Dietary emulsifier polysorbate 80 exposure accelerates age-related cognitive decline.

Gut microbial homeostasis is crucial for the health of cognition in elderly. Previous study revealed that polysorbate 80 (P80) as a widely used emulsifier in food industries and pharmaceutical formulations could directly alter the human gut microbiota compositions. However, whether long-term exposure to P80 could accelerate age-related cognitive decline via gut-brain axis is still unknown. Accordingly, in this study, we used the senescence accelerated mouse prone 8 (SAMP8) mouse model to investigate the effects of the emulsifier P80 intake (1 % P80 in drinking water for 12 weeks) on gut microbiota and cognitive function. Our results indicated that P80 intake significantly exacerbated cognitive decline in SAMP8 mice, along with increased brain pathological proteins deposition, disruption of the blood-brain barrier and activation of microglia and neurotoxic astrocytes. Besides, P80 intake could also induce gut microbiota dysbiosis, especially the increased abundance of secondary bile acids producing bacteria, such as Ruminococcaceae, Lachnospiraceae, and Clostridium scindens. Moreover, fecal microbiota transplantation from P80 mice into 16-week-old SAMP8 mice could also exacerbated cognitive decline, microglia activation and intestinal barrier impairment. Intriguingly, the alterations of gut microbial composition significantly affected bile acid metabolism profiles after P80 exposure, with markedly elevated levels of deoxycholic acid (DCA) in serum and brain tissue. Mechanically, DCA could activate microglial and promote senescence-associated secretory phenotype production through adenosine triphosphate-binding cassette transporter A1 (ABCA1) importing lysosomal cholesterol. Altogether, the emulsifier P80 accelerated cognitive decline of aging mice by inducing gut dysbiosis, bile acid metabolism alteration, intestinal barrier and blood brain barrier disruption as well as neuroinflammation. This study provides strong evidence that dietary-induced gut microbiota dysbiosis may be a risk factor for age-related cognitive decline.

Comprehensive pan-cancer analysis of FUTs family as prognostic and immunity markers based on multi-omics data.

BACKGROUND: The dysregulation of fucosyltransferases (FUTs) contributes to alterations in fucosylated epitope expression, which serve as distinctive features of cancer cells. Nonetheless, a comprehensive elucidation of the prognostic biological marker and therapeutic target of the FUTs family in pan-cancer remains elusive. METHODS: Over 10,000 individuals' profiling information was examined, including information on 750 small molecule drugs, 33 types of cancer, and 24 types of immune cells. We focused on POFUT2's function and applied GSVA (Gene Set Variation Analysis) to calculate the FUT score. Survival and cancer pathways were found to be correlated with this score. After deriving a signature via univariate Cox and LASSO regression, we generated and analyzed the ROC curve and developed a nomogram. RESULTS: Our comprehensive analysis revealed epigenetic, genomic, and immunogenomic changes in FUTs, particularly POFUT2, resulting in aberrant expression. Elevated frequencies of CNV (Copy number variation), SNV (Single Nucleotide Variant), and hypermethylation were observed in FUTs. Additionally, the survival of patients with various types of cancers may be predicted by FUT expression. Immune response and prognosis in numerous types of cancer were found to be strongly linked to aberrant POFUT2 expression. Pathway analysis unveiled the role of FUTs in apoptosis, epithelial-to-mesenchymal transition (EMT), cell cycle, DNA damage response, RAS/MAPK, TSC/mTOR, PI3K/AKT, AR, ER, and RTK. A prognostic index for patients diagnosed with adrenocortical carcinoma (ACC) was established by applying a risk model incorporating nine FUTs and based on the findings of the GSVA. CONCLUSIONS: FUTs, particularly POFUT2, emerge as candidate targets for improving the outcomes of immune therapy. The significance of aberrant MUC12 expression, cancer immune therapy, and patient survival in the context of diverse malignancies is enhanced by the strong correlation observed among these factors. Our five-gene risk signature provides patients with ACC with an independent prognostic indicator, emphasizing the critical function of these genes in inhibiting the immune system's response in ACC.

CSF1R blockade slows progression of cerebral hemorrhage by reducing microglial proliferation and increasing infiltration of CD8 + CD122+ T cells into the brain.

Microglia play a pivotal role in the neuroinflammatory response after brain injury, and their proliferation is dependent on colony-stimulating factors. In the present study, we investigated the effect of inhibiting microglia proliferation on neurological damage post intracerebral hemorrhage (ICH) in a mouse model, an aspect that has never been studied before. Using a colony-stimulating factor-1 receptor antagonist (GW2580), we observed that inhibition of microglia proliferation significantly ameliorated neurobehavioral deficits, attenuated cerebral edema, and reduced hematoma volume after ICH. This intervention was associated with a decrease in pro-inflammatory factors in microglia and an increased infiltration of peripheral regulatory CD8 + CD122+ T cells into the injured brain tissue. The CXCR3/CXCL10 axis is the mechanism of brain homing of regulatory CD8 + CD122+ T cells, and the high expression of IL-10 is the hallmark of their synergistic anti-inflammatory effect with microglia. And activated astrocytes around the insult site are a prominent source of CXCL10. Thus, inhibition of microglial proliferation offers a new perspective for clinical translation. The cross-talk between multiple cells involved in the regulation of the inflammatory response highlights the comprehensive nature of neuroimmunomodulation.

IL-33/ST2 Axis: A Potential Therapeutic Target in Neurodegenerative Diseases.

Interleukin 33 (IL-33) belongs to the IL-1 family and is localized in the nucleus. IL-33 is primarily composed of three distinct domains, namely the N-terminal domain responsible for nuclear localization, the intermediate sense protease domain, and the C-terminal cytokine domain. Its specific receptor is the suppression of tumorigenicity 2 (ST2), which is detected in serum-stimulated fibroblasts and oncogenes. While most other cytokines are actively produced in cells, IL-33 is passively produced in response to tissue damage or cell necrosis, thereby suggesting its role as an alarm following cell infection, stress, or trauma. IL-33 plays a crucial role in congenital and acquired immunity, which assists in the response to environmental stress and maintains tissue homeostasis. IL-33/ST2 interaction further produces many pro-inflammatory cytokines. Moreover, IL-33 is crucial for central nervous system (CNS) homeostasis and the pathogenic mechanisms underlying CNS degenerative disorders. The present work summarizes the structure of IL-33, its fundamental activities, and its role in immunoregulation and neurodegenerative diseases. Therefore, this work proposes that IL-33 may play a role in the pathogenic mechanism of diseases and can be used in the development of treatment strategies.

Event-based Semantic Segmentation with Posterior Attention.

In the past years, attention-based Transformers have swept across the field of computer vision, starting a new stage of backbones in semantic segmentation. Nevertheless, semantic segmentation under poor light conditions remains an open problem. Moreover, most papers about semantic segmentation work on images produced by commodity frame-based cameras with a limited framerate, hindering their deployment to auto-driving systems that require instant perception and response at milliseconds. An event camera is a new sensor that generates event data at microseconds and can work in poor light conditions with a high dynamic range. It looks promising to leverage event cameras to enable perception where commodity cameras are incompetent, but algorithms for event data are far from mature. Pioneering researchers stack event data as frames so that event-based segmentation is converted to framebased segmentation, but characteristics of event data are not explored. Noticing that event data naturally highlight moving objects, we propose a posterior attention module that adjusts the standard attention by the prior knowledge provided by event data. The posterior attention module can be readily plugged into many segmentation backbones. Plugging the posterior attention module into a recently proposed SegFormer network, we get EvSegFormer (the event-based version of SegFormer) with state-of-the-art performance in two datasets (MVSEC and DDD-17) collected for event-based segmentation. Code is available at https://github.com/zexiJia/EvSegFormer to facilitate research on event-based vision.

Intranasal Delivery of Gene-Edited Microglial Exosomes Improves Neurological Outcomes after Intracerebral Hemorrhage by Regulating Neuroinflammation.

Neural inflammatory response is a crucial pathological change in intracerebral hemorrhage (ICH) which accelerates the formation of perihematomal edema and aggravates neural cell death. Although surgical and drug treatments for ICH have advanced rapidly in recent years, therapeutic strategies that target and control neuroinflammation are still limited. Exosomes are important carriers for information transfer among cells. They have also been regarded as a promising therapeutic tool in translational medicine, with low immunogenicity, high penetration through the blood-brain barrier, and ease of modification. In our previous research, we have found that exogenous administration of miRNA-124-overexpressed microglial exosomes (Exo-124) are effective in improving post-injury cognitive impairment. From this, we evaluated the potential therapeutic effects of miRNA-124-enriched microglial exosomes on the ICH mice in the present study. We found that the gene-edited exosomes could attenuate neuro-deficits and brain edema, improve blood-brain barrier integrity, and reduce neural cell death. Moreover, the protective effect of Exo-124 was abolished in mice depleted of Gr-1+ myeloid cells. It suggested that the exosomes exerted their functions by limiting the infiltration of leukocyte into the brain, thus controlling neuroinflammation following the onset of ICH. In conclusion, our findings provided a promising therapeutic strategy for improving neuroinflammation in ICH. It also opens a new avenue for intranasal delivery of exosome therapy using miRNA-edited microglial exosomes.