How early-life colonization and subsequent exposure to the microbiota affect long-term tissue immunity remains poorly understood. Here, we show that the development of mucosal-associated invariant T ...(MAIT) cells relies on a specific temporal window, after which MAIT cell development is permanently impaired. This imprinting depends on early-life exposure to defined microbes that synthesize riboflavin-derived antigens. In adults, cutaneous MAIT cells are a dominant population of interleukin-17A (IL-17A)-producing lymphocytes, which display a distinct transcriptional signature and can subsequently respond to skin commensals in an IL-1-, IL-18-, and antigen-dependent manner. Consequently, local activation of cutaneous MAIT cells promotes wound healing. Together, our work uncovers a privileged interaction between defined members of the microbiota and MAIT cells, which sequentially controls both tissue-imprinting and subsequent responses to injury.
Mucosal-associated invariant T (MAIT) cells are innate-like lymphocytes that recognize microbial vitamin B metabolites and have emerging roles in infectious disease, autoimmunity, and cancer. ...Although MAIT cells are identified by a semi-invariant TCR, their phenotypic and functional heterogeneity is not well understood. Here we present an integrated single cell transcriptomic analysis of over 76,000 human MAIT cells during early and prolonged Ag-specific activation with the MR1 ligand 5-OP-RU and nonspecific TCR stimulation. We show that MAIT cells span a broad range of homeostatic, effector, helper, tissue-infiltrating, regulatory, and exhausted phenotypes, with distinct gene expression programs associated with CD4
or CD8
coexpression. During early activation, MAIT cells rapidly adopt a cytotoxic phenotype characterized by high expression of
,
and
In contrast, prolonged stimulation induces heterogeneous states defined by proliferation, cytotoxicity, immune modulation, and exhaustion. We further demonstrate a FOXP3 expressing MAIT cell subset that phenotypically resembles conventional regulatory T cells. Moreover, scRNAseq-defined MAIT cell subpopulations were also detected in individuals recently exposed to
, confirming their presence during human infection. To our knowledge, our study provides the first comprehensive atlas of human MAIT cells in activation conditions and defines substantial functional heterogeneity, suggesting complex roles in health and disease.
We present the method of online self-tuning PD controller for the problem of contouring control of robot manipulators. Previously, the dynamics of the robot is transformed into dynamic errors problem ...by considering the equivalent errors method. It becomes the control problem of stabilization such that it is suitable for advanced control to improve control performance regarding contouring control, i.e., contour accuracy with high speed. Conventional PD tuned by the fuzzy controller with robust extended Kalman filter where it was acting as the robust adaptive controller is utilized to stabilize that control problem. It could determine the stationary point of different processes without knowing prior. In practice, the proposed controller is easily dealt with the problem of stabilization. The experiment results reveal that the proposed technique yields excellent performance under a large disturbance.
In this paper, we investigate the global exponential stability and periodicity of nonautonomous cellular neural networks with reaction-diffusion, impulses, and time-varying delays. By establishing a ...new differential inequality for nonautonomous systems, using the properties of M-matrix and inequality techniques, some new sufficient conditions for the global exponential stability of the system are obtained. Moreover, sufficient conditions for the periodic solutions of the system are obtained by using the Poincare mapping and the fixed point theory. The validity and superiority of the main results are verified by numerical examples and simulations.
Because of favourable stability, facile fabrication, non-toxicity, tunable bandgap and high extinction coefficient, Sb2(S1-xSex)3 combined the advantages of Sb2S3 and Sb2Se3 have attracted extensive ...attention. Unlike previous studies using a preformed target or source of a single composition, our study offered a high‐throughput closed-space sublimation method based on a single mixed powder source of Sb2S3 and Sb2Se3. We fabricated single-phase and highly crystalline Sb2(S1-xSex)3 films with strong (221) orientation, which is beneficial for the rapid transmission of photon-generated carriers. The bandgap of films evolved from 1.79 eV to 1.38 eV that accompany the varying x value of Se content from 0.14 to 0.85. The corresponding solar cells with the structure of FTO/CdS/Sb2(S1-xSex)3/Au were fabricated, and then the relationship between performance, source temperature and alloy composition were investigated. The open-circuit voltage and short circuit current density showed opposite trends with increased Se content. Finally, the champion device with a PCE of 2.70% was obtained employing Sb2(S0.25Se0.75)3 absorber, which had optimal grain orientation, favourable surface morphology. The bandgap is 1.45 eV, which falls into the ideal bandgap in the Shockley–Queisser limit. A low reverse saturation current density (2.35 × 10−5 mA/cm2) and the relevant diode ideality factor (1.38) were obtained, which implies favourable junction quality. The CSS technique is expected to improve production efficiency and promote Sb2(S1-xSex)3 solar cell commercial applications, worth further optimization.
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A specific small-molecule inhibitor of p97 would provide an important tool to investigate diverse functions of this essential ATPase associated with diverse cellular activities (AAA) ATPase and to ...evaluate its potential to be a therapeutic target in human disease. We carried out a high-throughput screen to identify inhibitors of p97 ATPase activity. Dual-reporter cell lines that simultaneously express p97-dependent and p97-independent proteasome substrates were used to stratify inhibitors that emerged from the screen. N², N⁴-ḏiḇe̱nzylq̱uinazoline-2,4-diamine (DBeQ) was identified as a selective, potent reversible, and ATP-competitive p97 inhibitor. DBeQ blocks multiple processes that have been shown by RNAi to depend on p97, including degradation of ubiquitin fusion degradation and endoplasmic reticulum-associated degradation pathway reporters, as well as autophagosome maturation. DBeQ also potently inhibits cancer cell growth and is more rapid than a proteasome inhibitor at mobilizing the executioner caspases-3 and -7. Our results provide a rationale for targeting p97 in cancer therapy.
In this paper, the finite-time synchronization issue is addressed for discontinuous fuzzy neural networks with mixed time-varying delays and impulsive disturbances. The dynamic impulsive gain about ...the impulsive moment is proposed as an alternative to the previous static impulsive gain. The time-varying impulsive gain can combine the synchronizing and desynchronizing impulses to directly observe their effects on the system, avoiding the classification discussion. In order to study the finite-time synchronization of the drive–response system, we obtain an equivalent system from the original fuzzy neural networks based on the concepts of Filippov solutions and differential inclusion theory. Furthermore, by constructing new Lyapunov functions that combine the 1-norm and the comparative system method, some algebraic sufficient conditions for the synchronization of the drive system and the response system in finite time are established, which are based on two types of novel non-chattering controllers. In addition, the parameters of the system itself can simply demonstrate the sufficient conditions that have been obtained her e, avoiding the time-consuming calculation of matrix inequalities. Moreover, the settling time estimation scheme have been established. Eventually, numerical examples are provided to demonstrate the effectiveness of the control scheme.
Abstract Deletion of the maternal UBE3A allele causes Angelman syndrome (AS) ; because paternal UBE3A is epigenetically silenced by a long non-coding antisense ( UBE3A-ATS ) in neurons, this nearly ...eliminates UBE3A protein in the brain. Reactivating paternal UBE3A holds promise for treating AS. We previously showed topoisomerase inhibitors can reactivate paternal UBE3A , but their therapeutic challenges prompted our search for small molecule unsilencers with a different mechanism of action. Here, we found that ( S )-PHA533533 acts through a novel mechanism to significantly increase paternal Ube3a mRNA and UBE3A protein levels while downregulating Ube3a-ATS in primary neurons derived from AS model mice. Furthermore, peripheral delivery of ( S )-PHA533533 in AS model mice induces widespread neuronal UBE3A expression. Finally, we show that ( S )-PHA533533 unsilences paternal UBE3A in AS patient-derived neurons, highlighting its translational potential. Our findings provide a lead for developing a small molecule treatment for AS that could be safe, non-invasively delivered, and capable of brain-wide unsilencing of paternal UBE3A .
This paper considers the fixed-time synchronization of complex-valued coupled networks (CVCNs) with hybrid perturbations (nonlinear bounded external perturbations and stochastic perturbations). To ...accomplish the target of fixed-time synchronization, the CVCNs can be separated into their real and imaginary parts and establish real-valued subsystems, a novel quantized controller is designed to overcome the difficulties induced by complex parameters, variables, and disturbances. By means of the Lyapunov stability theorem and the properties of the Wiener process, some sufficient conditions are presented for the selection of control parameters to guarantee the fixed-time synchronization, and an upper bound of the setting time is also obtained, which is only related to parameters of both systems and the controller, not to the initial conditions of the systems. Finally, a numerical simulation is given to show the correctness of theoretical results and the effectiveness of the control strategy.
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