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  1. Free, publicly-accessible full text available September 1, 2024
  2. Abstract

    Digoxin extracted from the foxglove plant is a widely prescribed natural product for treating heart failure. It is listed as an essential medicine by the World Health Organization. However, how the foxglove plant synthesizes digoxin is mostly unknown, especially the cytochrome P450 sterol side chain cleaving enzyme (P450scc), which catalyzes the first and rate-limiting step. Here we identify the long-speculated foxglove P450sccthrough differential transcriptomic analysis. This enzyme converts cholesterol and campesterol to pregnenolone, suggesting that digoxin biosynthesis starts from both sterols, unlike previously reported. Phylogenetic analysis indicates that this enzyme arises from a duplicated cytochrome P450CYP87Agene and is distinct from the well-characterized mammalian P450scc. Protein structural analysis reveals two amino acids in the active site critical for the foxglove P450scc’s sterol cleavage ability. Identifying the foxglove P450sccis a crucial step toward completely elucidating digoxin biosynthesis and expanding the therapeutic applications of digoxin analogs in future work.

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  3. Abstract

    The H3 methyltransferases ATXR5 and ATXR6 deposit H3.1K27me1 to heterochromatin to prevent genomic instability and transposon re-activation. Here, we report thatatxr5 atxr6mutants display robust resistance to Geminivirus. The viral resistance is correlated with activation of DNA repair pathways, but not with transposon re-activation or heterochromatin amplification. We identify RAD51 and RPA1A as partners of virus-encoded Rep protein. The two DNA repair proteins show increased binding to heterochromatic regions and defense-related genes inatxr5 atxr6vs wild-type plants. Consequently, the proteins have reduced binding to viral DNA in the mutant, thus hampering viral amplification. Additionally, RAD51 recruitment to the host genome arise via BRCA1, HOP2, and CYCB1;1, and this recruitment is essential for viral resistance inatxr5 atxr6. Thus, Geminiviruses adapt to healthy plants by hijacking DNA repair pathways, whereas the unstable genome, triggered by reduced H3.1K27me1, could retain DNA repairing proteins to suppress viral amplification inatxr5 atxr6.

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  4. Multiparameter Franck–Condon analyses of absorption spectra of Y6 in dilute solutions reveals that Y6 exhibits a high conformation uniformity and the smallest intra-molecular reorganization energy among the materials studied.

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  5. We study the collective elastic behavior of semiflexible polymer solutions in a nematic liquid-crystalline state using polymer field theory. Our polymer field-theoretic model of semiflexible polymer solutions is extended to include second-order fluctuation corrections to the free energy, permitting the evaluation of the Frank elastic constants based on orientational order fluctuations in the nematic state. Our exact treatment of wormlike chain statistics permits the evaluation of behavior from the nematic state, thus accurately capturing the impact of single-chain behavior on collective elastic response. Results for the Frank elastic constants are presented as a function of aligning field strength and chain length, and we explore the impact of conformation fluctuations and hairpin defects on the twist, splay, and bend moduli. Our results indicate that the twist elastic constant Ktwist is smaller than both bend and splay constants (Kbend and Ksplay, respectively) for the entire range of polymer rigidity. Splay and bend elastic constants exhibit regimes of dominance over the range of chain stiffness, where Ksplay > Kbend for flexible polymers (large-N limit) while the opposite is true for rigid polymers. Theoretical analysis also suggests the splay modulus tracks exactly to that of the end-to-end distance in the transverse direction for semiflexible polymers at intermediate to large-N. These results provide insight into the role of conformation fluctuations and hairpin defects on the collective response of polymer solutions.

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  6. Abstract

    Cardenolides are steroidal metabolites in Digitalis lanata with potent cardioactive effects on animals. In plants, cardenolides are likely involved in various stress responses. However, the molecular mechanism of cardenolide increase during stresses is mostly unknown. Additionally, cardenolides are proposed to arise from cholesterol, but indirect results show that phytosterols may also be substrates for cardenolide biosynthesis. Here, we show that cardenolides increased after methyl jasmonate (MJ), sorbitol, potassium chloride (KCl) and salicylic acid analog [2,1,3-benzothiadiazole (BTH)] treatments. However, the expression of three known genes for cardenolide biosynthesis did not correlate well with these increases. Specifically, the expression of progesterone-5β-reductases (P5βR and P5βR2) did not correlate with the cardenolide increase. The expression of 3β-hydroxysteroid dehydrogenase (3βHSD) correlated with changes in cardenolide levels only during the BTH treatment. Mining the D. lanata transcriptome identified genes involved in cholesterol and phytosterol biosynthesis: C24 sterol sidechain reductase 1 (SSR1), C4 sterol methyl oxidase 1, and 3 (SMO1 and SMO3). Surprisingly, the expression of all three genes correlated well with the cardenolide increase after the BTH treatment. Phylogenetic analysis showed that SSR1 is likely involved in both cholesterol and phytosterol biosynthesis. In addition, SMO1 is likely specific to phytosterol biosynthesis, and SMO3 is specific to cholesterol biosynthesis. These results suggest that stress-induced increase of cardenolides in foxglove may correlate with cholesterol and phytosterol biosynthesis. In summary, this work shows that cardenolides are important for stress responses in D. lanata and reveals a potential link between phytosterol and cardenolide biosynthesis.

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  7. The concept of metalla-aromaticity proposed by Thorn–Hoffmann ( Nouv. J. Chim . 1979, 3, 39) has been expanded to organometallic molecules of transition metals that have more than one independent electron-delocalized system. Lanthanides, with highly contracted 4f atomic orbitals, are rarely found in multiply aromatic systems. Here we report the discovery of a doubly aromatic triatomic lanthanide-boron molecule PrB 2 − based on a joint photoelectron spectroscopy and quantum chemical investigation. Global minimum structural searches reveal that PrB 2 − has a C 2v triangular structure with a paramagnetic triplet 3 B 2 electronic ground state, which can be viewed as featuring a trivalent Pr(III,f 2 ) and B 2 4− . Chemical bonding analyses show that this cyclo-PrB 2 − species is the smallest 4f-metalla-aromatic system exhibiting σ and π double aromaticity and multiple Pr–B bonding characters. It also sheds light on the formation of the rare B 2 4− tetraanion by the high-lying 5d orbitals of the 4f-elements, completing the isoelectronic B 2 4− , C 2 2− , N 2 , and O 2 2+ series. 
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