Search

Abstract Background Human adenovirus type 7 (HAdV7) has become a major public health threat due to its widespread transmission, severe associated pneumonia, and a lack of effective anti-HAdV7 drugs. The aim of the current study is to design a humanized monoclonal antibody (mAb) demonstrating efficacy against HAdV-7 infections in vitro and in vivo. Methods The humanized neutralizing antibody, 3G5-hu, was derived from the murine mAb 3G5. Antibody activity was evaluated using a flow cytometry-based neutralization (FCN) assay to identify humanized mAbs retaining potent neutralizing activity. Additionally, a humanized hDSG2/hCD46 dual-receptor transgenic mouse model was developed to simulate HAdV-7 infection. Results Using recombinant HAdV-7 expressing enhanced green fluorescent protein and clinically isolated wild-type HAdV-7, the half-maximal effective concentration of 3G5-hu against HAdV-7 was determined to be

Abstract DNA methylation plays a significant role in regulating transcription and exhibits a systematic change with age. These changes can be used to predict an individual’s age. First, to identify methylation sites associated with biological age; second, to construct a biological age prediction model and preliminarily explore the biological significance of methylation-associated genes using machine learning. A biological age prediction model was constructed using human methylation data through data preprocessing, feature selection procedures, statistical analysis, and machine learning techniques. Subsequently, 15 methylation data sets were subjected to in-depth analysis using SHAP, GO enrichment, and KEGG analysis. XGBoost, LightGBM, and CatBoost identified 15 groups of methylation sites associated with biological age. The cg23995914 locus was identified as the most significant contributor to predicting biological age by calculating SHAP values. Furthermore, GO enrichment and KEGG analyses were employed to initially explore the methylated loci’s biological significance.

Abstract Despite extensive astrocyte activation in patients suffering from HIV-associated neurocognitive disorders (HAND), little is known about the contribution of astrocytes to HAND neuropathology. Here, we report that the robust activation of neurotoxic astrocytes (A1 astrocytes) in the CNS promotes neuron damage and cognitive deficits in HIV-1 gp120 transgenic mice. Notably, knockout of α7 nicotinic acetylcholine receptors (α7nAChR) blunted A1 astrocyte responses, ultimately facilitating neuronal and cognitive improvement in the gp120tg mice. Furthermore, we provide evidence that Kynurenic acid (KYNA), a tryptophan metabolite with α7nAChR inhibitory properties, attenuates gp120-induced A1 astrocyte formation through the blockade of α7nAChR/JAK2/STAT3 signaling activation. Meanwhile, compared with gp120tg mice, mice fed with tryptophan showed dramatic improvement in cognitive performance, which was related to the inhibition of A1 astrocyte responses. These initial and determinant findings mark a turning point in our understanding of the role of α7nAChR in gp120-mediated A1 astrocyte activation, opening up new opportunities to control neurotoxic astrocyte generation through KYNA and tryptophan administration.

Despite the availability of antibiotics over the last several decades, excessive antibiotic treatments for bacterial sepsis and meningitis (BSM) in children may result in several adverse outcomes. Hematogenous pathogens may directly induce permeability increases in human brain microvascular endothelial cells (HBMECs) and blood–brain barrier (BBB) dysfunctions. Our preliminary studies demonstrated that the alpha7 nicotinic acetylcholine receptor (α7nAChR) played an important role in the pathogenesis of BSM, accompanied by increasing cytokine-inducible SH2-containing protein (CISH) at the transcriptome level, but it has remained unclear how α7nAChR-CISH works mechanistically. The study aims to explore the underlying mechanism of α7nAChR and CISH during E. coli-induced BSM in vitro (HBMECs) and in vivo (α7nAChR-KO mouse). We found that in the stage of E. coli K1-induced BBB disruptions, α7nAChR functioned as the key regulator that affects the integrity of HBMECs by activating the JAK2–STAT5 signaling pathway, while CISH inhibited JAK2–STAT5 activation and exhibited protective effects against E. coli infection. Notably, we first validated that the expression of CISH could be regulated by α7nAChR in HBMECs. In addition, we determined the protective effects of MLA (methyllycaconitine citrate) and MEM (memantine hydrochloride) (functioning as α7nAChR antagonists) on infected HBMECs and suggested that the α7nAChR–CISH axis could explain the protective effects of the two small-molecule compounds on E. coli-induced HBMECs injuries and BBB disruptions. In conclusion, we dissected the α7nAChR/CISH/JAK2/STAT5 axis as critical for the pathogenesis of E. coli-induced brain microvascular leakage and BBB disruptions and provided novel evidence for the development of α7nAChR antagonists in the prevention of pediatric E. coli BSM.

Fertility preservation and assisted reproductive medicine require effective culture systems for the successful proliferation and differentiation of spermatogonial stem cells (SSCs). Many SSC culture systems require the addition of feeder cells at each subculture, which is tedious and inefficient. Here, we prepared decellularized testicular matrix (DTM) from testicular tissue, which preserved essential structural proteins of testis. The DTM was then solubilized and induced to form a porous hydrogel scaffold with randomly oriented fibrillar structures that exhibited good cytocompatibility. The viability of SSCs inoculated onto DTM hydrogel scaffolds was significantly higher than those inoculated on Matrigel or laminin, and intracellular gene expression and DNA imprinting patterns were similar to that of native SSCs. Additionally, DTM promoted SSC differentiation into round spermatids. More importantly, the DTM hydrogel supported SSC proliferation and differentiation without requiring additional somatic cells. The DTM hydrogel scaffold culture system provided an alternative and simple method for culturing SSCs that eliminates potential variability and contamination caused by feeder cells. It might be a valuable tool for reproductive medicine.