Development of central nervous system (CNS) is regulated by both intrinsic and peripheral signals. Previous studies have suggested that environmental factors affect neurological activities under both ...physiological and pathological conditions. Although there is anatomical separation, emerging evidence has indicated the existence of bidirectional interaction between gut microbiota, i.e., (diverse microorganisms colonizing human intestine), and brain. The cross-talk between gut microbiota and brain may have crucial impact during basic neurogenerative processes, in neurodegenerative disorders and tumors of CNS. In this review, we discuss the biological interplay between gut-brain axis, and further explore how this communication may be dysregulated in neurological diseases. Further, we highlight new insights in modification of gut microbiota composition, which may emerge as a promising therapeutic approach to treat CNS disorders.
Harnessing the immune system to eradicate malignant cells is becoming a most powerful new approach to cancer therapy. FDA approval of the immunotherapy-based drugs, sipuleucel-T （Provenge）, ...ipilimumab （Yervoy, anti-CT- LA-4）, and more recently, the programmed cell death （PD）-I antibody （pembroliznmab, Keytruda）, for the treatment of multiple types of cancer has greatly advanced research and clinical studies in the field of cancer immunotherapy. Furthermore, recent clinical trials, using NY-ESO-l-specific T cell receptor （TCR） or CD19-chimeric antigen re- ceptor （CAR）, have shown promising clinical results for patients with metastatic cancer. Current success of cancer immunotherapy is built upon the work of cancer antigens and co-inhibitory signaling molecules identified 20 years ago. Among the large numbers of target antigens, CD19 is the best target for CAR T cell therapy for blood cancer, but CAR-engineered T cell immunotherapy does not yet work in solid cancer. NY-ESO-1 is one of the best targets for TCR-based immunotherapy in solid cancer. Despite the great success of checkpoint blockade therapy, more than 50% of cancer patients fail to respond to blockade therapy. The advent of new technologies such as next-generation sequencing has enhanced our ability to search for new immune targets in onco-immunology and accelerated the de- velopment of immunotherapy with potentially broader coverage of cancer patients. In this review, we will discuss the recent progresses of cancer immunotherapy and novel strategies in the identification of new immune targets and mu- tation-derived antigens （neoantigens） for cancer immunotherapy and immunoprecision medicine.
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.
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.
Abstract
As one of the most important photocatalysts, TiO
2
has triggered broad interest and intensive studies for decades. Observation of the interfacial reactions between water and TiO
2
at ...microscopic scale can provide key insight into the mechanisms of photocatalytic processes. Currently, experimental methodologies for characterizing photocatalytic reactions of anatase TiO
2
are mostly confined to water vapor or single molecule chemistry. Here, we investigate the photocatalytic reaction of anatase TiO
2
nanoparticles in water using liquid environmental transmission electron microscopy. A self-hydrogenated shell is observed on the TiO
2
surface before the generation of hydrogen bubbles. First-principles calculations suggest that this shell is formed through subsurface diffusion of photo-reduced water protons generated at the aqueous TiO
2
interface, which promotes photocatalytic hydrogen evolution by reducing the activation barrier for H
2
(H–H bond) formation. Experiments confirm that the self-hydrogenated shell contains reduced titanium ions, and its thickness can increase to several nanometers with increasing UV illuminance.
For a long time, optical imaging of the deep brain with high resolution has been a challenge. Recently, with the advance in second near‐infrared (NIR‐II) bioimaging techniques and imaging contrast ...agents, NIR‐II window bioimaging has attracted great attention to monitoring deeper biological or pathophysiological processes with high signal‐to‐noise ratio (SNR) and spatiotemporal resolution. Assisted with NIR‐II bioimaging, the modulation of structure and function of brain is promising to be noninvasive and more precise. Herein, in this review, first the advantage of NIR‐II light in brain imaging from the interaction between NIR‐II and tissue is elaborated. Then, several specific NIR‐II bioimaging technologies are introduced, including NIR‐II fluorescence imaging, multiphoton fluorescence imaging, and photoacoustic imaging. Furthermore, the corresponding contrast agents are summarized. Next, the application of various NIR‐II bioimaging technologies in visualizing the characteristics of cerebrovascular network and monitoring the changes of the pathology signals will be presented. After that, the modulation of brain structure and function based on NIR‐II bioimaging will be discussed, including treatment of glioblastoma, guidance of cell transplantation, and neuromodulation. In the end, future perspectives that would help improve the clinical translation of NIR‐II light are proposed.
Second near‐infrared (NIR‐II) light opens up a new nonradiative and cheap opportunity for understanding brain physiological structure and modulating brain function. Given the advances in bioimaging systems and nanomaterials, nanoprobes‐assisted NIR‐II bioimaging technologies have broad application prospects in the fields of imaging brain structure, diagnosing pathological signals, and treating neurological diseases.
Ultrathin 2D porous carbon-based materials offer numerous fascinating electrical, catalytic, and mechanical properties, which hold great promise in various applications. However, it remains a ...formidable challenge to fabricate these materials with tunable morphology and composition by a simple synthesis strategy. Here, a facile one-step self-flowering method without purification and harsh conditions is reported for large-scale fabrication of high-quality ultrathin (≈1.5 nm) N-doped porous carbon nanosheets (NPC) and their composites. It is demonstrated that the layered tannic/oxamide (TA/oxamide) hybrid is spontaneously blown, exfoliated, bloomed, in situ pore-formed, and aromatized during pyrolysis to form flower-like aggregated NPC. This universal one-step self-flowering system is compatible with various precursors to construct multiscale NPC-based composites (Ru@NPC, ZnO@NPC, MoS
@NPC, Co@NPC, rGO@NPC, etc.). Notably, the programmable architecture enables NPC-based materials with excellent multifunctional performances, such as microwave absorption and hydrogen evolution. This work provides a facile, universal, scalable, and eco-friendly avenue to fabricate functional ultrathin porous carbon-based materials with programmability.
Autophagy, mediated by a number of autophagy‐related (ATG) proteins, plays an important role in the bulk degradation of cellular constituents. Beclin‐1 (also known as Atg6 in yeast) is a core protein ...essential for autophagic initiation and other biological processes. The activity of Beclin‐1 is tightly regulated by multiple post‐translational modifications, including ubiquitination, yet the molecular mechanism underpinning its reversible deubiquitination remains poorly defined. Here, we identified ubiquitin‐specific protease 19 (USP19) as a positive regulator of autophagy, but a negative regulator of type I interferon (IFN) signaling. USP19 stabilizes Beclin‐1 by removing the K11‐linked ubiquitin chains of Beclin‐1 at lysine 437. Moreover, we found that USP19 negatively regulates type I IFN signaling pathway, by blocking RIG‐I‐MAVS interaction in a Beclin‐1‐dependent manner. Depletion of either USP19 or Beclin‐1 inhibits autophagic flux and promotes type I IFN signaling as well as cellular antiviral immunity. Our findings reveal novel dual functions of the USP19‐Beclin‐1 axis by balancing autophagy and the production of type I IFNs.
Synopsis
USP19 stabilizes Beclin‐1 by cleaving K11‐linked ubiquitin chains on Beclin‐1, thereby promoting autophagy and inhibiting the type I IFN signaling pathway.
USP19 facilitates autophagosome formation and functions as a new component of the Beclin‐1 complex.
USP19 rescues the proteasomal degradation of Beclin‐1 by removing K11‐linked ubiquitin chains at Lys437.
USP19 inhibits RIG‐I‐mediated type I IFN signaling as well as antiviral immune responses in a Beclin‐1‐dependent manner.
USP19‐Beclin‐1 blocks RIG‐I‐MAVS association, thereby suppressing type I IFN signaling.
USP19 stabilizes Beclin‐1 by cleaving K11‐linked ubiquitin chains on Beclin‐1, thereby promoting autophagy and inhibiting the type I IFN signaling pathway.
Electrochemical nitrate reduction to ammonia (eNO3RR) is a green and appealing method for ammonia synthesis, but is hindered by the multistep chemical reaction and competitive hydrogen generation. ...Herein, the synthesis of 2D SnS nanosheets with tailored interlayer spacing is reported, including both expansion and compression, through the active diatomic Pt‐Ce pairs. Taking together the experimental results, in situ Raman spectra, and DFT calculations, it is found that the compressed interlayer spacing can tune the electron density of localized p‐orbital in Sn into its delocalized states, thus enhancing the chemical affinity towards NO3− and NO2− but inhibiting hydrogen generation simultaneously. This phenomenon significantly facilitates the rate‐determining step (*NO3→*NO2) in eNO3RR, and realizes an excellent Faradaic efficiency (94.12%) and yield rate (0.3056 mmol cm−2 h−1) for NH3 at −0.5 V versus RHE. This work provides a powerful strategy for tailoring flexible interlayer spacing of 2D materials and opens a new avenue for constructing high‐performance catalysts for ammonia synthesis.
An interlayer spacing engineering of 2D SnS nanosheets is reported that involves adopting active diatomic Pt‐Ce, that tunes the electron density of localized p‐orbitals in Sn into its delocalized states, thus significantly improving NO3−‐to‐NH3 conversion for both activity and selectivity.
The adaptor protein TRAF6 has a central function in Toll-like receptor (TLR) signalling, yet the molecular mechanisms controlling its activity and stability are unclear. Here we show that NLRP11, a ...primate specific gene, inhibits TLR signalling by targeting TRAF6 for degradation. NLRP11 recruits the ubiquitin ligase RNF19A to catalyze K48-linked ubiquitination of TRAF6 at multiple sites, thereby leading to the degradation of TRAF6. Furthermore, deficiency in either NLRP11 or RNF19A abrogates K48-linked ubiquitination and degradation of TRAF6, which promotes activation of NF-κB and MAPK signalling and increases the production of proinflammatory cytokines. Therefore, our findings identify NLRP11 as a conserved negative regulator of TLR signalling in primate cells and reveal a mechanism by which the NLRP11-RNF19A axis targets TRAF6 for degradation.
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