Biology subjects

Si, X.

Publications and source records attributed to Si, X..

5 recordsLinked to original sources

bioRxiv2023

Lactose and its derivatives are a new class of immune checkpoint inhibitors for cancer therapy

Understanding the mechanisms by which the immune system surveils cancer is the key to developing better tumor immunotherapy strategies. By CRISPR/Cas9 screenings, we identified that inactivation of beta-1,4-galactosyltransferase-1 (B4GALT1), a key enzyme in glycoconjugate biosynthesis, leads to enhanced T-cell receptor (TCR) activation and functions of CD8+ T-cells. Via proximity-dependent-intercellular-protein-spreading (PDICPS), cancer cells transfer surface-bound galectin-1 (Gal-1) proteins, which recognize and bind galactosylated membrane proteins, to CD8+ T-cells, thereby suppressing T-cell-mediated cytolysis. B4GALT1-deficiency leads to reduced cell-surface galactosylation and Gal-1 binding of CD8+ T-cells. Proteomic analysis revealed reduced binding of Gal-1 with TCR and its coreceptor CD8 on B4GALT1-deficient CD8+ T-cells, leading to enhanced TCR-CD8 colocalization and T-cell activation. Lactose, a structure-mimicking competitive inhibitor of N-glycan galactosylation, enhances the functions of CD8+ T-cells and tumor immunosurveillance. Results from various preclinical tumor models demonstrate that lactose and its derivatives are a new class of immune checkpoint inhibitors for tumor immunotherapy.

immunology↗

bioRxiv2023

Discovery of a Novel Chemotype as DYRK1A Inhibitors against Alzheimer's disease: Computational Modeling and Biological Evaluation

Dual specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) plays an essential role in tau and A{beta} pathology closely related to Alzheimers disease (AD). Accumulative evidence has demonstrated DYRK1A inhibition is able to reduce the pathological features of AD. Nevertheless, there is no approved DYRK1A inhibitors for clinical use as anti-AD drugs. This is somewhat the lack of effective and safe chemotypes of DYRK1A inhibitors. To address this issue, we carried out in silico screening, in vitro assays and in vivo efficacy evaluation with the aim to discover a new class of DYRK1A inhibitors for potential treatment of AD. By in silico screening, we selected and purchased 16 potential DYRK1A inhibitors from the Specs chemical library. Among them, compound Q17 (Specs ID: AO-476/40829177) potently inhibited DYRK1A. The hydrogen bonds between compound Q17 and each of three amino acid residues named GLU239, LEU241 and LYS188, were uncovered by molecular docking and molecular dynamics simulation. The cell-based assays showed that compound Q17 could protect SH-SY5Y cells from okadaic acid (OA)-induced injury by targeting DYRK1A. More importantly, compound Q17 significantly improved cognitive dysfunction in 3xTg-AD mice, ameliorated pathological changes, and reduced the expression of DYRK1A, GSK-3{beta} and GSK-3{beta} (pSer9), attenuated tau hyperphosphorylation and A{beta} deposition as well. In summary, our computational modeling strategy is effective to identify novel chemotypes of DYRK1A inhibitors with great potential to treat AD, and the identified compound Q17 in this study is worthy of further study. Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=182 SRC="FIGDIR/small/565431v1_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@75abecorg.highwire.dtl.DTLVardef@16a3611org.highwire.dtl.DTLVardef@39aeborg.highwire.dtl.DTLVardef@afc8ab_HPS_FORMAT_FIGEXP M_FIG C_FIG

pharmacology and toxicology↗

bioRxiv2023

AutoMolDesigner for Antibiotic Discovery: An AI-based Open-source Software for Automated Design of Small-molecule Antibiotics

Discovery of small-molecule antibiotics with novel chemotypes serves as one of the essential strategies to address antibiotic resistance. Although a considerable number of computational tools committed to molecular design have been reported, there is a deficit in the holistic and efficient tool specifically developed for small-molecule antibiotic discovery. To address this issue, we report AutoMolDesigner, a computational modeling software dedicated to small-molecule antibiotic design. It is a generalized framework comprising two functional modules, i.e., generative deep learning-enabled molecular generation and automated machine learning based-antibacterial activity/property prediction, wherein individually trained models and curated datasets are out-of-the-box for whole cell-based antibiotic screening and design. It is open-source thus allows for the incorporation of new features for flexible use. Unlike most software programs based on Linux and command lines, this application equipped with Qt-based graphical user interface can be run on personal computers with multiple operating systems, making it much easier to use for experimental scientists. The software and related materials are freely available at GitHub (https://github.com/taoshen99/AutoMolDesigner) and Zenodo (https://zenodo.org/record/8366085).

bioinformatics↗

bioRxiv2023

Natural Circulation of Tick-borne Severe Fever with Thrombocytopenia Syndrome Virus in the City Ecosystem, China

Severe fever with thrombocytopenia syndrome virus (SFTSV) is rapidly expanding its range in China, because of the accelerated spread of the parthenogenetic Haemaphysalis longicornis, Asian long-horned tick (ALT). In this letter, we report the urban circulation of SFTSV between ALTs and hedgehogs in Beijing, China. HighlightsHedgehogs and ALTs can maintain the natural circulation of SFTSV in the city ecosystem. Hedgehogs and ALTs are becoming common in Beijing. Parthenogenetic ALTs are discovered in Beijing.

microbiology↗

bioRxiv2022

Hedgehogs are the major amplifying hosts of severe fever with thrombocytopenia syndrome virus

Severe fever with thrombocytopenia syndrome virus (SFTSV) is a tick-borne bandavirus mainly transmitted by Haemaphysalis longicornis in East Asia, mostly in rural areas. To date, the amplifying host involved in the natural transmission of SFTSV remains unidentified. Our epidemiological field survey conducted in endemic areas in China showed that hedgehogs were widely distributed, had heavy tick infestations, and had high SFTSV seroprevalence and RNA prevalence. After experimental infection of Erinaceus amurensis and Atelerix albiventris hedgehogs with SFTSV, robust but transitory viremias were detected, which lasted for around nine to eleven days. The infected hedgehogs experienced light weight loss and histopathology of the spleen showed hemorrhagic necrosis and lymphopenia, with infected hedgehogs recovering after viral clearance. Remarkably, SFTSV transmission cycle between hedgehogs and nymph/adult H. longicornis was easily accomplished under laboratory condition with 100% efficiency. Furthermore, naive H. longicornis ticks could be infected by SFTSV-positive ticks co-feeding on naive hedgehogs, with transstadial transmission of SFTSV also confirmed. We also found that SFTSV viremia remained high in hedgehogs during hibernation, suggesting that this mechanism might contribute to the persistence of SFTSV from one year to the next. Of concern, we recently found evidence of the natural circulation of SFTSV in the urban area of Beijing City in China involving H. longicornis ticks and E. amurensis hedgehogs. Our study suggests that the hedgehogs are the major wildlife amplifying hosts of SFTSV and that urban outbreaks of SFTSV might occur in the future.

microbiology↗