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Lipopeptides, a class of compounds consisting of a peptide ring and a fatty acid chain, are secondary metabolites produced by Bacillus spp. As their hydrophilic and oleophilic properties, lipopeptides are widely used in food, medicine, environment and other industrial or agricultural fields. Compared with artificial synthetic surfactants, microbial lipopeptides have the advantages of low toxicity, high efficiency and versatility, resulting in urgent market demand and broad development prospect of lipopeptides. However, due to the complex metabolic network and precursor requirements of synthesis, the specific and strict synthesis pathway, and the coexistence of multiple homologous substances, the production of lipopeptides by microorganisms has the problems of high cost and low production efficiency, limiting the mass production of lipopeptides and large-scale application in industry. This review summarizes the types of Bacillus-produced lipopeptides and their biosynthetic pathways, introduces the versatility of lipopeptides, and describes the methods to improve the production of lipopeptides, including genetic engineering and optimization of fermentation conditions. [ABSTRACT FROM AUTHOR]

The primary objective of this investigation was to elucidate the manner in which ginsenoside Rg5 (Rg5) ameliorates nonalcoholic fatty liver disease (NAFLD) via the modulation of the gut microbiota milieu. We administered either a standard diet (ND) or a high-fat diet (HFD), coupled with 12-week treatment employing two distinct doses of Rg5 (50 and 100 mg/kg/d), to male C57BL/6J mice. In comparison to the HFD cohort, the Rg5-treated group demonstrated significant enhancements in biochemical parameters, exemplified by a substantial decrease in lipid concentrations, as well as the reduced expression of markers indicative of oxidative stress and liver injury. This signifies a mitigation of hepatic dysfunction induced by an HFD. Simultaneously, Rg5 demonstrates the capacity to activate the LKB1/AMPK/mTOR signaling pathway, instigating energy metabolism and consequently hindering the progression of NAFLD. Furthermore, we underscored the role of Rg5 in the treatment of NAFLD within the gut-microbiota-liver axis. Analysis via 16S rRNA sequencing unveiled that Rg5 intervention induced alterations in gut microbiota composition, fostering an increase in beneficial bacteria, such as Bacteroides and Akkermansia, while concurrently reducing the relative abundance of detrimental bacteria, exemplified by Olsenella. Furthermore, employing fecal microbiota transplantation (FMT) experiments, we observed analogous outcomes in mice subjected to fecal bacterial transplants, providing additional verification of the capacity of Rg5 to mitigate NAFLD in mice by actively participating in the restoration of gut microbiota via FMT. Drawing from these data, the regulation of the gut microbiota is recognized as an innovative strategy for treating or preventing NAFLD and metabolic syndrome. Consequently, these research findings suggest that Rg5 holds promise as a potential therapeutic agent for NAFLD management. [ABSTRACT FROM AUTHOR]

Ramie is one of the most ancient cellulose fiber crops, having been used for at least 6000 years. It is also one of the strongest and longest natural fine textile fibers in the world and is principally used for fabric production. Although ramie is very important and has a high economic value, the genetic basis of its yield-related and fiber quality traits remains poorly understood and is insufficient owing to the lack of assessment in multiple environments. Here, we evaluated the population structure and genomic variation in ramie based on resequencing of 319 core accessions and detected several candidate genes associated with fiber yield and quality traits by combining them with linkage mapping. We obtained approximately 3.49 million high-quality single nucleotide polymorphisms (SNPs), 2,089,798 insertions and deletions (Indels), and 88,087 structure variations (SVs). The investigation of phenotypes for plant height (PL), stem diameter (SD), bark thickness (BT), fiber diameter (FD), fiber fineness (FF), and ramet number (RN) found these traits showed abundant variation and correlation. Several genetic loci and candidate genes were identified associated with three yield-related traits and fiber fineness. A gene within pleiotropic loci encoding NAC domain containing protein (BnNAC29) was found to be significantly correlated with stem diameter and bark thickness. Another variation of large fragment insertions and deletions in two candidate genes, BnVIT1 and BnAEP, may also be responsible for the increase of stem diameter and bark thickness, respectively. Favorable gene haplotypes were identified as having the same tendency in stem diameter and bark thickness. Moreover, we presumed that plant height-related genes had undergone selection from landraces to breeding cultivars, even though there was minor differentiation during domestication. Our study provides new insights into the genetic architecture of yield and fiber quality traits in ramie. Moreover, the identification of fiber yield-related genetic loci and large-scale genomic variation represent valuable resources for genomics-assisted breeding of this fiber crop. [ABSTRACT FROM AUTHOR]

Plants are commonly exposed to abiotic stressors, which can affect their growth, productivity, and quality. Previously, the maize transcription factor ZmCCT was shown to be involved in the photoperiod response, delayed flowering, and quantitative resistance to Gibberella stalk rot. In this study, we demonstrate that ZmCCT can regulate plant responses to drought. ZmCCT physically interacted with ZmFra a 1, ZmWIPF2, and ZmAux/IAA8, which localized to the cell membrane, cytoplasm, and nucleus, respectively, both in vitro and in vivo in a yeast two-hybrid screen in response to abiotic stress. Notably, ZmCCT recruits ZmWIPF2 to the nucleus, which has strong E3 self-ubiquitination activity dependent on its RING-H2 finger domain in vitro. When treated with higher indole-3-acetic acid/abscisic acid ratios, the height and root length of Y331-ΔTE maize plants increased. Y331-ΔTE plants exhibited increased responses to exogenously applied auxin or ABA compared to Y331 plants, indicating that ZmCCT may be a negative regulator of ABA signalling in maize. In vivo , ZmCCT promoted indole-3-acetic acid biosynthesis in ZmCCT -overexpressing Arabidopsis. RNA-sequencing and DNA affinity purification-sequencing analyses showed that ZmCCT can regulate the expression of ZmRD17 , ZmAFP3 , ZmPP2C , and ZmARR16 under drought. Our findings provide a detailed overview of the molecular mechanism controlling ZmCCT functions and highlight that ZmCCT has multiple roles in promoting abiotic stress tolerance. [ABSTRACT FROM AUTHOR]

This paper studies the heterogeneous responses of firms to monetary policy shocks and the possible adverse effect of expansionary monetary policy on resource reallocation. Using Chinese firm‐level data, we find that when expansionary monetary shock hits the economy, less productive firms are more responsive than productive firms in terms of resource accumulation. We identify two mechanisms for this effect. First, less productive firms accumulate net worth more slowly. They have higher leverage ratio and are more sensitive to monetary policy changes (the intensive margin). Second, monetary expansion relaxes borrowing constraints, which enables unproductive firms to survive. The congestion effect prevents resources from allocating to more productive firms. Our finding is robust even if we use private firm subsamples or avoid the massive fiscal stimulus in China around 2009. We provide a simple model of firm dynamics to capture these effects. [ABSTRACT FROM AUTHOR]

Allogeneic grafts are vulnerable to the attack launched by host alloreactive T cells, which accounts primarily for allograft failure in the clinic. Conventional pharmacological intervention mainly involves broad‐acting, nonspecific immunosuppressants that provide limited protection over the graft and may cause deleterious side effects due to insufficient allospecificity. Here, core–shell structured nanoparticles co‐loaded with allogeneic antigen (Ag) and immunosuppressive agent Tacrolimus (Ag@FK506‐NPs) are constructed. Dendritic cells (DCs) pulsed with Ag@FK506‐NPs present alloantigenic epitopes on the cell surface as a bait to capture specific T cells, especially CD8+ T cells, for intercellular FK506 transfer and alloreactive T‐cell deletion. Meanwhile, DCs are maintained in an immature tolerogenic state that induces the functional inactivation of recruited T cells. Compared with free FK506, the adoptive transfer of low immunosuppressant dose (25 000‐fold lower) of Ag@FK506‐NPs pulsed DCs is enough to yield a superior antirejection effect in a major histocompatibility complex‐mismatched murine skin transplant model. Of note, due to the cell–cell communication conferred selective T‐cell suppression, the recipient mouse is able to respond to the subsequent stimulation of an irrelevant Ag, indicating that off‐target toxicity is bypassed. Overall, this work may address some of the limitations of current allograft therapeutics. [ABSTRACT FROM AUTHOR]

Background: To explore the role of anti-Mullerian hormone (AMH) in predicting the need to step up recombinant FSH (rFSH) dose following long GnRH agonist protocol in IVF/ICSI cycles of polycystic ovarian syndrome (PCOS) women. Methods: This is a retrospective cohort study of 825 PCOS women undergoing long GnRH agonist protocol enrolled from Jan 2019 to Dec 2021. The daily rFSH dose at which the first response to rFSH were recorded. The dose at which the first response to rFSH was based on folliculometry during follow up in which two or more follicles reached ≥ 11 mm. A receiver operating characteristic (ROC) curve analysis was done to investigate the ability of AMH to predict the need to step up initial rFSH dose. Results: PCOS women who needed to step up initial rFSH dose had a significantly higher AMH compared with those didn't step up initial rFSH dose (11.37 ± 3.25ng/ml vs. 8.69 ± 3.16ng/ml, p < 0.001). In multivariate logistic regression analysis, increased AMH level was an independent factor for the need to step up initial rFSH dose in PCOS patients after adjusted for confounding factors. ROC curve analysis showed AMH could predict the need to step up initial rFSH dose (AUC = 0.738, 95%CI: 0.704–0.773), having 75.4% specificity and 63% sensitivity when the threshold AMH concentration was 9.30ng/ml. 58.8% PCOS women with AMH > 9.30 ng/ml required increased rFSH dose compared to 18.8% of women with AMH ≤ 9.30ng/ml (p < 0.001). Although the clinical pregnancy rate and live birth rate were not significantly different, there was a higher incidence of OHSS among women with AMH > 9.30 ng/ml vs. AMH ≤ 9.30ng/ml (20.8% vs. 15.3%, p = 0.043). Conclusion: PCOS women with AMH > 9.30 ng/ml were resistant to rFSH stimulation and require increased dose for the cycle recruitment of ovarian follicles. [ABSTRACT FROM AUTHOR]

This study explores and explains how duality enables disruptive innovation to encroach on the market and redefine its boundaries under constraints of consumer preferences, purchasing power, technological performance, and complementary technologies. The findings indicate (1) disruptive innovation introduces a new value dimension into the market and enhances the heterogeneity of consumers' demand, which creates prerequisites for its market encroachment while avoiding competing directly with incumbent enterprises; (2) when considering purchasing power constraints, the disadvantage of disruptive innovation in the preexisting value dimension becomes a price advantage of encroaching on the low-end market; (3) under the constraint of complementary technologies, disruptive innovation can open up new markets that incumbent enterprises have not yet touched by virtue of its advantages in the new value dimension; (4) disruptive innovation does not rely on technological performance to encroach on the market, indicating technological performance is not a necessity for identifying disruptive innovations. [ABSTRACT FROM AUTHOR]

Ferroptosis, featuring an iron‐dependent peroxidation of lipids, is a novel form of programmed cell death that may hold great potential in cancer therapy. Our study found that palmitic acid (PA) inhibited colon cancer cell viability in vitro and in vivo, in conjunction with an accumulation of reactive oxygen species and lipid peroxidation. The ferroptosis inhibitor Ferrostatin‐1 but not Z‐VAD‐FMK (a pan‐caspase inhibitor), Necrostatin‐1 (a potent necroptosis inhibitor), or CQ (a potent inhibitor of autophagy), rescued the cell death phenotype induced by PA. Subsequently, we verified that PA induces ferroptotic cell death through excess iron as cell death was inhibited by iron chelator deferiprone (DFP), while it was exacerbated by a supplement of ferric ammonium citrate. Mechanistically, PA affects intracellular iron content by inducing endoplasmic reticulum (ER) stress leading to ER calcium release and regulating transferrin (TF) transport through increasing cytosolic calcium levels. Furthermore, we observed that cells with high expression of CD36 were more vulnerable to PA‐induced ferroptosis. Altogether, our findings reveal that PA engages in anti‐cancer properties by activating ER stress/ER calcium release/TF‐dependent ferroptosis, and PA might serve as a compound to activate ferroptosis in colon cancer cells with high CD36 expression. [ABSTRACT FROM AUTHOR]

Radiation resistance is the leading cause of radiotherapy failure in patients with cancer. Enhanced DNA damage repair is the main reason for cancer cells to develop resistance to radiation. Autophagy has been widely reported to be linked to increased genome stability and radiation resistance. Mitochondria are highly involved in the cell response to radiotherapy. However, the autophagy subtype mitophagy has not been studied in terms of genome stability. We have previously demonstrated that mitochondrial dysfunction is the cause of radiation resistance in tumour cells. In the present study, we found that SIRT3 was highly expressed in colorectal cancer cells with mitochondrial dysfunction, leading to PINK1/Parkin‐mediated mitophagy. Excessive activation of mitophagy enhanced DNA damage repair, therefore promoting the resistance of tumour cells to radiation. Mechanistically, mitophagy resulted in decreased RING1b expression, which led to a reduction in the ubiquitination of histone H2A at K119, thereby enhancing the repair of DNA damage caused by radiation. Additionally, high expression of SIRT3 was related to a poor tumour regression grade in rectal cancer patients treated with neoadjuvant radiotherapy. These findings suggest that restoring mitochondrial function could be an effective method for increasing the radiosensitivity of patients with colorectal cancer. [ABSTRACT FROM AUTHOR]

Magnaporthe oryzae (M. oryzae) is a devastating pathogenic fungal disease that has a serious threat to the global rice security. Recently, an in‐depth study of the pathogenic mechanism and developmental process of M. oryzae became a primary model in the study of host–fungal pathogen interactions. Here, we have identified a gene MoJMJD3 (MGG_02032, accession XM_003708733) encoding the JumonjiC (JmjC) domain through bioinformatics analysis in M. oryzae. The ΔMojmjd3 deletion mutants showed defects in early appressorium formation and fungal virulence during pathogenesis. At 4 h after inoculation, the early appressorium formation of ΔMojmjd3 was decreased when compared with that of the wild‐type P131. Analysis of intracellular localization of MoJMJD3 with RFP fluorescence observation showed that MoJMJD3 was mainly localized in the cytoplasm of the conidia, appressoria, hyphae, and infective hyphae. Furthermore, by spray inoculation analysis, the ΔMojmjd3deletion mutants reduced virulence on the leaves of rice. These data suggest that MoJMJD3 plays important roles in fungal virulence during pathogenesis in M. oryzae. [ABSTRACT FROM AUTHOR]

Compared to fixed orthodontic appliances with brackets, thermoplastic invisible orthodontic aligners offer several advantages, such as high aesthetic performance, good comfort, and convenient oral health maintenance, and are widely used in orthodontic fields. However, prolonged use of thermoplastic invisible aligners may lead to demineralization and even caries in most patients' teeth, as they enclose the tooth surface for an extended period. To address this issue, we have created PETG composites that contain piezoelectric barium titanate nanoparticles (BaTiO3NPs) to obtain antibacterial properties. First, we prepared piezoelectric composites by incorporating varying amounts of BaTiO3NPs into PETG matrix material. The composites were then characterized using techniques such as SEM, XRD, and Raman spectroscopy, which confirmed the successful synthesis of the composites. We cultivated biofilms of Streptococcus mutans (S. mutans) on the surface of the nanocomposites under both polarized and unpolarized conditions. We then activated piezoelectric charges by subjecting the nanocomposites to 10 Hz cyclic mechanical vibration. The interactions between the biofilms and materials were evaluated by measuring the biofilm biomass. The addition of piezoelectric nanoparticles had a noticeable antibacterial effect on both the unpolarized and polarized conditions. Under polarized conditions, nanocomposites demonstrated a greater antibacterial effect than under unpolarized conditions. Additionally, as the concentration of BaTiO3NPs increased, the antibacterial rate also increased, with the surface antibacterial rate reaching 67.39% (30 wt% BaTiO3NPs). These findings have the potential for application in wearable, invisible appliances to improve clinical services and reduce the need for cleaning methods. [ABSTRACT FROM AUTHOR]

Anlotinib, as a promising oral small-molecule antitumor drug, its role in glioma has been only reported in a small number of case reports. Therefore, anlotinib has been considered as a promising candidate in glioma. The aim of this study was to investigate the metabolic network of C6 cells after exposure to anlotinib and to identify anti-glioma mechanism from the perspective of metabolic reprogramming. Firstly, CCK8 method was used to evaluate the effects of anlotinib on cell proliferation and apoptosis. Secondly, ultra-high performance liquid chromatography-high resolution mass spectrometry (UHPLC-HRMS)-based metabolomic and lipidomic were developed to characterize the metabolite and lipid changes in cell and cell culture medium (CCM) caused by anlotinib in the treatment of glioma. As a result, anlotinib had concentration-dependent inhibitory effect with the concentration range. In total, twenty-four and twenty-three disturbed metabolites in cell and CCM responsible for the intervention effect of anlotinib were screened and annotated using UHPLC-HRMS. Altogether, seventeen differential lipids in cell were identified between anlotinib exposure and untreated groups. Metabolic pathways, including amino acid metabolism, energy metabolism, ceramide metabolism, and glycerophospholipid metabolism, were modulated by anlotinib in glioma cell. Overall, anlotinib has an effective treatment against the development and progression of glioma, and these remarkable pathways can generate the key molecular events in cells treated with anlotinib. Future research into the mechanisms underlying the metabolic changes is expected to provide new strategies for treating glioma. [ABSTRACT FROM AUTHOR]

Treatment of Staphylococcus aureus infections is a constant challenge due to emerging resistance to vancomycin, a last-resort drug. S-nitrosylation, the covalent attachment of a nitric oxide (NO) group to a cysteine thiol, mediates redox-based signaling for eukaryotic cellular functions. However, its role in bacteria is largely unknown. Here, proteomic analysis revealed that S-nitrosylation is a prominent growth feature of vancomycin-intermediate S. aureus. Deletion of NO synthase (NOS) or removal of S-nitrosylation from the redox-sensitive regulator MgrA or WalR resulted in thinner cell walls and increased vancomycin susceptibility, which was due to attenuated promoter binding and released repression of genes involved in cell wall metabolism. These genes failed to respond to H2O2-induced oxidation, suggesting distinct transcriptional responses to alternative modifications of the cysteine residue. Furthermore, treatment with a NOS inhibitor significantly decreased vancomycin resistance in S. aureus. This study reveals that transcriptional regulation via S-nitrosylation underlies a mechanism for NO-mediated bacterial antibiotic resistance. Antibiotic resistance in Staphylococcus aureus is increasingly emerging. Here, Shu et al demonstrate that transcriptional regulation by S-nitrosylation underlies vancomycin resistance. [ABSTRACT FROM AUTHOR]

Treatment of Staphylococcus aureus infections is a constant challenge due to emerging resistance to vancomycin, a last-resort drug. S-nitrosylation, the covalent attachment of a nitric oxide (NO) group to a cysteine thiol, mediates redox-based signaling for eukaryotic cellular functions. However, its role in bacteria is largely unknown. Here, proteomic analysis revealed that S-nitrosylation is a prominent growth feature of vancomycin-intermediate S. aureus. Deletion of NO synthase (NOS) or removal of S-nitrosylation from the redox-sensitive regulator MgrA or WalR resulted in thinner cell walls and increased vancomycin susceptibility, which was due to attenuated promoter binding and released repression of genes involved in cell wall metabolism. These genes failed to respond to H2O2-induced oxidation, suggesting distinct transcriptional responses to alternative modifications of the cysteine residue. Furthermore, treatment with a NOS inhibitor significantly decreased vancomycin resistance in S. aureus. This study reveals that transcriptional regulation via S-nitrosylation underlies a mechanism for NO-mediated bacterial antibiotic resistance. Antibiotic resistance in Staphylococcus aureus is increasingly emerging. Here, Shu et al demonstrate that transcriptional regulation by S-nitrosylation underlies vancomycin resistance. [ABSTRACT FROM AUTHOR]

Objective: To explore the molecular mechanism of γ-glutamylcysteine (γ-GC) in response to inflammation in vivo and in vitro on regulating the polarization of macrophages. Methods: The expressions of gene or protein were assessed by qPCR and Western blot assays, respectively. Cell viability was investigated by CCK-8 assay. Eight-week-old male BALB/c mice were established to examine the therapeutic effects of γ-GC in vivo. The release of TNF-α and IL-4 was determined by ELISA assay. Macrophages polarization was identified by flow cytometry assay. Results: Our data showed that γ-GC treatment significantly improved the survival, weight loss, and colon tissue damage of IBD mice. Furthermore, we established M1- and M2-polarized macrophages, respectively, and our findings provided evidence that γ-GC switched M1/M2-polarized macrophages through activating AMPK/SIRT1 axis and inhibiting inflammation-related signaling pathway. Conclusion: Collectively, both in vivo and in vitro experiments suggested that γ-GC has the potential to become a promising novel therapeutic dipeptide for the treatment of IBD, which provide new ideas for the treatment of inflammatory diseases in the future. [ABSTRACT FROM AUTHOR]

Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by flora disequilibrium and mucosal immunity disorder. Here, we report that salidroside effectively restricts experimental colitis from two aspects of intestinal macrophage pyroptosis and dysbacteriosis‐derived colonic Th17/Treg imbalance. In innate immunity, the upregulated TREM1 and pyroptosis‐related proteins in inflamed colons were inhibited by salidroside administration and further experiments in vitro showed that salidroside suppressed LPS/ATP‐induced bone marrow‐derived macrophages (BMDMs) pyroptosis evident by the decline of LDH and IL‐1β release as well as the protein level of NLRP3, caspase‐1, and GSDMD p30. Moreover, the TREM1 inhibitor weakened the effect of salidroside on BMDMs pyroptosis, whereas salidroside still could downregulate TREM1 when NLRP3 was inhibited. In adaptive immunity, salidroside improved the gut microflora diversity and Th17/Treg ratio in DSS‐induced mice, especially promoting the abundance of Firmicutes. Clearance of the gut flora blocked the benefit of salidroside on colonic inflammation and Th17/Treg adaptive immunity, but transplanting salidroside‐treated foecal bacterium into flora‐depleted wild mice reproduced the resistance of salidroside to gut inflammation. Taken together, our data demonstrated that salidroside protected experimental colitis via skewing macrophage pyroptosis and Th17/Treg balance, indicating its potential effect on UC and other immune disorders. [ABSTRACT FROM AUTHOR]

Hand, foot, and mouth disease (HFMD) is a common infectious disease in children. Enterovirus A71 (EV-A71) is one of the main pathogens, and coxsackievirus A6 (CVA6) has gradually become the dominant pathogen of HFMD in recent years. This study was conducted mainly to assess the serological prevalence of EV-A71 and CVA6 antibodies in people of different ages, sexes, and regions through a systematic review and meta-analysis. A comprehensive study was performed based on the EV-A71 and CVA6 serological literature published before May 2022. Heterogeneity analysis (Cochrane's Q test and the I2 statistic) and random effect models were adopted. Subgroup and meta-regression analyses were used to identify potential sources of heterogeneity in the data, and all analysis was performed using STATA version 16.0. This study included 71 studies involving 55,176 people from 13 countries that met the inclusion criteria. The serological prevalence of EV-A71 antibody in different studies was 4.31-88.8%, and that of CVA6 antibody was 40.8-80.9%. Meta-analysis results showed that the serum positive rate for EV-A71 antibody was 45.9% (95% CI: 37.6-54.1%). The rate in the Chinese population was 47.8% (95% CI: 42.4-53.2%), and in the other countries, it was 38% (95% CI: 23-55%). The serum positive rate for CVA6 antibody was 58.3% (95% CI: 46.5-70.2%). The rate in the Chinese population was 49.1% (95% CI: 38.3-59.9%), and in the other countries, it was 68% (95% CI: 51-83%). Subgroup analysis was also conducted. The seroprevalence of EV-A71 and CVA6 antibodies is related to age rather than gender or region. The rates of EV-A71 and CVA6 seropositivity are considerably lower in children younger than five years of age. However, the rates gradually increase with age. The findings of this study suggest that children under five years of age may be susceptible to EV-A71 and CVA6. Thus, safety education and vaccination should be strengthened accordingly. This study provides a basis for understanding the risk factors for EV-A71 and CVA6 infection in China and for deciding how to formulate standard preventive measures to prevent the spread of the virus. [ABSTRACT FROM AUTHOR]

With the advent of the digital economy era, the relationship between consumers and brands is changing. The mode of marketing, especially the paradigm of brand management, also needs to be adapted to change. Brand orientation has triggered a heated discussion on the dominant paradigm of market orientation and a new revolution in brand management. In view of the primary position of brand orientation in the management domain, it is necessary to sort out a systematic scientific knowledge mapping, clarify the research context and progress, and discover research focuses and limitations for strengthening the construction of brand-oriented theories. This study conducts a scientific quantitative analysis of 169 literatures and 7187 references from the Web of Science in the field of brand orientation by comprehensively using methods of scientific knowledge mapping and traditional literature review. The findings show that: (1) Concentrating on the core issue that "whether and how brand orientation becomes an effective strategic orientation of an organization", brand orientation research includes six major hot spots and has been extended to fields including non-profit organizations, retail, service, manufacturing, e-commerce, and tourism. (2) As a multi-dimensional construct, brand orientation affects organizational performance directly through internal branding and external customer perception, and it is influenced by organizational culture, leadership, competition environment, funding sources, and brand cooperation. The relationship between brand orientation and market orientation has evolved from mutual substitution to synergy. [ABSTRACT FROM AUTHOR]

In recent years, hazardous wastewater treatment has been a complex and global problem. In this work, by considering the antimicrobial activity of Ag nanoparticles (AgNPs) and reduced graphene oxide (rGO), we constructed an antibacterial device (G-AgNP) with AgNPs conformably deposited onto a 3D scaffold of reduced graphene oxide in situ. The major limitation, which is difficult to recycle, of two-dimensional graphene-silver composite materials in previous studies is improved. Characterization techniques, SEM, TEM, XRD, and XPS, confirmed the synthesis of nanocomposites. Attributed to its larger specific area, more active sites, and synergistic enhancement, the G-AgNP device demonstrated the best bacterial removal capacity, with an antibacterial rate for both E. coli and S. aureus as high as 100% at quite low AgNP contents. The reported G-AgNP has potential application as a wearable sewage treatment device and for the protection of wearable sensors as a promising sterilizing candidate based on its high and stable antibacterial efficiency. [ABSTRACT FROM AUTHOR]

Background: Inflammation is involved in the healing process; however, when inflammation is overactivated, multiple diseases can occur. The continued discovery of new anti-inflammatory drugs is crucial in the treatment of inflammation-linked diseases. Objectives: Ferulic acid (FA), a precursor necessary for lignan synthesis, is widely distributed in plant-based whole foods and is a strong antioxidant. However, the effect of FA on the expression level of inflammatory factors in macrophages has not been fully clarified. The current study aimed to explore the anti-inflammatory effect and mechanism of ferulic acid. Results: The results showed that THP-1 cells were induced to differentiate into macrophages by Phorbol-12-myristate-13-acetate (PMA), and THP-1-derived macrophages were stimulated by LPS to establish an inflammatory cell model. Compared with the control group, low (5 μmol·mL−1), medium (10 μmol·mL−1), and high (20 μmol·mL−1) concentration ferulic acid groups have decreased cell viability and increased apoptosis rate in a dose-dependent manner. FA reduced the transcriptional levels of Interleukin-1β (IL-1β), Interleukin-6 (IL-6) and tumor necrosis factor α (TNF-α). Importantly, FA-induced autophagy and inhibited NLRP3 inflammasome activation. 3-MA (a widely used autophagy inhibitor) enhanced the secretion of TNF-α, IL-6 and IL-1β. Moreover, autophagy inhibition by 3-MA resulted in increased proteins expression associated with NLRP3 inflammasome signaling pathway. Besides, the inhibition of inflammasome activation by MCC950 reduced the expression of TNF-α, IL-6 and IL-1β. Conclusion: It is concluded that FA enhanced autophagy, inhibited the activation of NLRP3 inflammasome and reduced the expression and release of inflammatory factors. [ABSTRACT FROM AUTHOR]

Primarily responsible for the biogenesis and metabolism of biomolecules, endoplasmic reticulum (ER) and mitochondria are gradually becoming the targets of therapeutic modulation, whose physiological activities and pathological manifestations determine the functional capacity and even the survival of cells. Drug delivery systems with specific physicochemical properties (passive targeting), or modified by small molecular compounds, polypeptides, and biomembranes demonstrating tropism for ER and mitochondria (active targeting) are able to reduce the nonselective accumulation of drugs, enhancing efficacy while reducing side effects. Lipid nanoparticles feature high biocompatibility, diverse cargo loading, and flexible structure modification, which are frequently used for subcellular organelle‐targeted delivery of therapeutics. However, there is still a lack of systematic understanding of lipid nanoparticle‐based ER and mitochondria targeting. Herein, we review the pathological significance of drug selectively delivered to the ER and mitochondria. We also summarize the molecular basis and application prospects of lipid nanoparticle‐based ER and mitochondria targeting strategies, which may provide guidance for the prevention and treatment of associated diseases and disorders. This article is categorized under:Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic DiseaseBiology‐Inspired Nanomaterials > Lipid‐Based StructuresNanotechnology Approaches to Biology > Nanoscale Systems in BiologyDiagnostic Tools > In Vivo Nanodiagnostics and Imaging [ABSTRACT FROM AUTHOR]

Developing efficient and inexpensive oxygen evolution reaction (OER) electrocatalysts is crucial to address the ever‐increasing energy crisis and environment pollution. In this work, bimetallic nickel‐iron carbonate hydroxide arrays were strongly grown on a conductive carbon cloth (NiFeCH/CC) through a facile one‐step hydrothermal method, which were used as oxygen evolution reaction (OER) electrocatalysts. Ni0.8Fe0.2CH/CC requires overpotential of just 246 mV at 10 mA cm−2, Tafel slope of 43 mV dec−1, and charge transfer resistance of 3.1 Ω for OER in 1 M KOH. The catalyst also shows excellent durability by a long‐term operation for 10 h. A post‐OER study of Ni0.8Fe0.2CH/CC reveals that the NiFeOOH species form on the surface during OER and the carbonate ions still intercalate between the cationic layers. Benefiting from a three‐dimensional structure and Fe doping strategy, the performance of Ni0.8Fe0.2CH/CC has been improved. This work provides an effective strategy to design efficient OER electrocatalysts in alkaline media. [ABSTRACT FROM AUTHOR]

Adoptive cell therapy (ACT) was one of the most promising anti-tumor modalities that has been confirmed to be especially effective in treating hematological malignancies. However, the clinical efficacy of ACT on solid tumor was greatly hindered by the insufficient tumor-infiltration of cytotoxic CD8 + T cells. Herein, we constructed a nanoplatform termed dual-binding magnetic nanoparticles (DBMN) that comprised PEG-maleimide (Mal), hyaluronic acid (HA) and Fe3O4 for adoptive T cell-modification and ACT-sensitization. After a simple co-incubation, DBMN was anchored onto the cell membrane (Primary linking) via Michael addition reaction between the Mal and the sulfhydryl groups on the surface of T cells, generating magnetized T cells (DBMN-T). Directed by external magnetic field and in-structure Fe3O4, DBMN-T was recruited to solid tumor where HA bond with the highly expressed CD44 on tumor cells (Secondary Linking), facilitating the recognition and effector-killing of tumor cells. Bridging adoptive T cells with host tumor cells, our DBMN effectively boosted the anti-solid tumor efficacy of ACT in a mouse model and simultaneously reduced toxic side effects. [ABSTRACT FROM AUTHOR]

Background: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) caused by NOTCH3 mutations is the most common monogenic hereditary pattern of cerebral small vessel disease. The aggregation of the mutant NOTCH3 may play a cytotoxic role in CADASIL. However, the main mechanism of this process remains unclear.Objective: We aimed to investigate the possible pathogenesis of the mutant NOTCH3 in CADASIL.Methods: The clinical information of two pedigrees were collected and analyzed. Furthermore, we constructed cell lines corresponding to this mutation in vitro. The degradation of the extracellular domain of NOTCH3 (NOTCH3ECD) was analyzed by Cycloheximide Pulse-Chase Experiment. Flow cytometry and cell counting kit-8 assay were performed to observe the effects of the NOTCH3 mutation on mitochondrial function and apoptosis.Results: We confirmed a de novo heterozygous missense NOTCH3 mutation (c.1690G > A, p. A564T) in two pedigrees. In vitro, the NOTCH3ECD aggregation of A564T mutant may be related to their more difficult to degrade. The mitochondrial membrane potential was attenuated, and cell viability was significant decreased in NOTCH3ECD A564T group. Interestingly, BAX and cytochrome c were significantly increased, which are closely related to the mitochondrial-mediated pathway to apoptosis.Conclusion: In our study, the aggregation of NOTCH3ECD A564T mutation may be associated with more difficult degradation of the mutant, and the aggregation may produce toxic effects to induce apoptosis through the mitochondrial-mediated pathway. Therefore, we speculated that mitochondrial dysfunction may hopefully become a new breakthrough point to explain the pathogenesis of cysteine-sparing NOTCH3 mutations. [ABSTRACT FROM AUTHOR]

Objective. Oral leukoplakia (OLK) is the most common precancerous lesion in the oral cavity. This study aimed to explore key biomarkers for monitoring OLK for early diagnosis of oral squamous cell carcinoma (OSCC) and screen small-molecule drugs for the prevention of OSCC. Method. The Gene Expression Omnibus (GEO) database was explored to extract two microarray datasets, namely, GSE85195 and GSE25099. The data of the normal group, OLK group, and OSCC group were analyzed by weighted gene coexpression network analysis (WGCNA) to identify the most significant gene module and differentially expressed genes (DEGs). The intersection genes were extracted as the key genes of OLK carcinogenesis. Subsequently, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were analyzed in the module. Connectivity Map and molecular docking were used to screen small-molecule drugs. The diagnostic values of four key genes were identified and verified in the GSE26549 dataset. Results. WGCNA obtained the red module (r = −0.91, p < 0.05) with the strongest correlation with cancerous phenotype. GO enrichment analysis showed 60 pathways, including 28 biological processes, 11 cell components, and 21 molecular functions, and KEGG enrichment analysis showed 4 pathways (p < 0.05). In the differential expression analysis, there was no intersection between the upregulated genes and the red module genes. However, the intersection of the downregulated genes and the red module genes yielded 4 key genes: dopachrome tautomerase (DCT), keratin 3 (KRT3), keratin 76 (KRT76), and FAM3 metabolic regulation signal molecule B (FAM3B). The area under the curve of the diagnostic model constructed by these four genes was 0.963 (CI = 0.913–1.000). The sensitivity was 0.933, and the specificity was 0.923. The diagnostic model was successfully verified in GSE26549 (AUC = 0.745, CI = 0.638–0.851). Compared with the diagnostic models of the previous studies, the diagnostic efficiency of this model was the highest. The small-molecule drugs, selumetinib and benidipine, were selected according to the gene expression profile and showed binding activity when docking with the above molecules. Conclusions. This study provides new targets and drugs for OLK. These targets could be used as the key diagnostic molecules for long-term follow-up of OLK. The small-molecule drugs selumetinib and benidipine could be used for the prevention and treatment of OSCC. [ABSTRACT FROM AUTHOR]

Recombination plays important roles in the genetic diversity and evolution of Enterovirus A71 (EV-A71). The phylogenetics of EV-A71 in mainland China found that one strain DL71 formed a new subgenotype C6 with unknown origin. This study investigated the detailed genetic characteristics of the new variant. DL71 formed a distinct cluster within genotype C based on the genome and individual genes (5′UTR, VP4, VP1, 2A, 2B, 2C, 3D, and 3′UTR). The average genetic distances of the genome and individual genes (VP3, 2A, 2B, 2C, 3A, 3C, and 3D) between DL71 and reference strains were greater than 0.1. Nine recombination events involving smaller fragments along DL71 genome were detected. The strains Fuyang-0805a (C4) and Tainan/5746/98 (C2) were identified as the parental strains of DL71. In the non-recombination regions, DL71 had higher identities with Fuyang-0805a than Tainan/5746/98, and located in the cluster with C4 strains. However, in the recombination regions, DL71 had higher identities with Tainan/5746/98 than Fuyang-0805a, and located in the cluster with C2 strains. Thus, DL71 was a novel multiple inter-subgenotype recombinant derived from the dominant subgenotype C4 and the sporadic subgenotype C2 strains. Monitoring the emergence of new variants by the whole-genome sequencing remains essential for preventing disease outbreaks and developing new vaccines. [ABSTRACT FROM AUTHOR]

A rare occurrence of bilateral peripapillary choroidal neovascularization (CNV) in an 18-year-old idiopathic intracranial hypertension (IIH) patient regressed with systemic acetazolamide treatment alone. Multimodal imaging was done, including OCT angiography (OCTA), which showed CNV. No injections were given even though she had macular fluid in her left eye. Nonetheless, the subretinal fluid resolved, and visual acuity improved. This report shows that CNV secondary to IIH can be managed with systemic therapy alone. Moreover, we showed for the first time the ability to diagnose IIH-associated CNV using OCTA. [ABSTRACT FROM AUTHOR]

Background: Gene therapy shows great promise for a broad array of diseases. However, we found that hypoxic tumor microenvironment (TME) exerted significant inhibitory effects on transfection efficiency of a variety of gene vectors (such as Lipo 2000 and PEI) in an oxygen-dependent manner. Solid tumors inevitably resulted in acute hypoxic areas due to the rapid proliferation of tumor cells and the aberrant structure of blood vessels. Thus, the hypoxic TME severely limited the efficiency and application of gene therapy. Methods: In our previous study, we constructed endoplasmic reticulum-targeted cationic liposomes, PAR-Lipo, which could effectively deliver genes and ensure high transfection efficiency under normoxia. Unsatisfactorily, the transfection efficiency of PAR-Lipo was rather poor under hypoxia. We believed that reoxygenation was the most direct and effective means to rescue the low transfection under hypoxia. Hence, we fabricated liposomes modified with perfluorooctyl bromide (PFOB@Lipo) to load oxygen and deliver it to tumor sites, which effectively alleviated the hypoxic nature of tumor. Then PAR-Lipo were applied to mediate high-efficiency delivery of tumor suppressor gene pTP53 to inhibit tumor progression. Results: The results showed that such staged strategy augmented the expression of P53 protein in tumors and extremely suppressed tumor growth. Conclusion: This work was the first attempt to utilize an oxygen nanocarrier to assist the therapeutic effect of gene therapy under hypoxia, providing a new reference for gene therapy in malignant tumors. Graphical Abstarct: [ABSTRACT FROM AUTHOR]

Background: Oral squamous cell carcinoma (OSCC) is the most malignant neoplasm in oral cancer. There is growing evidence that its progression involves altered metabolism. The current method of evaluating prognosis is very limited, and metabolomics may provide a new approach for quantitative evaluation. The aim of the study is to evaluate the use of metabolomics as prognostic markers for patients with OSCC. Methods: An analytical platform, Ultra-Performance Liquid Chromatography-Quadrupole/Orbitrap High Resolution Mass Spectrometry (UHPLC-Q-Orbitrap HRMS), was used to acquire the serum fingerprinting profiles from a total of 103 patients of OSCC before and after the operation. In total, 103 OSCC patients were assigned to either a training set (n = 73) or a test set (n = 30). The potential biomarkers and the changes of serum metabolites were profiled and correlated with the clinicopathological parameters and survival of the patients by statistical analysis. To further verify our results, we linked them to gene expression using data from the Kyoto Encyclopedia of Genes and Genomes (KEGG). Results: In total, 14 differential metabolites and five disturbed pathways were identified between the preoperative group and postoperative group. Succinic acid change-low, hypoxanthine change-high tumor grade, and tumor stage indicated a trend towards improved recurrence-free survival (RFS), whether in a training set or a test set. In addition, succinic acid change-low, hypoxanthine change-high, and tumor grade provided the highest predictive accuracy of the patients with OSCC. KEGG enrichment analysis showed that the imbalance in the amino acid and purine metabolic pathway may affect the prognosis of OSCC. Conclusions: The changes of metabolites before and after operation may be related to the prognosis of OSCC patients. UHPLC-Q-Orbitrap HRMS serum metabolomics analysis could be used to further stratify the prognosis of patients with OSCC. These results can better understand the mechanisms related to early recurrence and help develop more effective therapeutic targets. [ABSTRACT FROM AUTHOR]

To understand the characteristics and influencing factors related to cluster infections in Jiangsu Province, China, we investigated case reports to explore transmission dynamics and influencing factors of scales of cluster infection. The effectiveness of interventions was assessed by changes in the time-dependent reproductive number (Rt). From 25th January to 29th February, Jiangsu Province reported a total of 134 clusters involving 617 cases. Household clusters accounted for 79.85% of the total. The time interval from onset to report of index cases was 8 days, which was longer than that of secondary cases (4 days) (χ2 = 22.763, P < 0.001) and had a relationship with the number of secondary cases (the correlation coefficient (r) = 0.193, P = 0.040). The average interval from onset to report was different between family cluster cases (4 days) and community cluster cases (7 days) (χ2 = 28.072, P < 0.001). The average time interval from onset to isolation of patients with secondary infection (5 days) was longer than that of patients without secondary infection (3 days) (F = 9.761, P = 0.002). Asymptomatic patients and non-familial clusters had impacts on the size of the clusters. The average reduction in the Rt value in family clusters (26.00%, 0.26 ± 0.22) was lower than that in other clusters (37.00%, 0.37 ± 0.26) (F = 4.400, P = 0.039). Early detection of asymptomatic patients and early reports of non-family clusters can effectively weaken cluster infections. [ABSTRACT FROM AUTHOR]

In order to optimize the plate-shell heat exchanger, the shell-side flow channel of a certain type of plate-shell heat exchanger was taken as the research object, and the single channel physical model was established to simulate the flow performance and resistance performance of shell-side fluid with FLUENT software. The simulation results show that with the increase of corrugated pitch, the flowing streamline changes from crisscross pattern into zigzag pattern, the average velocity and turbulent kinetic energy of fluid accordingly decrease gradually. When the corrugated pitch is 3.9 mm, the better flowing performance can be obtained. The pressure drop will decrease with the growing corrugated pitch. Under the same corrugated pitch, the pressure drop increases with the increase of Reynolds number. When the corrugated pitch reaches 15.9 mm, the resistance performance is relatively good. Better shell side flow performance can be obtained by decreasing the pitch, while better shell side resistance performance can be obtained by increasing the pitch. [ABSTRACT FROM AUTHOR]

Introduction: Individuals with metabolic syndrome (MetS) are at increasing risk of coronary artery disease (CAD). We investigated the common metabolic perturbations of CAD and MetS via serum metabolomics to provide insight into potential associations. Methods: Non-targeted serum metabolomics analyses were performed using ultra high-performance liquid chromatography coupled with Q Exactive hybrid quadrupole-orbitrap high-resolution accurate mass spectrometry (UHPLC-Q-Orbitrap HRMS) in samples from 492 participants (272 CAD vs. 121 healthy controls (HCs) as cohort 1, 55 MetS vs. 44 HCs as cohort 2). Cross-sectional data were obtained when the participants were recruited from the First Affiliated Hospital of Zhengzhou University. Multivariate statistics and Student's t test were applied to obtain the significant metabolites [with variable importance in the projection (VIP) values >1.0 and p values <0.05] for CAD and MetS. Logistic regression was performed to investigate the association of identified metabolites with clinical cardiac risk factors, and the association of significant metabolic perturbations between CAD and MetS was visualized by Cytoscape software 3.6.1. Finally, the receiver operating characteristic (ROC) analysis was evaluated for the risk prediction values of common changed metabolites. Results: Thirty metabolites were identified for CAD, mainly including amino acids, lipid, fatty acids, pseudouridine, niacinamide; 26 metabolites were identified for MetS, mainly including amino acids, lipid, fatty acids, steroid hormone, and paraxanthine. The logistic regression results showed that all of the 30 metabolites for CAD, and 15 metabolites for MetS remained significant after adjustments of clinical risk factors. In the common metabolic signature association analysis between CAD and MetS, 11 serum metabolites were significant and common to CAD and MetS outcomes. Out of this, nine followed similar trends while two had differing directionalities. The nine common metabolites exhibiting same change trend improved risk prediction for CAD (86.4%) and MetS (90.9%) using the ROC analysis. Conclusion: Serum metabolomics analysis might provide a new insight into the potential mechanisms underlying the common metabolic perturbations of CAD and MetS. [ABSTRACT FROM AUTHOR]

Fly ash cenospheres have lots of applications in many industrial fields because of their good physicochemical properties. The formation stage, physicochemical properties, mineral phase composition and separation method of fly ash ashcenospheres are introduced. The applications of fly ash cenospheres as rubber and plastic filler, thermal insulation refractory, building material, composite foam, environmental functional material and wave absorbing material are reviewed. Some problems of low added value, low utilization rate and slow industrialization process in the application of fly ash ashcenospheres are analyzed. The future development direction is pointed out: the products should be developed at different levels according to the physicochemical characteristics of fly ash cenospheres in the direction of graded utilization and increasing product added value. The functional products of fly ash cenospheres in metal matrix composites, soil modifiers, coatings, ceramics and other aspects should be actively developed in order to widen the application fields. [ABSTRACT FROM AUTHOR]

Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is caused by biallelic HTRA1 pathogenic variants. Recent studies have shown that heterozygous HTRA1 mutations are associated with autosomal dominant cerebral small vessel disease (CSVD). However, large studies evaluating heterozygous HTRA1 carriers are lacking and the genotype–phenotype correlation is unknown. This study aimed to describe these mutations to clarify factors playing a role in the clinical phenotype amongst these patients. We reported two unrelated families and performed a systematic review of all published cases of heterozygous HTRA1-related CSVD. The clinical phenotype severity was independently related to the pathogenicity score (CADD score; p < 0.05) and mutation in the loop 3/loop D domains (p = 0.05); the pathogenicity score was also associated with exon distribution. More importantly, patients with mutations in exon 4 (p = 0.0001) or vascular risk factors (p < 0.05) presented with more severe clinical symptoms. Thus, clinical phenotype severity is influenced by the mutation domain and vascular risk factors. Applying the pathogenicity score to predict clinical outcomes and adopting preventive measures against cerebral vascular risk factors is advantageous. [ABSTRACT FROM AUTHOR]

A new monoterpene (1) along with eight known compounds were isolated from the roots of Astilbe grandis Stapf ex E.H. Wilson. Their structures were determined by extensive spectroscopic analysis and ECD experiments as (S)-3-(2-hydroxyethyl)-5-(2-methylprop-1-en-1-yl)furan-2(5H)-one (1), caffeic acid (2), mandelic acid (3), sonchifolinin B (4), α-viniferin (5), euscaphic acid (6), cianidanol (7), β-sitosterol (8), and stigmasterol (9), respectively. Compounds 5 and 6 exhibited inhibitory effects against BRD4 protein with IC50 values of 13.20 and 17.39 µM, respectively. In vitro, compounds 5 and 6 showed moderate cytotoxicity to A549 cells, HCC827 cells and Hela cells with IC50 values ranging from 31.98 to 154.90 µM. [ABSTRACT FROM AUTHOR]

Sulfonated carbon is a 'green,' solid-acid catalyst. For applications purposes, its surface area needs to be improved and its preparation needs to be made environmentally friendly. The objective of the present study was to provide a green and economical method of preparing a sulfonated carbon catalyst by using palygorskite (Plg) fiber as a support for sulfonated carbon. Sulfonated carbon/palygorskite solid-acid catalyst (SC-Plg) was synthesized via one-step carbonization-sulfonation by mixing palygorskite with sucrose as the carbon source and p-toluenesulfonic acid as the sulfonating agent. The catalyst was characterized by SEM, EDX, TEM, FTIR, and nitrogen adsorption-desorption isotherms. The results indicated that sucrose-derived carbon was loaded uniformly on the surface of Plg fibers and formed the SC-Plg catalyst. The inexpensive Plg fibers could replace sucrose-derived carbon and increase the surface area of the resulting catalyst. The SC-Plg shows significant catalytic performance and excellent stability when used in the esterification of oleic acid with methanol. The conversion of oleic acid reached 68.09%, even after five cycles. This work paves the way for the development of highly active, carbon-based, solid-acid composite catalysts using a natural Plg nanofiber template. [ABSTRACT FROM AUTHOR]

Background: Mitochondrial ribosomal protein L15 (MRPL15), a member of mitochondrial ribosomal proteins whose abnormal expression is related to tumorigenesis. However, the prognostic value and regulatory mechanisms of MRPL15 in non-small-cell lung cancer (NSCLC) remain unclear. Methods: GEPIA, ONCOMINE, Gene Expression Omnibus (GEO), UALCAN, Kaplan–Meier plotter, PrognoScan, LinkedOmics and GeneMANIA database were utilized to explore the expression and prognostic value of MRPL15 in NSCLC. Additionally, immune infiltration patterns were evaluated via ESTIMATE algorithm and TISIDB database. Furthermore, the expression and prognostic value of MRPL15 in lung cancer were validated via immunohistochemistry (IHC) assays. Results: In NSCLC, multiple cohorts including GEPIA, ONCOMINE and 8 GEO series (GSE8569, GSE101929, GSE33532, GSE27262, GSE21933, GSE19804, GSE19188, GSE18842) described that MRPL15 was up-regulated. Moreover, MRPL15 was notably linked to gender, clinical stage, lymph node status and the TP53 mutation status. And patients with high MRPL15 expression showed poor overall survival (OS), progression-free survival (PFS), disease-free survival (DFS) and relapse-free survival (RFS) in NSCLC. Then, functional network analysis suggested that MRPL15 participated in metabolism-related pathways, DNA replication and cell cycle signaling via pathways involving several kinases, miRNAs and transcription factors. Additionally, it was found that MRPL15 expression was negatively related to immune infiltration, including immune scores, stromal scores and several tumor-infiltrating lymphocytes (TILs). Furthermore, IHC results further confirmed the high MRPL15 expression and its prognostic potential in lung cancer. Conclusions: These findings demonstrate that high MRPL15 expression indicates poor prognosis in NSCLC and reveal potential regulatory networks as well as the negative relationship with immune infiltration. Thus, MRPL15 may be an attractive predictor and therapeutic strategy for NSCLC. [ABSTRACT FROM AUTHOR]

Background: Exosomes are nano-sized extracellular vesicles which are secreted by cells and usually found in body fluids. Previous research has shown that exosomal secretion and autophagy-lysosomal pathway synergistically participates in intracellular abnormal protein elimination. The main pathological manifestations of Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is abnormal accumulation of mutant NOTCH3, and CADASIL vascular smooth muscle cells have been found with autophagy-lysosomal dysfunction. However, whether plasma exosomes change in CADASIL patients is still unclear.Objective: We are aimed to investigate the differences of plasma exosomes between CADASIL patients and healthy controls.Methods: The subjects included 30 CADASIL patients and 30 healthy controls without NOTCH3 mutation. The severity of white matter lesions (WMLs) of CADASIL patients was quantified by Fazekas score. Transmission electron microscopy and nanoparticle tracking analysis were performed to characterize plasma exosomes. In addition, NOTCH3, Neurofilament light and Aβ42 levels in plasma exosomes were quantified by enzyme-linked immunosorbent assays.Results: We found that exosomes from CADASIL patients were lower in quantity. In addition, CADASIL plasma exosomes had significantly lower levels of NOTCH3 and significantly increased levels of NFL than those of matched healthy subjects. Interestingly, plasma exosome NOTCH3 levels of CADASIL patients significantly correlated with severity of WMLs.Conclusion: The exosome NOTCH3 may be related to the pathological changes of CADASIL, which provides a basis for the pathogenesis research of CADASIL. In addition, plasma exosome NOTCH3 and NFL levels may act as biomarkers to monitor and predict disease progression and measure therapeutic effectiveness in the future clinical trials. [ABSTRACT FROM AUTHOR]