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Abstract Background The way of testicular tissue fixation directly affects the correlation and structural integrity between connective tissue and seminiferous tubules, which is essential for the study of male reproductive development. This study aimed to find the optimal fixative and fixation time to produce high-quality testicular histopathological sections, and provided a suitable foundation for in-depth study of male reproductive development with digital pathology technology. Methods Testes were removed from both sides of 25 male C57BL/6 mice. Samples were fixed in three different fixatives, 10% neutral buffered formalin (10% NBF), modified Davidson’s fluid (mDF), and Bouin’s Fluid (BF), for 8, 12, and 24 h, respectively. Hematoxylin and eosin (H&E) staining, periodic acid Schiff-hematoxylin (PAS-h) staining, and immunohistochemistry (IHC) were used to evaluate the testicle morphology, staging of mouse seminiferous tubules, and protein preservation. Aperio ScanScope CS2 panoramic scanning was used to perform quantitative analyses. Results H&E staining showed 10% NBF resulted in an approximately 15–17% reduction in the thickness of seminiferous epithelium. BF and mDF provided excellent results when staining acrosomes with PAS-h. IHC staining of synaptonemal complexes 3 (Sycp3) was superior in mDF compared to BF-fixed samples. Fixation in mDF and BF improved testis tissue morphology compared to 10% NBF. Conclusions Quantitative analysis showed that BF exhibited a very low IHC staining efficiency and revealed that mouse testes fixed for 12 h with mDF, exhibited morphological details, excellent efficiency of PAS-h staining for seminiferous tubule staging, and IHC results. In addition, the morphological damage of testis was prolonged with the duration of fixation time.

Abstract Cocrystal engineering is an efficient and simple strategy to construct functional materials, especially for the exploitation of novel and multifunctional materials. Herein, we report two kinds of nucleic-acid-base cocrystal systems that imitate the strong hydrogen bond interactions constructed in the form of complementary base pairing. The two cocrystals studied exhibit different colors of phosphorescence from their monomeric counterparts and show the feature of rare high-temperature phosphorescence. Mechanistic studies reveal that the strong hydrogen bond network stabilizes the triplet state and suppresses non-radiative transitions, resulting in phosphorescence even at 425 K. Moreover, the isolation effects of the hydrogen bond network regulate the interactions between the phosphor groups, realizing the manipulation from aggregation to single-molecule phosphorescence. Benefiting from the long-lived triplet state with a high quantum yield, the generation of reactive oxygen species by energy transfer is also available to utilize for some applications such as in photodynamic therapy and broad-spectrum microbicidal effects. In vitro experiments show that the cocrystals efficiently kill bacteria on a tooth surface and significantly help prevent dental caries. This work not only provides deep insight into the relationship of the structure-properties of cocrystal systems, but also facilitates the design of multifunctional cocrystal materials and enriches their potential applications.

Mechanical pretreatment is an indispensable process in biological treatment plants that remove plastics and other impurities from household biogenic waste (HBW). However, the imperfect separation of plastics in these pretreatment methods has raised concerns that they pose a secondary formation risk for microplastics (MPs). To validate this presumption, herein, quantities and properties of plastic debris and MPs larger than 50 μm were examined in the full chain of three different pretreatment methods in six plants. These facilities received HBW with or without prior depackaging at the source. The key points in the secondary formation of MPs were identified. Moreover, flux estimates of MPs were released, and an analysis of MPs sources was provided to develop an overview of their fate in HBW pretreatment. Pretreated output can contain a maximum of (1673 ± 279) to (3198 ± 263) MP particles per kilogram of wet weight (particles·kg−1 ww) for those undepackaged at source, and secondary MPs formation is primarily attributed to biomass crushers, biohydrolysis reactors, and rough shredders. Comparatively, HBW depackaged at the source can greatly reduce MPs by 8%–72%, regardless of pretreatment processes. Before pretreatment, 4.6–205.6 million MP particles were present in 100 tonnes of HBW. MPs are produced at a rate of 741.11–33 124.22 billion MP particles annually in anaerobic digester feedstock (ADF). This study demonstrated that HBW pretreatment is a competitive source of MPs and emphasized the importance of implementing municipal solid waste segregation at the source. Furthermore, depackaging biogenic waste at the source is recommended to substantially alleviate the negative effect of pretreatment on MPs formation.

Abstract Purpose This research was conducted to investigate the potential of short-chain fatty acids (SCFAs) in protecting organs from heat stress-induced injuries and gut microbiota modulation. Methods Sprague–Dawley rats were randomly assigned to various groups including a control group, a room temperature training group, a hyperthermia training group, SCFAs pretreatment group, and recipients received feces from the HT group. After strenuous training at high temperatures, the levels of plasma enzymes AST, ALT, BUN, and Cr were evaluated. The changes in gut microbiota and fecal metabolites were detected using 16S rRNA sequencing and GC–MS methods. Pathological examination of colon and liver tissues was conducted, and immunohistochemical techniques were employed to assess intestinal barrier function. Results The findings indicate that SCFAs hold the potential for mitigating liver and colon damage caused by heat stress. With the intervention of SCFAs, there were observable changes in the structure and metabolites of the intestinal microbiota, as well as improvements in intestinal barrier function. Further support for the benefits of SCFAs was found through fecal microbiota transplantation, which demonstrated that modified gut microbiota can effectively reduce organ damage. Conclusions This study provides evidence that SCFAs, as metabolites of the gut microbiota, have a valuable role to play in regulating gut health and mitigating the harmful effects of heat stress.

Abstract Background Exosomes play a crucial role in intercellular communication in clear cell renal cell carcinoma (ccRCC), while the long non‐coding RNAs (lncRNAs) are implicated in tumorigenesis and progression. Aims The purpose of this study is to construction a exosomes‐related lncRNA score and a ceRNA network to predict the response to immunotherapy and potential targeted drug in ccRCC. Methods Data of ccRCC patients were obtained from the TCGA database. Pearson correlation analysis was used to identify eExosomes‐related lncRNAs (ERLRs) from Top10 exosomes‐related genes that have been screened. The entire cohort was randomly divided into a training cohort and a validation cohort in equal scale. LASSO regression and multivariate cox regression was used to construct the ERLRs‐based score. Differences in clinicopathological characteristics, immune microenvironment, immune checkpoints, and drug susceptibility between the high‐ and low‐risk groups were also investigated. Finally, the relevant ceRNA network was constructed by machine learning to analyze their potential targets in immunotherapy and drug use of ccRCC patients. Results A score consisting of 4ERLRs was identified, and patients with higher ERLRs‐based score tended to have a worse prognosis than those with lower ERLRs‐based score. ROC curves and multivariate Cox regression analysis demonstrated that the score could be considered as a risk factor for prognosis in both training and validation cohorts. Moreover, patients with high scores are predisposed to experience poor overall survival, a larger prevalence of advanced stage (III‐IV), a greater tumor mutational burden, a higher infiltration of immunosuppressive cells, and a greater likelihood of responding favorably to immunotherapy. The importance of EMX2OS was determined by mechanical learning, and the ceRNA network was constructed, and EMX2OS may be a potential therapeutic target, possibly exerting its function through the EMX2OS/hsa‐miR‐31‐5p/TLN2 axis. Conclusions Based on machine learning, a novel ERLRs‐based score was constructed for predicting the survival of ccRCC patients. The ERLRs‐based score is a promising potential independent prognostic factor that is closely correlated with the immune microenvironment and clinicopathological characteristics. Meanwhile, we screened out key lncRNAEMX2OS and identified the EMX2OS/hsa‐miR‐31‐5p/TLN2 axis, which may provide new clues for the targeted therapy of ccRCC.

Ferroptosis, a cell death pathway dependent on iron, has been shown in research to play a role in the development, advancement, and outlook of tumours through ferroptosis-related lncRNAs (FRLRs). However, the value of the FRLRs in bladder cancer (BLCA) has not been thoroughly investigated. This research project involved developing a predictive model using ten specific FRLRs (AC099850.4, AL731567.1, AL133415.1, AC021321.1, SPAG5-AS1, HMGA2-AS1, RBMS3-AS3, AC006160.1, AL583785.1, and AL662844.4) through univariate COX and LASSO regression techniques. The validation of this signature as a standalone predictor was confirmed in a group of 65 patients from the urology bladder tumour database at the First Affiliated Hospital of Wenzhou Medical University in Wenzhou, China. Patients were categorized based on their median risk score into either a low-risk group or a high-risk group. Enrichment analysis identified possible molecular mechanisms that could explain the variations in clinical outcomes observed in high-risk and low-risk groups. Moreover, we explored the correlation between FLPS and immunotherapy-related indicators. The ability of FLPS to forecast the effectiveness of immunotherapy was validated by the elevated levels of immune checkpoint genes (PD-L1, CTLA4, and PD-1) in the group at high risk. We also screened the crucial FRLR (HMGA2-AS1) through congruent expression and prognostic conditions and established a ceRNA network, indicating that HMGA2-AS1 may affect epithelial-mesenchymal transition by modulating the Wnt signalling pathway through the ceRNA mechanism. We identified the top five mRNAs (NFIB, NEGR1, JAZF1, JCAD, and ESM1) based on random forest algorithm and analysed the relationship between HMGA2-AS1, the top five mRNAs, and immunotherapy, and their interactions with drug sensitivities. Our results suggest that patients with BLCA have a greater sensitivity to four drugs (dasatinib, pazopanib, erismodegib and olaparib). Our study provides new insights into the TME, key signalling pathways, genome, and potential therapeutic targets of BLCA, with future guidance for immunotherapy and targeted precision drugs.

Lung injury leads to respiratory dysfunction, low quality of life, and even life-threatening conditions. Circular RNAs (circRNAs) are endogenous RNAs produced by selective RNA splicing. Studies have reported their involvement in the progression of lung injury. Understanding the roles of circRNAs in lung injury may aid in elucidating the underlying mechanisms and provide new therapeutic targets. Thus, in this review, we aimed to summarize and discuss the characteristics and biological functions of circRNAs, and their roles in lung injury from existing research, to provide a theoretical basis for the use of circRNAs as a diagnostic and therapeutic target for lung injury.

Abstract Background Cuproptosis is a newly discovered programmed cell death dependent on mitochondrial respiratory disorder induced by copper overload. Pyruvate dehydrogenase E1 subunit beta (PDHB) is one of the cuproptosis genesand is a nuclear-encoded pyruvate dehydrogenase, which catalyzes the conversion of pyruvate to acetyl coenzyme A. However, the mechanism of PDHB in clear cell renal cell carcinoma (ccRCC) remains unclear. Methods We used data from TCGA and GEO to assess the expression of PDHB in normal and tumor tissues. We further analyzed the relationship between PDHB and somatic mutations and immune infiltration. Finally, we preliminarily explored the impact of PDHB on ccRCC. Results The expression level of PDHB was lower in tumor tissue compared with normal tissue. Meanwhile, the expression level of PDHB was also lower in high-grade tumors than low-grade tumors. PDHB is positively correlated with prognosis in ccRCC. Furthermore, PDHB may be associated with decreased risk of VHL, PBRM1 and KDM5C mutations. In 786-O cells, copper chloride could promote the expression of cuproptosis genes (DLAT, PDHB and FDX1) and inhibit cell growth. Last but not least, we found that PDHB could inhibit the proliferation and migration of ccRCC cells. Conclusion Our results demonstrated that PDHB could inhibit the proliferation, migration and invasion in ccRCC cells, which might be a prognostic predictor of ccRCC. Targeting this molecular might provide a new therapeutic strategy for patients with advanced ccRCC.

Octopus tentacles are equipped with numerous suckers, wherein the muscles contract and expel air, creating a pressure difference. Subsequently, when the muscular tension is released, objects can be securely adhered to. This mechanism has been widely employed in the development of adhesive systems. However, most existing octopus-inspired structures are passive and static, lacking dynamic and controllable adhesive switching capabilities and excellent locomotion performance. Here, we present an octopus-inspired soft robot (OISR). Attracted by the magnetic gradient field, the suction cup structure inside the OISR can generate a strong adsorption force, producing dynamically controllable adsorption and separation in the gastrointestinal (GI) tract. The experimental results show that the OISR has a variety of controllable locomotion behaviors, including quick scrolling and rolling motions, generating fast locomotion responses, rolling over gastric folds, and tumbling and swimming inside liquids. By carrying drugs that are absorbable by GI epithelial cells to target areas, the OISR enables continuous drug delivery at lesions or inflamed regions of the GI tract. This research may be a potential approach for achieving localized slow drug release within the GI tract.

To address the difficulty in conducting fire tests to verify the fire-resistance limit of large one-way slabs with heavy loads in a metro, a scale fire test method is proposed based on the bearing capacity calculation of the one-way slab under fire. The scale fire test method adapted the hypothesis that the deflection of the one-way slab under fire is close to a half-sine function and the plane section hypothesis. The validity of this hypothesis is verified through fire tests and finite element simulations. The scale fire test method achieves a similar temperature field and mechanical behavior between the scaled model and full-scale model of the one-way slab. The results of the fire tests showed that the temperature field and mechanical behavior of the scaled model were consistent with those of the full-scale model, with an error in fire resistance of 4.7%. The calculation results and fire test results are essentially consistent, with an error of 6.5%, and according to the calculation of the one-way slab fire-resistance limit, the key factor affecting the fire resistance of the one-way slab under fire is the temperature of the bottom rebars. Using the scale fire test method, the size effect of the one-way slab under fire still exists, and larger slabs have a greater deformation capacity.

Magnetic microgrippers, with their miniaturized size, flexible movement, untethered actuation, and programmable deformation, can perform tasks such as cell manipulation, targeted drug delivery, biopsy, and minimally invasive surgery in hard-to-reach regions. However, common external magnetic-field-driving devices suffer from low efficiency and utilization due to the significant size disparity with magnetic microgrippers. Here, we introduce a microgripper robot (MGR) driven by end electromagnetic and permanent magnet collaboration. The magnetic field generated by the microcoils can be amplified by the permanent magnets and the direction can be controlled by changing the current, allowing for precise control over the opening and closing of the magnetic microgripper and enhancing its operational range. Experimental results demonstrate that the MGR can be flexibly controlled in complex constrained environments and is highly adaptable for manipulating objects. Furthermore, the MGR can achieve planar and antigravity object grasping and transportation within complex simulated human cavity pathways. The MGR’s grasping capabilities can also be extended to specialized tasks, such as circuit connection in confined spaces. The MGR combines the required safety and controllability for in vivo operations, making it suitable for potential clinical applications such as tumor or abnormal tissue sampling and surgical assistance.

Abstract Background Oral squamous cell carcinoma (OSCC) is one of the most prevalent and fatal oral cancers. Mitochondria-targeting therapies represent promising strategies against various cancers, but their applications in treating OSCC are limited. Alantolactone (ALT) possesses anticancer properties and also regulates mitochondrial events. In this study, we explored the effects of ALT on OSCC and the related mechanisms. Methods The OSCC cells were treated with varying concentrations and duration of ALT and N-Acetyl-l-cysteine (NAC). The cell viability and colony formation were assessed. The apoptotic rate was evaluated by flow cytometry with Annexin V-FITC/PI double staining. We used DCFH-DA and flow cytometry to detect reactive oxygen species (ROS) production and DAF-FM DA to investigate reactive nitrogen species (RNS) level. Mitochondrial function was reflected by mitochondrial reactive oxygen species (ROS), mitochondrial membrane potential (MMP), and ATP levels. KEGG enrichment analyses determined the mitochondrial-related hub genes involved in OSCC progression. Dynamin-related protein 1 (Drp1) overexpression plasmids were further transfected into the cells to analyze the role of Drp1 in OSCC progression. Immunohistochemistry staining and western blot verified the expression of the protein. Results ALT exerted anti-proliferative and pro-apoptosis effects on OSCC cells. Mechanistically, ALT elicited cell injury by promoting ROS production, mitochondrial membrane depolarization, and ATP depletion, which were reversed by NAC. Bioinformatics analysis showed that Drp1 played a crucial role in OSCC progression. OSCC patients with low Drp1 expression had a higher survival rate. The OSCC cancer tissues presented higher phosphorylated-Drp1 and Drp1 levels than the normal tissues. The results further showed that ALT suppressed Drp1 phosphorylation in OSCC cells. Moreover, Drp1 overexpression abolished the reduced Drp1 phosphorylation by ALT and promoted the cell viability of ALT-treated cells. Drp1 overexpression also reversed the mitochondrial dysfunction induced by ALT, with decreased ROS production, and increased mitochondrial membrane potential and ATP level. Conclusions ALT inhibited proliferation and promoted apoptosis of oral squamous cell carcinoma cells via impairment of mitochondrial homeostasis and regulation of Drp1. The results provide a solid basis for ALT as a therapeutic candidate for treating OSCC, with Drp1 being a novel therapeutic target in treating OSCC.

Abstract To achieve highly‐efficient organic light‐emitting diodes (OLEDs), great efforts have been devoted into constructing thermally activated delayed fluorescence (TADF) with high horizontal dipole ratios (Θ//). Here, we proposed a design strategy by integrating a rigid electron‐accepting oxygen‐bridged boron core with triple electron‐donating groups, which exhibited a “shamrock‐shape”, namely BO‐3DMAC and BO‐3DPAC. Benefiting from the rigid and large‐planar skeletons brought by shamrock‐shaped design, BO‐3DMAC and BO‐3DPAC exhibit high Θ// of 84%/70% and 93%/94% in neat/doped films, respectively, and finally furnish excellent external quantum efficiencies (EQEs) of up to 28.3% and 38.7% in 20 wt% doped OLEDs with sky‐blue emission, as well as adequate EQEs of up to 21.0% and 16.7% in nondoped OLEDs. This work unveils a promising strategy to establish high‐Θ// TADF emitters by constructing large‐planar molecular structures using shamrock‐shaped design.

Abstract Statins have been proven to be effective in minimizing the risk of cardiovascular adverse events, however, their effect on BP variability is debatable with respect to their significance and their use as a potential anti‐hypertensive. Using a meta‐analysis approach, the aim of this study was to explore whether certain statins have the potential to lower blood pressure (BP). For the period 2002–2022, Scopus, PubMed, Web of Science, and the Cochrane Central Register of Controlled Trials databases were searched for the studies that examined the effect of statins on blood pressure in normotensive or hypertensive individuals. Randomized controlled clinical trials that investigated this effect were included based on our inclusion criteria. Our primary outcomes were changes in systolic and diastolic blood pressure (DBP). The final analysis of the study included 49 RCTs involving 45 173 participants randomized to receive either statins or placebo. Among the two groups, the total weighted mean difference (WMD) for systolic blood pressure (ΔSBP) was –1.42 (95% CI: –2.38, –0.46; p = .004) and diastolic blood pressure (ΔDBP) was 0.82 (95% CI: –1.28, –0.36; p = .0005). Despite various studies suggesting the efficacy of statins in blood pressure lowering to be significant and non‐significant both, we observed a decrease in SBP and DBP both, although the change was not as large and could be considered significant. A large multicenter, multi‐ethnic, large sample pool size, and a long period follow‐up study is still required to assert these claims.

Abstract 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.

Laser additive repair technology is suitable to repair the metal parts of military aircraft. It is an important thrust to prolong the flight service life and improve the ability of independent maintenance. This paper introduced the characteristics of laser additive repair technologies such as selective laser melting forming, laser direct deposition forming, laser cladding and laser arc composite additive manufacturing. The common types of defects with different scales, such as edge collapse, surface spheroidization, porosity and crack in the process of laser additive repair were described, and the corresponding control methods were proposed. The laser energy density, overlap ratio, feeding speed of filler materials, shielding gas flow, time parameters and scanning path of laser additive repair technology were summarized, and the repair performance was improved by the application of external energy field and optimization design of special filler materials. Finally, the application of laser additive repair technology in the maintenance of aircraft wing beams, turbine blades, single crystal blades, landing gear and other metal parts was listed. The future research trend of laser additive repair technology in auxiliary system design, multi energy field fusion, evaluation standard formulation was emphasized, the research and development of mobile laser additive repair equipment were discussed.

Abstract 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.

Nickel titanate (NiTiO3) semiconductors and graphitic carbon nitride (g-C3N4) have attracted great attention as photocatalysts in the degradation of environmental pollutants because of their visible-light-driven activity. But the utilizations of both semiconductors are limited by their low specific surface area. In this study, a nano-NiTiO3/g-C3N4 photocatalyst was successfully synthesized by optimizing the preparation method of photocatalyst precursors. Compared with the bulk g-C3N4 and bulk NiTiO3/g-C3N4 composite photocatalysts, the nano-NiTiO3/g-C3N4 composite catalyst displayed a larger specific surface area, a more abundant pore size structure, and superior carrier separation capabilities. According to the pseudo-first-order, the degradation rate of MB was more than 2.5–19.7 times higher than that of previous studies. The superoxide radicals (·O2−) and holes (h+) played significant roles in the photocatalytic reaction of MB. This study provides a new idea for the synthesis of photocatalysts and the improvement in photocatalytic performance.

BackgroundSevere fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease that was caused by the Dabie bandavirus (DBV), and it has become a global public health threat. Cytokine storm is considered to be an important pathogenesis of critical SFTS. Tripartite motif-containing 3 (TRIM3), as a member of the TRIM protein family, may contribute to the regulation of the immune and inflammatory responses after viral infection. However, whether TRIM3 plays a major role in the pathogenesis of SFTS has not yet been investigated.MethodsTRIM3 mRNA levels were detected in PBMCs between 29 SFTS patients and 29 healthy controls by qRT-PCR. We established the pathogenic IFNAR−/− SFTS mouse model successfully by inoculating subcutaneously with DBV and testing the expression levels of TRIM3 mRNA and protein by qRT-PCR and immunofluorescence in the livers, spleens, lungs, and kidneys. TRIM3OE THP-1 cells and peritoneal macrophages extracted from TRIM3−/− mice were infected with DBV. The effect of TRIM3 on cytokines was detected by qRT-PCR and ELISA. Then we examined Toll-like receptor 3 (TLR3) and protein phosphorylation in the MAPK pathway after DBV infection using Western blot. Flow cytometry was used to verify TLR3 expression on peripheral blood monocytes in SFTS patients. We further explored the interaction between TRIM3 and TLR3 using CO-IP and Western blot.ResultsCompared to healthy controls, TRIM3 mRNA expression in PBMCs is decreased in SFTS patients, especially in severe cases. TRIM3 mRNA and protein were synchronously reduced in the livers, spleens, lungs, and kidney tissues of the IFNAR−/− SFTS mice model. In the DBV-infected cell model, TRIM3 overexpression can inhibit the DBV-induced release of IL-1β, IL-6, and TNF-α, the expression of TLR3, and protein phosphorylation in the MAPK pathway, which plays an anti-inflammatory role, while TRIM3 deficiency exacerbates the pro-inflammatory effects. We further found that TRIM3 can promote TLR3 degradation through K48-linked ubiquitination.ConclusionTRIM3 can inhibit the production of cytokines by regulating the degradation of TLR3 through K48-linked ubiquitination, which can be a therapeutic target for improving the prognosis of SFTS.

Abstract Background Exosomes play an important role in the tumor microenvironment (TME) and the mechanisms of tumor immune escape in hepatocellular carcinoma (HCC). It is known that immunosuppressive genes, involved in the processes of tumor immunosuppression, are associated with cancer progression. This study aimed to explore the prognostic values of exosome-related immunosuppression genes (ERIGs) in HCC. Methods The RNA-seq transcriptome data of 374 HCC patients were obtained from the Cancer Genome Atlas (TCGA) database. The TCGA cohort was randomly divided into the training cohort and validation cohort in a 1:1 ratio. WGCNA analysis and Pearson correlation analysis were used to identify ERIGs. The Lasso regression method was used to construct a 5-ERIG signature. The prognostic value of our signature was examined in the First Affiliated Hospital of Wenzhou Medical University (FAHWMU) cohort. Results Univariate Cox regression analysis was used to screen prognostic ERIGs. Subsequently, these prognostic ERIGs were included in Lasso regression analyses to identify 5 key ERIGs (ASAP1, IARS1, GTF3C2, TPD5L2 and SLC52A2) and construct a 5-ERIG signature. The patients in the low-risk group had better prognosis than those in the high-risk group. Univariate and multivariate cox regression revealed that risk score was an independent prognostic risk factor of HCC. Gene set enrichment analysis (GSEA) showed that this signature was highly associated with TME-related pathways. Subsequent analyses revealed the potential role of the signature in regulating the TME in HCC. In addition, a lower immunotherapy score was found in patients with high risk-score. Of note, this signature was confirmed to have a good performance in predicting HCC prognosis in the FAHWMU cohort. Moreover, knockdown of 5 ERIGs of this signature contributed to the suppression the Hep3B cell proliferation. Conclusions We generated a novel prognostic 5-ERIG signature to accurately predict the prognosis of patients with HCC, and this signature may serve as an indicator of immunotherapy for HCC.

KLF4-induced phenotypic switching of vascular smooth muscle cells occurs in atherosclerosis. Now, KLF4 is shown to induce a glycolytic shift involving upregulation of PFKFB3 expression through circular RNA CTDP1 and eukaryotic elongation factor eEF1A2.

Abstract 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.

A series of Bi2WO6/TiO2-nanotube (Bi2WO6/TiO2-NT) heterostructured composites were prepared by utilizing natural cellulose (e.g., laboratory filter paper) as the structural template. The obtained nanoarchitectonics, namely Bi2WO6/TiO2-NT nanocomposites, displayed three-dimensionally interwoven structures which replicated the initial cellulose template. The composite Bi2WO6/TiO2-NT nanotubes were formed by TiO2 nanotubes that uniformly anchored with Bi2WO6 nanoparticles of various densities on the surface. The composites exhibited improved photocatalytic activities toward the reduction of Cr(VI) and degradation of rhodamine B under visible light (λ > 420 nm), which were attributed to the uniform anchoring of Bi2WO6 nanoparticles on TiO2 nanotubes, as well as strong mutual effects and well-proportioned formation of heterostructures in between the Bi2WO6 and TiO2 phases. These improvements arose from the cellulose-derived unique structures, leading to an enhanced absorption of visible light together with an accelerated separation and transfer of the photogenerated electron–hole pairs of the nanocomposites, which resulted in increased effective amounts of photogenerated carriers for the photocatalytic reactions. It was demonstrated that the photoinduced electrons dominated the photocatalytic reduction of Cr(VI), while hydroxyl radicals and reactive holes contributed to the photocatalytic degradation of rhodamine B.

Abstract LncRNA N6-methylandenosine (m6A) modification has been shown to be associated with the constitution of the tumor microenvironment (TME) and tumorigenesis. It’s essential to understand the mechanisms of lncRNA m6A modification in hepatocellular carcinoma (HCC) and identify relative prognostic predictors to guide therapy and explore potential therapeutic targets. Pearson correlation analysis was performed to identify m6A-related lncRNAs in 374 patients with HCC. Unsupervised cluster analysis of the potential m6A-related lncRNA-based HCC subtypes was conducted, followed by the concurrent analysis of their relationship with TME characteristics, immune checkpoints, immune features, and prognosis through single sample gene set enrichment analysis and ESTIMATE algorithm. Cox regression analyses were performed to screen prognostic m6A-related lncRNA, construct an m6A-related lncRNA signature (m6A-RLRS), and establish an integrated nomogram for the prognosis of patients with HCC. We identified 61 m6A-related lncRNAs and two HCC subtypes defined by consensus cluster of m6A-related lncRNAs with distinct clinical features. Progression-free survival (PFS), three TME-related scores, 15 immune-associated gene sets, and two immune checkpoints expression were found to be significantly different among the two subtypes. Twenty-five prognostic m6A-related lncRNAs were determined, four of which were included to establish an m6A-RLRS with favorable discrimination, and the signature was validated in the validation set and an independent FAHWMU cohort (n = 60). Furthermore, a novel nomogram combining signature and clinical predictors was generated with a C-index of 0.703, and an original ceRNA regulatory network consisting of 9 lncRNAs, 28 miRNAs, and 75 target mRNAs was constructed. Finally, the differential expression of four m6A-related lncRNA was verified by qRT-PCR. In conclusion, m6A-related lncRNA prognostic signature and molecular subtype contributes to accurately predict the prognosis of HCC and provide potential novel therapeutic targets.

Introduction: Hypoxia-inducible factor (HIF)1α has been shown to be activated and induces a glycolytic shift under hypoxic condition, however, little attention was paid to the role of HIF1α-actuated fructolysis in hypoxia-induced heart injury. Objectives: In this study, we aim to explore the molecular mechanisms of miR-155-mediated fructose metabolism in hypoxic cardiac fibroblasts (CFs). Methods: Immunostaining, western blot and quantitative real-time reverse transcription PCR (qRT-PCR) were performed to detect the expression of glucose transporter 5 (GLUT5), ketohexokinase (KHK)-A and KHK-C in miR-155−/− and miR-155wt CFs under normoxia or hypoxia. A microarray analysis of circRNAs was performed to identify circHIF1α. Then CoIP, RIP and mass spectrometry analysis were performed and identified SKIV2L2 (MTR4) and transformer 2 alpha (TRA2A), a member of the transformer 2 homolog family. pAd-SKIV2L2 was administrated after coronary artery ligation to investigate whether SKIV2L2 can provide a protective effect on the infarcted heart. Results: When both miR-155−/− and miR-155wt CFs were exposed to hypoxia for 24 h, these two cells exhibited an increased glycolysis and decreased glycogen synthesis, and the expression of KHK-A and KHK-C, the central fructose-metabolizing enzyme, was upregulated. Mechanistically, miR-155 deletion in CFs enhanced SKIV2L2 expression and its interaction with TRA2A, which suppresses the alternative splicing of HIF1α pre-mRNA to form circHIF1α, and then decreased circHIF1α contributed to the activation of fructose metabolism through increasing the production of the KHK-C isoform. Finally, exogenous delivery of SKIV2L2 reduced myocardial damage in the infarcted heart. Conclusion: In this study, we demonstrated that miR-155 deletion facilitates the activation of fructose metabolism in hypoxic CFs through regulating alternative splicing of HIF1α pre-mRNA and thus circHIF1ɑ formation.

Sertoli cell -only syndrome (SCOS) is a type of testicular pathological failure that causes male infertility and no effective treatment strategy, is available for this condition. Moreover, the molecular mechanism underlying its development remains unknown. We identified DExD/H-Box helicase 58 (DDX58) as a key gene in SCOS based on four datasets of testicular tissue samples obtained from the Gene Expression Synthesis database. DDX58 was significantly upregulated in SCOS testicular Sertoli cells. Moreover, high expression of DDX58 was positively correlated with the expression of several testicular inflammatory factors, such as IL -1β, IL-18, and IL-6. Interestingly, DDX58 could be induced in the D-galactose (D-gal)-stimulated TM4 cell injury model. Whereas silencing of DDX58 inhibited D-gal -mediated p65 expression, inflammatory cytokine release, and growth arrest. Mechanistically, we found that DDX58 acts as an RNA-binding protein, which enhances p65 expression by promoting mRNA stability. Furthermore, p65 gene silencing decreased the expression of inflammatory cytokines and inhibition of cell growth in D-gal-induced cells. In conclusion, our findings demonstrate that DDX58 promotes inflammatory responses and growth arrest in SCOS Sertoli cells by stabilizing p65 mRNA. Accordingly, the DDX58/p65 regulatory axis might be a therapeutic target for SCOS.

Abstract 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.

Excessive inflammation post-traumatic spinal cord injury (SCI) induces microglial activation, which leads to prolonged neurological dysfunction. However, the mechanism underlying microglial activation-induced neuroinflammation remains poorly understood. Ruxolitinib (RUX), a selective inhibitor of JAK1/2, was recently reported to inhibit inflammatory storms caused by SARS-CoV-2 in the lung. However, its role in disrupting inflammation post-SCI has not been confirmed. In this study, microglia were treated with RUX for 24 hours and then activated with interferon-γ for 6 hours. The results showed that interferon-γ-induced phosphorylation of JAK and STAT in microglia was inhibited, and the mRNA expression levels of pro-inflammatory cytokines tumor necrosis factor-α, interleukin-1β, interleukin-6, and cell proliferation marker Ki67 were reduced. In further in vivo experiments, a mouse model of spinal cord injury was treated intragastrically with RUX for 3 successive days, and the findings suggest that RUX can inhibit microglial proliferation by inhibiting the interferon-γ/JAK/STAT pathway. Moreover, microglia treated with RUX centripetally migrated toward injured foci, remaining limited and compacted within the glial scar, which resulted in axon preservation and less demyelination. Moreover, the protein expression levels of tumor necrosis factor-α, interleukin-1β, and interleukin-6 were reduced. The neuromotor function of SCI mice also recovered. These findings suggest that RUX can inhibit neuroinflammation through inhibiting the interferon-γ/JAK/STAT pathway, thereby reducing secondary injury after SCI and producing neuroprotective effects.

IntroductionSevere fever with thrombocytopenia syndrome (SFTS) has become a global threat to public health since its first report in China in 2009. However, the pathogenesis of SFTS virus (SFTSV) in humans remains unclear. Also, there are no effective therapeutics for SFTS. Cyclophilin A (CyPA) regulates protein folding and trafficking involved in various viral infectious diseases, but its role in SFTSV infection has not been elucidated.MethodsWe detected plasma CyPA levels in 29 healthy subjects and 30 SFTS patients by ELISA. In THP-1 cells and normal human peripheral blood mononuclear cells (PBMCs), SFTSV-induced extracellular CyPA (eCyPA) was also detected by ELISA. In THP-1, the effects of CyPA on Mitogen-activated protein kinase (MAPK) pathway and NF-κB were determined by Western blot. We validated the interaction between CypA and CD147 by human recombinant CyPA (hrCyPA) and the CD147 inhibitor. Effects of CyPA inhibitor Cyclosporine A (CsA) on cytokines and SFTSV replication in THP-1 cells was also detected. 8-week-old Interferon-α/β Receptor (IFNAR) knockout (IFNAR-/-) C57BL/6 mice were divided into mock group, 106TCID50 SFTSV (Untreated) group and 106TCID50 SFTSV+CsA (CsA-treated) group. The changes of body weight, animal behavior and survival time of each group were recorded. Blood samples were collected from tail vein regularly. After death, the liver, spleen, lung, kidney and brain were collected for pathological HE staining and SFTSV-NP immunohistochemical staining.ResultsCompared to healthy subjects and SFTS patients in the febrile phase of the disease, plasma CyPA levels in SFTS patients at the multi-organ dysfunction (MOD) phase showed significantly elevated (P < 0.01). Extracellular CyPA activates the MAPK pathway by binding to CD147 in THP-1 infected with SFTSV. CsA inhibits the pro-inflammatory and promoting replication effects of CyPA after SFTSV infection in vitro. In vivo, CsA can prolong the survival time and delay the weight loss of SFTSV mice. CsA reduces multi-organ dysfunction in IFNAR−/− mice infected with SFTSV.DiscussionOur results indicate that CyPA is associated with SFTSV-induced cytokine storm, which can be a potential target for SFTS therapy.

ObjectivesTo examine the association of protein intake from different sources with cognitive decline.MethodsOur analysis included 3,083 participants aged 55–93 years from the China Health and Nutrition Survey. Cognition was assessed in 1997, 2000, 2004, 2006, and 2015. Diet intake was assessed using weighing methods in combination with 24-h dietary recalls for three consecutive days at each survey.ResultsParticipants consumed 13.94% of energy intake from total protein, with 11.47 and 2.47% from plant and animal sources, respectively. During a follow-up of 9 years, participants in quintile 5 of plant protein intake (% energy) had a higher risk [odds ratio (95% CI): 3.03 (1.22–7.53)] of cognitive decline compared with those in quintile 1. Higher animal protein intake (% total protein) was associated with a lower risk of cognitive decline [odds ratio (95% CI) for quintile 5 vs. quintile 1: 0.22 (0.07–0.71)]. Grains (plant source) protein intake was inversely but fish/shrimp and poultry (animal source) protein intake were positively associated with change in cognitive Z-score.ConclusionIncreasing animal protein consumption in a population with plant dominant diets may help to prevent cognitive decline.

Abstract Numerous studies have shown that microRNA (miRNA) serves as key regulatory factors in the origin and development of cancers. However, the biological mechanisms of miRNAs in kidney renal clear cell carcinoma (KIRC) are still unknown. It is necessary to construct an effective miRNA‐clinical model to predict the prognosis of KIRC. In this study, 94 differentially expressed miRNAs were found between para‐tumor and tumor tissues based on the Cancer Genome Atlas (TCGA) database. Seven miRNAs (hsa‐miR‐21‐5p, hsa‐miR‐3613‐5p, hsa‐miR‐144‐5p, hsa‐miR‐376a‐5p, hsa‐miR‐5588‐3p, hsa‐miR‐1269a, and hsa‐miR‐137‐3p) were selected as prognostic indicators. According to their cox coefficient, a risk score formula was constructed. Patients with risk scores were divided into high‐ and low‐risk groups based on the median score. Kaplan–Meier curves analysis showed that the low‐risk group had a better survival probability compared to the high‐risk group. The area under the ROC curve (AUC) value of the miRNA model was 0.744. In comparison with clinical features, the miRNA model risk score was considered as an independent prognosis factor in multivariate Cox regression analysis. In addition, we built a nomogram including age, metastasis, and miRNA prognostic model based on the results of multivariate Cox regression analysis. The decision curve analysis (DCA) revealed the clinical net benefit of the prognostic model. Gene set enrichment analysis (GSEA) results suggested that several important pathways may be the potential pathways for KIRC. The results of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis for the target genes of 7 miRNAs revealed that miRNAs may participate in KIRC progression via many specific pathways. Additionally, the levels of seven prognostic miRNAs showed a significant difference between KIRC tissues and adjacent non‐tumorous tissues. In conclusion, the miRNA‐clinical model provides an effective and accurate way to predict the prognosis of KIRC.

Abstract 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.

ABSTRACT Acetaminophen (APAP) overdose is one of the most common causes of acute liver injury (ALI) in Western countries. Many studies show that the gut microbiota plays an important role in liver injury. Currently, the only approved treatment for APAP-induced ALI is N-acetylcysteine; therefore, it is essential to develop new therapeutic agents and explore the underlying mechanisms. We developed a novel monoclonal anti-Toll-like receptor 4 (TLR4) antibody (ATAB) and hypothesized that it has therapeutic effects on APAP-induced ALI and that gut microbiota may be involved in the underlying mechanism of ATAB treatment. Male C57BL/6 mice were treated with APAP and ATAB, which produced a therapeutic effect on ALI and altered the gut microbiota and their metabolic pathway, such as Roseburia, Lactobacillus, Akkermansia, and the fatty acid pathway, etc. Furthermore, we verified that purified short-chain fatty acids (SCFAs) could alleviate ALI. Moreover, a separate group of mice that received feces from the ATAB group showed less severe liver injury compared with the mice receiving feces from the APAP group. ATAB therapy also improved the gut barrier functions in mice and reduced the expression of protein zonulin. Our results revealed that gut microbiota plays an important role in the therapeutic effect of ATAB on APAP-induced ALI. IMPORTANCE In this study, we found the monoclonal anti-Toll-like receptor 4 antibody can alleviate APAP-induced acute liver injury through the change of the gut microbiota, metabolic pathways, and gut barrier function. This work suggested the gut microbiota can be the therapeutic target of the APAP-induced acute liver injury, and we performed the fundamental research for further research.

Abstract Background Both E2F transcription factor and cyclin-dependent kinases (CDKs), which increase or decrease E2F activity by phosphorylating E2F or its partner, are involved in the control of cell proliferation, and some circRNAs and miRNAs regulate the expression of E2F and CDKs. However, little is known about whether dysregulation among E2Fs, CDKs, circRNAs and miRNAs occurs in human PCa. Methods The expression levels of CDK13 in PCa tissues and different cell lines were determined by quantitative real-time PCR and Western blot analysis. In vitro and in vivo assays were preformed to explore the biological effects of CDK13 in PCa cells. Co-immunoprecipitation anlysis coupled with mass spectrometry was used to identify E2F5 interaction with CDK13. A CRISPR-Cas9 complex was used to activate endogenous CDK13 and circCDK13 expression. Furthermore, the mechanism of circCDK13 was investigated by using loss-of-function and gain-of-function assays in vitro and in vivo. Results Here we show that CDK13 is significantly upregulated in human PCa tissues. CDK13 depletion and overexpression in PCa cells decrease and increase, respectively, cell proliferation, and the pro-proliferation effect of CDK13 is strengthened by its interaction with E2F5. Mechanistically, transcriptional activation of endogenous CDK13, but not the forced expression of CDK13 by its expression vector, remarkably promotes E2F5 protein expression by facilitating circCDK13 formation. Further, the upregulation of E2F5 enhances CDK13 transcription and promotes circCDK13 biogenesis, which in turn sponges miR-212-5p/449a and thus relieves their repression of the E2F5 expression, subsequently leading to the upregulation of E2F5 expression and PCa cell proliferation. Conclusions These findings suggest that CDK13 upregulation-induced formation of the positive feedback loop among circCDK13, miR-212-5p/miR-449a and E2F5 is responsible for PCa development. Targeting this newly identified regulatory axis may provide therapeutic benefit against PCa progression and drug resistance.

Sensors: measuring torque 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.

A hybrid core-shell structured nanowire is proposed for a long-term stable electron source based on an isolated platinum/multi-walled carbon nanotube (Pt/MWCNT). This hybrid nanowire is prepared by growing a Pt shell on a metallic MWCNT through a field-emission-induced deposition (FEID) method. An in situ field emission (FE) platform was constructed inside a scanning electron microscope (SEM) equipped with two nanorobotic manipulators (NRMs) for the preparation and testing of the hybrid nanowire. An in situ fatigue test was conducted with high current intensity (500 nA) to show the influence of the Pt shell. Compared with the pristine bare MWCNT, our hybrid-nanowire-based electron source has a lifetime of hundreds of times longer and can work continuously for up to 48 h under relatively high pressure (3.6×10-3 Pa) without having an apparent change in its structure or emission currents, demonstrating good stability and tolerance to poor working conditions. The anomalous long-term stability is attributed mainly to the shielding of oxygen by Pt from the carbon shells and less heating due to the work function lowering by Pt.

Autophagy is associated with the cytoprotection of physiological processes against inflammation and oxidative stress. Salvia miltiorrhiza possesses cardiovascular protective actions and has powerful anti-oxidative and anti-inflammatory effects; however, whether and how Salvia miltiorrhiza-derived microRNAs (miRNAs) protect vascular smooth muscle cells (VSMCs) by inducing autophagy across species are unknown. We first screened and identified Sal-miR-58 from Salvia miltiorrhiza as a natural autophagy inducer. Synthetic Sal-miR-58 suppresses chronic angiotensin II (Ang II) infusion-induced abdominal aortic aneurysm (AAA) formation in mice, as well as induces autophagy in VSMCs and attenuates the inflammatory response elicited by Ang II in vivo and in vitro. Mechanistically, Sal-miR-58 downregulates Krüppel-like factor 3 (KLF3) expression through direct binding to the 3′ UTR of KLF3, which in turn relieves KLF3 repression of E3 ubiquitin ligase neural precursor cell-expressed developmentally downregulated 4-like (NEDD4L) expression, whereas NEDD4L upregulation increases the ubiquitination and degradation of the platelet isoform of phosphofructokinase (PFKP), subsequently leading to a decrease in the activation of Akt/mammalian target of rapamycin (mTOR) signaling and facilitating VSMC autophagy induced by Sal-miR-58 in the context of chronic Ang II stimulation and aneurysm formation. Our results provide the first evidence that plant-derived Sal-miR-58 induces autophagy and attenuates inflammation in VSMCs through cross-species modulation of the KLF3/NEDD4L/PFKP regulatory pathway.

Abstract Background STAT5 plays an important role in the transformation of hematopoietic cells by BCR-ABL. However, the downstream target genes activated by STAT5 in chronic myeloid leukemia (CML) cells remain largely unclear. Here, we investigated the mechanistic functional relationship between STAT5A-regulated microRNA and CML cell apoptosis. Methods The expression of USP15, Caspase-6, STAT5A-regulated miR-202-5p and STAT5A was detected by qRT-PCR and Western blotting in CML cell lines and PBMCs of CML patients. Cell apoptosis was evaluated by flow cytometry. Both gain- and loss-of-function experiments were used to investigate the roles of USP15, miR-202-5p and STAT5A in CML. Luciferase reporter assay detected the effect of miR-202-5p on USP15 expression. Xenograft animal model was used to test the effect of anti-miR-202-5p and pimozide on K562 cell xenograft growth. Results USP15 expression was significantly downregulated in CML cell lines and PBMCs of CML patients. Depletion of USP15 increased, whereas overexpression of USP15 reduced the resistance of CML cells to Imatinib. Further, decreased deubiquitinating activity of USP15 by USP15 downregulation led to reduced caspase-6 level, thus attenuating CML cell apoptosis. Mechanistically, miR-202-5p was upregulated in K562G cells and negatively regulated USP15 expression by directly targeting USP15 3′-UTR. Correspondingly, upregulation of miR-202-5p enhanced the resistance of CML cells to Imatinib by inhibiting cell apoptosis. Importantly, STAT5A was upregulated in CML cells and directly activated miR-202-5p transcription by binding to the pre-miR-202 promoter. Pimozide induced CML cell apoptosis and significantly reduced K562 cell xenograft growth in vivo by blocking STAT5A/miR-202-5p/USP15/Caspase-6 regulatory axis. Conclusions we provide the first evidence that de-regulated STAT5A/miR-202-5p/USP15/Caspase-6 regulatory axis suppresses the apoptosis of CML cells, targeting this pathway might be a promising therapeutic approach for the treatment of CML.

Nickel-based superalloy lattice sandwich structures present higher stiffness, higher strength and higher temperature resistance in comparison with other metals. In this study, the Kagome unit was adopted to design the lattice sandwich structure and ProCAST software was used to simulate the filling and solidification processes of the nickel-based superalloy. Grain morphology and sizes of the nickel-based superalloy lattice sandwich structures were simulated by using of cellular automaton coupled with finite element model (CAFE), and indirect additive manufacture combining with investment casting were carried out to fabricate the nickel-based superalloy lattice sandwich structures. The calculated grain morphology and sizes are in good agreement with the experimental results. The grains are mainly equiaxed with an average size of about 500 μm. The simulated results also show that the superheat of melting and the mold preheated temperature have significant influence on the grain size of the Kagome lattice sandwich structures, lower superheat of melting and mold preheated temperatures are encouraged to obtain the fine grains while assuring the integrity of the Kagome lattice sandwich structures for industrial application.

Zinc-finger protein 304 (ZNF304) plays a critical role in silencing genes through transcription, regulating cell survival, proliferation, apoptosis, and differentiation during development. However, the roles of transcription factor ZNF304 and its clinical significance in clear cell renal carcinoma (ccRCC) remain unclear. In this study, we found that the expression of ZNF304 was downregulated in ccRCC tissues. Lower levels of ZNF304 were correlated with poor survival. Downregulation of ZNF304 promoted ccRCC cell growth in vitro, whereas overexpression of ZNF304 inhibited growth. Our results indicated that miR-183-5p/FOXO4 mediated ZNF304 regulation of cell growth. Interestingly, we revealed that ZNF304 promoted FOXO4 expression in ccRCC cells. Mechanistically, ZNF304 binds to miR-183 promoter and inhibits miR-183-5p transcription. Furthermore, the expression of miR-183-5p wes increased in ccRCC tissues, and the upregulation of miR-183-5p was related to the poor prognosis of ccRCC patients. miR-183-5p upregulation repressed the expression of FOXO4 and promoted ccRCC progression. These results demonstrated that ZNF304/miR-183-5p/FOXO4 axis played essential role in promoting ccRCC progression, which suggests that disruption of this axis may be a potential therapeutic target in ccRCC.