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Statins are inhibitors of HMG-CoA reductase, the rate-limiting enzyme of cholesterol biosynthesis, and have been clinically used to treat cardiovascular disease. However, a paradoxical increase of reductase protein following statin treatment may attenuate the effect and increase the side effects. Here we present a previously unexplored strategy to alleviate statin-induced reductase accumulation by inducing its degradation. Inspired by the observations that cholesterol intermediates trigger reductase degradation, we identify a potent degrader, namely Cmpd 81, through structure–activity relationship analysis of sterol analogs. Cmpd 81 stimulates ubiquitination and degradation of reductase in an Insig-dependent manner, thus dramatically reducing protein accumulation induced by various statins. Cmpd 81 can act alone or synergistically with statin to lower cholesterol and reduce atherosclerotic plaques in mice. Collectively, our work suggests that inducing reductase degradation by Cmpd 81 or similar chemicals alone or in combination with statin therapy can be a promising strategy for treating cardiovascular disease. Accumulated HMG-CoA reductase (HMGCR) limits the cholesterol-lowering effect of statins via a feedback loop. Here the authors developed a compound that degrades HMGCR, thus decreasing cholesterol levels and reducing atherosclerotic plaques.

This paper presents a review on the rock associations, geochemistry, and spatial distribution of Mesozoic-Paleogene igneous rocks in Northeast Asia. The record of magmatism is used to evaluate the spatial-temporal extent and influence of multiple tectonic regimes during the Mesozoic, as well as the onset and history of Paleo-Pacific slab subduction beneath Eurasian continent. Mesozoic-Paleogene magmatism at the continental margin of Northeast Asia can be subdivided into nine stages that took place in the Early-Middle Triassic, Late Triassic, Early Jurassic, Middle Jurassic, Late Jurassic, early Early Cretaceous, late Early Cretaceous, Late Cretaceous, and Paleogene, respectively. The Triassic magmatism is mainly composed of adakitic rocks, bimodal rocks, alkaline igneous rocks, and A-type granites and rhyolites that formed in syn-collisional to post-collisional extensional settings related to the final closure of the Paleo-Asian Ocean. However, Triassic calc-alkaline igneous rocks in the Erguna-Xing’an massifs were associated with the southward subduction of the Mongol-Okhotsk oceanic slab. A passive continental margin setting existed in Northeast Asia during the Triassic. Early Jurassic calc-alkaline igneous rocks have a geochemical affinity to arc-like magmatism, whereas coeval intracontinental magmatism is composed of bimodal igneous rocks and A-type granites. Spatial variations in the potassium contents of Early Jurassic igneous rocks from the continental margin to intracontinental region, together with the presence of an Early Jurassic accretionary complex, reveal that the onset of the Paleo- Pacific slab subduction beneath Eurasian continent occurred in the Early Jurassic. Middle Jurassic to early Early Cretaceous magmatism did not take place at the continental margin of Northeast Asia. This observation, combined with the occurrence of low-altitude biological assemblages and the age population of detrital zircons in an Early Cretaceous accretionary complex, indicates that a strike-slip tectonic regime existed between the continental margin and Paleo-Pacific slab during the Middle Jurassic to early Early Cretaceous. The widespread occurrence of late Early Cretaceous calc-alkaline igneous rocks, I-type granites, and adakitic rocks suggests low-angle subduction of the Paleo-Pacific slab beneath Eurasian continent at this time. The eastward narrowing of the distribution of igneous rocks from the Late Cretaceous to Paleogene, and the change from an intracontinental to continental margin setting, suggest the eastward movement of Eurasian continent and rollback of the Paleo- Pacific slab at this time.

Under low-potassium (K + ) stress, a Ca 2+ signaling network consisting of calcineurin B-like proteins (CBLs) and CBL-interacting kinases (CIPKs) play essential roles. Specifically, the plasma membrane CBL1/9-CIPK pathway and the tonoplast CBL2/3-CIPK pathway promotes K + uptake and remobilization, respectively, by activating a series of K + channels. While the dual CBL-CIPK pathways enable plants to cope with low-K + stress, little is known about the early events that link external K + levels to the CBL-CIPK proteins. Here we show that K + status regulates the protein abundance and phosphorylation of the CBL-CIPK-channel modules. Further analysis revealed low K + -induced activation of VM-CBL2/3 happened earlier and was required for full activation of PM-CBL1/9 pathway. Moreover, we identified CIPK9/23 kinases to be responsible for phosphorylation of CBL1/9/2/3 in plant response to low-K + stress and the HAB1/ABI1/ABI2/PP2CA phosphatases to be responsible for CBL2/3-CIPK9 dephosphorylation upon K + -repletion. Further genetic analysis showed that HAB1/ABI1/ABI2/PP2CA phosphatases are negative regulators for plant growth under low-K + , countering the CBL-CIPK network in plant response and adaptation to low-K + stress. Potassium is essential for plant growth and development. Here the authors present evidence that plants respond to low potassium availability by modulating the abundance and phosphorylation status of proteins in CBL-CIPK-channel modules.

Emerging evidence has shown that dynamic crosstalk among cells in the tumor microenvironment modulates the progression and chemotherapeutic responses of cancer. Extracellular vesicles comprise a crucial form of intracellular communication through horizontal transfer of bioactive molecules, including long non–coding RNA (lncRNA), to neighboring cells. Three main types of extracellular vesicles are exosomes, microvesicles and apoptotic bodies, exhibiting a wide range of sizes and different biogenesis. Over the last decade, dysregulation of extracellular vesicle lncRNA has been revealed to remodel the tumor microenvironment and induce aggressive phenotypes of tumor cells, thereby facilitating tumor growth and development. This review will focus on extracellular vesicle lncRNA‐mediated crosstalk between tumor cells and recipient cells, including tumor cells as well as stromal cells in the tumor microenvironment, and overview the mechanisms by which lncRNA are selectively sorted into extracellular vesicles, which may pave the way for their clinical application in cancer diagnosis and treatment. Emerging evidence has shown that dynamic crosstalk among cells in the tumor microenvironment modulates the progression and chemotherapeutic responses of cancer. Recently, dysregulation of extracellular vesicle lncRNA has been revealed to remodel the tumor microenvironment and induce an aggressive phenotype of cancer cells, thereby facilitating tumor growth and development. This review focuses on extracellular vesicle lncRNA‐mediated crosstalk in the tumor microenvironment and the mechanisms by which lncRNA are selectively sorted into extracellular vesicles, which may pave the way for its clinical application in cancer diagnosis and treatment.

The grain contamination by Aspergillus spp. has been a serious issue. This study exhibited the excellent antifungal effects of the essential oil compounds (EOCs) geraniol and citral against common grain pathogens (A. flavus and A. ochraceus) in vitro and in situ. The inhibitory mechanisms were also evaluated from the perspective of cell membrane permeability, reactive oxygen species (ROS) generation, and Aspergillus spp. growth-related gene expression. Meanwhile, the combined effects of EOCs in the vapor phase and modified atmosphere packaging (MAP) were examined to find an alternative preservation method for controlling Aspergillus spp. The results indicated that citral exhibited the antifungal activity mainly by downregulating the sporulation- and growth-related genes for both pathogens. Geraniol displayed inhibitory effectiveness against A. flavus predominantly by inducing the intracellular ROS accumulation and showed toxicity against A. ochraceus principally by changing cell membrane permeability. Furthermore, the synthetic effects of EOCs and MAP (75% CO2 and 25% N2) induced better grain quality than the current commercial fumigant AlP. These findings reveal that EOCs have potential to be a novel grain preservative for further application.

Understanding land carbon stock dynamics is essential for sustainable land use and ecological conservation amid rapid urbanisation. This study investigates how land use changes contribute to carbon sequestration, offering insights to support China’s carbon peaking (2030) and carbon neutrality (2060) goals. Using high-resolution land use data (30 m) from 2000 to 2020 for the Chengdu Plain region, derived via Google Earth Engine and Random Forest classification, the Patch-generating Land Use Simulation (PLUS) model was applied to predict land use changes under four scenarios: natural development scenario (NDS), ecological protection scenario (EPS), cultivated land preservation scenario (CLDS), and economic development scenario (EDS) for 2030 and 2060. Carbon stock dynamics were quantified using the InVEST model, while the Optimised Parameter Geographical Detector (OPQD) model identified key drivers and their interactions. Between 2000 and 2020, cropland decreased by 4.14% while construction land increased by 4.15%, reflecting rapid urban expansion. Scenario simulations predict further cropland loss (2.80%–7.44%) and substantial construction land growth (26.89%–39.95%) by 2060, with forest and grassland recovery only under conservation scenarios. Carbon stock declined by 5.1%–5.5%, with the EPS and CLDS scenarios mitigating losses, while the NDS and EDS scenarios caused significant declines. Anthropogenic factors, such as urbanisation and economic growth, had a greater impact (> 15%) on carbon stock than natural factors (< 4%), with their interactions exhibiting nonlinear enhancement effects.This study underscores the benefits of conservation strategies and provides actionable insights for climate change mitigation, carbon trading, and sustainable urban planning. Further exploration of additional factors and predictive refinements will enhance regional ecological conservation efforts.

Two types of tonoplast proton pumps, H⁺-pyrophosphatase (V-PPase) and the H⁺-ATPase (V-ATPase), establish the proton gradient that powers molecular traffic across the tonoplast thereby facilitating turgor regulation and nutrient homeostasis. However, how proton pumps regulate development remains unclear. In this study, we investigated the function of two types of proton pumps in Arabidopsis embryo development and pattern formation. While disruption of either V-PPase or V-ATPase had no obvious effect on plant embryo development, knocking out both resulted in severe defects in embryo pattern formation from the early stage. While the first division in wild-type zygote was asymmetrical, a nearly symmetrical division occurred in the mutant, followed by abnormal pattern formation at all stages of embryo development. The embryonic defects were accompanied by dramatic differences in vacuole morphology and distribution, as well as disturbed localisation of PIN1. The development of mutant cotyledons and root, and the auxin response of mutant seedlings supported the hypothesis that mutants lacking tonoplast proton pumps were defective in auxin transport and distribution. Taking together, we proposed that two tonoplast proton pumps are required for vacuole morphology and PIN1 localisation, thereby controlling vacuole and auxin-related developmental processes in Arabidopsis embryos and seedlings.

The enhancer of zeste homolog 2 (EZH2), known as a member of the polycomb group (PcG) proteins, is an oncogene overexpressed in a variety of human cancers. Here, we found that EZH2 correlated with poor survival of oral squamous cell carcinoma (OSCC) patients using immunohistochemistry staining. EZH2 overexpression led to a significant induction in tumour glycolysis, Epithelial‐mesenchymal transition (EMT), migration and invasion of OSCC cells. Conversely, silencing of EZH2 inhibited tumour glycolysis, EMT, migration and invasion in OSCC cells. Ectopic overexpression of EZH2 increased phosphorylation of STAT3 at pY705 and decreased FoxO1 expression, and FoxO1 expression was enhanced when inhibiting STAT3. In addition, EZH2 overexpression led to a significant decrease in FoxO1 mRNA levels in nude mice xenograft. These results indicated that regulation of EZH2 might have the potential to be targeted for OSCC treatment.

Pesticides are widely used to increase agricultural productivity, however, weak adhesion and deposition lead to low efficient utilization. Herein, we prepare a nanopesticide formulation (tebuconazole nanopesticides) which is leaf-adhesive, and water-dispersed via a rapid nanoparticle precipitation method, flash nanoprecipitation, using temperature-responsive copolymers poly-(2-(dimethylamino)ethylmethylacrylate)- b -poly(ε-caprolactone) as the carrier. Compared with commercial suspensions, the encapsulation by the polymer improves the deposition of TEB, and the contact angle on foliage is lowered by 40.0°. Due to the small size and strong van der Waals interactions, the anti-washing efficiency of TEB NPs is increased by 37% in contrast to commercial ones. Finally, the acute toxicity of TEB NPs to zebrafish shows a more than 25-fold reduction as compared to commercial formulation indicating good biocompatibility of the nanopesticides. This work is expected to enhance pesticide droplet deposition and adhesion, maximize the use of pesticides, tackling one of the application challenges of pesticides. Weak adhesion is a common hindrance to efficient utilization of pesticides in agricultural applications. Here, authors demonstrate leaf-adhesive tebuconazole nanopesticides which can be water-dispersed via flash nanoprecipitation using temperature-responsive copolymers PDMAEMA-b-PCL as the carrier.