Toward repositioning the antitubercular clinical candidate SQ109 as an antimalarial, analogs were investigated for structure-activity relationships for activity against asexual blood stages of the human malaria parasite Plasmodium falciparum pathogenic forms, as well as transmissible, sexual stage gametocytes. We show that equipotent activity (IC50) in the 100-300 nM range could be attained for both asexual and sexual stages, with the activity of most compounds retained against a multidrug-resistant strain. The multistage activity profile relies on high lipophilicity ascribed to the adamantane headgroup, and antiplasmodial activity is critically dependent on the diamine linker. Frontrunner compounds showed conserved activity against genetically diverse southern African clinical isolates. We additionally validated that this series could block transmission to mosquitoes, marking these compounds as novel chemotypes with multistage antiplasmodial activity.

The eradication of tuberculosis remains a global challenge. Despite being the only licensed vaccine, Bacillus Calmette-Guérin (BCG) confers limited protective efficacy in adults and individuals with latent tuberculosis infections (LTBI). There is an urgent need to develop novel vaccines that can enhance the protective effect of BCG. Protein subunit vaccines have garnered significant research interest due to their safety and plasticity. Based on previous studies, we selected three antigens associated with LTBI (Rv2028c, Rv2029c, Rv3126c) and fused them with an immunodominant antigen Ag85A, resulting in the construction of a multistage protein subunit vaccine named A986. We evaluated the protective effect of recombinant protein A986 adjuvanted with MPL/QS21 as a booster vaccine for BCG against Mycobacterium tuberculosis (Mtb) infection in mice. The A986 + MPL/QS21 induced the secretion of antigen-specific Th1 (IL-2+, IFN-γ+ and TNF-α+) and Th17 (IL-17A+) cytokines in CD4+ and CD8+ T cells within the lung and spleen of mice, while also increased the frequency of central memory and effector memory T cells. Additionally, it also induced the enhanced production of IgG antibodies. Compared to BCG alone, A986 + MPL/QS21 boosting significantly augmented the proliferation of antigen-specific multifunctional T cells and effectively reduced bacterial load in infected mice. Taken together, A986 + MPL/QS21 formulation induced robust antigen-specific immune responses and provided enhanced protection against Mtb infection as a booster of BCG vaccine.

Generally, the recognition performance of lightweight models is often lower than that of large models. Knowledge distillation, by teaching a student model using a teacher model, can further enhance the recognition accuracy of lightweight models. In this paper, we approach knowledge distillation from the perspective of intermediate feature-level knowledge distillation. We combine a cross-stage feature fusion symmetric framework, an attention mechanism to enhance the fused features, and a contrastive loss function for teacher and student models at the same stage to comprehensively implement a multistage feature fusion knowledge distillation method. This approach addresses the problem of significant differences in the intermediate feature distributions between teacher and student models, making it difficult to effectively learn implicit knowledge and thus improving the recognition accuracy of the student model. Compared to existing knowledge distillation methods, our method performs at a superior level. On the CIFAR100 dataset, it boosts the recognition accuracy of ResNet20 from 69.06% to 71.34%, and on the TinyImagenet dataset, it increases the recognition accuracy of ResNet18 from 66.54% to 68.03%, demonstrating the effectiveness and generalizability of our approach. Furthermore, there is room for further optimization of the overall distillation structure and feature extraction methods in this approach, which requires further research and exploration.

One-quarter of the world\'s population is infected with Mycobacterium tuberculosis (Mtb). After initial exposure, more immune-competent persons develop asymptomatic latent tuberculosis infection (LTBI) but not active diseases, creates an extensive reservoir at risk of developing active tuberculosis. Previously, we constructed a novel recombinant Sendai virus (SeV)-vectored vaccine encoding two dominant antigens of Mtb, which elicited immune protection against acute Mtb infection. In this study, nine Mtb latency-associated antigens were screened as potential supplementary vaccine candidate antigens, and three antigens (Rv2029c, Rv2028c, and Rv3126c) were selected based on their immune-therapeutic effect in mice, and their elevated immune responses in LTBI human populations. Then, a recombinant SeV-vectored vaccine, termed SeV986A, that expresses three latency-associated antigens and Ag85A was constructed. In murine models, the doses, titers, and inoculation sites of SeV986A were optimized, and its immunogenicity in BCG-primed and BCG-naive mice were determined. Enhanced immune protection against the Mtb challenge was shown in both acute-infection and latent-infection murine models. The expression levels of several T-cell exhaustion markers were significantly lower in the SeV986A-vaccinated group, suggesting that the expression of latency-associated antigens inhibited the T-cell exhaustion process in LTBI infection. Hence, the multistage quarter-antigenic SeV986A vaccine holds considerable promise as a novel post-exposure prophylaxis vaccine against tuberculosis.

Wire rope breakage, as damage easily produced during the service period of wire rope, is an important factor affecting the safe operation of elevators. Especially in the high-speed elevator operation process, the problem of magnetization unsaturation caused by speed effects can easily lead to deformation of the magnetic flux leakage detection signal, thereby affecting the accuracy and reliability of wire breakage quantitative detection. Therefore, this article focuses on the problem that existing wire rope detection methods cannot perform non-destructive testing on high-speed elevator wire ropes and conducts design and experimental research on a high-speed running wire rope breakage detection device based on the principle of multi-stage excitation. The main research content includes simulation research on the multistage excitation, structural design, and simulation optimization of open-close copper sheet magnetizers and the building of a detection device for wire rope breakage detection experimental research. The simulation and experimental results show that the multistage magnetization method can effectively solve the problem of magnetization unsaturation caused by the velocity effect. The multistage excitation device has a good wire breakage recognition effect for speeds less than or equal to 3 m/s. It can detect magnetic leakage signals with a minimum of four broken wires and has good detection accuracy. It is a new and effective wire breakage detection device for high-speed elevator wire rope, providing important technical support for the safe and reliable operation of high-speed elevators.

Advances in nanotechnology have brought innovations to cancer therapy. Nanoparticle-based anticancer drugs have achieved great success from bench to bedside. However, insufficient therapy efficacy due to various physiological barriers in the body remains a key challenge. To overcome these biological barriers and improve the therapeutic efficacy of cancers, multistage self-assembled nanomaterials with advantages of stimuli-responsiveness, programmable delivery, and immune modulations provide great opportunities. In this review, we describe the typical biological barriers for nanomedicines, discuss the recent achievements of multistage self-assembled nanomaterials for stimuli-responsive drug delivery, highlighting the programmable delivery nanomaterials, in situ transformable self-assembled nanomaterials, and immune-reprogramming nanomaterials. Ultimately, we perspective the future opportunities and challenges of multistage self-assembled nanomaterials for cancer immunotherapy.

UNASSIGNED: Multiple stages including hemostasis, inflammation, proliferation, and remodeling were involved in the wound healing process. The increase in nanomaterials in recent years has extended the scope of tools for wound healing; however, it is still difficult to achieve the four multistage procedures simultaneously.
UNASSIGNED: In this study, graphene-spiky silica heterostructured nanoparticles (GS) were synthesized for the procedural acceleration of the multistage in wound healing process. The nanobridge effect of GS was analyzed through the adhesion of two skins, the antibacterial effect was assessed in Gram-negative Escherichia coli (E. coli) and Gram-positive Staphylococcus aureus (S. aureus) bacteria, cell proliferation and migration were investigated in mouse embryonic fibroblast (NIH-3T3) cells, and the in vivo wound healing effect was examined in female BALB/c mice with a cutting wound and E. coli or S. aureus bacteria infection on the back.
UNASSIGNED: First, GS has a strong nanobridge effect on the rapid closure of wounds because the spiky architecture on the surface of GS facilitates the adhesion of skins, promoting the hemostasis stage. Second, graphene exhibits antimicrobial activities both in chemical and physical interactions, especially under simulated sunlight irradiation. Third, graphene plays an important role in scaffolding function, together with the spiky topographical architecture of GS, accelerating the proliferation and maturation stages.
UNASSIGNED: By periodically promoting every stage of wound healing, GS combined with simulated sunlight irradiation could significantly accelerate wound healing. With a simple composition and compact structure but multiple functions, this strategy will be the guideline for the development of ideal wound-healing nanomaterials.

This study aimed to treat real wastewater from the desulfuration and denitration process in a petrochemical plant with high-strength nitrogen (TN≈200 mg/L, > 90% nitrate), sulfate (2.7%) and extremely low-strength organics (CODCr < 30 mg/L). Heterotrophic denitrification of multistage anoxic and oxic biofilm (MAOB) process in three tanks using facultative denitrifying bacteria inoculum was developed to simultaneously achieve desirable effluent nitrogen and organics at different hydraulic retention time (HRT) and carbon to nitrogen (C/N) mass ratios. The optimum condition was recommended as a C/N ratio of 1.5 and a HRT of A (24 h)/O (12-24 h) to achieve > 90% of nitrogen and organics removal as well as no significant variation of sulfate. The denitrifying biofilm in various tanks was dominant by Hyphomicrobium (8.9%-25.7%), Methylophaga (18.6%-25.8%) and Azoarcus (3.3%-19.6%), etc., containing > 20% aerobic denitrifiers. This explained that oxic zone in MAOB process also exhibited simultaneous nitrogen and organics removal.

Improved healthcare is leading to older populations and increasing numbers of individuals experiencing multiple diseases, possibly concurrently (multimorbidity). This article asks whether the observed number of new diseases is more than expected based on age and established risk factors alone, assuming that disease risk is unchanged by prior or pre-existing disease. This is accomplished by designing a new epidemiological approach, where the expected number of disease types are estimated for individuals without prior disease, by combining individual risk predictions with a \"Poisson-Binomial\" model to estimate the expected number of new diseases and its confidence interval. For 123 diseases in men and 99 diseases in women, the expected number of new diseases based on age and established risk factors was approximately 2/3 of that observed, with the observed number of new diseases approximately 1.5 times that predicted. The differences could not be explained by natural statistical variation, and provide a rigorous statistical demonstration of lower disease risk for individuals without any previous disease. The multiple of 1.5 was sufficiently consistent across different diseases to prevent its use for classification of disease types, but there were differences for subgroups such as smokers with high body mass index, and for some classes of disease (as defined by the International Classification of Diseases, version 10). The results suggest that empirical modeling might allow reliable predictions of future hospital admissions, and confirm the value of conventional epidemiological approaches that study disease risk in healthy individuals. The implications and future possibilities of this new approach are discussed.

The wastewater with a high concentration of organics and salt is a major contaminant in the production of sauerkraut. In this study, a multistage active biological process (MSABP) system was constructed to treat sauerkraut wastewater. The key process parameters of the MSABP system were analyzed and optimized by response surface methodology. The optimization results indicated that the most optimal removal efficiencies and removal loading rates of chemical oxygen demand (COD) and NH4+-N were 87.9%, 95.5%, 2.11 kg·m-3·d-1 and 0.12 kg·m-3·d-1, respectively, with hydraulic retention time (HRT) of 2.5 d and pH of 7.3. Meanwhile, this system could also be improved for the further treatment of COD and total nitrogen by effluent recycle and ozone oxidation. The COD and total nitrogen removal efficiencies of the modified MSABP system were 99.9% and 60.2%, respectively. In addition, the modified system could also reduce the potential harm from high concentrations of NO2--N.