Activated macrophages switch from oxidative phosphorylation to aerobic glycolysis, similar to the Warburg effect, presenting a potential therapeutic target in inflammatory disease. The endogenous ...metabolite itaconate has been reported to regulate macrophage function, but its precise mechanism is not clear. Here, we show that 4-octyl itaconate (4-OI, a cell-permeable itaconate derivative) directly alkylates cysteine residue 22 on the glycolytic enzyme GAPDH and decreases its enzyme activity. Glycolytic flux analysis by U
C glucose tracing provides evidence that 4-OI blocks glycolytic flux at GAPDH. 4-OI thereby downregulates aerobic glycolysis in activated macrophages, which is required for its anti-inflammatory effects. The anti-inflammatory effects of 4-OI are replicated by heptelidic acid, 2-DG and reversed by increasing wild-type (but not C22A mutant) GAPDH expression. 4-OI protects against lipopolysaccharide-induced lethality in vivo and inhibits cytokine release. These findings show that 4-OI has anti-inflammatory effects by targeting GAPDH to decrease aerobic glycolysis in macrophages.
Numerous proteins, including cytokines and chemokines, enzymes and enzyme inhibitors, extracellular matrix proteins, and membrane receptors, bind heparin. Although they are traditionally classified ...as heparin-binding proteins, under normal physiological conditions these proteins actually interact with the heparan sulfate chains of one or more membrane or extracellular proteoglycans. Thus, they are more appropriately classified as heparan sulfate-binding proteins (HSBPs). This review provides an overview of the various modes of interaction between heparan sulfate and HSBPs, emphasizing biochemical and structural insights that improve our understanding of the many biological functions of heparan sulfate.
Fast radio bursts (FRBs), bright transients with millisecond durations at ∼GHz and typical redshifts probably >0.8, are likely to be gravitationally lensed by intervening galaxies. Since the time ...delay between images of strongly lensed FRB can be measured to extremely high precision because of the large ratio ∼10
between the typical galaxy-lensing delay time Formula: see text (10 days) and the width of bursts Formula: see text (ms), we propose strongly lensed FRBs as precision probes of the universe. We show that, within the flat ΛCDM model, the Hubble constant H
can be constrained with a ~0.91% uncertainty from 10 such systems probably observed with the square kilometer array (SKA) in <30 years. More importantly, the cosmic curvature can be model independently constrained to a precision of ∼0.076. This constraint can directly test the validity of the cosmological principle and break the intractable degeneracy between the cosmic curvature and dark energy.
Abstract
Many high quality studies have emerged from public databases, such as Surveillance, Epidemiology, and End Results (SEER), National Health and Nutrition Examination Survey (NHANES), The ...Cancer Genome Atlas (TCGA), and Medical Information Mart for Intensive Care (MIMIC); however, these data are often characterized by a high degree of dimensional heterogeneity, timeliness, scarcity, irregularity, and other characteristics, resulting in the value of these data not being fully utilized. Data-mining technology has been a frontier field in medical research, as it demonstrates excellent performance in evaluating patient risks and assisting clinical decision-making in building disease-prediction models. Therefore, data mining has unique advantages in clinical big-data research, especially in large-scale medical public databases. This article introduced the main medical public database and described the steps, tasks, and models of data mining in simple language. Additionally, we described data-mining methods along with their practical applications. The goal of this work was to aid clinical researchers in gaining a clear and intuitive understanding of the application of data-mining technology on clinical big-data in order to promote the production of research results that are beneficial to doctors and patients.
Local anesthetic toxicity is closely related to neuronal death and activation of the inflammatory response. Dexmedetomidine (Dex) is an adrenergic α2 receptor agonist that can reduce the ...neurotoxicity induced by lidocaine. It also has anti-inflammatory effects. However, the mechanism underlying the neuroprotective effects of Dex against lidocaine-induced toxicity remains to be defined. We hypothesized that Dex exerts its neural protective effect through inhibiting inflammasome activation and through anti-pyroptosis effects against local anesthetic-induced nerve injury. In a rat model of lidocaine-induced spinal cord injury, we studied the protective effect of Dex on lidocaine-induced changes in spinal cord function, inflammasome formation and pyroptosis, pro-inflammatory cytokine expression, and protein kinase C (PKC)-δ phosphorylation. Dex reduced lidocaine-induced neurotoxicity and inhibited PKC-δ phosphorylation in the spinal cord of rats. Furthermore, Dex inhibited pyroptosis and inflammasome formation (caspase-1, NLRP3, and apoptosis-associated speck-like protein (ASC)). Finally, Dex attenuated interleukin (IL)-1β and IL-18 expression, as well as microglia response. In conclusion, Dex can reduce the severity of lidocaine-induced spinal cord injury in rats by inhibiting priming and inflammasome activation and reducing pyroptosis via PKC-δ phosphorylation.
Abstract Starting from more than 11,200 short-period (less than 0.5 days) EW-type eclipsing binary candidates with the All-Sky Automated Survey for Supernovae V -band light curves, we use the Markov ...Chain Monte Carlo algorithm and neural networks to obtain the mass ratio ( q ), orbital inclination ( incl ), fill-out factor ( f ), and temperature ratio ( T s / T p ). After crossmatching with the Gaia DR3 database, the final sample contains parameters of 2399 A-type and 8712 W-type contact binaries (CBs). We present the distributions of parameters of these 11,111 short-period CBs. The mass ratio ( q ) and fill-out factor ( f ) are found to obey log-normal distributions, and the remaining parameters obey normal distributions. There is a significant period–temperature correlation of these CBs. Additionally, the temperature ratio ( T s / T p ) tends to increase as the orbital period decreases for W-type CBs. There is no significant correlation between them for A-type CBs. The mass ratio and fill-out factor ( q − f ) diagram suggest there is no significant correlation between these two parameters. A clear correlation exists between the mass ratio and radius ratio. The radius ratio increases with the mass ratio. Moreover, the deep fill-out CBs tend to fall on the upper boundary of the q − R s / R p distribution, while the shallow fill-out CBs fall on the lower boundary.
Halide methyltransferases (HMTs) provide an effective way to regenerate S‐adenosyl methionine (SAM) from S‐adenosyl homocysteine and reactive electrophiles, such as methyl iodide (MeI) and methyl ...toluene sulfonate (MeOTs). As compared with MeI, the cost‐effective unnatural substrate MeOTs can be accessed directly from cheap and abundant alcohols, but shows only limited reactivity in SAM production. In this study, we developed a dynamic cross‐correlation network analysis (DCCNA) strategy for quickly identifying hot spots influencing the catalytic efficiency of the enzyme, and applied it to the evolution of HMT from Paraburkholderia xenovorans. Finally, the optimal mutant, M4 (V55T/C125S/L127T/L129P), exhibited remarkable improvement, with a specific activity of 4.08 U/mg towards MeOTs, representing an 82‐fold increase as compared to the wild‐type (WT) enzyme. Notably, M4 also demonstrated a positive impact on the catalytic ability with other methyl donors. The structural mechanism behind the enhanced enzyme activity was uncovered by molecular dynamics simulations. Our work not only contributes a promising biocatalyst for the regeneration of SAM, but also offers a strategy for efficient enzyme engineering.
S‐Adenosylmethionine assumes a crucial role in biocatalytic alkylation. To improve the catalytic ability of BxHMT towards methyl toluene sulfonate, a strategy named dynamic cross‐correlation network analysis (DCCNA) was proposed for the identification of potential mutation sites, both distal and proximal. Experimental results proved the efficiency of the approach, which is expected to be a useful tool for other enzyme engineering studies.
During the water cycle, the energy and water vapor between the sea and the air are converted. Changes in water evaporation and water vapor encountering cold precipitation will have an important ...impact on the water flow in the ocean. There is a non-adiabatic heating rate and moisture in the air. The flow of fresh water from the sea plays an extremely important role in the circulation of the sea, especially in the circulation of salt-containing seawater. Water is presented in different forms. There are two functions of heating and cooling in the air temperature circulation system. With the rapid development of remote sensing information and geographic information technology, the use of GIS technology proves that the system has a very large data storage capacity. The coverage is relatively wide, and the information update speed is fast. It can create quick and accurate theoretical knowledge support for the public and promotes the scientific development of eco-environmental resources and the rapid and healthy development of social economy in the surrounding area of the study area. This article discusses the impact of changes in the flow of fresh water in the world’s oceans on global temperature warming. Correlative experimental researches on the water cycle and water vapor content on different time scales are carried out. Through research, it is found that there are certain problems in the internal management structure of fishery enterprises. Based on the theory of internal standards, suggestions and measures for improvement of related issues can be put forward, which can provide reference and reference for the healthy development of fishery companies.
This letter considers a wireless powered underlay cognitive radio network where secondary users (SUs) first harvest energy in the downlink wireless power transfer (WPT) phase and then use the energy ...for data transmission in the uplink wireless information transmission phase adopting the time-division multiple access. Our aim is to maximize the sum rate of the SUs under the interference power constraint enforced by the primary user and the transmit power constraints. The optimal joint power control for the WPT phase and time allocation among the SUs is obtained. Simulation results show that the obtained optimal scheme outperforms the scheme that employs only the optimal time allocation or the optimal power control.
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