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The utilization of flue gas waste heat is an important measure to improve the power efficiency of coal-fired units. Traditional method is to arrange the heating surface after the air preheater, which can just recover the low-grade heat, low efficiency. For the engineering practice of a 1000MW double-reheat unit, three feasible schemes are proposed, namely scheme 1 “two-stage gas cooler plus cold air heater”, scheme 2 “air preheater bypass + two-stage flue gas cooler plus cold air heating” and scheme 3 “air preheater bypass + hot primary air temperature adjustment plus two-stage flue gas cooler plus cold air heater”. For the sake of evaluating the actual effects of different schemes objectively, the thermal characteristic calculation model of the four-part rotary air preheater was established by finite difference method, and then the effect of the inlet air temperature and the share of bypass flue gas on the thermal efficiency of the boiler were studied. The equivalent enthalpy drop method was used to establish the thermal characteristic model of steam turbine, and the influence of different heat distribution modes on the heat consumption rate of steam turbine was studied.. Considering the technical economy, the optimal bypass flue gas share of this scheme is 12%, which corresponds to the reduction of coal consumption for power supply of the unit by about 3.23g/kWh. Taking into account comprehensively, scheme 3 is recommended.

Deep utilization of flue gas waste heat is an important means to ameliorate the power generation productivity of coal-fired units. Aiming at the waste heat cascade utilization system which is composed of “air preheater bypass + two-stage low-temperature coal economizer + thermal primary air temperature regulating device” proposed in a certain project, using the energy balance method and the equivalent enthalpy drop method, the mathematical model of the impact of waste heat utilization devices at all levels on the unit economy is established from the boiler efficiency and steam engine heat rate. Combined with the rated operation data of the unit, the thermal economy of the system is analyzed. The results show that the bypass of the air preheater and the temperature regulating device of the hot primary air can effectively improve the utilization efficiency of the waste heat of the flue gas at the tail of the boiler, the coal consumption of power supply can be reduced by 3.47 g/kWh under rated working conditions.

This study globally investigates the allelic splicing pattern in multiple tissues of an F1 hybrid mouse and reveals the underlying driving forces shaping such tissue-dependent splicing divergence., Alternative splicing is ubiquitous, but the mechanisms underlying its pattern of evolutionary divergence across mammalian tissues are still underexplored. Here, we investigated the cis-regulatory divergences and their relationship with tissue-dependent trans-regulation in multiple tissues of an F1 hybrid between two mouse species. Large splicing changes between tissues are highly conserved and likely reflect functional tissue-dependent regulation. In particular, micro-exons frequently exhibit this pattern with high inclusion levels in the brain. Cis-divergence of splicing appears to be largely non-adaptive. Although divergence is in general associated with higher densities of sequence variants in regulatory regions, events with high usage of the dominant isoform apparently tolerate more mutations, explaining why their exon sequences are highly conserved but their intronic splicing site flanking regions are not. Moreover, we demonstrate that non-adaptive mutations are often masked in tissues where accurate splicing likely is more important, and experimentally attribute such buffering effect to trans-regulatory splicing efficiency.

Epithelial-mesenchymal transition (EMT) program, which facilitates tumor metastasis, stemness and therapy resistance, is a reversible biological process that is largely orchestrated at the epigenetic level under the regulation of different cell signaling pathways. EMT state is often heterogeneous within individual tumors, though the epigenetic drivers underlying such heterogeneity remain elusive. In colon cancer, hyperactivation of the Wnt/β-catenin signaling not only drives tumor initiation, but also promotes metastasis in late stage by promoting EMT program. However, it is unknown whether the intratumorally heterogeneous Wnt activity could directly drive EMT heterogeneity, and, if so, what are the underlying epigenetic driver(s). Here, by analyzing a phenotypically and molecularly heterogeneous colon cancer cell line using single-cell RNA sequencing, we identified two distinct cell populations with positively correlated Wnt activity and EMT state. Integrative multi-omics analysis of these two cell populations revealed RUNX2 as a critical transcription factor epigenetically driving the EMT heterogeneity. Both in vitro and in vivo genetic perturbation assays validated the EMT-enhancing effect of RUNX2, which remodeled chromatin landscape and activated a panel of EMT-associated genes through binding to their promoters and/or potential enhancers. Finally, by exploring the clinical data, we showed that RUNX2 expression is positively correlated with metastasis development and poor survival of colon cancer patients, as well as patients afflicted with other types of cancer. Taken together, our work revealed RUNX2 as a new EMT-promoting epigenetic regulator in colon cancer, which may potentially serve as a prognostic marker for tumor metastasis.

Background: Differences in gene expression, which arises from divergence in cis-regulatory elements or alterations in transcription factors (TFs) binding specificity, are one of the most important causes of phenotypic diversity during evolution. On one hand, changes in the cis-elements located in the vicinity of target genes affect TF binding and/or local chromatin environment, thereby modulating gene expression in one-to-one manner. On the other hand, alterations in trans-factors influence the expression of their target genes in a more pleiotropic fashion. Although evolution of amino acid sequences is much slower than that of non-coding regulatory elements, particularly for the TF DNA binding domains (DBD)， it is still possible that changes in TF-DBD might have the potential to drive large phenotypic changes if the resulting effects have a net positive effect on the organism’s fitness. If so, species-specific changes in TF-DBD might be positively selected. So far, however, this possibility has been largely unexplored.Results: By protein sequence analysis, we observed high sequence conservation in the DNA binding domain (DBD) of the transcription factor Cdx2 across many vertebrates, whereas three amino acid changes were exclusively found in mouse Cdx2 (mCdx2), suggesting potential positive selection in the mouse lineage. Multi-omics analyses were then carried out to investigate the effects of these changes. Surprisingly, there were no significant functional differences between mCdx2 and its rat homologue (rCdx2), and none of the three amino acid changes had any impact on its function. Finally, we used rat-mouse allodiploid embryonic stem cells (RMES) to study the cis effects of Cdx2-mediated gene regulation between the two rodents. Interestingly, whereas Cdx2 binding is largely divergent between mouse and rat, the transcriptional effect induced by Cdx2 is conserved to a much larger extent.Conclusions: There were no significant functional differences between mCdx2 and its rat homologue (rCdx2), and none of the three amino acid changes had any impact on its function. Moreover, Cdx2 binding is largely divergent between mouse and rat, the transcriptional effect induced by Cdx2 is conserved to a much larger extent.

Sample multiplexing facilitates single‐cell sequencing by reducing costs, revealing subtle difference between similar samples, and identifying artifacts such as cell doublets. However, universal and cost‐effective strategies are rather limited. Here, we reported a concanavalin A‐based sample barcoding strategy (CASB), which could be followed by both single‐cell mRNA and ATAC (assay for transposase‐accessible chromatin) sequencing techniques. The method involves minimal sample processing, thereby preserving intact transcriptomic or epigenomic patterns. We demonstrated its high labeling efficiency, high accuracy in assigning cells/nuclei to samples regardless of cell type and genetic background, and high sensitivity in detecting doublets by three applications: 1) CASB followed by scRNA‐seq to track the transcriptomic dynamics of a cancer cell line perturbed by multiple drugs, which revealed compound‐specific heterogeneous response; 2) CASB together with both snATAC‐seq and scRNA‐seq to illustrate the IFN‐γ‐mediated dynamic changes on epigenome and transcriptome profile, which identified the transcription factor underlying heterogeneous IFN‐γ response; and 3) combinatorial indexing by CASB, which demonstrated its high scalability., CASB is a new method for sample multiplexing compatible with both single‐cell RNA‐seq and ATAC‐seq. CASB is highly accurate, efficient and sensitive and allows more diverse types of information to be incorporated in single‐cell sequencing experiments.

Differences in gene expression, which can arise from divergence in cis-regulatory elements or alterations in transcription factors binding specificity, are one of the most important causes of phenotypic diversity during evolution. By protein sequence analysis, we observed high sequence conservation in the DNA binding domain (DBD) of the transcription factor Cdx2 across many vertebrates, whereas three amino acid changes were exclusively found in mouse Cdx2 (mCdx2), suggesting potential positive selection in the mouse lineage. Multi-omics analyses were then carried out to investigate the effects of these changes. Surprisingly, there were no significant functional differences between mCdx2 and its rat homologue (rCdx2), and none of the three amino acid changes had any impact on its function. Finally, we used rat-mouse allodiploid embryonic stem cells (RMES) to study the cis effects of Cdx2-mediated gene regulation between the two rodents. Interestingly, whereas Cdx2 binding is largely divergent between mouse and rat, the transcriptional effect induced by Cdx2 is conserved to a much larger extent.Author summaryOur study 1) represented a first systematic analysis of species-specific adaptation in DNA binding pattern of transcription factor. Although the mouse-specific amino acid changes did not manifest functional impact in our system, several explanations may account for it (See Discussion part for the detail); 2) represented a first study of cis-regulation between two reproductively isolated species by using a novel allodiploid system; 3) demonstrated a higher conservation of transcriptional output than that of DNA binding, suggesting the evolvability/plasticity of the latter; 4) finally provided a rich data resource for Cdx2 mediated regulation, including gene expression, chromatin accessibility and DNA binding etc.

Cellular RNA is decorated with over 170 types of chemical modifications. Many modifications in mRNA, including m6A and m5C, have been associated with critical cellular functions under physiological and/or pathological conditions. To understand the biological functions of these modifications, it is vital to identify the regulators that modulate the modification rate. However, a high‐throughput method for unbiased screening of these regulators is so far lacking. Here, we report such a method combining pooled CRISPR screen and reporters with RNA modification readout, termed CRISPR integrated gRNA and reporter sequencing (CIGAR‐seq). Using CIGAR‐seq, we discovered NSUN6 as a novel mRNA m5C methyltransferase. Subsequent mRNA bisulfite sequencing in HAP1 cells without or with NSUN6 and/or NSUN2 knockout showed that NSUN6 and NSUN2 worked on non‐overlapping subsets of mRNA m5C sites and together contributed to almost all the m5C modification in mRNA. Finally, using m1A as an example, we demonstrated that CIGAR‐seq can be easily adapted for identifying regulators of other mRNA modification., CIGAR‐seq is a new method combining pooled CRISPR screen with an epitranscriptomic reporter for identifying mRNA modification regulators. NSUN6 is discovered as a novel mRNA m5C methyltransferase, which together with NSUN2, contributes to almost all the m5C modification in mRNA.

Sample multiplexing facilitates single cell sequencing by reducing costs, revealing subtle difference between similar samples, and identifying artifacts such as cell doublets. However, universal and cost-effective strategies are rather limited. Here, we reported a Concanavalin A-based Sample Barcoding strategy (CASB), which could be followed by both single-cell mRNA and ATAC (assay for transposase accessible chromatin) sequencing techniques. The method involves minimal sample processing, thereby preserving intact transcriptomic or epigenomic patterns. We demonstrated its high labeling efficiency, high accuracy in assigning cells/nuclei to samples regardless of cell type and genetic background, as well as high sensitivity in detecting doublets by two applications: 1) CASB followed by scRNA-seq to track the transcriptomic dynamics of a cancer cell line perturbed by multiple drugs, which revealed compound-specific heterogeneous response; 2) CASB together with both snATAC-seq and scRNA-seq to illustrate the IFN-γ-mediated dynamic changes on epigenome and transcriptome profile, which identified the transcription factor underlying heterogeneous IFN-γ response.

Cellular RNA is decorated with over 170 types of chemical modifications. Many modifications in mRNA, including m6A and m5C, have been associated with critical cellular functions under physiological and/or pathological conditions. To understand the biological functions of these modifications, it is vital to identify the regulators that modulate the modification rate. However, a high-throughput method for unbiased screening of these regulators is so far lacking. Here, we report such a method combining pooled CRISPR screen and reporters with RNA modification readout, termed CRISPR integrated gRNA and reporter sequencing (CIGAR-seq). Using CIGAR-seq, we discovered NSUN6 as a novel mRNA m5C methyltransferase. Subsequent mRNA bisulfite sequencing in HAP1 cells without or with NSUN6 and/or NSUN2 knockout showed that NSUN6 and NSUN2 worked on non-overlapping subsets of mRNA m5C sites, and together contributed to almost all the m5C modification in mRNA. Finally, using m1A as an example, we demonstrated that CIGAR-seq can be easily adapted for identifying regulators of other mRNA modification.

There is an increasing interest in understanding how three-dimensional organization of the genome is regulated. Different strategies have been used to identify genome-wide chromatin interactions. However, owing to current limitations in resolving genomic contacts, visualization and validation of these genomic loci at subkilobase resolution remain unsolved to date. Here, we describe Tn5 transposase-based fluorescence in situ hybridization (Tn5-FISH), a polymerase chain reaction-based, cost-effective imaging method, which can colocalize the genomic loci at subkilobase resolution, dissect genome architecture, and verify chromatin interactions detected by chromatin configuration capture-derived methods. To validate this method, short-range interactions in the keratin-encoding gene (KRT) locus in the topologically associated domain were imaged by triple-color Tn5-FISH, indicating that Tn5-FISH is very useful to verify short-range chromatin interactions inside the contact domain and TAD. Therefore, Tn5-FISH can be a powerful molecular tool for clinical detection of cytogenetic changes in numerous genetic diseases such as cancers.

Chromatin conformation plays a key role in regulating gene expression and controlling cell differentiation. However, the whole-genome chromatin conformation changes that occur during leukemia cell differentiation are poorly understood. Here, we characterized the changes in chromatin conformation, histone states, chromatin accessibility, and gene expression using an all-trans retinoic acid (ATRA)-induced HL-60 cell differentiation model. The results showed that the boundaries of topological associated domains (TADs) were stable during differentiation; however, the chromatin conformations within several specific TADs were obviously changed. By combining H3K4me3, H3K27ac, and Hi-C signals, we annotated the differential gene-regulatory chromatin interactions upon ATRA induction. The gains and losses of the gene-regulatory chromatin interactions are significantly correlated with gene expression and chromatin accessibility. Finally, we found that the loss of GATA2 expression and DNA binding are crucial for the differentiation process, and changes in the chromatin structure around the GATA2 regulate its expression upon ATRA induction. This study provided both statistical insights and experimental details regarding the relationship between chromatin conformation changes and transcription regulation during leukemia cell differentiation, and the results suggested that the chromatin conformation is a new type of potential drug target for cancer therapy.

Epithelial-mesenchymal transition (EMT) program, which facilitates tumor metastasis, stemness and therapy resistance, is a reversible biological process that is largely orchestrated at the epigenetic level under the regulation of different cell signaling pathways. EMT state is often heterogeneous within individual tumors, though the epigenetic drivers underlying such heterogeneity remain elusive. In colon cancer, hyperactivation of the Wnt/β-catenin signaling not only drives tumor initiation, but also promotes metastasis in late stage by promoting EMT program. However, it is unknown whether the intratumorally heterogeneous Wnt activity could directly drive EMT heterogeneity, and, if so, what are the underlying epigenetic driver(s). Here, by analyzing a phenotypically and molecularly heterogeneous colon cancer cell line using single-cell RNA sequencing, we identified two distinct cell populations with positively correlated Wnt activity and EMT state. Integrative multi-omics analysis of these two cell populations revealed RUNX2 as a critical transcription factor epigenetically driving the EMT heterogeneity. Both in vitro and in vivo genetic perturbation assays validated the EMT-enhancing effect of RUNX2, which remodeled chromatin landscape and activated a panel of EMT-associated genes through binding to their promoters and/or potential enhancers. Finally, by exploring the clinical data, we showed that RUNX2 expression is positively correlated with metastasis development and poor survival of colon cancer patients, as well as patients afflicted with other types of cancer. Taken together, our work revealed RUNX2 as a new EMT-promoting epigenetic regulator in colon cancer, which may potentially serve as a prognostic marker for tumor metastasis.

Genome-wide chromatin interaction analysis has become important for understanding 3D topological structure of a genome as well as for linking distal cis-regulatory elements to their target genes. Compared to the Hi-C method, chromatin interaction analysis by paired-end tag sequencing (ChIA-PET) is unique, in that one can interrogate thousands of chromatin interactions (in a genome) mediated by a specific protein of interest at high resolution and reasonable cost. However, because of the noisy nature of the data, efficient analytical tools have become necessary. Here, we review some new computational methods recently developed by us and compare them with other existing methods. Our intention is to help readers to better understand ChIA-PETresults and to guide the users on selection of the most appropriate tools for their own projects.

Low NOx burners and air staging technology are the most economic and effective means of reducing NOx emissions from coal-fired furnaces. However, it is difficult to significantly reduce NOx emissions through air-staged combustion in the furnace without reducing the boiler efficiency. The aim of this work was to study the effect of the inner secondary air cone length of a centrally fuel-rich swirl coal combustion burner on combustion and NOx characteristics using a 0.5 MW laboratory furnace with air-staging. Gas temperature and concentrations of gaseous species (O2, CO, and NOx) were measured in the primary combustion and burnout zones for different inner secondary air cone lengths. It was found that the inner secondary air cone length had significant effects on NOx emissions, unburned carbon content in the fly ash, and ignition performance of the burner. As the inner secondary air cone length increased, the unburned carbon content in the fly ash level increased, NOx emissions decreased, and pulverized-coal ignition occurred later. The optimized results provide an important reference for engineering design. © 2015 Curtin University of Technology and John Wiley & Sons, Ltd.

This paper presents research on a 660 MW e Foster Wheeler (FW) type down-fired boiler. The arch-supplied over-fire air (OFA) plan and high efficiency measures are proposed for the boiler. The influence of different OFA ratios on flow field, temperature distribution, and O 2 and NO x concentration distributions inside the furnace are investigated by numerical simulation using Fluent 6.3.26 software. Also, the average temperature, the carbon content in the fly ash, and the O 2 and NO x concentrations at the exit of the furnace are calculated. Three high-temperature zones are identified in the furnace: at the front and rear wall under the arch, and at the bottom of the upper furnace. As the OFA ratio increases, the gas temperature, the carbon content in the fly ash, and the O 2 concentration increase, but the NO x concentration decreases significantly at the exit of the furnace. In particular, when the OFA ratio increases from 20% to 25%, the amplitude of the decrease of the NO x emissions is smaller, but the combustible content in the fly ash increases more obviously. Considering the NO x emissions and the combustible content in the fly ash, an OFA ratio of 20% is advisable for the arch-supplied OFA program.

The effects on combustion characteristics and NO x formation of the particle concentration variation in the primary air duct were investigated on a 0.5-MW pulverized-coal combustion test facility with swirl burners. The gas temperature, components and fly ash in the near-burner region and furnace center were sampled and measured. It shows that the pulverized-coal concentration variation in the primary air duct is of great importance as for defining the flame structure, gas temperature profile and gas components. With the burner changing from general type to inner-lean-outer-rich to inner-rich-outer-lean types I and II, the flame diffusion zone shrinks, its color less bright, the O 2 concentration in the flame zone decreases and the CO concentration increases significantly. Additionally, the NO x concentration decreases, with NO x emissions at the furnace exit dropping from 1182 to 861 mg/m 3 (a reduction of 27.15%). Finally, the release rates of carbon, hydrogen and nitrogen and the burnout rate of carbon all decrease. The gas temperatures observed in the inner-rich-outer-lean types I and II burners are lower than those of the general and the inner-lean-outer-rich type burners in the near-burner region. The release rates of elements and the burnout rate of carbon are close to 100% for all four burners.

In human cells, DNA is hierarchically organized and assembled with histones and DNA-binding proteins in three dimensions. Chromatin interactions play important roles in genome architecture and gene regulation, including robustness in the developmental stages and flexibility during the cell cycle. Here we propose in situ Hi-C method named Bridge Linker-Hi-C (BL-Hi-C) for capturing structural and regulatory chromatin interactions by restriction enzyme targeting and two-step proximity ligation. This method improves the sensitivity and specificity of active chromatin loop detection and can reveal the regulatory enhancer-promoter architecture better than conventional methods at a lower sequencing depth and with a simpler protocol. We demonstrate its utility with two well-studied developmental loci: the beta-globin and HOXC cluster regions., Chromatin interactions and genome architecture are key regulators of gene expression. Here the authors present Bridge-Linker-Hi-C to map active chromatin loops and enhancer-promoter interactions.

The Hirnantia Fauna is a globally-represented, cool water brachiopod fauna that originated and flourished in shallow marine environments at intermediate to low latitudes after the first episode of the end-Ordovician mass extinction. It was well-developed, widely distributed, long in stratigraphical range, and complex in palaeoecological differentiation on the Upper Yangtze Platform of the South China paleoplate, where it has been extensively studied. Qualitative and quantitative analyses show that the FAD of the Hirnantia Fauna in South China becomes stratigraphically higher from nearshore to offshore localities on the Yangtze Platform, while the range of the fauna becomes shorter whereas the taxonomic diversity increases. Over its stratigraphical range the diversity of the Hirnantia Fauna at nearshore localities consistently decreases, but trends in the opposite direction at offshore, deeper water localities. The fauna was represented by different communities, subcommunities or associations with changing environmental factors (such as water depth and substrate) at different localities or horizons.

Various efforts have been made to elucidate the cooperating proteins involved in maintaining chromatin interactions; however, many are still unknown. Here, we present 3CPET, a tool based on a non-parametric Bayesian approach, to infer the set of the most probable protein complexes involved in maintaining chromatin interactions and the regions that they may control, making it a valuable downstream analysis tool in chromatin conformation studies. 3CPET does so by combining data from ChIA-PET, transcription factor binding sites, and protein interactions. 3CPET results show biologically significant and accurate predictions when validated against experimental and simulation data. Electronic supplementary material The online version of this article (doi:10.1186/s13059-015-0851-6) contains supplementary material, which is available to authorized users.

The complex hybrid flexible flowshop problems in the real-world industries scheduling were researched, including constraints of unrelated machines, skipping some stages etc. Though several researches were done to address some of the constraints, modeling these constraints was seldom done simultaneously. This paper modeled the problem in the perspective of constraint programming and solved the problem utilizing the Gecode system. The simulation results showed that our proposed method was efficiently and effectively on solving the complex hybrid flexible flowshop problems. It was the first proposed method to investigate and solve the hybrid flexible flowshop problems using constraint programming.

All supplementary figures (S1 to S23) and their corresponding legends. (DOCX 6465 kb)

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Rapidly increasing amounts of (physical and genetic) protein-protein interaction (PPI) data are produced by various high-throughput techniques, and interpretation of these data remains a major challenge. In order to gain insight into the organization and structure of the resultant large complex networks formed by interacting molecules, using simulated annealing, a method based on the node connectivity, we developed ModuleRole, a user-friendly web server tool which finds modules in PPI network and defines the roles for every node, and produces files for visualization in Cytoscape and Pajek. For given proteins, it analyzes the PPI network from BioGRID database, finds and visualizes the modules these proteins form, and then defines the role every node plays in this network, based on two topological parameters Participation Coefficient and Z-score. This is the first program which provides interactive and very friendly interface for biologists to find and visualize modules and roles of proteins in PPI network. It can be tested online at the website http://www.bioinfo.org/modulerole/index.php, which is free and open to all users and there is no login requirement, with demo data provided by “User Guide” in the menu Help. Non-server application of this program is considered for high-throughput data with more than 200 nodes or user’s own interaction datasets. Users are able to bookmark the web link to the result page and access at a later time. As an interactive and highly customizable application, ModuleRole requires no expert knowledge in graph theory on the user side and can be used in both Linux and Windows system, thus a very useful tool for biologist to analyze and visualize PPI networks from databases such as BioGRID. Availability ModuleRole is implemented in Java and C, and is freely available at http://www.bioinfo.org/modulerole/index.php. Supplementary information (user guide, demo data) is also available at this website. API for ModuleRole used for this program can be obtained upon request.

ChIA-PET2 is a versatile and flexible pipeline for analyzing different types of ChIA-PET data from raw sequencing reads to chromatin loops. ChIA-PET2 integrates all steps required for ChIA-PET data analysis, including linker trimming, read alignment, duplicate removal, peak calling and chromatin loop calling. It supports different kinds of ChIA-PET data generated from different ChIA-PET protocols and also provides quality controls for different steps of ChIA-PET analysis. In addition, ChIA-PET2 can use phased genotype data to call allele-specific chromatin interactions. We applied ChIA-PET2 to different ChIA-PET datasets, demonstrating its significantly improved performance as well as its ability to easily process ChIA-PET raw data. ChIA-PET2 is available at https://github.com/GuipengLi/ChIA-PET2.