Search

A20 is an anti-inflammatory molecule in nucleus pulposus (NP) cells. The anti-inflammatory properties of A20 are mainly attributed to its ability to suppress the NF-κB pathway. However, A20 can protect cells from death independently of NF-κB regulation. This study aimed to investigate the effects of A20 on pyroptosis and apoptosis of NP cells induced by lipopolysaccharide (LPS).NP cells induced by LPS were used as an in vitro model of the inflammatory environment of the intervertebral disc. Pyroptosis, apoptosis, and mitophagy marker proteins were detected. Then, NP cells were transfected with A20 overexpressed lentivirus or A20-siRNA. Annexin V FITC/PI, Western blotting, and immunofluorescence assays were used to detect the apoptosis, pyroptosis, and mitophagy of NP cells. Furthermore, the expressions of A20, related proteins, and related inflammatory cytokines were detected by western blotting, and ELISA.Apoptosis and pyroptosis of NP cells increased gradually treated with LPS for 12 h, 24 h, and 48 h. Differently, the level of mitophagy increased first and then decreased, and was the highest at LPS treatment for 12 h. Overexpression or knockdown of A20 in NP cells revealed that A20 attenuated the pyroptosis, apoptosis, and production of inflammatory cytokines of NP cells induced by LPS, while A20 sponsored mitophagy, reduced ROS production and collapse of mitochondrial membrane potential (ΔΨm). Moreover, A20 also promoted mitochondrial dynamic homeostasis and attenuated LPS-induced excessive mitochondrial fission. Excitingly, inhibition of mitophagy attenuated the effect of A20 on the negative regulation of pyroptosis of NP cells induced by LPS. Pyroptosis was accompanied by a large release of inflammatory cytokines. Inhibition of pyroptosis also significantly reduced apoptosis of NP cells. Finally, The mitochondria-targeted active peptide SS-31 inhibited LPS-induced pyroptosis and ROS production in NP cells.To sum up, A20 attenuates pyroptosis and apoptosis of NP cells via promoting mitophagy and stabilizing mitochondrial dynamics. Besides, A20 reduces LPS-induced NP cell apoptosis by inhibiting NLRP3 inflammasome-mediated pyroptosis. It provides theoretical support for the reduction of functional NP cell loss in the intervertebral disc through the gene-targeted intervention of A20.

Polycomb group RING finger protein 6 (PCGF6) plays an important role as a regulator of transcription in a variety of cellular processes, including tumorigenesis. However, the function and expression of PCGF6 in papillary RCC (pRCC) remain unclear. In the present study, we found that PCGF6 expression was significantly elevated in pRCC tissues, and high expression of PCGF6 was associated with poor survival of patients with pRCC. The overexpression of PCGF6 promoted while depletion of PCGF6 depressed the proliferation of pRCC cells in vitro. Interestingly, myc-related zinc finger protein (MAZ), a downstream molecular of PCGF6, was upregulated in pRCC with hypomethylation promoter. Mechanically, PCGF6 promoted MAZ expression by interacting with MAX and KDM5D to form a complex, and MAX recruited PCGF6 and KDM5D to the CpG island of the MAZ promoter and facilitated H3K4 histone demethylation. Furthermore, CDK4 was a downstream molecule of MAZ that participated in PCGF6/MAZ-regulated progression of pRCC. These results indicated that the upregulation of PCGF6 facilitated MAZ/CDK4 axis expression and pRCC progression by hypomethylation of the MAZ promoter. The PCGF6/MAZ/CDK4 regulatory axis may be a potential target for the treatment of ccRCC.

Splicing factor 3B subunit 4 (SF3B4) plays important functional roles not only in pre-mRNA splicing, but also in the regulation of transcription, translation, and cell signaling, and its dysregulation contributes to various diseases including Nager syndrome and tumorigenesis. However, the role of SF3B4 and underlying mechanisms in clear cell renal cell carcinoma (ccRCC) remain obscure. In the present study, we found that the expression of SF3B4 was significantly elevated in ccRCC tissues and negatively correlated with the overall survival of ccRCC patients. Upregulation of SF3B4 promotes migration and invasion of ccRCC cells in vitro and in vivo. The promoting effect of SF3B4 on cell migration and invasion is mediated by Twist1, a key transcription factor to mediate EMT. Interestingly, SF3B4, a component of the pre-mRNA spliceosome, is able to promote KLF16 expression by facilitating the transport of KLF16 mRNA into the cytoplasm. Mechanistically, SF3B4 promotes the export of KLF16 mRNA from the nucleus to the cytoplasm and thus enhances KLF16 expression, and in turn elevated KLF16 directly binds to the Twist1 promoter to activate its transcription, leading to EMT and ccRCC progression. Our findings provide evidence that the SF3B4-KLF16-Twist1 axis plays important functional roles in the development and progression of ccRCC, and manipulating this pathway may be a novel therapeutic target for the treatment of ccRCC.

Vascular smooth muscle cells (VSMCs) within atherosclerotic lesions undergo a phenotypic switching in a KLF4-dependent manner. Glycolysis plays important roles in transdifferentiation of somatic cells, however, it is unclear whether and how KLF4 mediates the link between glycolytic switch and VSMCs phenotypic transitions. Here, we show that KLF4 upregulation accompanies VSMCs phenotypic switching in atherosclerotic lesions. KLF4 enhances the metabolic switch to glycolysis through increasing PFKFB3 expression. Inhibiting glycolysis suppresses KLF4-induced VSMCs phenotypic switching, demonstrating that glycolytic shift is required for VSMCs phenotypic switching. Mechanistically, KLF4 upregulates expression of circCTDP1 and eEF1A2, both of which cooperatively promote PFKFB3 expression. TMAO induces glycolytic shift and VSMCs phenotypic switching by upregulating KLF4. Our study indicates that KLF4 mediates the link between glycolytic switch and VSMCs phenotypic transitions, suggesting that a previously unrecognized KLF4-eEF1A2/circCTDP1-PFKFB3 axis plays crucial roles in VSMCs phenotypic switching.

Metastasis is the leading cause of death in breast cancer patients. Osthole, as an active compound detected in the traditional Chinese medicine Wenshen Zhuanggu Formula, has shown a promising anti-metastatic activity in human breast cancer cells, but the underlying mechanisms remain ambiguous. In this study we elucidated the anti-metastatic mechanisms of osthole in highly metastatic breast cancer cells and a zebrafish xenograft model. We showed that the expression of integrin α3 (ITGα3) and integrin β5 (ITGβ5) was upregulated in highly metastatic MDA-MB-231, MDA-MB-231BO breast cancer cell lines but was downregulated in poorly metastatic MCF-7 breast cancer cell line, which might be the key targets of osthole's anti-metastatic action. Furthermore, we showed that knockdown of ITGα3 and ITGβ5 attenuated breast cancer cell migration and invasion possibly via suppression of FAK/Src/Rac1 pathway, whereas overexpression of ITGα3 and ITGβ5 caused the opposite effects. Consistently, osthole significantly inhibited breast cancer metastasis by downregulating ITGα3/ITGβ5 signaling in vitro and in vivo. These results provide new evidence that osthole may be developed as a candidate therapeutic drug for metastatic breast cancer.

Newts can regenerate their limbs throughout their life-span. Focusing on muscle, certain species of newts such as Cynops pyrrhogaster dedifferentiate muscle fibers in the limb stump and mobilize them for muscle creation in the regenerating limb, as they grow beyond metamorphosis. However, which developmental process is essential for muscle dedifferentiation, metamorphosis or body growth, is unknown. To address this issue, we tracked muscle fibers during limb regeneration under conditions in which metamorphosis and body growth were experimentally shifted along the axis of development. Our results indicate that a combination of metamorphosis and body growth is necessary for muscle dedifferentiation. On the other hand, ex vivo tracking of larval muscle fibers revealed that newt muscle fibers have the ability to dedifferentiate independently of metamorphosis and body growth. These results suggest that newt muscle fibers have an intrinsic ability to dedifferentiate, but that metamorphosis and body growth are necessary for them to exhibit this hidden ability. Presumably, changes in the extracellular environment (niche) during developmental processes allow muscle fibers to contribute to limb regeneration through dedifferentiation. This study can stimulate research on niches as well as gene regulation for dedifferentiation, contributing to a further understanding of regeneration and future medical applications.

RNA–binding motif protein 24 (RBM24) acts as a multifunctional determinant of cell fate, proliferation, apoptosis, and differentiation during development by regulating premRNA splicing and mRNA stability. It is also implicated in carcinogenesis, but the functions of RBM24 in bladder cancer (BC) remain unclear. In the present study, we revealed that RBM24 was upregulated in BC tissues. Importantly, we found that a higher level of RBM24 was correlated with poor prognosis in BC patients. Overexpression of RBM24 promoted BC cell proliferation, while depletion of RBM24 inhibited BC cell proliferation in vivo and in vitro. Mechanistically, RBM24 positively regulated Runx1t1 expression in BC cells by binding to and enhancing Runx1t1 mRNA stability. Furthermore, Runx1t1 in turn promoted RBM24 expression by interacting with the transcription factor TCF4 and suppressing the transcription of miR-625-5p, which directly targets RBM24 and suppresses RBM24 expression. RBM24-regulated BC cell proliferation was moderated via the Runx1t1/TCF4/miR-625-5p feedback loop. These results indicate that the RBM24/Runx1t1/TCF4/miR-625-5p positive feedback loop participates in BC progression. Disruption of this pathway may be a potential therapeutic strategy for BC treatment., Bladder cancer: Tracking down the molecular mechanisms A protein called RBM24 promotes progression of bladder cancer (BC) by forming a positive feedback loop with a specific transcription factor, driving cancer cell proliferation. Survival rates for BC are low, and the current imperfect understanding of the underlying mechanisms makes it difficult to treat. Ping-Ying Guo at Hebei Medical University in Shijiazhuang, China, and co-workers investigated the role of RBM24, known to be involved in other cancers, and found increased levels in BC tissues. Higher levels were associated with a poor prognosis. Further investigation revealed that RBM24 boosts levels of the transcription factor, which suppresses a molecule that in turn suppresses RBM24, forming a positive feedback loop promoting BC cell proliferation. Interrupting the feedback loop decreased tumor size in a mouse model. These results may help identify better treatments for BC.

Privacy-preserving cross-modal retrieval is a significant problem in the area of multimedia analysis. As the amount of data is exploding, cross-modal data analysis and retrieval is often realized on cloud computing environment. Therefore, the privacy protection of large-scale cross-modal data has become a problem that can not be ignored. To further improve the accuracy and efficiency of privacy-preserving search, this paper proposes a novel cross-modal hashing scheme, named deep adversarial privacy-preserving cross-modal hashing (DAP $$^2$$ CMH). This method consists of a deep cross-modal hashing model termed DACMH, and a secure index structure called CMH $$^2$$ -Tree. The former is a combination of deep hashing and adversarial learning to capture intra-modal and inter-modal correlation. The latter is a hierarchical hashing index structure that can provide efficient data organization based on cross-modal hash codes. We conduct comprehensive experiments on three common used benchmarks. The results show that the proposed approach DAP $$^2$$ CMH outperforms the state-of-the-arts.

White-light emitting (WLE) polymers have attracted continuous attention for their promising applications in solid-state lighting, flexible display and related fields. However, achieving dual-emission and pure white-light emission in a single-component polymer is still challenging. In this study, a brominated single-component polymer BrOD-TFB was designed and synthesized, which shows dual-emission and white light emission properties in solution and room-temperature phosphorescence (RTP) in thin films. The dual-emission properties can be tuned by concentration, solvent polarity, and excitation energy. Spectral analyses and theoretical calculations reveal that the origin of the high-energy emission band (HEB) is intramolecular charge transfer (ICT) along the polymer chain, whilst the low-energy emission band (LEB) originates from the excited-state related to the intra-chain and inter-chain C-Br⋯π interactions as demonstrated by the single-crystal structure of the model compound. Appropriate control of the formation and the destruction of the halogen-assisted interactions can initiate white-light emission in the single-component polymer. More interestingly, by dispersing BrOD-TFB (0.1 wt%) in a non-emissive, colorless and transparent polymer, the characteristics of this white-light emission can be fully demonstrated while exhibiting unexpected RTP properties, with photoluminescence quantum efficiency (ΦPL) of up to 23% and CIE coordinates of (0.32, 0.32).

Background Abnormal expression of splicing factor 3A subunit 3 (SF3A3), a component of the spliceosome, has been confirmed to be related to the occurrence and development of various cancers. However, the expression and function of SF3A3 in bladder cancer (BC) remains unclear. Methods The SF3A3 mRNA and protein level were measured in clinical samples and cell lines by quantitative real-time PCR, Western blot and immunofluorescence staining. Evaluate the clinical correlation between SF3A3 expression and clinicopathological characteristics through statistical analysis in BC patients. The function of SF3A3 in BC cells was determined in vitro using MTT and colony analysis. Co-immunoprecipitation (CoIP) assay was used to detected E2F6 and KDM5C interaction. Luciferase reporter and chromatin immunoprecipitation (ChIP) were used to examine the relationship between E2F6/KDM5C and SF3A3 expression. Results In the present study, we demonstrated that expression of SF3A3 was elevated in BC tissue compared to the normal bladder tissue. Importantly, the upregulation of SF3A3 in patients was correlated with poor prognosis. Additionally, overexpression of SF3A3 promoted while depletion of SF3A3 reduced the growth of BC cells in vivo and in vitro. Data from the TCGA database and clinical samples revealed that hypomethylation of the DNA promoter leads to high expression of SF3A3 in BC tissue. We found that upregulation of lysine-specific demethylase 5C (KDM5C) promotes SF3A3 expression via hypomethylation of the DNA promoter. The transcription factor E2F6 interacts with KDM5C, recruits KDM5C to the SF3A3 promoter, and demethylates the GpC island of H3K4me2, leading to high SF3A3 expression and BC progression. Conclusions The results demonstrated that depletion of the KDM5C/SF3A3 prevents the growth of BC in vivo and in vitro. The E2F6/KDM5C/SF3A3 pathway may be a potential therapeutic target for BC treatment.

Background The dysfunction of myc-related zinc finger protein (MAZ) has been proven to contribute to tumorigenesis and development of multiple cancer types. However, the biological roles and clinical significance of MAZ in clear cell renal carcinoma (ccRCC) remain unclear. Methods MAZ expression was examined in ccRCC and normal kidney tissue by quantitative real-time PCR and Western blot. Statistical analysis was used to evaluate the clinical correlation between MAZ expression and clinicopathological characteristics to determine the relationship between MAZ expression and the survival of ccRCC patients. The biological roles of MAZ in cells were investigated in vitro using MTT and colony assays. Luciferase reporter assays and chromatin immunoprecipitation (ChIP) were used to investigate the relationship between MAZ and its potential downstream signaling molecules. Results MAZ expression is elevated in ccRCC tissues, and higher levels of MAZ were correlated with poor survival of patients with ccRCC. MAZ upregulation elevates the proliferation ability of ccRCC cells in vitro, whereas silencing MAZ represses this ability. Our results further reveal that MAZ promotes cell growth, which is dependent on ERK signaling. Importantly, we found that MAZ positively regulates MAP2K2 expression in ccRCC cells. Mechanistically, MAZ binds to the MAP2K2 promoter and increases MAP2K2 transcription. Furthermore, MAP2K2 levels were shown to be increased in ccRCC tissues and to be associated with a poor prognosis of ccRCC patients. MAP2K2 upregulation activates the ERK signaling pathway and promotes ccRCC progression. Conclusion These results reveal that the MAZ/MAP2K2/ERK signaling axis plays a crucial role in promoting ccRCC progression, which suggests the potential therapeutic utility of MAZ in ccRCC.

The period approximating 100 ka relates to Middle Paleolithic or Middle Stone Age technological behaviors that are generally characterized by prepared core technology, an expanding range of retouched tools, and the novel exploitation and sourcing of raw materials. As opposed to other regions of the world, the technological features of this period in China are deeply debated and remain unclear. Presently, it is suggested that Chinese lithic technology during this period is marked by the continuation of mode 1 artifacts that are characterized by simple cores, flakes, and tools that lack standardization. Here, we present a lithic assemblage associated with the discovery of two archaic human crania at the Lingjing site, securely dated to ~ 125–90 ka. A detailed analysis of stone artifacts shows increased technological advancement of the Lingjing humans during this period, including bi-conical discoidal core reduction strategies, discrete small-sized tool types, and refined retouch on blanks. Those features are also shared by the contemporaneous sites documented across the broader Eurasian and African continents. However, the rarity of prepared core technologies at Lingjing, such as Levallois or laminar flaking, likely indicates a unique technological trajectory compared to sites outside of China. It is due to this that we herein adopt the term Chinese Middle Paleolithic to more clearly refer to the variations we have identified at Lingjing. The Lingjing lithic assemblage, overall, could potentially represent a regional expression of the Middle Paleolithic technocomplex in China, although details about the processes behind its development are still unclear. The study contributes to a new understanding of the long-standing view of the simplified technological behaviors in China before ~ 40 ka and sheds light on the interpretations of the implied human behavioral transformations in the early Late Pleistocene of China.

In situ scanning electron microscope (SEM) characterization have enabled the stretching, compression, and bending of micro/nanomaterials and have greatly expanded our understanding of small-scale phenomena. However, as one of the fundamental approaches for material analytics, torsion tests at a small scale remain a major challenge due to the lack of an ultrahigh precise torque sensor and the delicate sample assembly strategy. Herein, we present a microelectromechanical resonant torque sensor with an ultrahigh resolution of up to 4.78 fN∙m within an ultrawide dynamic range of 123 dB. Moreover, we propose a nanorobotic system to realize the precise assembly of microscale specimens with nanoscale positioning accuracy and to conduct repeatable in situ pure torsion tests for the first time. As a demonstration, we characterized the mechanical properties of Si microbeams through torsion tests and found that these microbeams were five-fold stronger than their bulk counterparts. The proposed torsion characterization system pushes the limit of mechanical torsion tests, overcomes the deficiencies in current in situ characterization techniques, and expands our knowledge regarding the behavior of micro/nanomaterials at various loads, which is expected to have significant implications for the eventual development and implementation of materials science. A microelectromechanical resonant sensor is proposed for small-scale torsion tests and demonstrated for the testing of silicon microbeams. It is important to understand the mechanical properties of small-scale materials used in MEMS and NEMS. Various systems have been reported for this under a range of loading conditions, but the application of torque to small-scale samples is particularly hard to measure. Here, a joint team led by Xueyong Wei from Xi’an Jiaotong University and Yajing Shen from City University of Hong Kong reports a MEMS-based resonator sensor that can measure bending and torsion over a wide dynamic range with a high force resolution. They demonstrate their system for the testing of silicon microbeams, which are found to be five times stronger than bulk silicon under pure torsion.

Due to the advances in mobile computing and multimedia techniques, there are vast amount of multimedia data with geographical information collected in multifarious applications. In this paper, we propose a novel type of image search named interactive geo-tagged image search which aims to find out a set of images based on geographical proximity and similarity of visual content, as well as the preference of users. Existing approaches for spatial keyword query and geo-image query cannot address this problem effectively since they do not consider these three type of information together for query. In order to solve this challenge efficiently, we propose the definition of interactive top-$k$ geo-tagged image query and then present a framework including candidate search stage , interaction stage and termination stage. To enhance the searching efficiency in a large-scale database, we propose the candidate search algorithm named GI-SUPER Search based on a new notion called superior relationship and GIR-Tree, a novel index structure. Furthermore, two candidate selection methods are proposed for learning the preferences of the user during the interaction. At last, the termination procedure and estimation procedure are introduced in brief. Experimental evaluation on real multimedia dataset demonstrates that our solution has a really high performance., 24 pages

Since the amplitude and frequency of irregular waves change with time, great difficulties are brought for solving ship load responses in random waves. To take the effect of various frequencies of irregular waves into consideration in load responses of hull, the wave memory effect is necessary. A semi-analytical method is introduced for the time-domain retardation functions, and then a nonlinear hydroelastic method considering memory effect for ships in irregular waves is proposed. Segmented self-propelling model experiments of a container ship were carried out in a towing tank, a ship motion measuring device for self-propelling model test was designed. Whipping responses of the ship in regular and irregular waves are analyzed. Finally, the calculation results are compared with those measured by segmented model experiments, and the result indicates that the memory effect has little effect on load responses of ship in regular waves, but pronounced effect on results in irregular waves. Moreover, the presented method is reasonable for the prediction of ship load responses in irregular waves.

The potential contaminations of 16 trace elements (Cr, Mn, Ni, Cu, Zn, As, Cd, Sb, Ba, Pb, Co, Be, V, Ti, Tl, Al) in drinking water collected in two remote areas in China were analyzed. The average levels of the trace elements were lower than the allowable concentrations set by national agencies, except for several elements (As, Sb, Mn, and Be) in individual samples. A health risk assessment model was conducted and carcinogenic and non-carcinogenic risks were evaluated separately. The results indicated that the total carcinogenic risks were higher than the maximum allowed risk level set by most organizations (1 × 10(-6)). Residents in both study areas were at risk of carcinogenic effects from exposure to Cr, which accounted for 80-90 % of the total carcinogenic risks. The non-carcinogenic risks (Cu, Zn, Ni) were lower than the maximum allowance levels. Among the four population groups, infants incurred the highest health risks and required special attention. Correlation analysis revealed significant positive associations among most trace elements, indicating the likelihood of a common source. The results of probabilistic health risk assessment of Cr based on Monte-Carlo simulation revealed that the uncertainty of system parameters does not affect the decision making of pollution prevention and control. Sensitivity analysis revealed that ingestion rate of water and concentration of Cr showed relatively high sensitivity to the health risks.