Inflammatory caspases cleave the gasdermin D (GSDMD) protein to trigger pyroptosis, a lytic form of cell death that is crucial for immune defences and diseases. GSDMD contains a functionally ...important gasdermin-N domain that is shared in the gasdermin family. The functional mechanism of action of gasdermin proteins is unknown. Here we show that the gasdermin-N domains of the gasdermin proteins GSDMD, GSDMA3 and GSDMA can bind membrane lipids, phosphoinositides and cardiolipin, and exhibit membrane-disrupting cytotoxicity in mammalian cells and artificially transformed bacteria. Gasdermin-N moved to the plasma membrane during pyroptosis. Purified gasdermin-N efficiently lysed phosphoinositide/cardiolipin-containing liposomes and formed pores on membranes made of artificial or natural phospholipid mixtures. Most gasdermin pores had an inner diameter of 10–14 nm and contained 16 symmetric protomers. The crystal structure of GSDMA3 showed an autoinhibited two-domain architecture that is conserved in the gasdermin family. Structure-guided mutagenesis demonstrated that the liposome-leakage and pore-forming activities of the gasdermin-N domain are required for pyroptosis. These findings reveal the mechanism for pyroptosis and provide insights into the roles of the gasdermin family in necrosis, immunity and diseases.
New Delhi metallo-β-lactamases (NDMs), the recent additions to metallo-β-lactamases (MBLs), pose a serious public health threat due to its highly efficient hydrolysis of β-lactam antibiotics and ...rapid worldwide dissemination. The MBL-hydrolyzing mechanism for carbapenems is less studied than that of penicillins and cephalosporins. Here, we report crystal structures of NDM-1 in complex with hydrolyzed imipenem and meropenem, at resolutions of 1.80-2.32 Å, together with NMR spectra monitoring meropenem hydrolysis. Three enzyme-intermediate/product derivatives, EI
, EI
, and EP, are trapped in these crystals. Our structural data reveal double-bond tautomerization from Δ
to Δ
, absence of a bridging water molecule and an exclusive β-diastereomeric product, all suggesting that the hydrolytic intermediates are protonated by a bulky water molecule incoming from the β-face. These results strongly suggest a distinct mechanism of NDM-1-catalyzed carbapenem hydrolysis from that of penicillin or cephalosporin hydrolysis, which may provide a novel rationale for design of mechanism-based inhibitors.
To conquer the bottleneck of sluggish kinetics in cathodic oxygen reduction reaction (ORR) of metal‐air batteries, catalysts with dual‐active centers have stood out. Here, a “pre‐division metal ...clusters” strategy is firstly conceived to fabricate a N,S‐dual doped honeycomb‐like carbon matrix inlaid with CoN4 sites and wrapped Co2P nanoclusters as dual‐active centers (Co2P/CoN4@NSC‐500). A crystalline {CoII2} coordination cluster divided by periphery second organic layers is well‐designed to realize delocalized dispersion before calcination. The optimal Co2P/CoN4@NSC‐500 executes excellent 4e− ORR activity surpassing the benchmark Pt/C. Theoretical calculation results reveal that the CoN4 sites and Co2P nanoclusters can synergistically quicken the formation of *OOH on Co sites. The rechargeable Zn‐air battery (ZAB) assembled by Co2P/CoN4@NSC‐500 delivers ultralong cycling stability over 1742 hours (3484 cycles) under 5 mA cm−2 and can light up a 2.4 V LED bulb for ≈264 hours, evidencing the promising practical application potentials in portable devices.
A “pre‐division metal clusters” strategy is first conceived to fabricate dual‐active center catalysts (Co2P/CoN4@NSC‐500) with dispersed CoN4 and Co2P sites. The optimal catalyst executes superior ORR activity and was applied in ultralong Zn‐air batteries surpassing the benchmark 20 % Pt/C. Theoretical calculations demonstrate that the dual‐active sites synergistically quicken the formation of the *OOH intermediate, greatly boosting the performance.
Immune recognition of pathogen-associated molecular patterns (PAMPs) by pattern recognition receptors often activates proinflammatory NF-κB signalling
. Recent studies indicate that the bacterial ...metabolite D-glycero-β-D-manno-heptose 1,7-bisphosphate (HBP) can activate NF-κB signalling in host cytosol
, but it is unclear whether HBP is a genuine PAMP and the cognate pattern recognition receptor has not been identified. Here we combined a transposon screen in Yersinia pseudotuberculosis with biochemical analyses and identified ADP-β-D-manno-heptose (ADP-Hep), which mediates type III secretion system-dependent NF-κB activation and cytokine expression. ADP-Hep, but not other heptose metabolites, could enter host cytosol to activate NF-κB. A CRISPR-Cas9 screen showed that activation of NF-κB by ADP-Hep involves an ALPK1 (alpha-kinase 1)-TIFA (TRAF-interacting protein with forkhead-associated domain) axis. ADP-Hep directly binds the N-terminal domain of ALPK1, stimulating its kinase domain to phosphorylate and activate TIFA. The crystal structure of the N-terminal domain of ALPK1 and ADP-Hep in complex revealed the atomic mechanism of this ligand-receptor recognition process. HBP was transformed by host adenylyltransferases into ADP-heptose 7-P, which could activate ALPK1 to a lesser extent than ADP-Hep. ADP-Hep (but not HBP) alone or during bacterial infection induced Alpk1-dependent inflammation in mice. Our findings identify ALPK1 and ADP-Hep as a pattern recognition receptor and an effective immunomodulator, respectively.
To investigate whether machine learning, which is widely used in disease prediction and diagnosis based on demographic data and serological markers, can predict herpes occurrence in patients with ...systemic lupus erythematosus (SLE).
A total of 286 SLE patients were included in this study, including 200 SLE patients without herpes and 86 SLE patients with herpes. SLE patients were randomly divided into a training group and a test group, and 18 demographic characteristics and serological indicators were compared between the two groups.
We selected basophil, monocyte, white blood cell, age, immunoglobulin E, SLE Disease Activity Index, complement 4, neutrophil, and immunoglobulin G as the basic features of modeling. A random forest model had the best performance, but logistic and decision tree analyses had better clinical decision-making benefits. Random forest had a good consistency between feature importance judgment and feature selection. The 10-fold cross-validation showed the optimization of five model parameters.
The random forest model may be an excellently performing model, which may help clinicians to identify SLE patients whose disease is complicated by herpes early.
Tetracyclines are commonly used antibiotics in the swine industry for disease treatment and growth promotion. Tetracycline resistance was determined in soils sampled from farmlands in the vicinity of ...nine swine farms located in three cities in China. Totally, 15 tetracycline resistance (tet) genes were commonly detected in soil samples, including seven efflux pump genes (tetA, tetC, tetE, tetG, tetK, tetL, tetA/P), seven ribosomal protection proteins (RPPs) genes (tetM, tetO, tetQ, tetS, tetT, tetW, tetB/P), and one enzymatic modification gene (tetX). The quantitative real-time PCR was further used to quantify five RPPs genes (tetM, tetO, tetQ, tetW, tetT) and 16S rRNA gene abundances. The concentrations of total tetracyclines (5 typical tetracyclines and 10 of their degradation products) in these soils were measured using liquid chromatography-electrospray tandem mass spectrometry (LC-MS/MS) and were found to range from 5.4 to 377.8 μg·kg−1 dry soil. Bivariate correlation analysis confirmed that absolute tet gene copies (sum of tetM, tetO, tetQ, tetW genes) were strongly correlated with the concentrations of tetracycline residues (r 2 = 0.45, P < 0.05), ambient bacterial 16S-rRNA gene copies in each soil sample (r 2 = 0.65, P < 0.01), and organic matter in soil (r 2 = 0.46, P < 0.05), respectively. Finally, the phylogenetic analysis on tetM combined with culture-independent molecular techniques revealed at least five genotypes of tetM in nine soil samples.
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•A neutral polysaccharide was isolated from Epimedium koreanum Nakai.•FPN-1 was a heteropolysaccharide containing over 60% of glucose.•The backbone of EFPN-1 was composed of 4- and 4, ...6-α-D-Glcp.•EFPN-1 was a branched polysaccharide with a degree of branching of 40.40%.•EFPN-1 possessed better antioxidant activity in vitro.
The structure and antioxidant activity of a neutral polysaccharide (named as EFPN-1) from Epimedium koreanum Nakai were studied. Based on the results from high performance gel permeation chromatography, methylation GC–MS and 1D/2D nuclear magnetic resonance spectroscopy, EFPN-1 was a branched polysaccharide with a molecular weight of 21.9 kD and containing over 60% of glucose. Its backbone was composed of (1 → 4)-β-d-Glcp and (1 → 3)-β-d-Galp, branched partially at O-6 of both residues, with a degree of branching of 40.4% and terminated mainly with Ara and Gal, as well as trace amount of Gal. Antioxidant tests showed that EFPN-1 exhibited a strong capacity on DPPH and hydroxyl radical scavenging, ferrous ion chelation and reducing antioxidant powder. EFPN-1 has potential to be developed as a natural antioxidant.
Spectral line shapes feature many essential resonant phenomena when diagnosing light–matter interactions. Particularly, tailoring spectral line shapes in photonics unveils a robust scheme to control ...electromagnetic waves and design functional optical devices. Here, the symmetry‐assisted manipulation of spectral line shapes in dielectric double‐Fano metasurfaces is theoretically proposed and experimentally demonstrated. Composed by a free‐standing silicon membrane with subwavelength aperture arrays, the metasurfaces simultaneously support two orthogonal localized modes (symmetric and antisymmetric) with high‐quality (high‐Q) factors and a propagating mode with a low‐Q factor. The symmetric and antisymmetric modes interfere with the propagating mode, resulting in the double‐Fano resonances with opposite signs of Fano parameters. The superposition of such double‐Fano resonances can produce multiple spectral line shapes, including double‐Fano resonances, a single Fano resonance, an electromagnetic‐induced‐transparency‐like (EIT‐like) window, and a complementary EIT‐like window, which have been analytically, numerically, and experimentally verified. Moreover, the EIT‐like window exhibits a steep dispersion, which is beneficial in slow light devices. Due to the anisotropy of the design, this EIT‐like window can transform into a complementary EIT‐like window when the incident polarization is rotated by 90°. Thus, such asymmetry‐assisted double‐Fano metasurfaces provide a new route to reveal photonic phenomena and construct multifunctional metadevices.
Symmetry‐assisted dielectric double‐Fano metasurfaces are theoretically proposed and experimentally validated for multiple spectral line‐shape manipulation. By controlling the interference and superposition of double‐Fano resonances with distinct symmetries, double‐Fano, single‐Fano, electromagnetic‐induced transparency (EIT)‐like, and complementary EIT‐like line shapes can be generated. Giant group delay and EIT‐like to complementary EIT‐like transformation are demonstrated in a single metasurface.
The construction of an efficient oxygen reduction reaction and oxygen evolution reaction (ORR/OER) bifunctional electrocatalyst is of great significance but still remains a giant challenge for ...high-performance metal–air batteries. In this study, uniform FeS/Fe3C nanoparticles embedded in a porous N,S-dual doped carbon honeycomb-like composite (abbr. FeS/Fe3C@NS-C-900) have been conveniently fabricated by pyrolysis of a single-crystal Fe-MOF, which has a low potential gap ΔE of ca. 0.72 V, a competitive power density of 90.9 mW/cm2, a specific capacity as high as 750 mAh/g Zn , and excellent cycling stabilities over 865 h (1730 cycles) at 2 mA/cm2 when applied as a cathode material for rechargeable zinc–air batteries. In addition, the two series-linked Zn–air batteries successfully powered a 2.4 V LED light as a real power source. The efficient ORR/OER bifunctional electrocatalytic activity and long-term durability of the obtained composite might be attributed to the characteristic honeycomb-like porous structure with sufficient accessible active sites, the synergistic effect of FeS and Fe3C, and the N,S codoped porous carbon, which provides a promising application potential for portable electronic Zn–air battery related devices.
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