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A kind of N, P, C, O-containing polymer was easily prepared via microwave heating of phytic acid and thiourea just for 90 s. After impregnation and reduction of H2PdCl4, highly dispersed Pd single atoms/sub-nano clusters loaded on the phytic acid/thiourea polymer (Pd-CNSP) were successfully obtained. Owing to the synergetic effect of the polymer support and Pd, the catalyst Pd-CNSP achieves a great atomic efficiency of Pd species and exhibits an outstanding catalytic ability in the reduction of 4-nitrophenol. The k value of the catalyst Pd-CNSP (2.17 min-1 mg-1) is about 19 times higher than that of the commercial Pd/C (5 wt %) catalyst. The turnover frequency value is as high as 848 min-1, which is the highest value reported so far. Pd-CNSP also has good selectivity for the reduction of halogen-substituted (Cl and Br) nitroaromatics. It is expected to be mass-produced and used in other industrial hydrogenation reactions.

CRISPR/Cas9-based genome editing has revolutionized experimental molecular biology and entered the clinical world for targeted gene therapy. Identifying DNA modifications occurring at CRISPR/Cas9 target sites is critical to determine efficiency and safety of editing tools. Here we show that insertions of LINE-1 (L1) retrotransposons can occur frequently at CRISPR/Cas9 editing sites. Together with PolyA-seq and an improved amplicon sequencing, we characterize more than 2500 de novo L1 insertions at multiple CRISPR/Cas9 editing sites in HEK293T, HeLa and U2OS cells. These L1 retrotransposition events exploit CRISPR/Cas9-induced DSB formation and require L1 RT activity. Importantly, de novo L1 insertions are rare during genome editing by prime editors (PE), cytidine or adenine base editors (CBE or ABE), consistent with their reduced DSB formation. These data demonstrate that insertions of retrotransposons might be a potential outcome of CRISPR/Cas9 genome editing and provide further evidence on the safety of different CRISPR-based editing tools.

The accretion of oceanic plateaus has played a significant role in continental growth during Earth's history, which is evidenced by the presence of oceanic island basalts (OIB) and plume-type ophiolites in many modern orogens. However, oceanic plateaus can also be subducted into the deeper mantle, as revealed by seismic tomography. The controlling factors of accretion versus subduction of oceanic plateaus remain unclear. Here, we investigate the dynamics of oceanic plateau accretion at active continental margins using a thermo-mechanical numerical model. Three major factors for the accretion of oceanic plateaus are studied: (1) a thinned continental margin of the overriding plate, (2) “weak” layers in the oceanic lithosphere, and (3) a young oceanic plateau. For a large oceanic plateau, the modes of oceanic plateau accretion can be classified into one-sided and two-sided subduction–collisional regimes, which mainly depend on the geometry of the continental margin (normal or thinned). For smaller-sized seamounts, accretion occurs only if all three factors are satisfied, of which a thinned continental margin is the most critical. Possible geological analogues for the two-sided subduction–collisional mode include the Taiwan orogenic belt and subduction of the Ontong Java Plateau. The accretion model for small oceanic plateaus applies to the Nadanhada Terrane in Northeast China.

A facile liquid phase reduction method for the preparation of ternary PdNiP-reduced graphene oxide (PdNiP/RGO) nanocomposites is reported. The PdNiP nanoalloys are well dispersed on RGO without obvious aggregation. Relying on the synergistic electronic effect between Pd, Ni, P and RGO, the PdNiP/RGO nanocomposites exhibit superior catalytic activity toward reduction of 4-nitrophenol (4-NP). The 4-NP can be totally reduced to 4-aminophenol (4-AP) by NaBH4 over PdNiP/RGO catalyst at room temperature very quickly. The maximum reaction rate constant k obtained with PdNiP loading of 20 wt% (20%PdNiP/RGO) was calculated to be 1.41 min−1, which is 7.8 times higher than the value of unsupported PdNiP.

3'3'-cyclic GMP-AMP (3'3'-cGAMP) belongs to a family of the bacterial secondary messenger cyclic dinucleotides. It was first discovered in the Vibrio cholerae seventh pandemic strains and is involved in efficient intestinal colonization and chemotaxis regulation. Phosphodiesterases (PDEs) that degrade 3'3'-cGAMP play important regulatory roles in the relevant signaling pathways, and a previous study has identified three PDEs in V. cholerae, namely, V-cGAP1, V-cGAP2, and V-cGAP3, functioning in 3'3'-cGAMP degradation. We report the crystal structure, biochemical, and structural analyses of V-cGAP3, providing a foundation for understanding the mechanism of 3'3'-cGAMP degradation and regulation in general. Our crystal and molecular dynamic (MD)-simulated structures revealed that V-cGAP3 contains tandem HD-GYP domains within its N- and C-terminal domains, with similar three-dimensional topologies despite their low-sequence identity. Biochemical and structural analyses showed that the N-terminal domain plays a mechanism of positive regulation for the catalytic C-terminal domain. We also demonstrated that the other homologous Vibrio PDEs, V-cGAP1/2, likely function via a similar mechanism.

A Ni-based cage-like C–SiO2–Al2O3 (Ni/CL-CSA) catalyst was synthesized successfully via a facile dual-templating method and used for the hydrotreatment of phenol. The catalyst was characterized by SEM, TEM, XRD, TG and N2 adsorption techniques. Results show that Ni/CL-CSA has three-dimensional connected macroporous structure with pore size of about 100 nm and ordered mesoporous windows with average pore size of approximately 3.8 nm. Size of nickel particle is 6.1 nm. BET surface area of the catalyst is 212 m2/g and pore volume is 0.24 cm3/g. Hydrogenation and the stability performance of the catalyst was studied for bio-oil model compound phenol. Results reveal that adding macropores into Ni-based mesoporous C–SiO2–Al2O3 (Ni/MP-CSA) can improve the mass transfer rate and reduce the particles growth, thus improve the catalytic activities in the hydrotreatment of phenol, reducing catalyst sintering at high temperature and improving the stability of the catalyst.

The Qinling-Dabie-Sulu Orogen was formed by the collision of the North and South China blocks during the Indosinian Period. The intracontinental deformation was subsequently developed during the Late Triassic to Early Jurassic in the northeastern, eastern, and southeastern parts of eastern North China Block with different structural patterns. In this paper, we present structural analysis of the Indosinian deformation in the western Shandong and southern Liaoning provinces and synthesized the previous studies of the Triassic-Early Jurassic deformation in different areas of the eastern North China Block, from the northeastern, central to southeastern parts. Integrating the previous studies of petrology, geochronology, and geophysics, we suggested that (1) a series of top-to-the-northwest thrust-nappes were formed in the Sulu Orogen, and the southeastward antithetic faults developed in the South China Block. In the eastern North China Block, the Indosinian intracontinental deformation is intensely developed near the orogenic belt as thrust-nappes and away from the belt developed open folds. (2) The present-day structural lines in the northeastern, central, and southeastern parts of eastern North China Block show the S-N-, E-W-, and NE-trending lines, respectively. It could be the structural response to the dynamics of an orocline or indentation induced by Triassic collision of the North and South China blocks; (3) the eastern margin of the North China Block subducted southeastward beneath the South China Block along the Wulian-Qingdao-Yantai Fault during the Indosinian Period.

The cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS) mediates innate immune responses against invading pathogens, or against self-dsDNA, which causes autoimmune disorders. Upon nonspecific binding of cytosolic B–form DNA, cGAS synthesizes the second messenger 2′3′-cGAMP and triggers STING-dependent signaling to produce type I IFNs. The cGAS comprises less-conserved N-terminal residues and highly conserved nucleotidyltransferase/Mab21 domains. The function and structure of the well-conserved domains have been extensively studied, whereas the physiological function of the N-terminal domain of cGAS is largely uncharacterized. In this study we used a single-molecule technique combined with traditional biochemical and cellular assays to demonstrate that binding of nonspecific dsDNA by the N-terminal domain of cGAS promotes its activation. We have observed that the N terminus of human cGAS (hcGAS-N160) undergoes secondary structural change upon dsDNA binding in solution. Furthermore, we showed that the hcGAS-N160 helps full length hcGAS to expand the binding range on λDNA and facilitates its binding efficiency to dsDNA compared with hcGAS without the 160 N-terminal residues (hcGAS-d160). More importantly, hcGAS-N160 endows full length hcGAS relatively higher enzyme activity and stronger activation of STING/IRF3-mediated cytosolic DNA signaling. These findings strongly indicate that the N-terminal domain of cGAS plays an important role in enhancing its function.

Innate immunity is the first line of host defense against invading pathogens. The detection of aberrant nucleic acids which represent some conserved PAMPs triggers robust type I IFN-mediated innate immune responses. Host- or pathogen-derived cytosolic DNA binds and activates the DNA sensor cGAS, which synthesizes the second messenger 2'3'-cGAMP and triggers STING-dependent downstream signaling. Here, we highlight recent progress in cGAS-cGAMP-STING, the Three Musketeers of cytosolic DNA sensing and signaling, and their essential roles in infection, autoimmune diseases, and cancer. We also focus on the regulation of these critical signal components by variant host/pathogen proteins and update our understanding of this indispensable pathway to provide new insights for drug discovery. © 2016 IUBMB Life, 68(11):858-870, 2016.

Fluency in a common language allows individuals to convey information and carry out complex activities that otherwise would be difficult or even impossible without the benefit of shared communication. Cyclic (di)nucleotides have recently been recognized as such an accessible language understood by both microbe and the host, ever since remarkable progresses have revealed the molecular details of these nucleotide second messengers used in cellular communication systems. Though undergoing separate evolutionary pathways in prokaryotes and eukaryotes, cyclic (di)nucleotides enable microbes to influence host cells immediately and fiercely by modulating a variety of cellular activities. Here we highlight recent insights in cyclic (di)nucleotides and focus on the balancing of these indispensable signaling molecules by synthases and phosphodiesterases.

Co3O4/red phosphorus (Co3O4/RP) photocatalysts were synthesized via facile hydrothermal and mechanically grinding approach. The catalysts were characterized via XRD, TEM, XPS, N2 sorption, photoelectro chemical measurements and UV–vis DRS. The results showed that the Co3O4 nanocrystals were assembled on the surface of the RP. The loading of Co3O4 on RP was beneficial to enhance the light absorption compared with pure RP. Under visible light, 94.5% of malachite green (MG) can be photodegraded within 20 min over 10% Co3O4/RP composite, while only 17.3% and 59.9% of MG can be photodegraded over pure Co3O4 and RP. The reaction rate constant k obtained over 10% Co3O4/RP heterojunction (0.1464 min−1) is approximately 3.2 times that of pure RP (0.0457 min−1), and 15.3 times that of bare Co3O4 (0.0096 min−1). The cycle experiments showed that the catalyst had high photocatalytic stability. Co3O4 nanocrystals inhibit the photoelectron-hole pair recombination of red phosphorus semiconductor, and exhibit improved visible light absorption. Consequently, the catalytic performance of Co3O4/RP has been enhanced under visible light.

Cyclic dinucleotides act as intracellular second messengers, modulating a variety of cellular activities including innate immune activation. Although phosphodiesterases (PDEs) hydrolyzing c-di-GMP and c-di-AMP have been identified, no PDEs for cGAMPs have been reported. Here we identified the first three cGAMP-specific PDEs in V. cholerae (herein designated as V-cGAP1/2/3). V-cGAPs are HD-GYP domain-containing proteins and specifically break 3′3′-cGAMP, but not other forms of cGAMP. 3′3′-cGAMP is first linearized by all three V-cGAPs to produce 5′-pApG, which is further hydrolyzed into 5′-ApG by V-cGAP1. In this two-step reaction, V-cGAP1 functions as both a PDE and a 5′-nucleotidase. In vivo experiments demonstrated that V-cGAPs play non-redundant roles in cGAMP degradation. The high specificity of V-cGAPs on 3′3′-cGAMP suggests the existence of specific PDEs for other cGAMPs, including 2′3′-cGAMP in mammalian cells. The absolute requirement of the GYP motif for 3′3′-cGAMP degradation suggests that HD domain-containing PDEs in eukaryotes are probably unable to hydrolyze cGAMPs. The fact that all V-cGAPs attack 3′3′-cGAMP on one specific phosphodiester bond suggests that PDEs for other cGAMPs would utilize a similar strategy. These results will provide valuable information for identification and characterization of mammalian 2′3′-cGAMP-specific PDEs in future studies.

Mitochondrial antiviral-signaling protein (MAVS) transmits signals from RIG-I-like receptors after RNA virus infections. However, the mechanism by which MAVS activates downstream components, such as TBK1 and IKKα/β, is unclear, although previous work suggests the involvement of NEMO or TBK1-binding proteins TANK, NAP1, and SINTBAD. Here, we report that MAVS-mediated innate immune activation is dependent on TRAFs, partially on NEMO, but not on TBK1-binding proteins. MAVS recruited TBK1/IKKε by TRAFs that were pre-associated with TBK1/IKKε via direct interaction between the coiled-coil domain of TRAFs and the SDD domain of TBK1/IKKε. TRAF2−/−3−/−5−/−6−/− cells completely lost RNA virus responses. TRAFs’ E3 ligase activity was required for NEMO activation by synthesizing ubiquitin chains that bound to NEMO for NF-κB and TBK1/IKKε activation. NEMO-activated IKKα/β were important for TBK1/IKKε activation through IKKα/β-mediated TBK1/IKKε phosphorylation. Moreover, individual TRAFs differently mediated TBK1/IKKε activation and thus fine-tuned antiviral immunity under physiological conditions., Author summary Innate immunity is the first line of defense against virus infection. RIG-I-like receptors (RLRs) recognize various viral RNA from RNA viruses and initiate host antiviral responses to produce type I interferons (IFNs) and other cytokines. RLRs sense distinct types of viruses by sharing a common adaptor protein called mitochondrial antiviral-signaling protein (MAVS). Although it has been well studied how RLRs recruit and activate MAVS upon virus infection, it remains to be elucidated how MAVS activates its downstream components, including kinases TBK1/IKKε and the IKK complex. Here, by using TANK−/−NAP1−/−SINTBAD−/−, TRAF2−/−3−/−5−/−6−/− and TRAF2−/−3−/−5−/−6−/−NEMO−/− 293T cells combined with reconstitution experiments, we discovered that MAVS recruited TBK1/IKKε via TRAFs through pre-associated TRAFs-TBK1/IKKε complex. TBK1/IKKε activation required both TRAFs-mediated TBK1 autophosphorylation and TRAFs-NEMO-IKKβ-mediated TBK1 phosphorylation. We demonstrated that TRAFs’ E3 ligase activity was solely required for NEMO and IKKα/β activation. IKKα/β were crucial for both TBK1 and NF-κB activation. Our results thus demonstrated that MAVS activates TBK1/IKKε through TRAFs in both NEMO-dependent and independent manner. Importantly, a minimal amount of IFNs was produced independent of NF-κB activation during virus infection and that individual TRAFs differently mediated TBK1/IKKε activation, thus fine-tuned antiviral immunity under physiological conditions.

Innate immunity is the first line of host defense against invading pathogens. The detection of aberrant nucleic acids which represent some conserved PAMPs triggers robust type I IFN-mediated innate immune responses. Host- or pathogen-derived cytosolic DNA binds and activates the DNA sensor cGAS, which synthesizes the second messenger 2'3'-cGAMP and triggers STING-dependent downstream signaling. Here, we highlight recent progress in cGAS-cGAMP-STING, the Three Musketeers of cytosolic DNA sensing and signaling, and their essential roles in infection, autoimmune diseases, and cancer. We also focus on the regulation of these critical signal components by variant host/pathogen proteins and update our understanding of this indispensable pathway to provide new insights for drug discovery. © 2016 IUBMB Life, 68(11):858-870, 2016.

Cyclic dinucleotides (CDNs) and antitumor/antiviral agents (DMXAA and CMA) trigger STING-dependent innate immunity activation. Accumulative evidences have showed that DMXAA and CMA selectively activate mouse, but not human STING signaling. The mechanism underlying this species selectivity remains poorly understood. In this report, we have shown that human and rat STINGs display more similar signaling profiles toward DMXAA and CMA than that of human and mouse STINGs, suggesting that rat is more suitable for preclinical testing of STING-targeted drugs. We have also determined the crystal structures of both apo rat STING and its complex with cyclic GMP-AMP with 2′5′ and 3′5′ phosphodiester linkage (2′3′-cGAMP), a human endogenous CDN. Structure-guided biochemical analysis also revealed the functional importance of the connecting loop (A140-N152) between membrane and cytosolic domains in STING activation. Taken together, these findings reveal that rat STING is more closely related to human STING in terms of substrate preference, serving as a foundation for the development of STING-targeted drugs.