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Necrotrophic fungi cause devastating diseases in both horticultural and agronomic crops, but our understanding of plant defense responses against these pathogens is still limited. In this study, we demonstrated that AtWRKY75 positively regulates the jasmonate (JA)-mediated plant defense against necrotrophic fungal pathogens Botrytis cinerea and Alternaria brassicicola and also affects plants’ sensitivity to JA-inhibited seed germination and root growth. Quantitative RT-PCR analysis indicated that the expression of several JA-associated genes, such as ORA59 and PDF1.2, was significantly reduced in wrky75 mutants and significantly enhanced in 35S:WRKY75 transgenic plants. Immunoprecipitation assays revealed that WRKY75 directly binds to ORA59 promoters and represses its transcription. In vivo and in vitro experiments suggested that WRKY75 interacts with several JASMONATE ZIM-domain proteins, which are repressors of the JA signaling pathway. We determined that JAZ8 represses the transcriptional function of WRKY75, thereby attenuating the expression of its regulon. Consistent with this finding, overexpression of JAZ8 repressed plant defense response to B. cinerea. Taken together, our study provides evidence that WRKY75 functions as a critical component of the JA-mediated signaling pathway to positively regulate Arabidopsis defense response to necrotrophic pathogens.

Quantifying the impact of climate change and human activities on grassland dynamics is an essential step for developing sustainable grassland ecosystem management strategies. However, the direction and magnitude of climate change and human activities in driving alpine grassland dynamic over the Tibetan Plateau remain under debates. Here, we systematically reviewed the relevant studies on the methods, main conclusions, and causes for the inconsistency in distinguishing the respective contribution of climatic and anthropogenic forces to alpine grassland dynamic. Both manipulative experiments and traditional statistical analysis show that climate warming increase biomass in alpine meadows and decrease in alpine steppes, while both alpine steppes and meadows benefit from an increase in precipitation or soil moisture. Overgrazing is a major factor for the degradation of alpine grassland in local areas with high level of human activity intensity. However, across the entire Tibetan Plateau and its subregions, four views characterize the remaining controversies: alpine grassland changes are primarily due to (1) climatic force, (2) nonclimatic force, (3) combination of anthropogenic and climatic force, or (4) alternation of anthropogenic and climatic force. Furthermore, these views also show spatial inconsistencies. Differences on the source and quality of remote sensing products, the structure and parameter of models, and overlooking the spatiotemporal heterogeneity of human activity intensity contribute to current disagreements. In this review, we highlight the necessity for taking the spatiotemporal heterogeneity of human activity intensity into account in the models of attribution assessment, and the importance for accurate validation of climatic and anthropogenic contribution to alpine grassland variation at multiple scales for future studies.

The acetylcholinesterase (AChE) inhibitors remain key therapeutic drugs for the treatment of Alzheimer's disease (AD). However, the low-safety window limits their maximum therapeutic benefits. Here, a novel kinetics-driven drug design strategy was employed to discover new-generation AChE inhibitors that possess a longer drug-target residence time and exhibit a larger safety window. After detailed investigations, compound 12 was identified as a highly potent, highly selective, orally bioavailable, and brain preferentially distributed AChE inhibitor. Moreover, it significantly ameliorated cognitive impairments in different mouse models with a lower effective dose than donepezil. The X-ray structure of the cocrystal complex provided a precise binding mode between 12 and AChE. Besides, the data from the phase I trials demonstrated that 12 had good safety, tolerance, and pharmacokinetic profiles at all preset doses in healthy volunteers, providing a solid basis for its further investigation in phase II trials for the treatment of AD.

Fluorescent imaging of β-amyloid (Aβ) is one of the most promising methods for Alzheimer's disease diagnosis. Several fluorescent probes have been reported to detect Aβ both in vitro and in vivo. However, highly sensitive and highly selective probes with low background signals are still greatly needed. Herein, we rationally designed and synthesized a PIET quenched near-infrared probe QAD-1 to detect Aβ. This probe contains BODIPY as fluorophore and tetrahydroquinoxaline as the quenching group. QAD-1 exhibited significant fluorescent switch-on after binding to soluble and insoluble Aβ species, and the probe had the benefit of low background signal to stain Aβ plaques without the need of wash-out procedures in vitro, which was specially found by the fluorescence off-on probe. QAD-1 could identify the overproduced Aβ in transgenic (APP/PSEN 1dE9) AD mice as early as 6 months old in vivo, which indicated that QAD-1 may be a potential probe for monitoring Aβ species at an early stage of AD.

The chemical investigation of the South China Sea soft coral Sinularia humilis has resulted in the isolation of a library of diverse diterpenoids, including four new cembranoids, namely, humilisins A−D (1−4), two new uncommon diterpenoids possessing a tetradecahydrocyclopenta[3′,4′]cyclobuta[1′,2′:4,5]cyclonona[1,2-b]oxirene ring system, namely, humilisins E and F (5 and 6), and eight known related compounds (7−14). Humilisin A (1) is the first cembranoid with an ether linkage between C-3 and C-7. The structures and absolute configurations of 1−8 were determined by extensive spectroscopic data analyses, chemical reactions, and a series of quantum chemical calculations including quantum mechanical−nuclear magnetic resonance (QM-NMR), time-dependent density functional theory−electronic circular dichroism (TDDFT-ECD), and optical rotatory dispersion (ORD) methods. In bioassay, compound 6 displayed anti-inflammatory activity in lipopolysaccharide (LPS)-stimulated BV-2 microglia cells.

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