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Abstract: The aim of this study was to investigate the antiviral effects of salidroside, a major component of Rhodiola rosea L. First, the antiviral effects of salidroside against coxsackievirus B3 (CVB3) were determined in vitro and in vivo. Then, the effect of salidroside on the mRNA expression of some important cytokines was measured in hearts of infected BALB/c mice by RT-PCR. Salidroside exhibited obvious antiviral effects both in in vitro and in vivo experiments. Salidroside was found to modulate the mRNA expression of interferon-γ (IFN-γ), interleukin-10 (IL-10), tumor necrosis factor-α (TNF-α), and interleukin-2 (IL-2). In conclusion, salidroside possesses antiviral activities against CVB3 and it may represent a potential therapeutic agent for viral myocarditis. [Copyright &y& Elsevier]

• Local and systematic inflammation reactions induced by OVA could be attenuated by alpha-linolenic acid in vivo. • Alpha-linolenic acid could inhibit IgE-mediated Ca2+ mobilization, degranulation, and cytokine release in mast cells. • Alpha-linolenic acid downregulates the FcεRI/Lyn/Syk signaling pathway by suppressing Lyn kinase activity. • Alpha-linolenic acid could serve as a therapeutic drug for preventing IgE-mediated anaphylaxis. Excessive reactions to allergens can induce systemic, life-threatening physiological dysfunction (anaphylaxis) in humans. The surface of mast cells expresses high-affinity IgE receptors that play a vital role during anaphylaxis. Alpha-linolenic acid (ALA) is an essential non-toxic fatty acid in humans. Since it has been reported having potential to regulate pro-inflammatory reactions, we postulated that ALA could inhibit anaphylaxis by down-regulating Lyn kinase phosphorylation. We found that local and systematic inflammation induced by albumin from chicken egg white (OVA) were attenuated by ALA in vivo. Furthermore, ALA inhibited IgE-mediated Ca2+ mobilization, degranulation, and cytokine release in Laboratory of Allergic Disease 2 (LAD2) cells. The western blot results showed that ALA down-regulate the FcεRI/Lyn/Syk signaling pathway by suppressing Lyn kinase activity. Therefore, ALA could serve as a therapeutic drug candidate for preventing IgE-mediated anaphylaxis. [ABSTRACT FROM AUTHOR]

• Modeling of adsorption performance using composite materials. • Modeling adsorption on functionalized mesoporous silica-polyamide 6 composite. • Studying the effect of adsorption parameters on Cd removal. The current work presents a simulation methodology for adsorption of Cd(II) ions from water onto the surface a functionalized mesoporous silica-polyamide 6 composite. The simulations were carried out using artificial intelligence and the training was performed using experimental data collected from literature. The type of adsorbent in this work was carboxylic acid-functionalized KCC-1 silica and polyamide 6 nanocomposite material. In the artificial intelligence simulations, the adsorbent dosage and solution pH were taken into account as the input parameters for the training and validation, whereas adsorption capacity of the adsorbent was taken into account as the predicted output. The training and validation of the artificial intelligence for Cd(II) ions revealed great agreement with experimental data with high R2 more than 0.99 for both cases of training and validation. The effect of adsorption parameters on the ion removal was evaluated using the developed model, and turned out that pH of solution had more significant effect on the adsorption removal. [ABSTRACT FROM AUTHOR]

Mas-related G-protein-coupled receptor X2 (MRGPRX2) has recently been reported to be associated with anaphylaxis. Detection of MRGPRX2 levels in human peripheral blood might serve as a powerful tool for predicting the predisposition of patients to anaphylactic reactions. For rapid measurement of MRGPRX2, we established a paper-based double-antibody sandwich enzyme-linked immunosorbent assay (ELISA) using mouse monoclonal antibody and horseradish peroxidase (HRP)-labelled rabbit polyclonal antibody as capture antibody and detection antibody, respectively. We avoided chemical functionalization of the cellulose paper by introducing bovine serum albumin (BSA) to provide COOH and NH 2 groups for covalent immobilization of the capture antibody. Through amide condensation, a two-layer immobilization strategy was applied with BSA-BSA and BSA-capture antibody networks as the first and second layers, respectively. This strategy improved the quantity, activity and stability of the immobilized antibody. We then established a paper-based ELISA to detect MRGPRX2 in human peripheral blood. Our method is less laborious, easier to implement, and more cost-effective than conventional ELISA, while offering similar sensitivity, specificity, and accuracy. Therefore, it could serve as an innovative clinical point-of-care diagnostic tool, especially in areas that lack advanced clinical equipment. [Display omitted] • A rapid and sensitive paper-based ELISA method was established to detect MRGPRX2. • A two-layer capture antibody immobilization strategy was applied. • Improved capture antibody immobilization effect and enhanced stability were achieved. • The established method is less laborious, easier to implement, and more cost-effective than conventional ELISA. [ABSTRACT FROM AUTHOR]

The stiffness and failure properties of the materials are a pair of opposing physical quantities, which are often mutually constrained and fettered. Therefore, it is extraordinary meaningful and essential to explore the failure behavior of the lightweight porous materials under the design strategy of the optimal stiffness. In this paper, the failure modes of a stiffness-guided lattice specimen, which is designed by the topology optimization method and manufactured by the 3D printing technique, are investigated under quasi-static and dynamic compressions. The results illustrate that the failure behavior of the stiffness-guided lattices is strongly dependent on the non-optimized structural parameter and the loading strain-rates when the base material for 3D printing is polyamide 12 (PA12). The failure modes are mainly manifested as three categories: the unstable collapse mode, the bending collapse mode and the brittle collapse mode. In addition, the Young's modulus, initial crushing stress, and energy absorption behavior of the stiffness-guided lattices have been studied. The results indicate that the lattices' crush behavior and energy absorption behavior are highly dependent on the failure modes. Remarkably, the stiffness-guided lattices exhibit superior specific energy absorption, stable deformation mode, and a high compressive modulus in the bending collapse mode. [ABSTRACT FROM AUTHOR]

Acute hemorrhage is a major cause of death in many emergency cases. Although many hemostatic materials have been studied in recent years, it is still necessary to develop new hemostatic materials with remarkable efficiency, biosafety, convenient preparation, low cost, and good biodegradability. In this work, novel chitosan (CS)/β-glycerophosphate (β-GP) composite porous microsphere with a uniform size of 210.00 ± 2.14 μm was fabricated through water-in-water (W/W) emulsion via microencapsulation, which can avoid the use of toxic crosslink chemicals and organic solvents to achieve facile and efficient preparation of microspheres. β-GP could promote the formation of microspheres by enhancing the hydrogen-bonding interaction between CS chains, which contributed to the macro-porous structure. Owing to their large pore size (6.0 μm) and high specific surface area (37.8 m2/g), the CS/β-GP microspheres could absorb water quickly and adsorb protein, red blood cells, and platelets through electrostatic forces to promote blood coagulation. Furthermore, the CS/β-GP microspheres achieved a significantly shortened hemostatic time (45 s) and reduced blood loss (0.03 g) in a rat liver injury model. Rat tail amputation test also showed a satisfactory hemostatic effect. Overall, the green and porous CS/β-GP microspheres can be used as a facile and topical rapid hemostatic material. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to investigate the effect of MYO3B on endometrial cancer (EC) proliferation and invasion. Methods: The expression of MYO3B in EC tissues and cells was analyzed using TCGA database, immunohistochemical staining, real-time PCR, and western blot (WB). Cell proliferation was detected by CCK8, Annexin V-APC/PI flow cytometry was used to detect apoptosis, intracellular calcium ion (Ca2+) was detected by flow cytometry with Fluo-4 AM fluorescent probe, cell migration by scratch assay, and cell invasion by Transwell assay, and the expression of proteins related to Ca2+ homeostasis and RhoA/ROCK1 signaling pathway was detected by WB and immunofluorescence staining. Results: The expression of MYO3B was an influential factor in EC recurrence, and the expression of MYO3B was significantly up-regulated in EC tissues and cells, but down-regulated in KLE cells, and MYO3B knockdown inhibited the proliferation, migration, and invasion ability of EC cells and promoted apoptosis, suggesting that MYO3B plays a tumor-promoting role in EC. Furthermore, MYO3B knockdown decreased Ca2+ concentration in EC cells and the RhoA/ROCK1 signaling pathway was inhibited, and the effect of MYO3B knockdown on RhoA/ROCK1 signaling was reversed by treatment with the Calmodulin agonist CALP-2, and the effects of MYO3B knockdown on cell proliferation, migration, and invasion were reversed after treatment with the RhoA agonist U-46,619. Conclusion: MYO3B promotes the proliferation and migration of endometrial cancer cells via Ca2+-RhoA/ROCK1 signaling pathway. High expression of MYO3B may be a biomarker for EC metastasis. [ABSTRACT FROM AUTHOR]

Weeds are one of the most important factors affecting agricultural production. The waste and pollution of farmland ecological environment caused by full-coverage chemical herbicide spraying are becoming increasingly evident. With the continuous improvement in the agricultural production level, accurately distinguishing crops from weeds and achieving precise spraying only for weeds are important. However, precise spraying depends on accurately identifying and locating weeds and crops. In recent years, some scholars have used various computer vision methods to achieve this purpose. This review elaborates the two aspects of using traditional image-processing methods and deep learning-based methods to solve weed detection problems. It provides an overview of various methods for weed detection in recent years, analyzes the advantages and disadvantages of existing methods, and introduces several related plant leaves, weed datasets, and weeding machinery. Lastly, the problems and difficulties of the existing weed detection methods are analyzed, and the development trend of future research is prospected. [ABSTRACT FROM AUTHOR]

Galectins are a family of lectins that bind β -galactoside sugars through their conserved carbohydrate-recognition domains (CRDs) and play integral roles in the innate immune systems of vertebrates and invertebrates. Accumulating amounts of evidence have shown that galectin-related protein (GRP) plays a crucial role in fish immunity. In this study, the GRP cDNA with a 546 bp open reading frame from Paralichthys olivaceus was identified and characterized and was designated as PoGRP. PoGRP was 92.82% similar to the GRP sequences of Seriola dumerili and Anabas testudineus. PoGRP was found to be widely expressed in all tested P. olivaceus tissues, with the highest expression levels being observed in the brain, spleen and liver. Additionally, after this fish species was challenged with Edwardsiella tarda , PoGRP expression was significantly upregulated. The recombinant PoGRP protein (rPoGRP) exhibited binding to various pathogen-associated molecular patterns (PAMPs) and to gram-negative and gram-positive bacteria. In addition, rPoGRP exhibited the ability to agglutinate different bacteria in the presence of Ca2+. In summary, our findings indicated that PoGRP plays a vital role in the immune system to protect against bacterial infection. This study lays the foundation for further functional characterization of GRP in aquatic animal immunity. • Galectin-related protein was identified from Paralichthys olivaceus. • PoGRP was widely expressed in all tested tissues. • PoGRP was up-regulated after challenged with E. tarda. • PoGRP can bind to various PAMPs and some gram-negative and gram-positive bacteria. • PoGRP may play vital roles in the immune system of P. olivaceus. [ABSTRACT FROM AUTHOR]

Background: Pseudo-allergic reactions are potentially fatal hypersensitivity responses caused by mast cell activation. α-linolenic acid (ALA) is known for its anti-allergic properties. However, its potential anti-pseudo-allergic effects were not much investigated.Purpose: To investigate the inhibitory effects of ALA on IgE-independent allergy in vitro, and in vivo, as well as the mechanism underlying its effects.Methods/study Designs: The anti-anaphylactoid activity of ALA was evaluated in passive cutaneous anaphylaxis reaction (PCA) and systemic anaphylaxis models. Calcium imaging was used to assess intracellular Ca2+ mobilization. The release of cytokines and chemokines was measured using enzyme immunoassay kits. Western blot analysis was conducted to investigate the molecules of Lyn-PLCγ-IP3R-Ca2+ and Lyn-p38/NF-κB signaling pathway.Results: ALA (0, 1.0, 2.0, and 4.0 mg/kg) dose-dependently reduced serum histamine, chemokine release, vasodilation, eosinophil infiltration, and the percentage of degranulated mast cells in C57BL/6 mice. In addition, ALA (0, 50, 100, and 200 μM) reduced Compound 48/80 (C48/80) (30 μg/ml)-or Substance P (SP) (4 μg/ml)-induced calcium influx, mast cell degranulation and cytokines and chemokine release in Laboratory of Allergic Disease 2 (LAD2) cells via Lyn-PLCγ-IP3R-Ca2+ and Lyn-p38/NF-κB signaling pathway. Moreover, ALA (0, 50, 100, and 200 μM) inhibited C48/80 (30 μg/ml)- and SP (4 μg/ml)-induced calcium influx in Mas-related G-protein coupled receptor member X2 (MrgX2)-HEK293 cells and in vitro kinase assays confirmed that ALA inhibited the activity of Lyn kinase. In response to 200 μM of ALA, the activity of Lyn kinase by (7.296 ± 0.03751) × 10-5 units/μl and decreased compared with C48/80 (30 μg/ml) by (8.572 ± 0.1365) ×10-5 units/μl.Conclusion: Our results demonstrate that ALA might be a potential Lyn kinase inhibitor, which could be used to treat pseudo-allergic reaction-related diseases such as urticaria. [ABSTRACT FROM AUTHOR]

Graded cellular material is a superb sandwich candidate for blast alleviation, but it has a disadvantage for the anti-blast design of sacrificial cladding, i.e., the supporting stress for the graded cellular material cannot maintain a constant level. Thus, a density graded-uniform cellular sacrificial cladding was developed, and its anti-blast response was investigated theoretically and numerically. One-dimensional nonlinear plastic shock models were proposed to analyze wave propagation in density graded-uniform cellular claddings under blast loading. There are two shock fronts in a positively graded-uniform cladding; while there are three shock fronts in a negatively graded-uniform cladding. Response features of density graded-uniform claddings were analyzed, and then a comparison with the cladding based on the uniform cellular material was carried out. Results showed that the cladding with uniform cellular materials is a good choice for the optimal mass design, while the density graded-uniform cladding is more advantageous from the perspective of the critical length design indicator. A partition diagram for the optimal length of sacrificial claddings under a defined blast loading was proposed for engineering design. Finally, cell-based finite element models were applied to verify the anti-blast response results of density graded-uniform claddings. [ABSTRACT FROM AUTHOR]

Background: Immunoglobulin E (IgE)-mediated mast cell (MC) activation is crucial in multiple allergic diseases. Parkinson disease protein 7 (DJ-1) and Lyn kinase were reported as the receptor-proximal events in IgE receptor (FcεRI) signals in human MC. Kaempferol, a natural flavonol mainly derived from the rhizome of traditional Chinese herb Kaempferia galanga L. (Zingiberaceae), has been known to inhibit allergic reactions, but it was limited to the receptor-distal signals on rat basophilic leukemia cells. A thorough investigation of the inhibitory effects of kaempferol on human MC has not been done.Purpose: To investigate the inhibitory effects of kaempferol on IgE-mediated anaphylaxis in vivo and in human MCs, as well as the mechanism underlying its effects, especially the receptor-proximal signals.Methods: IgE-mediated passive cutaneous anaphylaxis and systemic anaphylaxis model were applied to elucidate the antiallergic activity of kaempferol in vivo. The degranulation assay, calcium imaging, the release of cytokines and chemokines on the laboratory of allergic disease 2 (LAD2) cells were used to evaluate the antiallergic effect of kaempferol in vitro. Western blot analysis was performed to investigate the DJ-1/Lyn signaling pathway and downstream molecules. Kinase activity assay, immunofluorescence, and molecular docking were conducted to confirm the influence of kaempferol on DJ-1/Lyn molecules.Results: Kaempferol dose-dependently attenuated ovalbumin/IgE-induced mice paw swelling, primary MC activation from paw skin, as well as rehabilitated the hypothermia, and reduced the serum concentrations of histamine, tumor necrosis factor-alpha, interleukin-8, and monocyte chemo-attractant protein-1. Additionally, kaempferol suppressed IgE-mediated LAD2 cell degranulation and calcium fluctuation. Remarkably, kaempferol was found to bind with DJ-1 protein, and initially prevented DJ-1 from translocating to the plasma membrane, thereby inhibited full activation of Lyn, and eventually restrained those receptor-distal signaling molecules, involved Syk, Btk, PLCγ, IP3R, PKC, MAPKs, Akt and NF-κB.Conclusion: Kaempferol could be used as a DJ-1 modulator for preventing MC-mediated allergic disorders through attenuating Lyn activation. [ABSTRACT FROM AUTHOR]

Background: The novel coronavirus disease (2019-nCoV) has been affecting global health since the end of 2019 and there is no sign that the epidemic is abating . The major issue for controlling the infectious is lacking efficient prevention and therapeutic approaches. Chloroquine (CQ) and Hydroxychloroquine (HCQ) have been reported to treat the disease, but the underlying mechanism remains controversial.Purpose: The objective of this study is to investigate whether CQ and HCQ could be ACE2 blockers and used to inhibit 2019-nCoV virus infection.Methods: In our study, we used CCK-8 staining, flow cytometry and immunofluorescent staining to evaluate the toxicity and autophagy of CQ and HCQ, respectively, on ACE2 high-expressing HEK293T cells (ACE2h cells). We further analyzed the binding character of CQ and HCQ to ACE2 by molecular docking and surface plasmon resonance (SPR) assays, 2019-nCoV spike pseudotyped virus was also used to observe the viropexis effect of CQ and HCQ in ACE2h cells.Results: Results showed that HCQ is slightly more toxic to ACE2h cells than CQ. Both CQ and HCQ could bind to ACE2 with KD = (7.31 ± 0.62)e-7 M and (4.82 ± 0.87)e-7 M, respectively. They exhibit equivalent suppression effect for the entrance of 2019-nCoV spike pseudotyped virus into ACE2h cells.Conclusions: CQ and HCQ both inhibit the entrance 2019-nCoV into cells by blocking the binding of the virus with ACE2. Our findings provide novel insights into the molecular mechanism of CQ and HCQ treatment effect on virus infection. [ABSTRACT FROM AUTHOR]

• High Mw pullulan of 1 × 106 was purified from the culture broth of A. melanogenum. • High Mw pullulan-gellan composite film had an excellent barrier ability. • High Mw pullulan-gellan composite capsule had a standard shape and high tightness. • This composite capsule had a low brittleness and leakage. • This composite capsule exhibited a gastric extended drug release property. Albeit gelatin hard capsules were predominantly applied, their disadvantages call for endeavours on non-gelatin capsules in healthcare aspects. Herein, high molecular weight (Mw = 1 × 106) pullulan was purified from yeast fermentation broth. This high Mw pullulan and commercial low Mw pullulan were respectively co-blended with gellan to prepare the optimal solutions for capsule production. Further investigations, including loss-on-drying, brittleness and tightness, showed that the obtained pullulan-gellan capsules were of low water content, brittleness, leakage, and of high tightness. These capsules exhibited an extended release of amoxicillin over 60 min in simulated gastric fluid. Although the use of high and low Mw pullulan produced composite capsules with similar properties, the required concentration of high Mw pullulan was nearly half of that for low Mw pullulan, suggesting a cost-saving characteristic of using high Mw pullulan. This work proposes a potential substitution of gelatin with pullulan-gellan composites for preparing hard capsules. [ABSTRACT FROM AUTHOR]

Fruit size and shape are important qualities and yield traits in cucumber (Cucumis sativus L.), but the factors that influence fruit size and shape remain to be explored. In this study, we investigated the dynamic changes of fruit size and shape from the aspects of morphology, cellular levels and endogenous hormones for nine typical cucumber inbred lines. The results show that fruit length had a strong positive correlation to the cell number in the longitudinal section of fruit throughout the four stages of 0, 6, 12, and 30 DAA (days after anthesis). However, the significant negative correlations were found between fruit length and the fruit cell size at 12 and 30 DAA. Furthermore, fruit diameter was positively correlated to the cell number in the cross section at all the investigated fruit growth stages. The indole-3-acetic acid (IAA) content showed significant positive correlations to the fruit length at all fruit growth stages of −6, −3, 0, 3, 6, 9 and 12 DAA, but IAA content and fruit diameter showed significant negative correlations for all the stages except for at −6 DAA. The trans-zeatin riboside (tZR), zeatin (ZT), gibberellic acid (GA3) and jasmonic acid (JA) content had a positive or negative correlation with fruit length or diameter only at certain stages. Neither fruit length nor diameter had significant correlations to abscisic acid (ABA) content. These results indicate that variations in fruit size and shape of different cucumber inbred lines mainly result from the differences in fruit cell number and endogenous IAA content. The present work is the first to propose cucumber fruit size and shape changes from the combined aspects of morphology, cellular levels, and endogenous hormones. [ABSTRACT FROM AUTHOR]

Background: Mast cells (MCs) are crucial effectors in allergic disorders by secreting inflammatory mediators. The Mas-related G-protein-coupled receptor X2 (Mrgprx2) was shown to have a key role in IgE-independent allergic reactions. Therefore, potential drug candidates that directly target Mrgprx2 could be used to treat pseudo-allergic diseases. Shikonin, an active ingredient derived from Lithospermum erythrorhizon Sieb. et Zucc has been used for its anti-inflammatory properties since ancient China.Purpose: To investigate the inhibitory effects of Shikonin on IgE-independent allergy both in vitro and in vivo, as well as the mechanism underlying its effects.Methods/study Designs: The anti-anaphylactoid activity of Shikonin was evaluated in PCA and systemic anaphylaxis models, Calcium imaging was used to assess intracellular Ca2+ mobilization. The release of cytokines and chemokines was measured using enzyme immunoassay kits. Western blot analysis was conducted to investigate the molecules of PLCγ-PKC-IP3 signaling pathway. The analytical method of surface plasmon resonance was employed to study the interaction between Shikonin and potential target protein Mrgprx2.Results: Shikonin can suppress compound 48/80 (C48/80)-induced PCA, active systemic anaphylaxis, and MCs degranulation in mice in a dose-dependent manner. In addition, Shikonin reduced C48/80-induced calcium flux and suppressed LAD2 cell degranulation via PLCγ-PKC-IP3 signaling pathway. Moreover, Shikonin was found to inhibit C48/80-induced Mrgprx2 expression in HEK cells, displaying specific interactions with the Mrgprx2 protein.Conclusion: Shikonin could be a potential antagonist of Mrgprx2, thereby inhibiting pseudo-allergic reactions through Ca2+ mobilization. [ABSTRACT FROM AUTHOR]

A new kind of core-crosslinked zwitterionic polymer nano aggregates was prepared by two steps: (1) terpolymers of lipoic acid, polyethylene glycol diglycidyl ether and l -lysine were prepared, forming nano aggregates with hydrodynamic radius of 80 nm–183 nm by self-assembly; (2) the crosslinking of the nano aggregates took place through a reaction of side chain group in lipoic acid structural unit with 1,4-dimercaptothreotol, producing zwitterionic polymer core-crosslinked nano aggregates. The aggregates were stable against dilution and protein adsorption, and they demonstrated good pH/redox dual-responsiveness due to the introduction of disulfide bonds and zwitterionic groups to the nano aggregates. Doxorubicin (DOX) was loaded into the nano aggregates for controlled release. The drug-loaded nano aggregates exhibited obvious pH and reduction sensitivities in response to the environmental conditions in tumor cells. The nano aggregates were biocompatible and could be potentially applied as anticancer drug vehicles for enhancement of cellular uptake of anticancer drugs. Image 1 • New core-crosslinked zwitterionic polymer nano agregates were prepared. • They demonstrated good pH/redox dual-responsiveness. • The agregates were stable against dilution and protein adsorption. • The drug could be loaded in the agregates. • The release could be controlled by pH/redox conditions in tumor cells. [ABSTRACT FROM AUTHOR]

Allergic conjunctivitis (AC) resulting from conjunctival reactive inflammation is a common ocular surface disease. Quercetin is known for its anti-allergic properties but its effects on conjunctivitis are less well understood. In this study, we evaluated the anti-allergic effects of quercetin in animal models of conjunctivitis, and explored its molecular mechanism(s) of action in cultured human mast cells (MCs). Quercetin inhibited the ovalbumin (OVA) induced expression of IgE, HA, IL-4, TNF-α and substance-P in the peripheral blood of AC mouse models. Quercetin also attenuated OVA induced MC degranulation, eosinophil number, substance P concentrations, and mRNA IL-4/TNF-α expression in the conjunctival tissue of AC models. In vitro analysis showed that quercetin reduced DNP-HSA/IgE induced calcium (Ca2+) influx, and suppressed degranulation and chemokine release in LAD2 cells (human primary mast cell). Quercetin also inhibited DNP-HSA/IgE induced Lyn/PLCγ/IP3R–Ca2+ activation, Lyn/ERK1/2 signaling, and Lyn/NF-κB activation in LAD2 cells, all of which promote inflammation. When added alone, quercetin had no effect on PLCγ1 phosphorylation or expression, but potently inhibited Lyn and phosphorylation-Lyn. Quercetin (200 μM) and Lyn inhibitors (Bafetinib, 10 μM) inhibit the activity of Lyn kinase, and quercetin can reduce the activation of Lyn kinase by Lyn agonist (Tolimidone, 10 μM). These data can be preliminarily determined that quercetin can inhibit allergic conjunctivitis as a Lyn kinase inhibitor. This study illustrated the use of quercetin for the treatment of allergic conjunctivitis, which might act through its ability to inhibit Lyn/PLCγ/IP3R–Ca2+, Lyn/ERK1/2, and Lyn/NF-κB signaling. The inhibition of Lyn likely represents a major mechanism by which quercetin dampens the inflammatory response in AC disease models. • Quercetin can be use as a treatment for allergic conjunctivitis. • Quercetin treatment of allergic conjunctivitis acts through Lyn/Fyn/PLCγ/IP3R–Ca2+ signaling. • Quercetin acts as a Lyn kinase inhibitor to dampen the inflammatory response. [ABSTRACT FROM AUTHOR]

In machining process of the ultra-precision turning lathe, the vibration of the spindle is closely related to the machining quality. Coupling misalignment is one of the most common faults that lead to vibration problems of the spindle. Most of the studies on the misalignment of coupling focus on the vibration response in radial direction, and the axial motion of spindle is rarely studied. In this paper, the model of a machining system with misaligned coupling is established. Each part of the system has complete 6 degree-of-freedom (DOF) of motion, and system's responses when idling and cutting are simulated. Furthermore, the machined surface topography is simulated according to the responses results. It is found that there are abundant low-order harmonics besides the operating frequency in the vibration of the spindle, both in the radial and axial direction. These harmonics in response will be reflected to the surface through the relative motion of the spindle and the cutting tool. The influence of spindle's angular vibration on the surface is also especially noteworthy. Meanwhile, an experiment is carried out that the vibration of the spindle is detected by the capacitive displacement sensor, and the surface topography is directly measured by a laser interferometer. The experimental results verify this relationship between the vibration and the machined surface. This study is of considerable significance to deeply understand the influence of misalignment on rotor's motion and machined surface. The research results also have value for spindle error diagnosis and machined surface prediction. [ABSTRACT FROM AUTHOR]

As an intermittent cutting process, fly-cutting machining often results in unwanted and non-negligible vibrations, which adversely affect the surface quality of the machined workpiece. This work presents a dynamic simulation and active vibration control approach for the ultra-precision fly-cutting machine tool based on the transfer matrix method for multibody systems (MSTMM) and the independent modal space control method. The dynamic model of the ultra-precision fly-cutting machine tool system, incorporating rigid body elements, beam elements, flexible body elements, and hinge elements is established. The dynamic equations of the system are derived by directly combining the body dynamic equations of all body elements and decoupling them using augmented eigenvectors. Further, the state-space representation of the system is obtained and expressed within each independent modal space. The structure of the active vibration control system, including the modal filter and controller, has been meticulously designed. The controlled modes are selected based on H 2 norm of each mode, while the optimization of actuator positions is performed using the controllability Gramian. Finally, numerical simulations are conducted to verify the efficacy of the proposed modal space control approach in effectively reducing the tool-tip vibration and improving the machining accuracy. [ABSTRACT FROM AUTHOR]

• A hybrid numerical method for vibration analysis of linear multibody systems. • Combining transfer matrix method for multibody systems with finite element method and Craig-Bampton reduction method. • Dynamics modelling and vibration analysis of the machine tool with a flexible fly-cutting head. This paper presents a novel hybrid numerical method combining the transfer matrix method for multibody systems with the finite element method and the Craig-Bampton reduction method. In the proposed method, the multibody system is divided into two types of subsystems, depending on the shape and stiffness of each component. All the subsystems are independently analysed by the transfer matrix method for multibody systems or the finite element method and the Craig-Bampton reduction method. The whole system is recombined by deriving the relation equations of the connection points amongst subsystems. Then, the overall transfer equation and the eigenvalue equation of the whole system are obtained. Verifications on a simple system and rigid-flexible manipulator system show that the natural frequencies and modal shapes agree well with the finite element method. The dynamic model of the ultra-precision fly-cutting machine tool concerning the linearly elastic deformation of the fly-cutting head is established by the proposed method and validated by the experimental modal test. According to the comparison of computational speed with the finite element method, the proposed method has advantages in easy programming, low matrix order, low computational effort, and high applicability to the linear time-invariant mechanical system with flexible components. [ABSTRACT FROM AUTHOR]

Galectin-9 is a β -galactoside-binding lectin which could modulate a variety of biological functions including recognition, aggregation and clearance of pathogen. In this study, one Galectin-9 (named PoGalectin-9) was identified from Japanese flounder Paralichthys olivaceus. PoGalectin-9 belongs to the tandem-repeat type, containing one 127-amino acids CRD domain within N terminal and one 122-amino acids CRD domain within C-terminal. The open reading frame of PoGalectin-9 cDNA was 921 bp encoding 306 amino acids. Sequence similarity comparison confirmed that PoGalectin-9 shared high homology with other Galectin-9. The tissue distribution and expression profiles after bacterial infection were also investigated. PoGalectin-9 was widely distributed in all of the examined tissues of Japanese flounder but was predominantly expressed in the spleen, kidney and intestine. After Edwardsiella tarda challenge, the expression of PoGalectin-9 was up-regulated in spleen and down regulated in kidney. ELISA experiment showed that recombinant PoGalectin-9 (rPoGalectin-9) exhibit binding capacity to lipopolysaccharide (LPS) and peptidoglycan (PGN), which is significantly correlated with the concentration of rPoGalectin-9. Meanwhile, the rPoGalectin-9 protein showed strong agglutinating activities against both Gram-negative bacteria and Gram-positive bacteria. Bacterial binding experiments showed that rPoGalectin-9 could bind all examined bacteria. In conclusion, the present study indicate that PoGalectin- 9 might play important roles during the immune responses of Japanese flounder against bacterial pathogens. • One isoform of Galectin-9 from Japanese Flounder were cloned and characterized, named PoGalectin-9. • PoGalectin-9 was ubiquitously expressed in all tested tissues. • PoGalectin-9 was up-regulated in spleen after challenged with E. tarda. • The recombinant PoGalectin-9 showed high affinity to lipopolysaccharide. • PoGalectin-9 may play important roles during immune responses. [ABSTRACT FROM AUTHOR]

Pooling layer in Convolutional Neural Networks (CNNs) is designed to reduce dimensions and computational complexity. Unfortunately, CNN is easily disturbed by noise in images when extracting features from input images. The traditional pooling layer directly samples the input feature maps without considering whether they are affected by noise, which brings about accumulated noise in the subsequent feature maps as well as undesirable network outputs. To address this issue, a robust Local Binary Pattern (LBP) Guiding Pooling (G-RLBP) mechanism is proposed in this paper to down sample the input feature maps and lower the noise impact simultaneously. The proposed G-RLBP method calculates the weighted average of all pixels in the sliding window of this pooling layer as the final results based on their corresponding probabilities of being affected by noise, thus lowers the noise impact from input images at the first several layers of the CNNs. The experimental results show that the carefully designed G-RLBP layer can successfully lower the noise impact and improve the recognition rates of the CNN models over the traditional pooling layer. The performance gain of the G-RLBP is quite remarkable when the images are severely affected by noise. [ABSTRACT FROM AUTHOR]

Cardiac biomarkers (CBs) are substances that appear in the blood when the heart is damaged or stressed. Measurements of the level of CBs can be used in course of diagnostics or monitoring the state of the health of group risk persons. A multi-region bio-analytical system (MRBAS) based on magnetoimpedance (MI) changes was proposed for ultrasensitive simultaneous detection of CBs myoglobin (Mb) and C-reactive protein (CRP). The microfluidic device was designed and developed using standard microfabrication techniques for their usage in different regions, which were pre-modified with specific antibody for specified detection. Mb and CRP antigens labels attached to commercial Dynabeads with selected concentrations were trapped in different detection regions. The MI response of the triple sensitive element was carefully evaluated in initial state and in the presence of biomarkers. The results showed that the MI-based bio-sensing system had high selectivity and sensitivity for detection of CBs. Compared with the control region, ultrasensitive detections of CRP and Mb were accomplished with the detection limits of 1.0 pg/mL and 0.1 pg/mL, respectively. The linear detection range contained low concentration detection area and high concentration detection area, which were 1 pg/mL–10 ng/mL, 10–100 ng/mL for CRP, and 0.1 pg/mL–1 ng/mL, 1 n/mL–80 ng/mL for Mb. The measurement technique presented here provides a new methodology for multi-target biomolecules rapid testing. [ABSTRACT FROM AUTHOR]

Background: Depression is a prevalent psychiatric disorder with high long‐term morbidities, recurrences, and mortalities. Despite extensive research efforts spanning decades, the cellular and molecular mechanisms of depression remain largely unknown. What's more, about one third of patients do not have effective anti‐depressant therapies, so there is an urgent need to uncover more mechanisms to guide the development of novel therapeutic strategies. Adenosine triphosphate (ATP) plays an important role in maintaining ion gradients essential for neuronal activities, as well as in the transport and release of neurotransmitters. Additionally, ATP could also participate in signaling pathways following the activation of postsynaptic receptors. By searching the website PubMed for articles about "ATP and depression" especially focusing on the role of extracellular ATP (eATP) in depression in the last 5 years, we found that numerous studies have implied that the insufficient ATP release from astrocytes could lead to depression and exogenous supply of eATP or endogenously stimulating the release of ATP from astrocytes could alleviate depression, highlighting the potential therapeutic role of eATP in alleviating depression. Aim: Currently, there are few reviews discussing the relationship between eATP and depression. Therefore, the aim of our review is to conclude the role of eATP in depression, especially focusing on the evidence and mechanisms of eATP in alleviating depression. Conclusion: We will provide insights into the prospects of leveraging eATP as a novel avenue for the treatment of depression. [ABSTRACT FROM AUTHOR]

Crop residue‐derived carbon (C) emissions and priming effects (PE) in cropland soils can influence the global C cycle. However, their corresponding generality, driving factors, and responses to nitrogen (N) inputs are poorly understood. As a result, the total C emissions and net C balance also remain mysterious. To address the above knowledge gaps, a meta‐analysis of 1123 observations, taken from 51 studies world‐wide, has been completed. The results showed that within 360 days, emission ratios of crop residues C (ER) ranged from 0.22% to 61.80%, and crop residues generally induced positive PE (+71.76%). Comparatively, the contribution of crop residue‐derived C emissions (52.82%) to total C emissions was generally higher than that of PE (12.08%), emphasizing the importance of reducing ER. The ER and PE differed among crop types, and both were low in the case of rice, which was attributed to its saturated water conditions. The ER and PE also varied with soil properties, as PE decreased with increasing C addition ratio in soils where soil organic carbon (SOC) was less than 10‰; in contrast, the opposite phenomenon was observed in soils with SOC exceeding 10‰. Moreover, N inputs increased ER and PE by 8.31% and 3.78%, respectively, which was predominantly attributed to (NH4)2SO4. The increased PE was verified to be dominated by microbial stoichiometric decomposition. In summary, after incorporating crop residues, the total C emissions and relative net C balance in the cropland soils ranged from 0.03 to 23.47 mg C g−1 soil and 0.21 to 0.97 mg C g−1 residue‐C g−1 soil, respectively, suggesting a significant impact on C cycle. These results clarify the value of incorporating crop residues into croplands to regulate global SOC dynamics and help to establish while managing site‐specific crop return systems that facilitate C sequestration. [ABSTRACT FROM AUTHOR]

With regard to wind farms connected to the main system via dedicated overhead transmission lines, the available wind power absorbed by the system relies on not only the power generation capacity but also the power transmission threshold. Thus, this study centers on the close relationship between environmental conditions and power transfer limits that involve the thermal limit and steady-state stability limit. Simultaneous equations representing both overhead conductors’ heat balance and power transmission operation are established. In addition, formulations of the maximum transmission power for the steady-state stability limit are derived and then expressed as functions of environmental factors and the line length. The presented approach allows one to analyze the threshold considering not only the thermal limit but also the steady-state stability limit, which could be remarkably different under certain environmental and transmission distance conditions. Then, a scheme to identify the primary limitation and obtain the corresponding threshold value is proposed. Moreover, a simple treatment of wind speed correlation is deployed because of the close distance between a wind farm and its tie-line. Case studies demonstrate that, for a certain wind speed level, the process of transmission rather than generation could become the key factor determining the threshold value. [ABSTRACT FROM AUTHOR]

Cellular material under high-velocity impact exhibits a typical feature of layerwise collapse. A cell-based finite element model is employed herein to simulate the direct impact of a closed-cell foam, and one-dimensional velocity field distributions are obtained to characterize the crushing band propagating through a cellular material. An explicit expression for the continuous velocity distribution is derived based on the features of the velocity gradient distribution. The velocity distribution function is adopted to determine the dynamic stress–strain states of cellular materials under dynamic loading. The local stress–strain history distribution reveals that sectional cells experience a process from the precursor elastic behavior to the shock stress state, passing through the dynamic initial crushing state. A power-law relation between the dynamic initial crushing stress and the strain rate is established, which confirms the strain rate effect of cellular materials. By extracting the critical points immediately before the unloading stage in the local dynamic stress–strain history curves, the dynamic stress–strain states of cellular materials are determined. They exhibit loading rate dependence but are independent of the initial impact velocity. Furthermore, with increase of the relative density, the dynamic hardening behavior of the cellular specimen is enhanced and the crushing process event is advanced. The particle velocity-based analytical method is applied to analyze the dynamic responses of cellular materials. This method is better than continuum-based shock models, since it does not require a preassumed constitutive relation. Therefore, the particle velocity-based analytical method proposed herein may provide new ideas to carry out dynamic experimental measurements, which is especially applicable to inhomogeneous materials. [ABSTRACT FROM AUTHOR]

As a typical hybrid lattice, vertical-reinforced lattices, i.e., adding vertical struts to traditional lattices, have not been extensively studied, especially from the aspects of deformation mechanism, energy absorption performance and structural optimization. In this paper, body-centered cubic (BCC), face-centered cubic (FCC), as well as vertical-reinforced BCC and FCC (VBCC and VFCC) lattices were established and fabricated by the selective laser melting technique to elucidate the influence of the vertical struts on the mechanical behavior of the lattices. Uniaxial quasi-static compression tests were conducted on lattice samples made of stainless steel 316L. Moreover, numerical simulations were performed to facilitate analysis of the deformation modes of the specimens and further optimization designs. The results show that the VBCC and VFCC lattices exhibit stronger stiffness and higher initial strength compared to the BCC and FCC lattices. Typically, the effective specific energy absorption of the vertical-reinforced lattices can be increased by about 60%–75% compared with those of non-reinforced lattices, since more plastic hinges are formed in the lattice via adding vertical struts to dissipate energy. The present study also demonstrates that increasing the diameter of the vertical struts plays a vital role in improving energy absorption capabilities of the vertical-reinforced lattice, and the highest effective specific energy absorption of optimized VBCC and VFCC lattices are 21.7 J/g and 27.9 J/g, notably far above the general trend of most metal lattices. • Vertical-reinforced lattices exhibit excellent energy absorption performance. • Mesoscopic deformation mechanisms of vertical-reinforced lattices are elucidated. • A theoretical model of plateau stress is proposed for vertical-reinforced lattices. • Energy absorption regulation of vertical-reinforced lattice through optimal design. [ABSTRACT FROM AUTHOR]

The decision to initiate pediatric mechanical ventilation via tracheostomy ("home ventilation") is complex and parents often desire information from other parents who have faced this decision. However, parent-to-parent communication is challenging as it is difficult to connect new families to experienced families in ways that optimize informed, balanced decision-making. Create a parent-to-parent web-based tool to support decision-making about pediatric home ventilation. The tool was created based on interviews and feedback from parents. We interviewed parents who previously chose for, or against, home ventilation for their child. Interview themes and family comments guided website development. Viewer feedback was solicited via an embedded survey in the tool. We created 6 composite character families to communicate 6 themes about home ventilation: 1) Considering treatment options, 2) Talking with medical team, 3) Impact on life at home, 4) Impact on relationships, 5) Experience for the child, and 6) If the child's life is short. Nine families who reviewed the draft tool felt it would have helped with their decision about home ventilation. Specifically, it supported families in thinking through what was "most important about their child's breathing problems" (7 of 9 parents) and feeling "more at peace with the decision" (8 of 9 parents). Between 6/1/20–12/31/22, nearly 5500 viewers have accessed the tool and 56 viewers completed the survey (including 13 families and 39 clinicians). Feedback from experienced families and clinicians reported the tool taught them something new. This novel parent-to-parent tool shows promise for expanding access to balanced, family-centered information about pediatric home ventilation. The diverse stories and decisions let parents access multiple family perspectives. The tool's focus is on family-centric information that parents reported was usually missing from clinician counseling. This work was supported by the National Palliative Care Research Center. • Parents considering pediatric home ventilation often desire information from other parents. • Hearing experiences of one or two families yields limited information. • We created a web-based tool based on multiple family interviews and feedback. • The diverse stories and decisions let parents access multiple family perspectives. • Clinicians report the tool will help them counsel families. [ABSTRACT FROM AUTHOR]

Highlights • Mivacurium induces mast cell degranulation in a dose-dependent manner. • Mivacurium induced anaphylactoid reactions in mice via Mrgprb2. • Mivacurium induced the release of pro-synthetic inflammatory molecules. • MRGPRX2 mediated the mivacurium-induced mast cell activation. • MRGPRX2 mediates mivacurium-triggered calcium mobilization during anaphylactic reactions by activating PLC-γ and IP3R. Abstract Background Mivacurium is a non-depolarizing muscle relaxant and widely used as a short-acting anesthetic. Pseudo-allergic reactions to mivacurium occur when it is administered during perioperative anesthesia. These reactions may present a serious threat to the patient’s life, particularly in children. Methods MAS-related G protein coupled receptor-related pseudo-allergic reactions that were induced by mivacurium were investigated using skin swelling and extravasation assays in vivo and mast cell degranulation assay in vitro. Results Mivacurium caused pseudo-allergic reactions in wild-type mice by inducing mast cells to release histamine. However, it did not induce a similar phenomenon in KitW-sh/W-sh mice. Furthermore, MrgprB2-knockout mice displayed no inflammatory response to mivacurium. Mivacurium induced LAD2 cell degranulation in a dose-dependent manner. Mivacurium stimulated intracellular calcium ion (Ca2+) influx in MRGPRX2-HEK293 cells but not in NC-HEK293 cells. However, mivacurium induced the release of only low levels of mediators in LAD2 cells transfected with MRGPRX2-targeted small interfering (si)RNA. Notably, cytokine release was not observed in LAD2 cells even when stimulated with high concentrations of mivacurium. Conclusion Mivacurium activated MRGPRX2 and triggered mast cell degranulation, leading to anaphylactoid reactions. However, mivacurium did not induce the release of other cytokines. Therefore, the targeting of MRGPRX2 can potentially block mivacurium-induced adverse drug effects, particularly pseudo-allergic reactions. [ABSTRACT FROM AUTHOR]

In a previous study, we constructed a MHSP65-TCL anti-lung cancer vaccine with Lewis lung carcinoma TCL plus MHSP65, and illustrated its anti-lung cancer effect through specific and nonspecific anti-tumor immunity. However, TCL contains some immunoinhibit components such as FasL. If this component can be eliminated from TCL, the anti-tumor immunity of MHSP65-TCL constructed with TCL should be improved. In the present study, we knocked down FasL from Lewis lung carcinoma cells and prepared MHSP65-(FasL-/TCL) with this cell line's TCL. After further investigation, MHSP65-(FasL-/TCL) exhibited a better ability to reduce splenocytes apoptosis, promote its activation and secretion of secretingTNF-β, IL-2 compared with MHSP65-(FasL +/TCL). Accordingly, specific and nonspecific antitumor immunity induced by MHSP65-(FasL-/TCL) is stronger than that of MHSP65-(FasL +/TCL). In vivo, MHSP65-(FasL-/TCL) immunization can prolong survival of Lewis lung carcinoma bearing mice. Thus, we report that the anti-lung cancer effect of MHSP65-TCL can be improved by removal of FasL from the TCL. It provides a new route to construct MHSP65-TCL and other antitumor vaccines based on TCL. [ABSTRACT FROM AUTHOR]

Bolted joints are widely adopted in various mechanical structures. However, the uncertainty and complexity of the contact surfaces affect accurate modeling. Herein, an interfacial micromechanics model is proposed to characterize the contact behaviors of bolted joints in an ultra-precision machine tool (UMT). The bolted joint is modeled as a virtual material layer with transversely isotropic behaviors, whose constitutive relation is identified by fractal theory. The proposed model accurately formulates the multi-scale contact characteristics and allows convenient integration with the structural dynamic modeling of UMT. Dynamic analysis of the simulation results and the experimental measurements in the time and frequency domains was conducted to identify the most sensitive factor affecting the tool tip vibration. On this basis, the structural optimization for the UMT was further implemented, which effectively reduced vibration by 15.5 %. The dynamic predictions were validated by modal and vibration response tests. [ABSTRACT FROM AUTHOR]

Background: The purpose of this study was to study the effect of STING-IFN-I pathway on incision induced postoperative pain in rats and its possible mechanisms. Methods: The pain thresholds were evaluated by measuring the mechanical withdrawal threshold and the thermal withdrawal latency. The satellite glial cell and macrophage of DRG were analyzed. The expression of STING, IFN-a, P-P65, iNOS, TNF-α, IL-1β and IL-6 in DRG was evaluated. Results: The activation of STING-IFN-I pathway can reduce the mechanical hyperalgesia, thermal hyperalgesia, down-regulate the expression of P-P65, iNOS, TNF-α, IL-1β and IL-6, and inhibit the activation of satellite glial cell and macrophage in DRG. Conclusions: The activation of STING-IFN-I pathway can alleviate incision induced acute postoperative pain by inhibiting the activation of satellite glial cell and macrophage, which reducing the corresponding neuroinflammation in DRG. [ABSTRACT FROM AUTHOR]

The deubiquitinating enzyme USP14 has been established as a crucial regulator in various diseases, including tumors, neurodegenerative diseases, and metabolic diseases, through its ability to stabilize its substrate proteins. Our group has utilized proteomic techniques to identify new potential substrate proteins for USP14, however, the underlying signaling pathways regulated by USP14 remain largely unknown. Here, we demonstrate the key role of USP14 in both heme metabolism and tumor invasion by stabilizing the protein BACH1. The cellular oxidative stress response factor NRF2 regulates antioxidant protein expression through binding to the antioxidant response element (ARE). BACH1 can compete with NRF2 for ARE binding, leading to the inhibition of the expression of antioxidant genes, including HMOX-1. Activated NRF2 also inhibits the degradation of BACH1, promoting cancer cell invasion and metastasis. Our findings showed a positive correlation between USP14 expression and NRF2 expression in various cancer tissues from the TCGA database and normal tissues from the GTEx database. Furthermore, activated NRF2 was found to increase USP14 expression in ovarian cancer (OV) cells. The overexpression of USP14 was observed to inhibit HMOX1 expression, while USP14 knockdown had the opposite effect, suggesting a role for USP14 in regulating heme metabolism. The depletion of BACH1 or inhibition of heme oxygenase 1 (coded by HMOX-1) was also found to significantly impair USP14-dependent OV cell invasion. In conclusion, our results highlight the importance of the NRF2-USP14-BACH1 axis in regulating OV cell invasion and heme metabolism, providing evidence for its potential as a therapeutic target in related diseases. • USP14 binds directly to BACH1 protein in ovarian cancer cells. • USP14 regulates protein half-life and ubiquitination modifications of BACH1 in ovarian cancer cells. • Activated NRF2 promotes the expression of USP14, and USP14 can regulate heme metabolism. • USP14 regulates ovarian cancer cell invasion dependent on BACH1 protein. [ABSTRACT FROM AUTHOR]

Mixed metal oxides Co 5 − x Cu x Al ( x = 0–0.5) were prepared from Co-Cu-Al layered double hydroxides (LDHs) and tested for benzene total oxidation. By calcination, Co-Cu-Al LDHs were mainly transformed to (Co, Cu)(Co, Al) 2 O 4 spinels, where both Cu 2 + and Al 3 + cations were incorporated into the spinel structure. The incorporation of Cu significantly improved the Co oxide reducibility and remarkably enhanced the light-off activity as well as the total conversion activity, indicative a strong interaction between Cu 2 + and Co 3 + active sites. The optimum Co 4.75 Cu 0.25 Al spinel mixed oxide was comparable with a 0.3%Pd/γ-Al 2 O 3 catalyst, highlighting the promoting effect of structural modification with Cu. [ABSTRACT FROM AUTHOR]

Both reactive oxygen species (ROS) from redox-biology and pro-inflammatory cytokines from innate immunity/and other sources, in addition to their role in redox-biology, and in defense and repair, have long been regarded as potentially harmful factors associated with oxidative stress and inflammatory states. However, their important physiological functions as signaling molecules have been demonstrated to be of importance, also in Geroscience, particularly when ROS are at balanced basal levels (redox-biology) and pro-inflammatory cytokines are at very low levels (cold-inflammaging). Under these conditions, both of these components (alone or in combination) may act as signaling/response molecules involved in regulating/maintaining or restoring adaptive homeostasis during aging, particularly in the early phases of even very-mild non-damaging internal or external environmental stimuli that could nevertheless elicit low-grade warnings-signals for homeostatic stability. If signals potentially perturbing homeostasis persist, the levels of ROS and pro-inflammatory mediators increase resulting in a switch from adaptive to maladaptive responses which may lead to oxidative stress and overt-inflammaging (or even to an overt inflammatory state), thus paving the way to the risks of aging-related diseases (ARDs). Conversely, upon adaptive-responses, low-levels of ROS and very-low-levels of pro-inflammatory-cytokines, alone or in combination, can result in an amplified capacity to prevent or slow-down overt-inflammaging (2-fold to 4-fold increase of pro-inflammatory cytokines) thus maintaining or restoring homeostasis. Therefore, these signaling molecules may also have the sequential incremental potential to prevent or slow the subsequent decline of adaptive homeostasis that will occur later in the lifespan. These scenarios may lead us to conceive of, and conceptualize, both these molecules and their basal-low levels, as well as their dynamics and the time-course of responses, as 'potential important pillars of adaptive-homeostasis in aging' since the earliest phases of the occurrence of any even very- mild environmental potential imbalance. • ROS and pro-inflammatory cytokines as molecules that cause damage (e.g., oxidative stress and inflammaging), but to appreciate their role in regulating signaling pathways that affect normal physiological and biological responses. • The effects of these two pathways: (a) basal-low levels ROS and (b) very low levels of pro-inflammatory mediators, can, working alone or in concert, prevent and/or intervene on even minor homeostatic imbalances since the very early phases, thus initiating signal transductions for the regulation maintenance or restoration of adaptive homeostasis in aging. • "Basic Pillars of adaptive-homeostasis in ageing", whose combination can also prevent or slow-down the transition from cold-inflammaging tot overt-inflammaging. [ABSTRACT FROM AUTHOR]

Background: Perioperative neurocognitive disorders (PND) with a high incidence frequently occur in elderly surgical patients closely associated with prolonged anesthesia-induced neurotoxicity. The neuromorphopathological underpinnings of anesthesia-induced neurotoxicity have remained elusive. Methods: Prolonged anesthesia with sevoflurane was used to establish the sevoflurane-induced neurotoxicity (SIN) animal model. Morris water maze, elevated plus maze, and open field test were employed to track SIN rats' cognitive behavior and anxiety-like behaviors. We investigated the neuropathological basis of SIN through techniques such as transcriptomic, electrophysiology, molecular biology, scanning electron microscope, Golgi staining, TUNEL assay, and morphological analysis. Our work further clarifies the pathological mechanism of SIN by depleting microglia, inhibiting neuroinflammation, and C1q neutralization. Results: This study shows that prolonged anesthesia triggers activation of the NF-κB inflammatory pathway, neuroinflammation, inhibition of neuronal excitability, cognitive dysfunction, and anxiety-like behaviors. RNA sequencing found that genes of different types of synapses were downregulated after prolonged anesthesia. Microglial migration, activation, and phagocytosis were enhanced. Microglial morphological alterations were also observed. C1qa, the initiator of the complement cascade, and C3 were increased, and C1qa tagging synapses were also elevated. Then, we found that the "Eat Me" complement pathway mediated microglial synaptic engulfment in the hippocampus after prolonged anesthesia. Afterward, synapses were remarkably lost in the hippocampus. Furthermore, dendritic spines were reduced, and their genes were also downregulated. Depleting microglia ameliorated the activation of neuroinflammation and complement and rescued synaptic loss, cognitive dysfunction, and anxiety-like behaviors. When neuroinflammatory inhibition or C1q neutralization occurred, complement was also decreased, and synaptic elimination was interrupted. Conclusions: These findings illustrated that prolonged anesthesia triggered neuroinflammation and complement-mediated microglial synaptic engulfment that pathologically caused synaptic elimination in SIN. We have demonstrated the neuromorphopathological underpinnings of SIN, which have direct therapeutic relevance for PND patients. [ABSTRACT FROM AUTHOR]