The NLRP3 inflammasome is a well-studied target for the treatment of multiple inflammatory diseases, but how to promote the current therapeutics remains a large challenge. CRISPR/Cas9, as a gene editing tool, allows for direct ablation of NLRP3 at the genomic level. In this study, we screen an optimized cationic lipid-assisted nanoparticle (CLAN) to deliver Cas9 mRNA (mCas9) and guide RNA (gRNA) into macrophages. By using CLAN encapsulating mCas9 and gRNA-targeting NLRP3 (gNLRP3) (CLANmCas9/gNLRP3), we disrupt NLRP3 of macrophages, inhibiting the activation of the NLRP3 inflammasome in response to diverse stimuli. After intravenous injection, CLANmCas9/gNLRP3 mitigates acute inflammation of LPS-induced septic shock and monosodium urate crystal (MSU)-induced peritonitis. In addition, CLANmCas9/gNLRP3 treatment improves insulin sensitivity and reduces adipose inflammation of high-fat-diet (HFD)-induced type 2 diabetes (T2D). Thus, our study provides a promising strategy for treating NLRP3-dependent inflammatory diseases and provides a carrier for delivering CRISPR/Cas9 into macrophages.

Summary Pharmaceutical inhibitors of aminoacyl-tRNA synthetases demand high species and family specificity. The antimalarial ATP-mimetic cladosporin selectively inhibits P. falciparum LysRS (PfLysRS). How the binding to a universal ATP site achieves the specificity is unknown. Here we report 3 crystal structures of cladosporin with human LysRS, PfLysRS, and a Pf-like human LysRS mutant. In all 3 structures, cladosporin occupies the class defining ATP-binding pocket, replacing the adenosine portion of ATP. Three residues holding the methyltetrahydro-pyran moiety of cladosporin are critical for cladosporin's specificity against LysRS over other class II tRNA synthetase families. The species-exclusive inhibition of PfLysRS is linked to a structural divergence beyond the active site that mounts a lysine-specific stabilizing response to binding cladosporin. These analyses reveal that inherent divergence of tRNA synthetase structural assembly may allow for highly specific inhibition even through the otherwise universal substrate binding pocket and highlight the potential for structure driven drug development.

The polyketide natural product borrelidin displays antibacterial, antifungal, antimalarial, anticancer, insecticidal and herbicidal activities through the selective inhibition of threonyl-tRNA synthetase (ThrRS). How borrelidin simultaneously attenuates bacterial growth and suppresses a variety of infections in plants and animals is not known. Here we show, using X-ray crystal structures and functional analyses, that a single molecule of borrelidin simultaneously occupies four distinct subsites within the catalytic domain of bacterial and human ThrRSs. These include the three substrate-binding sites for amino acid, ATP and tRNA associated with aminoacylation, and a fourth ‘orthogonal’ subsite created as a consequence of binding. Thus, borrelidin competes with all three aminoacylation substrates, providing a potent and redundant mechanism to inhibit ThrRS during protein synthesis. These results highlight a surprising natural design to achieve the quadrivalent inhibition of translation through a highly conserved family of enzymes.

using artificial synapses is an essential step to accomplish the neuromorphic computing system. [9,10] Formerly, artificial synapses were realized by complementary metal-oxide-semiconductor (CMOS) circuitry containing dozens of electronic components. [11] However, many electronic components result in complicated architecture and high energy consumption. As comparison, two-terminal memristors, especially resistive random access memory and phase change random access memory, that recently entered our field of vision have been widely discussed as artificial synapses owing to their structures which is similar to that of synapses and the reproducible tuning of resistance. [12][13][14][15][16] Also, for an ideal synapse device it is better to meet these requirements, such as symmetric potentiation-depression characteristics, 5-bit/cell analog levels, and high non-volatility with ≈100 conductance ON/OFF ratio. They are the key points we need to take into account. [17,18] In particular, HfO 2 -based memristors have been demonstrated as a leading alternative as synapse in virtue of its distinctive superiority, such as simple structure, <10 ns switching speed, <10 pJ power consumption, multilevel ability, and compatibility with CMOS fabrication process. [19][20][21] However, the resistance contrast (ON/OFF ratio) of HfO 2 -based memristors ranges from ≈40 to ≈150. [22] Considering the resistance fluctuation of these memristors across a silicon wafer, larger ON/OFF ratio is needed to guarantee high recognition accuracy (>97%). [23] Recently, several works were reported on improvement of the memristors' performance with thin interfacial layer. [24][25][26] As one of the most important multiferroic materials, bismuth iron oxide with perovskite structure has come into notice for its potential in multifunctional device applications. [27] Moreover, BiFeO 3 (BFO) has attracted much attention because it possesses superior characteristics of resistance switching (RS) such as large ON/OFF ratio in some researches. [28] It is also confirmed that BFO can be applied in bi-layer design memristor to significantly improve RS characteristics, [29] which gives inspiration to insert BFO thin film as the goal of high device performances.In this work, ultrathin BFO film was inserted to fabricate Pt/BFO/HfO 2 /TiN memristor to improve the RS characteristic of HfO 2 -based memristor. The material characterization and RS behavior were systemically analyzed. The role of the inserting BFO layer on the RS behavior was evaluated and the RS mechanism triggered by inserting BFO film was explored.HfO 2 -based memristors that remembers the history of the current that has passed through them have attracted great interest for use as artificial synapses in neuromorphic systems. However, the low resistance contrast exhibited by HfO 2 -based memristors seriously decreases their recognition accuracy. By inserting a 2 nm BiFeO 3 layer a large memory window of 10 4 and remarkable pulse endurance of 10 8 cycles are achieved. Multilevel storage capability is also d...

The synthesis of chromeno[2,3-b]indole from simple starting materials remains a demanding process. Herein, 2-bromoindole undergoes nucleophilic attack from salicylaldehyde, followed by intramolecular insertion of an aldehyde group and aromatization to generate the desired chromeno[2,3-b]indoles. Moreover, various functional groups were tolerated and a gram-scale synthesis of the product could be achieved under the optimized condition.

Tumor metastasis remains the primary cause of treatment failure in cancer patients, and the high-sensitivity preoperative and intraoperative detection of occult micrometastases continues to pose a notorious challenge. Therefore, we have designed an in situ albumin-hitchhiking near-infrared window II (NIR-II) fluorescence probe, IR1080, for the precise detection of micrometastases and subsequent fluorescence image-guided surgery. IR1080 rapidly covalently conjugates with albumin in plasma, resulting in a stronger fluorescence brightness upon binding. Moreover, the albumin-hitchhiked IR1080 has a high affinity for secreted protein acidic and rich in cysteine (SPARC), an albumin-binding protein that is overexpressed in micrometastases. The interaction between SPARC and IR1080-hitchhiked albumin enhances IR1080's capacity to track and anchor micrometastases, leading to a high detection rate and margin delineation ability, as well as a high tumor-to-normal tissue ratio. Therefore, IR1080 represents a highly efficient strategy for the diagnosis and image-guided resection surgery of micrometastases.

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