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Background The dynamic interaction between cancer cells and tumour-associated macrophages (TAMs) in the hypoxic tumour microenvironment (TME) is an active barrier to the effector arm of the antitumour immune response. Cancer-secreted exosomes are emerging mediators of this cancer-stromal cross-talk in the TME; however, the mechanisms underlying this interaction remain unclear. Methods Exosomes were isolated with ExoQuick exosome precipitation solution. The polarizing effect of TAMs was evaluated by flow cytometry, western blot analysis, immunofluorescence staining and in vitro phagocytosis assays. Clinical cervical cancer specimens and an in vivo xenograft model were also employed. Results Our previous study showed that hypoxia increased the expression of ZEB1 in cervical squamous cell carcinoma (CSCC) cells, which resulted in increased infiltration of TAMs. Here, we found that hypoxia-induced ZEB1 expression is closely correlated with CD47-SIRPα axis activity in CSCC, which enables cancer cells to evade phagocytosis by macrophages and promotes tumour progression. ZEB1 was found to directly activate the transcription of the CD47 gene in hypoxic CSCC cells. We further showed that endogenous ZEB1 was characteristically enriched in hypoxic CSCC cell-derived exosomes and transferred into macrophages via these exosomes to promote SIRPα + TAM polarization. Intriguingly, exosomal ZEB1 retained transcriptional activity and reprogrammed SIRPα + TAMs via activation of the STAT3 signalling pathway in vitro and in vivo. STAT3 inhibition reduced the polarizing effect induced by exosomal ZEB1. Knockdown of ZEB1 increased the phagocytosis of CSCC cells by macrophages via decreasing CD47 and SIRPα expression. Conclusions Our results suggest that hypoxia-induced ZEB1 promotes immune evasion in CSCC by strengthening the CD47-SIRPα axis. ZEB1-targeted therapy in combination with CD47-SIRPα checkpoint immunotherapy may improve the outcomes of CSCC patients in part by disinhibiting innate immunity.

The dynamic interaction between cancer cells and tumour-associated macrophages (TAMs) in the hypoxic tumour microenvironment (TME) is an active barrier to the effector arm of the antitumour immune response. Cancer-secreted exosomes are emerging mediators of this cancer-stromal cross-talk in the TME; however, the mechanisms underlying this interaction remain unclear. Exosomes were isolated with ExoQuick exosome precipitation solution. The polarizing effect of TAMs was evaluated by flow cytometry, western blot analysis, immunofluorescence staining and in vitro phagocytosis assays. Clinical cervical cancer specimens and an in vivo xenograft model were also employed. Our previous study showed that hypoxia increased the expression of ZEB1 in cervical squamous cell carcinoma (CSCC) cells, which resulted in increased infiltration of TAMs. Here, we found that hypoxia-induced ZEB1 expression is closely correlated with CD47-SIRP[alpha] axis activity in CSCC, which enables cancer cells to evade phagocytosis by macrophages and promotes tumour progression. ZEB1 was found to directly activate the transcription of the CD47 gene in hypoxic CSCC cells. We further showed that endogenous ZEB1 was characteristically enriched in hypoxic CSCC cell-derived exosomes and transferred into macrophages via these exosomes to promote SIRP[alpha].sup.+ TAM polarization. Intriguingly, exosomal ZEB1 retained transcriptional activity and reprogrammed SIRP[alpha].sup.+ TAMs via activation of the STAT3 signalling pathway in vitro and in vivo. STAT3 inhibition reduced the polarizing effect induced by exosomal ZEB1. Knockdown of ZEB1 increased the phagocytosis of CSCC cells by macrophages via decreasing CD47 and SIRP[alpha] expression. Our results suggest that hypoxia-induced ZEB1 promotes immune evasion in CSCC by strengthening the CD47-SIRP[alpha] axis. ZEB1-targeted therapy in combination with CD47-SIRP[alpha] checkpoint immunotherapy may improve the outcomes of CSCC patients in part by disinhibiting innate immunity.

Hepatocellular carcinoma (HCC) is a highly heterogeneous and malignant disease with the complex immune microenvironment, which ultimately influence clinic outcomes of patients. However, the spatial expression patterns of diverse immune cells among tumor microenvironment remain to be further deciphered. Spatial transcriptomics sequencing (ST) was implemented on two portions of HCC specimens. Differentially expressed genes, cell cycle phases, epithelial-mesenchymal features, pseudo-time and immune infiltration analysis were applied to demonstrate the intratumor heterogeneity and define the specific immune-related regions, and the results were further validated by a second analysis on another ST study. and experiments were conducted to confirm the functional mechanisms of key molecules such as CCL15, CCL19 and CCL21. Clinical tissue samples were used to assess their potential prognostic and therapeutic values. Totally, 7553 spots were categorized into 15 subsets by hierarchical clustering, and malignant subsets with intratumor heterogeneity phenotypes were identified. Spatial heterogeneity from distinct sectors highlights specific chemokines: CCL15 is remarkable in the core region of the carcinoma sector and facilitates the immunosuppressive microenvironment by recruiting and polarizing M2-like macrophages and ; High expression of CCL15 and CD163 respectively predicts poor prognosis of HCC patients, and the combined application of them has better predictive value. CCL19 and CCL21, sharing similar spatial expression patterns, are highly-correlated and prominent in the immune infiltration enrichment and recruit CD3 T cells and CD20 B cells to inhibit the growth of HCC, indicating a good prognosis of HCC patients. Taken together, our studies preliminarily reveal intratumor heterogeneity of HCC based on ST techniques and unravel the previously unexplored spatial expression patterns in the immune microenvironment. We also highlight the clinical significance and spatial discrepancy of key molecules, providing novel insight for further developing therapeutic strategies in HCC.

Background CRISPR/Cas9 systems have been repurposed as canonical genome editing tools in a variety of species, but no application for the model strain Rhodobacter sphaeroides 2.4.1 was unveiled. Results Here we showed two kinds of programmable base editing systems, cytosine base editors (CBEs) and adenine base editors (ABEs), generated by fusing endonuclease Cas9 variant to cytosine deaminase PmCDA1 or heterodimer adenine deaminase TadA–TadA*, respectively. Using CBEs, we were able to obtain C-to-T mutation of single and double targets following the first induction step, with the efficiency of up to 97% and 43%; while the second induction step was needed in the case of triple target, with the screening rate of 47%. Using ABEs, we were only able to gain A-to-G mutation of single target after the second induction step, with the screening rate of 30%. Additionally, we performed a knockout analysis to identify the genes responsible for coenzyme Q10 biosynthesis and found that ubiF , ubiA , ubiG , and ubiX to be the most crucial ones. Conclusions Together, CBEs and ABEs serve as alternative methods for genetic manipulation in Rhodobacter sphaeroides and will shed light on the fundamental research of other bacteria that are hard to be directly edited by Cas9-sgRNA.

Objective Sarcopenic obesity is a prevalent geriatric syndrome, characterized by concurrence of sarcopenia and obesity. Sleep duration is linked to both obesity and sarcopenia. However, little was known regarding the association of sleep duration with sarcopenic obesity. In this study, we aimed to examine the association of sleep duration with sarcopenic obesity in multi-ethnic community-dwelling older adults. Methods Sarcopenia was defined according to the criteria established by Asian Working Group for Sarcopenia (AWGS) 2019. Obesity was defined as body fat percentage above the 60th percentile specified by sex. Sarcopenic obesity was defined as concurrence of obesity and sarcopenia. Sleep duration was collected by a self-reported questionnaire and was further divided into 5 groups: “<6 h”, “6–7 h”, “7–8 h”, “8–9 h” (reference group) and “≥9 h” (long sleep). Logistic regressions were adopted to examine the association. Results 2256 multi-ethnic adults aged 60 and over from the West China Health and Aging Trend (WCHAT) study were involved for present study. Overall, 6.25% of the participants were classified as sarcopenic obesity. In the fully adjusted model, long sleep duration (≥ 9 h) was significantly associated with sarcopenic obesity compared with reference group (OR = 1.81, 95%CI = 1.10–2.98, P = 0.019). However, in subgroup analysis, this association can only be observed in male (OR 1.98, 95% CI = 1.02–3.87, P = 0.043) not in female (OR = 1.83, 95%CI = 0.85–3.94, P = 0.118). Regarding ethnic difference, Han older adults with long sleep duration (≥ 9 h) presented increased risk of sarcopenic obesity while ethnic minorities did not. Conclusion This study disclosed that long sleep duration significantly increased the risk of sarcopenic obesity among older adults. And our findings highlight the critical role of assessing sleep duration to identify individuals at risk of sarcopenic obesity.

Research on optoelectronic synapses that can integrate both detection and processing functions is essential for the development of efficient neuromorphic computing. Here, we experimentally demonstrated an Ga2O3‐based metal–semiconductor–metal (MSM) solar‐blind ultraviolet (UV) photodetector (PD) with asymmetric interdigital electrodes. The Ga2O3 PD exhibits a responsivity of 732 A/W under a forward bias of 6 V. The tunable conductance properties of PDs provide a novel approach to synaptic performance. The proposed PDs as artificial synapse realized several essential synaptic function, including excitatory postsynaptic current, paired‐pulse facilitation, long‐term potentiation, the transition from short‐term memory to long‐term memory, and learning experience behaviors successfully. At a reverse bias, an ultra‐low energy consumption of 140 fJ was achieved. In addition, the optoelectronic synapses demonstrated a recognition accuracy of over 95% in the MNIST handwritten number recognition task. These results suggest that Ga2O3 MSM solar‐blind UV PDs have high potential for efficient optoelectronic neuromorphic computing applications. A Ga2O3‐based neuromorphic device is designed to mimic biological synapses and neural networks. The device exhibits learning and forgetting behaviors under UV light with high energy efficiency. Applied to image recognition tasks, it demonstrates significant potential for optoelectronic artificial intelligence applications.

Treg cells play a crucial role in immune tolerance, but mechanisms that induce Treg cells are poorly understood. We here have described eosinophils in lamina propria (LP) that displayed high aldehyde dehydrogenase (ALDH) activity, a rate-limiting step during all-trans retinoic acid (ATRA) synthesis, and expressed TGF-β1 mRNA and high levels of ATRA. Co-incubation assay confirmed that LP eosinophils induced the differentiation of naïve T cells into Treg cells. Differentiation promoted by LP eosinophils were inhibited by blocked either TGF-β1 or ATRA. Peripheral blood (PB) eosinophils did not produce ATRA and could not induce Treg differentiation. These data identifies LP eosinophils as effective inducers of Treg cell differentiation through a mechanism dependent on TGF-β1 and ATRA.

This study was aimed to investigate 3.0 T unenhanced Dixon water-fat whole-heart CMRA (coronary magnetic resonance angiography) using compressed-sensing sensitivity encoding (CS-SENSE) and conventional sensitivity encoding (SENSE) in vitro and in vivo. The key parameters of CS-SENSE and conventional 1D/2D SENSE were compared in vitro phantom study. In vivo study, fifty patients with suspected coronary artery disease (CAD) completed unenhanced Dixon water-fat whole-heart CMRA at 3.0 T using both CS-SENSE and conventional 2D SENSE methods. We compared mean acquisition time, signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR) and the diagnostic accuracy between two techniques. In vitro study, CS-SENSE achieved better effectiveness between higher SNR/CNR and shorter scan times using the appropriate acceleration factor compared with conventional 2D SENSE. In vivo study, CS-SENSE CMRA had better performance than 2D SENSE in terms of the mean acquisition time, SNR and CNR (7.4 ± 3.2 min vs. 8.3 ± 3.4 min, P = 0.001; SNR: 115.5 ± 35.4 vs. 103.3 ± 32.2; CNR: 101.1 ± 33.2 vs. 90.6 ± 30.1, P < 0.001 for both). The diagnostic accuracy between CS-SENSE and 2D SENSE had no significant difference on a patient-based analysis (sensitivity: 97.3% vs. 91.9%; specificity: 76.9% vs. 61.5%; accuracy: 92.0% vs. 84.0%; P > 0.05 for each). Unenhanced CS-SENSE Dixon water-fat separation whole-heart CMRA at 3.0 T can improve the SNR and CNR, shorten the acquisition time while providing equally satisfactory image quality and diagnostic accuracy compared with 2D SENSE CMRA.

Leptospira-induced macrophage death has been confirmed to play a crucial role in pathogenesis of leptospirosis, a worldwide zoonotic infectious disease. Intracellular free Ca(2+) concentration ([Ca(2+)]i) elevation induced by infection can cause cell death, but [Ca(2+)]i changes and high [Ca(2+)]i-induced death of macrophages due to infection of Leptospira have not been previously reported. We first used a Ca(2+)-specific fluorescence probe to confirm that the infection of L. interrogans strain Lai triggered a significant increase of [Ca(2+)]i in mouse J774A.1 or human THP-1 macrophages. Laser confocal microscopic examination showed that the [Ca(2+)]i elevation was caused by both extracellular Ca(2+) influx through the purinergic receptor, P2X7, and Ca(2+) release from the endoplasmic reticulum, as seen by suppression of [Ca(2+)]i elevation when receptor-gated calcium channels were blocked or P2X7 was depleted. The LB361 gene product of the spirochete exhibited phosphatidylinositol phospholipase C (L-PI-PLC) activity to hydrolyze phosphatidylinositol-4,5-bisphosphate (PIP2) into inositol-1,4,5-trisphosphate (IP3), which in turn induces intracellular Ca(2+) release from endoplasmic reticulum, with the Km of 199 µM and Kcat of 8.566E-5 S(-1). Secretion of L-PI-PLC from the spirochete into supernatants of leptospire-macrophage co-cultures and cytosol of infected macrophages was also observed by Western Blot assay. Lower [Ca(2+)]i elevation was induced by infection with a LB361-deficient leptospiral mutant, whereas transfection of the LB361 gene caused a mild increase in [Ca(2+)]i. Moreover, PI-PLCs (PI-PLC-β3 and PI-PLC-γ1) of the two macrophages were activated by phosphorylation during infection. Flow cytometric detection demonstrated that high [Ca(2+)]i increases induced apoptosis and necrosis of macrophages, while mild [Ca(2+)]i elevation only caused apoptosis. This study demonstrated that L. interrogans infection induced [Ca(2+)]i elevation through extracellular Ca(2+) influx and intracellular Ca(2+) release cause macrophage apoptosis and necrosis, and the LB361 gene product was shown to be a novel PI-PLC of L. interrogans responsible for the [Ca(2+)]i elevation.

Attribute reduction, as an important preprocessing step for knowledge acquiring in data mining, is one of the key issues in rough set theory. It can only deal with attributes of a specific type in the information system by using a specific binary relation. However, there may be attributes of multiple different types in information systems in real-life applications. A composite relation is proposed to process attributes of multiple different types simultaneously in composite information systems. In order to solve the time-consuming problem of traditional heuristic attribute reduction algorithms, a novel attribute reduction algorithm based on structure discernibility matrix was proposed in this paper. The proposed algorithms can choose the same attribute reduction as its previous version, but it can be used to accelerate a heuristic process of attribute reduction by avoiding the process of intersection and adopting the forward greedy attribute reduction approach. The theoretical analysis and experimental results with UCI data sets show that the proposed algorithm can accelerate the heuristic process of attribute reduction.