Soluble immune checkpoints in cancer: production, function and biological significance

Abstract Immune checkpoints play important roles in immune regulation, and blocking immune checkpoints on the cell membrane is a promising strategy in the treatment of cancer. Based on this, monoclonal antibodies are having much rapid development, such as those against CTLA-4 (cytotoxic T lymphocyte antigen 4) and PD-1 (programmed cell death protein 1).But the cost of preparation of monoclonal antibodies is too high and the therapeutic effect is still under restrictions. Recently, a series of soluble immune checkpoints have been found such as sCTLA-4 (soluble CTLA-4) and sPD-1 (soluble PD-1). They are functional parts of membrane immune checkpoints produced in different ways and can be secreted by immune cells. Moreover, these soluble checkpoints can diffuse in the serum. Much evidence has demonstrated that these soluble checkpoints are involved in positive or negative immune regulation and that changes in their plasma levels affect the development, prognosis and treatment of cancer. Since they are endogenous molecules, they will not induce immunological rejection in human beings, which might make up for the deficiencies of monoclonal antibodies and enhance the utility value of these molecules. Therefore, there is an increasing need for investigating novel soluble checkpoints and their functions, and it is promising to develop relevant therapies in the future. In this review, we describe the production mechanisms and functions of various soluble immune checkpoint receptors and ligands and discuss their biological significance in regard to biomarkers, potential candidate drugs, therapeutic targets, and other topics

Numerical Simulation of Sulfur Deposit with Particle Release

Sulfur deposition commonly occurs during the development of a high-sulfur gas reservoirs. Due to the high gas flow velocity near the wellbore, some of the deposited sulfur particles re-enter the pores and continue to migrate driven by the high-speed gas flow. The current mathematical model for sulfur deposition ignores the viscosity between particles, rising flow caused by turbulence, and the corresponding research on the release ratio of particles. In order to solve the above problems, firstly, the viscous force and rising force caused by turbulence disturbance are introduced, and the critical release velocity of sulfur particles is derived. Then, a release model of sulfur particles that consider the critical release velocity and release ratio is proposed by combining the probability theory with the hydrodynamics theory. Notably, based on the experimental data, the deposition ratio of sulfur particles and the damage coefficient in the sulfur damage model are determined. Finally, a comprehensive particle migration model considering the deposition and release of sulfur particles is established. The model is then applied to the actual gas wells with visible sulfur deposition that target the Da-wan gas reservoir, and the results show that the model correctly reflects flow transport during the process of sulfur deposition in porous media. In addition, through the numerical simulation experiments, it was found that considering the release of sulfur particles reduces the saturation of sulfur particles within a specific range around the well and improve the reservoir permeability in this range. From the perspective of gas production rate, the release of sulfur particles has a limited effect on the gas production rate, which is mainly due to the sulfur particle release being limited, having only a 5 m range near the wellbore area, and thus the amount of gas flow from the unaffected area is basically unchanged

Microstructures and Mechanical Properties of a Laser-Welded Joint of Ti3Al-Nb Alloy Using Pure Nb Filler Metal

Ti3Al-Nb alloy (Ti-24Al-15Nb) was welded by a pulsed laser welding system without and with pure Nb filler metal. The results indicated that pure Nb filler metal had profound effects on the microstructures and mechanical properties of the laser-welded joints. The joint without filler metal consisted of the weld zone (α’2 + B2), heat affected zone HAZ1 (α2 + B2), HAZ2 (α2 + O + B2) and base metal (α2 + O + B2), and gas pores were generated in the weld resulting in the deterioration of the joint strength (330 MPa) and elongation (1.9%). When the Nb filler metal was used, the weld microstructure (NbTi solid solution + O + B2) was obtained, and the joint properties were significantly improved, which was associated with the strengthening effect of the NbTi solid solution, O phase precipitation and the slip transmission between O and B2 phases, and the restraining of the formation of martensite (α’2) and gas pores in the weld. The strength (724 MPa) and elongation (5.1%) of the joint increased by 119.4% and 168.4% compared with those of the joint without filler metal, and the joint strength was able to reach 81.7% of the base metal strength (886 MPa). It is favorable to use pure Nb filler metal for improving the mechanical properties of laser-welded Ti3Al-Nb alloy joints

Methylparaben induces hepatic glycolipid metabolism disorder by activating the IRE1α-XBP1 signaling pathway in male mice

Methylparaben (MP), a preservative widely used in daily supplies, exists in both the environment and the human body. However, the potential health risks posed by MP remain unclear. This study aimed to unravel the mechanisms by which MP disrupts glucose and lipid homeostasis. For this, we administered MP to mice and observed changes in glucose and lipid metabolism. MP exposure led to hyperglycemia, hyperlipidemia, visceral organ injury, and hepatic lipid accumulation. RNA sequencing results from mice livers indicated a close association between MP exposure and endoplasmic reticulum (ER) stress, inflammatory response, and glucose and lipid homeostasis. Western blotting and quantitative reverse transcription–polymerase chain reaction revealed that MP activated ER stress, particularly the inositol-requiring enzyme 1 (IRE1)/X-box binding protein 1 (XBP1) pathway, which further promoted the activation of the nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) pathways. The activation of these pathways phosphorylated insulin receptor substrate-1 (IRS1) (ser 307), resulting in decreased phosphorylation of protein kinase B (Akt) (ser 473), leading to insulin resistance. Additionally, MP exposure promoted lipogenesis through ER stress. To explore potential remedies, we administered the ER stress inhibitor 4-phenylbutyric acid (4-PBA) and the IRE1α-XBP1 pathway inhibitor toyocamycin to mice, both of which protected against metabolic disorders and organ injury caused by MP. These findings suggest that MP induces disruptions in glucose and lipid metabolism through ER stress, primarily through the IRE1α-XBP1 pathway

Corrigendum to Calorie Restriction Protects against Contrast-Induced Nephropathy via SIRT1/GPX4 Activation

[This corrects the article DOI: 10.1155/2021/2999296.]