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Taking into account the effects of the immune response and delay, and complexity on HIV-1 transmission, a multiscale AIDS/HIV-1 model is formulated in this paper. The multiscale model is described by a within-host fast time model with intracellular delay and immune delay, and a between-host slow time model with latency delay. The dynamics of the fast time model is analyzed, and includes the stability of equilibria and properties of Hopf bifurcation. Further, for the coupled slow time model without an immune response, the basic reproduction number R 0 h is defined, which determines whether the model may have zero, one, or two positive equilibria under different conditions. This implies that the slow time model demonstrates more complex dynamic behaviors, including saddle-node bifurcation, backward bifurcation, and Hopf bifurcation. For the other case, that is, the coupled slow time model with an immune response, the threshold dynamics, based on the basic reproduction number R ˜ 0 h , is rigorously investigated. More specifically, if R ˜ 0 h < 1 , the disease-free equilibrium is globally asymptotically stable; if R ˜ 0 h > 1 , the model exhibits a unique endemic equilibrium that is globally asymptotically stable. With regard to the coupled slow time model with an immune response and stable periodic solution, the basic reproduction number R 0 is derived, which serves as a threshold value determining whether the disease will die out or lead to periodic oscillations in its prevalence. The research results suggest that the disease is more easily controlled when hosts have an extensive immune response and the time required for new immune particles to emerge in response to antigenic stimulation is within a certain range. Finally, numerical simulations are presented to validate the main results and provide some recommendations for controlling the spread of HIV-1. [ABSTRACT FROM AUTHOR]

Immunomodulatory biomaterials are increasingly used in regenerative medicine. Biomimetic glycopeptide hydrogel is found to accelerate cutaneous wound healing by inducing macrophage M2‐type polarization, however, it is unclear whether this will possibly orchestrate a pro‐regenerative T cell immunity. Here the aim of this study is to elucidate the reparative T‐cell immune response in tissue regeneration by augmenting macrophage‐T cell crosstalk with a novel immunomodulatory glycopeptide hydrogel (termed as GRKgel) self‐assembled by mannose receptor‐binding glucomannan (GM) chemically grafted with RADA16‐conjugated T‐cell epitope. The glycopeptide can be phagocytized and processed by macrophages, which then presents peptides to naïve T cells and polarizes them into T helper 2 (TH2) cells through IL‐4‐dependent STAT6/GATA3 or c‐Maf pathways. Strikingly, full‐thickness skin wound repair in mice indicates a superior efficacy of GRKgel on restoring the pathological structure and hair follicle by provoking TH2 immune response, increasing the residence of M2 macrophages, as well as promoting angiogenesis at the local tissue environment. Furthermore, genomics results illustrates the role of GRKgel serving as an immunomodulatory niche, orchestrating immune cell crosstalk and promoting extracellular matrix (ECM) reconstruction. Collectively, this study highlights the significance of crosstalk between immune cells in evoking pro‐healing T‐cell immunity, providing a promising drug‐/cytokine‐free strategy for endogenous tissue regeneration. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is one of the most common malignant tumours and the third most common cause of cancer deaths worldwide, with high morbidity and mortality. Circadian clocks are widespread in humans and temporally regulate physiologic functions to maintain homeostasis. Recent studies showed that circadian components were strong regulators of the tumour immune microenvironment (TIME) and the immunogenicity of CRC cells. Therefore, insight into immunotherapy from the perspective of circadian clocks can be promising. Although immunotherapy, especially immune checkpoint inhibitor (ICI) treatment, has been a milestone in cancer treatment, greater accuracy is still needed for selecting patients who will respond positively to immunotherapy with minimal side effects. In addition, there were few reviews focusing on the role of the circadian components in the TIME and the immunogenicity of CRC cells. Therefore, this review highlights the crosstalk between the TIME in CRC and the immunogenicity of CRC cells based on the circadian clocks. With the goal to achieve the possibility that patients with CRC can benefit most from the ICI treatment, we provide potential evidence and a novel idea for building a predictive framework combined with circadian factors, searching for enhancers of ICIs targeting circadian components and clinically implementing the timing of ICI treatment for patients with CRC. [ABSTRACT FROM AUTHOR]

Rab GTPases not only play a crucial role in the exocytosis and membrane transport of all eukaryotic cells, but are also gradually being found to be involved in innate immunity in mammals. However, the immunological function of Rab3a in fish remains unclear. In this study, two members of Rab3a, CiRab3aa and CiRab3ab, were cloned from grass carp (Ctenopharyngodon idella) for the first time. It was observed that CiRab3aa exhibited a prompt response to grass carp reovirus (GCRV) infection, and suppressing the expression of the CiRab3aa effectively inhibited GCRV replication, whereas the expression level of the CiRab3ab gene did not affect GCRV replication. Furthermore, overexpression of CiRab3aa significantly suppressed the mRNA levels of TLR9 , TNF-α , IL-1β , IL-6 , IL-10 , ERK , and IFN-I following stimulation with CpG ODN 1670 A, suggesting that CiRab3aa is a negative regulator of TLR9 signaling pathway. In conclusion, this study not only revealed functional differences between CiRab3aa and CiRab3ab in grass carp immunity, providing new sights into understanding their function in teleost fish, but also provided a new target for the treatment strategy of grass carp hemorrhagic disease. These results will help address the harm and economic losses caused by GCRV infection in grass carp breeding industry. • CiRab3aa and CiRab3ab genes were cloned and characterized in grass carp. • There are 7 amino acid differences in the Rab domain of Rab3aa and Rab3aa protein. • Knockdown of CiRab3aa significantly inhibited the replication of GCRV. • CiRab3aa was a negative regulator of the TLR9 signaling pathway. [ABSTRACT FROM AUTHOR]

Background: Grass carp are an important farmed fish in China that are infected by many pathogens, especially grass carp reovirus (GCRV). Notably, grass carp showed age-dependent susceptibility to GCRV; that is, grass carp not older than one year were sensitive to GCRV, while those over three years old were resistant to this virus. However, the underlying mechanism remains unclear. Herein, whole genome-wide DNA methylation and gene expression variations between susceptible five-month-old (FMO) and resistant three-year-old (TYO) grass carp were investigated aiming to uncover potential epigenetic mechanisms. Results: Colorimetric quantification revealed that the global methylation level in TYO fish was higher than that in FMO fish. Whole-genome bisulfite sequencing (WGBS) of the two groups revealed 6214 differentially methylated regions (DMRs) and 4052 differentially methylated genes (DMGs), with most DMRs and DMGs showing hypermethylation patterns in TYO fish. Correlation analysis revealed that DNA hypomethylation in promoter regions and DNA hypermethylation in gene body regions were associated with gene expression. Enrichment analysis revealed that promoter hypo-DMGs in TYO fish were significantly enriched in typical immune response pathways, whereas gene body hyper-DMGs in TYO fish were significantly enriched in terms related to RNA transcription, biosynthesis, and energy production. RNA-seq analysis of the corresponding samples indicated that most of the genes in the above terms were upregulated in TYO fish. Moreover, gene function analysis revealed that the two genes involved in energy metabolism displayed antiviral effects. Conclusions: Collectively, these results revealed genome-wide variations in DNA methylation between grass carp of different ages. DNA methylation and gene expression variations in genes involved in immune response, biosynthesis, and energy production may contribute to age-dependent susceptibility to GCRV in grass carp. Our results provide important information for disease-resistant breeding programs for grass carp and may also benefit research on age-dependent diseases in humans. [ABSTRACT FROM AUTHOR]