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Fungal keratitis (FK) is an infectious keratopathy can cause serious damage to vision. Its severity is related to the virulence of fungus and response of inflammatory. Rosmarinic acid (RA) extracted from Rosmarinus officinalis exhibits antioxidant, anti-inflammatory and anti-viral properties. The aim of this study was to investigate the effect of RA on macrophage autophagy and its therapeutic effect on FK. In this study, we demonstrated that RA reduced expression of proinflammatory cytokine, lessened the recruitment of inflammatory cells in FK. The relative contents of autophagy markers, such as LC3 and Beclin-1, were significantly up-regulated in RAW 264.7 cells and FK. In addition, RA restored mitochondrial membrane potential (MMP) of macrophage to normal level. RA not only reduced the production of intracellular reactive oxygen species (ROS) but also mitochondria ROS (mtROS) in macrophage. At the same time, RA induced macrophage to M2 phenotype and down-regulated the mRNA expression of IL-6, IL-1β, TNF-α. All the above effects could be offset by the autophagy inhibitor 3-Methyladenine (3-MA). Besides, RA promote phagocytosis of RAW 264.7 cells and inhibits spore germination, biofilm formation and conidial adherence, suggesting a potential therapeutic role for RA in FK. • RA reduced the severity of keratitis and proinflammatory cytokine expression in vivo. • RA up-regulated the autophagy in RAW 264.7 cells and infected corneas. • 3-MA significantly counteracted the effects of RA on ameliorating FK. • RA reduced the ROS and mtROS in infected RAW 264.7 cells. • RA induced M2 phenotype of macrophage and exhibited antifungal property. [ABSTRACT FROM AUTHOR]

The fungicide Mancozeb is an endocrine-disrupting chemical and the mode of action of Mancozeb on embryo implantation is largely unknown. Mancozeb (1 and 3 μg/ml) significantly reduced Jeg-3 trophoblastic spheroids attachment to endometrial epithelial Ishikawa cells. Mancozeb treatment from gestation day (GD) 1 to GD8 or from GD4 to GD8 significantly lowered the number of implantation sites with higher incidence of morphological abnormalities in the reproductive tissues. However, these were not seen in the treatment from GD1 to GD4. Mancozeb at 30 mg/kg BW/d did not alter the expression of p53, COX-2, or PGFS transcripts in the uterus, but down-regulated the PGES transcript and protein. Mancozeb treatment in human endometrial stromal cells did not alter the decidualization response, but the morphological transformation was impaired. Taken together, exposure to Mancozeb affected embryo implantation probably through the modulation of decidualization and to delineate the exact mode of action needs further investigations. • Mancozeb reduces trophoblastic spheroids attachment to endometrial epithelial cells. • Mancozeb effects on early pregnancy is main via modulating decidualization. • Mancozeb can down-regulate PGES mRNA and up regulate COX-2 protein. • Mancozeb hinders morphological transformation of stromal cell in dicidualization [ABSTRACT FROM AUTHOR]

Most clinical stroke patients may have difficulty moving, affecting their self-care ability and quality of life, and causing serious interference with the normal life and work of other family members. At present, in clinical literature, researchers provide functional training for patients with motor disorders through repeated and effective training, which can ultimately effectively promote the recovery of limb function. Therefore, the near-infrared spectroscopy imaging technology (fNIRS) used in this study combines the diagnosis of sports injury with the mechanism of brain function. FNIRS technology has many advantages, such as fast, and non-invasive, and has shown great value in detecting brain activity. Therefore, it has become a promising method in the biomedical field, especially in the field of brain science. Based on the clinical effects of sports injury treatment, fNIRS technology is used to detect the hemodynamic changes of hemoglobin circulation in the patient's brain tissue during training, and to detect the brain activity mechanism in the exercise mechanism, providing a basis for the clinical application of this method. • Functional training for patients with motor disorders through repeated and effective training • FNIRS is used to combines the diagnosis of sports injury with the mechanism of brain function. • FNIRS is used to detect the hemodynamic changes of hemoglobin circulation in the patient's brain tissue. [ABSTRACT FROM AUTHOR]

Abstract In aircraft design, structural optimization concerning transonic aeroelastic issues is computationally impractical, due to a great number of aeroelastic analyses are required in iterative process. Reduced-Order Model (ROM) method is convenient for transonic aeroelastic analyses; however, current ROMs are not reusable during iteration, hence the time consumption is still too high. To solve the problem, this study proposes an improved ROM suitable for Arbitrary Mode Shapes (ROM-AMS), which is reusable in iterative process. By adopting Principal Component Analysis, ROM-AMS method significantly reduces the number of basis mode shapes, while improves the accuracy of flutter analysis. In an optimization case, the weight of a cropped delta wing is reduced by 28.46%, and the efficiency is 900 times higher than that of traditional ROM approaches, which demonstrates the feasibility of this method in aeroelastic optimization. Highlights • A Reduced-Order Modeling method for transonic aeroelastic optimization is proposed. • Number of basis modes can be largely reduced by Principal Component Analysis. • Efficiency of optimization is two orders of magnitudes higher than previous ROMs. [ABSTRACT FROM AUTHOR]

The workpiece is prone to self-excited vibration when turning a slender shaft and the flexibility cannot be ignored in this condition. In this paper, a new flexible tool-workpiece system is developed to investigate the nonlinear dynamics and chatter stability for in a turning process. The piecewise-nonlinear restoring function of the tool system is derived by calculating axial deformations and forces of the ball screw feed system. With the variation of time delay, the dynamic behaviors of the cutting system are analyzed by numerical method, which manifests as periodic, quasi-periodic, and chaotic motions. Through determining the critical chip width under different spindle speed, the stability lobe diagram (SLD) of nonlinear system is obtained to distinguish stable and unstable states. In addition, the dynamic characteristics and SLD of nonlinear system are compared with linear system. An experiment is carried out to observe the vibration phenomenon under stable and unstable turning conditions and verify the accuracy of stability prediction. [ABSTRACT FROM AUTHOR]

Recently, accumulating studies have reported the roles of competitive endogenous RNA (ceRNA) networks in ischemia/reperfusion (I/R) injury in several organs, including the liver, kidney, heart, brain, and intestine. However, the functions and mechanisms of long noncoding RNAs (lncRNAs)—which serve as ceRNA networks in intestinal I/R injury—remain elusive. RNA expression data were retrieved from the National Center for Biotechnology Information-Gene Expression Omnibus database. Differentially expressed microRNAs (miRNAs) (miDEGs) were explored between the sham and intestinal I/R injury samples. Next, targeted lncRNAs and messenger RNAs in the database were matched based on miDEGs. Hub ceRNA networks were constructed and visualized via Cytoscape. Intersection analysis was performed to screen mDEGs between two datasets. Finally, the vital nodes of the ceRNA networks were validated by quantitative PCR. A total of 189 miDEGs were identified. Forty miRNAs were found to be associated with 240 predicted target genes from miRWalk 3.0. The ceRNA network was constructed with 10 miRNAs, including the 1700020114Rik/mmu-miR-7a-5p/Klf4 axis. Furthermore, the expression of lncRNA 1700020114Rik (P < 0.05) and messenger RNA Klf4 (P < 0.01) was markedly decreased in mouse models of intestinal I/R injury, whereas the expression level of mmu-miR-7a-5p was significantly increased (P < 0.05). The results provide novel insights into the molecular mechanism of ceRNA networks in intestinal I/R injury and highlight the potential of the 170002700020114Rik/mmu-miR-7a-5p/Klf4 axis in the prevention and treatment of intestinal I/R injury. [ABSTRACT FROM AUTHOR]

Urban green spaces play a crucial role in cities by providing near-natural environments that greatly impacts the health of residents. However, these green spaces have recently been scrutinized as potential reservoirs of antibiotic resistance genes (ARGs), posing significant ecological risks. Despite this concern, our understanding of the distribution, sources, and ecological risks associated with ARGs remains limited. In this study, we investigated the spatial distribution of soil ARGs using spatial interpolation and auto-correlation analysis. To apportion the source of soil ARGs in urban green spaces of Tianjin, Geo-detector method (GDM) was employed. Furthermore, we evaluated the ecological risk posed by ARGs employing risk quotients (RQ). The results of our study showed a significantly higher abundance of Quinolone resistance genes in the soil of urban green spaces in Tianjin. These genes were mainly found in the northwest, central, and eastern regions of the city. Our investigation identified three main factors contributing to the presence of soil ARGs: antibiotic production, precipitation, livestock breeding, and hospital. The results of ecological risk in RQ value showed a high risk associated with Quinolone resistance genes, followed by Aminoglycoside, Tetracycline, Multidrug, MLSB, Beta Lactam, Sulfonamide, and Chloramphenicol. Mantel-test and correlation analysis revealed that the ecological risk of ARGs was greatly influenced by soil properties and heavy metals. This study provides a new perspective on source apportionment and the ecological risk assessment of soil ARGs in urban green spaces. • Explore the spatial distribution of soil antibiotic resistance genes. • Identify the sources of soil antibiotic resistance genes via multiple models. • Assess the ecological risk of soil antibiotic resistance genes in urban green space. [ABSTRACT FROM AUTHOR]

Fungal keratitis (FK) is a refractory keratitis caused by excessive inflammation and fungal damage. Excessive inflammation can lead to tissue damage and corneal opacity, resulting in a poor prognosis for FK. Oxymatrine (OMT) is a natural alkaloid, which has rich pharmacological effects, such as antioxidant and anti-inflammation. However, its antifungal activity and the mechanism of action in FK have not been elucidated. This study confirmed that OMT suppressed Aspergillus fumigatus growth, biofilm formation, the integrity of fungal cell and conidial adherence. OMT not only effectively reduced corneal fungal load but also inflammation responses. OMT lessened the recruitment of neutrophils and macrophages in FK. In addition, OMT up-regulated the expression of Nrf2 and down-regulated the expression of IL-18, IL-1β, caspase-1, NLRP3 and GSDMD. Pre-treatment with Nrf2 inhibitor up-regulated the expression of IL-1β, IL-18, caspase-1, NLRP3 and GSDMD supressed by OMT. In conclusion, OMT has efficient anti-inflammatory and antifungal effects by suppressing fungal activity and restricting pyroptosis via Nrf2 pathway. OMT is considered as a potential option for the treatment of FK. • Oxymatrine alleviated the severity of mouse fungal keratitis. • Oxymatrine exerted antifungal effects to suppress A. fumigatus growth. • Oxymatrine lessened infiltration of neutrophils and macrophages in mouse fungal keratitis. • Oxymatrine suppressed the excessive inflammatory response by inhibiting pyroptosis via Nrf2 pathway during fungal infections. [ABSTRACT FROM AUTHOR]

[Display omitted] • SASH1 is identified as a novel binding partner for Eph receptors through SAM-SAM interactions, with the highest affinity for EphA8. • The high-resolution crystal structure of the EphA8/SASH1 SAM-SAM complex reveals molecular basis governing the specific inter-molecular interactions. • Cancer mutations (EphA8 R942H or G978D) impair the interaction between EphA8 and SASH1, highlighting potential implications in tumorigenesis. • SASH1 enhances EphA8 receptor kinase activation through their SAM-SAM interaction. The Eph (erythropoietin-producing human hepatocellular) receptor family, the largest subclass of receptor tyrosine kinases (RTKs), plays essential roles in embryonic development and neurogenesis. The intracellular Sterile Alpha Motif (SAM) domain presents a critical structural feature that distinguishes Eph receptors from other RTKs and participates in recruiting and binding downstream molecules. This study identified SASH1 (SAM and SH3 domain containing 1) as a novel Eph receptor-binding partner through SAM-SAM domain interactions. Our comprehensive biochemical analyses revealed that SASH1 selectively interacts with Eph receptors via its SAM1 domain, displaying the highest affinity for EphA8. The high-resolution crystal structure of the EphA8-SASH1 complex provided insights into the specific intermolecular interactions between these proteins. Cellular assays confirmed that EphA8 and SASH1 co-localize and co-precipitate in mammalian cells, with cancer mutations (EphA8 R942H or G978D) impairing this interaction. We demonstrated that SAM-SAM interaction is critical for SASH1-mediated regulation of EphA8 kinase activity, shedding new light on the Eph signaling pathway and expanding our understanding of the molecular basis of the tumor suppressor gene SASH1. [ABSTRACT FROM AUTHOR]

Pathological fractures caused by osteolytic lesions seriously threaten the health of patients. Osteoclasts play important roles in bone resorption whose hyperfunction are closely related to osteolytic lesions. Studies on osteoclast differentiation and function assist in the prevention of excessive bone loss associated diseases. We screened a variety of natural compounds with anti-inflammatory effect and found that poria cocos polysaccharide (PCP) inhibited RANKL-induced osteoclast formation and bone resorption via TRAcP staining, immunofluorescence, RT-PCR and western blot. PCP down-regulated phosphorylation of STAT3, P38, ERK and JNK, and thus repressed the expression of NFAcT1 and c-Fos during RANKL-induced osteoclastogenesis. Besides, the expression of bone resorption related genes such as TRAcP and CTSK was suppressed by PCP. The results suggest that PCP can be invoked as a candidate for the treatment of osteolytic diseases by inhibiting osteoclastogenesis. [ABSTRACT FROM AUTHOR]

Identification of rotor unbalance is critical for normal operation of rotating machinery. The single-disc and single-span rotor, as the most fundamental rotor-bearing system, has attracted research attention over a long time. In this paper, the continuous single-disc and single-span rotor is modeled as a homogeneous and elastic Euler-Bernoulli beam, and the forces applied by bearings and disc on the shaft are considered as point forces. A fourth-order non-homogeneous partial differential equation set with homogeneous boundary condition is solved for analytical solution, which expresses the unbalance response as a function of position, rotor unbalance and the stiffness and damping coefficients of bearings. Based on this analytical method, a novel Measurement Point Vector Method (MPVM) is proposed to identify rotor unbalance while operating. Only a measured unbalance response registered for four selected cross-sections of the rotor-shaft under steady-state operating conditions is needed when using the method. Numerical simulation shows that the detection error of the proposed method is very small when measurement error is negligible. The proposed method provides an efficient way for rotor balancing without test runs and external excitations. [ABSTRACT FROM AUTHOR]

[Display omitted] • M2 (PD) is the main metabolite of dammarane ginsenoside AD-1 in vivo. • Compound M3 was isolated from metabolites in vivo for the first time. • PD could significantly inhibit the proliferation and migration of MDA-MB-231 cells and induce G1-phase arrest. • PD could significantly inhibit the proliferation and migration of breast cancer in nude mice. • PD inhibited proliferation and metastasis of breast cancer cells by inducing the p38 MAPK/MMP9 pathway. Previous studies have shown that 20 (R)-25-methoxyl-dammarane-3 β , 12 β , 20 triol (AD-1) can inhibit various cancer cell lines. This study aimed to explore the effect and mechanism of AD-1 metabolite M2 (Panaxadiol; PD) on breast cancer cells of nude mice. Five AD-1 metabolites were isolated and identified using various chromatographic techniques. PD was the main component. In vitro results showed that PD could inhibit the proliferation and migration of MDA-MB-231 cells by inducing G1-phase arrest. In addition, PD down-regulated the expression of Cyclin D1, cdk2, cdk4, cdk6, P-p38, and MMP9, and up-regulated p21 and p27. In vivo results showed that PD could effectively reduce the volume, weight, and migration of breast cancer Transcriptomics analyzed 491 differentially expressed genes by GO and KEGG enrichment. RT-PCR verification confirmed that the significant down-regulation of MMP9 was consistent with transcriptomics results. In further research showed that PD regulated the protein expression of P-p38 and MMP9 in MAPK pathway. In summary, in vivo and in vitro studies showed that PD significantly inhibit the occurrence and development of breast cancer, possibly through the MAPK pathway. [ABSTRACT FROM AUTHOR]

Abstract: An integrative non-conjugative extrachromosomal genetic element, denoted as pSSVi, has been isolated from a Sulfolobus solfataricus P2 strain and was characterized. This genetic element is a double-stranded DNA of 5740 bp in size and contains eight open reading frames (ORFs). It resembles members of the pRN plasmid family in genome organization but shows only weak similarity to the latter in conserved regions. pSSVi has a copG gene similar to that of a pRN plasmid, encodes a large replication protein which, unlike a typical pRN RepA, contains no polymerase/primase domain, and lacks the plrA gene. Interestingly, pSSVi encodes an SSV-type integrase which probably catalyzes the integration of its genome into a specific site (a tRNAArg gene) in the S. solfataricus P2 genome. Like pSSVx, pSSVi can be packaged into a spindle-like viral particle and spread with the help of SSV1 or SSV2. In addition, both SSV1 and SSV2 appeared to replicate more efficiently in the presence of pSSVi. Given the versatile genetic abilities, pSSVi appears to be well suited for a role in horizontal gene transfer. [Copyright &y& Elsevier]

Note: ARC inhibits osteoclastogenesis by suppressing RANKL-induced MAPK (including JNKs and ERKs), calcium, and NFATc1 signaling pathway, as well as by promoting the expression of ROS scavenging enzymes in Nrf2/Keap1/ARE signaling pathway. Osteoporosis, characterized by disrupted bone resorption and formation, is viewed as a global health challenge. Arctiin (ARC) is a main component of Arctium lappa L, which exerts chemopreventive effects against various tumor cells. However, the role of ARC in bone remodeling is still unclear. Here, we first demonstrated that ARC inhibits osteoclast formation and bone resorption function induced by the receptor activator of nuclear factor-κB ligand (RANKL) in a dose- and time-dependent manner without exerting cytotoxic effects. Mechanistic analysis revealed that ARC not only suppresses RANKL-induced mitogen-activated protein kinase (MAPK) and calcium signaling pathways, but also enhances the expression of cytoprotective enzymes that are involved in scavenging reactive oxygen species (ROS). Further, ARC inhibits the activation of the major transcription factor nuclear factor of activated T cells 1 (NFATc1) during RANKL-induced osteoclast formation. Preclinical studies showed that ARC protects bone loss in an ovariectomy (OVX) mouse model. Conclusively, our data confirmed that ARC could potentially inhibit osteoclastogenesis by abrogating RANKL-induced MAPK, calcium, and NFATc1 signaling pathway, as well as by promoting the expression of ROS scavenging enzymes in Nrf2/Keap1/ARE signaling pathway, thereby 2 2 Atp6v0d2 preventing OVX-induced bone loss. Thus, ARC may serve as a novel therapeutic agent for the treatment of osteoporosis. [ABSTRACT FROM AUTHOR]

• For the first time, 16 metabolites of 20(R)-25-OCH 3 -PPD were isolated and identified, of which 10 were new compounds. • We first discovered the biotransformation of dammarane-type sapogenins into oleanane-type sapogenins in rats, found a series of metabolites that changed mainly at C-29. • We studied the anticancer mechanisms of active oleanane-type sapogenin (M6). All the results suggested that M6 manifested higher efficacy on inhibiting cancer cells proliferation by inducing cell apoptosis. 20(R)-25-methoxyl-dammarane-3 β ,12 β ,20-triol (AD-1, CN Patent: 201010107476.7) is a novel derivative of dammarane-type ginsenoside. AD-1 has been shown to inhibit cancer cell proliferation without significant host toxicity in vivo , and has excellent development potential as a new anti-cancer agent. This study was designed systematically to explore the metabolic pathway of ginseng sapogenins. The metabolism of drugs in the body is a complex biotransformation process where drugs are structurally modified to different molecules (metabolites) through various metabolizing enzymes. The compounds responsible for the effects of orally administered ginseng are believed to be metabolites produced in the gastrointestinal tract, so understanding the metabolism of the drug candidate can help to optimize its pharmacokinetics. In this study, faeces samples were collected and extracted after oral administration of AD-1. The 16 metabolites of AD-1 were isolated and identified for the first time with various chromatographic techniques, including semi-preparative high performance liquid chromatography, nuclear magnetic resonance spectroscopy, and mass spectrometry; of these 16 metabolites, 10 were novel compounds. We first discovered the biotransformation of dammarane-type sapogenins into oleanane-type sapogenins in rats and found a series of metabolites that changed, mainly at C-25 and C-29. This study provides new ideas for the metabolic pathway of ginseng sapogenins. The isolated compounds were screened for their effect on the viability and proliferation against cancer cell lines (Human A549, MCF-7, HELA, HO-8901 and U87). The discovery of novel active metabolites 3 β ,12 β ,21 α ,22 β -Hydroxy-24-norolean-12-ene (M6) may lead to a new or improved drug candidate. For one, M6 could inhibit the growth of all the tested cancer cells. Among the tested cell lines, M6 exhibited the most remarkable inhibitory effect on ovarian cancer HO-8901 cells, with IC 50 value of 2.086 μM. On this basis, we studied the anticancer mechanisms of M6. The results indicated that the pro-apoptotic feature of M6 acts via a mitochondrial pathway. Our results indicated that M6 exhibited a higher inhibitory effect on cancer-cell proliferation than AD-1 by inducing cell apoptosis. Our work provides data for future investigations on the metabolic mechanism of AD-1 in vivo and the potential for future research on developing a new drug. [ABSTRACT FROM AUTHOR]