The RIG‐I‐like receptors (RLRs) are critical for protection against RNA virus infection, and their activities must be stringently controlled to maintain immune homeostasis. Here, we report that ...leucine‐rich repeat containing protein 25 (LRRC25) is a key negative regulator of RLR‐mediated type I interferon (IFN) signaling. Upon RNA virus infection, LRRC25 specifically binds to ISG15‐associated RIG‐I to promote interaction between RIG‐I and the autophagic cargo receptor p62 and to mediate RIG‐I degradation via selective autophagy. Depletion of either LRRC25 or ISG15 abrogates RIG‐I‐p62 interaction as well as the autophagic degradation of RIG‐I. Collectively, our findings identify a previously unrecognized role of LRRC25 in type I IFN signaling activation by which LRRC25 acts as a secondary receptor to assist RIG‐I delivery to autophagosomes for degradation in a p62‐dependent manner.
Synopsis
Upon RNA virus infection, LRRC25 recognizes ISG15‐associated immune receptor RIG‐I and facilitates its degradation via p62‐mediated selective autophagy, thereby limiting RIG‐I‐dependent type I interferon signaling.
LRRC25 negatively regulates type I interferon signaling upon RNA virus infection.
LRRC25 promotes autophagic degradation of RIG‐I in a p62‐dependent manner.
ISG15 serves as a signal for LRRC25‐mediated RIG‐I degradation.
The interaction between RIG‐I, ISG15 and LRRC25 forms a negative feedback loop to avoid prolonged immune activation upon viral infection.
Upon RNA virus infection, LRRC25 recognizes ISG15‐associated immune receptor RIG‐I and facilitates its degradation via p62‐mediated selective autophagy, thereby limiting RIG‐I‐dependent type I interferon signaling.
Innate immunity is the first defense system against invading pathogens. Toll-like receptors (TLRs) are well-defined pattern recognition receptors responsible for pathogen recognition and induction of ...innate immune responses. Since their discovery, TLRs have revolutionized the field of immunology by filling the gap between the initial recognition of pathogens by innate immune cells and the activation of the adaptive immune response. TLRs critically link innate immunity to adaptive immunity by regulating the activation of antigen-presenting cells and key cytokines. Furthermore, recent studies also have shown that TLR signaling can directly regulate the T cell activation, growth, differentiation, development, and function under diverse physiological conditions. This review provides an overview of TLR signaling pathways and their regulators and discusses how TLR signaling, directly and indirectly, regulates cell-mediated immunity. In addition, we also discuss how TLR signaling is critically important in the host's defense against infectious diseases, autoimmune diseases, and cancer.
Due to the upstream pressure of lithium resources, low‐cost sodium‐ion batteries (SIBs) have become the most potential candidates for energy storage systems in the new era. However, anode materials ...of SIBs have always been a major problem in their development. To address this, V2C/Fe7S8@C composites with hierarchical structures prepared via an in situ synthesis method are proposed here. The 2D V2C‐MXene as the growth substrate for Fe7S8 greatly improves the rate capability of SIBs, and the carbon layer on the surface provides a guarantee for charge–discharge stability. Unexpectedly, the V2C/Fe7S8@C anode achieves satisfactory sodium storage capacity and exceptional rate performance (389.7 mAh g−1 at 5 A g−1). The sodium storage mechanism and origin of composites are thoroughly studied via ex situ characterization techniques and first‐principles calculations. Furthermore, the constructed sodium‐ion capacitor assembled with N‐doped porous carbon delivers excellent energy density (135 Wh kg−1) and power density (11 kW kg−1), showing certain practical value. This work provides an advanced system of sodium storage anode materials and broadens the possibility of MXene‐based materials in the energy storage.
In this work, V2C/Fe7S8@C composites prepared via an in‐situ synthesis method are proposed, leading to the high reversible capacity and outstanding rate performance. The mechanisms are revealed by theoretical calculations and ex‐situ characterizations. Furthermore, sodium‐ion capacitors assembled with N‐doped porous carbon deliver excellent energy density (135 Wh kg−1) and power density (11 kW kg−1), showing certain practical value.
The controlled size and surface treatment of magnetic nanoparticles (NPs) make one‐stage combination feasible for enhanced magnetic resonance imaging (MRI) contrast and effective hyperthermia. ...However, superparamagnetic behavior, essential for avoiding the aggregation of magnetic NPs, substantially limits their performance. Here, a superparamagnetic core–shell structure is developed, which promotes the formation of vortex‐like intraparticle magnetization structures in the remanent state, leading to reduced dipolar interactions between two neighboring NPs, while during an MRI scan, the presence of a DC magnetic field induces the formation of NP chains, introducing increased local inhomogeneous dipole fields that enhance relaxivity. The core–shell NPs also reveal an augmented anisotropy, due to exchange coupling to the high anisotropy core, which enhances the specific absorption rate. This in vivo tumor study reveals that the tumor cells can be clearly diagnosed during an MRI scan and the tumor size is substantially reduced through hyperthermia therapy by using the same FePt@iron oxide nanoparticles, realizing the concept of theranostics.
The magnetic interaction among nanoparticles is demonstrated to be able to be manipulated by a core–shell structure to enhance the resolution of magnetic resonance imaging and the specific absorption rate of nanoparticles. It is rather remarkable that the magnetic configuration of the assembly shape can be controlled under a magnetic field toimprove the relaxivity of the contrast agent and the effectiveness of hyperthermia, making theranostics feasible.
In this paper, we are concerned with numerical methods for the solution of initial–boundary value problems of anomalous diffusion equations of order α∈(1,2). The classical Crank–Nicholson method is ...used to discretize the fractional diffusion equation and then the spatial extrapolation is used to obtain temporally and spatially second-order accurate numerical estimates. Two preconditioned iterative methods, namely, the preconditioned generalized minimal residual (preconditioned GMRES) method and the preconditioned conjugate gradient for normal residual (preconditioned CGNR) method, are proposed to solve relevant linear systems. Numerical experiments are given to illustrate the efficiency of the methods.
Intranasal administration of phospholipid-based gelatin nanoparticles (GNP) was prepared to investigate the neuro-recovery effects of neuropeptide Substance P (SP) on hemiparkinsonian rats.
The ...SP-loaded gelatin nanoparticles (SP-GNP) were prepared by a water-in-water emulsion method and possessed high stability, encapsulating efficiency and loading capacity. PC-12 cells were used to examine the growth enhancement of SP-GNP in vitro by MTT assays and flow cytometry (FCM). The therapeutic effects of SP-GNP on 6-hydroxydopamine (6-OHDA) induced hemiparkinsonian rats were assessed by quantifying rotational behavior and the levels of tyrosine hydroxylase (TH), phosphorylated c-Jun protein (p-c-Jun) and Caspase-3 (Cas-3) expressed in substantia nigra (SN) region of hemiparkinsonian rats.
PC-12 cells under SP-GNP treatment showed better cell viability and lower degree of apoptosis than those under SP solution treatment. Hemiparkinsonian rats under intranasal SP-GNP administration demonstrated better behavioral improvement, higher level of TH in SN along with much lower extent of p-c-Jun and Cas-3 than those under intranasal SP solution administration and intravenous SP-GNP administration.
With the advantages of GNP and nose-to-brain pathway, SP can be effectively delivered into the damaged SN region and exhibit its neuro-recovery function through the inhibition on JNK pathway and dopaminergic neuron apoptosis.
In our research on naturally occurring sesquiterpenes, eight shizukaol-type dimers, one chlorahololide-type dimer, and one sarcanolide-type dimer were isolated from the roots of
As the project was ...implemented, we accidentally discovered that shizukaol-type dimers can be converted into peroxidized chlorahololide-type dimers. This potential change was discovered after simulations of the changes in corresponding shizukaols showed that three peroxide products were generated (
), indicating that peroxidation reactions occurred. HPLC-HR-MS analysis results obtained for the shizukaol derivatives further demonstrate that the reaction occurred, and the type of substituent of small organic ester moieties at positions C-15' and C-13' of unit B were not decisively related to the reaction. Quantum chemical calculations of the mode dimer further demonstrated this phenomenon. The highest occupied molecular orbital (HOMO)-lowest unoccupied molecular orbital (LUMO) energy of the precursor and production revealed the advantageous yield of 4
-hydroperoxyl production. Additionally, the potential reaction mechanism was speculated and validated using the free energy in the reaction which successfully explained the feasibility of the reaction. Finally, the anti-inflammatory activity of the precursors and products was evaluated, and the products of peroxidation showed better anti-inflammatory activity.
Aims
To assess the associations of diabetes duration and glycaemic control (defined by plasma glycated haemoglobin HbA1c level) with the risks of cardiovascular disease (CVD) and all‐cause mortality ...and to determine whether the addition of either or both to the established CVD risk factors can improve predictions.
Materials and Methods
A total of 435 679 participants from the UK Biobank without CVD at baseline were included. Cox models adjusting for classic risk factors (sociodemographic and anthropometric characteristics, lipid profiles and medication use) were used, and predictive utility was determined by the C‐index and net reclassification improvement (NRI).
Results
Compared with participants without diabetes, participants with longer diabetes durations and poorer glycaemic control had a higher risk of fatal/nonfatal CVD. Among participants with diabetes, the fully‐adjusted hazard ratios (HRs) for diabetes durations of 5 to <10 years, 10 to <15 years and ≥15 years were 1.15 (95% confidence interval CI 0.99, 1.34), 1.50 (95% CI 1.26, 1.79) and 2.22 (95% CI 1.90, 2.58; P‐trend <0.01), respectively, compared with participants with diabetes durations <5 years. In addition, those with the longest disease duration (≥15 years) and poorer glycaemic control (HbA1c ≥64 mmol/mol 8%) had the highest risk of fatal/nonfatal CVD (HR 3.12, 95% CI 2.52, 3.86). Among participants with diabetes, the addition of both diabetes duration and glycaemic control levels significantly improved both the C‐index (change in C‐index +0.0254; 95% CI 0.0111, 0.0398) and the overall NRI for fatal/nonfatal CVD (0.0992; 95% CI 0.0085, 0.1755) beyond the use of the classic risk factors.
Conclusions
Both longer diabetes duration and poorer glycaemic control were associated with elevated risks of CVD and mortality. Clinicians should consider not only glycaemic control but also diabetes duration in CVD risk assessments for participants with diabetes.
The inflammasome plays a critical role in inflammation and immune responses against pathogens. However, whether or how inflammasome activation regulates type I interferon (IFN-I) signaling in the ...context of malaria infection remain unknown. Here we show mice deficient in inflammasome sensors AIM2, NLRP3 or adaptor Caspase-1 produce high levels of IFN-I cytokines and are resistant to lethal Plasmodium yoelii YM infection. Inactivation of inflammasome signaling reduces interleukin (IL)-1β production, but increases IFN-I production. Mechanistically, we show inflammsome activation enhances IL-1β-mediated MyD88-TRAF3-IRF3 signaling and SOCS1 upregulation. However, SOCS1 inhibits MyD88-IRF7-mediated-IFN-I signaling and cytokine production in plasmacytoid dendritic cells. By contrast, ablation of inflammsome components reduces SOCS1 induction, and relieves its inhibition on MyD88-IRF7-dependent-IFN-I signaling, leading to high levels of IFN-α/β production and host survival. Our study identifies a previously unrecognized role of inflammasome activation in the negative regulation of IFN-I signaling pathways and provides potential targets for developing effective malaria vaccines.
Microbial products, such as lipopolysaccharide (LPS), can elicit efficient innate immune responses against invading pathogens. However, priming with LPS can induce a form of innate immune memory, ...termed innate immune “tolerance”, which blunts subsequent NF‐κB signaling. Although epigenetic and transcriptional reprogramming has been shown to play a role in innate immune memory, the involvement of post‐translational regulation remains unclear. Here, we report that ubiquitin‐specific protease 3 (USP3) participates in establishing “tolerance” innate immune memory through non‐transcriptional feedback. Upon NF‐κB signaling activation, USP3 is stabilized and exits the nucleus. The cytoplasmic USP3 specifically removes the K63‐linked polyubiquitin chains on MyD88, thus negatively regulating TLR/IL1β‐induced inflammatory signaling activation. Importantly, cytoplasmic translocation is a prerequisite step for USP3 to deubiquitinate MyD88. Additionally, LPS priming could induce cytoplasmic retention and faster and stronger cytoplasmic translocation of USP3, enabling it to quickly shut down NF‐κB signaling upon the second LPS challenge. This work identifies a previously unrecognized post‐translational feedback loop in the MyD88–USP3 axis, which is critical for inducing normal “tolerance” innate immune memory.
Synopsis
USP3 controls innate immune signaling and inflammatory responses by regulating the NF‐κB pathway through the deubiquitination of MyD88. LPS‐priming‐induced cytoplasmic translocation and retention of USP3 are essential for establishing normal “tolerance” innate immune memory.
USP3 strongly inhibits the TLRs/IL1β‐induced inflammatory response and NF‐κB signaling by directly targeting MyD88.
Upon NF‐κB pathway activation, USP3 is stabilized and moves out of the nucleus to deubiquitinate MyD88 in the cytoplasm.
LPS‐priming induces cytoplasmic retention of USP3, resulting in the rapid deubiquitination of MyD88.
Cytoplasmic USP3 allows for the robust suppression of NF‐κB signaling upon subsequent challenge with various TLR ligands.
Deficiency of USP3 severely disrupts the establishment of normal innate immune tolerance both in vitro and in vivo.
USP3 controls innate immune signaling and inflammatory responses by regulating the NF‐κB pathway by deubiquitinating MyD88. LPS‐priming‐induced cytoplasmic translocation and retention of USP3 are essential for establishing normal “tolerance” innate immune memory.
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