Affinity-based screening of MDM2/MDMX-p53 interaction inhibitors by chemical array: Identification of novel peptidic inhibitors.

MDM2 and MDMX are oncoproteins that negatively regulate the activity and stability of the tumor suppressor protein p53. The inhibitors of protein-protein interactions (PPIs) of MDM2-p53 and MDMX-p53 represent potential anticancer agents. In this study, a novel approach for identifying MDM2-p53 and MDMX-p53 PPI inhibitor candidates by affinity-based screening using a chemical array has been established. A number of compounds from an in-house compound library, which were immobilized onto a chemical array, were screened for interaction with fluorescence-labeled MDM2 and MDMX proteins. The subsequent fluorescent polarization assay identified several compounds that inhibited MDM2-p53 and MDMX-p53 interactions

Crystal structure of Arabidopsis DWARF14‐LIKE2 (DLK2) reveals a distinct substrate binding pocket architecture

Abstract In Arabidopsis thaliana, the Sigma factor B regulator RsbQ‐like family of α/β hydrolases contains the strigolactone (SL) receptor DWARF14 (AtD14), the karrikin receptor KARRIKIN INSENSITIVE2 (AtKAI2), and DWARF14‐LIKE2 (AtDLK2), a protein of unknown function. Despite very similar protein folds, AtD14 and AtKAI2 differ in size and architecture of their ligand binding pockets, influencing their substrate specificity. We present the 1.5 Å crystal structure of AtDLK2, revealing the smallest ligand binding pocket in the protein family, bordered by two unique glycine residues. We identified a gatekeeper residue in the protein's lid domain and present a pyrrolo‐quinoline‐dione compound that inhibits AtDLK2's enzymatic activity

A 25-Year Study of the Population Dynamics of a Harvested Population of Sika Deer on Kyushu Island, Japan

Sika deer (Cervus nippon) populations have damaged habitats, agricultural crops, and commercial forests in many parts of the world, including Asia, Europe, northern America, and New Zealand. Population management of sika deer is an important task in those areas. To better understand large-scale management and improve management efficiency, the authors estimated spatio-temporal changes of density distribution and population dynamics of a managed population of sika deer on Kyushu Island (approximately 36,750 km2), Japan. The authors estimated these changes by using fecal pellet count surveys conducted from 1995 to 2019 and results from a vector autoregressive spatio-temporal model. No decreasing trend of populations were observed at the island and prefectural scales, even though the management goal has been to reduce the population by half, and harvesting on the island increased annually until it reached about 110,000 sika deer in 2014. A possible explanation for the stable population dynamics is that the population used to determine the harvest number under the prefectural management plan was originally underestimated. This study highlights not only the difficulties of wide-area management of sika deer but also three important factors for successful management: reducing the risk of management failure, using an adaptive management approach, and appropriate management scale

Inhibition of mitochondrial complex I by the novel compound FSL0260 enhances high salinity-stress tolerance in Arabidopsis thaliana

Chemical priming is an attractive and promising approach to improve abiotic stress tolerance in a broad variety of plant species. We screened the RIKEN Natural Products Depository (NPDepo) chemical library and identified a novel compound, FSL0260, enhancing salinity-stress tolerance in Arabidopsis thaliana and rice. Through transcriptome analysis using A. thaliana seedlings, treatment of FSL0260 elevated an alternative respiration pathway in mitochondria that modulates accumulation of reactive oxygen species (ROS). From comparison analysis, we realized that the alternative respiration pathway was induced by treatment of known mitochondrial inhibitors. We confirmed that known inhibitors of mitochondrial complex I, such as rotenone and piericidin A, also enhanced salt-stress tolerance in Arabidopsis. We demonstrated that FSL0260 binds to complex I of the mitochondrial electron transport chain and inhibits its activity, suggesting that inhibition of mitochondrial complex I activates an alternative respiration pathway resulting in reduction of ROS accumulation and enhancement of tolerance to salinity in plants. Furthermore, FSL0260 preferentially inhibited plant mitochondrial complex I rather than a mammalian complex, implying that FSL0260 has a potential to be an agent for improving salt-stress tolerance in agriculture that is low toxicity to humans