Mechanistic Insights into the Inhibition of a Common CTLA-4 Gene Mutation in the Cytoplasmic Domain.

Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is a pivotal immune checkpoint receptor, playing a crucial role in modulating T-cell activation. In this study, we delved into the underlying mechanism by which a common mutation, G199R, in the cytoplasmic domain of CTLA-4 impacts its inhibitory function. Utilizing nuclear magnetic resonance (NMR) spectroscopy and biochemical techniques, we mapped the conformational changes induced by this mutation and investigated its role in CTLA-4 activity. Our findings reveal that this mutation leads to a distinct conformational alteration, enhancing protein-membrane interactions. Moreover, functional assays demonstrated an improved capacity of the G199R mutant to downregulate T-cell activation, underscoring its potential role in immune-related disorders. These results not only enhance our understanding of CTLA-4 regulatory mechanisms but also provide insights for targeted therapeutic strategies addressing immune dysregulation linked to CTLA-4 mutations.

Fibrous MXene Synapse-Based Biomimetic Tactile Nervous System for Multimodal Perception and Memory.

Biomimetic tactile nervous system (BTNS) inspired by organisms has motivated extensive attention in wearable fields due to its biological similarity, low power consumption, and perception-memory integration. Though many works about planar-shape BTNS are developed, few researches could be found in the field of fibrous BTNS (FBTNS) which is superior in terms of strong flexibility, weavability, and high-density integration. Herein, a FBTNS with multimodal sensibility and memory is proposed, by fusing the fibrous poly lactic acid (PLA)/Ag/MXene/Pt artificial synapse and MXene/EMIMBF4 ionic conductive elastomer. The proposed FBTNS can successfully perceive external stimuli and generate synaptic responses. It also exhibits a short response time (23 ms) and low set power consumption (17 nW). Additionally, the proposed device demonstrates outstanding synaptic plasticity under both mechanical and electrical stimuli, which can simulate the memory function. Simultaneously, the fibrous devices are embedded into textiles to construct tactile arrays, by which biomimetic tactile perception and temporary memory functions are successfully implemented. This work demonstrates the as-prepared FBTNS can generate biomimetic synaptic signals to serve as artificial feeling signals, it is thought that it could offer a fabric electronic unit integrating with perception and memory for Human-Computer interaction, and has great potential to build lightweight and comfortable Brain-Computer interfaces.

K+-Dependent Photocycle and Photocurrent Reveal the Uptake of K+ in Light-Driven Sodium Pump.

Engineering light-controlled K+ pumps from Na+-pumping rhodopsins (NaR) greatly expands the scope of optogenetic applications. However, the limited knowledge regarding the kinetic and selective mechanism of K+ uptake has significantly impeded the modification and design of light-controlled K+ pumps, as well as their practical applications in various fields, including neuroscience. In this study, we presented K+-dependent photocycle kinetics and photocurrent of a light-driven Na+ pump called Nonlabens dokdonensis rhodopsin 2 (NdR2). As the concentration of K+ increased, we observed the accelerated decay of M intermediate in the wild type (WT) through flash photolysis. In 100 mM KCl, the lifetime of the M decay was approximately 1.0 s, which shortened to around 0.6 s in 1 M KCl. Additionally, the K+-dependent M decay kinetics were also observed in the G263W/N61P mutant, which transports K+. In 100 mM KCl, the lifetime of the M decay was approximately 2.5 s, which shortened to around 0.2 s in 1 M KCl. According to the competitive model, in high KCl, K+ may be taken up from the cytoplasmic surface, competing with Na+ or H+ during M decay. This was further confirmed by the K+-dependent photocurrent of WT liposome. As the concentration of K+ increased to 500 mM, the amplitude of peak current significantly dropped to approximately ~60%. Titration experiments revealed that the ratio of the rate constant of H+ uptake (kH) to that of K+ uptake (kK) is >108. Compared to the WT, the G263W/N61P mutant exhibited a decrease of approximately 40-fold in kH/kK. Previous studies focused on transforming NaR into K+ pumps have primarily targeted the intracellular ion uptake region of Krokinobacter eikastus rhodopsin 2 (KR2) to enhance K+ uptake. However, our results demonstrate that the naturally occurring WT NdR2 is capable of intracellular K+ uptake without requiring structural modifications on the intracellular region. This discovery provides diverse options for future K+ pump designs. Furthermore, we propose a novel photocurrent-based approach to evaluate K+ uptake, which can serve as a reference for similar studies on other ion pumps. In conclusion, our research not only provides new insights into the mechanism of K+ uptake but also offers a valuable point of reference for the development of optogenetic tools and other applications in this field.

Associations of Death Anxiety, Inclusion of Smartphone in the Self, and Affiliation Motivation with Smartphone use and Addiction: A Multiple Mediation Study.

This study is the first to apply terror management theory to understanding smartphone addiction by examining the potential indirect effect of death anxiety on smartphone addiction via inclusion of smartphone in the self (i.e., self-expansion), affiliation motivation (the desire to connect with others) for emotional support, and smartphone use. The sample consisted of 1483 Chinese university students between the ages of 18 and 24 (M = 19.14, SD = 1.03) who voluntarily completed an anonymous questionnaire survey. As hypothesized, death anxiety, inclusion of smartphone in the self, affiliation motivation, and smartphone use were directly, positively correlated with smartphone addiction. In addition, death anxiety exerted significant indirect effects via various pathways, including (i) affiliation motivation for emotional support and smartphone use and (ii) inclusion of smartphone in the self and smartphone use. Findings suggest that effective interventions for smartphone addiction should include targeting death anxiety, self-expansion, and affiliation need frustration.

Effect of the Coil Excitation Method on the Performance of a Dual-Coil Inductive Displacement Transducer.

A dual-coil inductive displacement transducer is a non-contact type measuring element for measuring displacement and is widely used in large power equipment systems such as construction machinery and agricultural equipment. However, the effect of the coil excitation method on the performance of dual-coil inductive displacement sensors has not been studied. This paper investigates the impact of different coil excitation methods on the operating performance of displacement transducers. The working principle, electromagnetic characteristics, and electrical characteristics were analyzed by building a mathematical model. A transducer measurement device was used to determine the relationship between core displacement and coil inductance. Three coil excitation methods were proposed, and the effects of the three coil excitation methods on the amplitude variation, phase shift, linearity, and sensitivity of the output signal were studied by simulation based on the AD630 chip as the core of the conditioning circuit. Finally, the study's feasibility was demonstrated by comparing the experiment to the simulation. The results show that, under the uniform magnetic field strength distribution in the coil, the coil voltage variation is proportional to the inductive core displacement. The amplitude variation is the largest for the dual-coil series three-wire (DCSTW) and is the same for the dual-coil series four-wire (DCSFW) and dual-coil parallel differential (DCPD). DCSFW has an enormous phase shift. DCSTW has the best linearity. The research in this paper provides a theoretical basis for selecting a suitable coil excitation, which is conducive to further improving the operating performance of dual-coil inductive displacement transducers.

Effect of Excitation Signal on Double-Coil Inductive Displacement Transducer.

A double-coil inductive displacement transducer is a non-contact element for measuring displacement and is widely used in large power equipment systems such as construction machinery and agricultural machinery equipment. The type of coil excitation signal has an impact on the performance of the transducer, but there is little research on this. Therefore, the influence of the coil excitation signal on transducer performance is investigated. The working principle and characteristics of the double-coil inductive displacement transducer are analyzed, and the circuit simulation model of the transducer is established. From the aspects of phase shift, linearity, and sensitivity, the effects of a sine signal, a triangle signal, and a pulse signal on the transducer are compared and analyzed. The results show that the average phase shift, linearity, and sensitivity of the sine signal were 11.53°, 1.61%, and 0.372 V/mm, respectively; the average phase shift, linearity and sensitivity of the triangular signal were 1.38°, 1.56%, and 0.300 V/mm, respectively; and the average phase shift, linearity, and sensitivity of the pulse signal were 0.73°, 1.95%, and 0.621 V/mm, respectively. It can be seen that the phase shift of a triangle signal and a pulse signal is smaller than that of a sine signal, which can result in better signal phase-locked processing. The linearity of the triangle signal is better than the sine signal, and the sensitivity of the pulse signal is better than that of the sine signal.

Ni2+ Catalyzed Cleavage of TrpLE-Fused Small Transmembrane Peptides.

In addition to a membrane anchor, the transmembrane domain (TMD) of single-pass transmembrane proteins (SPTMPs) recently has shown essential roles in the cross-membrane activity or receptor assembly/clustering. However, these small TMD peptides are generally hydrophobic and dynamic, difficult to be expressed and purified. Here, we have integrated the power of TrpLE fusion protein and a sequence-specific nickel-assisted cleavage (SNAC)-tag to produce small TMD peptides in a highly efficient way under mild conditions, which uses Ni2+ as the cleavage reagent, avoiding the usage of toxic cyanogen bromide (CNBr). Furthermore, this method simplifies the downstream protein purification and reconstitution. Two representative TMDs, including the Spike-TMD from severe acute respiratory syndrome coronavirus 2 (SARS2), were successfully produced with high-quality nuclear magnetic resonance (NMR) spectra. Therefore, our study provides a more efficient and practical approach for general structural characterization of the small TM proteins.

Numerical Simulations of the Influence of Inert Gases (N2/CO2) on Combustion Characteristics of Laminar-Premixed Biosyngas Flame.

In this work, the influence of different N2/CO2 contents (up to 60% in fuel volume) on combustion features of laminar-premixed CO/CH4/H2 flame with various equivalence ratios (0.6-1.6) at standard conditions was numerically calculated using ANSYS CHEMKIN-PRO with the GRI-Mech 3.0 mechanism. The mole fraction profiles of the major species and the rate of production of dominant elementary reactions in the flames of CO/CH4/H2/N2/CO2/air were obtained. The effect of inert gas addition on the formation of NO X , H, O, and OH was analyzed, and the sensitivity coefficient of the active radical mole fraction was obtained. The results suggest that the addition of inert gas of the fuel mixture with various equivalence ratios reduces laminar burning velocity and adiabatic temperature, which have always had a good positive correlation and the maximum peak point shifted left. CO2 has obvious inhibitory effect on the formation of NO by reducing the amount of O radicals and obstructing the conduct of the reaction of NNH + O ⇔ NH + NO, but it promotes the formation of NO2 mainly through the reaction HO2 + NO ⇔ NO2 + OH. The reactions H + O2 + H2O ⇔ HO2 + H2O, H + O2 ⇔ O + OH, and OH + CO ⇔ H + CO2 are three very important reactions for the molar fractions of H, O, and OH that decrease significantly with an increase of inert gas concentration.