The high-risk (HR) human papillomaviruses (HPV) are causative agents of anogenital tract dysplasia and cancers and a fraction of head and neck cancers. The HR HPV E6 oncoprotein possesses canonical ...oncogenic functions, such as p53 degradation and telomerase activation. It is also capable of stimulating expression of several oncogenes, but the molecular mechanism underlying these events is poorly understood. Here, we provide evidence that HPV16 E6 physically interacts with histone H3K4 demethylase KDM5C, resulting in its degradation in an E3 ligase E6AP- and proteasome-dependent manner. Moreover, we found that HPV16-positive cancer cell lines exhibited lower KDM5C protein levels than HPV-negative cancer cell lines. Restoration of KDM5C significantly suppressed the tumorigenicity of CaSki cells, an HPV16-positive cervical cancer cell line. Whole genome ChIP-seq and RNA-seq results revealed that CaSki cells contained super-enhancers in the proto-oncogenes
and
Ectopic KDM5C dampened these super-enhancers and reduced the expression of proto-oncogenes. This effect was likely mediated by modulating H3K4me3/H3K4me1 dynamics and decreasing bidirectional enhancer RNA transcription. Depletion of KDM5C or HPV16 E6 expression activated these two super-enhancers. These results illuminate a pivotal relationship between the oncogenic E6 proteins expressed by HR HPV isotypes and epigenetic activation of super-enhancers in the genome that drive expression of key oncogenes like
and
This study suggests a novel explanation for why infections with certain HPV isotypes are associated with elevated cancer risk by identifying an epigenetic mechanism through which E6 proteins expressed by those isotypes can drive expression of key oncogenes.
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Bone marrow mesenchymal stem cells (BMSCs) are widely used for therapeutic applications in tissue engineering and regenerative medicine. Nevertheless, the function of BMSCs is adversely affected by ...senescence. Thus, understanding the molecular mechanisms that contribute to BMSC senescence is critical for the development of BMSC-based tissue engineering and regenerative medicine. In this study, senescent BMSCs were characterized with >80 % of BMSCs stained positive for SA-β-gal, increased expressions of senescence-related genes (p16INK4a and p21Waf1). These senescent characters were accompanied by elevated autophagic activity, up-regulation of interleukin 6 (IL-6), IL-8, and FoxO3a. Autophagic activity inhibition alleviated the senescent state with reduced levels of IL-6 and IL-8 during BMSC senescence. The enhanced autophagic activity upregulated the levels of IL-6 and IL-8 which is associated with up-regulation of FoxO3a, and knockdown of FoxO3a reduced IL-6 and IL-8 expression in senescent BMSCs. Therefore, this study indicated the pivotal role of autophagic activity in the expressions of IL-6 and IL-8 during BMSC senescence, which is regulated by FoxO3a.
•Autophagy affects the progression of BMSC senescence.•Autophagic activity modulates the levels of IL-6 and IL-8 during BMSC senescence.•FoxO3a plays a critical role in the expression of IL6 and IL8 that allows autophagy to enhance senescent phenotype of BMSCs.
This paper evaluates the effect of High Speed Rail (HSR) projects on the economic growth of targeted city nodes (HSR cities) in China using prefectural-level city data from 1990 to 2013. Employing a ...panel data program evaluation method devised by Hsiao, Ching, and Wan (2012), we construct hypothetical counterfactuals for per capita real GDP of HSR cities in the absence of their respective HSR projects using the outcomes in selected non-HSR cities. We find that the responses to HSR treatment are heterogeneous with regard to location, route, and region. The location-level impact ranges between 5% and 59% and is not temporary. HSR cities with positive effects concentrate along the Hu-Ning Segment, the Yong-Tai-Wen-Fu-Xia Segment, and within the Hunan province along the Wu-Guang HSR. These cities are mainly located in the eastern coastal regions of China, in core urban agglomeration regions that allow them to be transportation hubs. In general, the gain for local economies is greater for cities that are more industrialized, with more ability of the service sector to absorb enough labor, and with better supporting infrastructure. On the other hand, local protectionism hampers the development of HSR cities. We also show that at different project stages, HSR cities experience different gains.
Abstract
Background
Images from magnetic resonance imaging (MRI) are crucial unstructured data for prognostic evaluation in nasopharyngeal carcinoma (NPC). We developed and validated a prognostic ...system based on the MRI features and clinical data of locoregionally advanced NPC (LA-NPC) patients to distinguish low-risk patients with LA-NPC for whom concurrent chemoradiotherapy (CCRT) is sufficient.
Methods
This multicenter, retrospective study included 3444 patients with LA-NPC from January 1, 2010, to January 31, 2017. A 3-dimensional convolutional neural network was used to learn the image features from pretreatment MRI images. An eXtreme Gradient Boosting model was trained with the MRI features and clinical data to assign an overall score to each patient. Comprehensive evaluations were implemented to assess the performance of the predictive system. We applied the overall score to distinguish high-risk patients from low-risk patients. The clinical benefit of induction chemotherapy (IC) was analyzed in each risk group by survival curves.
Results
We constructed a prognostic system displaying a concordance index of 0.776 (95% confidence interval CI = 0.746 to 0.806) for the internal validation cohort and 0.757 (95% CI = 0.695 to 0.819), 0.719 (95% CI = 0.650 to 0.789), and 0.746 (95% CI = 0.699 to 0.793) for the 3 external validation cohorts, which presented a statistically significant improvement compared with the conventional TNM staging system. In the high-risk group, patients who received induction chemotherapy plus CCRT had better outcomes than patients who received CCRT alone, whereas there was no statistically significant difference in the low-risk group.
Conclusions
The proposed framework can capture more complex and heterogeneous information to predict the prognosis of patients with LA-NPC and potentially contribute to clinical decision making.
Maize
and
transcription factors belong to the MYB-type and bHLH families, respectively, and control anthocyanin biosynthesis. In this study,
-mediated transformation was used to generate transgenic ...wheat plants that overexpress
and
or both, with the objective of developing anthocyanin-enriched wheat germplasm. Three kinds of stable transgenic wheat lines were obtained. The integration of target genes in the transgenic wheat plants was confirmed by fluorescence in situ hybridization (FISH) analysis. We found that single overexpression of
regulates pigmentation in the vegetative tissues such as coleoptiles, auricles, and stems. The single overexpression of
controls the coloration in reproductive tissue like spikelets and seeds. The simultaneous overexpression of
and
showed the strongest pigmentation in almost all tissues. Furthermore, quantitative real-time PCR (qRT-PCR) analysis revealed that expression of the two transgenes, and of two conserved homologous and six associated structural genes involved in anthocyanin biosynthesis in wheat were greatly up-regulated in the transgenic plants. Similarly, quantitative analysis for anthocyanin amounts based on HPLC-MS also confirmed that the transgenic wheat plants with combined overexpression of
and
accumulated the highest quantity of pigment products. Moreover, developing seeds overexpressing
exposed to light conditions showed up-regulated transcript levels of anthocyanin biosynthesis-related genes compared to dark exposure, which suggests an important role of light in regulating anthocyanin biosynthesis. This study provides a foundation for breeding wheat materials with high anthocyanin accumulation and understanding the mechanism of anthocyanin biosynthesis in wheat.
The standard Fast Iterative Shrinkage-Thresholding Algorithm (FISTA) adopts a search approach consisting of linear increases to determine the step size of the internal gradient. If the input of the ...initial step-size is not accurate, the convergence of FISTA may be restricted when the linear search scheme is applied. To overcome this problem, we tentatively reduce the step size before each iteration to then obtain the most suitable step-size using a linear search approach. To ensure the convergence of the algorithm, we introduce the step size for the previous and subsequent iterations during the calculation process. This has allowed us sparse-spike deconvolution based on an adaptive step size algorithm (ASFISTA), which to a certain extent solves the problem of the degree of convergence of the standard method. In this paper we first present the new algorithm and then we test its convergence. In order to check the effectiveness of the modified algorithm, we use both the standard FISTA method and the improved ASFISTA method to conduct sparse spike deconvolution on a theoretical model. Finally, we carry out a similar analysis aimed at the recovery of the sparse real signal.
•The method is an adaptive step-size fast iterative shrinkage-thresholding algorithm.•The method is more accurate as that of the standard FISTA method.•The method has a great potential in applications of deconvolution.
Some painted pottery figurines were excavated from the tomb of Qibi Ming of the Tang Dynasty. A series of analytical techniques were employed to understand the craftsmanship of these painted pottery ...figurines. The pigment, cross-section, adhesive, and firing temperature were analyzed using microscopy (OM), energy X-ray fluorescence spectrometry (EDX), micro-Raman spectroscopy, pyrolysis-gas chromatography-mass spectrometry (Py-GC/MS), and a dilatometer (DIL). The results demonstrated that the surface of the pigment layers had degraded to different degrees. The pigment particles were litharge, gypsum, malachite, cinnabar, hematite, minium, white lead, and carbon black. The cross-sectional images show that the painted layer of figurines 10-0966 and 10-0678 included a pigment layer and a preparation layer. The preparation layer of both pigments was lead white. Animal glue was used as an adhesive. The firing temperature of the pottery figurines was likely 1080 °C. This study can provide more accurate information with regard to the composition of the raw materials utilized in the making of these artifacts and support the selection of appropriate substances for the purposes of conservation and restoration of the painted pottery figurines.
•Expression of 1Dy12 in wheat mutant AS273 was decreased during grain development.•A stop codon caused by base change led to truncated translation of 1Dy12 in AS273.•The absence of 1Dy12 influenced ...the accumulation of seed storage proteins and GMPs.•The absence of 1Dy12 led to a larger size PBs and an inferior flour-processing quality.
Dissecting the functions of high molecular weight glutenin subunits (HMW-GSs) is helpful for improving wheat quality via breeding. In this study, we used a wheat mutant AS273 in which HMW-GS 1Dy12 was silenced to investigate the silencing mechanism of 1Dy12 and its effects on gluten accumulation and flour-processing quality. Results suggested that the expression of 1Dy12 in AS273 was decreased by one fifth during grain development; a stop codon produced by a base mutation (C/T) led to truncated translation; the absence of 1Dy12 stimulated the accumulation of low molecular weight glutenin subunits (LMW-GSs), gliadins, and glutenin macropolymers, and was resulted in larger protein bodies; AS273 had an inferior flour-processing performance. Based on the outputs achieved in this study it is concluded that 1Dy12 makes important contributions to bread, sponge cake and biscuit-processing quality.
Parkinson's disease (PD) is a neurodegenerative disorder caused by various factors such as neuroinflammation, oxidative stress, mitochondrial dysfunction, and neuronal apoptosis. Recent studies have ...shown that H2S supplementation reverses neuronal loss and mitigates motor deficits in PD patients through anti-inflammatory, antioxidant, improved mitochondrial function and proautophagic. Therefore, the discovery and use of H2S donors may be an exciting and intriguing strategy for the treatment of PD. Herein, we report a red emission mitochondria-targetable fluorescent probe, Rho-H2S, which can specifically and sensitively detect H2S with a limit of detection of 62.5 nM. Bioimaging experiments have shown that the probe has excellent mitochondrial targeting and good imaging capabilities for the detection of exogenous and endogenous H2S in cells. More importantly, based on the Rho-H2S probe, we first confirmed the sulforaphane (SFN) among 15 glucosinolate and isothiocyanate compounds from cruciferous vegetables with an outstanding ability to release H2S and we further proved that SFN could alleviate the symptoms of PD in vivo. All results demonstrate that Rho-H2S could be an effective tool for screening H2S donors and can contribute to the development of new therapeutic strategies for PD.
Ferroptosis is an iron-regulated, caspase-mediated pathway of cell death that is associated with the excessive aggregation of lipid-reactive oxygen species and is extensively involved in the ...evolution of many diseases, including epilepsy. The superoxide anion (O2 •–), as the primary precursor of ROS, is closely related to ferroptosis-mediated epilepsy. Therefore, it is crucial to establish a highly effective and convenient method for the real-time dynamic monitoring of O2 •– during the ferroptosis process in epilepsy for the diagnosis and therapy of ferroptosis-mediated epilepsy. Nevertheless, no probes for detecting O2 •– in ferroptosis-mediated epilepsy have been reported. Herein, we systematically conceptualized and developed a novel near-infrared (NIR) fluorescence probe, NIR-FP, for accurately tracking the fluctuation of O2 •– in ferroptosis-mediated epilepsy. The probe showed exceptional sensitivity and outstanding selectivity toward O2 •–. In addition, the probe has been utilized effectively to bioimage and evaluate endogenous O2 •– variations in three types of ferroptosis-mediated epilepsy models (the kainic acid-induced chronic epilepsy model, the pentylenetetrazole-induced acute epilepsy model, and the pilocarpine-induced status epilepticus model). The above applications illustrated that NIR-FP could serve as a reliable and suitable tool for guiding the accurate diagnosis and therapy of ferroptosis-mediated epilepsy.
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