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SUMMARY: Carrot (Daucus carota) is one of the most popular and nutritious vegetable crops worldwide. However, significant yield losses occur every year due to leaf blight, a disease caused by a fungal pathogen (Alternaria dauci). Past research on resistance to leaf blight disease in carrots has been slow because of the low‐quality genome assemblies of both carrot and the pathogen. Here, we report the greatly improved assemblies and annotations of telomere‐to‐telomere (T2T) reference genomes of carrot DH13M14 (451.04 Mb) and A. dauci A2016 (34.91 Mb). Compared with the previous carrot genome versions, our assembly featured notable improvements in genome size, continuity, and completeness of centromeres and telomeres. In addition, we generated a time course transcriptomic atlas during the infection of carrots by A. dauci and captured their dynamic gene expression reprogramming during the interaction process. During infection, A. dauci genes encoding effectors and enzymes responsible for the degradation of plant cell wall components, e.g., cellulose and pectin, were identified, which appeared to increase pathogenic ability through upregulation. In carrot, the coordinated gene expression of components of pattern‐ and effector‐triggered immunity (PTI and ETI) in response to A. dauci attack was characterized. The biosynthesis or signal transduction of plant hormones, including JA, SA, and ethylene, was also involved in the carrot response to A. dauci. This work provides a foundation for understanding A. dauci pathogenic progression and carrot defense mechanisms to improve carrot resistance to leaf blight disease. The Carrot Database (CDB) developed also provides a useful resource for the carrot community. Significance Statement: Here, we report the improved assemblies and annotations of telomere‐to‐telomere (T2T) reference genomes of carrot and its leaf blight pathogen Alternaria dauci. Genome‐wide alterations in gene expression in both carrot and A. dauci during carrot leaf blight disease provide a foundation for understanding A. dauci pathogenic progression and carrot defense mechanisms to improve carrot resistance to leaf blight disease. [ABSTRACT FROM AUTHOR]

Epigenetic mechanisms such as DNA methylation and hydroxymethylation play a significant role in depression. This research has shown that Ten‐eleven translocation 2 (Tet2) deficiency prompts depression‐like behaviors, but Tet2's transcriptional regulation remains unclear. In the study, bioinformatics is used to identify nuclear receptor subfamily 2 group E member 3 (Nr2e3) as a potential Tet2 regulator. Nr2e3 is found to enhance Tet2's transcriptional activity by binding to its promoter region. Nr2e3 knockdown in mouse hippocampus leads to reduced Tet2 expression, depression‐like behaviors, decreased hydroxymethylation of synaptic genes, and downregulation of synaptic proteins like postsynaptic density 95 KDa (PSD95) and N‐methy‐d‐aspartate receptor 1 (NMDAR1). Fewer dendritic spines are also observed. Nr2e3 thus appears to play an antidepressant role under stress. In search of potential treatments, small molecule compounds to increase Nr2e3 expression are screened. Azacyclonal (AZA) is found to enhance the Nr2e3/Tet2 pathway and exhibited antidepressant effects in stressed mice, increasing PSD95 and NMDAR1 expression and dendritic spine density. This study illuminates Tet2's upstream regulatory mechanism, providing a new target for identifying early depression biomarkers and developing treatments. [ABSTRACT FROM AUTHOR]

Vericiguat (Verquvo; US: Merck, other countries: Bayer) is a novel drug for the treatment of chronic heart failure. Preclinical studies have demonstrated that the primary route of metabolism for vericiguat is glucuronidation, mainly catalyzed by uridine diphosphate‐glucuronosyltransferase (UGT)1A9 and to a lesser extent UGT1A1. Whereas a drug–drug interaction (DDI) study of the UGT1A9 inhibitor mefenamic acid showed a 20% exposure increase, the effect of UGT1A1 inhibitors has not been assessed clinically. This modeling study describes a physiologically‐based pharmacokinetic (PBPK) approach to complement the clinical DDI liability assessment and support prescription labeling. A PBPK model of vericiguat was developed based on in vitro and clinical data, verified against data from the mefenamic acid DDI study, and applied to assess the UGT1A1 DDI liability by running an in silico DDI study with the UGT1A1 inhibitor atazanavir. A minor effect with an area under the plasma concentration‐time curve (AUC) ratio of 1.12 and a peak plasma concentration ratio of 1.04 was predicted, which indicates that there is no clinically relevant DDI interaction anticipated. Additionally, the effect of potential genetic polymorphisms of UGT1A1 and UGT1A9 was evaluated, which showed that an average modest increase of up to 1.7‐fold in AUC may be expected in the case of concomitantly reduced UGT1A1 and UGT1A9 activity for subpopulations expressing non‐wild‐type variants for both isoforms. This study is a first cornerstone to qualify the PK‐Sim platform for use of UGT‐mediated DDI predictions, including PBPK models of perpetrators, such as mefenamic acid and atazanavir, and sensitive UGT substrates, such as dapagliflozin and raltegravir. [ABSTRACT FROM AUTHOR]