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Friction properties are significantly affected by third bodies (films formed on friction surfaces). However, the study of their composition and structure remains incomplete. For this reason, an organic composite railway brake shoe was tested at an initial braking speed of 125 km/h using a full-scale dynamometer. A third body with a thickness of ~120 μm was obtained, and its morphology and composition were analyzed using a multiple techniques. The results indicated that the third body had a layered structure. The upper surface was smoother than the lower surface. The carbon content on the upper surface decreased by 68.01%, and the iron content increased by 11.85 times in relation to that on the lower surface. Compared to the brake shoe, the iron content of the third body increased by 272.81%, and most of the iron was oxidized. Furthermore, the content of barium, calcium, and silicon decreased by more than 33%, and the crystalline structures of the inorganic filler materials, such as graphite and barium sulfate, were destroyed, with new crystalline structures appearing. Finally, the residual weight at 650 °C increased from 90.35% to 96.59%. This research could provide a reference for exploring the friction and wear mechanisms of organic composite railway brake shoes.

Supplementary Figures - Supplementary Figures S1-9. Supplementary Figure S1. Mutual co-immunoprecipitation of HPV16 E6 and KDM5C; Supplementary Figure S2. HPV16 E6 attenuates the KDM5C protein level and KDM5C mRNA quantification; Supplementary Figure S3. HPV16 E6 destabilizes KDM5C and alters the global H3K4 methylation; Supplementary Figure S4. KDM5C does not visibly alters HPV 16E6, HPV 16E7 mRNA and protein levels; Supplementary Figure S5. KDM5C knock out increases tumorigenicity in mice xenograft assay; Supplementary Figure S6. H3K27Ac recruitment to chromatin in the parental cells was examined by the genomic analysis of ChIP-seq signals. ; Supplementary Figure S7. Normalized ChIP-seq signal for H3K27Ac across the EGFR gene and c-MET gene. Supplementary Figure S8. Normalized H3K4me1 levels at KDM5C-bound super enhancers in CaSki-vector and CaSki-KDM5C cells. Supplementary Figure S9. HPV 16E6 depletion leads to EGFR and c-MET super-enhancer inhibition. Supplementary Methods - Description of additional experimental methods including Transfection, siRNA and MG132 treatment, Antibodies, Co-immunoprecipitation and ubiquitination assays, Immunofluorescence Microscopy, Maltose Binding Protein (MBP) Pull-down Assay, Chromatin immunoprecipitation (ChIP)-PCR and ChIP-Seq, Cell Invasion Assay, Real Time Cell Proliferation Assay, Wound healing Assay, Trypsin Digestion and Mass spectrometry analysis Supplementary Tables - Supplementary Tables S1-2. Supplementary Table S1. List of qPCR primers used in this study. Table S2. List of DNA oligonucleotides used in this study.

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 EGFR and c-MET. 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 EGFR and c-MET.Significance: 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. Cancer Res; 78(6); 1418–30. ©2018 AACR.

The detection of circular RNA molecules (circRNAs) is typically based on short-read RNA sequencing data processed by computational detection tools. During the last decade, a plethora of such tools have been developed, but a systematic comparison with orthogonal validation is missing. Here, we set up a circRNA detection tool benchmarking study, in which 16 tools were used and detected over 315,000 unique circRNAs in three deeply sequenced human cell types. Next, 1,516 predicted circRNAs were empirically validated using three orthogonal methods. Generally, tool-specific precision values are high and similar (median of 98.8%, 96.3%, and 95.5% for qPCR, RNase R, and amplicon sequencing, respectively) whereas the sensitivity and number of predicted circRNAs (ranging from 1,372 to 58,032) are the most significant tool differentiators. Furthermore, we demonstrate the complementarity of tools through the increase in detection sensitivity by considering the union of highly-precise tool combinations while keeping the number of false discoveries low. Finally, based on the benchmarking results, recommendations are put forward for circRNA detection and validation.

The significant function of circRNAs in cancer was recognized in recent work, so a well-organized resource is required for characterizing the interactions between circRNAs and other functional molecules (such as microRNA and RNA-binding protein) in cancer. We previously developed cancer-specific circRNA database (CSCD), a comprehensive database for cancer-specific circRNAs, which is widely used in circRNA research. Here, we updated CSCD to CSCD2 (http://geneyun.net/CSCD2 or http://gb.whu.edu.cn/CSCD2), which includes significantly more cancer-specific circRNAs identified from a large number of human cancer and normal tissues/cell lines. CSCD2 contains >1000 samples (825 tissues and 288 cell lines) and identifies a large number of circRNAs: 1 013 461 cancer-specific circRNAs, 1 533 704 circRNAs from only normal samples and 354 422 circRNAs from both cancer and normal samples. In addition, CSCD2 predicts potential miRNA–circRNA and RBP–circRNA interactions using binding motifs from >200 RBPs and 2000 microRNAs. Furthermore, the potential full-length and open reading frame sequence of these circRNAs were also predicted. Collectively, CSCD2 provides a significantly enhanced resource for exploring the function and regulation of circRNAs in cancer.

Different from the common face gear pair fixed rotation motion between intersecting axes, the compound transmission of the curve-face gear is a new motion form, which can convert rotational motion into rotation and movement motion. To solve the contact fatigue life problem of this new motion form gear pair, a new contact fatigue life calculation method of the compound transmission curve-face gear pair was proposed. Based on the space gear engagement principle and the fracture mechanics theory, the theoretical contact fatigue model of the curve-face gear composite transmission was established. Considering that the contact load for every tooth is time-varying in the half-period of the curve-face gear, the contact fatigue life stage of the curve-face gear was divided into crack initiation and crack growth, and the crack growth fatigue life for each tooth was calculated using the finite element method. The curve-face gear pair was processed in the five-axis NC machining center and the compound transmission experiment platform of the curve-face gear was set up to measure the tooth surface dynamic contact stress, and the overall life of the curve-face gear was predicted. The comparison analysis between theoretical and experimental results verified the correctness of the theoretical contact fatigue calculation model.

Background Deregulated circular RNAs (circRNAs) are associated with the development of cancer and therapy resistance. However, functional research of circRNAs mostly focus on potential miRNA or protein binding and more potential regulation of circRNA on host gene DNA in cancers are yet to be inspected. Method We performed total RNA sequencing on clinical breast cancer samples and identified the expression patterns of circRNAs and corresponding host genes in patient blood, tumor and adjacent normal tissues. qPCR, northern blot and in situ hybridization were used to validate the dysregulation of circRNA circSMARCA5. A series of procedures including R-loop dot-blotting, DNA-RNA immunoprecipitation and mass spectrum, etc. were conducted to explore the regulation of circSMARCA5 on the transcription of exon 15 of SMARCA5. Moreover, immunofluorescence and in vivo experiments were executed to investigate the overexpression of circSMARCA5 with drug sensitivities. Results We found that circRNAs has average higher expression over its host linear genes in peripheral blood. Compared to adjacent normal tissues, circSMARCA5 is decreased in breast cancer tissues, contrary to host gene SMARCA5. The enforced expression of circSMARCA5 induced drug sensitivity of breast cancer cell lines in vitro and in vivo. Furthermore, we demonstrated that circSMARCA5 can bind to its parent gene locus, forming an R-loop, which results in transcriptional pausing at exon 15 of SMARCA5. CircSMARCA5 expression resulted in the downregulation of SMARCA5 and the production of a truncated nonfunctional protein, and the overexpression of circSMARCA5 was sufficient to improve sensitivity to cytotoxic drugs. Conclusion Our results revealed a new regulatory mechanism for circRNA on its host gene and provided evidence that circSMARCA5 may serve as a therapeutic target for drug-resistant breast cancer patients.

Objectives YTHDF1 is known as a m6A reader protein, and many researches of YTHDF1 focused on the regulation of mRNA translation efficiency. However, YTHDF1 is also related to RNA degradation, but how YTHDF1 regulates mRNA degradation is indefinite. Liquid‐liquid phase separation (LLPS) underlies the formation of membraneless compartments in mammal cells, and there are few reports focused on the correlation of RNA degradation with LLPS. In this research, we focused on the mechanism of YTHDF1 degraded mRNA through LLPS. Materials and Methods The CRISPR/Cas9 knock out system was used to establish the YTHDF1 knock out (YTHDF1‐KO) cell lines (HEK293 and HeLa) and METTL14 knock out (METTL14‐KO) cell line (HEK293). 4SU‐TT‐seq was used to check the half‐life changes of mRNAs. Actinomycin D and qPCR were used to test the half‐life changes of individual mRNA. RNA was stained with SYTO RNA‐select dye in wild type (WT) and YTHDF1‐KO HeLa cell lines. Co‐localization of YTHDF1 and AGO2 was identified by immunofluorescence. The interaction domain of YTHDF1 and AGO2 was identified by western blot. Phase separation of YTHDF1 was performed in vitro and in vivo. Fluorescence recovery after photobleaching (FRAP) was performed on droplets as an assessment of their liquidity. Results In this research, we found that deletion of YTHDF1 led to massive RNA patches deposited in cytoplasm. The results of 4SU‐TT‐seq showed that deletion of YTHDF1 would prolong the half‐life of mRNAs. Immunofluorescence data showed that YTHDF1 and AGO2 could co‐localize in P‐body, and Co‐IP results showed that YTHDF1 could interact with AGO2 through YT521‐B homology (YTH) domain. We confirmed that YTHDF1 could undergo phase separation in vitro and in vivo, and compared with AGO2, YTHDF1 was more important in P‐body formation. The FRAP results showed that liquid AGO2 droplets would convert to gel/solid when YTHDF1 was deleted. As AGO2 plays important roles in miRISCs, we also found that miRNA‐mediate mRNA degradation is related to YTHDF1. Conclusions YTHDF1 recruits AGO2 through the YTH domain. YTHDF1 degrades targeting mRNAs by promoting P‐body formation through LLPS. The deletion of YTHDF1 causes the P‐body to change from liquid droplets to gel/solid droplets, and form AGO2/RNA patches, resulting in a degradation delay of mRNAs. These findings reveal a previously unrecognized crosstalk between YTHDF1 and AGO2, raising a new sight of mRNA post‐transcriptional regulation by YTHDF1., Working model: YTHDF1 interacts with AGO2 (AGO2 perhaps along with miRNA) through YTH domain, then undergoes LLPS to aggregate more components of miRISCs, and leading to P‐body formation for mRNA degradation. Deficiency of YTHDF1 disrupts the interaction between YTHDF1 and AGO2, leads to the conversion of AGO2 liquid droplets to gels/solids and substantially increases the mRNA stability.

The curve-face gear pair is a new type of gear pair with variable transmission ratio for spatial finite helical motion. In this paper, mathematical models of a new developed curve-face gear were simplified and obtained directly by the standard shaper. The subsequent studies on the curve-face gear compound transmission characteristics were further analyzed by the combinations of the principle of space gearing and screw theory. Firstly, the conjugate tooth surface geometry as well the point contact traces of curve-face gears were derived. Secondly, the geometric relationships between gear pair and the corresponding meshing characteristics were evaluated by several basic geometric elements, including instantaneous screw, axodes, striction curve, and conjugate pitch surface. Based on that analysis, it was found that the tooth contact normal was reciprocal to the instantaneous twist, which demonstrated that the conjugate motion with the desired transmission ratio could be realized in current curve-face gear compound transmission. Moreover, the time-varying slip characteristics of the curve-face gear pair were also revealed, that is, rolling and sliding action coexist at all contact on the tooth surfaces. In brief, this work provided the theoretical basis for following researches on machining curve-face gear with standard shaper.

To satisfy the requirements of transmission mechanisms with variable transmission ratio, the curve face gear mechanism of compound motion has been proposed, which can build variable transmission ratio and rotation/movement compound motion simultaneously with fewer components and more compact structure. The transmission equation was established and the anti-floating design of the pinion was presented. Combined with critical floating conditions, the relationship among engagement state, rotation speed, stiffness and some other parameters have been shown obviously. According to the discrete method, the difference of meshing tooth pair in a half cycle was set up and converted as the equivalent model with time-varying properties. The dynamic response equations of this gear pair were obtained and the influence of parameters on response displacements were analyzed. Compared with the experimental results, the correctness and rationality of the theory was verified, laying a theoretical foundation for the following research and application of this gear pair.

A single genome gives rise to diverse tissues through complex epigenomic mechanisms, including N6-methyladenosine (m6A), a widespread RNA modification that is implicated in many biological processes. Here, to explore the global landscape of m6A in human tissues, we generated 21 whole-transcriptome m6A methylomes across major fetal tissues using m6A sequencing. These data reveal dynamic m6A methylation, identify large numbers of tissue differential m6A modifications and indicate that m6A is positively correlated with gene expression homeostasis. We also report m6A methylomes of long intergenic non-coding RNA (lincRNA), finding that enhancer lincRNAs are enriched for m6A. Tissue m6A regions are often enriched for single nucleotide polymorphisms that are associated with the expression of quantitative traits and complex traits including common diseases, which may potentially affect m6A modifications. Finally, we find that m6A modifications preferentially occupy genes with CpG-rich promoters, features of which regulate RNA transcript m6A. Our data indicate that m6A is widely regulated by human genetic variation and promoters, suggesting a broad involvement of m6A in human development and disease.

Gene expression and immune status in human tissues are changed with aging. There is a need to develop a comprehensive platform to explore the dynamics of age-related gene expression and immune profiles across tissues in genome-wide studies. Here, we collected RNA-Seq datasets from GTEx project, containing 16 704 samples from 30 major tissues in six age groups ranging from 20 to 79 years old. Dynamic gene expression along with aging were depicted and gene set enrichment analysis was performed among those age groups. Genes from 34 known immune function categories and immune cell compositions were investigated and compared among different age groups. Finally, we integrated all the results and developed a platform named ADEIP (http://gb.whu.edu.cn/ADEIP or http://geneyun.net/ADEIP), integrating the age-dependent gene expression and immune profiles across tissues. To demonstrate the usage of ADEIP, we applied two datasets: severe acute respiratory syndrome coronavirus 2 and human mesenchymal stem cells-assoicated genes. We also included the expression and immune dynamics of these genes in the platform. Collectively, ADEIP is a powerful platform for studying age-related immune regulation in organogenesis and other infectious or genetic diseases.

Aiming at the problems of low protection accuracy and long time consumption in traditional privacy data protection methods, a privacy data protection method based on trusted computing and blockchain is proposed. Set up the Internet node secure transmission protocol through the trusted node uplink transmission protocol and the downlink transmission protocol, and according to the transmission protocol, combined with the blockchain technology, the ECC elliptic curve encryption algorithm is used to encrypt the amount of data existing in the blockchain, and the AES symmetric encryption algorithm is used to encrypt the private data that exists in the nonblockchain, thereby completing the protection of network private data. The simulation experiment results show that the privacy data protection accuracy of the proposed method is higher and the work efficiency is faster.

With the development of terminal technology and the expansion of application fields, the Internet of Things’ application value and service requirements continue to increase. Efficient data transmission is a reliable guarantee for the development and application of the Internet of Things. Blockchain technology provides a solution for storing and delivering distributed data. On this basis, taking the Industrial Internet of Things as the research object, a blockchain-based data transmission optimization method was established. First, an undirected complete graph model is used to describe the network scene. A matrix grid model is used to replace the randomly distributed set of data nodes. Then, a double optimization method is proposed. We designed the mathematical description and modeling method of the lattice matching decision problem and designed the artificial neural network to find the optimal solution to the problem. Finally, an example is used to verify the government data transmission method’s technical performance and packet loss rate. It has achieved at least 20% and 30% improvements in optimizing the network life of static aggregation nodes and data transmission, respectively. While improving the robustness of the network, it also shows a stable advantage in terms of network energy efficiency indicators.

Continuously variable transmission (CVT) of noncircular gears has the technical advantages of large bearing capacity and high transmission efficiency. This paper focuses on the linear functional noncircular gear pair to realize continuously variable transmission. According to the required working section transmission ratio of noncircular gear pair, the transmission ratio function in the non-working section, was constructed by using polynomial, and then the influence of pitch curve parameters in working section on which in non-working section was also analyzed. Furthermore, the pitch curve of the linear functional noncircular gear pair, which are suitable for transmission, were obtained. In order to improve the stability and bearing capacity of gear transmission, the noncircular gear pair transmission with high contact ratio was designed, and an indirect method to verify the contact ratio by detecting the contact length error of tooth profile was proposed. The error was calculated by comparing the actual contact tooth profile length obtained from the rolling experiment with the accurate value of contact tooth profile length based on the principle of gear and the property of involute profile, and the noncircular gear transmission with high contact ratio was verified.

Epilepsy is a common brain disorder, repeated seizures of epilepsy may lead to a series of brain pathological changes such as neuronal or glial damage. However, whether circular RNAs are involved in neuronal injury during epilepsy is not fully understood. Here, we screened circIgf1r in the status epilepticus model through circRNA sequencing, and found that it was upregulated after the status epilepticus model through QPCR analysis. Astrocytes polarizing toward neurotoxic A1 phenotype and neurons loss were observed after status epilepticus. Through injecting circIgf1r siRNA into the lateral ventricle, it was found that knocking down circIgf1r in vivo would induce the polarization of astrocytes to phenotype A2 and reduce neuronal loss. The results in vitro further confirmed that inhibiting the expression of circIgf1r in astrocytes could protect neurons by converting reactive astrocytes from A1 to the protective A2. In addition, knocking down circIgf1r in astrocytes could functionally promote astrocyte autophagy and relieve the destruction of 4-AP-induced autophagy flux. In terms of mechanism, circIgf1r promoted the polarization of astrocytes to phenotype A1 by inhibiting autophagy. Taken together, our results reveal circIgf1r may serve as a potential target for the prevention and treatment of neuron damage after epilepsy.

Background: Chronic nonspecific low back pain (CNLBP) has become a major global public health problem. Its high incidence rate and high disability rate are so damaging both to individuals and communities. At present, many countries’ clinical guidelines recommend exercise therapy. Breath therapy is one of the exercise therapies, playing an important role in exercise therapy. Some studies have shown that breath therapy has a considerable therapeutic effect on low back pain, but there is no specific conclusion. The aim of our study is to answer the question: if breath therapy is effective and safe for CNLBP? Methods: The following databases will be searched: English databases (including Web of Science, the Cochrane Library (Central), EMBASE, MEDLINE, Allied and Alternative Medicine) and Chinese databases (including Chinese National Knowledge Infrastructure, Wanfang data and Chinese Scientific Journals Database [VIP]). The literature search will be constructed around search terms for breath therapy, search terms for chronic nonspecific low back pain and search terms for randomized controlled trials. The primary outcomes were related to duration, intensity, attack frequency of pain, and the secondary outcomes were related to physical function, quality of life, and adverse events related to interventions. Endnote software 9.1 will be applied in selecting study, Review Manager software 5.3 will be applied in analyzing and synthesizing. Results: The results will provide evidence to judge whether breath therapy is effective and safe for CNLBP. Conclusion: Our research will provide reliable evidence of breath therapy for CNLBP. Registration: International Prospective Register of Systematic Reviews (PROSPERO) CRD42020156340.

Recently, more and more non-circular gear pairs have been used in gear transmission mechanism. The transmission ratio of some non-circular gear pairs have been presented, however, the relative motions of the two gears are different in different gear pairs. The analytical model and mathematical equations for the classification of the transmission pattern, transmission ratio and relative motions of non-circular gear pair have been established. The classification model illustrates the non-circular gear pairs with both fixed axis and movable axis are existing, presents some other possible new transmission patterns. This paper focuses on the complex governing equations for the compound motion of this curve-face gear pair and shows that the kinematical response of pinion-spring system is continuous intermittent collisions with incomplete vibrations in the meshing process. The limitation conditions for the critical velocity of this gear pair are proposed in this paper. The results indicate that the vibration of this gear pair at low velocity is obvious and the critical velocity should be limited to not more than 700 rpm, which is affected by the parameters of this gear pair. These theoretical results, which have been verified by the experimental rolling, provide the theoretical support for further analysis and application of this compound motion face gear pair.

Considering the wide use of bevel gear, a new bevel gear type with variable transmission ratio has been proposed. Based on the manufacturing and generating theory of gear, the mathematical equations for the tooth surface of this gear type has been established with two different methods: lead crowning, which meets the commonly used industrial methods with higher efficiency, lower cost and the method with rack cutter shows much clear relationship of gear meshing process. The contact points and characteristics of transmission errors with different misalignment conditions have been presented. Also the feature of contact area on the tooth surface in a whole cycle was developed in this paper. Compared the contact results of elliptical bevel gear with curve face gear, the former has less misalignments sensitivity and better loaded capability.