Acetylation Blocks cGAS Activity and Inhibits Self-DNA-Induced Autoimmunity.

The presence of DNA in the cytoplasm is normally a sign of microbial infections and is quickly detected by cyclic GMP-AMP synthase (cGAS) to elicit anti-infection immune responses. However, chronic activation of cGAS by self-DNA leads to severe autoimmune diseases for which no effective treatment is available yet. Here we report that acetylation inhibits cGAS activation and that the enforced acetylation of cGAS by aspirin robustly suppresses self-DNA-induced autoimmunity. We find that cGAS acetylation on either Lys384, Lys394, or Lys414 contributes to keeping cGAS inactive. cGAS is deacetylated in response to DNA challenges. Importantly, we show that aspirin can directly acetylate cGAS and efficiently inhibit cGAS-mediated immune responses. Finally, we demonstrate that aspirin can effectively suppress self-DNA-induced autoimmunity in Aicardi-Goutières syndrome (AGS) patient cells and in an AGS mouse model. Thus, our study reveals that acetylation contributes to cGAS activity regulation and provides a potential therapy for treating DNA-mediated autoimmune diseases.

Lactate Is a Natural Suppressor of RLR Signaling by Targeting MAVS.

RLR-mediated type I IFN production plays a pivotal role in elevating host immunity for viral clearance and cancer immune surveillance. Here, we report that glycolysis, which is inactivated during RLR activation, serves as a barrier to impede type I IFN production upon RLR activation. RLR-triggered MAVS-RIG-I recognition hijacks hexokinase binding to MAVS, leading to the impairment of hexokinase mitochondria localization and activation. Lactate serves as a key metabolite responsible for glycolysis-mediated RLR signaling inhibition by directly binding to MAVS transmembrane (TM) domain and preventing MAVS aggregation. Notably, lactate restoration reverses increased IFN production caused by lactate deficiency. Using pharmacological and genetic approaches, we show that lactate reduction by lactate dehydrogenase A (LDHA) inactivation heightens type I IFN production to protect mice from viral infection. Our study establishes a critical role of glycolysis-derived lactate in limiting RLR signaling and identifies MAVS as a direct sensor of lactate, which functions to connect energy metabolism and innate immunity.

Publisher Correction: K33-linked polyubiquitination of Zap70 by Nrdp1 controls CD8+ T cell activation.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

G3BP1 promotes DNA binding and activation of cGAS.

Cyclic GMP-AMP synthase (cGAS) is a key sensor responsible for cytosolic DNA detection. Here we report that GTPase-activating protein SH3 domain-binding protein 1 (G3BP1) is critical for DNA sensing and efficient activation of cGAS. G3BP1 enhanced DNA binding of cGAS by promoting the formation of large cGAS complexes. G3BP1 deficiency led to inefficient DNA binding by cGAS and inhibited cGAS-dependent interferon (IFN) production. The G3BP1 inhibitor epigallocatechin gallate (EGCG) disrupted existing G3BP1-cGAS complexes and inhibited DNA-triggered cGAS activation, thereby blocking DNA-induced IFN production both in vivo and in vitro. EGCG administration blunted self DNA-induced autoinflammatory responses in an Aicardi-Goutières syndrome (AGS) mouse model and reduced IFN-stimulated gene expression in cells from a patient with AGS. Thus, our study reveals that G3BP1 physically interacts with and primes cGAS for efficient activation. Furthermore, EGCG-mediated inhibition of G3BP1 provides a potential treatment for cGAS-related autoimmune diseases.

K33-linked polyubiquitination of Zap70 by Nrdp1 controls CD8(+) T cell activation.

The key molecular mechanisms that control signaling via T cell antigen receptors (TCRs) remain to be fully elucidated. Here we found that Nrdp1, a ring finger-type E3 ligase, mediated Lys33 (K33)-linked polyubiquitination of the signaling kinase Zap70 and promoted the dephosphorylation of Zap70 by the acidic phosphatase-like proteins Sts1 and Sts2 and thereby terminated early TCR signaling in CD8(+) T cells. Nrdp1 deficiency significantly promoted the activation of naive CD8(+) T cells but not that of naive CD4(+) T cells after engagement of the TCR. Nrdp1 interacted with Zap70 and with Sts1 and Sts2 and connected K33 linkage of Zap70 to Sts1- and Sts2-mediated dephosphorylation. Our study suggests that Nrdp1 terminates early TCR signaling by inactivating Zap70 and provides new mechanistic insights into the non-proteolytic regulation of TCR signaling by E3 ligases.

NLRP3 Phosphorylation Is an Essential Priming Event for Inflammasome Activation.

Many infections and stress signals can rapidly activate the NLRP3 inflammasome to elicit robust inflammatory responses. This activation requires a priming step, which is thought to be mainly for upregulating NLRP3 transcription. However, recent studies report that the NLRP3 inflammasome can be activated independently of transcription, suggesting that the priming process has unknown essential regulatory steps. Here, we report that JNK1-mediated NLRP3 phosphorylation at S194 is a critical priming event and is essential for NLRP3 inflammasome activation. We show that NLRP3 inflammasome activation is disrupted in NLRP3-S194A knockin mice. JNK1-mediated NLRP3 S194 phosphorylation is critical for NLRP3 deubiquitination and facilitates its self-association and the subsequent inflammasome assembly. Importantly, we demonstrate that blocking S194 phosphorylation prevents NLRP3 inflammasome activation in cryopyrin-associated periodic syndromes (CAPS). Thus, our study reveals a key priming molecular event that is a prerequisite for NLRP3 inflammasome activation. Inhibiting NLRP3 phosphorylation could be an effective treatment for NLRP3-related diseases.

Constitutive MHC class I molecules negatively regulate TLR-triggered inflammatory responses via the Fps-SHP-2 pathway.

The molecular mechanisms that fine-tune Toll-like receptor (TLR)-triggered innate inflammatory responses remain to be fully elucidated. Major histocompatibility complex (MHC) molecules can mediate reverse signaling and have nonclassical functions. Here we found that constitutively expressed membrane MHC class I molecules attenuated TLR-triggered innate inflammatory responses via reverse signaling, which protected mice from sepsis. The intracellular domain of MHC class I molecules was phosphorylated by the kinase Src after TLR activation, then the tyrosine kinase Fps was recruited via its Src homology 2 domain to phosphorylated MHC class I molecules. This led to enhanced Fps activity and recruitment of the phosphatase SHP-2, which interfered with TLR signaling mediated by the signaling molecule TRAF6. Thus, constitutive MHC class I molecules engage in crosstalk with TLR signaling via the Fps-SHP-2 pathway and control TLR-triggered innate inflammatory responses.

The stress granule protein G3BP1 promotes pre-condensation of cGAS to allow rapid responses to DNA.

Cyclic GMP-AMP synthase (cGAS) functions as a key sensor for microbial invasion and cellular damage by detecting emerging cytosolic DNA. Here, we report that GTPase-activating protein-(SH3 domain)-binding protein 1 (G3BP1) primes cGAS for its prompt activation by engaging cGAS in a primary liquid-phase condensation state. Using high-resolution microscopy, we show that in resting cells, cGAS exhibits particle-like morphological characteristics, which are markedly weakened when G3BP1 is deleted. Upon DNA challenge, the pre-condensed cGAS undergoes liquid-liquid phase separation (LLPS) more efficiently. Importantly, G3BP1 deficiency or its inhibition dramatically diminishes DNA-induced LLPS and the subsequent activation of cGAS. Interestingly, RNA, previously reported to form condensates with cGAS, does not activate cGAS. Accordingly, we find that DNA - but not RNA - treatment leads to the dissociation of G3BP1 from cGAS. Taken together, our study shows that the primary condensation state of cGAS is critical for its rapid response to DNA.

The enhancement of temporal binding effect after negative social feedback.

The present study investigated the effect of social feedback on the experiences of our actions and the outcomes (e.g. temporal binding between an action and its outcome, reflecting individuals' causal beliefs modulated by their agency judgments). In Experiment 1a, participants freely decided (voluntary action) their action timing to cause an outcome, which was followed by social feedback. A larger temporal binding (TB) following negative vs. positive events was found. This effect appeared neither in the random context where the causal belief between the action and outcome was absent (Experiment 1b) nor in the involuntary action context where participants' action timing was instructed (Experiment 1c). Experiments 2a and 2b examined the effect when the action-outcome was occluded, including reversing the order of outcome and feedback in Experiment 2b. Experiments 3a and 3b investigated the effect with only social feedback or only action-outcome presented. Results revealed that the effect found in Experiment 1 was driven by social feedback and independent of the availability of the action-outcome and the position of social feedback. Our findings demonstrate a stronger temporal integration of the action and its outcome following negative social feedback, reflecting fluctuations in sense of agency when faced with social feedback.

A Snapshot Multi-Spectral Demosaicing Method for Multi-Spectral Filter Array Images Based on Channel Attention Network.

Multi-spectral imaging technologies have made great progress in the past few decades. The development of snapshot cameras equipped with a specific multi-spectral filter array (MSFA) allow dynamic scenes to be captured on a miniaturized platform across multiple spectral bands, opening up extensive applications in quantitative and visualized analysis. However, a snapshot camera based on MSFA captures a single band per pixel; thus, the other spectral band components of pixels are all missed. The raw images, which are captured by snapshot multi-spectral imaging systems, require a reconstruction procedure called demosaicing to estimate a fully defined multi-spectral image (MSI). With increasing spectral bands, the challenge of demosaicing becomes more difficult. Furthermore, the existing demosaicing methods will produce adverse artifacts and aliasing because of the adverse effects of spatial interpolation and the inadequacy of the number of layers in the network structure. In this paper, a novel multi-spectral demosaicing method based on a deep convolution neural network (CNN) is proposed for the reconstruction of full-resolution multi-spectral images from raw MSFA-based spectral mosaic images. The CNN is integrated with the channel attention mechanism to protect important channel features. We verify the merits of the proposed method using 5 × 5 raw mosaic images on synthetic as well as real-world data. The experimental results show that the proposed method outperforms the existing demosaicing methods in terms of spatial details and spectral fidelity.

Detection of Electromagnetic Seismic Precursors from Swarm Data by Enhanced Martingale Analytics.

The detection of seismic activity precursors as part of an alarm system will provide opportunities for minimization of the social and economic impact caused by earthquakes. It has long been envisaged, and a growing body of empirical evidence suggests that the Earth's electromagnetic field could contain precursors to seismic events. The ability to capture and monitor electromagnetic field activity has increased in the past years as more sensors and methodologies emerge. Missions such as Swarm have enabled researchers to access near-continuous observations of electromagnetic activity at second intervals, allowing for more detailed studies on weather and earthquakes. In this paper, we present an approach designed to detect anomalies in electromagnetic field data from Swarm satellites. This works towards developing a continuous and effective monitoring system of seismic activities based on SWARM measurements. We develop an enhanced form of a probabilistic model based on the Martingale theories that allow for testing the null hypothesis to indicate abnormal changes in electromagnetic field activity. We evaluate this enhanced approach in two experiments. Firstly, we perform a quantitative comparison on well-understood and popular benchmark datasets alongside the conventional approach. We find that the enhanced version produces more accurate anomaly detection overall. Secondly, we use three case studies of seismic activity (namely, earthquakes in Mexico, Greece, and Croatia) to assess our approach and the results show that our method can detect anomalous phenomena in the electromagnetic data.

The mediation effect of health literacy on social support and health lifestyle of patients with chronic diseases.

BACKGROUND: Previous studies have identified the antecedents of the lifestyle of many patients with chronic diseases. However, the mechanism of social support affecting the lifestyle of patients with chronic diseases is unclear, and the role of health literacy in social support affecting the lifestyle of patients with chronic diseases has not been found. Therefore, this study aims to explore the status quo of social support, health literacy and healthy lifestyle of patients with chronic diseases in China and the relationship among them. METHODS: Through convenient sampling, 356 patients with chronic diseases were surveyed using a health promoting lifestyle scale, a chronic disease patients' health literacy scale and a social support scale. RESULTS: There was a pairwise positive correlation between social support, health lifestyle and health literacy (R = 0.397,0.356,0.556, P < 0.01). After controlling gender, age and education level, it is found that social support has a positive impact on health lifestyle, and health literacy plays an intermediary role between social support and health lifestyle, accounting for 45.78 % of the total effect. CONCLUSION: To promote the healthy lifestyle of patients with chronic diseases and delay the development of the disease, we should strengthen social support for patients with chronic diseases; We should simultaneously take various measures to improve their health literacy.

Rosmarinic acid ameliorates autoimmune responses through suppression of intracellular nucleic acid-mediated type I interferon expression.

Recognition of intracellular nucleic acids is a vital step for host to mount prompt immune responses against microbial pathogens. However, inappropriate response to self-nucleic acids leads to sustained type I interferon (IFN) production, which is implicated in the development of several autoimmune diseases, such as Aicardi-Goutières syndrome (AGS). Therefore, effective confinement of intracellular nucleic acid-induced IFN expression is a potential strategy for the treatment of such autoimmune diseases. In this study, we found that rosmarinic acid (RA), a natural compound isolated from rosemary, inhibits intracellular nucleic acid-stimulated IFN expression. Mechanistic investigation revealed that RA binds to both G3BP1 and cGAS, and impairs cGAS activation through disrupting the binding of DNA with cGAS. More importantly, we showed that RA could effectively attenuate the expression of IFN-stimulated genes (ISGs) in the well-established cell models for AGS. Thus, our study provides a promising compound for the treatment of autoimmune responses induced by aberrant nucleic acid-sensing.

Preparation of One-Dimensional Hollow Metal-Organic Frameworks via the Marangoni Effect.

The fabrication of one-dimensional hollow metal-organic frameworks (1D HMOFs) has attracted considerable attention for the catalysis and separation because of their large surface areas and short and continuous axial diffusion pathways. However, the fabrication of 1D HMOFs requires the use of a sacrificial template and multiple steps, limiting their potential applications. This study proposes a novel Marangoni-assisted method to synthesize 1D HMOFs. Using this method, the MOF crystals can undergo heterogeneous nucleation and growth, affording a morphology self-regulation process under kinetic control and forming tubular 1D HMOFs in one step without requiring additional treatment. This method is expected to open new avenues for synthesizing 1D HMOFs.

Au Nanoparticles@UiO-66 Composite Film-Coated Carbon Cloth Substrate for High-Performance H2O2 Electrochemical Sensing.

Due to the strong oxidizability of H2O2, rapid, accurate, sensitive, and stable sensors of hydrogen peroxide (H2O2) have attracted wide attention in the chemical industry, food, medicine, household detergents, and environmental monitoring fields. Here, a high-performance H2O2 electrochemical sensing platform is proposed based on an Au nanoparticles@UiO-66 film coated on a carbon cloth (CC) electrode (Au NPs@UiO-66/CC electrode). The Au NPs@UiO-66/CC electrode was prepared through solvothermal growth of a UiO-66 film on a functionalized three-dimensional CC electrode, followed by in situ deposition of Au NPs into the UiO-66 film under a periodic galvanostatic pulse current. The in situ preparation strategy greatly improves the electrical interaction between Au NPs@UiO-66 and the CC substrate without sacrificing the electrochemical activity of the Au NPs@UiO-66/CC electrode. Meanwhile, thanks to the high specific surface area of the three-dimensional Au NPs@UiO-66/CC electrode, the optimized Au NPs@UiO-66/CC electrode illustrates excellent electrochemical detection capability for H2O2 with an extensive linear range (0.1-21 mM), high sensitivity (1048.01 µA mM-1 cm-2), and lower limit of detection [0.033 µM (S/N = 3)] and limit of quantification [0.109 µM (S/N = 3)]. At the same time, the encapsulated structure of Au NPs in the UiO-66 film also endows the composite electrode with specific sensing performance owing to the regular opening channels of the UiO-66 films that prevent large-size interferents from reacting to the electrochemically active Au NPs. Together with all these advantages, the proposed sensing platform would exhibit great potential for electrochemical sensors and bioelectronics.

The Protective Effects of Cinnamyl Alcohol Against Hepatic Steatosis, Oxidative and Inflammatory Stress in Nonalcoholic Fatty Liver Disease Induced by Childhood Obesity.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive intracellular lipid accumulation, oxidative stress, and inflammation. Cinnamyl alcohol (CA), one of the cinnamon extracts, has been shown to exhibit anti-oxidative and anti-inflammatory activities. We proposed that CA was beneficial to NAFLD. METHODS: Serum cytokines and components of the lipid metabolism were determined in children with NAFLD against age-matched comparisons. A NAFLD mouse model was established by high fat and high carbohydrate (HFHC) diet in male C57BL/6 mouse pups, followed by administration of CA. The effects of CA on lipid metabolism, oxidative stress, and inflammation in hepatic tissues were assessed. RESULTS: Abnormal lipid metabolism and inflammatory responses were observed in the children with NAFLD as compared with the controls. CA reduced the weight of obese mice without affecting food intake as well as alleviating liver injury caused by HFHC feeding. CA was found to mitigate dyslipidemia and reduce hepatic steatosis in HFHC-fed mice by down-regulating genes related to lipogenesis, including peroxisome proliferator-activated receptor gamma (PPARγ), sterol regulatory element-binding transcription factor-1c (SREBP-1c), and acetyl-CoA carboxylase 1 (ACC1). Additionally, CA treatment reversed HFHC-induced oxidative stress and inflammation, evidenced by the decreased liver reactive oxygen species (ROS), hepatic inflammatory cytokine levels, and F4/80-positive macrophage infiltration in HFHC diet mice. CA reduced the protein levels of pyrin domain-containing protein 3 (NLRP3), adapter protein apoptosis-associated speck-like protein (ASC), and caspase-1 in the liver tissues significantly. CONCLUSION: CA alleviates HFHC-induced NAFLD in mice, which is associated with the amelioration in lipid metabolism, oxidative stress, and inflammation.

G3BP1 Inhibition Alleviates Intracellular Nucleic Acid-Induced Autoimmune Responses.

The detection of intracellular nucleic acids is a fundamental mechanism of host defense against infections. The dysregulated nucleic acid sensing, however, is a major cause for a number of autoimmune diseases. In this study, we report that GTPase-activating protein SH3 domain-binding protein 1 (G3BP1) is critical for both intracellular DNA- and RNA-induced immune responses. We found that in both human and mouse cells, the deletion of G3BP1 led to the dampened cGAS activation by DNA and the insufficient binding of RNA by RIG-I. We further found that resveratrol (RSVL), a natural compound found in grape skin, suppressed both intracellular DNA- and RNA-induced type I IFN production through inhibiting G3BP1. Importantly, using experimental mouse models for Aicardi-Goutières syndrome, an autoimmune disorder found in humans, we demonstrated that RSVL effectively alleviated intracellular nucleic acid-stimulated autoimmune responses. Thus, our study demonstrated a broader role of G3BP1 in sensing different kinds of intracellular nucleic acids and presented RSVL as a potential treatment for autoimmune conditions caused by dysregulated nucleic acid sensing.

The pursuit of the end: The effects of action-goal choices on temporal binding.

The effect of action choice (whether one can choose their actions freely) on temporal binding (TB), the temporal contraction between a voluntary action and its effect, is controversial. The present study tried to distinguish action-goal choice (whether one could pursue the action-effect freely) from action choice. Experiments 1 and 2 focused on the effect of action-goal choice on TB while the congruency between actions and outcomes was manipulated (i.e., 50% in Experiment 1 and 80% in Experiment 2). Experiment 3 investigated the effect of action choice on TB when the outcome congruency was 80%. Results showed that free and instructed action-goals led to comparable magnitudes of TB while free actions led to a larger TB than instructed actions. Furthermore, the effect of outcome congruency on TB varied by action-goal choices (Experiment 2) but not action choices (Experiment 3). These results demonstrate the potential differences between action choice and action-goal choice.

Working memory capacity predicts focus back effort under different task demands.

According to the cognitive flexibility view, individuals with higher cognitive control ability are more flexible in experiencing on task or mind wandering during tasks with different loads. On the other hand, the resource-control theory posits that executive control is essential for allocating attentional resources between mind wandering and tasks. Focus back effort may reflect the adjustment of executive control in the resource-control theory. Here, 121 participants completed two span tasks, as well as high- and low-load tasks, while mind wandering and focus back effort were measured. Our findings indicated that mind wandering was influenced by working memory capacity (WMC) and focus back effort. Additionally, participants demonstrated a higher focus back effort during the higher load task. This effect was particularly pronounced in individuals with lower WMC, which was treated as a continuous variable. These findings integrate the cognitive flexibility view and resource-control theory to describe how individuals modulate mind wandering.

Better Controlled, Better Maintained: Sense of Agency Facilitates Working Memory.

The cognitive effects of sense of agency (SoA) attract increasing attention. It is unclear how SoA influences working memory (WM). In the present study, participants first moved several boxes. One of the boxes was more or less controllable than the majority. After boxes stopped moving, to-be-remembered items appeared. Memory performance and SoA over them were subsequently tested. In Experiments 1a and 1b, the majority of boxes, serving as context, were under low and high control respectively. To further examine whether the maintenance stage was influenced, the effect of selective encoding was minimized in Experiments 2a and 2b. Experiment 2b further eliminated the impact of agency judgments and tested the relationship among SoA, WM, and preference. Memory was better for items with strong SoA in the high and low control contexts. The effect partly stems from the modulation of the maintenance stage in WM, in which reward-based processes could be engaged.