU plastics is pivotal for the development of a green recycling process for PU. This study aimed to isolate and characterize PU-degrading fungi from the soil of a waste transfer station in Luoyang, China. We isolated four different fungal strains from the soil. Among the isolates, the P2072 and P2073 strains were identified as Rhizopus oryzae (internal transcribed spacer identity, 99.66%) and Alternaria alternata (internal transcribed spacer identity, 99.81%), respectively, through microscopic, morphologic, as well as 18S rRNA sequencing. The degradation ability of strains P2072 and P2073 was analyzed through measurement of weight loss, and they exhibited a degradation rate of 2.7% and 3.3%, respectively, for the PU films after 2 months' growth in mineral salt medium (MSM) with PU films as the sole carbon source. In addition, the P2073 strain exhibited protease activity in the presence of PU. To our knowledge, R. oryzae has never been reported as a PU-degrading fungus. This study provides a new perspective on the biodegradation of PU.
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Poluentes Ambientais , Poliuretanos , Poliuretanos/metabolismo , Solo , Microbiologia do Solo , Fungos/genética , Fungos/metabolismo , Biodegradação Ambiental , Poluentes Ambientais/metabolismoRESUMO
Transcriptome analysis for the original Bacillus subtilis K1 strain and UV mutagenic strain UW07 with high yield of pectate lyase was implemented with RNA-seq. The function of genes was annotated and metabolic pathways were classified to look for different expression genes and classify these genes into related metabolic pathways to reveal the high-yield mechanism of pectate lyase in UW07. The results showed that 397 genes were up-regulated and 617 genes were down-regulated compared with the original strain. The up-regulated genes were mainly involved in ABC transporters, two-component system, biosynthesis of amino acids, and carbon metabolism.
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Bacillus subtilis , Perfilação da Expressão Gênica , Polissacarídeo-Liases , Bacillus subtilis/enzimologia , Bacillus subtilis/genética , Polissacarídeo-Liases/genéticaRESUMO
Cell traction mediates the biochemical and mechanical interactions between the cell and its extracellular matrix (ECM). Traction force microscopy (TFM) is a powerful technique for quantitative cellular scale traction analysis. However, it is challenging to characterize macromolecular scale traction events with current TFM due to the limited sampling density and algorithmic precision. In this article, we introduce a super-resolution TFM by utilizing a novel substrate surface modification method. Our TFM technique achieved a spatial resolution comparable to fluorescence microscopy and precision comparable to the rupture force of an integrin-ligand bond. Correlated imaging of TFM with fluorescence microscopy demonstrated that the residing paxillin highly correlated with traction while α5 integrin was located differently. Time-lapse TFM imaging captured a transient traction variation as the adhesion protein passed by. Thus, the novel super-resolution TFM benefits the studies on cellular biochemical and mechanical interactions.
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Fenômenos Mecânicos , Tração , Microscopia de Força Atômica/métodos , Microscopia de Fluorescência/métodos , Matriz ExtracelularRESUMO
Type I keratin 9 encoded by the KRT9 gene serves an important special function either in the mature palmar and plantar skin tissue. The changes in skin conditions and thickening of the outer layer of the skin may be affected by environmental variables. A missense mutation rs209302038 (NC_037346.1: g.41782870 G > A) was detected in KRT9, which changing the isoleucine into valine. This study aimed to identify the frequency of allele in this locus in Chinese indigenous cattle, and analyze the connection with heat stress. Our results indicated that the frequency of allele A gradually decreases from south to north, while the frequency of G allele showed the opposite pattern. Further analysis of the association of the different genotypes with three climate factors, which showed that the genotypes (GG, GA, AA) were significantly related to climatic conditions (p < 0.01). Therefore, we speculated that the mutation of the rs209302038 in Chinese indigenous cattle might be a genetic marker to detect heat stress.
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Resposta ao Choque Térmico , Mutação de Sentido Incorreto , Bovinos/genética , Animais , Mutação , Resposta ao Choque Térmico/genética , Genótipo , Marcadores Genéticos , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
Accumulating evidence has shown that cell dedifferentiation or reprogramming is a pivotal procedure for animals to deal with injury and promote endogenous tissue repair. Tissue damage is a critical factor that triggers cell dedifferentiation or reprogramming in vivo. By contrast, microenvironmental changes, including the loss of stem cells, hypoxia, cell senescence, inflammation and immunity, caused by tissue damage can return cells to an unstable state. If the wound persists in the longterm due to chronic damage, then dedifferentiation or reprogramming of the surrounding cells may lead to carcinogenesis. In recent years, extensive research has been performed investigating cell dedifferentiation or reprogramming in vivo, which can have significant implications for wound repair, treatment and prevention of cancer in the future. The current review summarizes the molecular events that are known to drive cell dedifferentiation directly following tissue injury and the effects of epigenetic modification on dedifferentiation or reprogramming in vivo. In addition, the present review explores the intracellular mechanism of endogenous tissue repair and its relationship with cancer, which is essential for balancing the risk between tissue repair and malignant transformation after injury.
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Reprogramação Celular , Neoplasias , Animais , Desdiferenciação Celular , Carcinogênese , Transformação Celular NeoplásicaRESUMO
Ribonuclease targeting chimeras (RiboTACs) induce degradation of an RNA target by facilitating an interaction between an RNA and a ribonuclease (RNase). We describe the screening of a DNA-encoded library (DEL) to identify binders of monomeric RNase L to provide a compound that induced dimerization of RNase L, activating its ribonuclease activity. This compound was incorporated into the design of a next-generation RiboTAC that targeted the microRNA-21 (miR-21) precursor and alleviated a miR-21-associated cellular phenotype in triple-negative breast cancer cells. The RNA-binding module in the RiboTAC is Dovitinib, a known receptor tyrosine kinase (RTK) inhibitor, which was previously identified to bind miR-21 as an off-target. Conversion of Dovitinib into this RiboTAC reprograms the known drug to selectively affect the RNA target. This work demonstrates that DEL can be used to identify compounds that bind and recruit proteins with effector functions in heterobifunctional compounds.
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MicroRNAs , Neoplasias de Mama Triplo Negativas , Humanos , Ribonucleases , DNARESUMO
Objective: To evaluate the effect of warm needle acupuncture plus Xitong Waixi lotion on the levels of IL-1, TNF-α, and MMP-3 in patients with knee osteoarthritis. Methods: Eighty patients with knee osteoarthritis admitted to our hospital from October 2019 to June 2021 were recruited and assigned via the random number table method at a ratio of 1 : 1 to receive either Xitong Waixi lotion (conventional group) or warm needle acupuncture plus Xitong Waixi lotion (combined group). Outcome measures included clinical efficacy, inflammatory cytokine level, Western Ontario and McMaster Universities Arthritis Index (WOMAC) score, visual analogue scale (VAS) score, Hospital for Special Surgery (HSS) knee score, and adverse reactions. Results: Warm needle acupuncture plus Xitong Waixi lotion was associated with a significantly higher clinical efficacy versus Xitong Waixi lotion alone (P=0.006). Patients in the combined group had significantly lower levels of interleukin (IL)-1, tumor necrosis factor-α (TNF-α), and matrix metalloproteinase-3 (MMP-3) than those in the conventional group (P=0.020). Warm needle acupuncture plus Xitong Waixi lotion resulted in significantly lower WOMAC scores and VAS scores and higher HSS scores for the patients versus Xitong Waixi lotion (P=0.012). The two groups had a similar incidence of adverse events (P=0.068). Conclusion: Warm needle acupuncture plus Xitong Waixi lotion effectively alleviates the inflammatory response and knee pain in patients with knee osteoarthritis, with significant clinical effects and a high safety profile.
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RNA adopts 3D structures that confer varied functional roles in human biology and dysfunction in disease. Approaches to therapeutically target RNA structures with small molecules are being actively pursued, aided by key advances in the field including the development of computational tools that predict evolutionarily conserved RNA structures, as well as strategies that expand mode of action and facilitate interactions with cellular machinery. Existing RNA-targeted small molecules use a range of mechanisms including directing splicing - by acting as molecular glues with cellular proteins (such as branaplam and the FDA-approved risdiplam), inhibition of translation of undruggable proteins and deactivation of functional structures in noncoding RNAs. Here, we describe strategies to identify, validate and optimize small molecules that target the functional transcriptome, laying out a roadmap to advance these agents into the next decade.
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MicroRNAs , RNA Longo não Codificante , Humanos , MicroRNAs/metabolismo , RNA/metabolismo , Splicing de RNA , RNA Longo não Codificante/genética , RNA não Traduzido/metabolismoRESUMO
Proteoglycans are heterogeneous macromolecular glycoconjugates that orchestrate many important cellular processes. While much attention has focused on the poly-sulfated glycosaminoglycan chains that decorate proteoglycans, other important elements of their architecture, such as core proteins and membrane localization, have garnered less emphasis. Hence, comprehensive structure-function relationships that consider the replete proteoglycan architecture as glycoconjugates are limited. Here we present an extensive approach to study proteoglycan structure and biology by fabricating defined semisynthetic modular proteoglycans that can be tailored for cell surface display. The expression of proteoglycan core proteins with unnatural amino acids permits bioorthogonal click chemistry with functionalized glycosaminoglycans for methodical dissection of the parameters required for optimal binding and function of various proteoglycan-binding proteins. We demonstrate that these sophisticated materials can recapitulate the functions of native proteoglycan ectodomains in mouse embryonic stem cell differentiation and cancer cell spreading while permitting the analysis of the contributing architectural elements toward function.
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Proteoglicanas , Animais , Membrana Celular/metabolismo , Camundongos , Proteoglicanas/análise , Proteoglicanas/metabolismoRESUMO
Background: Non-small-cell lung cancer (NSCLC) is the most common malignant tumor among males and females worldwide. Hypoxia is a typical feature of the tumor microenvironment, and it affects cancer development. Circular RNAs (circRNAs) have been reported to sponge miRNAs to regulate target gene expression and play an essential role in tumorigenesis and progression. This study is aimed at identifying whether circRNAs could be used as the diagnostic biomarkers for NSCLC. Methods: The heterogeneity of samples in this study was assessed by principal component analysis (PCA). Furthermore, the Gene Expression Omnibus (GEO) database was normalized by the affy R package. We further screened the differentially expressed genes (DEGs) and differentially expressed circular RNAs (DEcircRNAs) using the DEseq2 R package. Moreover, we analyzed the Gene Ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment of DEGs using the cluster profile R package. Besides, the Gene Set Enrichment Analysis (GSEA) was used to identify the biological function of DEGs. The interaction between DEGs and the competing endogenous RNAs (ceRNA) network was detected using STRING and visualized using Cytoscape. Starbase predicted the miRNAs of target hub genes, and miRanda predicted the target miRNAs of circRNAs. The RNA-seq profiler and clinical information were downloaded from The Cancer Genome Atlas (TCGA) database. Then, the variables were assessed by the univariate and multivariate Cox proportional hazard regression models. Significant variables in the univariate Cox proportional hazard regression model were included in the multivariate Cox proportional hazard regression model to analyze the association between the variables of clinical features. Furthermore, the overall survival of variables was determined by the Kaplan-Meier survival curve, and the time-dependent receiver operating characteristic (ROC) curve analysis was used to calculate and validate the risk score in NSCLC patients. Moreover, predictive nomograms were constructed and used to predict the prognostic features between the high-risk and low-risk score groups. Results: We screened a total of 2039 DEGs, including 1293 upregulated DEGs and 746 downregulated DEGs in hypoxia-treated A549 cells. A549 cells treated with hypoxia had a total of 70 DEcircRNAs, including 21 upregulated and 49 downregulated DEcircRNAs, compared to A549 cells treated with normoxia. The upregulated genes were significantly enriched in 284 GO terms and 42 KEGG pathways, while the downregulated genes were significantly enriched in 184 GO terms and 25 KEGG pathways. Moreover, the function analysis by GSEA showed enrichment in the enzyme-linked receptor protein signaling pathway, hypoxia-inducible factor- (HIF-) 1 signaling pathway, and G protein-coupled receptor (GPCR) downstream signaling. Furthermore, six hub modules and 10 hub genes, CDC45, EXO1, PLK1, RFC4, CCNB1, CDC6, MCM10, DLGAP5, AURKA, and POLE2, were identified. The ceRNA network was constructed, and it consisted of 4 circRNAs, 14 miRNAs, and 38 mRNAs. The ROC curve was constructed and calculated. The area under the curve (AUC) value was 0.62, and the optimal threshold was 0.28. Based on the optimal threshold, the patients were divided into the high-risk score and low-risk score groups. The survival rate in the high-risk score group was lower than that in the low-risk score group. The expression of SERPINE1, STC2, and LPCAT1; clinical stage; and age of the patient were significantly correlated with the high-risk score. Moreover, nomograms were established based on the risk factors in multivariate analysis, and the median survival time, 3-year survival probability, and 5-year survival were possibly predicted according to nomograms. Conclusion: The ceRNA network associated with NSCLC was identified, and the hub genes, circRNAs, might act as the potential biomarkers for NSCLC.
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Riboflavin is the precursor of essential cofactors for diverse metabolic processes. Unlike animals, plants can de novo produce riboflavin through an ancestrally conserved pathway, like bacteria and fungi. However, the mechanism by which riboflavin regulates seed development is poorly understood. Here, we report a novel maize (Zea mays L.) opaque mutant o18, which displays an increase in lysine accumulation, but impaired endosperm filling and embryo development. O18 encodes a rate-limiting bifunctional enzyme ZmRIBA1, targeted to plastid where to initiate riboflavin biosynthesis. Loss of function of O18 specifically disrupts respiratory complexes I and II, but also decreases SDH1 flavinylation, and in turn shifts the mitochondrial tricarboxylic acid (TCA) cycle to glycolysis. The deprivation of cellular energy leads to cell-cycle arrest at G1 and S phases in both mitosis and endoreduplication during endosperm development. The unexpected up-regulation of cell-cycle genes in o18 correlates with the increase of H3K4me3 levels, revealing a possible H3K4me-mediated epigenetic back-up mechanism for cell-cycle progression under unfavourable circumstances. Overexpression of O18 increases riboflavin production and confers osmotic tolerance. Altogether, our results substantiate a key role of riboflavin in coordinating cellular energy and cell cycle to modulate maize endosperm development.