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Abstract In view of the problem of poor coupling adaptability and easy rib spalling of coal wall in large mining height comprehensive mining, based on the effective inhibition effect of face guard mechanism on coal wall spalling, the structural characteristics and bearing capacity of different structural forms of the face guard mechanism are compared and analyzed. According to the surrounding rock adaptability of the face guard mechanism, established a numerical analysis model for rigid-flexible coupling of the face guard mechanism under different spalling forms. In order to accurately simulate the stress state of the protective mechanism, a variable stiffness spring damping system is used to replace the hydraulic cylinder. The load-bearing performance and response characteristics of the face guard mechanism under rib spalling coupling conditions were analyzed by applying uniform normal load and impact load to the face guard. The findings indicated that, the integral-type face guard mechanism has a better effect on suppressing rib spalling. When the face guard mechanism bears the static load of the coal wall, the entire response process of the face guard jack can be divided into three stages: initial support, increasing resistance bearing, constant resistance bearing; both the impact load position and the coupling state of the rib spalling will affect the characteristics of force transmission at the face guard mechanism’s hinge point, the hinge point between the extensible canopy and the primary face guard is most sensitive to biased load. The research results can provide reference for optimizing the face guard mechanism of large mining height hydraulic support and improving the reliability of coal wall support.

BackgroundStudies have shown that gut dysbiosis contributes to the pathophysiology of type 2 diabetes mellitus (T2DM). Identifying specific gut microbiota dysbiosis may provide insight into the pathogenesis of T2DM.PurposeThis study investigated the causal relationship between gut microbiota and T2DM using meta-analysis and Mendelian randomization (MR).MethodsIn the first part, we searched for literature on gut microbiota and T2DM, and conducted a meta-analysis. We observed differences in glycosylated hemoglobin and fasting blood glucose levels in both groups. Second, we obtained GWAS data from genome-wide association study database 19 (GWAS). We used two-sample MR analysis to verify the forward and reverse causal associations between gut microbiota and T2DM. Additionally, we selected the European GWAS data from the European Bioinformatics Institute (EBI) as a validation set for external validation of the MR analysis. In the third part, we aimed to clarify which gut microbiota contribute to the degree of causal association between group disorders and T2DM through multivariate MR analysis and Bayesian model averaging (MR-BMA).Results1. According to the meta-analysis results, the glycated hemoglobin concentration in the gut probiotic intervention group was significantly lower than in the control group. Following treatment, fasting blood glucose levels in the intervention group were significantly lower than those in the control group. 2. The results of two samples MR analysis revealed that there were causal relationships between six gut microbiota and T2DM. Genus Haemophilus and order Pasteurellaceae were negatively correlated with T2DM. Genus Actinomycetes, class Melanobacteria and genus Lactobacillus were positively correlated. Reverse MR analysis demonstrated that T2DM and gut microbiota did not have any reverse causal relationship. The external validation data set showed a causal relationship between gut microbiota and T2DM. 3. Multivariate MR analysis and MR-BMA results showed that the independent genus Haemophilus collection had the largest PP.ConclusionOur research results suggest that gut microbiota is closely related to T2DM pathogenesis. The results of further MR research and an analysis of the prediction model indicate that a variety of gut microbiota disorders, including genus Haemophilus, are causally related to the development of T2DM. The findings of this study may provide some insight into the diagnosis and treatment of T2DM.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO

Abstract Macrophages play an important role as effector cells in innate immune system. Meanwhile, macrophages activated in a pro-inflammatory direction alter intracellular metabolism and damage intact tissues by increasing reactive oxygen species (ROS). Electrical stimulation (ES), a predominant physical agent to control metabolism in cells and tissues, has been reported to exert anti-inflammatory effect on immune cells. However, the mechanism underlying the anti-inflammatory effects by ES is unknown. This study aimed to investigate the effect of ES on metabolism in glycolytic-tricarboxylic acid cycle (TCA) cycle and inflammatory responses in macrophages. ES was performed on bone marrow-derived macrophages and followed by a stimulation with LPS. The inflammatory cytokine expression levels were analyzed by real-time polymerase chain reaction and ELISA. ROS production was analyzed by CellRox Green Reagent and metabolites by capillary electrophoresis-mass spectrometry. As a result, ES significantly reduced proinflammatory cytokine expression levels and ROS generation compared to the LPS group and increased glucose-1-phosphate, a metabolite of glycogen. ES also increased intermediate metabolites of the pentose phosphate pathway (PPP); ribulose-5-phosphate, rebose-5 phosphate, and nicotinamide adenine dinucleotide phosphate, a key factor of cellular antioxidation systems, as well as α-Ketoglutarate, an anti-oxidative metabolite in the TCA cycle. Our findings imply that ES enhanced NADPH production with enhancement of PPP, and also decreased oxidative stress and inflammatory responses in macrophages.

The regulation of inflammatory responses is an important intervention in biological function and macrophages play an essential role during inflammation. Skeletal muscle is the largest organ in the human body and releases various factors which mediate anti-inflammatory/immune modulatory effects. Recently, the roles of extracellular vesicles (EVs) from a large variety of cells are reported. In particular, EVs released from skeletal muscle are attracting attention due to their therapeutic effects on dysfunctional organs and tissues. Also, ultrasound (US) promotes release of EVs from skeletal muscle. In this study, we investigated the output parameters and mechanisms of US-induced EV release enhancement and the potential of US-treated skeletal muscle-derived EVs in the regulation of inflammatory responses in macrophages. High-intensity US (3.0 W/cm2) irradiation increased EV secretion from C2C12 murine muscle cells via elevating intracellular Ca2+ level without negative effects. Moreover, US-induced EVs suppressed expression levels of pro-inflammatory factors in macrophages. miRNA sequencing analysis revealed that miR-206-3p and miR-378a-3p were especially abundant in skeletal myotube-derived EVs. In this study we demonstrated that high-intensity US promotes the release of anti-inflammatory EVs from skeletal myotubes and exert anti-inflammatory effects on macrophages.

Ischemic stroke, a primary cause of disability and the second leading cause of mortality, has emerged as an urgent public health issue. Growing evidence suggests that the Cyclic GMP-AMP synthase (cGAS)- Stimulator of interferon genes (STING) pathway, a component of innate immunity, is closely associated with microglia activation, neuroinflammation, and regulated cell death in ischemic stroke. However, the mechanisms underlying this pathway remain inadequately understood. This article comprehensively reviews the existing literature on the cGAS-STING pathway and its multifaceted relationship with ischemic stroke. Initially, it examines how various risk factors and pre-disease mechanisms such as metabolic dysfunction and senescence (e.g., hypertension, hyperglycemia, hyperlipidemia) affect the cGAS-STING pathway in relation to ischemic stroke. Subsequently, we explore in depth the potential pathophysiological relationship between this pathway and oxidative stress, endoplasmic reticulum stress, neuroinflammation as well as regulated cell death including ferroptosis and PANoptosis following cerebral ischemia injury. Finally, it suggests that intervention targeting the cGAS-STING pathway may serve as promising therapeutic strategies for addressing neuroinflammation associated with ischemic stroke. Taken together, this review concludes that targeting the microglia cGAS-STING pathway may shed light on the exploration of new therapeutic strategies against ischemic stroke.

IntroductionMacrophages play an important role in the innate immunity. While macrophage inflammation is necessary for biological defense, it must be appropriately controlled. Extracellular vesicles (EVs) are small vesicles released from all types of cells and play a central role in intercellular communication. Skeletal muscle has been suggested to release anti-inflammatory factors, but the effect of myotube-derived EVs on macrophages is unknown. As an anti-inflammatory mechanism of macrophages, the immune responsive gene 1 (IRG1)-itaconate pathway is essential. In this study, we show that skeletal muscle-derived EVs suppress macrophage inflammatory responses, upregulating the IRG1-itaconate pathway.MethodsC2C12 myoblasts were differentiated into myotubes and EVs were extracted by ultracentrifugation. Skeletal myotube-derived EVs were administered to mouse bone marrow-derived macrophages, then lipopolysaccharide (LPS) stimulation was performed and inflammatory cytokine expression was measured by RT-qPCR. Metabolite abundance in macrophages after addition of EVs was measured by CE/MS, and IRG1 expression was measured by RT-PCR. Furthermore, RNA-seq analysis was performed on macrophages after EV treatment.ResultsEVs attenuated the expression of LPS-induced pro-inflammatory factors in macrophages. Itaconate abundance and IRG1 expression were significantly increased in the EV-treated group. RNA-seq analysis revealed activation of the PI3K-Akt and JAK-STAT pathways in macrophages after EV treatment. The most abundant miRNA in myotube EVs was miR-206-3p, followed by miR-378a-3p, miR-30d-5p, and miR-21a-5p.DiscussionSkeletal myotube EVs are supposed to increase the production of itaconate via upregulation of IRG1 expression and exhibited an anti-inflammatory effect in macrophages. This anti-inflammatory effect was suggested to involve the PI3K-Akt and JAK-STAT pathways. The miRNA profiles within EVs implied that miR-206-3p, miR-378a-3p, miR-30d-5p, and miR-21a-5p may be responsible for the anti-inflammatory effects of the EVs. In summary, in this study we showed that myotube-derived EVs prevent macrophage inflammatory responses by activating the IRG1-itaconate pathway.

The wheel–rail interaction will be intensified on account of the complexity of the wheel–rail contact geometry on a curved track. It also may become more complicated and/or have significant difference as the train speed increases, since the dynamic effects cannot be ignored then. In this study, based on explicit Finite Element (FE) software LS-DYNA 971, a Three-Dimensional (3D) elastic-plastic FE model was built to simulate the dynamic wheel–rail contact behaviour of curve negotiating, where the superelevation and roll angle as well as the strain rate effect were considered. The evolution of contact patch and pressure, wheel–rail contact force, the stress/strain state and the acceleration of the axle were employed to examine the wheel–rail transient dynamic response. Furthermore, the influences of axle load, curve radius and strain rate effect were also discussed. It is found that the maximum vertical contact force, contact pressure, stress and strain on the curved track increase with the decreasing curve radius, and they increase with the increasing axle load except for lateral contact force. The wheel–rail dynamic responses on the curved track are significantly enhanced compared to the straight track. Moreover, the strain rate effect can enhance von-Mises stress and contact pressure, suppress the plastic deformation of the rail and wheel, but it has little effect on the vertical and lateral contact forces and stable acceleration of axle. The Rate-Sensitive Factors (RSF) of the wheel and rail on the curved track are weaker than those on the straight track. These findings will be very helpful to study the competitive relationship between the rolling contact fatigue and wear, as well as the crack initiation and propagation problem.

The continuous development of VANET has accelerated the development of V2X communication. In the DSRC communication mode of VANET, the location information of the vehicles is interfered by factors such as high-density broadcasting and electromagnetic radiation, which can lead to the loss of the original vehicle information data collected by GPS easily. To solve it, this paper proposed the Least Squared SVM based Beacon Data Complete Algorithm. Unlike previous studies that historical trends of vehicle operation were mainly used to predict vehicle location., this method attempts to find a function, which is used to establish the relationship between the lost value and the past value of the vehicle. On this basis, a nonlinear function approximation strategy is used to predict the position of the missing vehicle. Part of the original data was lost artificially to complete checking calculation and to verify the effectiveness of it. The results show that the average relative error between the complemented vehicle position data and the real data is 0.45% and the maximum absolute relative error is 8.25%. This method has the advantage of not needing to extract historical trend data and high calculation accuracy compared with the methods such as PWHOG algorithm, difference matrix, and moving average data preprocessing. It is suitable for real-time acquisition of vehicle position of VANET and can reduce the complexity of detection time.

FeCoB films with different B doping contents and different thicknesses were deposited by composition gradient sputtering. The results show that in-plane anisotropy fields and exchange constants change with the increasing B contents and increasing thickness, respectively. Both results of the composition-gradient films and the thickness-dependent films and the micromagnetic simulation indicate that multiple order spin-wave resonances are easy to obtain in the films with the large in-plane anisotropy field. We observed four resonance peaks including three perpendicular standing spin waves. The hysteresis loop and magnetic domain results indicate that such films also have good magnetic softness and an in-plane homogeneous domain structure.

Abstract With changing climates globally, we see changes in not just average conditions, but also in extreme events, and such events require special attention due to their unpredictable yet significant impact on native biotas. One such event is the formation of a landscape scar at Zonag Lake caused by a climate change‐induced outburst flooding event that occurred on 15 September 2011. During the winter, the scar region became a new birthplace for sandstorms, and since the flooding, remote sensing monitoring shows that between 2011 and 2020, there were 285 sandstorm days (between November and March), relative to none prior. The outburst flooding event and consequential sandstorms threaten the key lambing area of the Tibetan antelope (Chiru), affect the water balance of the Zonag Lake and downstream lakes, and may even impact on the flow in the Yangtze River. Active human intervention may be needed to repair this new desert spit and reverse the slew of consequences which may otherwise lead to significant population declines in one of the major Chiru breeding grounds due to the progressive loss of vegetation productivity across their main breeding area.

The dynamic wheel–rail responses during the rolling contact process for high-speed trains were investigated using the explicit finite element code LS-DYNA 971. The influence of train speed on the wheel–rail contact forces (including the vertical, longitudinal, and lateral forces), von Mises equivalent stress, equivalent plastic strain, vertical acceleration of the axle, and the lateral displacement of the initial contact point on the tread, were examined and discussed. Simulation results show that the lateral and longitudinal wheel–rail contact forces are very smaller than the corresponding vertical contact forces, and they seem to be insensitive to train speed. The peak value of dynamic vertical wheel–rail contact force is approximately 2.66 times larger than the average quasi-static value. The elliptical wheel–rail contact patches have multiple stress extreme points due to the plastic deformation of the wheel tread and top surface of the rail. The vertical acceleration value of the axle in the steady condition is around ±5 m/s 2 for the perfected wheel–rail system with the running speed below 300 km/h.

Abstract Olaparib has been approved as a therapeutic option for metastatic pancreatic ductal adenocarcinoma patients with BRCA1/2 mutations. However, a significant majority of pancreatic cancer patients have inherent resistance or develop tolerance to olaparib. It is crucial to comprehend the molecular mechanism underlying olaparib resistance to facilitate the development of targeted therapies for pancreatic cancer. In this study, we conducted an analysis of the DepMap database to investigate gene expression variations associated with olaparib sensitivity. Our findings revealed that NLRP4 upregulation contributes to increased resistance to olaparib in pancreatic cancer cells, both in vitro and in vivo. RNA sequencing and Co-IP MS analysis revealed that NLRP4 is involved in the DNA damage response and autophagy pathway. Our findings confirmed that NLRP4 enhances the capacity for DNA repair and induces the production of significant levels of reactive oxygen species (ROS) and autophagy in response to treatment with olaparib. Specifically, NLRP4-generated mitochondrial ROS promote autophagy in pancreatic cancer cells upon exposure to olaparib. However, NLRP4-induced ROS do not affect DNA damage. The inhibition of mitochondrial ROS using MitoQ and autophagy using chloroquine (CQ) may render cells more susceptible to the effects of olaparib. Taken together, our findings highlight the significant roles played by NLRP4 in the processes of autophagy and DNA repair when pancreatic cancer cells are treated with olaparib, thereby suggesting the potential therapeutic utility of olaparib in pancreatic cancer patients with low NLRP4 expression.