PCK2 maintains intestinal homeostasis and prevents colitis by protecting antibody-secreting cells from oxidative stress.

Maintaining intracellular redox balance is essential for the survival, antibody secretion, and mucosal immune homeostasis of immunoglobulin A (IgA) antibody-secreting cells (ASCs). However, the relationship between mitochondrial metabolic enzymes and the redox balance in ASCs has yet to be comprehensively studied. Our study unveils the pivotal role of mitochondrial enzyme PCK2 in regulating ASCs' redox balance and intestinal homeostasis. We discover that PCK2 loss, whether globally or in B cells, exacerbates dextran sodium sulphate (DSS)-induced colitis due to increased IgA ASC cell death and diminished antibody production. Mechanistically, the absence of PCK2 diverts glutamine into the TCA cycle, leading to heightened TCA flux and excessive mitochondrial reactive oxygen species (mtROS) production. In addition, PCK2 loss reduces glutamine availability for glutathione (GSH) synthesis, resulting in a decrease of total glutathione level. The elevated mtROS and reduced GSH expose ASCs to overwhelming oxidative stress, culminating in cell apoptosis. Crucially, we found that the mitochondria-targeted antioxidant Mitoquinone (Mito-Q) can mitigate the detrimental effects of PCK2 deficiency in IgA ASCs, thereby alleviating colitis in mice. Our findings highlight PCK2 as a key player in IgA ASC survival and provide a potential new target for colitis treatment.

An LC-MS-based workflow measures the export activity of S1P transporters.

Sphingosine-1-phosphate (S1P) is an active signaling metabolite synthesized by blood cells, exported into blood stream, and can trigger many downstream signaling pathways with disease implications. Understanding how S1P is transported is of great values for dissecting the function of S1P, but most existing methods for measuring S1P transporter activity use radioactive substrates or involve multiple workup steps, hindering their broader uses. In this study, we develop a workflow combining sensitive LC-MS measurement and a cell-based transporter protein system to measure the export activity of S1P transporter proteins. Our workflow demonstrated good applications in studying different S1P transporters SPNS2 and MFSD2B, WT and mutated protein, and different protein substrates. In summary, we provide a simple yet versatile workflow for measuring the export activity of S1P transporters, facilitating future studies of S1P transport mechanism and drug development.

Cysteine-Based Coupling: Challenges and Solutions.

Antibody-drug conjugates (ADCs) have attracted great attention in recent years in the wake of an accelerated FDA approval rate and several large-scale acquisitions. To date, there are ten ADC drugs on the market and more than 70 in various stages of clinical trials. Yet, due to the complicated nature of ADC molecules, considerations need to cover many aspects for the success of ADCs, including target specificity, linker-payload stability, tumor permeability, and clearance rate. This topical review summarizes and discusses current methods used to increase stability and homogeneity of ADCs of cysteine conjugation. We believe that they will lead to improvement of efficacy and pharmacokinetics (PK) of ADC drugs.

Multiplexing-oriented plasmon-MoS2 hybrid metasurfaces driven by nonlinear quasi bound states in the continuum.

Rapid progress in nonlinear plasmonic metasurfaces enabled many novel optical characteristics for metasurfaces, with potential applications in frequency metrology [Zimmermann et al. Opt. Lett. 29:310 (2004)], timing characterization [Singh et al. Laser Photonics Rev. 14:1 (2020)] and quantum information [Kues et al. Nature. 546:622 (2017)]. However, the spectrum of nonlinear optical response was typically determined from the linear optical resonance. In this work, a wavelength-multiplexed nonlinear plasmon-MoS2 hybrid metasurface with suppression phenomenon was proposed, where multiple nonlinear signals could to be simultaneously processed and optionally tuned. A clear physical picture to depict the nonlinear plasmonic bound states in the continuum (BICs) was presented, from the perspective of both classical and quantum approaches. Particularly, beyond the ordinary plasmon-polariton effect, we numerically demonstrated a giant BIC-inspired second-order nonlinear susceptibility 10-5m/V of MoS2 in the infrared band. The novelty in our study lies in the presence of a quantum oscillator that can be adopted to both suppress and enhance the nonlinear quasi BICs. This selectable nonlinear BIC-based suppression and enhancement effect can optionally block undesired modes, resulting in narrower linewidth as well as smaller quantum decay rates, which is also promising in slow-light-associated technologies.

Anisotropic Hardening and Plastic Evolution Characterization on the Pressure-Coupled Drucker Yield Function of ZK61M Magnesium Alloy.

This paper studies the plastic behavior of the ZK61M magnesium alloy through a combination method of experiments and theoretical models. Based on a dog-bone specimen under different loading directions, mechanical tests under uniaxial tension were carried out, and the hardening behavior was characterized by the Swift-Voce hardening law. The von Mises yield function and the pressure-coupled Drucker yield function were used to predict the load-displacement curves of the ZK61M magnesium alloy under various conditions, respectively, where the material parameters were calibrated by using inverse engineering. The experimental results show that the hardening behavior of the ZK61M magnesium alloy has obvious anisotropy, but the effect of the stress state is more important on the strain hardening behavior of the alloy. Compared with the von Mises yield function, the pressure-coupled Drucker yield function is more accurate when characterizing the plastic behavior and strain hardening in different stress states of shear, uniaxial tension, and plane strain tension for the ZK61M alloy.