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The realization of online prediction in rolling production line is an innovative breakthrough in key rolling technology. The deformation behavior of metal clad plate in the deformation zone under different roll diameters is modeled and analyzed in this paper based on the flow function method. The volume flow through the unit section at the rolling inlet is maximum. The maximum volume flow of carbon steel layer occurs at the near bonding surface. The maximum volume flow of stainless steel layer occurs near the top surface. The strong shear effect caused by the velocity break mainly occurs on the side of the carbon steel layer, which plays a decisive role in the composite of metal plate. Meanwhile, the position of the maximum shear stress has a tendency to move towards the outlet of the deformation zone with the increase of the reduction rate, contained within the rolling zone. According to the flow function field, the velocity field model of the clad plate in the rolling deformation zone is established. Based on the upper bound method, the layer thickness and every power proportion can be obtained by the principle of minimum energy. Further, the equivalent strain model of the element is established based on the velocity field and strain rate field models. The accuracy of the model is verified by rolling simulation, experiments and microscopic characterization under different working conditions. The model can provide theoretical guidance and technical support for the online prediction and control of deformation behavior in the rolling process.

Abstract Background Enhancer dysregulation is one of the important features for cancer cells. Enhancers enriched with H3K4me3 have been implicated to play important roles in cancer. However, their detailed features and regulatory mechanisms have not been well characterized. Results Here, we profile the landscape of H3K4me3-enriched enhancers (m3Es) in 43 pairs of colorectal cancer (CRC) samples. M3Es are widely distributed in CRC and averagely possess around 10% of total active enhancers. We identify 1322 gain variant m3Es and 367 lost variant m3Es in CRC. The target genes of the gain m3Es are enriched in immune response pathways. We experimentally prove that repression of CBX8 and RPS6KA5 m3Es inhibits target gene expression in CRC. Furthermore, we find histone methyltransferase MLL1 is responsible for depositing H3K4me3 on the identified Vm3Es. We demonstrate that the transcription factor AP1/JUN interacts with MLL1 and regulates m3E activity. Application of a small chemical inhibitor for MLL1 activity, OICR-9429, represses target gene expression of the identified Vm3Es, enhances anti-tumor immunity and inhibits CRC growth in an animal model. Conclusions Taken together, our study illustrates the genome-wide landscape and the regulatory mechanisms of m3Es in CRC, and reveals potential novel strategies for cancer treatment.

Accurate prediction of deformation behavior of metal plate in deformation zone is the key point for rolling cladding process. At present, there is a lack of accurate analytical model about the deformation of metal plate in deformation zone. Therefore, an analytical model of the deformation characteristics in deformation zone for the two-layered metal clad plate produced by asymmetric rolling is established according to the practical requirements. Firstly, the stream function field model of the clad plate in the deformation zone is founded by using the stream function method. Based on the stream function field, the velocity field model of the clad plate in the deformation zone is established, and the precision of the velocity field model is demonstrated by the comparison between the finite element and the model analytical results. Based on upper bound theory, the layer thickness of the clad plate after rolling and the ratio of deformation power, friction power and shear power to the total power were calculated by minimizing the total rolling power. Finally, based on the thickness of clad plate after rolling and velocity field model, an analytical model is established to calculate the equivalent strain of the clad plate in the deformation zone. The accuracy of the analytical model is tested by the rolling cladding experiments and the finite element simulations. The results indicate that the analytical model has high precision and which makes it useful to predict the deformation behavior in the clad plate rolling process.

Abstract Purpose The present study aimed to explore the potential components and mechanisms of Rhodiola rosea–Euonymus alatus drug pair (TY) that ameliorate rheumatoid arthritis (RA). Methods The main active components, core targets, and important pathways of TY against RA were predicted by network pharmacology analysis. The binding activity between the main active components and the core targets was verified by the molecular docking technique. Collagen‐induced arthritis (CIA) rat model and tumor necrosis factor (TNF)‐α‐induced fibroblast‐like synovial cells in human RA (HFLS‐RA) model were established, respectively. The core targets were verified by cell counting kit‐8 assay, hematoxylin eosin, enzyme‐linked immunosorbent assay, real‐time polymerase chain reaction, and Western blot analysis, and the therapeutic effect of TY was evaluated. Results A total of 18 possible components and 34 core targets were obtained by network pharmacology, among which inflammatory response, phosphatidylinositide 3‐kinases (PI3K)‐AKT and MAPK pathways were involved in the therapeutic effect of TY on RA. The results of molecular docking showed that kaempferol and quercetin had high binding affinity to interleukin (IL)‐1β, IL‐6, matrix metalloproteinase (MMP)9, and TNF‐α. In vivo and in vitro experiments showed that TY dose‐dependently inhibited the proliferation of HFLS‐RA cells induced by TNF‐α, and significantly reduced the paw swelling and arthritis scores in CIA rats. At the same time, TY inhibited the production of inflammatory factors in CIA rat serum and TNF‐α‐induced HFLS‐RA cells. It also decreased the expression of PI3K, phospho‐protein kinase B, MMP1, MMP3, MMP9, and increased the protein and mRNA levels of tissue inhibitors of MMPs (TIMP)1 in synovial tissue. Conclusion TY can inhibit the PI3K/AKT signaling pathway and regulate the balance between MMPs and TIMP, thus playing a therapeutic role in RA.

Abstract When plates with edge cracks in the rolling process is straightened by cyclic tensile and compressive stress, the tip of edge crack always accompanied by stress concentration, which leads to crack propagation. In this paper, damage parameters are imported into the plate straightening model based on determining the GTN damage parameters of magnesium alloy materials by inverse finite element calibration method, the influence of different straightening process schemes and prefabricated V-shaped crack geometry on crack growth is analyzed through the way of the combination of simulation and straightening experiment. The results show that the peak values of equivalent stress and equivalent strain under each straightening roll appear at the crack tip. The value of longitudinal stress and equivalent stain decrease with the distance to crack tip becomes larger. The peak value of longitudinal stress appears when the crack circumferential angle is about 100°, and the crack tip is easy to form crack propagation; when the plate passes roll 2 and roll 4, the equivalent stress and strain concentration at the crack tip are most obvious; when the reduction reaches a certain degree, the void volume fraction (VVF) reaches the VVF of the material breaking; with the increase of the entrance reduction, the number of VVF at the crack tip which reaches the material fracture increases, and the length of crack propagation increases; the stress concentration at the tip of V-shaped crack with large length–width ratio is obvious, and the VVF is more likely to reach the VVF at the time of material fracture, crack initiates and propagates easily.

Binary stars ubiquitous throughout the Universe are important. Contact binaries (CBs) possessing period–luminosity (PL) relations could be adopted as distance tracers. The PL relations of CBs are influenced by metallicity abundance and color index, which are connected to both the radius and luminosity of stars. Here we propose fine relations of the period–luminosity–metallicity–color (PLZC) from the ultraviolet to infrared bands based on current surveys. The accuracy of the distance estimation is 6% and 8%, respectively, depending on the PLZC relations of the CBs in the infrared and optical bands of the collected data. PLZC models are still more accurate than PLC models in determining intrinsic luminosity, notwithstanding their limited improvement. Meanwhile, these relations based on synthetic photometry are also calibrated. On the basis of the synthetic photometry, a 6% accuracy of distance is estimated. The measured or synthetic data of PLZC or PLC relations in infrared bands comes first in the list of suggestions for distance estimations and is followed by the measured data of optical bands.

Abstract Abnormality of enhancer regulation has emerged as one of the critical features for cancer cells. KDM5C is a histone H3K4 demethylase and frequently mutated in several types of cancer. It is critical for H3K4me3 and activity of enhancers, but its regulatory mechanisms remain elusive. Here, we identify TRIM11 as one ubiquitin E3 ligase for KDM5C. TRIM11 interacts with KDM5C, catalyzes K48-linked ubiquitin chain on KDM5C, and promotes KDM5C degradation through proteasome. TRIM11 deficiency in an animal model represses the growth of breast tumor and stabilizes KDM5C. In breast cancer patient tissues, TRIM11 is highly expressed and KDM5C is lower expressed, and their expression is negatively correlated. Mechanistically, TRIM11 regulates the enhancer activity of genes involved in cell migration and immune response by targeting KDM5C. TRIM11 and KDM5C regulate MCAM expression and cell migration through targeting H3K4me3 on MCAM enhancer. Taken together, our study reveals novel mechanisms for enhancer regulation during breast cancer tumorigenesis and development.

The harvest period of cultivated ginseng is generally 4–6 years. Ginseng flowers (GFs), the nonmedicinal parts, are usually removed every autumn, in which components are generally believed to stay unchanged with the increasing cultivation age. Recently, few documents were reported on the variation of volatile organic compounds (VOCs) and other components about ginseng flowers. This study had an insight into the variation of the chemical constituents with the cultivation ages through the comparison of the volatile organic compounds, gross ginsenosides, crude polysaccharide, and gross proteins of ginseng flowers from 3-, 4-, 5-, and 6-yr-old (GF3, GF4, GF5, and GF6) which were conducted by headspace solid-phase microextraction-gas chromatography-triple quadrupole mass spectrometry (HS-SPME-GC-QQQ/MS) and spectroscopic analysis combined with multivariate statistical analysis, including one-way ANOVA analysis and T test. The results indicated that the crude polysaccharide contents raised significantly depending on cultivation age except 6-yr-old, whereas the gross ginsenosides and the gross protein content were indistinctive. According to the peak intensity of determined VOCs, the contents of most differential compounds arranged in an order from high to low are GF3, GF4, GF5, and GF6, such as the compounds 2–15, 17–19, 22, and 25–26, therefore, they can be inferred that they are important markers to identify the age of GFs. 461 common differential compounds were gained and 26 common volatile organic compounds were identified with RSI >800 and RI and RIx no more than 30, including alcohols (such as 11, 12, and 15), sesquiterpenes (such as 2, 3, and 4), esters (such as 1 and 26), naphthalene and naphthol (such as 7 and 20), which had potential effects on curing Alzheimer’s disease, inflammatory diseases, and prostate cancer based on network pharmacology analysis. This paper firstly revealed the variation rules of constitutions of GFs, which may provide a reference for the harvest and making rational application.

Background: There have been no reports about the application of random survival forest (RSF) model to predict disease progression of HIV-associated B-cell lymphoma. Methods: A total of 44 patients with HIV-associated B-cell lymphoma who were referred to Nanjing Second Hospital from 2012 to 2019 were included. The RSF model was used to find predictors of survival, and the results of the RSF model were compared with those of the Cox model. The data were analyzed using R software (version 4.1.1). Results: One-, 2-, and 3-year survival rates were 74.5%, 57.7%, and 48.6%, respectively, and the median survival was 59.0 months. The first 3 most important predictors of survival included lactate dehydrogenase (LDH), absolute monocyte count (AMC), and white blood cells (WBCs) count. The median survival of high-risk patients was only 4.0 months. Areas under the curve (AUCs) of the RSF model remained at more than 0.90 at 1, 2, and 3 years. The RSF model displayed a lower prediction error rate (21.9%) than the Cox model (25.4%). Conclusions: Lactate dehydrogenase, AMC, and WBCs count are the most important prognostic predictors for patients with HIV-associated B-cell lymphoma. Much larger prospective and/or multicentre studies are required to validtae this RSF model. [ABSTRACT FROM AUTHOR]

Proper transcription regulation by key transcription factors, such as IRF3, is critical for anti-viral defense. Dynamics of enhancer activity play important roles in many biological processes, and epigenomic analysis is used to determine the involved enhancers and transcription factors. To determine new transcription factors in anti-DNA-virus response, we have performed H3K27ac ChIP-Seq and identified three transcription factors, NR2F6, MEF2D and MAFF, in promoting HSV-1 replication. NR2F6 promotes HSV-1 replication and gene expression in vitro and in vivo, but not dependent on cGAS/STING pathway. NR2F6 binds to the promoter of MAP3K5 and activates AP-1/c-Jun pathway, which is critical for DNA virus replication. On the other hand, NR2F6 is transcriptionally repressed by c-Jun and forms a negative feedback loop. Meanwhile, cGAS/STING innate immunity signaling represses NR2F6 through STAT3. Taken together, we have identified new transcription factors and revealed the underlying mechanisms involved in the network between DNA viruses and host cells. Author summary: DNA virus infection, such as KSHV and HSV-1, affects a large population of human beings and difficult to be cleared from human bodies. The change of enhancer activity on chromatin reflects the cellular response upon viral infections, and Epigenomic profiling of active enhancers has been found to be a powerful tool to identify key transcription factors in biological processes. Here, we have performed H3K27ac ChIP-Seq to determine new transcription factors in anti-DNA-virus response, and identified three transcription factors, NR2F6, MEF2D and MAFF, in promoting HSV-1 replication. Further studies show that NR2F6 promotes HSV-1 replication and gene expression in vitro and in vivo, but not dependent on cGAS/STING pathway. NR2F6 is critical for AP-1/c-Jun pathway activation through direct targeting the promoter of MAP3K5, which is critical for DNA virus replication. On the other hand, host cell controls the expression of NR2F6 via c-Jun, which forms a negative feedback loop in anti-DNA-virus response. Meanwhile, cGAS/STING innate immunity signaling pathway represses NR2F6 expression through STAT3. Taken together, we have identified new transcription factors and revealed the underlying mechanisms involved in the interaction between DNA viruses and host cells. [ABSTRACT FROM AUTHOR]

Active enhancers are still understudied in colorectal cancers (CRC). Here the authors analyse active enhancers in CRC patients using genomics, transcriptomics, and epigenomics, identifying and validating variant super-enhancer loci as well as KLF3 as a relevant transcription factor.

Abstract Heat stress can significantly affect the immune function of the animal body. Heat stress stimulates oxidative stress in intestinal tissue and suppresses the immune responses of mice. The protecting effects of chitosan on heat stress induced colitis have not been reported. Therefore, the aim of this study was to investigate the protective effects of chitosan on immune function in heat stressed mice. Mice were exposed to heat stress (40 °C per day for 4 h) for 14 consecutive days. The mice (C57BL/6J), were randomly divided into three groups including: control group, heat stress, Chitosan group (LD: group 300 mg/kg/day, MD: 600 mg/kg/day, HD: 1000 mg/kg/day). The results showed that tissue histology was improved in chitosan groups than heat stress group. The current study showed that the mice with oral administration of chitosan groups had improved body performance as compared with the heat stress group. The results also showed that in chitosan treated groups the production of HSP70, TLR4, p65, TNF-α, and IL-10 was suppressed on day 1, 7, and 14 as compared to the heat stress group. In addition Claudin-2, and Occludin mRNA levels were upregulated in mice receiving chitosan on day 1, 7, and 14 of heat stress. Furthermore, the IL-6, IL-10, and TNF-α plasma levels were down-regulated on day 1, 7, and 14 of heat stress in mice receiving the oral administration of chitosan. In conclusion, the results showed that chitosan has an anti-inflammatory ability to tolerate hot environmental conditions.

Multiple diseases, such as cancer and neural degeneration diseases, are related with the latent infection of DNA viruses. However, it is still difficult to clean up the latent DNA viruses and new anti-viral strategies are critical for disease treatment. Here, we screen a pool of small chemical molecules and identify UNC0379, an inhibitor for histone H4K20 methyltransferase SETD8, as an effective inhibitor for multiple DNA viruses. UNC0379 not only enhances the expression of anti-viral genes in THP-1 cells, but also repress DNA virus replication in multiple cell lines with defects in cGAS pathway. We prove that SETD8 promotes DNA virus replication in a manner dependent on its enzyme activity. Our results further indicated that SETD8 is required for PCNA stability, one factor critical for viral DNA replication. Viral infection stimulates the interaction between SETD8 and PCNA and thus enhances PCNA stability and viral DNA replication. Taken together, our study reveals a new mechanism for regulating viral DNA replication and provides a potential strategy for treatment of diseases related with DNA viruses.

Abstract MLL3 is a histone H3K4 methyltransferase that is frequently mutated in cancer, but the underlying molecular mechanisms remain elusive. Here, we found that MLL3 depletion by CRISPR/sgRNA significantly enhanced cell migration, but did not elevate the proliferation rate of cancer cells. Through RNA-Seq and ChIP-Seq approaches, we identified TNS3 as the potential target gene for MLL3. MLL3 depletion caused downregulation of H3K4me1 and H3K27ac on an enhancer ~ 7 kb ahead of TNS3. 3C assay indicated the identified enhancer interacts with TNS3 promoter and repression of enhancer activity by dCas9-KRAB system impaired TNS3 expression. Exogenous expression of TNS3 in MLL3 deficient cells completely blocked the enhanced cell migration phenotype. Taken together, our study revealed a novel mechanism for MLL3 in suppressing cancer, which may provide novel targets for diagnosis or drug development.

Abstract Background With evidence of warming climates, it is important to understand the effects of heat stress in farm animals in order to minimize production losses. Studying the changes in the brain proteome induced by heat stress may aid in understanding how heat stress affects brain function. The hypothalamus is a critical region in the brain that controls the pituitary gland, which is responsible for the secretion of several important hormones. In this study, we examined the hypothalamic protein profile of 10 pigs (15 ± 1 kg body weight), with five subjected to heat stress (35 ± 1 °C; relative humidity = 90%) and five acting as controls (28 ± 3 °C; RH = 90%). Result The isobaric tags for relative and absolute quantification (iTRAQ) analysis of the hypothalamus identified 1710 peptides corresponding to 360 proteins, including 295 differentially expressed proteins (DEPs), 148 of which were up-regulated and 147 down-regulated, in heat-stressed animals. The Ingenuity Pathway Analysis (IPA) software predicted 30 canonical pathways, four functional groups, and four regulatory networks of interest. The DEPs were mainly concentrated in the cytoskeleton of the pig hypothalamus during heat stress. Conclusions In this study, heat stress significantly increased the body temperature and reduced daily gain of body weight in pigs. Furthermore, we identified 295 differentially expressed proteins, 147 of which were down-regulated and 148 up-regulated in hypothalamus of heat stressed pigs. The IPA showed that the DEPs identified in the study are involved in cell death and survival, cellular assembly and organization, and cellular function and maintenance, in relation to neurological disease, metabolic disease, immunological disease, inflammatory disease, and inflammatory response. We hypothesize that a malfunction of the hypothalamus may destroy the host physical and immune function, resulting in decreased growth performance and immunosuppression in heat stressed pigs.