Suppression of DNMT2/3 by proinflammatory cytokines inhibits CtBP1/2-dependent genes to promote the occurrence of atrophic nonunion.

Failure of bone healing after fracture often results in nonunion, but the underlying mechanism of nonunion pathogenesis is poorly understood. Herein, we provide evidence to clarify that the inflammatory microenvironment of atrophic nonunion (AN) mice suppresses the expression levels of DNA methyltransferases 2 (DNMT2) and 3A (DNMT3a), preventing the methylation of CpG islands on the promoters of C-terminal binding protein 1/2 (CtBP1/2) and resulting in their overexpression. Increased CtBP1/2 acts as transcriptional corepressors that, along with histone acetyltransferase p300 and Runt-related transcription factor 2 (Runx2), suppress the expression levels of six genes involved in bone healing: BGLAP (bone gamma-carboxyglutamate protein), ALPL (alkaline phosphatase), SPP1 (secreted phosphoprotein 1), COL1A1 (collagen 1a1), IBSP (integrin binding sialoprotein), and MMP13 (matrix metallopeptidase 13). We also observe a similar phenomenon in osteoblast cells treated with proinflammatory cytokines or treated with a DNMT inhibitor (5-azacytidine). Forced expression of DNMT2/3a or blockage of CtBP1/2 with their inhibitors can reverse the expression levels of BGLAP/ALPL/SPP1/COL1A1/IBSP/MMP13 in the presence of proinflammatory cytokines. Administration of CtBP1/2 inhibitors in fractured mice can prevent the incidence of AN. Thus, we demonstrate that the downregulation of bone healing genes dependent on proinflammatory cytokines/DNMT2/3a/CtBP1/2-p300-Runx2 axis signaling plays a critical role in the pathogenesis of AN. Disruption of this signaling may represent a new therapeutic strategy to prevent AN incidence after bone fracture.

Accumulation of advanced glycation end products promotes atrophic nonunion incidence in mice through a CtBP1/2-dependent mechanism.

Atrophic nonunion (AN) is a complex and poorly understood pathological condition resulting from impaired fracture healing. Advanced glycation end products (AGEs) have been implicated in the pathogenesis of several bone disorders, including osteoporosis and osteoarthritis. However, the role of AGEs in the development of AN remains unclear. This study found that mice fed a high-AGE diet had a higher incidence of atrophic nonunion (AN) compared to mice fed a normal diet following tibial fractures. AGEs induced two C-terminal binding proteins (CtBPs), CtBP1 and CtBP2, which were necessary for the development of AN in response to AGE accumulation. Feeding a high-AGE diet after fracture surgery in CtBP1/2-/- and RAGE-/- (receptor of AGE) mice did not result in a significant occurrence of AN. Molecular investigation revealed that CtBP1 and CtBP2 formed a heterodimer that was recruited by histone deacetylase 1 (HDAC1) and runt-related transcription factor 2 (Runx2) to assemble a complex. The CtBP1/2-HDAC1-Runx2 complex was responsible for the downregulation of two classes of bone development and differentiation genes, including bone morphogenic proteins (BMPs) and matrix metalloproteinases (MMPs). These findings demonstrate that AGE accumulation promotes the incidence of AN in a CtBP1/2-dependent manner, possibly by modulating genes related to bone development and fracture healing. These results provide new insights into the pathogenesis of AN and suggest new therapeutic targets for its prevention and treatment.

A single nucleotide polymorphism in an R2R3 MYB transcription factor gene triggers the male sterility in soybean ms6 (Ames1).

KEY MESSAGE: Identification and functional analysis of the male sterile gene MS6 in Glycine max. Soybean (Glycine max (L.) Merr.) is an important crop providing vegetable oil and protein. The male sterility-based hybrid breeding is a promising method for improving soybean yield to meet the globally growing demand. In this research, we identified a soybean genic male sterile locus, MS6, by combining the bulked segregant analysis sequencing method and the map-based cloning technology. MS6, highly expressed in anther, encodes an R2R3 MYB transcription factor (GmTDF1-1) that is homologous to Tapetal Development and Function 1, a key factor for anther development in Arabidopsis and rice. In male sterile ms6 (Ames1), the mutant allele contains a missense mutation, leading to the 76th leucine substituted by histidine in the DNA binding domain of GmTDF1-1. The expression of soybean MS6 under the control of the AtTDF1 promoter could rescue the male sterility of attdf1 but ms6 could not. Additionally, ms6 overexpression in wild-type Arabidopsis did not affect anther development. These results evidence that GmTDF1-1 is a functional TDF1 homolog and L76H disrupts its function. Notably, GmTDF1-1 shows 92% sequence identity with another soybean protein termed as GmTDF1-2, whose active expression also restored the fertility of attdf1. However, GmTDF1-2 is constitutively expressed at a very low level in soybean, and therefore, not able to compensate for the MS6 deficiency. Analysis of the TDF1-involved anther development regulatory pathway showed that expressions of the genes downstream of TDF1 are significantly suppressed in ms6, unveiling that GmTDF1-1 is a core transcription factor regulating soybean anther development.

Melatonin rescues cardiac thioredoxin system during ischemia-reperfusion injury in acute hyperglycemic state by restoring Notch1/Hes1/Akt signaling in a membrane receptor-dependent manner.

Stress hyperglycemia is commonly observed in patients suffering from ischemic heart disease. It not only worsens cardiovascular prognosis but also attenuates the efficacies of various cardioprotective agents. This study aimed to investigate the protective effect of melatonin against myocardial ischemia-reperfusion (MI/R) injury in acute hyperglycemic state with a focus on Notch1/Hes1/Akt signaling and intracellular thioredoxin (Trx) system. Sprague Dawley rats were subjected to MI/R surgery and high-glucose (HG, 500 g/L) infusion (4 mL/kg/h) to induce temporary hyperglycemia. Rats were treated with or without melatonin (10 mg/kg/d) during the operation. Furthermore, HG (33 mmol/L)-incubated H9c2 cardiomyoblasts were treated in the presence or absence of luzindole (a competitive melatonin receptor antagonist), DAPT (a γ-secretase inhibitor), LY294002 (a PI3-kinase/Akt inhibitor), or thioredoxin-interacting protein (Txnip) adenoviral vectors. We found that acute hyperglycemia aggravated MI/R injury by suppressing Notch1/Hes1/Akt signaling and intracellular Trx activity. Melatonin treatment effectively ameliorated MI/R injury by reducing infarct size, myocardial apoptosis, and oxidative stress. Moreover, melatonin also markedly enhanced Notch1/Hes1/Akt signaling and rescued intracellular Trx system by upregulating Notch1, N1ICD, Hes1, and p-Akt expressions, increasing Trx activity, and downregulating Txnip expression. However, these effects were blunted by luzindole, DAPT, or LY294002. Additionally, Txnip overexpression not only decreased Trx activity, but also attenuated the cytoprotective effect of melatonin. We conclude that impaired Notch1 signaling aggravates MI/R injury in acute hyperglycemic state. Melatonin rescues Trx system by reducing Txnip expression via Notch1/Hes1/Akt signaling in a membrane receptor-dependent manner. Its role as a prophylactic/therapeutic drug deserves further clinical study.

Melatonin reduces PERK-eIF2α-ATF4-mediated endoplasmic reticulum stress during myocardial ischemia-reperfusion injury: role of RISK and SAFE pathways interaction.

Recently, we demonstrated that melatonin reduced protein kinase RNA (PKR)-like ER kinase (PERK)-eukaryotic initiation factor 2 alpha (eIF2α)-activating transcription factor-4 (ATF4)-mediated myocardial endoplasmic reticulum (ER) stress and apoptosis during myocardial ischemia-reperfusion (MI/R) injury. However, the underlying mechanisms are still not clear. Myocardial reperfusion injury salvage kinase (RISK) pathway as well as survivor activating factor enhancement (SAFE) pathway are two pivotal intrinsic pro-survival signaling cascades. In this study, we performed in vivo and in vitro experiment to investigate the ameliorative effect of melatonin on ER stress with a focus on RISK and SAFE pathways interaction. Male C57Bl/6 mice received melatonin (300 µg/25 g/day, 3 days before MI/R surgery; 300 µg/25 g, 25 min before the onset of ischemia) pre-treatment with or without the administration of LY294002 (a PI3K/Akt inhibitor), U0126 (an ERK1/2 inhibitor) or AG490 (a STAT3 pathway inhibitor). H9c2 cells were pre-treated with melatonin (100 µM, 8 h) in the presence or absence of LY294002, U0126 or AG490. Compared with the I/R-injured group, melatonin effectively reduced myocardial apoptosis, oxidative stress and improved cardiac function. In addition, melatonin pre-treatment also increased the phosphorylation of Akt, GSK-3ß, ERK1/2 and STAT3 and reduced PERK-eIF2α-ATF4-mediated ER stress. However, these effects were blocked by LY294002, U0126 or AG490. Additionally, either LY294002 or U0126 treatment could inhibit STAT3 phosphorylation, whereas AG490 administration also reduced both Akt and ERK1/2 phosphorylation, indicating an interplay exists between RISK and SAFE pathways in melatonin's cardioprotective effect. In summary, our study demonstrates that RISK and SAFE pathways mediate the cardioprotective effect of melatonin against MI/R injury. Melatonin pre-treatment attenuates PERK-eIF2α-ATF4-mediated ER stress and apoptosis during MI/R injury via RISK and SAFE pathways interaction.

Berberine protects rat heart from ischemia/reperfusion injury via activating JAK2/STAT3 signaling and attenuating endoplasmic reticulum stress.

AIM: Berberine (BBR), an isoquinoline-derived alkaloid isolated from Rhizoma coptidis, exerts cardioprotective effects. Because endoplasmic reticulum (ER) stress plays a pivotal role in myocardial ischemia/reperfusion (MI/R)-induced apoptosis, it was interesting to examine whether the protective effects of BBR resulted from modulating ER stress levels during MI/R injury, and to define the signaling mechanisms in this process. METHODS: Male rats were treated with BBR (200 mg · kg(-1) · d(-1), ig) for 2 weeks, and then subjected to MI/R surgery. Cardiac dimensions and function were assessed using echocardiography. Myocardial infarct size and apoptosis was examined. Total serum LDH levels and CK activities, superoxide production, MDA levels and the antioxidant SOD activities in heart tissue were determined. An in vitro study was performed on cultured rat embryonic myocardium-derived cells H9C2 exposed to simulated ischemia/reperfusion (SIR). The expression of apoptotic, ER stress-related and signaling proteins were assessed using Western blot analyses. RESULTS: Pretreatment with BBR significantly reduced MI/R-induced myocardial infarct size, improved cardiac function, and suppressed myocardial apoptosis and oxidative damage. Furthermore, pretreatment with BBR suppressed MI/R-induced ER stress, evidenced by down-regulating the phosphorylation levels of myocardial PERK and eIF2α and the expression of ATF4 and CHOP in heart tissues. Pretreatment with BBR also activated the JAK2/STAT3 signaling pathway in heart tissues, and co-treatment with AG490, a specific JAK2/STAT3 inhibitor, blocked not only the protective effects of BBR, but also the inhibition of BBR on MI/R-induced ER stress. In H9C2 cells, treatment with BBR (50 µmol/L) markedly reduced SIR-induced cell apoptosis, oxidative stress and ER stress, which were abolished by transfection with JAK2 siRNA. CONCLUSION: BBR ameliorates MI/R injury in rats by activating the AK2/STAT3 signaling pathway and attenuating ER stress-induced apoptosis.

[Proanthocyanidin protects H9C2 cells against hypoxia/reoxygenation injury via JAK2/STAT3 signaling pathway].

The present study was aimed to investigate the underlying mechanisms of the protective effect of proanthocyanidin (Pro) against hypoxia/reoxygenation (H/R) injury in H9C2 cells with a focus on Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling pathway. H9C2 cells were randomly assigned to 5 groups, including the control group (Con), the H/R-injured group (H/R), the Pro-treated group (H/R+Pro), the JAK2 siRNA-treated group (H/R+Pro+JAK2 siRNA) and the JAK2 siRNA control group (H/R+JAK2 siRNA). The cells were pretreated with Pro (40 µmol/L) for 8 h before 2 h of hypoxia and 4 h of reoxygenation. Cellular viability and apoptosis rate were detected by MTT and TUNEL methods, and superoxide generation was measured. JAK2/STAT3 signaling, oxidative stress markers and endoplasmic reticulum stress markers were also detected by Western blot. We found that Pro treatment significantly improved cellular viability and reduced apoptosis rate in H/R-treated H9C2 cells. In addition, Pro treatment significantly up-regulated the phosphorylation levels of JAK2 and STAT3, down-regulated the superoxide generation, gp91phox, glucose-regulated protein 78 (GRP78), CCAAT/enhancer binding protein homologous protein (CHOP) and caspase-12 expression. However, these protective effects of Pro were all attenuated by JAK2 siRNA administration. Taken together, we demonstrated that Pro protects H9C2 cells against H/R-induced oxidative stress and endoplasmic reticulum stress injury via JAK2/STAT3 signaling pathway.

Protective effect of berberine against myocardial ischemia reperfusion injury: role of Notch1/Hes1-PTEN/Akt signaling.

Berberine (BBR) confers cardioprotective effect against myocardial ischemia reperfusion injury (MI/RI). Activation of Notch1/Hairy and enhancer of split 1 (Hes1) signaling also reduces MI/RI. We hypothesize that BBR may protect against MI/RI by modulating Notch1/Hes1-Phosphatase and tensin homolog deleted on chromosome ten (PTEN)/Akt signaling. In this study, male Sprague-Dawley rats were exposed to BBR treatment (200 mg/kg/d) for 2 weeks and then subjected to MI/RI. BBR significantly improved cardiac function recovery and decreased myocardial apoptosis, infarct size, serum creatine kinase and lactate dehydrogenase levels. Furthermore, in cultured H9c2 cardiomyocytes, BBR (50 µmol/L) attenuated simulated ischemia/reperfusion-induced myocardial apoptosis. Both in vivo and in vitro study showed that BBR treatment up-regulates Notch1 intracellular domain, Hes1, Bcl-2 expression and p-Akt/Akt ratio, down-regulates Bax Caspase-3 and cleaved Caspase-3 expression. However, the anti-apoptotic effect conferred by BBR was blocked by Notch1 siRNA, Hes1 siRNA or LY294002 (the specific inhibitor of Akt signaling) in the cultured cardiomyocytes. In summary, our results demonstrate that BBR treatment attenuates MI/RI by modulating Notch1/Hes1-PTEN/Akt signaling.

Membrane receptor-dependent Notch1/Hes1 activation by melatonin protects against myocardial ischemia-reperfusion injury: in vivo and in vitro studies.

Melatonin confers profound protective effect against myocardial ischemia-reperfusion injury (MI/RI). Activation of Notch1/Hairy and enhancer of split 1 (Hes1) signaling also ameliorates MI/RI. We hypothesize that melatonin attenuates MI/RI-induced oxidative damage by activating Notch1/Hes1 signaling pathway with phosphatase and tensin homolog deleted on chromosome 10 (Pten)/Akt acting as the downstream signaling pathway in a melatonin membrane receptor-dependent manner. Male Sprague Dawley rats were treated with melatonin (10 mg/kg/day) for 4 wk and then subjected to MI/R surgery. Melatonin significantly improved cardiac function and decreased myocardial apoptosis and oxidative damage. Furthermore, in cultured H9C2 cardiomyocytes, melatonin (100 µmol/L) attenuated simulated ischemia-reperfusion (SIR)-induced myocardial apoptosis and oxidative damage. Both in vivo and in vitro study demonstrated that melatonin treatment increased Notch1, Notch1 intracellular domain (NICD), Hes1, Bcl-2 expressions, and p-Akt/Akt ratio and decreased Pten, Bax, and caspase-3 expressions. However, these protective effects conferred by melatonin were blocked by DAPT (the specific inhibitor of Notch1 signaling), luzindole (the antagonist of melatonin membrane receptors), Notch1 siRNA, or Hes1 siRNA administration. In summary, our study demonstrates that melatonin treatment protects against MI/RI by modulating Notch1/Hes1 signaling in a receptor-dependent manner and Pten/Akt signaling pathways are key downstream mediators.

Reduced silent information regulator 1 signaling exacerbates myocardial ischemia-reperfusion injury in type 2 diabetic rats and the protective effect of melatonin.

Diabetes mellitus (DM) increases myocardial oxidative stress and endoplasmic reticulum (ER) stress. Melatonin confers cardioprotective effect by suppressing oxidative damage. However, the effect and mechanism of melatonin on myocardial ischemia-reperfusion (MI/R) injury in type 2 diabetic state are still unknown. In this study, we developed high-fat diet-fed streptozotocin (HFD-STZ) rat, a well-known type 2 diabetic model, to evaluate the effect of melatonin on MI/R injury with a focus on silent information regulator 1 (SIRT1) signaling, oxidative stress, and PERK/eIF2α/ATF4-mediated ER stress. HFD-STZ treated rats were exposed to melatonin treatment in the presence or the absence of sirtinol (a SIRT1 inhibitor) and subjected to MI/R surgery. Compared with nondiabetic animals, type 2 diabetic rats exhibited significantly decreased myocardial SIRT1 signaling, increased apoptosis, enhanced oxidative stress, and ER stress. Additionally, further reduced SIRT1 signaling, aggravated oxidative damage, and ER stress were found in diabetic animals subjected to MI/R surgery. Melatonin markedly reduced MI/R injury by improving cardiac functional recovery and decreasing myocardial apoptosis in type 2 diabetic animals. Melatonin treatment up-regulated SIRT1 expression, reduced oxidative damage, and suppressed PERK/eIF2α/ATF4 signaling. However, these effects were all attenuated by SIRT1 inhibition. Melatonin also protected high glucose/high fat cultured H9C2 cardiomyocytes against simulated ischemia-reperfusion injury-induced ER stress by activating SIRT1 signaling while SIRT1 siRNA blunted this action. Taken together, our study demonstrates that reduced cardiac SIRT1 signaling in type 2 diabetic state aggravates MI/R injury. Melatonin ameliorates reperfusion-induced oxidative stress and ER stress via activation of SIRT1 signaling, thus reducing MI/R damage and improving cardiac function.

Impact of job control on hospital workers' safety performance: A moderated mediation analysis of the influences of hospital safety climate and social support.

AIM: To improve the level of hospital workers' safety performance in response to emergencies (e.g. COVID-19), this paper examines the relationship between hospital workers' job control on safety performance, and the mediating role of hospital safety climate and the moderating role of social support. DESIGN: In this cross-sectional questionnaire survey, a convenience sampling of hospital workers from three hospitals that have COVID-19 cases from Beijing and Shandong Province in China. METHODS: These questionnaires were used to obtain self-reported data on hospital workers' job control, hospital safety climate, social support and safety performance. Mplus software was used to calculate CFA. SPSS25.0 software was used to calculate mean values, standard deviations, correlations and regression analyses. RESULTS: The participants were 241 hospital workers from three hospitals in China (male = 55.2%, female = 44.8%; age range <30 to >45; physician = 58%, nurse = 22%, other hospital worker = 20%). A moderated mediation model among job control, hospital safety climate, social support and safety performance was supported. Moderated mediation analysis indicates hospital workers' job control effectively improves the level of safety performance; hospital safety climate plays a partially mediating role in the process of job control affecting hospital workers' safety performance; social support moderates the effect of work control on medical workers' safety climate. Hence, it is important to increase job control and hospital safety climate. Further, social support for hospital workers should be encouraged, advocated and supported.

Effects of shared governance and cost redistribution on air pollution control: a study of game theory-based cooperation.

This study seeks cost-effective strategies for PM2.5 reduction to generate insights into minimizing pollution abatement costs subject to different scenarios. This study theorizes that the cooperation of PM2.5 abatement has potential gains for participants and develop an empirical way to compare the costs and efficiency of PM2.5 abatement involving the variation of environmental conditions. This study revises the cooperative game model in the context of threshold effects using data obtained from the Beijing-Tianjin-Hebei metropolitan cluster in China. In general, the results support the key assertion that cooperation in the metropolitan cluster plays a vital role in optimizing the efficiency and costs of PM2.5 abatement. In addition to extending the application of the revised model, this study provides a way to estimate the costs and the mitigation benefits of meeting the pollution targets for each coparticipant and take the scenario of multiparty cooperation into account as well as the scenarios involving other types of pollutants. The empirical findings have important policy implications for regional shared governance, decentralization, and resource reallocation. Economic incentive-based shared governance and cost reallocation work better than traditional regulations.

Effect of Cutting Surface Integrity on Fatigue Properties of TC17 Titanium Alloy.

The turning process of titanium alloy material will affect the surface structure of the material and lead to a change in its service life. In this paper, the fatigue behavior of the TC17 titanium alloy turning sample was studied through the bending fatigue test. The fatigue life variation rule under the action of thermal coupling was then discussed. This revealed the fatigue fracture mechanism of TC17; the cracks originated from the surface of the source region, and the transient fault region was a ductile fracture. The mathematical model of turning parameters and surface integrity (roughness, microhardness and residual stress) was established, and the influence of turning parameters on fatigue life was analyzed with a mathematical relationship. Drawing a conclusion, the effects of turning parameters on fatigue life at normal temperature are as follows: Feed > Cutting depth > Cutting speed. The fatigue life of vc = 30 m/min, f = 0.25 mm/r, ap = 0.3 mm is only 40,586 cycles per week, the fatigue life of vc = 30 m/min, f = 0.05 mm/r, ap = 0.1 mm has 539,400 cycles per week, that is, the longest fatigue life is 16.6 times the smallest. Small cutting speed, feed, and large cut depth can be chosen based on ensuring practical processing efficiency. The fatigue fracture of the TC17 sample occurred after a certain cycle, and the fatigue fracture mechanism was revealed in this paper.

Measurement of Creep Stress Exponent of TC17 Titanium Alloy by Nanoindentation Method at Room Temperature.

The creep stress exponent is commonly employed to characterize the deformation mechanism during the steady-state creep stage, serving as an indicator of creep behavior. The creep phenomenon of high melting point metallic materials is not obvious at room temperature. However, the nanoindentation method proves suitable for investigating the creep properties of metallic materials under such conditions. Consequently, this paper places emphasis on measuring the creep stress exponent of TC17 titanium alloy at room temperature using the load preservation stage of the nanoindentation method with a constant loading rate. In order to investigate the effects of loading rate and maximum load on the experimental results, different loading rates were applied to the diamond Berkovich indenter to reach different maximum loads. The indenter was held under the maximum load for a duration of 360 s, and the relationship between the indentation strain rate and indentation stress during the holding process was used to obtain the creep stress exponent of the material at room temperature. The findings indicate that within the loading rate range of 1.25 to 15 mN/s and maximum load range of 50 to 300 mN, the influence on the experimental results is insignificant. Ultimately, the distribution range of the creep stress exponent for TC17 titanium alloy at room temperature was measured to be 8.524-8.687.

Research on Surface Integrity and Fatigue Properties in the Turning of TC17 Titanium Alloy Based on the Response Surface Method.

Titanium alloy parts are more and more widely used in the field of aerospace. In order to improve the service life of titanium alloy parts, the response surface method was used to study surface residual stress and roughness under different turning parameters. In addition, a mathematical model was established through multiple linear regression to determine the relationship between surface integrity parameters and fatigue life. The test results indicate that the turning parameters have an effect on surface residual stress in the order of feed rate > depth of cut > cutting speed and on surface roughness in the order of feed rate > cutting speed > depth of cut. The analysis results of surface integrity show that the residual compressive stress on the surface has the greatest impact on fatigue life, followed by surface roughness. The fatigue life increases with the increase in residual compressive stress and decreases linearly with the increase in surface roughness. The feed rate has a significant impact on residual stress and surface roughness. Therefore, under the experimental conditions of this paper, the appropriate feed rate can be selected to ensure that the Ra < 2 µm and a large residual compressive stress is obtained.

Job Control and Employee Innovative Behavior: A Moderated Mediation Model.

The revolution of self-management and organizational democracy is gaining momentum with the development of new technologies. How to stimulate high employee innovation behavior is critical to an organization's success. In this study, we built and verified a theoretical model to explore the effect of job control (JC) on employee innovative behavior (EIB), the mediating effect of creative self-efficacy (CSE), and the moderating effect of mindfulness (MF), based on the self-determination theory (SDT). For this quantitative study, a 31-item questionnaire was used to collect data from five Internet companies with 329 Chinese employees. AMOS 24.0 software was used to calculate CFA. SPSS26.0 software was used to calculate means, standard deviations, correlations, and regression analysis. The results indicate that a moderated mediation model among JC, CSE, EIB, and MF is supported. Further, JC was positively related to EIB via CSE. Moreover, MF moderated the relationship between JC and EIB and the mediating role of CSE.

Research on Clamping Action Control Technology for Floating Fixtures.

By adaptively releasing deformation during machining, floating clamping significantly raises the machining quality of aircraft structural parts. The fundamental issue to be resolved is how to precisely control the clamping action of the floating fixtures. In this study, the machining process of aircraft beams was studied, utilizing the finite element method (FEM) from the perspective of strain energy evolution. The study found that the increment of deformation and the variation of the strain energy between adjacent removed layers of the material showed the same trend of change, and targeted clamping loosening at the stage of an excessive strain energy evolution gradient is beneficial to reducing the final deformation of the workpiece. Therefore, a clamping action control method based on strain energy evolution gradient regulation is proposed, and a clamping action control strategy of floating fixtures was formulated. Furthermore, a cutting experiment was carried out, and the results showed that the maximum deformation of the aircraft beam using the clamping action control strategy was only 0.112 mm, which was reduced by 74.6% compared to traditional clamping.

Design, synthesis and promising anti-tumor efficacy of novel imidazo[1,2-a]pyridine derivatives as potent autotaxin allosteric inhibitors.

Aiming to track the potential antitumor effect of novel allosteric autotaxin (ATX) inhibitors, a hybrid strategy was utilized by merging ATX inhibitors PF-8380 and GLPG1690, while the piperazinyl group in GLPG1690 was replaced with benzene ring to furnish imidazo[1,2-a]pyridine derivatives 10ã10k. Based on ATX enzymatic assay, we further changed the substituents within benzyl carbamate moiety and tuned the carbamate linker to urea group. Delightfully, compound 10c bearing a N-hydroxyethyl piperazinyl group was identified as the optimal ATX inhibitor with an IC50 value of 3.4 nM 10c exerted the most impressive antitumor effects, especially on Hep3B (0.58 µM) and RAW264.7 (0.63 µM) cell lines highly expressing ATX mRNA. Moreover, 10c could dose-dependently suppress the RAW264.7 cell migration rate in wound healing assay and significantly inhibit RAW264.7 cell colony formation. Meanwhile, 10c was capable of inducing weak to moderate apoptosis and achieved notable G2 phase arrest on RAW264.7 cells. Taken together, 10c may serve as a novel lead to probe possible role of ATX allosteric inhibitors in tumor diseases.

Estimation of Machining Sustainability Using Fuzzy Rule-Based System.

Quantification of a highly qualitative term 'sustainability', especially from the perspective of manufacturing, is a contemporary issue. An inference mechanism, based on approximate reasoning, is required to tackle the complexities and uncertainties of the manufacturing domain. The work presents development of a fuzzy rule-based system to quantify sustainability of the most widely utilized manufacturing process: machining. The system incorporates the effects of key control parameters of machining on several sustainability measures, as reported in the literature. The measures are categorized under the three dimensions of sustainability and contribute to the sustainability scores of the respective dimensions with different weightages. The dimensions' scores are added up in different proportions to obtain the holistic sustainability score of the process. The categories of the control parameters incorporated into the system include type of the process, work material, material hardness, tool substrate and coating, tool geometry, cutting fluids, and cutting parameters. The proposed method yields sustainability scores, ranging between 0 and 100 of machining processes against the given values of their prominent control parameters. Finally, the rule-based system is applied to three different machining processes to obtain the measures of their accomplishment levels regarding economic, environmental, and societal dimensions of sustainability. The sustainability score of each process is then obtained by summing up the three accomplishment levels under the respective weightages of the dimensions. The presented approach holds immense potentials of industrial application as it can conveniently indicate the current sustainability level of a manufacturing process, leading the practitioners to decide on its continuation or improvement.

Experimental Study on Fabrication of CVD Diamond Micro Milling Tool by Picosecond Pulsed Laser.

Because of the many advantages of high-precision micromachining, picosecond pulsed lasers (PSPLs) can be used to process chemical-vapor-deposited diamonds (CVD-D). With the appropriate PSPL manufacturing technique, sharp and smooth edges of CVD-D micro tools can be generated. In this study, a PSPL is used to cut CVD-D. To optimize PSPL cutting, the effects of its parameters including fluence, pulse pitch, and wavelength on the cutting results were investigated. The results showed that the wavelength had the greatest impact on the sharpness of CVD-D. With PSPL cutting, sharp cutting edges, and smooth fabricated surfaces of the CVD-D, micro tools were achieved. Finally, the fabrication of CVD-D micro milling tools and micro milling experiments were also demonstrated.