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The development and application of virtual reality technology can help the innovative application of environmental design. This paper first focuses on the application of virtual reality technology in the natural environment based on the development of environmental design and the integration of natural geographical conditions. In fact, the focus is on the analysis of virtual reality technology. Selected 3D reconstruction technology algorithms, including camera calibration profile, pair of polar geometry and single response matrix, matching cost and quality assessment index. Finally, the natural environment simulation experiment is constructed based on virtual reality technology. The average real-time rendering FPS of the unoptimized vegetation distribution interval decreases continuously with the increase in the number of vegetation models. When the average vegetation number is around 54,672, the average FPS decreases to around per 53. When the average vegetation count is at 97,713, the average FPS drops to about 28 frames per second. The average real-time dye FPS stabilizes at around 50 after using the LOD multi-detail hierarchical model.

Severe respiratory infections can result in acute respiratory distress syndrome (ARDS) 1 . There are no effective pharmacological therapies that have been shown to improve outcomes for patients with ARDS. Although the host inflammatory response limits spread of and eventually clears the pathogen, immunopathology is a major contributor to tissue damage and ARDS 1 , 2 . Here we demonstrate that respiratory viral infection induces distinct fibroblast activation states, which we term extracellular matrix (ECM)-synthesizing, damage-responsive and interferon-responsive states. We provide evidence that excess activity of damage-responsive lung fibroblasts drives lethal immunopathology during severe influenza virus infection. By producing ECM-remodelling enzymes—in particular the ECM protease ADAMTS4—and inflammatory cytokines, damage-responsive fibroblasts modify the lung microenvironment to promote robust immune cell infiltration at the expense of lung function. In three cohorts of human participants, the levels of ADAMTS4 in the lower respiratory tract were associated with the severity of infection with seasonal or avian influenza virus. A therapeutic agent that targets the ECM protease activity of damage-responsive lung fibroblasts could provide a promising approach to preserving lung function and improving clinical outcomes following severe respiratory infections. Viral infection of the respiratory system induces exuberant fibroblast activity, resulting in extensive remodelling of the extracellular matrix and cytokine release, which promote immune cell infiltration of the affected area at the expense of respiratory function.

Ageing is the single greatest cause of disease and death worldwide, and understanding the associated processes could vastly improve quality of life. Although major categories of ageing damage have been identified—such as altered intercellular communication, loss of proteostasis and eroded mitochondrial function 1 —these deleterious processes interact with extraordinary complexity within and between organs, and a comprehensive, whole-organism analysis of ageing dynamics has been lacking. Here we performed bulk RNA sequencing of 17 organs and plasma proteomics at 10 ages across the lifespan of Mus musculus , and integrated these findings with data from the accompanying Tabula Muris Senis 2 —or ‘Mouse Ageing Cell Atlas’—which follows on from the original Tabula Muris 3 . We reveal linear and nonlinear shifts in gene expression during ageing, with the associated genes clustered in consistent trajectory groups with coherent biological functions—including extracellular matrix regulation, unfolded protein binding, mitochondrial function, and inflammatory and immune response. Notably, these gene sets show similar expression across tissues, differing only in the amplitude and the age of onset of expression. Widespread activation of immune cells is especially pronounced, and is first detectable in white adipose depots during middle age. Single-cell RNA sequencing confirms the accumulation of T cells and B cells in adipose tissue—including plasma cells that express immunoglobulin J—which also accrue concurrently across diverse organs. Finally, we show how gene expression shifts in distinct tissues are highly correlated with corresponding protein levels in plasma, thus potentially contributing to the ageing of the systemic circulation. Together, these data demonstrate a similar yet asynchronous inter- and intra-organ progression of ageing, providing a foundation from which to track systemic sources of declining health at old age. Bulk RNA sequencing of organs and plasma proteomics at different ages across the mouse lifespan is integrated with data from the Tabula Muris Senis , a transcriptomic atlas of ageing mouse tissues, to describe organ-specific changes in gene expression during ageing.

Skeletal muscle regenerates through the activation of resident stem cells. Termed satellite cells, these normally quiescent cells are induced to proliferate by wound-derived signals 1 . Identifying the source and nature of these cues has been hampered by an inability to visualize the complex cell interactions that occur within the wound. Here we use muscle injury models in zebrafish to systematically capture the interactions between satellite cells and the innate immune system after injury, in real time, throughout the repair process. This analysis revealed that a specific subset of macrophages ‘dwell’ within the injury, establishing a transient but obligate niche for stem cell proliferation. Single-cell profiling identified proliferative signals that are secreted by dwelling macrophages, which include the cytokine nicotinamide phosphoribosyltransferase (Nampt, which is also known as visfatin or PBEF in humans). Nampt secretion from the macrophage niche is required for muscle regeneration, acting through the C-C motif chemokine receptor type 5 (Ccr5), which is expressed on muscle stem cells. This analysis shows that in addition to their ability to modulate the immune response, specific macrophage populations also provide a transient stem-cell-activating niche, directly supplying proliferation-inducing cues that govern the repair process that is mediated by muscle stem cells. This study demonstrates that macrophage-derived niche signals for muscle stem cells, such as NAMPT, can be applied as new therapeutic modalities for skeletal muscle injury and disease. Specific macrophage populations provide a transient niche that activates muscle stem cells after muscle injury and supply proliferation-inducing cues that govern the repair process mediated by these cells in both zebrafish and mouse injury models.

ObjectiveIncreasing evidence suggests that impaired cartilage is a substantial risk factor for the progression from hyperuricaemia to gout. Since the relationship between cartilage matrix protein and gout flares remains unclear, we investigated its role in monosodium urate (MSU) crystallisation and following inflammation.MethodsBriefly, we screened for cartilage matrix in synovial fluid from gouty arthritis patients with cartilage injuries. After identifying a correlation between crystals and matrix molecules, we conducted image analysis and classification of crystal phenotypes according to their morphology. We then evaluated the differences between the cartilage matrix protein-MSU complex and the pure MSU crystal in their interaction with immune cells and identified the related signalling pathway.ResultsType II collagen (CII) was found to be enriched around MSU crystals in synovial fluid after cartilage injury. Imaging analysis revealed that CII regulated the morphology of single crystals and the alignment of crystal bows in the co-crystalline system, leading to greater phagocytosis and oxidative stress in macrophages. Furthermore, CII upregulated MSU-induced chemokine and proinflammatory cytokine expression in macrophages, thereby promoting the recruitment of leucocytes. Mechanistically, CII enhanced MSU-mediated inflammation by activating the integrin β1(ITGB1)-dependent TLR2/4-NF-κB signal pathway.ConclusionOur study demonstrates that the release of CII and protein-crystal adsorption modifies the crystal profile and promotes the early immune response in MSU-mediated inflammation. These findings open up a new path for understanding the relationship between cartilage injuries and the early immune response in gout flares.

Objective: The aim of the present study was to investigate the association of polymorphic variants in matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-3 (MMP-3) genes and the occurrence of persistent apical periodontitis (PAP). Methods: DNA samples from 180 individuals were recruited and divided into two groups: Case group, 79 subjects with a history of PAP; control group, 101 healthy subjects. Five single nucleotide polymorphisms (SNPs) were selected for genotyping: rs243865, rs2285053, and rs2287074 in the MMP-2 gene, and rs679620 and rs522616 in the MMP-3 gene. The chi-square test or Exact Fisher (p < 0.05) and Odds Ratio (CI = 95%) were used to compare the frequencies of genotypes and alleles between the two groups. Results: A positive association was found for the MMP-3 rs522616 AG genotype (p = 0.025), the AG + GG genotypes (p = 0.015), and the G allele (p = 0.016) with PAP. Conclusions: The MMP-3 variant rs522616 was associated with PAP. Similar studies are needed analyzing other genes involved in extracellular matrix dynamics under inflammatory conditions to clarify the role of the genetic factors of PAP.

Cardiovascular diseases (CVD) and type 2 diabetes (T2D) are closely interrelated complex diseases likely sharing overlapping pathogenesis driven by aberrant activities in gene networks. However, the molecular circuitries underlying the pathogenic commonalities remain poorly understood. We sought to identify the shared gene networks and their key intervening drivers for both CVD and T2D by conducting a comprehensive integrative analysis driven by five multi-ethnic genome-wide association studies (GWAS) for CVD and T2D, expression quantitative trait loci (eQTLs), ENCODE, and tissue-specific gene network models (both co-expression and graphical models) from CVD and T2D relevant tissues. We identified pathways regulating the metabolism of lipids, glucose, and branched-chain amino acids, along with those governing oxidation, extracellular matrix, immune response, and neuronal system as shared pathogenic processes for both diseases. Further, we uncovered 15 key drivers including HMGCR, CAV1, IGF1 and PCOLCE, whose network neighbors collectively account for approximately 35% of known GWAS hits for CVD and 22% for T2D. Finally, we cross-validated the regulatory role of the top key drivers using in vitro siRNA knockdown, in vivo gene knockout, and two Hybrid Mouse Diversity Panels each comprised of >100 strains. Findings from this in-depth assessment of genetic and functional data from multiple human cohorts provide strong support that common sets of tissue-specific molecular networks drive the pathogenesis of both CVD and T2D across ethnicities and help prioritize new therapeutic avenues for both CVD and T2D.

Juvenile scleroderma (JS), comprising localized (JLSd) and systemic (JSSc) forms, is a rare autoimmune disorder. This study investigated associations of polymorphisms in extracellular matrix (MMP1, MMP9) and vascular homeostasis (NOS3) genes with JS risk and immunological phenotypes. A case–control study involved 215JS patients (194 JLSd, 21 JSSc) and 72 controls. SNPs (MMP1 rs1799750, MMP9 rs3918242, NOS3 rs1799983) were genotyped using real-time PCR followed by minisequencing and mass spectrometric analysis of reaction products. Associations with disease risk, subtypes, and immunological markers were analyzed statistically. The MMP9 (rs3918242) CT genotype was significantly associated with JLSd (OR = 2.23, 95% CI: 1.14–4.37, p = 0.022), showing a trend in linear facial forms. The NOS3 (rs1799983) GG genotype demonstrated a trend toward association with JSSc (OR = 2.61, 95% CI: 0.92–7.37, p = 0.065). No significant associations were found for rs1799750 MMP1 and risk of disease development. The MMP9 risk genotype did not correlate with scleroderma-specific autoantibodies, while the NOS3 GG genotype was associated with lower serum levels of anti-collagen IV antibodies (p = 0.039). Genetic associations differ for JS subtypes: MMP9 with JLSd and NOS3 with JSSc. Children with CT polymorphism MMP9 (rs3918242) and with NOS3 (rs1799983) GG genotype were found to be genetically predisposed for the development of JS.

Influenza, commonly referred to as “flu,” is a major global public health concern and a huge economic burden to societies. Current influenza vaccines need to be updated annually to match circulating strains, resulting in low take-up rates and poor coverage due to inaccurate prediction. Broadly protective universal flu vaccines that do not need to be updated annually have therefore been pursued. The highly conserved 24–amino acid ectodomain of M2 protein (M2e) is a leading candidate, but its poor immunogenicity has been a major roadblock in its clinical development. Here, we report a targeting strategy that shuttles M2e to a specific dendritic cell subset (cDC1) by engineering a recombinant anti-Clec9A monoclonal antibody fused at each of its heavy chains with three copies of M2e. Single administration in mice of 2 μg of the Clec9A–M2e construct triggered an exceptionally sustained anti-M2e antibody response and resulted in a strong anamnestic protective response upon influenza challenge. Furthermore, and importantly, Clec9A–M2e immunization significantly boosted preexisting anti-M2e titers from prior flu exposure. Thus, the Clec9A-targeting strategy allows antigen and dose sparing, addressing the shortcomings of current M2e vaccine candidates. As the cDC1 subset exists in humans, translation to humans is an exciting and realistic avenue.

Among the emerging strategies for cancer theranostics, nanomedicines offer significant promise in advancing both patients’ diagnosis and treatment. In combination with nanobodies, nanomedicines can potentially enhance the precision and efficiency of drug or imaging agent delivery, addressing key limitations of current approaches, such as off-target toxicities. The development of nanomedicines will be further accelerated by the creation of smart nanoparticles, and their integration with immunotherapy. Obviously, the success of nano-immunotherapy will depend on a comprehensive understanding of the tumor microenvironment, including the complex interplay of mechanisms that drive cancer-mediated immunosuppression and immune escape. Hence, effective therapeutic targeting of the tumor microenvironment requires modulation of immune cell function, overcoming resistance mechanisms associated with stromal components or the extracellular matrix, and/or direct elimination of cancer cells. Identifying key molecules involved in cancer progression and drug resistance is, therefore, essential for developing effective therapies and diagnostic tools that can predict patient responses to treatment and monitor therapeutic outcomes. Current nanomedicines are being designed with careful consideration of factors such as the choice of carrier (e.g., biocompatibility, controlled cargo release) and targeting moiety. The unique properties of nanobodies make them an effective engineering tool to target biological molecules with high affinity and specificity. In this review, we focus on the latest applications of nanobodies for targeting various components of the tumor microenvironment for diagnostic and therapeutic purposes. We also explore the main types of nanoparticles used as a carrier for cancer immunotherapies, as well as the strategies for formulating nanoparticle-nanobody conjugates. Finally, we highlight how nanobody-nanoparticle formulations can enhance current nanomedicines.