Diverse accessory subunits are involved in the recruitment of polycomb repressive complex 2 (PRC2) to CpG island (CGI) chromatin. Here we report the crystal structure of a SUZ12-RBBP4 complex bound ...to fragments of the accessory subunits PHF19 and JARID2. Unexpectedly, this complex adopts a dimeric structural architecture, accounting for PRC2 self-association that has long been implicated. The intrinsic PRC2 dimer is formed via domain swapping involving RBBP4 and the unique C2 domain of SUZ12. MTF2 and PHF19 associate with PRC2 at around the dimer interface and stabilize the dimer. Conversely, AEBP2 binding results in a drastic movement of the C2 domain, disrupting the intrinsic PRC2 dimer. PRC2 dimerization enhances CGI DNA binding by PCLs in pairs in vitro, reminiscent of the widespread phenomenon of transcription factor dimerization in active transcription. Loss of PRC2 dimerization impairs histone H3K27 trimethylation (H3K27me3) on chromatin at developmental gene loci in mouse embryonic stem cells.
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•Crystal structure reveals the molecular mechanism of PRC2 dimerization•Polycomb-like (PCL) proteins MTF2 and PHF19 stabilize the intrinsic PRC2 dimer•Dimerization enhances PRC2-PCL binding to an endogenous CGI DNA in vitro•Loss of PRC2 dimerization impairs H3K27me3 deposition on chromatin in mESCs
PRC2 dimerization has long been noted, with unclear functions. Chen et al. reveal the structural basis of PRC2 dimerization in the context of PRC2-PCL (PRC2.1), which is drastically different from PRC2-AEBP2 (PRC2.2) in structural architecture. PRC2 dimerization controls CGI DNA binding in vitro and H3K27me3 deposition in vivo, possibly through an avidity effect.
Naturally occurring plant compounds including tannins, saponins and essential oils are extensively assessed as natural alternatives to in-feed antibiotics. Tannins are a group of polyphenolic ...compounds that are widely present in plant region and possess various biological activities including antimicrobial, anti-parasitic, anti-viral, antioxidant, anti-inflammatory, immunomodulation, etc. Therefore, tannins are the major research subject in developing natural alternative to in-feed antibiotics. Strong protein affinity is the well-recognized property of plant tannins, which has successfully been applied to ruminant nutrition to decrease protein degradation in the rumen, and thereby improve protein utilization and animal production efficiency. Incorporations of tannin-containing forage in ruminant diets to control animal pasture bloat, intestinal parasite and pathogenic bacteria load are another 3 important applications of tannins in ruminant animals. Tannins have traditionally been regarded as “anti-nutritional factor” for monogastric animals and poultry, but recent researches have revealed some of them, when applied in appropriate manner, improved intestinal microbial ecosystem, enhanced gut health and hence increased productive performance. The applicability of plant tannins as an alternative to in-feed antibiotics depends on many factors that contribute to the great variability in their observed efficacies.
Resource-based cities often face problems such as resource scarcity and insufficient electricity to achieve complex high-quality growth. At present, there is relatively little research on the impact ...on the high-quality development of such cities. To study the key variables that affect the high-quality growth of resource-based cities, we adopt entropy weighted TOPSIS technology, spatial correlation analysis, and spatial econometric models. The main conclusions are as follows: (1) The overall high-quality development of resource-based cities in China is on the rise year by year; The cities with the highest growth rates are those that are mature, rejuvenated, growing, and declining. (2) Resource-based cities have a positive geographical correlation in high-quality development, and different numbers of clusters are displayed by changing the Moran I index score. (3) High quality development is strongly influenced by human capital, urbanization, technological innovation, and global market openness. There are significant differences in the ways in which these variables affect various types of resource-based cities. Policy makers who strive to reduce regional inequality and encourage high-quality growth in resource-based communities may benefit greatly from the insights provided by this study.
Polycomb repressive complex 2 (PRC2) is a multisubunit histone-modifying enzyme complex that mediates methylation of histone H3 lysine 27 (H3K27). Trimethylated H3K27 (H3K27me3) is an epigenetic ...hallmark of gene silencing. PRC2 plays a crucial role in a plethora of fundamental biological processes, and PRC2 dysregulation has been repeatedly implicated in cancers and developmental disorders. Here, we review the current knowledge on mechanisms of cellular regulation of PRC2 function, particularly regarding H3K27 methylation and chromatin targeting. PRC2-related disease mechanisms are also discussed. The mode of action of PRC2 in gene regulation is summarized, which includes competition between H3K27 methylation and acetylation, crosstalk with transcription machinery, and formation of high-order chromatin structure. Recent progress in the structural biology of PRC2 is highlighted from the aspects of complex assembly, enzyme catalysis, and chromatin recruitment, which together provide valuable insights into PRC2 function in close-to-atomic detail. Future studies on the molecular function and structure of PRC2 in the context of native chromatin and in the presence of other regulators like RNAs will continue to deepen our understanding of the stability and plasticity of developmental transcriptional programs broadly impacted by PRC2.
The paper established a double filtering method (DFM) to visualize the skeleton industrial structure (SIS) of one economy and find its evolution rule. Different with the previous researches, this ...method is from a new view of industrial conjunctions combined by leading sectors to depict the industrial structure. It was proved that the leading sector selected by DFM must be key sector selected by Hirschman-Rasmussen method. Applied DFM to input-output tables of China, Japan and USA and MFA to Japan and USA, the results analysis showed that DFM could overtake the two main shortcomings of minimum flow analysis (MFA), scratch SIS of each economy with its own characteristics, visualize the general evolution rules of the industrial structure with crisscrossed conjunctions among leading sectors.
•Pol II pausing is a rate-limiting step in the transcription of many metazoan genes.•Pol II pausing can be regulated by cellular signaling pathways.•Pol II pausing and/or release can be regulated as ...an endpoint of signaling pathways.•Regulation of Pol II pausing and release allows fine-tuning of gene expression.
Promoter-proximal pausing by RNA polymerase II (Pol II) is a well-established mechanism to control the timing, rate, and possibly the magnitude of transcriptional responses. Recent studies have shown that cellular signaling pathways can regulate gene transcription and signaling outcomes by controlling Pol II pausing in a wide array of biological systems. Identification of the proteins and small molecules that affect the establishment and release of paused Pol II is shedding new light on the mechanisms and biology of Pol II pausing. This review focuses on the interplay between cellular signaling pathways and Pol II pausing during normal development and under disease conditions.
•Coordination between urbanization and eco-environment in China is assessed.•A multi-model evaluation method is used to assess the coordination.•The degree of coordination exhibits a slow upward ...trend.•Different urbanization and eco-environment policies should be adopted for different areas.
The coupling between urbanization and the eco-environment plays an important role in advancing China’s urbanization. This study applies systems theory to build a set of indicators for urbanization and the eco-environment and uses the entropy method to determine the weights of the indicators. Furthermore, a coupling coordination degree model, spatial autocorrelation method and decoupling model are used to comprehensively analyse the spatial–temporal differentiation in the coupling coordination between urbanization and the eco-environment in China from 2001 to 2016. The results indicate that during the study period, the level of urbanization in eastern China was higher than that in other regions, while the western region reached the highest eco-environment level. Generally, the eco-environment index of each province was greater than the urbanization index. The degree of coupling between urbanization and the eco-environment exhibited a reversed U-shape trend, while the degree of coordination exhibited a slow upward trend. The eastern region demonstrated a significantly higher degree than the middle and western regions. The coupling coordination degree exhibited evident spatial autocorrelation along with a trend of increasing and then decreasing. The cold and hot spots of spatial clustering revealed a spatial evolution and migration trend, albeit to a limited extent. From 2001 to 2016, most regions of China evolved towards a strong decoupling state between urbanization and the eco-environment.
Hepatocyte cell death via apoptosis and necrosis are major hallmarks of ethanol‐induced liver injury. However, inhibition of apoptosis is not sufficient to prevent ethanol‐induced hepatocyte injury ...or inflammation. Because receptor‐interacting protein kinase (RIP) 3–mediated necroptosis, a nonapoptotic cell death pathway, is implicated in a variety of pathological conditions, we tested the hypothesis that ethanol‐induced liver injury is RIP3‐dependent and RIP1‐independent. Increased expression of RIP3 was detected in livers of mice after chronic ethanol feeding, as well as in liver biopsies from patients with alcoholic liver disease. Chronic ethanol feeding failed to induce RIP3 in the livers of cytochrome P450 2E1 (CYP2E1)‐deficient mice, indicating CYP2E1‐mediated ethanol metabolism is critical for RIP3 expression in response to ethanol feeding. Mice lacking RIP3 were protected from ethanol‐induced steatosis, hepatocyte injury, and expression of proinflammatory cytokines. In contrast, RIP1 expression in mouse liver remained unchanged following ethanol feeding, and inhibition of RIP1 kinase by necrostatin‐1 did not attenuate ethanol‐induced hepatocyte injury. Ethanol‐induced apoptosis, assessed by terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate nick‐end labeling–positive nuclei and accumulation of cytokeratin‐18 fragments in the liver, was independent of RIP3. Conclusion: CYP2E1‐dependent RIP3 expression induces hepatocyte necroptosis during ethanol feeding. Ethanol‐induced hepatocyte injury is RIP3‐dependent, but independent of RIP1 kinase activity; intervention of this pathway could be targeted as a potential therapeutic strategy. (HEPATOLOGY 2013)
The oral anti-diabetic drug metformin has been found to reduce cardiovascular complications independent of glycemic control in diabetic patients. However, its role in diabetic retinal microvascular ...complications is not clear. This study is to investigate the effects of metformin on retinal vascular endothelium and its possible mechanisms, regarding two major pathogenic features of diabetic retinopathy: angiogenesis and inflammation. In human retinal vascular endothelial cell culture, metformin inhibited various steps of angiogenesis including endothelial cell proliferation, migration, and tube formation in a dose-dependent manner. Its anti-angiogenic activity was confirmed in vivo that metformin significantly reduced spontaneous intraretinal neovascularization in a very-low-density lipoprotein receptor knockout mutant mouse (p<0.05). Several inflammatory molecules upregulated by tumor necrosis factor-α in human retinal vascular endothelial cells were markedly reduced by metformin, including nuclear factor kappa B p65 (NFκB p65), intercellular adhesion molecule-1 (ICAM-1), monocyte chemotactic protein-1 (MCP-1), and interleukin-8 (IL-8). Further, metformin significantly decreased retinal leukocyte adhesion (p<0.05) in streptozotocin-induced diabetic mice. Activation of AMP-activated protein kinase was found to play a partial role in the suppression of ICAM-1 and MCP-1 by metformin, but not in those of NFκB p65 and IL-8. Our findings support the notion that metformin has considerable anti-angiogenic and anti-inflammatory effects on retinal vasculature. Metformin could be potentially used for the purpose of treating diabetic retinopathy in addition to blood glucose control in diabetic patients.
Abstract
Computer-assisted diagnosis is key for scaling up cervical cancer screening. However, current recognition algorithms perform poorly on whole slide image (WSI) analysis, fail to generalize ...for diverse staining and imaging, and show sub-optimal clinical-level verification. Here, we develop a progressive lesion cell recognition method combining low- and high-resolution WSIs to recommend lesion cells and a recurrent neural network-based WSI classification model to evaluate the lesion degree of WSIs. We train and validate our WSI analysis system on 3,545 patient-wise WSIs with 79,911 annotations from multiple hospitals and several imaging instruments. On multi-center independent test sets of 1,170 patient-wise WSIs, we achieve 93.5%
Specificity
and 95.1%
Sensitivity
for classifying slides, comparing favourably to the average performance of three independent cytopathologists, and obtain 88.5% true positive rate for highlighting the top 10 lesion cells on 447 positive slides. After deployment, our system recognizes a one giga-pixel WSI in about 1.5 min.
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