The cytosolic DNA sensor cGAS recognizes viral DNA and synthesizes the second messenger cGAMP upon viral infection. cGAMP binds to the adaptor protein MITA/STING to activate downstream signaling events, leading to induction of type I interferons (IFNs) and antiviral effector genes. Here we identify the human cytomegalovirus (HCMV) protein UL31 as an inhibitor of cGAS. UL31 interacts directly with cGAS and disassociates DNA from cGAS, thus inhibiting cGAS enzymatic functions and reducing cGAMP production. UL31 overexpression markedly reduces antiviral responses stimulated by cytosolic DNA, while knockdown or knockout of UL31 heightens HCMV-triggered induction of type I IFNs and downstream antiviral genes. Moreover, wild-type HCMV replicates more efficiently than UL31-deficient HCMV, a phenotype that is reversed in cGAS null cells. These results highlight the importance of cGAS in the host response to HCMV as well as an important viral strategy to evade this innate immune sensor.

The highly specific affinity between probes and phosphopeptides is the fundamental interaction for selective identification of phosphoproteomes that uncover the mechanisms of signal transduction, cell cycle, enzymatic regulation, and gene expression in biological systems. In this study, a metal-affinity probe possessing both interactions of metal oxide affinity chromatography (MOAC) and immobilized metal ion affinity chromatography (IMAC) was facilely prepared by immobilizing zirconium(IV) on a zirconium-organic framework of UiO-66-NH, which holds dual-metal centers of not only the inherent Zr-O cluster but also the immobilized Zr(IV) center. This dual-metal centered zirconium-organic framework (DZMOF) demonstrates as a highly specific metal-affinity probe toward the extraction of phosphopeptides due to the metal-affinity interactions of MOAC and IMAC toward either mono-phosphorylated or multi-phosphorylated peptides. The binding energies of zirconium 3d and 3d in this DZMOF are 183.07 and 185.47 eV, respectively, which are higher than those of the intact UiO-66-NH (182.84 and 185.17 eV, respectively), confirming the higher metal-affinity interaction between the DZMOF and phosphopeptides. This high metal-affinity probe presents an unprecedented strong performance in anti-nonspecific interference during the capturing of phosphopeptides of β-casein with the molar ratio of β-casein vs bovine serum albumin up to ca. 1:5000. The enrichment of phosphopeptides from a human saliva sample by DZMOF further confirms the great potential of DZMOF in the extraction of low-abundance phosphopeptides for real complex biological samples.

Attaining consistently high performance of diagnostic and therapeutic functions in one single nanoplatform is of great significance for nanomedicine. This study demonstrates the use of donor–acceptor (D–A) structured polymer (TBT) to develop a smart “all‐five‐in‐one” theranostic that conveniently integrates fluorescence/photoacoustic/thermal imaging and photodynamic/photothermal therapy into single nanoparticle. The prepared nanoparticles (TBTPNPs) exhibit near‐infrared emission, high water solubility, excellent light resistance, good pH stability, and negligible toxicity. Additionally, the TBTPNPs exhibit an excellent singlet oxygen (1O2) quantum yield (40%) and high photothermal conversion efficiency (37.1%) under single‐laser irradiation (635 nm). Apart from their two phototherapeutic modalities, fluorescence, photoacoustic signals, and thermal imaging in vivo can be simultaneously achieved because of their enhanced permeability and retention effects. This work demonstrates that the prepared TBTPNPs are “all‐five‐in‐one” phototheranostic agents that can exhibit properties to satisfy the “one‐fits‐all” requirement for future phototheranostic applications. Thus, the prepared TBTPNPs can provide fundamental insights into the development of PNP‐based nanoagents for cancer therapy.

Clinical applications of current photodynamic therapy (PDT) photosensitizers (PSs) are often limited by their absorption in the UV-vis range that possesses limited tissue penetration ability, leading to ineffective therapeutic response for deep-seated tumors. Alternatively, two-photon excited PS (TPE-PS) using NIR light triggered is one the most promising candidates for PDT improvement. Herein, multimodal polymer nanoparticles (PNPs) from polythiophene derivative as two-photon fluorescence imaging as well as two-photon-excited PDT agent are developed. The prepared PNPs exhibit excellent water dispersibility, high photostability and pH stability, strong fluorescence brightness, and low dark toxicity. More importantly, the PNPs also possess other outstanding features including: (1) the high O quantum yield; (2) the strong two-photon-induced fluorescence and efficient O generation; (3) the specific accumulation in lysosomes of HeLa cells; and (4) the imaging detection depth up to 2100 µm in the mock tissue under two-photon. The multifunctional PNPs are promising candidates as TPE-PDT agent for simultaneous cellular, deep-tissue imaging, and highly efficient in vivo PDT of cancer.

Multisite phosphorylation of a protein, generally occurring in biological processes, plays important roles in the regulation of cellular functions. However, the identification of multi-phosphopeptides especially at low abundance is a big challenge as the extreme hydrophilicity and poor ionization efficiency of the multiphosphorylated peptides restrict the deep inspection of multisite phosphorylation processes. In this study, the highly specific enrichment of multiphosphorylated peptides was achieved via the modification of the dual-metal-centered zirconium-organic framework with the diphosphorylated fructose. The diphosphorylated fructose-modified dual-metal-centered zirconium-organic framework (DZMOF-FDP) demonstrated the highly specific affinity to the multiple phosphorylated peptides, with the density functional theory calculations explaining the plausible mechanism for multi-phosphopeptides on the DZMOF-FDP. The selective capture of multi-phosphopeptides from mimic samples confirmed the superior performance of the DZMOF-FDP, with comprehensive comparisons to other modification agents, such as orthophosphate and pyrophosphate. A number of 1871 multiphosphorylated peptides captured by DZMOF-FDP from tryptic digests of HeLa cell lysate could be identified, significantly higher than that by the pristine DZMOF. The deliberately designed modification with diphosphorylated fructose for the dual-zirconium-centered metal-organic framework materials suggests an efficient strategy to develop new enrichment methods in the selective capture of target analytes by judiciously optimizing specific modifiers for adsorbents.

Mediator of IRF3 activation (MITA, also known as stimulator of interferon genes, STING) senses the second messenger cyclic GMP-AMP (cGAMP) which is synthesized upon DNA virus infection and activates innate antiviral immune response. It has been demonstrated that the activity of MITA is delicately regulated by various post-translational modifications including polyubiquitination. In this study, we identified the deubiquitinating enzyme USP44 as a positive regulator of MITA. USP44 is recruited to MITA following DNA virus infection and removes K48-linked polyubiquitin moieties from MITA at K236, therefore prevents MITA from proteasome mediated degradation. USP44-deficiency results in acceleration of HSV-1-induced degradation of MITA and reduced induction of type I interferons (IFNs) and proinflammatory cytokines. Consistently, Usp44-/mice are more susceptible to HSV-1 infection as indicated by higher tissue viral titers, greater tissue damage and lower survival rate. These findings suggest that USP44 plays a specific and critical role in the regulation of innate immune response against DNA viruses.

The effect of tumor-targeted photodynamic therapy (PDT) was improved by designing nanotheranostics to promote oxygenation in a tumor microenvironment (TME) wherein hypoxia, acidosis, and the elevated levels of H 2 O 2 are three main characteristics. In this study, a carbon dot (CD) PDT agent recently developed by our group was firstly applied as reducing agent to react with potassium permanganate for fabricating CDs/manganese dioxide (CDs/MnO 2) composites, which were in turn modified with polyethylene glycol (PEG) to form water-soluble CDs/MnO 2-PEG nanohybrids. In a normal physiological environment, the as-prepared nanohybrids exhibited quenched fluorescence, weak singlet oxygen generation, and low magnetic resonance imaging (MRI) signal. However, given the high sensitivity of MnO 2 to the TME, the CDs/MnO 2-PEG nanohybrids changed from an "off" to an "on" state with synchronously enhanced fluorescence, singlet oxygen generation, and MRI signal in the TME. In vitro and in vivo analyses have revealed that CDs/MnO 2-PEG nanohybrids could be applied as TME-driven, turn-on nanotheranostics for the MR/fluorescence bimodal imaging-guided PDT of cancer. Moreover, complete clearance of CDs/MnO 2-PEG nanohybrids from the body of mice was observed, indicating their low long-term toxicity and good biocompatibility. This work offers a new nanotheranostic candidate for modulating the unfavorable TME, particularly for the targeted PDT of cancer through precise positioning and oxygen generation.

Prevotella, Gemmiger, and Roseburia were significantly upregulated at the genus level in NSCLC patients.• Nervonic acid/all-trans-retinoic acid was negatively related to Prevotella.• CRP, LBP, and CD14 were identified as potential biomarkers for NSCLC.• Transplantation of faecal microbiota from patients with NSCLC or Prevotella copri-colonized recipient mice caused inflammation and immune dysregulation in Lewis lung cancer (LLC) cells-bearing C57BL/6 mice.• Nervonic acid/all-trans-retinoic acid improved the Prevotella copri-treated LLC cells-bearing C57BL/6 mice phenotype.