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Adjusting intracellular metabolic pathways and adopting suitable live state such as biofilms, are crucial for bacteria to survive environmental changes. Although substantial progress has been made in understanding how the histone-like nucleoid-structuring (H-NS) protein modulates the expression of the genes involved in biofilm formation, the precise modification that the H-NS protein undergoes to alter its DNA binding activity is still largely uncharacterized. This study revealed that acetylation of H-NS at Lys19 inhibits biofilm development in Shewanella oneidensis MR-1 by downregulating the expression of glutamine synthetase, a critical enzyme in glutamine synthesis. We further found that nitrogen starvation, a likely condition in biofilm development, induces deacetylation of H-NS and the trimerization of nitrogen assimilation regulator GlnB. The acetylated H-NS strain exhibits significantly lower cellular glutamine concentration, emphasizing the requirement of H-NS deacetylation in Shewanella biofilm development. Moreover, we discovered in vivo that the activation of glutamine biosynthesis pathway and the concurrent suppression of the arginine synthesis pathway during both pellicle and attached biofilms development, further suggesting the importance of fine tune nitrogen assimilation by H-NS acetylation in Shewanella. In summary, posttranslational modification of H-NS endows Shewanella with the ability to respond to environmental needs by adjusting the intracellular metabolism pathways.
Assuntos
Histonas , Shewanella , Acetilação , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Biofilmes , Glutamina/genética , Histonas/metabolismo , Homeostase , Processamento de Proteína Pós-Traducional , Shewanella/genética , Shewanella/metabolismoRESUMO
As microRNAs (miRNAs) are involved in many essential biological processes, their abnormal expressions can serve as biomarkers and prognostic indicators to prevent the development of complex diseases, thus providing accurate early detection and prognostic evaluation. Although a number of computational methods have been proposed to predict miRNA-disease associations (MDAs) for further experimental verification, their performance is limited primarily by the inadequacy of exploiting lower order patterns characterizing known MDAs to identify missing ones from MDA networks. Hence, in this work, we present a novel prediction model, namely HiSCMDA, by incorporating higher order network structures for improved performance of MDA prediction. To this end, HiSCMDA first integrates miRNA similarity network, disease similarity network and MDA network to preserve the advantages of all these networks. After that, it identifies overlapping functional modules from the integrated network by predefining several higher order connectivity patterns of interest. Last, a path-based scoring function is designed to infer potential MDAs based on network paths across related functional modules. HiSCMDA yields the best performance across all datasets and evaluation metrics in the cross-validation and independent validation experiments. Furthermore, in the case studies, 49 and 50 out of the top 50 miRNAs, respectively, predicted for colon neoplasms and lung neoplasms have been validated by well-established databases. Experimental results show that rich higher order organizational structures exposed in the MDA network gain new insight into the MDA prediction based on higher order connectivity patterns.
Assuntos
Neoplasias do Colo , Neoplasias Pulmonares , MicroRNAs , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Biologia Computacional/métodos , Neoplasias Pulmonares/genética , Bases de Dados Factuais , Algoritmos , Predisposição Genética para DoençaRESUMO
The 53BP1-RIF1 pathway restricts the resection of DNA double-strand breaks (DSBs) and promotes blunt end-ligation by non-homologous end joining (NHEJ) repair. The Shieldin complex is a downstream effector of the 53BP1-RIF1 pathway. Here, we identify a component of this pathway, CCAR2/DBC1, which is also required for restriction of DNA end-resection. CCAR2 co-immunoprecipitates with the Shieldin complex, and knockout of CCAR2 in a BRCA1-deficient cell line results in elevated DSB end-resection, RAD51 loading, and PARP inhibitor (PARPi) resistance. Knockout of CCAR2 is epistatic with knockout of other Shieldin proteins. The S1-like RNA-binding domain of CCAR2 is required for its interaction with the Shieldin complex and for suppression of DSB end-resection. CCAR2 functions downstream of the Shieldin complex, and CCAR2 knockout cells have delayed resolution of Shieldin complex foci. Forkhead-associated (FHA)-dependent targeting of CCAR2 to DSB sites re-sensitized BRCA1-/-SHLD2-/- cells to PARPi. Taken together, CCAR2 is a functional component of the 53BP1-RIF1 pathway, promotes the refill of resected DSBs, and suppresses homologous recombination.
Assuntos
Quebras de DNA de Cadeia Dupla , Inibidores de Poli(ADP-Ribose) Polimerases , Reparo do DNA por Junção de Extremidades , Recombinação Homóloga , DNARESUMO
The zero-valent iron (ZVI) has attracted increasing attention due to the enhanced reactivity of ZVI to uranium wastewater. However, ZVI practical application is hampered due to its susceptibility to oxidation and the formation of passivation layers during storage and in situ restoration. To address these issues, we used a biosulfuration approach to modify ZVI for application in uranium ore wastewater treatment. A series of physicochemical characterization tools and photoelectronic analyses showed that BS-ZVI considerably increased carrier separation efficiency and visible light absorption capacity, resulting in a significant photoassisted enhancement effect on uranium extraction. Accordingly, the uranium removal efficiency of BS-ZVI reached 91% within 60 min, and its maximum adsorption capacity was 336.3 mg/g. By analyzing the mechanism, the improved U(VI) removal performance was mostly responsible on the dissolution of the passivation layer on the surface of ZVI, the generation of Fe(II) and FeS, and the important role of Shewanella putrefaciens extracellular polymers (EPS). Overall, the BS-ZVI biohybrid merges with the high activity of ZVI, bio-FeS, and self-regeneration ability of bacteria, expanding a promising new approach for sustainable treatment of uranium mine wastewater.
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Limited DNA end resection is the key to impaired homologous recombination in BRCA1-mutant cancer cells. Here, using a loss-of-function CRISPR screen, we identify DYNLL1 as an inhibitor of DNA end resection. The loss of DYNLL1 enables DNA end resection and restores homologous recombination in BRCA1-mutant cells, thereby inducing resistance to platinum drugs and inhibitors of poly(ADP-ribose) polymerase. Low BRCA1 expression correlates with increased chromosomal aberrations in primary ovarian carcinomas, and the junction sequences of somatic structural variants indicate diminished homologous recombination. Concurrent decreases in DYNLL1 expression in carcinomas with low BRCA1 expression reduced genomic alterations and increased homology at lesions. In cells, DYNLL1 limits nucleolytic degradation of DNA ends by associating with the DNA end-resection machinery (MRN complex, BLM helicase and DNA2 endonuclease). In vitro, DYNLL1 binds directly to MRE11 to limit its end-resection activity. Therefore, we infer that DYNLL1 is an important anti-resection factor that influences genomic stability and responses to DNA-damaging chemotherapy.
Assuntos
Proteína BRCA1/deficiência , Dineínas do Citoplasma/metabolismo , DNA/metabolismo , Genes BRCA1 , Proteína Homóloga a MRE11/metabolismo , Reparo de DNA por Recombinação , Proteína BRCA1/genética , Sistemas CRISPR-Cas/genética , Linhagem Celular Tumoral , Aberrações Cromossômicas , Dano ao DNA/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Edição de Genes , Instabilidade Genômica/efeitos dos fármacos , Recombinação Homóloga/efeitos dos fármacos , Humanos , Mutação , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Platina/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Ligação Proteica , Reparo de DNA por Recombinação/efeitos dos fármacos , Fatores de Transcrição/metabolismoRESUMO
As a multigenic trait, rice tillering can optimize plant architecture for the maximum agronomic yield. SQUAMOSA PROMOTER BINDING PROTEIN-LIKE14 (OsSPL14) has been demonstrated to be necessary and sufficient to inhibit rice branching, but the underlying mechanism remains largely unclear. Here, we demonstrated that OsSPL14, which is cleaved by miR529 and miR156, inhibits tillering by fine-tuning auxin transport in rice. RNA interference of OsSPL14 or miR529 and miR156 overexpression significantly increased the tiller number, whereas OsSPL14 overexpression decreased the tiller number. Histological analysis revealed that the OsSPL14-overexpressing line had normal initiation of axillary buds but inhibited outgrowth of tillers. Moreover, OsSPL14 was found to be responsive to indole-acetic acid and 1-naphthylphthalamic acid, and RNA interference of OsSPL14 reduced polar auxin transport and increased 1-naphthylphthalamic acid sensitivity of rice plants. Further analysis revealed that OsSPL14 directly binds to the promoter of PIN-FORMED 1b (OsPIN1b) and PIN-LIKE6b (PILS6b) to regulate their expression positively. OsPIN1b and PILS6b were highly expressed in axillary buds and proved involved in bud outgrowth. Loss of function of OsPIN1b or PILS6b increased the tiller number of rice. Taken together, our findings suggested that OsSPL14 could control axillary bud outgrowth and tiller number by activating the expression of OsPIN1b and PILS6b to fine-tune auxin transport in rice.
Assuntos
Oryza , Transporte Biológico , Regulação da Expressão Gênica de Plantas , Ácidos Indolacéticos/metabolismo , Oryza/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismoRESUMO
A Gram-stain-negative, aerobic, non-motile and pleomorphic bacterium designated as YG55T was isolated from a coastal sediment sample. Growth was found to occur at 10-37 °C (optimum, 28 °C), at pH 6-9 (optimum, pH 8) and in 0-6â% NaCl (optimum, 1â%). The results of 16S rRNA gene-based analysis showed that strain YG55T was related to the members of the genus Tsuneonella and shared the highest identity of 99.4â% with Tsuneonella dongtanensis GDMCC 1.2307T, followed by Tsuneonella troitsensis JCM 17037T (98.4â%). The phylogenomic results indicated that strain YG55T formed an independent branch distinct from the reference type strains. The 22.7 and 21.8â% digital DNA-DNA hybridization (dDDH) values and 83.0 and 81.8â% average nucleotide identity (ANI) values between strain YG55T and the two relatives were below the species definition thresholds of 70â% (dDDH) and 95-96â% (ANI), indicating that the strain represents a novel genospecies. The results of chemotaxonomic characterization indicated that the major cellular fatty acids of strain YG55T were summed feature 8 (C18â:â1 ω6c and/or C18â:â1 ω7c), C14â:â0 2OH and C16â:â0; the main polar lipids comprised diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylcholine and sphingoglycolipid; the respiratory quinone was ubiquinone-10. The genomic size and DNA G+C contents were 3.03 Mbp and 66.98â%. The strain contained carotenoid biosynthesis genes and could produce carotenoids. Based on its genotypic and phenotypic characteristics, strain YG55T is concluded to represent a novel species of the genus Tsuneonella, for which the name Tsuneonella litorea sp. nov. is proposed. The type strain is YG55T (=GDMCC 1.2590 T=KCTC 82812T).
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Ácidos Graxos , Fosfolipídeos , Ácidos Graxos/química , Fosfolipídeos/química , RNA Ribossômico 16S/genética , DNA Bacteriano/genética , Filogenia , Composição de Bases , Técnicas de Tipagem Bacteriana , Análise de Sequência de DNA , Ubiquinona/químicaRESUMO
P53-binding protein 1 (53BP1) is a multi-functional double-strand break repair protein that is essential for class switch recombination in B lymphocytes and for sensitizing BRCA1-deficient tumours to poly-ADP-ribose polymerase-1 (PARP) inhibitors. Central to all 53BP1 activities is its recruitment to double-strand breaks via the interaction of the tandem Tudor domain with dimethylated lysine 20 of histone H4 (H4K20me2). Here we identify an uncharacterized protein, Tudor interacting repair regulator (TIRR), that directly binds the tandem Tudor domain and masks its H4K20me2 binding motif. Upon DNA damage, the protein kinase ataxia-telangiectasia mutated (ATM) phosphorylates 53BP1 and recruits RAP1-interacting factor 1 (RIF1) to dissociate the 53BP1-TIRR complex. However, overexpression of TIRR impedes 53BP1 function by blocking its localization to double-strand breaks. Depletion of TIRR destabilizes 53BP1 in the nuclear-soluble fraction and alters the double-strand break-induced protein complex centring 53BP1. These findings identify TIRR as a new factor that influences double-strand break repair using a unique mechanism of masking the histone methyl-lysine binding function of 53BP1.
Assuntos
Proteínas de Transporte/metabolismo , Histonas/química , Histonas/metabolismo , Lisina/metabolismo , Proteína 1 de Ligação à Proteína Supressora de Tumor p53/antagonistas & inibidores , Proteína 1 de Ligação à Proteína Supressora de Tumor p53/metabolismo , Animais , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Sítios de Ligação , Quebras de DNA de Cadeia Dupla , Reparo do DNA , Feminino , Humanos , Metilação , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação , Ligação Proteica , Domínios Proteicos , Proteínas de Ligação a RNA , Proteínas de Ligação a Telômeros/metabolismo , Proteína 1 de Ligação à Proteína Supressora de Tumor p53/químicaRESUMO
OBJECTIVES: Delayed graft function (DGF) is a common early complication after kidney transplantation. The aim of the present study was to evaluate the value of contrast-enhanced ultrasonography (CEUS) in the early prediction of DGF after kidney transplantation. METHODS: A total of 89 renal transplant recipients were retrospectively enrolled and divided into DGF group or normal graft function (NGF) group according to the allograft function. Conventional Doppler ultrasound and CEUS examination data on the first postoperative day were collected and analyzed. RESULTS: The resistive indices of segmental and interlobar artery in the DGF group were significantly higher than those in the NGF group (0.71 ± 0.17 versus 0.63 ± 0.08, P = .006; 0.70 ± 0.16 versus 0.62 ± 0.08, P = .004, respectively). The patients experiencing DGF had significantly lower PI-c (14.7 dB ± 6.1 dB versus 18.5 dB ± 3.3 dB, P = .001) and smaller AUC-c (779.8 ± 375.8 dB·seconds versus 991.0 ± 211.7 dB·seconds, P = .003), as well as significantly lower PI-m (12.6 dB ± 5.9 dB versus 15.9 dB ± 3.9 dB, P = .006), shorter MTT-m (30.7 ± 9.4 seconds versus 36.3 ± 7.1 seconds, P = .01), and smaller AUC-m (P = .007). Multivariate analysis demonstrated that PI-c, AUC-c, and MTT-m were independent risk factors for DGF. The area under the receiver operating characteristic curve values of the combined predicted value (PI-c + MTT-m, PI-c + AUC-c + MTT-m) of DGF incidence were bigger than that of PI-c, AUC-c, or MTT-m. CONCLUSIONS: CEUS parameters of the cortex and medulla have a good value for an early prediction of DGF after renal transplantation.
Assuntos
Transplante de Rim , Ultrassonografia , Humanos , Função Retardada do Enxerto/epidemiologia , Função Retardada do Enxerto/etiologia , Sobrevivência de Enxerto , Transplante de Rim/efeitos adversos , Fator de Crescimento Neural , Estudos Retrospectivos , Fatores de Risco , Ultrassonografia/normasRESUMO
To address the issues of not accurately identifying ice types and thickness in current fiber-optic ice sensors, in this paper, we design a novel fiber-optic ice sensor based on the reflected light intensity modulation method and total reflection principle. The performance of the fiber-optic ice sensor was simulated by ray tracing. The low-temperature icing tests validated the performance of the fiber-optic ice sensor. It is shown that the ice sensor can detect different ice types and the thickness from 0.5 to 5 mm at temperatures of -5 °C, -20 °C, and -40 °C. The maximum measurement error is 0.283 mm. The proposed ice sensor provides promising applications in aircraft and wind turbine icing detection.
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BACKGROUND: Drug repositioning is a very important task that provides critical information for exploring the potential efficacy of drugs. Yet developing computational models that can effectively predict drug-disease associations (DDAs) is still a challenging task. Previous studies suggest that the accuracy of DDA prediction can be improved by integrating different types of biological features. But how to conduct an effective integration remains a challenging problem for accurately discovering new indications for approved drugs. METHODS: In this paper, we propose a novel meta-path based graph representation learning model, namely RLFDDA, to predict potential DDAs on heterogeneous biological networks. RLFDDA first calculates drug-drug similarities and disease-disease similarities as the intrinsic biological features of drugs and diseases. A heterogeneous network is then constructed by integrating DDAs, disease-protein associations and drug-protein associations. With such a network, RLFDDA adopts a meta-path random walk model to learn the latent representations of drugs and diseases, which are concatenated to construct joint representations of drug-disease associations. As the last step, we employ the random forest classifier to predict potential DDAs with their joint representations. RESULTS: To demonstrate the effectiveness of RLFDDA, we have conducted a series of experiments on two benchmark datasets by following a ten-fold cross-validation scheme. The results show that RLFDDA yields the best performance in terms of AUC and F1-score when compared with several state-of-the-art DDAs prediction models. We have also conducted a case study on two common diseases, i.e., paclitaxel and lung tumors, and found that 7 out of top-10 diseases and 8 out of top-10 drugs have already been validated for paclitaxel and lung tumors respectively with literature evidence. Hence, the promising performance of RLFDDA may provide a new perspective for novel DDAs discovery over heterogeneous networks.
Assuntos
Aprendizagem , Neoplasias Pulmonares , Humanos , Benchmarking , Descoberta de Drogas , PaclitaxelRESUMO
BACKGROUND: There is no formal diagnostic criterion for sepsis-induced cardiomyopathy (SICM), but left ventricular ejection fraction (LVEF) < 50% was the most commonly used standard. Tissue motion annular displacement (TMAD) is a novel speckle tracking indicator to quickly assess LV longitudinal systolic function. This study aimed to evaluate the feasibility and discriminatory value of TMAD for predicting SICM, as well as prognostic value of TMAD for mortality. METHODS: We conducted a single-center retrospective observational study in patients with sepsis or septic shock who underwent echocardiography examination within the first 24 h after admission. Basic clinical information and conventional echocardiographic data, including mitral annular plane systolic excursion (MAPSE), were collected. Based on speckle tracking echocardiography (STE), global longitudinal strain (GLS) and TMAD were, respectively, performed offline. The parameters acquisition rate, inter- and intra-observer reliability, time consumed for measurement were assessed for the feasibility analysis. Areas under the receiver operating characteristic curves (AUROC) values were calculated to assess the discriminatory value of TMAD/GLS/MAPSE for predicting SICM, defined as LVEF < 50%. Kaplan-Meier survival curve analysis was performed according to the cutoff values in predicting SICM. Cox proportional hazards model was performed to determine the risk factors for 28d and in-hospital mortality. RESULTS: A total of 143 patients were enrolled in this study. Compared with LVEF, GLS or MAPSE, TMAD exhibited the highest parameter acquisition rate, intra- and inter-observer reliability. The mean time for offline analyses with TMAD was significantly shorter than that with LVEF or GLS (p < 0.05). According to the AUROC analysis, TMADMid presented an excellent discriminatory value for predicting SICM (AUROC > 0.9). Patients with lower TMADMid (< 9.75 mm) had significantly higher 28d and in-hospital mortality (both p < 0.05). The multivariate Cox proportional hazards model revealed that BMI and SOFA were the independent risk factors for 28d and in-hospital mortality in sepsis cases, but TMAD was not. CONCLUSION: STE-based TMAD is a novel and feasible technology with promising discriminatory value for predicting SICM with LVEF < 50%.
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Cardiomiopatias , Sepse , Cardiomiopatias/complicações , Estudos de Viabilidade , Humanos , Reprodutibilidade dos Testes , Sepse/complicações , Volume Sistólico , Função Ventricular EsquerdaRESUMO
Human homolog of mouse double minute 2 (HDM2) is an oncogene frequently overexpressed in cancers with poor prognosis, but mechanisms of controlling its abundance remain elusive. In an unbiased biochemical search, we discovered Skp1-Cullin 1-FBXO22-ROC1 (SCFFBXO22) as the most dominating HDM2 E3 ubiquitin ligase from human proteome. The results of protein decay rate analysis, ubiquitination, siRNA-mediated silencing, and coimmunoprecipitation experiments support a hypothesis that FBXO22 targets cellular HDM2 for ubiquitin-dependent degradation. In human breast cancer cells, FBXO22 knockdown (KD) increased cell invasiveness, which was driven by elevated levels of HDM2. Moreover, mouse 4T1 breast tumor model studies revealed that FBXO22 KD led to a significant increase of breast tumor cell metastasis to the lung. Finally, low FBXO22 expression is correlated with worse survival and high HDM2 expression in human breast cancer. Altogether, these findings suggest that SCFFBXO22 targets HDM2 for degradation and possesses inhibitory effects against breast cancer tumor cell invasion and metastasis.
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Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Movimento Celular/fisiologia , Proteínas F-Box/metabolismo , Invasividade Neoplásica/patologia , Metástase Neoplásica/patologia , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Animais , Linhagem Celular Tumoral , Feminino , Células HCT116 , Células HeLa , Humanos , Células MCF-7 , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Processos Neoplásicos , RNA Interferente Pequeno/metabolismo , Transfecção/métodos , Ubiquitina/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação/fisiologiaAssuntos
Brassica napus , Glucosinolatos , Alelos , Brassica napus/genética , Edição de Genes , Melhoramento VegetalRESUMO
The photoperiodic response is one of the most important factors determining heading date in rice (Oryza sativa). Although rhythmic expression patterns of flowering time genes have been reported to fine-tune the photoperiodic response, posttranslational regulation of key flowering regulators has seldom been elucidated in rice. Heading date 1 (Hd1) encodes a zinc finger transcription factor that plays a crucial role in the photoperiodic response, which determines rice regional adaptability. However, little is known about the molecular mechanisms of Hd1 accumulation during the photoperiod response. Here, we identify a C3HC4 RING domain-containing E3 ubiquitin ligase, Heading date Associated Factor 1 (HAF1), which physically interacts with Hd1. HAF1 mediates ubiquitination and targets Hd1 for degradation via the 26S proteasome-dependent pathway. The haf1 mutant exhibits a later flowering heading date under both short-day and long-day conditions. In addition, the haf1 hd1 double mutant headed as late as hd1 plants under short-day conditions but exhibited a heading date similar to haf1 under long-day conditions, thus indicating that HAF1 may determine heading date mainly through Hd1 under short-day conditions. Moreover, high levels of Hd1 accumulate in haf1. Our results suggest that HAF1 is essential to precise modulation of the timing of Hd1 accumulation during the photoperiod response in rice.
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Flores/fisiologia , Oryza/fisiologia , Proteínas de Plantas/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Sequência de Aminoácidos , Regulação da Expressão Gênica de Plantas , Dados de Sequência Molecular , Mutação , Fotoperíodo , Proteínas de Plantas/genética , Plantas Geneticamente Modificadas , Saccharomyces cerevisiae/genética , Nicotiana/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitinação , Dedos de ZincoRESUMO
The tumor suppressor p53 has recently been shown to regulate energy metabolism through multiple mechanisms. However, the in vivo signaling pathways related to p53-mediated metabolic regulation remain largely uncharacterized. By using mice bearing a single amino acid substitution at cysteine residue 305 of mouse double minute 2 (Mdm2(C305F)), which renders Mdm2 deficient in binding ribosomal proteins (RPs) RPL11 and RPL5, we show that the RP-Mdm2-p53 signaling pathway is critical for sensing nutrient deprivation and maintaining liver lipid homeostasis. Although the Mdm2(C305F) mutation does not significantly affect growth and development in mice, this mutation promotes fat accumulation under normal feeding conditions and hepatosteatosis under acute fasting conditions. We show that nutrient deprivation inhibits rRNA biosynthesis, increases RP-Mdm2 interaction, and induces p53-mediated transactivation of malonyl-CoA decarboxylase (MCD), which catalyzes the degradation of malonyl-CoA to acetyl-CoA, thus modulating lipid partitioning. Fasted Mdm2(C305F) mice demonstrate attenuated MCD induction and enhanced malonyl-CoA accumulation in addition to decreased oxidative respiration and increased fatty acid accumulation in the liver. Thus, the RP-Mdm2-p53 pathway appears to function as an endogenous sensor responsible for stimulating fatty acid oxidation in response to nutrient depletion.
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Fenômenos Fisiológicos da Nutrição Animal/fisiologia , Carboxiliases/metabolismo , Ácidos Graxos/metabolismo , Metabolismo dos Lipídeos/fisiologia , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Proteínas Ribossômicas/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Animais , Células Cultivadas , Embrião de Mamíferos/citologia , Jejum , Fígado Gorduroso/genética , Fígado Gorduroso/fisiopatologia , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Immunoblotting , Metabolismo dos Lipídeos/genética , Camundongos , Camundongos Knockout , Análise de Sequência com Séries de Oligonucleotídeos , Oxirredução , Ligação Proteica , Proteínas Proto-Oncogênicas c-mdm2/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Estresse Fisiológico/fisiologia , Tamoxifeno/análogos & derivados , Tamoxifeno/farmacologia , Transcriptoma/efeitos dos fármacos , Proteína Supressora de Tumor p53/genética , Redução de Peso/genética , Redução de Peso/fisiologiaRESUMO
UNLABELLED: Hypoxia inducible factors (HIFs) are activated in many tumors and show either promoter or suppressor activity, depending on tumor cell biology and background. However, the role of HIF member HIF-2α remains unclear in hepatocellular carcinoma (HCC). Here, HIF-2α expression was measured in HCC and paired peritumoral tissues by quantitative real-time polymerase chain reaction, western blotting, and immunofluorescence assays, and the clinical significance was explored in 246 HCC patients. In cell culture, HIF-2α levels were up-regulated or down-regulated by use of expression or short hairpin RNA recombinant plasmid, respectively. Cells were analyzed by immunoblotting, chromatin immunoprecipitation coupled with microarray, coimmunoprecipitation, and immunohistochemical staining. In vivo tumor growth was analyzed in nude mice. We found that the average expression of HIF-2α was relatively low in HCC tissues, and the decreased level was associated with lower overall survival (P=0.006). High HIF-2α expression in HCC cells induced higher levels of apoptosis and expression of proapoptotic proteins and inhibited cell and tumor growth. Furthermore, HIF-2α inhibited expression of the novel target gene, transcription factor dimerization partner 3 (TFDP3). TFDP3 protein was found to bind with E2F transcription factor 1 (E2F1) and inhibit its transcriptional activity through both p53-dependent and -independent pathways. Reintroduction of TFDP3 expression reversed HIF-2α-induced apoptosis. CONCLUSIONS: Data gathered from cell lines, tumorigenicity studies, and primary HCC samples demonstrate a negative role of HIF-2α in tumors, which is mediated by the TFDP3/E2F1 pathway. Our study provides evidence supporting a possible tumor-suppressor role for HIF-2α and has uncovered a mechanism that links HIF-2α to a fundamental biological regulator, E2F1.
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Apoptose/fisiologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Carcinoma Hepatocelular/fisiopatologia , Fator de Transcrição E2F1/metabolismo , Neoplasias Hepáticas/fisiopatologia , Fator de Transcrição DP1/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/fisiologia , Fator de Transcrição E2F1/genética , Regulação Neoplásica da Expressão Gênica/fisiologia , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Nus , Fator de Transcrição DP1/genéticaRESUMO
Exploiting the intelligent photocatalysts capable of phase separation provides a promising solution to the removal of uranium, which is expected to solve the difficulty in separation and the poor selectivity of traditional photocatalysts in carbonate-containing uranium wastewater. In this paper, the γ-FeOOH/konjac glucomannan grafted with phenolic hydroxyl groups/poly-N-isopropylacrylamide (γ-FeOOH/KGM(Ga)/PNIPAM) thermosensitive hydrogel is proposed as the photocatalysts for extracting uranium from carbonate-containing uranium wastewater. The dynamic phase transformation is demonstrated to confirm the arbitrary transition of γ-FeOOH/KGM(Ga)/PNIPAM thermosensitive hydrogel from a dispersed state with a high specific surface area at low temperatures to a stable aggregated state at high temperatures. Notably, the γ-FeOOH/KGM(Ga)/PNIPAM thermosensitive hydrogel achieves a remarkably high rate of 92.3% in the removal of uranium from the wastewater containing carbonates and maintains the efficiency of uranium removal from uranium mine wastewater at over 90%. Relying on electron spin resonance and free radical capture experiment, we reveal the adsorption-reduction-nucleation-crystallization mechanism of uranium on γ-FeOOH/KGM(Ga)/PNIPAM thermosensitive hydrogel. Overall, this strategy provides a promising solution to treating uranium-contaminated wastewater, showing a massive potential in water purification.
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As post-transcriptional regulators of gene expression, micro-ribonucleic acids (miRNAs) are regarded as potential biomarkers for a variety of diseases. Hence, the prediction of miRNA-disease associations (MDAs) is of great significance for an in-depth understanding of disease pathogenesis and progression. Existing prediction models are mainly concentrated on incorporating different sources of biological information to perform the MDA prediction task while failing to consider the fully potential utility of MDA network information at the motif-level. To overcome this problem, we propose a novel motif-aware MDA prediction model, namely MotifMDA, by fusing a variety of high- and low-order structural information. In particular, we first design several motifs of interest considering their ability to characterize how miRNAs are associated with diseases through different network structural patterns. Then, MotifMDA adopts a two-layer hierarchical attention to identify novel MDAs. Specifically, the first attention layer learns high-order motif preferences based on their occurrences in the given MDA network, while the second one learns the final embeddings of miRNAs and diseases through coupling high- and low-order preferences. Experimental results on two benchmark datasets have demonstrated the superior performance of MotifMDA over several state-of-the-art prediction models. This strongly indicates that accurate MDA prediction can be achieved by relying solely on MDA network information. Furthermore, our case studies indicate that the incorporation of motif-level structure information allows MotifMDA to discover novel MDAs from different perspectives.
Assuntos
Biologia Computacional , MicroRNAs , MicroRNAs/genética , Humanos , Biologia Computacional/métodos , Predisposição Genética para Doença/genética , AlgoritmosRESUMO
It is unclear whether metabolic health corresponds to reduced oncogenesis or vice versa. We study Tudor-interacting repair regulator (TIRR), an inhibitor of p53 binding protein 1 (53BP1)-mediated p53 activation, and the physiological consequences of enhancing tumor suppressor activity. Deleting TIRR selectively activates p53, significantly protecting against cancer but leading to a systemic metabolic imbalance in mice. TIRR-deficient mice are overweight and insulin resistant, even under normal chow diet. Similarly, reduced TIRR expression in human adipose tissue correlates with higher BMI and insulin resistance. Despite the metabolic challenges, TIRR loss improves p53 heterozygous (p53HET) mouse survival and correlates with enhanced progression-free survival in patients with various p53HET carcinomas. Finally, TIRR's oncoprotective and metabolic effects are dependent on p53 and lost upon p53 deletion in TIRR-deficient mice, with glucose homeostasis and orexigenesis being primarily regulated by TIRR expression in the adipose tissue and the CNS, respectively, as evidenced by tissue-specific models. In summary, TIRR deletion provides a paradigm of metabolic deregulation accompanied by reduced oncogenesis.