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Alzheimer’s disease (AD) is a neurodegenerative disease with increasing prevalence worldwide, while there are no effective drugs at present. Curcumin, a natural polyphenolic substance isolated from turmeric, is a promising natural compound to combat AD, but its pharmacology remains to be fully understood for its poor in vivo bioavalibility. Inspired by the recently reported associations between gut microbiota and AD development, the present study investigated the interactions of curcumin with gut microbiota of APP/PS1 double transgenic mice from two directions: (i) curcumin influences gut microbiota, and (ii) gut microbiota biotransform curcumin. It was found that curcumin administration tended to improve the spatial learning and memory abilities and reduce the amyloid plaque burden in the hippocampus of APP/PS1 mice. On the one hand, curcumin administration altered significantly the relative abundances of bacterial taxa such as Bacteroidaceae, Prevotellaceae, Lactobacillaceae, and Rikenellaceae at family level, and Prevotella, Bacteroides, and Parabacteroides at genus level, several of which have been reported to be key bacterial species associated with AD development. On the other hand, a total of 8 metabolites of curcumin biotransformed by gut microbiota of AD mice through reduction, demethoxylation, demethylation and hydroxylation were identified by HPLC-Q-TOF/MS, and many of these metabolites have been reported to exhibit neuroprotective ability. The findings provided useful clues to understand the pharmacology of curcumin and microbiome-targeting therapies for AD.

Over the past decades, molecular knots and links have captivated the chemical community due to their promising mimicry properties in molecular machines and biomolecules and are being realized with increasing frequency with small molecules. Herein, we describe how to utilize stacking interactions and hydrogen-bonding patterns to form trefoil knots, figure-eight knots and [2]catenanes. A transformation can occur between the unique trefoil knot and its isomeric boat-shaped tetranuclear macrocycle by the complementary concentration effect. Remarkably, the realization and authentication of the molecular figure-eight knot with four crossings fills the blank about 4 1 knot in knot tables. The [2]catenane topology is obtained because the selective naphthalenediimide (NDI)-based ligand, which can engender favorable aromatic donor-acceptor π interactions due to its planar, electron-deficient aromatic surface. The stacking interactions and hydrogen-bond interactions play important roles in these self-assembly processes. The advantages provide an avenue for the generation of structurally and topologically complex supramolecular architectures. Molecular knots and links continue to fascinate synthetic chemists. Here, the authors use stacking and hydrogen-bonding interactions between a set of similar building blocks to construct several complex molecular topologies, including a figure-eight knot and a trefoil knot.

Membrane proteins can be stabilized in a native-like setting using lipid-bilayer-based nanodiscs encircled by a membrane scaffold protein. Covalently circularized nanodiscs now offer enhanced stability and control over nanodisc diameter size, improving the quality of structural data. We engineered covalently circularized nanodiscs (cNDs) which, compared with standard nanodiscs, exhibit enhanced stability, defined diameter sizes and tunable shapes. Reconstitution into cNDs enhanced the quality of nuclear magnetic resonance spectra for both VDAC-1, a β-barrel membrane protein, and the G-protein-coupled receptor NTR1, an α-helical membrane protein. In addition, we used cNDs to visualize how simple, nonenveloped viruses translocate their genomes across membranes to initiate infection.

The Toll/interleukin-1 receptor (TIR) domain is a key component of immune receptors that identify pathogen invasion in bacteria, plants and animals 1 – 3 . In the bacterial antiphage system Thoeris, as well as in plants, recognition of infection stimulates TIR domains to produce an immune signalling molecule whose molecular structure remains elusive. This molecule binds and activates the Thoeris immune effector, which then executes the immune function 1 . We identified a large family of phage-encoded proteins, denoted here as Thoeris anti-defence 1 (Tad1), that inhibit Thoeris immunity. We found that Tad1 proteins are ‘sponges’ that bind and sequester the immune signalling molecule produced by TIR-domain proteins, thus decoupling phage sensing from immune effector activation and rendering Thoeris inactive. Tad1 can also efficiently sequester molecules derived from a plant TIR-domain protein, and a high-resolution crystal structure of Tad1 bound to a plant-derived molecule showed a unique chemical structure of 1 ′′–2′ glycocyclic ADPR (gcADPR). Our data furthermore suggest that Thoeris TIR proteins produce a closely related molecule, 1′′–3′ gcADPR, which activates ThsA an order of magnitude more efficiently than the plant-derived 1′′–2′ gcADPR. Our results define the chemical structure of a central immune signalling molecule and show a new mode of action by which pathogens can suppress host immunity. We identified Tad1, a large family of phage-encoded proteins that inhibit Thoeris immunity, and define the chemical structure of a central immune signalling molecule, showing a new mode of action by which pathogens can suppress host immunity.

G-protein-coupled receptors (GPCRs) are the largest superfamily of transmembrane proteins and the targets of over 30% of currently marketed pharmaceuticals. Although several structures have been solved for GPCR–G protein complexes, few are in a lipid membrane environment. Here, we report cryo-EM structures of complexes of neurotensin, neurotensin receptor 1 and Gα i1 β 1 γ 1 in two conformational states, resolved to resolutions of 4.1 and 4.2 Å. The structures, determined in a lipid bilayer without any stabilizing antibodies or nanobodies, reveal an extended network of protein–protein interactions at the GPCR–G protein interface as compared to structures obtained in detergent micelles. The findings show that the lipid membrane modulates the structure and dynamics of complex formation and provide a molecular explanation for the stronger interaction between GPCRs and G proteins in lipid bilayers. We propose an allosteric mechanism for GDP release, providing new insights into the activation of G proteins for downstream signaling. Structures of GPCR neurotensin receptor 1 (NTSR1) in complex with neurotensin and Gα i1 β 1 γ 1 in a lipid bilayer environment and without stabilizing antibodies reveal extensive interactions at the GPCR–G protein interface.

Aseptic loosening caused by wear particles is a common complication after total hip arthroplasty. We investigated the effect of the quercetin on wear particle‐mediated macrophage polarization, inflammatory response and osteolysis. In vitro, we verified that Ti particles promoted the differentiation of RAW264.7 cells into M1 macrophages through p‐38α/β signalling pathway by using flow cytometry, immunofluorescence assay and small interfering p‐38α/β RNA. We used enzyme‐linked immunosorbent assays to confirm that the protein expression of M1 macrophages increased in the presence of Ti particles and that these pro‐inflammatory factors further regulated the imbalance of OPG/RANKL and promoted the differentiation of osteoclasts. However, this could be suppressed, and the protein expression of M2 macrophages was increased by the presence of the quercetin. In vivo, we revealed similar results in the mouse skull by μ‐CT, H&E staining, immunohistochemistry and immunofluorescence assay. We obtained samples from patients with osteolytic tissue. Immunofluorescence analysis indicated that most of the macrophages surrounding the wear particles were M1 macrophages and that pro‐inflammatory factors were released. Titanium particle‐mediated M1 macrophage polarization, which caused the release of pro‐inflammatory factors through the p‐38α/β signalling pathway, regulated OPG/RANKL balance. Macrophage polarization is expected to become a new clinical drug therapeutic target.

Background Salinity is a major abiotic stress seriously hindering crop yield. Development and utilization of tolerant varieties is the most economical way to address soil salinity. Upland cotton is a major fiber crop and pioneer plant on saline soil and thus its genetic architecture underlying salt tolerance should be extensively explored. Results In this study, genome-wide association analysis and RNA sequencing were employed to detect salt-tolerant qualitative-trait loci (QTLs) and candidate genes in 196 upland cotton genotypes at the germination stage. Using comprehensive evaluation values of salt tolerance in four environments, we identified 33 significant single-nucleotide polymorphisms (SNPs), including 17 and 7 SNPs under at least two and four environments, respectively. The 17 stable SNPs were located within or near 98 candidate genes in 13 QTLs, including 35 genes that were functionally annotated to be involved in salt stress responses. RNA-seq analysis indicated that among the 98 candidate genes, 13 were stably differentially expressed. Furthermore, 12 of the 13 candidate genes were verified by qRT-PCR. RNA-seq analysis detected 6640, 3878, and 6462 differentially expressed genes at three sampling time points, of which 869 were shared. Conclusions These results, including the elite cotton accessions with accurate salt tolerance evaluation, the significant SNP markers, the candidate genes, and the salt-tolerant pathways, could improve our understanding of the molecular regulatory mechanisms under salt stress tolerance and genetic manipulation for cotton improvement.

Lung cancer has the highest mortality rate among human cancers, and the majority of deaths can be attributed to metastatic spread. Lung cancer stem cells (CSCs) are a component of the tumour microenvironment that contributes to this process. Exosomes are small membrane vesicles secreted by all types of cells that mediate cell interactions, including cancer metastasis. Here, we show that lung CSC‐derived exosomes promote the migration and invasion of lung cancer cells, up‐regulate expression levels of N‐cadherin, vimentin, MMP‐9 and MMP‐1, and down‐regulate E‐cadherin expression. Moreover, we verified that these exosomes contribute to a pro‐metastatic phenotype in lung cancer cells via miR‐210‐3p transfer. The results of bioinformatics analysis and dual‐luciferase reporter assays further indicated that miR‐210‐3p may bind to fibroblast growth factor receptor‐like 1 (FGFRL1); silencing FGFRL1 enhanced the metastatic ability of lung cancer cells, whereas overexpressing FGFRL1 suppressed metastasis. Taken together, our results provide new insights into a potential molecular mechanism whereby lung CSC‐derived exosomal miR‐210‐3p targets FGFRL1 to promote lung cancer metastasis. FGFRL1 may be a promising therapeutic target in lung cancer.

The affine scale-invariant feature transform (ASIFT) algorithm is a feature extraction algorithm with affinity and scale invariance, which is suitable for image feature matching using unmanned aerial vehicles (UAVs). However, there are many problems in the matching process, such as the low efficiency and mismatching. In order to improve the matching efficiency, this algorithm firstly simulates image distortion based on the position and orientation system (POS) information from real-time UAV measurements to reduce the number of simulated images. Then, the scale-invariant feature transform (SIFT) algorithm is used for feature point detection, and the extracted feature points are combined with the binary robust invariant scalable keypoints (BRISK) descriptor to generate the binary feature descriptor, which is matched using the Hamming distance. Finally, in order to improve the matching accuracy of the UAV images, based on the random sample consensus (RANSAC) a false matching eliminated algorithm is proposed. Through four groups of experiments, the proposed algorithm is compared with the SIFT and ASIFT. The results show that the algorithm can optimize the matching effect and improve the matching speed.

Hirshleifer’s difference-form contest technology is a useful tool in the study of a class of conflict, especially military combats. We aim to highlight an important feature that the Hirshleifer contest model distinctively has, namely passivity (bidding zero effort) may stand as an effective choice in conflict even when the contest is highly deterministic (i.e., with small noise). For that purpose, we establish two propositions on the contest with n≥2 risk-neutral contestants under small noise. The first proposition states that every contestant bids arbitrarily close to zero (if not bidding zero with positive probability at all) under sufficiently small noise. The second proposition, more strikingly, states that every contestant either bids arbitrarily close to the second-highest valuation (among all the contestants’ valuations), or simply remains passive with certainty under any sufficiently small noise. We further show that the first proposition holds for the contest between risk-averse individuals endowed with constant absolute risk aversion as well, and illustrate by an example how quickly polarization in bidding among contestants, as is predicted by the propositions, may emerge as the noise of the contest abates. These results help pave the way toward a complete characterization of the difference-form contest.