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Hand, foot, and mouth disease is a common childhood illness primarily caused by coxsackievirus A16 (CVA16), for which there are no current vaccines or treatments. We identify three CVA16-specific neutralizing monoclonal antibodies (nAbs) with therapeutic potential: 18A7, 14B10, and NA9D7. We present atomic structures of these nAbs bound to all three viral particle forms-the mature virion, A-particle, and empty particle-and show that each Fab can simultaneously occupy the mature virion. Additionally, 14B10 or NA9D7 provide 100% protection against lethal CVA16 infection in a neonatal mouse model. 18A7 binds to a non-conserved epitope present in all three particles, whereas 14B10 and NA9D7 recognize broad protective epitopes but only bind the mature virion. NA9D7 targets an immunodominant site, which may overlap the receptor-binding site. These findings indicate that CVA16 vaccines should be based on mature virions and that these antibodies could be used to discriminate optimal virion-based immunogens.

Enterovirus D68 (EV-D68) undergoes structural transformation between mature, cell-entry intermediate (A-particle) and empty forms throughout its life cycle. Structural information for the various forms and antibody-bound capsids will facilitate the development of effective vaccines and therapeutics against EV-D68 infection, which causes childhood respiratory and paralytic diseases worldwide. Here, we report the structures of three EV-D68 capsid states representing the virus at major phases. We further describe two original monoclonal antibodies (15C5 and 11G1) with distinct structurally defined mechanisms for virus neutralization. 15C5 and 11G1 engage the capsid loci at icosahedral three-fold and five-fold axes, respectively. To block viral attachment, 15C5 binds three forms of capsids, and triggers mature virions to transform into A-particles, mimicking engagement by the functional receptor ICAM-5, whereas 11G1 exclusively recognizes the A-particle. Our data provide a structural and molecular explanation for the transition of picornavirus capsid conformations and demonstrate distinct mechanisms for antibody-mediated neutralization.

Coxsackievirus A10 (CVA10) recently emerged as a major pathogen of hand, foot, and mouth disease and herpangina in children worldwide, and lack of a vaccine or a cure against CVA10 infections has made therapeutic antibody identification a public health priority. By targeting a local isolate, CVA10-FJ-01, we obtained a potent antibody, 2G8, against all three capsid forms of CVA10. We show that 2G8 exhibited both 100% preventive and 100% therapeutic efficacy against CVA10 infection in mice. Comparisons of the near-atomic cryo-electron microscopy structures of the three forms of CVA10 capsid and their complexes with 2G8 Fab reveal that a single Fab binds a border region across the three capsid proteins (VP1 to VP3) and explain 2G8's remarkable cross-reactivities against all three capsid forms. The atomic structures of this first neutralizing antibody of CVA10 should inform strategies for designing vaccines and therapeutics against CVA10 infections.

Coxsackievirus A6 (CVA6) has recently emerged as a major cause of hand, foot and mouth disease in children worldwide but no vaccine is available against CVA6 infections. Here, we demonstrate the isolation of two forms of stable CVA6 particles-procapsid and A-particle-with excellent biochemical stability and natural antigenicity to serve as vaccine candidates. Despite the presence (in A-particle) or absence (in procapsid) of capsid-RNA interactions, the two CVA6 particles have essentially identical atomic capsid structures resembling the uncoating intermediates of other enteroviruses. Our near-atomic resolution structure of CVA6 A-particle complexed with a neutralizing antibody maps an immune-dominant neutralizing epitope to the surface loops of VP1. The structure-guided cell-based inhibition studies further demonstrate that these loops could serve as excellent targets for designing anti-CVA6 vaccines.Coxsackievirus A6 (CVA6) causes hand, foot and mouth disease in children. Here the authors present the CVA6 procapsid and A-particle cryo-EM structures and identify an immune-dominant neutralizing epitope, which can be exploited for vaccine development.

With the development of science and technology, the design of integrated circuit becomes more and more complex.In the design process, the division of hardware and software also produces more choices. In order to meet the complex design requirements for integrated circuits, the development and design of SystemC, which inherits the C + + extension library, came into being. SytemC can meet the requirements of hardware and software codesign, and can be quickly simulated and verified in the design process. In this paper, the communication protocol(ISO/IEC 18000-6C) is modeled and designed at a higher level. The protocol communication between interrogator and tag is realized by function call. For UHF RFID(Ultra High Frequency Radio Frequency Identification)communication protocol, from system level design to behavior level design, the top-down design of the protocol is realized, and the design of tag identification layer and baseband communication link layer is completed. Finally, the source code of this systemc is transformed into Verilog and other hardware description languages by using Vivado HLS synthesis software, and the software description of system level is synthesized into RTL code. This paper focuses on label baseband link encode_T module, after FM0 / Miller coding simulation of data "1001001001011001" in Microsoft Visual C++ 6.0, the waveform verification is completed in Modelsim, and it is transformed into RTL level circuit by Vivado HLS integrated software.

The simultaneous detection of multiple stimuli, such as pressure and temperature, has long been a persistent challenge for developing electronic skin (e‐skin) to emulate the functionality of human skin. Meanwhile, the demand for integrated power supply units is an additional pressing concern to achieve its lightweightness and flexibility. Herein, we propose a self‐powered dual temperature–pressure (SPDM) sensor, which utilizes a compressible ionic gel electrolyte driven by the potential difference between MXene and Al electrodes. The SPDM sensor exhibits a rapid and timely response to changes in pressure‐induced deformation, while exhibiting a slow and hysteretic response to temperature variations. These distinct response characteristics enable the differentiation of current signals generated by different stimuli through machine learning, resulting in an impressive accuracy rate of 99.1%. Furthermore, the developed SPDM sensor exhibits a wide pressure detection range of 0–800 kPa and a broad temperature detection range of 5–75°C, encompassing the environmental conditions encountered in daily human life. The dual‐mode coupled strategy by machine learning provides an effective approach for temperature and pressure detection and discrimination, showcasing its potential applications in wearable electronics, intelligent robots, human–machine interactions, and so on. [ABSTRACT FROM AUTHOR]

For fixing the parametric design problem of blasting with water-coupled medium and improving the rock breaking quality, efforts should be made to quantify and examine the blasthole pressure and the explosive crack growth length in the scenario of blasting with water-coupled medium. The water medium was treated as an ideal fluid on the precondition that its flow velocity and internal energy would change continuously with time. Under the elastic wave theory and combining the propagation law of shock wave in water and rock or rock-like medium, the pressure, velocity, and other parameters in relation to shock wave at the interface between explosive and water, in the water medium, and in the peripheral medium after the occurrence of transmission and reflection at the interface between water and hole wall, were subject to theoretical calculations. As a result, the equation for the peak blasthole pressure in the scenarios of explosive and hole wall medium parameters was derived. Further considering the weakening effect of sparse wave on shock wave and the effect of multiple reflections superimposed on shock wave by the hole wall medium, the equation for the attenuation of blasthole pressure as a function of the time constant T was obtained. Next, the prediction model for crack length in the scenario of blasting with water-coupled medium was constructed by the aforementioned equation for calculation of blasthole pressure in the scenario of blasting and according to the model for explosive gas-driven one-dimensional crack growth. Finally, the blasthole pressure and one-dimensional crack length applicable to the explosive and hole wall medium parameter with decoupled coefficients of 1.33, 1.67, 2.00, 2.67, and 3.33 at a given time point were examined by combining the derived equations for theoretical calculations and numerical simulations. Results showed that in the scenario of blasting with water-coupled medium, the blasthole pressure would reduce as the decoupled coefficient η increases, and it is significantly influenced by η, up to 25% even above 50%. Similarly, the crack length would reduce as the decoupled coefficient η increases, but it is slightly influenced by η, only at 15% or so in general. [ABSTRACT FROM AUTHOR]

Extracellular vesicles (EVs) have emerged as a promising platform for gene delivery owing to their natural properties and phenomenal functions, being able to circumvent the significant challenges associated with toxicity, problematic biocompatibility, and immunogenicity of the standard approaches. These features are of particularly interest for targeted delivery of the emerging clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated (Cas) systems. However, the current efficiency of EV-meditated transport of CRISPR/Cas components remains insufficient due to numerous exogenous and endogenous barriers. Here, we comprehensively reviewed the current status of EV-based CRISPR/Cas delivery systems. In particular, we explored various strategies and methodologies available to potentially improve the loading capacity, safety, stability, targeting, and tracking for EV-based CRISPR/Cas system delivery. Additionally, we hypothesise the future avenues for the development of EV-based delivery systems that could pave the way for novel clinically valuable gene delivery approaches, and may potentially bridge the gap between gene editing technologies and the laboratory/clinical application of gene therapies. [ABSTRACT FROM AUTHOR]

Psoriasis is a chronic and multifactorial skin disease which is caused by inflammatory infiltrates, keratinocyte hyperproliferation, and accumulation of immune cells. As part of the Aconitum species, Benzoylaconitine (BAC) shows potential antiviral, anti-tumor, and anti-inflammatory effects. In this study, we investigated the effects and mechanisms of BAC on tumor necrosis factor-alpha (TNF-α)/LPS-induced HaCaT keratinocytes in a imiquimod(IMQ)-induced mice model. The results showed that BAC could relieve the symptoms of psoriasis by inhibiting cell proliferation, the release of inflammatory factors, and the accumulation of Th17 cells, while no obvious effect on cell viability and safety was observed both in vitro and in vivo. Additionally, BAC can markedly inhibit the protein and mRNA levels of inflammatory cytokines in TNF-α/LPS-induced HaCaT keratinocytes by inhibiting the phosphorylation of STAT3. In brief, our data indicated that BAC could alleviate the progression of psoriasis and may be a potential therapeutic agent for treating psoriasis in clinical practice. [ABSTRACT FROM AUTHOR]