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.

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.

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.

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.

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.

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.

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.

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.

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.

On Coolant Flow Rate-Cutting Speed Trade-Off for Sustainability in Cryogenic Milling of Ti-6Al-4V.

Application of cryogenic fluids for efficient heat dissipation is gradually becoming part and parcel of titanium machining. Not much research is done to establish the minimum quantity of a cryogenic fluid required to sustain a machining process with respect to a given material removal rate. This article presents an experimental investigation for quantifying the sustainability of milling a commonly used titanium alloy (Ti-6Al-4V) by varying mass flow rates of two kinds of cryogenic coolants at various levels of cutting speed. The three cooling options tested are dry (no coolant), evaporative cryogenic coolant (liquid nitrogen), and throttle cryogenic coolant (compressed carbon dioxide gas). The milling sustainability is quantified in terms of the following metrics: tool damage, fluid cost, specific cutting energy, work surface roughness, and productivity. Dry milling carried out the at the highest level of cutting speed yielded the worst results regarding tool damage and surface roughness. Likewise, the evaporative coolant applied with the highest flow rate and at the lowest cutting speed was the worst performer with respect to energy consumption. From a holistic perspective, the throttle cryogenic coolant applied at the highest levels of mass flow rate and cutting speed stood out to be the most sustainable option.

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.

Between-the-Holes Cryogenic Cooling of the Tool in Hole-Making of Ti-6Al-4V and CFRP.

Lightweight materials are finding plentiful applications in various engineering sectors due to their high strength-to-weight ratios. Hole-making is an inevitable requirement for their structural applications, which is often marred by thermal damages of the drill causing unacceptable shortening of tool life. Efficient cooling of the tool is a prime requirement for enhancing the process viability. The current work presents a novel technique of cooling only the twist drill between drilling of holes with no effect of the applied cryogenic coolant transferred to the work material. The technique is applied in the drilling of two commonly used high-strength lightweight materials: carbon fibers reinforced polymer (CFRP) and an alloy of titanium (Ti-6Al-4V). The efficacy of the cooling approach is compared with those of conventionally applied continuous cryogenic cooling and no-cooling. The effectiveness is quantified in terms of tool wear, thrust force, hole quality, specific cutting energy, productivity, and consumption of the cryogenic fluid. The experimental work leads to a finding that between-the-holes cryogenic cooling possesses a rich potential in curbing tool wear, reducing thrust force and specific energy consumption, and improving hole quality in drilling of CFRP. Regarding the titanium alloy, it yields a much better surface finish and lesser consumption of specific cutting energy.

Core Self-Evaluations Increases Among Chinese Employees: A Cross-Temporal Meta-Analysis, 2010-2019.

The purpose of this paper is to investigate the changes in core self-evaluation (CSE) scores among Chinese employees during 2010-2019. We conducted a cross-temporal meta-analysis including 50 studies (17,400 Chinese employees) to evaluate the relationship between the year of data collection and levels of CSE. We found that correlations between levels of CSE and year of data collection were strong and positive (r > 0.500). Regression results showed that the year of data collection could predict the CSE score when the mean sample age and sex ratio (%female) were controlled. In addition, CSE scores were positively related to GDP per capita and negatively related to the unemployment rate.

Cytoplasm Types Affect DNA Methylation among Different Cytoplasmic Male Sterility Lines and Their Maintainer Line in Soybean (Glycine max L.).

Cytoplasmic male sterility (CMS) lines and their maintainer line have the same nucleus but different cytoplasm types. We used three soybean (Glycine max L.) CMS lines, JLCMS9A, JLCMSZ9A, and JLCMSPI9A, and their maintainer line, JLCMS9B, to explore whether methylation levels differed in their nuclei. Whole-genome bisulfite sequencing of these four lines was performed. The results show that the cytosine methylation level in the maintainer line was lower than in the CMS lines. Compared with JLCMS9B, the Gene Ontology (GO) enrichment analysis of DMR (differentially methylated region, DMR)-related genes of JLCMS9A revealed that their different 5-methylcytosine backgrounds were enriched in molecular function, whereas JLCMSZ9A and JLCMSPI9A were enriched in biological process and cellular component. The Kyoto Encyclopedia of Genes and Genome (KEGG) analysis of DMR-related genes and different methylated promoter regions in different cytosine contexts, hypomethylation or hypermethylation, showed that the numbers of DMR-related genes and promoter regions were clearly different. According to the DNA methylation and genetic distances separately, JLCMS9A clustered with JLCMS9B, and JLCMSPI9A with JLCMSZ9A. Thus, the effects of different cytoplasm types on DNA methylation were significantly different. This may be related to their genetic distances revealed by re-sequencing these lines. The detected DMR-related genes and pathways that are probably associated with CMS are also discussed.

Autologous ilium graft combination with Y-shaped titanium plate fixation for chest wall reconstruction after resection of primary sternal tumors-a clinical study from three institutions.

BACKGROUND: The technique for anterior chest wall reconstruction after resection of primary sternal tumors (PST) still continue to evolve. METHODS: A total of 12 PST patients from three hospitals who underwent en-bloc resection were included in our study. After finishing sternum resection, autologous iliac bone combined with Y-shaped titanium plate were applied to rebuild the anterior chest wall. Postoperative outcomes were analyzed. RESULTS: There were 10 different types of tumors located in manubrium (6 cases), sternum body (4 cases) and Louis's angle (2 cases) in our research. For these patients, the median resected tumor size and the area of defect after sternal resection were 279.0 cm3 and 215.0 cm2, respectively. The mean operative time was 299.2±65.2 min and intra-operative blood loss was 431.2±213.0 mL. Mean duration of drainage was 9.9±2.6 days. In their perioperative period, significant circulatory and respiratory complications occurred in 8 patients. Postoperative chest X-ray and tridimensional CT images showed autogenous reconstruction of the sternum and titanium in good position. No side effects were observed 6-12 months post reconstructive surgery, but one patient suffered from anchor loss and prosthesis migration. Y-shaped titanium plates from two patients were separately removed at 24 and 26 months when the reconstructive sternum integrated with skeleton anterior chest wall well. CONCLUSIONS: Our study demonstrates the safety and feasibility of this new technique for anterior chest wall reconstruction after sternectomies.

Experimental Investigation on Direct Micro Milling of Cemented Carbide.

Cemented carbide is currently used for various precise molds and wear resistant parts. However, the machining of cemented carbide still is a difficult challenge due to its superior mechanical properties. In this paper, an experimental study was conducted on direct micro milling of cemented carbide with a polycrystalline diamond (PCD) micro end mill. The cutting force characteristics, surface formation, and tool wear mechanisms were systematically investigated. Experimental results show that cemented carbide can be removed with ductile cutting utilizing the PCD tool with a large tool tip radius. Micro burrs, brittle pits, and cracks are the observed surface damage mechanisms. The tool wear process presents microchipping on the cutting edge and exfoliating on the rake face in the early stage, and then severe abrasive and adhesive wear on the bottom face in the following stage.

Honokiol induces endoplasmic reticulum stress-mediated apoptosis in human lung cancer cells.

AIMS: Honokiol is a hydroxylated biphenyl natural product and displays potent antitumor activity against several cancers including prostate cancer, melanoma, leukemia, and colorectal cancer. The present study was to investigate the in vitro activity of honokiol against A549 and 95-D human lung cancer cells. MAIN METHODS: A549 and 95-D cells were used with honokiol treatment. Cell viability was determined by CCK-8 assay. The cell migration and apoptosis were evaluated by wound healing assay and TUNEL staining method respectively. The expressions of ER-related proteins were analyzed by western blot and the CHOP siRNA was used to downregulate the CHOP expression. KEY FINDINGS: The results demonstrated that treatment of A549 and 95-D cells with honokiol significantly reduced cell viability in a dose- and time-dependent manner. Furthermore, honokiol treatment decreased cell migration and enhanced cell apoptosis, which is accompanied by the upregulation of the expressions of ER stress-induced apoptotic signaling molecules such as GRP78, phosphorylated PERK, phosphorylated eIF2α, CHOP, Bcl-2, Bax, and cleaved Caspase 9. Honokiol treatment-induced increase of ER stress-related signaling molecules and apoptotic proteins in A549 and 95-D cells were reversed by CHOP siRNA. SIGNIFICANCE: Collectively, we conclude that ER stress may participate in the action of the anticancer activity of honokiol in A549 and 95-D cells and induction of ER stress-related apoptosis may represent a novel therapeutic intervention for human lung cancer.