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Mitochondria, a highly metabolically active organelle, have been shown to play an essential role in regulating innate immune function. Mitochondrial Ca2+ uptake via the mitochondrial Ca2+ uniporter (MCU) is an essential process regulating mitochondrial metabolism by targeting key enzymes involved in the tricarboxylic acid cycle (TCA). Accumulative evidence suggests MCU-dependent mitochondrial Ca2+ signaling may bridge the metabolic reprogramming and regulation of immune cell function. However, the mechanism by which MCU regulates inflammation and its related disease remains elusive. Here we report a critical role of MCU in promoting phagocytosis-dependent activation of NLRP3 (nucleotide-binding domain, leucine-rich repeat containing family, pyrin domain-containing 3) inflammasome by inhibiting phagolysosomal membrane repair. Myeloid deletion of MCU (McuΔmye ) resulted in an attenuated phagolysosomal rupture, leading to decreased caspase-1 cleavage and interleukin (IL)-1β release, in response to silica or alum challenge. In contrast, other inflammasome agonists such as adenosine triphosphate (ATP), nigericin, poly(dA:dT), and flagellin induced normal IL-1β release in McuΔmye macrophages. Mechanistically, we demonstrated that decreased NLRP3 inflammasome activation in McuΔmye macrophages was caused by improved phagolysosomal membrane repair mediated by ESCRT (endosomal sorting complex required for transport)-III complex. Furthermore, McuΔmye mice showed a pronounced decrease in immune cell recruitment and IL-1β production in alum-induced peritonitis, a typical IL-1–dependent inflammation model. In sum, our results identify a function of MCU in promoting phagocytosis-dependent NLRP3 inflammatory response via an ESCRT-mediated phagolysosomal membrane repair mechanism.

To determine the effect of liquid nitrogen (LN2) cooling on the damage of heated rock, we conducted a series of physical and mechanical tests on Shandong granite samples. These granites were first slowly heated to the target temperatures (25~600 °C) and held for 10 h, followed by rapid cooling with a coolant. Three coolants were used and compared in our experiment: air, water and LN2. Physical properties and mechanical properties were tested after thermal treatments. Microstructural changes were also observed using scanning electron microscope and optical microscope. According to experimental results, permeability of the heated granites increases significantly after LN2-cooling, while density, P-wave velocity, strength and elastic modulus reduce. As heating temperature rises, changes in these properties become more pronounced. Compared to air-cooling and water-cooling, LN2-cooling induces greater changes in the physical and mechanical properties at any target temperature. This indicates that LN2-cooling can damage the heated rocks more remarkably than the other two cooling treatments. According to microscopic analysis, inter-granular cracking is the primary failure mode during thermal treatment, and most of the inter-granular cracks distribute at the boundaries of quartz. Our results in this paper are of great value for understanding the characteristics of thermal damage induced by rapid cooling.

Metabolite-mediated protein posttranslational modifications (PTM) represent highly evolutionarily conserved mechanisms by which metabolic networks participate in fine-tuning diverse cellular biological activities. Modification of proteins with the metabolite UDP-N-acetylglucosamine (UDP-GlcNAc), known as protein O -GlcNAcylation, is one well-defined form of PTM that is catalyzed by a single pair of enzymes, O -GlcNAc transferase (OGT) and O -GlcNAcase (OGA). Previous studies have discovered critical roles of protein O -GlcNAcylation in many fundamental biological activities via modifying numerous nuclear and cytoplasmic proteins. A common mechanism by which O -GlcNAc affects protein function is through the cross-regulation between protein O -GlcNAcylation and phosphorylation. This is of particular importance to innate immune cell functions due to the essential role of protein phosphorylation in regulating many aspects of innate immune signaling. Indeed, as an integral component of cellular metabolic network, profound alteration in protein O -GlcNAcylation has been documented following the activation of innate immune cells. Accumulating evidence suggests that O -GlcNAcylation of proteins involved in the NF-κB pathway and other inflammation-associated signaling pathways plays an essential role in regulating the functionality of innate immune cells. Here, we summarize recent studies focusing on the role of protein O -GlcNAcylation in regulating the NF-κB pathway, other innate immune signaling responses and its disease relevance.

Liquid nitrogen (LN2) fracturing is a technology that can dramatically enhance the stimulation performances of high-temperature reservoirs, such as hot dry rock geothermal and deep/ultra-deep hydrocarbon reservoirs. The aim of the present study was to investigate the damage characteristics of high-temperature rocks subjected to LN2 thermal shock, which is a critical concern in the engineering application of LN2 fracturing. In our work, the rocks (granite, shale and sandstone) were slowly heated to different temperatures (25 °C, 150 °C and 260 °C) and maintained at the target temperatures for 10 h, followed by LN2 quenching. After thermal treatments, we tested the physical and mechanical properties of the rocks to evaluate their damages. Additionally, sensitivities of the three rocks to thermal shock were also compared and analyzed. According to our experiments, LN2 thermal shock can enhance the permeability of the rocks and deteriorate their mechanical properties significantly. Increasing rock temperature helps strengthen the effect of LN2 thermal shock, leading to more severe damage. Inter-granular cracking is the primary contribution to the rock damage in the LN2 cooling process. Compared with granite and shale, sandstone is less sensitive to LN2 thermal shock. The lower sensitivity of sandstone to thermal shock is mainly attributed to its larger pore spaces and weaker heterogeneity of mineral thermal expansion. The present paper can provide some guidance for the engineering application of LN2 fracturing technology.

Objectives To evaluate the performance of velocity-selective (VS) ASL among patients with untreated gliomas by comparing with both pseudo-continuous (PC) ASL and dynamic susceptibility contrast-enhanced perfusion-weighted imaging (DSC-PWI). Methods Forty-four consecutive patients with newly diagnosed glioma who underwent preoperative perfusion MRI including VSASL, PCASL, and DSC-PWI between 2017 and 2019 were retrospectively evaluated. Visual inspection was performed to evaluate the tumor signal intensity relative to gray matter based on 1–5 score criteria and weighted kappa was used to evaluate the pair-wise concordance between VSASL or PCASL and DSC-PWI. The relative tumor blood flow (rTBF) was measured from sampling intra-tumoral areas of hot-spot on the blood flow map and normalized against the contralateral normal gray matter blood flow. Linear regression and Bland–Altman analyses were performed to evaluate the correlation and agreement of rTBF measurements between ASL methods and DSC-PWI. The ROC analysis was constructed to determine the diagnostic performance of three perfusion methods for grading gliomas. Results TBF maps derived from VSASL were more comparable with DSC-PWI than PCASL on visual inspection (weighted kappa of 0.90 vs 0.68). In quantitative analysis, VSASL-rTBF yielded higher correlation with the values from DSC-PWI than PCASL-rTBF ( R 2  = 80% vs 47%, p  < 0.001 for both). Both ASL and DSC-derived rTBF showed good distinction between low-grade and high-grade gliomas ( p  < 0.001). Compared to PCASL, VSASL yielded superior diagnostic sensitivity, specificity, and accuracy in glioma grading. Conclusions VSASL showed great promise for accurate quantification of TBF and could potentially improve the diagnostic performance of ASL in preoperative grading of gliomas. Key Points •  VSASL demonstrated a greater agreement with DSC-PWI than with PCASL on visual inspection and perfusion quantification . •  VSASL showed a higher diagnostic sensitivity, negative predictive value, and accuracy than PCASL for glioma grading . •  With the advantages of insensitivity to transit delay and no need of prescribing a labeling plane, VSASL could potentially improve the diagnostic performance of ASL for a more accurate, noninvasive quantification of TBF in patients with glioma .

The O -GlcNAc transferase (OGT) is an essential enzyme that mediates protein O -GlcNAcylation, a unique form of posttranslational modification of many nuclear and cytosolic proteins. Recent studies observed increased OGT and O -GlcNAcylation levels in a broad range of human cancer tissues compared to adjacent normal tissues, indicating a universal effect of OGT in promoting tumorigenesis. Here, we show that OGT is essential for tumor growth in immunocompetent mice by repressing the cyclic GMP-AMP synthase (cGAS)-dependent DNA sensing pathway. We found that deletion of OGT ( Ogt −/− ) caused a marked reduction in tumor growth in both syngeneic mice tumor models and a genetic mice colorectal cancer (CRC) model induced by mutation of the Apc gene ( Apc min ). Pharmacological inhibition or genetic deletion of OGT induced a robust genomic instability (GIN), leading to cGAS-dependent production of the type I interferon (IFN-I) and IFN-stimulated genes (ISGs). As a result, deletion of Cgas or Sting from Ogt −/− cancer cells restored tumor growth, and this correlated with impaired CD8 + T-cell-mediated antitumor immunity. Mechanistically, we found that OGT-dependent cleavage of host cell factor C1 (HCF-1) is required for the avoidance of GIN and IFN-I production in tumors. In summary, our results identify OGT-mediated genomic stability and activate cGAS-STING pathway as an important tumor-cell-intrinsic mechanism to repress antitumor immunity.

Hydraulic fracturing is a commonly used stimulation method in developing tight sandstone reservoirs. Creation of complex fracture networks to enlarge stimulated reservoir volume plays an increasingly significant role. However, planar fracture patterns are generally generated by water-based fluid fracturing. Besides, the water consumption and environmental burden of water-based fluid fracturing cannot be ignored. To solve the above issues, we investigated the liquid nitrogen (LN2) fracturing performance on tight sandstone with respect to breakdown pressures and fracture network patterns, and also compared the results with water fracturing in this paper. A comprehensive quantitative analysis was made for the fracture network induced by LN2 fracturing so as to enhance understandings of the fracturing mechanisms. Based on laboratory fracturing experiments and computed tomography (CT) scanning, we find that the breakdown pressure of LN2 fracturing can be reduced by 12.4–51.5% compared with water fracturing. Besides, LN2 fracturing can lead to volumetric fracturing patterns rather than planar fractures compared with water fracturing. The average tortuosity of LN2 fracturing was increased by 5.9% compared with water fracturing. Furthermore, the major fracture tends to traverse the bedding plane with an angle of around 45–80 degrees under lower horizontal stress difference. This study, for the first time, shows potential benefits of high-pressure LN2 fracturing in tight sandstone under triaxial in situ stress. It is expected to provide a viable alternative for the efficient development of tight sandstone reservoirs in a clean and waterless way.HighlightsThe performance of liquid nitrogen fracturing on tight sandstone was investigated.A comprehensive quantitative analysis was made for the induced fractures.Liquid nitrogen fracturing can lower fracture initiation pressure as a comparison with water fracturing.Liquid nitrogen fracturing can lead to volumetric fracturing and enhance the stimulated reservoir volume.Major fracture tends to traverse the bedding plane with an angle under a lower horizontal stress difference.

Intratumoral Tregs are key mediators of cancer immunotherapy resistance, including anti-programmed cell death (ligand) 1 [anti-PD-(L)1] immune checkpoint blockade (ICB). The mechanisms driving Treg infiltration into the tumor microenvironment (TME) and the consequence on CD8+ T cell exhaustion remain elusive. Here, we report that heat shock protein gp96 (also known as GRP94) was indispensable for Treg tumor infiltration, primarily through the roles of gp96 in chaperoning integrins. Among various gp96-dependent integrins, we found that only LFA-1 (αL integrin), and not αV, CD103 (αE), or β7 integrin, was required for Treg tumor homing. Loss of Treg infiltration into the TME by genetic deletion of gp96/LFA-1 potently induced rejection of tumors in multiple ICB-resistant murine cancer models in a CD8+ T cell-dependent manner, without loss of self-tolerance. Moreover, gp96 deletion impeded Treg activation primarily by suppressing IL-2/STAT5 signaling, which also contributed to tumor regression. By competing for intratumoral IL-2, Tregs prevented the activation of CD8+ tumor-infiltrating lymphocytes, drove thymocyte selection-associated high mobility group box protein (TOX) induction, and induced bona fide CD8+ T cell exhaustion. By contrast, Treg ablation led to striking CD8+ T cell activation without TOX induction, demonstrating clear uncoupling of the 2 processes. Our study reveals that the gp96/LFA-1 axis plays a fundamental role in Treg biology and suggests that Treg-specific gp96/LFA-1 targeting represents a valuable strategy for cancer immunotherapy without inflicting autoinflammatory conditions.

At present, there are few studies on seasonal differences in the aroma quality and volatile components of Rucheng Baimao (Camellia pubescens) black tea. In this study, sensory evaluation and volatile component analysis were carried out on one sample of Rucheng Baimao black tea corresponding to spring, summer, and autumn, respectively. The results of sensory evaluation showed that the black teas of all three seasons had floral aromas. However, the aroma quality of spring black tea was the best, followed by that of autumn black tea, and summer black tea was the worst. The analysis of volatile components showed that alcohols, esters, and alkanes were the main substance categories. In addition, the results of the aroma index were consistent with those of the sensory evaluation, indicating that spring black tea had the best aroma quality, followed by autumn black tea and then summer black tea. Eleven key differential volatile components were screened by combining PLS-DA analysis (VIP > 1, p < 0.05) and rOAV > 1. Among them, geraniol, methyl salicylate, nonanal, and (E)-citral accumulated the most in spring black tea, linalool, phenylacetaldehyde, benzaldehyde, phenethyl alcohol, benzyl alcohol, and β-ionone accumulated the most in summer black tea, and trans-nerolidol accumulated the most in autumn black tea. This study aims to provide a theoretical reference for the regulation of the aroma quality of Rucheng Baimao black tea.

Burkholderia cenocepacia ( B. cenocepacia ) is an opportunistic bacterium; causing severe life threatening systemic infections in immunocompromised individuals including cystic fibrosis patients. The lack of gasdermin D (GSDMD) protects mice against endotoxin lipopolysaccharide (LPS) shock. On the other hand, GSDMD promotes mice survival in response to certain bacterial infections. However, the role of GSDMD during B. cenocepacia infection is not yet determined. Our in vitro study shows that GSDMD restricts B. cenocepacia replication within macrophages independent of its role in cell death through promoting mitochondrial reactive oxygen species (mROS) production. mROS is known to stimulate autophagy, hence, the inhibition of mROS or the absence of GSDMD during B. cenocepacia infections reduces autophagy which plays a critical role in the restriction of the pathogen. GSDMD promotes inflammation in response to B. cenocepacia through mediating the release of inflammasome dependent cytokine (IL-1β) and an independent one (CXCL1) (KC). Additionally, different B. cenocepacia secretory systems (T3SS, T4SS, and T6SS) contribute to inflammasome activation together with bacterial survival within macrophages. In vivo study confirmed the in vitro findings and showed that GSDMD restricts B. cenocepacia infection and dissemination and stimulates autophagy in response to B. cenocepacia . Nevertheless, GSDMD promotes lung inflammation and necrosis in response to B. cenocepacia without altering mice survival. This study describes the double-edged functions of GSDMD in response to B. cenocepacia infection and shows the importance of GSDMD-mediated mROS in restriction of B. cenocepacia.