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Viral protein homeostasis depends entirely on the machinery of the infected cell. Accordingly, viruses can illuminate the interplay between cellular proteostasis components and their distinct substrates. Here, we define how the Hsp70 chaperone network mediates the dengue virus life cycle. Cytosolic Hsp70 isoforms are required at distinct steps of the viral cycle, including entry, RNA replication, and virion biogenesis. Hsp70 function at each step is specified by nine distinct DNAJ cofactors. Of these, DnaJB11 relocalizes to virus-induced replication complexes to promote RNA synthesis, while DnaJB6 associates with capsid protein and facilitates virion biogenesis. Importantly, an allosteric Hsp70 inhibitor, JG40, potently blocks infection of different dengue serotypes in human primary blood cells without eliciting viral resistance or exerting toxicity to the host cells. JG40 also blocks replication of other medically-important flaviviruses including yellow fever, West Nile and Japanese encephalitis viruses. Thus, targeting host Hsp70 subnetworks provides a path for broad-spectrum antivirals.
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Dengue/virologia , Proteínas de Choque Térmico HSP70/metabolismo , Replicação Viral , Animais , Proteínas do Capsídeo/metabolismo , Culicidae/virologia , Dengue/metabolismo , Vírus da Dengue , Proteínas de Choque Térmico HSP40/metabolismo , Proteínas de Choque Térmico HSP70/antagonistas & inibidores , Humanos , Replicação Viral/efeitos dos fármacosRESUMO
In diploid mammals, allele-specific three-dimensional (3D) genome architecture may lead to imbalanced gene expression. Through ultradeep in situ Hi-C sequencing of three representative somatic tissues (liver, skeletal muscle, and brain) from hybrid pigs generated by reciprocal crosses of phenotypically and physiologically divergent Berkshire and Tibetan pigs, we uncover extensive chromatin reorganization between homologous chromosomes across multiple scales. Haplotype-based interrogation of multi-omic data revealed the tissue dependence of 3D chromatin conformation, suggesting that parent-of-origin-specific conformation may drive gene imprinting. We quantify the effects of genetic variations and histone modifications on allelic differences of long-range promoter-enhancer contacts, which likely contribute to the phenotypic differences between the parental pig breeds. We also observe the fine structure of somatically paired homologous chromosomes in the pig genome, which has a functional implication genome-wide. This work illustrates how allele-specific chromatin architecture facilitates concomitant shifts in allele-biased gene expression, as well as the possible consequential phenotypic changes in mammals.
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Cromatina , Cromossomos , Animais , Suínos/genética , Cromatina/genética , Haplótipos , Cromossomos/genética , Genoma , Mamíferos/genéticaRESUMO
We extracted the molecular-frame elastic differential cross sections (MFDCSs) for electrons scattering from N_{2}^{+} based on elliptical laser-induced electron diffraction (ELIED), wherein the structural evolution is initialized by the same tunneling ionization and probed by incident angle-resolved laser-induced electron diffraction imaging. To establish ELIED, an intuitive interpretation of the ellipticity-dependent rescattering electron momentum distributions was first provided by analyzing the transverse momentum distribution. It was shown that the incident angle of the laser-induced returning electrons could be tuned within 20° by varying the ellipticity and handedness of the driving laser pulses. Accordingly, the incident angle-resolved DCSs of returning electrons for spherically symmetric targets (Xe^{+} and Ar^{+}) were successfully extracted as a proof-of-principle for ELIED. The MFDCSs for N_{2}^{+} were experimentally obtained at incident angles of 4° and 7°, which were well reproduced by the simulations. The ELIED approach is the only successful method so far for obtaining incident angle-resolved ionic MFDCS, which provides a new sensitive observable for the transient structure retrieval of N_{2}^{+}. Our results suggest that the ELIED has the potential to extract the structural tomographic information of polyatomic molecules with femtosecond and subangstrom spatiotemporal resolutions that can enable the visualization of the nuclear motions in complex chemical reactions as well as chiral recognition.
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Lacking PTRF (polymerase I and transcript release factor), an essential caveolae component, causes a secondary deficiency of caveolins resulting in muscular dystrophy. The transcriptome responses of different types of muscle fibers and mononuclear cells in skeletal muscle to muscular dystrophy caused by Ptrf deletion have not been explored. Here, we created muscular dystrophy mice by Ptrf knockout and applied single-nucleus RNA sequencing (snRNA-seq) to unveil the transcriptional changes of the skeletal muscle at single-nucleus resolution. 11 613 muscle nuclei (WT, 5838; Ptrf KO, 5775) were classified into 12 clusters corresponding to 11 nuclear types. Trajectory analysis revealed the potential transition between type IIb_1 and IIb_2 myonuclei upon muscular dystrophy. Functional enrichment analysis indicated that apoptotic signaling and enzyme-linked receptor protein signaling pathway were significantly enriched in type IIb_1 and IIb_2 myonuclei of Ptrf KO, respectively. The muscle structure development and the PI3K-AKT signaling pathway were significantly enriched in type IIa and IIx myonuclei of Ptrf KO. Meanwhile, metabolic pathway analysis showed a decrease in overall metabolic pathway activity of myonuclei subtypes upon muscular dystrophy, with the most decrease in type IIb_1 myonuclei. Gene regulatory network analysis found that the activity of Mef2c, Mef2d, Myf5, and Pax3 regulons was enhanced in type II myonuclei of Ptrf KO, especially in type IIb_2 myonuclei. In addition, we investigated the transcriptome changes in adipocytes and found that muscular dystrophy enhanced the lipid metabolic capacity of adipocytes. Our findings provide a valuable resource for exploring the molecular mechanism of muscular dystrophy due to Ptrf deficiency.
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Distrofias Musculares , Transcriptoma , Camundongos , Animais , Fosfatidilinositol 3-Quinases/metabolismo , Distrofias Musculares/genética , Músculo Esquelético/metabolismo , Fibras Musculares Esqueléticas/metabolismoRESUMO
OBJECTIVES: To examine the benefits of extended-field chemoradiation with simultaneous integrated boost to positive lymph nodes, followed by image-guided adaptive brachytherapy in patients with cervical cancer with para-aortic metastasis. METHODS: This retrospective cohort study enrolled 143 patients diagnosed between January 2011 and July 2023 at a single center. Survival and recurrence were evaluated using the Kaplan-Meier method and log-rank test. Cox regression was employed to identify prognostic factors and adjust for confounding factors. Patients were then stratified according to neoadjuvant chemotherapy, and its impact on survival outcomes was evaluated. RESULTS: A total of 129 patients completed the entire treatment course. The 5-year overall survival rate was 57.6%, and the para-aortic failure rate was 6.8% after a median follow-up of 61 months (95% CI 49 to 82 months). Multivariate analysis indicated that neoadjuvant chemotherapy, larger primary tumor or pelvic/para-aortic lymph nodes, and lower hemoglobin nadir (for widespread metastasis-free survival only) predicted poorer survival. After propensity score matching, the 5-year para-aortic recurrence-free, widespread metastasis-free, and overall survival rates were 92.2% vs 92.8% (p=0.85), 50.8% vs 72.1% (p=0.007), and 47.5% vs 65.5% (p=0.037), respectively, in groups receiving neoadjuvant chemotherapy or not. Sixteen patients (12.4%) experienced grade 3-4 late toxicities. Patients who received neoadjuvant chemotherapy had a significantly higher incidence of grade 3-4 anemia and neutropenia than those who did not (45.2% vs 26.7% and 38.1% vs 21.8%, respectively), if including another 14 patients who discontinued treatment due to acute vomiting. CONCLUSION: Chemoradiation with simultaneous integrated boost to positive lymph nodes demonstrates favorable outcomes and acceptable late toxicities in para-aortic metastatic cervical cancer. Neoadjuvant chemotherapy has been shown to adversely affect outcomes, and acute vomiting is a major cause of treatment abortion.
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Braquiterapia , Quimiorradioterapia , Metástase Linfática , Neoplasias do Colo do Útero , Humanos , Feminino , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/terapia , Neoplasias do Colo do Útero/mortalidade , Pessoa de Meia-Idade , Estudos Retrospectivos , Quimiorradioterapia/métodos , Adulto , Braquiterapia/métodos , Idoso , Linfonodos/patologia , Terapia Neoadjuvante , Taxa de Sobrevida , Estudos de CoortesRESUMO
Inherent chirality is used to describe chiral cyclic molecules devoid of central, axial, planar, or helical chirality and has tremendous applications in chiral recognition and enantioselective synthesis. Catalytic and divergent syntheses of inherently chiral molecules have attracted increasing interest from chemists. Herein, we report the enantioselective synthesis of inherently chiral tribenzocycloheptene derivatives via chiral phosphoric acid (CPA)-catalyzed condensation of cyclic ketones and hydroxylamines. This chemistry paves the way to accessing the less stable derivatives of 7-membered rings with inherent chirality. A series of chiral tribenzocycloheptene oxime ethers was synthesized in good yields (up to 97 %) with excellent enantioselectivities (up to 99 % ee).
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Skeletal muscle differentiation (myogenesis) is a complex and highly coordinated biological process regulated by a series of myogenic marker genes. Chromatin interactions between gene's promoters and their enhancers have an important role in transcriptional control. However, the high-resolution chromatin interactions of myogenic genes and their functional enhancers during myogenesis remain largely unclear. Here, we used circularized chromosome conformation capture coupled with next generation sequencing (4C-seq) to investigate eight myogenic marker genes in C2C12 myoblasts (C2C12-MBs) and C2C12 myotubes (C2C12-MTs). We revealed dynamic chromatin interactions of these marker genes during differentiation and identified 163 and 314 significant interaction sites (SISs) in C2C12-MBs and C2C12-MTs, respectively. The interacting genes of SISs in C2C12-MTs were mainly involved in muscle development, and histone modifications of the SISs changed during differentiation. Through functional genomic screening, we also identified 25 and 41 putative active enhancers in C2C12-MBs and C2C12-MTs, respectively. Using luciferase reporter assays for putative enhancers of Myog and Myh3, we identified eight activating enhancers. Furthermore, dCas9-KRAB epigenome editing and RNA-Seq revealed a role for Myog enhancers in the regulation of Myog expression and myogenic differentiation in the native genomic context. Taken together, this study lays the groundwork for understanding 3D chromatin interaction changes of myogenic genes during myogenesis and provides insights that contribute to our understanding of the role of enhancers in regulating myogenesis.
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Diferenciação Celular , Cromatina , Elementos Facilitadores Genéticos , Desenvolvimento Muscular , Mioblastos , Animais , Linhagem Celular , Cromatina/genética , Cromatina/metabolismo , Código das Histonas , Camundongos , Desenvolvimento Muscular/genética , Fibras Musculares Esqueléticas , Mioblastos/citologiaRESUMO
BACKGROUND: Skeletal muscles consist of fibers of differing contractility and metabolic properties, which are primarily determined by the content of myosin heavy chain (MYH) isoforms (MYH7, MYH2, MYH1, and MYH4). The regulation of Myh genes transcription depends on three-dimensional chromatin conformation interaction, but the mechanistic details remain to be determined. RESULTS: In this study, we characterized the interaction profiles of Myh genes using 4C-seq (circular chromosome conformation capture coupled to high-throughput sequencing). The interaction profile of Myh genes changed between fast quadriceps and slow soleus muscles. Combining chromatin immunoprecipitation-sequencing (ChIP-seq) and transposase accessible chromatin with high-throughput sequencing (ATAC-seq), we found that a 38 kb intergenic region interacting simultaneously with fast Myh genes promoters controlled the coordinated expression of fast Myh genes. We also identified four active enhancers of Myh7, and revealed that binding of MYOG and MYOD increased the activity of Myh7 enhancers. CONCLUSIONS: This study provides new insight into the chromatin interactions that regulate Myh genes expression.
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Músculo Esquelético , Cadeias Pesadas de Miosina , Cromatina/genética , Cromatina/metabolismo , Expressão Gênica , Músculo Esquelético/metabolismo , Cadeias Pesadas de Miosina/genética , Cadeias Pesadas de Miosina/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismoRESUMO
Sonodynamic therapy as a promising noninvasive modality is being developed for tumor therapy, but there is a lack of next-generation sonosensitizers that can generate full ROS at high yields and simultaneously deplete elevated levels of glutathione (GSH) in tumor cells. Semiconductor p-n junctions are engineered as high-efficacy sonosensitizers for sonodynamic tumor eradication using pyridine N-doped carbon dots (N-CDs) as a p-type semiconductor and oxygen-deficient TiO2-x nanosheets as a n-type semiconductor. The rate constants of 1 O2 and â¢OH generation by ultrasound-excited N-CD@TiO2-x p-n junctions are 4.3 and 4.5 times higher than those of TiO2 , respectively. A Z-scheme carrier migration mechanism in the p-n junction achieving the rapid spatial separation of the ultrasound-generated electron-hole pairs for enhanced full ROS production is proposed. GSH-cleavable, Pt-crosslinked, N-doped CD fluorescent probes to detect the presence of intracellular GSH are also constructed. A GSH-responsive, p-n junction platform (Pt/N-CD@TiO2-x ) with integrated GSH detection, GSH depletion, and enhanced sonodynamic performance is then assembled. Malignant tumors are completely eradicated without relapse via intravenous administration of low-dose Pt/N-CD@TiO2-x under ultrasound irradiation. This work substantiates the great potential of biocompatible, GSH-responsive p-n junctions as next-generation sonosensitizers via p-n junction-enhanced ROS generation and metal ion oxidation of intracellular GSH.
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Platina , Terapia por Ultrassom , Carbono , Linhagem Celular Tumoral , Glutationa , Humanos , Espécies Reativas de Oxigênio , RecidivaRESUMO
How the neighbor effect plays its role in the fragmentation of molecular clusters attracts great attention for physicists and chemists. Here, we study this effect in the fragmentation of N_{2}O dimer by performing three-body coincidence measurements on the femtosecond timescale. Rotations of bound N_{2}O^{+} triggered by neutral or ionic neighbors are tracked. The forbidden dissociation path between B^{2}Π and ^{4}Π is opened by the spin-exchange effect due to the existence of neighbor ions, leading to a new channel of N_{2}O^{+}âNO+N^{+} originating from B^{2}Π. The formation and dissociation of the metastable product N_{3}O_{2}^{+} from two ion-molecule reaction channels are tracked in real time, and the corresponding trajectories are captured. Our results demonstrate a significant and promising step towards the understanding of neighbor roles in the reactions within clusters.
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In this study, a nitrogen-boron codoped carbon layer, Na3V2(PO4)2F3 sample, obtained by using an ionic liquid-acrylic acid copolymer as the nitrogen-boron source was used as the cathode material for sodium-ion batteries. The optimized and modified nitrogen and boron codoped carbon layer, Na3V2(PO4)2F3 (denoted as NVPF-PCNB-20), illustrated better rate capability and cycling performance. The discharge capacities of NVPF-PCNB-20 at 0.5C and 10C were 109 and 90 mAh g-1, respectively, and the capacity retention rate was 93.2% after 100 cycles at 0.5C and 92.8% after 750 cycles at 10C. Through in situ X-ray diffraction analysis of NVPF-PCNB-20, the results show that the modified Na3V2(PO4)2F3 has excellent cycle reversibility. The scanning electron microscopy and transmission electron microscopy images reveal that NVPF-PCNB-20 particles were finer and covered by a uniform coating. The results show that the ionic liquid-acrylic acid copolymer not only make the material dispersion more uniform but also enhance the electronic conductivity and sodium storage performance of Na3V2(PO4)3F3 effectively. This study may provide an effective way to synthesize nitrogen and boron codoped carbon-coated Na3V2(PO4)2F3 with excellent electrochemical performance.
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BACKGROUND: CD97 is the most widely expressed G protein-coupled receptor in the epidermal growth factor seven-span transmembrane family. It plays a vital role in cell adhesion, migration, and cell connection regulation. We explored the role of CD97 in hepatocellular carcinoma (HCC). METHODS: We evaluated CD97 mRNA expression in HCC using TNMplot and the Gene Expression Omnibus database. The clinical prognostic significance of CD97 in HCC patients was evaluated by gene expression profiling interactive analysis, the Kaplan-Meier plotter, and the UALCAN database. The Tumor Immune Estimation Resource (TIMER) and CIBERSORT databases were used to analyze the relationships among CD97, genes positively related with CD97, and tumor-infiltrating immune cells. RESULTS: CD97 was highly expressed in HCC tissues and was associated with an adverse prognosis. CD97 and genes positively related with CD97 were positively correlated with the abundance of tumor-infiltrating immune cells and strongly correlated with tumor-infiltrating macrophages (all r ≥ 0.513, P < 0.001). CD97 was positively correlated with M2 macrophage and tumor-associated macrophage markers (both r ≥ 0.464, P < 0.001). CD97 was found to be an immune-related gene in HCC and positively correlated with the TOX, PD-L1, PD-L2, CTLA4, and PD-1 immune checkpoint genes. CD97 copy number alterations affect the level of immune cell infiltration and mRNA expression. CONCLUSIONS: CD97 can be used as a potential molecular marker of prognosis in HCC, which is associated with immune cell infiltration.
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Biomarcadores Tumorais , Carcinoma Hepatocelular , Neoplasias Hepáticas , Receptores Acoplados a Proteínas G , Humanos , Biomarcadores , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/patologia , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/imunologia , RNA Mensageiro/genética , RNA Mensageiro/imunologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/imunologia , Macrófagos Associados a Tumor/imunologia , Bases de Dados FactuaisRESUMO
OBJECTIVE: The prognostic role of the number of cycles of adjuvant chemotherapy (ACT) after total mesorectal excision in stage III and high-risk stage II rectal cancer is unknown. As a result of this, our study was designed to assess the effect of the number of cycles of ACT on the prediction of cancer-specific survival. METHODS: Four hundred patients that were diagnosed as stage III and high-risk stage II rectal cancer from January 2012 to January 2018 and who had received total mesorectal excision were enrolled in this study. A nomogram incorporating the number of cycles of ACT was also developed in this study. For internal validation, the bootstrap method was used and the consistency index was used to evaluate the accuracy of the model. The patients were stratified into risk groups according to their tumor characteristics by recursive partitioning analysis. RESULTS: We found that the risk of death was decreased by 26% (HR = 0.74, 95% CI: 0.61-0.89, P = 0.0016) with each increasing ACT cycle. The N stage, positive lymph node ratio (PLNR), carcinoembryonic antigen, neutrophil-to-lymphocyte ratio, and the number of cycles of ACT were chosen and entered into the nomogram model. Recursive partitioning analysis-based risk stratification revealed a significant difference in the prognosis in rectal cancer patients with high-risk, intermediate-risk, and low-risk (3-year cancer-specific survival: 0.246 vs. 0.795 vs. 0.968, P < 0.0001). Seven or more cycles of ACT yielded better survival in patients with PLNR ≥ 0.28 but not in patients with PLNR < 0.28. CONCLUSION: In conclusion, the nomogram prognosis model based on the number of cycles of ACT predicted individual prognosis in rectal cancer patients who had undergone total mesorectal excision. These findings further showed that in patients with PLNR ≥ 0.28, no fewer than 7 cycles of ACT are needed to significantly reduce the patient's risk of death.
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Neoplasias Retais , Neoplasias Testiculares , Quimioterapia Adjuvante , Humanos , Masculino , Estadiamento de Neoplasias , Nomogramas , Prognóstico , Neoplasias Retais/tratamento farmacológico , Neoplasias Retais/patologia , Neoplasias Retais/cirurgia , Estudos Retrospectivos , Neoplasias Testiculares/patologiaRESUMO
The novel strong field autoionization (SFAI) dynamics is identified and investigated by channel-resolved angular streaking measurements of two electrons and two ions for the double-ionized CO. Comparing with the laser-assisted autoionization calculations, we demonstrate the electrons from SFAI are generated from the field-induced decay of the autoionizing state with a following acceleration in the laser fields. The energy-dependent photoelectron angular distributions further reveal that the subcycle ac-Stark effect modulates the lifetime of the autoionizing state and controls the emission of SFAI electrons in molecular frame. Our results pave the way to control the emission of resonant high-harmonic generation and trace the electron-electron correlation and electron-nuclear coupling by strong laser fields. The lifetime modulation of quantum systems in the strong laser field has great potential for quantum manipulation of chemical reactions and beyond.
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Aging often leads to an increase risk of age-related diseases, and the development of anti-aging drugs have become the trend and focus of the current scientific research. In this experiment, serum samples from healthy people of different ages were analyzed based on clinical lipidomics, and a total of 10 potential biomarkers in middle-aged and youth group, 20 biomarkers in the youth and the elderly group were obtained. Furthermore, dhSph and dhCer involved above may affect the aging process through sphingolipid metabolic pathway. As the first and rate-limiting step of catalyzing de novo sphingolipid pathway, SPT may play a key role in human anti-aging, which is revealed by lipidomics liposome tracer analysis. The potential active components in ginseng on SPT was further verified by molecular docking virtual screening and atomic force microscope. Four ingredients of ginseng may reduce the levels of metabolites dhSph and dhCer by inhibiting the activity of SPT, and play an anti-aging effect by affecting the sphingolipid metabolism pathway.A clinical trials registration number: ChiCTR1900026836.
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Lipidômica , Panax , Adolescente , Idoso , Envelhecimento , Biomarcadores , Humanos , Pessoa de Meia-Idade , Simulação de Acoplamento MolecularRESUMO
The molecular chaperone, Heat Shock Protein 70 (Hsp70), is an emerging drug target for neurodegenerative diseases, because of its ability to promote degradation of microtubule-associated protein tau (MAPT/tau). Recently, we reported YM-08 as a brain penetrant, allosteric Hsp70 inhibitor, which reduces tau levels. However, the benzothiazole moiety of YM-08 is vulnerable to metabolism by CYP3A4, limiting its further application as a chemical probe. In this manuscript, we designed and synthesized seventeen YM-08 derivatives by systematically introducing halogen atoms to the benzothiazole ring and shifting the position of the heteroatom in a distal pyridine. In microsome assays, we found that compound JG-23 has 12-fold better metabolic stability and it retained the ability to reduce tau levels in two cell-based models. These chemical probes of Hsp70 are expected to be useful tools for studying tau homeostasis.
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Benzotiazóis/farmacologia , Proteínas de Choque Térmico HSP70/antagonistas & inibidores , Tiazolidinas/farmacologia , Proteínas tau/antagonistas & inibidores , Benzotiazóis/síntese química , Benzotiazóis/química , Relação Dose-Resposta a Droga , Proteínas de Choque Térmico HSP70/metabolismo , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Tiazolidinas/síntese química , Tiazolidinas/química , Proteínas tau/metabolismoRESUMO
Lamin proteins in animals are implicated in important nuclear functions, including chromatin organization, signalling transduction, gene regulation and cell differentiation. Nuclear Matrix Constituent Proteins (NMCPs) are lamin analogues in plants, but their regulatory functions remain largely unknown. We report that OsNMCP1 is localized at the nuclear periphery in rice (Oryza sativa) and induced by drought stress. OsNMCP1 overexpression resulted in a deeper and thicker root system, and enhanced drought resistance compared to the wild-type control. An assay for transposase accessible chromatin with sequencing (ATAC-seq) analysis revealed that OsNMCP1-overexpression altered chromatin accessibility in hundreds of genes related to drought resistance and root growth, including OsNAC10, OsERF48, OsSGL, SNAC1 and OsbZIP23. OsNMCP1 can interact with SWITCH/SUCROSE NONFERMENTING (SWI/SNF) chromatin remodelling complex subunit OsSWI3C. The reported drought resistance or root growth-related genes that were positively regulated by OsNMCP1 were negatively regulated by OsSWI3C under drought stress conditions, and OsSWI3C overexpression led to decreased drought resistance. We propose that the interaction between OsNMCP1 and OsSWI3C under drought stress conditions may lead to the release of OsSWI3C from the SWI/SNF gene silencing complex, thus changing chromatin accessibility in the genes related to root growth and drought resistance.
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Oryza , Cromatina , Secas , Regulação da Expressão Gênica de Plantas , Laminas , Oryza/genética , Oryza/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Plantas Geneticamente Modificadas/metabolismo , Estresse Fisiológico/genéticaRESUMO
Under acute hypoxia, multiple ion channels on the cell membrane are activated, causing cell swelling and eventually necrosis. LRRC8A is an indispensable protein of the volume-regulated anion channel (VRAC), which participates in swelling and the acceleration of cell necrosis. In this study, we revealed a dynamic change in the expression level of the LRRC8 family during hypoxia in 3T3-L1 cells. The disruption of LRRC8A in 3T3-L1 cells was also associated with a significant anti-necrotic phenotype upon hypoxia accompanied by the reduced expression of necrosis-related genes. In vivo, differential expression of LRRC8 family members was also identified between high-altitude pigs and their low-altitude relatives. Taken these findings together, this study demonstrates the involvement of LRRC8A in hypoxia-induced cell necrosis.
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Hipóxia Celular/genética , Expressão Gênica , Hipóxia/genética , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Células 3T3-L1 , Animais , Sistemas CRISPR-Cas , Sobrevivência Celular/genética , Feminino , Técnicas de Inativação de Genes , Camundongos , Mioblastos Cardíacos/metabolismo , Necrose/genética , Ratos , Mucosa Respiratória/metabolismo , Suínos , TransfecçãoRESUMO
A variety of adverse conditions including drought stress severely affect rice production. Root system plays a critical role in drought avoidance, which is one of the major mechanisms of drought resistance. In this study, we adopted genome-wide association study (GWAS) to dissect the genetic basis controlling various root traits by using a natural population consisting of 529 representative rice accessions. A total of 413 suggestive associations, containing 143 significant associations, were identified for 21 root traits, such as maximum root length, root volume, and root dry weight under normal and drought stress conditions at the maturation stage. More than 80 percent of the suggestive loci were located in the region of reported QTLs for root traits, while about 20 percent of suggestive loci were novel loci detected in this study. Besides, 11 reported root-related genes, including DRO1, WOX11, and OsPID, were found to co-locate with the association loci. We further proved that the association results can facilitate the efficient identification of causal genes for root traits by the two case studies of Nal1 and OsJAZ1. These loci and their candidate causal genes provide an important basis for the genetic improvement of root traits and drought resistance.
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Oryza/genética , Raízes de Plantas/genética , Locos de Características Quantitativas/genética , Mapeamento Cromossômico , Cromossomos de Plantas/genética , Secas , Regulação da Expressão Gênica de Plantas , Genoma de Planta , Estudo de Associação Genômica Ampla , Oryza/crescimento & desenvolvimento , Raízes de Plantas/crescimento & desenvolvimentoRESUMO
Magnetic resonance based electrical properties tomography (MREPT) is a different method from proton density imaging, Bloch-Siegert shift (BSS) is used in this paper to reconstruct the radiofrequency (RF) field amplitude and calculate the distribution of the permittivity constant. The phase of the RF field is approximated by the phase component of the magnetization intensity, and the conductivity distribution is calculated. In the experiment, Bruker 7.0 T magnetic resonance device was used to image two water models and in vivo Balb/c mice to obtain the image of electrical characteristics. Experimental results show that the Bloch-siegert B1+ image is significantly more efficient than the double-angle B1+ image. The study can provide a reference for selecting appropriate B1 mapping technology for B1 field imaging of electrical characteristics organizations, and provide basic research support for promoting the practical application of magnetic resonance characteristics.