Protective Regulatory T Cell Immune Response Induced by Intranasal Immunization With the Live-Attenuated Pneumococcal Vaccine SPY1 via the Transforming Growth Factor-β1-Smad2/3 Pathway

Vaccine effectiveness is mainly determined by the mechanism mediating protection, emphasizing the importance of unraveling the protective mechanism for novel pneumococcal vaccine development. We previously demonstrated that the regulatory T cell (Treg) immune response has a protective effect against pneumococcal infection elicited by the live-attenuated pneumococcal vaccine SPY1. However, the mechanism underlying this protective effect remains unclear. In this study, a short synthetic peptide (P17) was used to downregulate Tregs during immunization and subsequent challenges in a mouse model. In immunized mice, increase in immune cytokines (IL-12p70, IL-4, IL-5, and IL-17A) induced by SPY1 were further upregulated by P17 treatment, whereas the decrease in the infection-associated inflammatory cytokine TNF-α by SPY1 was reversed. P17 also inhibited the increase in the immunosuppressive cytokine IL-10 and inflammatory mediator IL-6 in immunized mice. More severe pulmonary injuries and more dramatic inflammatory responses with worse survival in P17-treated immunized mice indicated the indispensable role of the Treg immune response in protection against pneumococcal infection by maintaining a balance among acquired immune responses stimulated by SPY1. Further studies revealed that the significant elevation of active transforming growth factor β (TGF-β)1 by SPY1 vaccination activated FOXP3, leading to increased frequencies of CD4+CD25+Foxp3+ T cells. Moreover, SPY1 vaccination elevated the levels of Smad2/3 and phosphor-Smad2/3 and downregulated the negative regulatory factor Smad7 in a time-dependent manner during pneumococcal infection, and these changes were reversed by P17 treatment. These results illustrate that SPY1-stimulated TGF-β1 induced the generation of SPY1-specific Tregs via the Smad2/3 signaling pathway. In addition, SPY1-specific Tregs may participate in protection via the enhanced expression of PD-1 and CTLA-4. The data presented here extend our understanding of how the SPY1-induced acquired Treg immune response contributes to protection elicited by live-attenuated vaccines and may be helpful for the evaluation of live vaccines and other mucosal vaccine candidates

Humanity's Last Exam

Benchmarks are important tools for tracking the rapid advancements in large language model (LLM) capabilities. However, benchmarks are not keeping pace in difficulty: LLMs now achieve over 90\% accuracy on popular benchmarks like MMLU, limiting informed measurement of state-of-the-art LLM capabilities. In response, we introduce Humanity's Last Exam (HLE), a multi-modal benchmark at the frontier of human knowledge, designed to be the final closed-ended academic benchmark of its kind with broad subject coverage. HLE consists of 3,000 questions across dozens of subjects, including mathematics, humanities, and the natural sciences. HLE is developed globally by subject-matter experts and consists of multiple-choice and short-answer questions suitable for automated grading. Each question has a known solution that is unambiguous and easily verifiable, but cannot be quickly answered via internet retrieval. State-of-the-art LLMs demonstrate low accuracy and calibration on HLE, highlighting a significant gap between current LLM capabilities and the expert human frontier on closed-ended academic questions. To inform research and policymaking upon a clear understanding of model capabilities, we publicly release HLE at https://lastexam.ai

Adaptive fuzzy dynamic surface control for unknown time delay nonlinear systems preceded by unknown asymmetric hysteresis

In this paper, a fuzzy approximator based adaptive dynamic surface control scheme is proposed for a class of unknown time delay nonlinear systems preceded by asymmetric hysteresis nonlinearities. The features of the proposed method are: 1) by combining the approximated property of the fuzzy logic systems (FLSs) with the Finite Covering Lemma, the Krasovskii functionals are disposed of, achieving the L∞ norm of the tracking error by using the initializing technique; 2) the assumptions on the time-delay functions are removed due to the use of the Finite Covering Lemma and the FLSs; 3) the proposed adaptive fuzzy dynamic surface control scheme can also compensate the asymmetric shifted Prandtl Ishlinskii (ASPI) hysteresis without constructing the inverse of the ASPI model with the density function of ASPI model being unknown and estimated on-line to compensate the hysteresis. It is proved that all the signals in the closed-loop system are ultimately uniformly bounded and can be made arbitrarily small. Simulation results show the validity of the proposed method

Adaptive output-feedback inverse control for a class of time delay nonlinear hysteretic systems via fuzzy approximeter

In this paper, an fuzzy approximator based output feedback adaptive dynamic surface inverse control (DSIC) scheme is proposed for a class of time-delay systems preceded by unknown asymmetric hysteresis. The main advantages are as follows: 1) by combining the Finite Covering Lemma with fuzzy logic systems (FLSs), a novel time-delay function approx-imator is proposed with the benefits of the assumptions of the conservative upper bound functions on the time-delay functions are removed and the Krasovskii functionals are not required when deal with time delays. Also, the time delay functions extends to a more general one with states variables and time-delay variables being coupled; 2) by using the proposed initial technique, the Lnorm of the tracking error is obtained; 3) by constructing the inverse of the asymmetric hysteresis and approximating the unknown time-delay functions, both time delays and asymmetric hysteresis phenomena in the actuators are mitigated simultaneously when only the output of the system is available. It is proved that all the signals in the closed-loop systems are semi-globally ultimately uniformly bounded (SUUG). Simulation results show the validity of the proposed scheme

Study on the mechanism of a lean construction safety planning and control system: An empirical analysis in China

Despite the fact that lean construction (LC) has been shown to improve construction safety, little research has been conducted to investigate how LC technologies could be applied to safety management. This study aimed to close the gap by developing a safety planning and control (SPC) process based on LC technologies and evaluating it using structural equation modeling. The process was based on the last planner system (LPS) research framework and consisted of four sub-systems (i.e., the analysis layer, the planning layer, the control layer, and the performance layer). Data was gathered from 300 Chinese construction projects. The findings will serve as a guide for construction stakeholders looking to improve the efficiency of safety management by incorporating some LC technologies into the SPC process. And the four sub-systems work together to create a positive circulation system that aids in the long-term improvement of construction safety management