RESUMEN
Light-absorbing organic aerosols, referred to as brown carbon (BrC), play a vital role in the global climate and air quality. Due to the complexity of BrC chromophores, the identified absorbing substances in the ambient atmosphere are very limited. However, without comprehensive knowledge of the complex absorbing compounds in BrC, our understanding of its sources, formation, and evolution mechanisms remains superficial, leading to great uncertainty in climatic and atmospheric models. To address this gap, we developed a constrained non-negative matrix factorization (NMF) model to resolve the individual ultraviolet-visible spectrum for each substance in dissolved organic aerosols, with the power of ultrahigh-performance liquid chromatography-diode array detector-ultrahigh-resolution mass spectrometry (UHPLC-DAD-UHRMS). The resolved spectra were validated by selected standard substances and validation samples. Approximately 40,000 light-absorbing substances were recognized at the MS1 level. It turns out that BrC is composed of a vast number of substances rather than a few prominent chromophores in the urban atmosphere. Previous understanding of the absorbing feature of BrC based on a few identified compounds could be biased. Weak-absorbing substances missed previously play an important role in BrC absorption when they are integrated due to their overwhelming number. This model brings the property exploration of complex dissolved organic mixtures to a molecular level, laying a foundation for identifying potentially significant compositions and obtaining a comprehensive chemical picture.
RESUMEN
It has been reported that the two major types of RNA interference triggers, the classical Dicer-generated small RNAs (siRNAs), which function with all members of the Argonaute (Ago) protein family in mammals, and the Ago2-sliced small RNAs (sli-siRNAs), which function solely through Ago2, have similar potency in target cleavage and repression. Here, we show that sli-siRNAs are generally more potent than siRNAs in silencing mismatched targets. This phenomenon is usually more apparent in targets that have mismatched nucleotides in the 3' supplementary region than in targets with mismatches in the seed region. We demonstrate that Ago2 slicer activity is a major factor contributing to the greater silencing efficiency of sli-siRNA against mismatched targets and that participation of non-slicing Agos in silencing mismatched siRNA targets may dilute the slicing ability of Ago2. The difference in length of the mature guide RNA used in sli-RISCs and si-RISCs may also contribute to the observed difference in knockdown efficiency. Our data suggest that a sli-siRNA guide strand is likely to have substantially stronger off-target effects than a guide strand with the same sequence in a classical siRNA and that Dicer and non-slicing Agos may play pivotal roles in controlling siRNA target specificity.
Asunto(s)
Disparidad de Par Base , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Animales , Proteínas Argonautas/metabolismo , Línea Celular Tumoral , Células Cultivadas , Células HEK293 , Humanos , Ratones , MicroARNs/química , MicroARNs/metabolismo , Procesamiento Postranscripcional del ARN , ARN Interferente Pequeño/química , Complejo Silenciador Inducido por ARN/metabolismo , Ribonucleasa III/metabolismoRESUMEN
The levels and distribution of synthetic musks (ADBI, AHMI, ATII, HHCB, AHTN, MX and MK) were investigated in farmland soils from the Three Northeast Provinces of China. The total concentrations of SMs ranged from 2.40â¯ng/g to 12.2â¯ng/g (dry weight). HHCB and AHTN were the main pollutants that were detected in all samples, accounting for 99.35% of the total SMs. The hazard quotients were 0.0700 and 0.102 for AHTN and HHCB, respectively. Although the results indicate there is no serious environmental impact, the detection frequency of SMs in the farmland soil is high, which demonstrated that SMs are widely used in the Three Northeast Provinces of China. Therefore, more attention should be given to synthetic musks during environment monitoring and risk assessments for their bioaccumulation, lipophilicity and persistence.
Asunto(s)
Ácidos Grasos Monoinsaturados/análisis , Contaminantes del Suelo/análisis , Tetrahidronaftalenos/análisis , China , Monitoreo del Ambiente , GranjasRESUMEN
COH29 [N-(4-(3,4-dihydroxyphenyl)-5-phenylthiazol-2-yl)-3,4-dihydroxybenzamide], a novel antimetabolite drug developed at City of Hope Cancer Center, has anticancer activity that stems primarily from the inhibition of human ribonucleotide reductase (RNR). This key enzyme in deoxyribonucleotide biosynthesis is the target of established clinical agents such as hydroxyurea and gemcitabine because of its critical role in DNA replication and repair. Herein we report that BRCA-1-defective human breast cancer cells are more sensitive than wild-type BRCA-1 counterparts to COH29 in vitro and in vivo. Microarray gene expression profiling showed that COH29 reduces the expression of DNA repair pathway genes, suggesting that COH29 interferes with these pathways. It is well established that BRCA1 plays a role in DNA damage repair, especially homologous recombination (HR) repair, to maintain genome integrity. In BRCA1-defective HCC1937 breast cancer cells, COH29 induced more double-strand breaks (DSBs) and DNA-damage response than in HCC1937 + BRCA1 cells. By EJ5- and DR-green fluorescent protein (GFP) reporter assay, we found that COH29 could inhibit nonhomologous end joining (NHEJ) efficiency and that no HR activity was detected in HCC1937 cells, suggesting that repression of the NHEJ repair pathway may be involved in COH29-induced DSBs in BRCA1-deficient HCC1937 cells. Furthermore, we observed an accumulation of nuclear Rad51 foci in COH29-treated HCC1937 + BRCA1 cells, suggesting that BRCA1 plays a crucial role in repairing and recovering drug-induced DNA damage by recruiting Rad51 to damage sites. In summary, we describe here additional biologic effects of the RNR inhibitor COH29 that potentially strengthen its use as an anticancer agent.
Asunto(s)
Antimetabolitos Antineoplásicos/farmacología , Benzamidas/farmacología , Reparación del ADN/efectos de los fármacos , Ribonucleótido Reductasas/antagonistas & inhibidores , Tiazoles/farmacología , Animales , Antimetabolitos Antineoplásicos/uso terapéutico , Proteína BRCA1/genética , Benzamidas/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Línea Celular Tumoral , Roturas del ADN de Doble Cadena/efectos de los fármacos , Reparación del ADN por Unión de Extremidades/efectos de los fármacos , Femenino , Xenoinjertos , Humanos , Ratones Endogámicos NOD , Pruebas de Mutagenicidad , Trasplante de Neoplasias , Tiazoles/uso terapéutico , Pez CebraRESUMEN
Mutation of the tumor suppressor TP53 gene occurs in greater than half of all human cancers. In addition to loss of tumor suppressor function of wild-type TP53, gain-of-function mutations endow cancer cells with more malignant properties. R273 is a mutation hotspot with the p.R273H, p.R273C, and p.R273G variants occurring most commonly in patient samples. To better understand the consequences of these R273 mutations, we constructed cancer cell lines expressing TP53 p.R273H, p.R273C, or p.R273G and explored their characteristics. We found that p.R273H and p.R273C, but not p.R273G, enhanced proliferation, invasion, and drug resistance in vitro. Furthermore, breast cancer susceptibility protein 1 was upregulated by mutant TP53 p.R273H and p.R273C in response to DNA damage and repair. Transcriptional analysis of the TP53-R273 mutants by RNA-seq confirmed that the apoptosis pathway was less active in p.R273H and p.R273C, compared with R273G. Molecular dynamics simulation further revealed that TP53-R273G binds more tightly to DNA than TP53-R273H or TP53-R273C. These findings indicate that mutation of TP53 at a single codon has different effects, and likely clinical implications. p.R273H and p.R273C lead to a more aggressive phenotype than p.R273G. These findings may contribute to future diagnosis and therapy in TP53 mutant cancers.
Asunto(s)
Neoplasias de la Mama/genética , Resistencia a Antineoplásicos/genética , Invasividad Neoplásica/genética , Proteína p53 Supresora de Tumor/genética , Apoptosis/genética , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Línea Celular Tumoral , Proliferación Celular , Cisplatino/administración & dosificación , Femenino , Humanos , Simulación de Dinámica Molecular , Mutación , Conformación Proteica , Proteína p53 Supresora de Tumor/químicaRESUMEN
In the late stage of underground brine mining in salt lakes, the method of injecting fresh water is often used to extract the salt from the brine storage medium. This method of freshwater displacement breaks the original water-rock equilibrium and changes the evolution process of the original underground brine. To explore the mechanism of salt release in saline water-bearing media under conditions of relatively fresh lake water dissolution, this paper analyzes the changes in the chemical parameters of brine from 168 sampling points in the Mahai salt lake in the Qaidam Basin at three stages (before exploitation, during exploitation, and late exploitation) by correlation analysis, ion ratio analysis, and other methods and investigate the variations in porosity and the evolution laws of brine. The results show that the changes in the main ion content and brine mineralization during the exploitation process are small. The changes in Ca2+ content are significant due to the low solubility of calcium minerals, the precipitation of gypsum during the mixing process, and the adsorption of cations by alternating with Ca2+. Primary intergranular pore skeletons are easily corroded to form secondary pores, which increase the geological porosity. Na+ and Cl- are the dominant ions in the brine in the study area, but the concentration of Ca2 + decreased significantly under the influence of mining, by 41.7% in the middle period and 24.5% in the late period. The correlation between Ca2+ and salinity changes significantly in different mining stages, and the reason for the decrease of Ca2+ may be due to the influence of mineral dissolution, mixing, and anion-cation exchange. The porosity of the layer in the study area showed the opposite trend of Ca2+, and the porosity increased first and then decreased. The innovation of this paper lies in analyzing the reasons and mechanisms of the disturbance of artificial dissolution mining on stratum structure by comparing the hydrochemical characteristics and porosity of underground brine storage media in three different mining stages. The research in this paper provides a theoretical basis for the calculation of brine resource reserves and the sustainable development of underground brine in salt lake areas.
RESUMEN
Soil/sediment samples of four different land types were collected from aquaculture land, farmland, industrial land and river bottom sediment in the estuary area of Dagu River. The contents of Cr, Cu, Zn, As, Cd and Pb in 0-30 cm inner surface samples were detected, and the distribution characteristics of heavy metal content in surface soil/sediment of different land use types in the estuary area were analyzed. Local accumulation index method, potential risk index evaluation method and principal component analysis method were used to analyze the pollution status and sources of heavy metals. The results showed that the heavy metal accumulation levels in soil and sediment samples in the study area were As > Cd > Cu > Pb > Zn > Cr, and the heavy metal content exceeded the soil background value in Shandong Province, but the potential risks were all in a low risk state. The main sources of Cr, Zn and As are transportation sources and natural sources, while the main sources of Cd and Pb are agricultural.
Asunto(s)
Monitoreo del Ambiente , Metales Pesados , Ríos , Estuarios , Cadmio/análisis , Plomo/análisis , Medición de Riesgo , Metales Pesados/análisis , Suelo , ChinaRESUMEN
The overexpression of RRM2 [RR (ribonucleotide reductase) small subunit M2] dramatically enhances the ability of the cancer cell to proliferate and to invade. To investigate further the relevance of RRM2 and CRCs (colorectal cancers), we correlated the expression of RRM2 with the clinical outcome of CRCs. A retrospective outcome study was conducted on CRCs collected from the COH [(City of Hope) National Medical Center, 217 cases] and ZJU (Zhejiang University, 220 cases). IHC (immunohistochemistry) was employed to determine the protein expression level of RRM2, and quantitative real-time PCR was employed to validate. Multivariate logistic analysis indicated that the adjusted ORs (odds ratios) of RRM2-high for distant metastases were 2.06 [95% CI (confidence interval), 1.01-4.30] and 5.89 (95% CI, 1.51-39.13) in the COH and ZJU sets respectively. The Kaplan-Meier analysis displayed that high expression of RRM2 had a negative impact on the OS (overall survival) and PFS (progress-free survival) of CRC in both sets significantly. The multivariate Cox analysis further demonstrated that HRs (hazard ratios) of RRM2-high for OS were 1.88 (95% CI, 1.03-3.36) and 2.06 (95% CI, 1.10-4.00) in the COH and ZJU sets respectively. Stratification analysis demonstrated that the HR of RRM2 dramatically increased to 12.22 (95% CI, 1.62-258.31) in the MMR (mismatch repair) gene-deficient subgroup in the COH set. Meanwhile, a real-time study demonstrated that down-regulation of RRM2 by siRNA (small interfering RNA) could significantly and specifically reduce the cell growth and adhesion ability in HT-29 and HCT-8 cells. Therefore RRM2 is an independent prognostic factor and predicts poor survival of CRCs. It is also a potential predictor for identifying good responders to chemotherapy for CRCs.
Asunto(s)
Neoplasias Colorrectales/mortalidad , Ribonucleósido Difosfato Reductasa/antagonistas & inhibidores , Adulto , Biomarcadores de Tumor/análisis , Adhesión Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Humanos , Estimación de Kaplan-Meier , Metástasis de la Neoplasia/patología , Pronóstico , ARN Interferente Pequeño/farmacología , Estudios Retrospectivos , Ribonucleósido Difosfato Reductasa/biosíntesisRESUMEN
Four different types of 0-30 cm soil/sediment samples were collected from aquaculture land, farmland, industrial land and river bottom sediment in the estuary area of Dagu River, and the pollution status and sources of 7 PCB congeners were analyzed. The results showed that the mean values of Σ7PCBs in soil/sediments of different land use types were 5.01 ng g-1 dw for industrial land, 3.6 ng g-1 dw for estuarine sediments, 2.09 ng g-1 dw for farmland soil and 1.78 ng g-1 dw for farming land. All samples were at low pollution levels and pose little ecological risks. PCBs in the samples are mainly comprised of highly chlorinated biphenyls, and their content decreases gradually with increasing sampling depth. Based on the principal component analysis, it is concluded that the main source of PCBs in the study area is shipping activities, in addition to atmospheric transport and sedimentation sources.
Asunto(s)
Bifenilos Policlorados , Contaminantes Químicos del Agua , Bifenilos Policlorados/análisis , Estuarios , Ríos , Sedimentos Geológicos/análisis , Monitoreo del Ambiente/métodos , Contaminantes Químicos del Agua/análisis , Suelo , China , Medición de RiesgoRESUMEN
BACKGROUND: Hyalinising clear cell carcinoma (HCCC) of the lung is a rare tumor, with only 12 reported cases. To improve the differential diagnosis, the aim of this study was to clarify the clinicopathological characteristics, immunophenotype, and molecular characteristics of HCCC of the lung and relate these to prognosis. METHODS: Sections of HCCC of the lung were collected from a patient for pathological observation, immunohistochemistry, histochemistry, and fluorescence in situ hybridization; the clinical, pathological, and molecular characteristics were compared with those reported in the literature. RESULTS: The tumor had a well-demarcated border nodule with a maximal diameter of 2.5 cm. Microscopic findings showed either clear or eosinophilic cytoplasm in the tumor cells. Growth was predominantly in the sheets, nests, and trabeculae in a background of hyalinised, fibrotic stroma, and mucus degeneration. Immunohistochemistry showed that the tumor cells expressed cytokeratin 7, P63, P40, CK5/6, Pan Cytokeratin (PCK), and epithelial membrane antigen, whereas they were negative for thyroid transcription factor-1, napsin A, CD10, vimentin, and smooth muscle actin. The Ki67 proliferation index was 5%. The tumor was positive for both period acid-Schiff (PAS) and Alcian blue-PAS, with a small amount of mucus staining positive for PAS-diastase. Fluorescence in situ hybridization revealed Ewing sarcoma breakpoint region 1 rearrangement and Ewing sarcoma breakpoint region 1-activating transcription factor 1 fusion. CONCLUSIONS: HCCC is a low-grade carcinoma with excellent prognosis. Tumour necrosis may be a potential risk factor for recurrence and metastasis. Our review of reported cases suggests that regional lymph node dissection combined with lobectomy is a safer treatment than only lobectomy for HCCC of the lung.
Asunto(s)
Adenocarcinoma de Células Claras , Sarcoma de Ewing , Humanos , Hibridación Fluorescente in Situ , Queratinas/genética , Adenocarcinoma de Células Claras/diagnóstico , Adenocarcinoma de Células Claras/cirugía , Adenocarcinoma de Células Claras/genética , Pulmón/patología , Biomarcadores de TumorRESUMEN
Grasslands are one of the largest coupled human-nature terrestrial ecosystems on Earth, and severe anthropogenic-induced grassland ecosystem function declines have been reported recently. Understanding factors influencing grassland ecosystem functions is critical for making sustainable management policies. Canopy structure is an important factor influencing plant growth through mediating within-canopy microclimate (e.g., light, water, and wind), and it is found coordinating tightly with plant species diversity to influence forest ecosystem functions. However, the role of canopy structure in regulating grassland ecosystem functions along with plant species diversity has been rarely investigated. Here, we investigated this problem by collecting field data from 170 field plots distributed along an over 2000 km transect across the northern agro-pastoral ecotone of China. Aboveground net primary productivity (ANPP) and resilience, two indicators of grassland ecosystem functions, were measured from field data and satellite remote sensing data. Terrestrial laser scanning data were collected to measure canopy structure (represented by mean height and canopy cover). Our results showed that plant species diversity was positively correlated to canopy structural traits, and negatively correlated to human activity intensity. Canopy structure was a significant indicator for ANPP and resilience, but their correlations were inconsistent under different human activity intensity levels. Compared to plant species diversity, canopy structural traits were better indicators for grassland ecosystem functions, especially for ANPP. Through structure equation modeling analyses, we found that plant species diversity did not have a direct influence on ANPP under human disturbances. Instead, it had a strong indirect effect on ANPP by altering canopy structural traits. As to resilience, plant species diversity had both a direct positive contribution and an indirect contribution through mediating canopy cover. This study highlights that canopy structure is an important intermediate factor regulating grassland diversity-function relationships under human disturbances, which should be included in future grassland monitoring and management.
RESUMEN
An increasing number of people tend to live in cities, where they suffer from serious air pollution from anthropogenic sources. Vehicle exhaust and cooking emission are closely related to daily life of urban residents, and could be defined as "urban-lifestyle sources". The primary emissions of urban-lifestyle sources tend to form abundant secondary organic aerosols (SOA) through complicated atmospheric chemistry processes. The newly formed SOA is a kind of complex mixture and causes considerable health effects with high uncertainty. Most studies focus on formation pathway, mass growth potential and chemical feature of urban-lifestyle SOA under simple laboratory conditions. Few studies have measured the urban-lifestyle SOA in ambient air, let alone verified laboratory findings under complicated atmospheric conditions. In this work, we established a new method that combined laboratory simulation and field observation, which quantified the urban-lifestyle SOA with high time resolution under the real atmospheric condition. The complex SOA was measured and resolved by a high-resolution time-of-flight aerosol mass spectrometer (HR-ToF-AMS). The multilinear engine model (ME-2) and multilinear correction methods were used to apply laboratory results into ambient SOA apportionment. It was found that the vehicle source dominated the SOA formation during the diurnal photochemical process, and the SOA:POA ratio of vehicle source was about 1.4 times larger than that of cooking source. The vehicle emission may undergo an alcohol/peroxide & carboxylic acid oxidation pathway and form higher oxidized SOA, while the cooking emission may undergo an alcohol/peroxide oxidation pathway and form relatively lower oxidized SOA. The vehicle SOA and cooking SOA contributed 45.6 % and 24.8 % of OA during a local episode in 2021 winter of downtown Beijing. Our findings could not only provide a new way to quantify urban SOA but also demonstrate some laboratory hypotheses, conducing to understand its ambient contributions, chemical features, and environmental effects.
Asunto(s)
Contaminantes Atmosféricos , Emisiones de Vehículos , Humanos , Emisiones de Vehículos/análisis , Contaminantes Atmosféricos/análisis , Aerosoles/análisis , Culinaria , China , Estilo de Vida , Peróxidos , Material Particulado/análisisRESUMEN
Enterprises do not exist independently of the external environment, so uncertainty affects their earnings volatility and exacerbates the information asymmetry between internal and external stakeholders. As a major manifestation of capital market mispricing, the accrual anomaly is caused by investors' functional fixation on total surplus under information asymmetry. Against this backdrop, taking A-share listed companies in China from 2007 to 2019 as our research objects, this study explores the impact of environmental uncertainty on the accrual anomaly based on the information asymmetry and investor irrationality perspective. We find that environmental uncertainty enterprises facing exacerbates the accrual anomaly in the Chinese stock market, and internal control quality, state ownership and the media coverage will affect this impact. Furthermore, this study shows that there are three factors playing the mediating role in the effect, accounting information quality, investment growth and the investor attention. The results show that environmental uncertainty exacerbates the accrual anomaly driven by information manipulation, empire building and investor irrationality. Improving investor irrationality behavior and restraining the self-interest behavior of managers can help alleviate the mispricing of accruals caused by information asymmetry in psychology.
RESUMEN
As traditional methods of oil shale production emitting high levels of pollutants, in-situ exploitation has aroused great concerns. In order to study the effect of in-situ pyrolysis products on the underground environment, an in-situ oil shale exploitation of underground environment impact laboratory simulation system was designed. Based on the hydrogeological condition of oil shale area in Nong'an City, a physical simulation test was conducted. It was found the temperature of surrounding layers continued to be perturbed after heating of the formation had stopped. The time during which the temperature was perturbed was about 4-5 times the heating period. During the simulation test, stray gas migration through fractures and faults was considered a mechanism for groundwater contamination. In the test, the maximum TOC content in aquifer was the value of 97.0 mg/L. The maximum total petroleum hydrocarbon (TPH) content of the simulated formation was 129 mg/kg after oil pyrolysis.
Asunto(s)
Agua Subterránea , Petróleo , Minerales , Minería , Modelos TeóricosRESUMEN
Biomass burning emits large quantities of phenols, which readily partition into the atmospheric aqueous phase and subsequently may react to produce aqueous secondary organic aerosol (aqSOA). For the first time, we quantitatively explored the influence of phenols emitted from biomass burning on aqSOA formation in the winter of Beijing. A typical haze episode associated with significant aqSOA formation was captured. During this episode, aqueous-phase processing of biomass burning promoted aqSOA formation was identified. Furthermore, high-resolution mass spectrum analysis provided molecular-level evidence of the phenolic aqSOA tracers. Estimation of aqSOA formation rate (RaqSOA) with compiled laboratory kinetic data indicated that biomass-burning phenols can efficiently produce aqSOA at midday, with RaqSOA of 0.42 µg m-3 h-1 accounting for 15 % of total aqSOA formation rate. The results highlight that aqSOA formation of phenols contributes the haze pollution. This implies the importance of regional joint control of biomass burning to mitigate the heavy haze.
Asunto(s)
Contaminantes Atmosféricos , Aerosoles/análisis , Contaminantes Atmosféricos/análisis , Biomasa , Monitoreo del Ambiente , Material Particulado/análisis , Fenoles/análisis , Agua/análisisRESUMEN
Ribonucleotide reductase (RR) is a rate-limiting enzyme that catalyzes de novo conversion of ribonucleotide 5'-diphosphates to the corresponding 2'-deoxynucleotide, essential for DNA synthesis and replication. The mutations or knockout of RR small subunit, p53R2, results in the depletion of mitochondrial DNA (mtDNA) in human, implying that p53R2 might play a critical role for maintaining mitochondrial homeostasis. In this study, siRNA against p53R2 knockdown approach is utilized to examine the impact of p53R2 depletion on mitochondria and to derive underlying mechanism in KB and PC-3 cancer cells. Our results reveal that the p53R2 expression not only positively correlates with mtDNA content, but also partakes in the proper mitochondria function, such as ATP synthesis, cytochrome c oxidase activity and membrane potential maintenance. Furthermore, overexpression of p53R2 reduces intracellular ROS and protects the mitochondrial membrane potential against oxidative stress. Unexpectedly, knockdown of p53R2 has a modest, if any, effect on mitochondrial and total cellular dNTP pools. Taken together, our study provides functional evidence that mitochondria is one of p53R2-targeted organelles and suggests an unexpected function of p53R2, which is beyond known RR function on dNTP synthesis, in mitochondrial homeostatic control.
Asunto(s)
Proteínas de Ciclo Celular/metabolismo , Homeostasis , Mitocondrias/enzimología , Neoplasias/enzimología , Ribonucleótido Reductasas/metabolismo , Adenosina Trifosfato/biosíntesis , Proteínas de Ciclo Celular/genética , Línea Celular Tumoral , ADN Mitocondrial/genética , ADN Mitocondrial/metabolismo , Complejo IV de Transporte de Electrones/metabolismo , Humanos , Potencial de la Membrana Mitocondrial , Neoplasias/genética , Ribonucleótido Reductasas/genéticaRESUMEN
Ribonucleotide reductase small subunit p53R2 was identified as a p53 target gene that provides dNTP for DNA damage repair. However, the slow transcriptional induction of p53R2 in RNA may not be rapid enough for prompt DNA damage repair, which has to occur within a few hours of damage. Here, we demonstrate that p53R2 becomes rapidly phosphorylated at Ser(72) by ataxia telangiectasia mutated (ATM) within 30 min after genotoxic stress. p53R2, as well as its heterodimeric partner RRM1, are associated with ATM in vivo. Mutational studies further indicate that ATM-mediated Ser(72) phosphorylation is essential for maintaining p53R2 protein stability and conferring resistance to DNA damage. The mutation of Ser(72) on p53R2 to alanine results in the hyperubiquitination of p53R2 and reduces p53R2 stability. MDM2, a ubiquitin ligase for p53, interacts and facilitates ubiquitination of the S72A-p53R2 mutant more efficiently than WT-p53R2 after DNA damage in vivo. Our results strongly suggest a novel mechanism for the regulation of p53R2 activity via ATM-mediated phosphorylation at Ser(72) and MDM2-dependent turnover of p53R2 dephosphorylated at the same residue.
Asunto(s)
Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/fisiología , Daño del ADN , Proteínas de Unión al ADN/fisiología , Proteínas Serina-Treonina Quinasas/fisiología , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Ribonucleótido Reductasas/metabolismo , Serina/metabolismo , Proteínas Supresoras de Tumor/fisiología , Proteínas de la Ataxia Telangiectasia Mutada , Proteínas de Ciclo Celular/química , Reparación del ADN , Humanos , Fosforilación , Ribonucleótido Reductasas/química , Rayos UltravioletaRESUMEN
The annual mean PM2.5 mass concentration has decreased because of the stringent emission controls implemented in Beijing, China in recent years, whereas the nitrate NO3- mass fraction in PM2.5 increases gradually. Low-visibility events occur frequently even though PM2.5 pollution has been mitigated significantly, with the daily mean PM2.5 mass concentration mostly less than 75 µg/m3. In this study, the non-linear relationship was analyzed between atmospheric visibility and PM2.5 based on chemical composition from a two-year field observation. Our results showed that NO3- became the main constituent of PM2.5, especially during the haze pollution episodes. A localized parameterization scheme was proposed between the atmospheric extinction coefficient (σext) and major chemical constituents of PM2.5 by multiple linear regression (MLR). The contribution of NO3- to σext increased with increasing air pollution, and NO3- became the most important contributor for PM2.5 above 75 µg/m3. The visibility decreased with increasing NO3- mass fraction for the same PM2.5 mass concentration when PM2.5 was above 20 µg/m3. The hygroscopicity of PM2.5 increased with increasing mass fraction of hygroscopic NO3-. These results stressed the importance of reducing particulate NO3- and its precursors (for instance, NH3) through effective emission control measures as well as the tightening of PM2.5 standards to further improve air quality and visibility in Beijing.
Asunto(s)
Contaminantes Atmosféricos , Contaminación del Aire , Contaminantes Atmosféricos/análisis , Contaminación del Aire/análisis , Beijing , China , Monitoreo del Ambiente , Nitratos , Material Particulado/análisis , Estaciones del AñoRESUMEN
Vasculogenic Mimicry (VM) is the main source of blood supply in the early stage of tumor growth. Carcinoma-associated fibroblasts (CAFs) are one of the most important host cells in the tumor microenvironment. Some studies have found that CAFs can promote tumor angiogenesis, but there are few reports on the relationship between CAFs and VM. Tissue samples were collected from 60 cases of hepatocellular carcinoma (HCC) and 10 persons with normal liver function. The relationship between VM expression and clinicopathologic features was analyzed. Furthermore, the relationship between VM expression and vimentin or α-SMA expression was analyzed. Primary culture of hepatocellular CAFs and the collection of conditioned media were carried out. The effects of hepatocellular CAF conditioned medium on the formation of VM and the levels of VM-related proteins and genes in MHCC-97H cells were studied. The positive rate of VM was 35.0% in HCC tissues. There was no VM expression in normal liver tissues. VM expression was related to tumor diameter, Edmondson grade, clinical stage, and liver cirrhosis. The expression of vimentin and α-SMA in VM-positive patients was higher than in VM-negative patients. Different concentrations of hepatocellular CAF conditioned medium could promote the formation of VM and increase the expression of VM-related genes and proteins (MMP2 and EphA2) in MHCC-97H cells. The results show that there was a significant correlation between VM formation and the expression of vimentin or α-SMA in HCC tissues. The conditioned medium of hepatocellular CAFs may promote VM formation and the expression of VM-related genes and proteins (MMP2 and EphA2) in hepatoma cell line MHCC-97H.