The H3 histone variant CENP-A is an epigenetic marker critical for the centromere identity and function. However, the precise regulation of the spatiotemporal deposition and propagation of CENP-A at centromeres during the cell cycle is still poorly understood. Here, we show that CENP-A is phosphorylated at Ser68 during early mitosis by Cdk1. Our results demonstrate that phosphorylation of Ser68 eliminates the binding of CENP-A to the assembly factor HJURP, thus preventing the premature loading of CENP-A to the centromere prior to mitotic exit. Because Cdk1 activity is at its minimum at the mitotic exit, the ratio of Cdk1/PP1α activity changes in favor of Ser68 dephosphorylation, thus making CENP-A available for centromeric deposition by HJURP. Thus, we reveal that dynamic phosphorylation of CENP-A Ser68 orchestrates the spatiotemporal assembly of newly synthesized CENP-A at active centromeres during the cell cycle.
The cell wall is important for pollen tube growth, but little is known about the molecular mechanism that controls cell wall deposition in pollen tubes. Here, the functional characterization of the pollen-expressed Arabidopsis cellulose synthase-like D genes CSLD1 and CSLD4 that are required for pollen tube growth is reported. Both CSLD1 and CSLD4 are highly expressed in mature pollen grains and pollen tubes. The CSLD1 and CSLD4 proteins are located in the Golgi apparatus and transported to the plasma membrane of the tip region of growing pollen tubes, where cellulose is actively synthesized. Mutations in CSLD1 and CSLD4 caused a significant reduction in cellulose deposition in the pollen tube wall and a remarkable disorganization of the pollen tube wall layers, which disrupted the genetic transmission of the male gametophyte. In csld1 and csld4 single mutants and in the csld1 csld4 double mutant, all the mutant pollen tubes exhibited similar phenotypes: the pollen tubes grew extremely abnormally both in vitro and in vivo, which indicates that CSLD1 and CSLD4 are not functionally redundant. Taken together, these results suggest that CSLD1 and CSLD4 play important roles in pollen tube growth, probably through participation in cellulose synthesis of the pollen tube wall.
Transition-metal-catalyzed alkene hydrosilylation is one of the most important homogeneous catalytic reactions, and the development of methods that use base metals, especially iron, as catalysts for this transformation is a growing area of research. However, the limited number of ligand scaffolds applicable for base-metal-catalyzed alkene hydrosilylation has seriously hindered advances in this area. Herein, we report the use of 1,10-phenanthroline ligands in base-metal catalysts for alkene hydrosilylation. In particular, iron catalysts with 2,9-diaryl-1,10-phenanthroline ligands exhibit unexpected reactivity and selectivity for hydrosilylation of alkenes, including unique benzylic selectivity with internal alkenes, Markovnikov selectivity with terminal styrenes and 1,3-dienes, and excellent activity toward aliphatic terminal alkenes. According to the mechanistic studies, the unusual benzylic selectivity of this hydrosilylation initiates from π–π interaction between the phenyl of the alkene and the phenanthroline of the ligand. This ligand scaffold and its unique catalytic model will open possibilities for base-metal-catalyzed hydrosilylation reactions.
We have previously reported that prenatal progestin exposure induces autism-like behavior in offspring through ERβ (estrogen receptor β) suppression in the brain, indicating that progestin may induce autism spectrum disorders (ASD). In this study, we aim to investigate whether prenatal progestin exposure is associated with ASD. A population-based case-control epidemiology study was conducted in Hainan province of China. The ASD children were first screened with the Autism Behavior Checklist (ABC) questionnaire, and then diagnosed by clinical professionals using the ASD diagnosis criteria found in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V). Eventually, 235 cases were identified as ASD from 37863 children aged 0–6 years old, and 682 matched control subjects with typically developing children were selected for the analysis of potential impact factors on ASD prevalence using multivariate logistic regression. Our data show that the ASD prevalence rate in Hainan was 0.62% with a boy:girl ratio of 5.4:1. Interestingly, we found that the following factors were strongly associated with ASD prevalence: use of progestin to prevent threatened abortion, use of progestin contraceptives at the time of conception, and prenatal consumption of progestin-contaminated seafood during the first trimester of pregnancy. All the above factors were directly or indirectly involved with prenatal progestin exposure. Additionally, we conducted in vivo experiments in rats to further confirm our findings. Either endogenous (progesterone) or synthetic progestin (norethindrone)-treated seafood zebrafish were used to feed pregnant dams, and the subsequent offspring showed autism-like behavior, which further demonstrated that prenatal progestin exposure may induce ASD. We conclude that prenatal progestin exposure may be associated with ASD development.
A general and practical protocol for the construction of isoxazolidine-fused isoquinolin-1(2H)-ones has been described by electrochemical-oxidation-induced intramolecular annulation via amidyl radicals.
Direct inhibition of the protein-protein interaction of ERα and its endogenous coactivators with a cell permeable stabilized peptide may offer a novel, promising strategy for combating ERα positive breast cancers. Here, we report the co-crystal structure of a helical peptide stabilized by a N-terminal unnatural cross-linked aspartic acid (TD) in complex with the ERα ligand binding domain (LBD). We designed a series of peptides and peptide 6 that showed direct and high-affinity binding to ERα with selective antiproliferative activity in ERα positive breast cancer cells. The co-crystal structure of the TD-stabilized peptide 6 in complex with ERα LBD further demonstrates that it forms an α helical conformation and directly binds at the coactivator binding site of ERα. Further studies showed that peptide 6 could potently inhibit cellular ERα's transcriptional activity. This approach demonstrates the potential of TD stabilized peptides to modulate various intracellular protein-protein interactions involved in a range of disorders.
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