Cilia control homeostasis of the mammalian body by generating fluid flow. It has long been assumed that ciliary length-control mechanisms are essential for proper flow generation, because fluid flow generation is a function of ciliary length. However, the molecular mechanisms of ciliary length control in mammals remain elusive. Here, we suggest that KIF19A, a member of the kinesin superfamily, regulates ciliary length by depolymerizing microtubules at the tips of cilia. Kif19a(-/-) mice displayed hydrocephalus and female infertility phenotypes due to abnormally elongated cilia that cannot generate proper fluid flow. KIF19A localized to cilia tips, and recombinant KIF19A controlled the length of microtubules polymerized from axonemes in vitro. KIF19A had ATP-dependent microtubule-depolymerizing activity mainly at the plus end of microtubules. Our results indicated a molecular mechanism of ciliary length regulation in mammals, which plays an important role in the maintenance of the mammalian body.
The kinesin-8 motor, KIF19A, accumulates at cilia tips and controls cilium length.Defective KIF19A leads to hydrocephalus and female infertility because of abnormally elongated cilia. Uniquely among kinesins, KIF19A possesses the dual functions of motility along ciliary microtubules and depolymerization of microtubules. To elucidate the molecular mechanisms of these functions we solved the crystal structure of its motor domain and determined its cryoelectron microscopy structure complexed with a microtubule. The features of KIF19A that enable its dual function are clustered on its microtubule-binding side. Unexpectedly, a destabilized switch II coordinates with a destabilized L8 to enable KIF19A to adjust to both straight and curved microtubule protofilaments. The basic clusters of L2 and L12 tether the microtubule. The long L2 with a characteristic acidic-hydrophobic-basic sequence effectively stabilizes the curved conformation of microtubule ends. Hence, KIF19A utilizes multiple strategies to accomplish the dual functions of motility and microtubule depolymerization by ATP hydrolysis.
The
sealed anatomical features of the eye and its physiological activity
that rapidly removes drugs are called anatomical and physiological
barriers, which are the cause of more than 90% of drug loss. This
aspect remains a critical issue in eye surface medication. Thus, promoting
tissue permeability of drugs as well as prolonging their retention
on the eye surface can improve their bioavailability and enhance their
therapeutic effects. Thanks to the existence of a negatively charged
mucin layer on the eye surface, several peptide-decorated polymeric
micelles were prepared to enhance the interaction between the micelle
and eye surface, thus prolonging the drug retention on the eye surface
and promoting its tissue permeability. Tacrolimus (also known as FK506)
is a hydrophobic macrolide immunosuppressant used to treat dry eye
syndrome and other eye diseases. However, its hydrophobic nature makes
its delivery as a topical eye surface medication difficult, with the
risk of side effects due to overdoses. Therefore, the aim of this
work is to evaluate the ability of FK506 micelles in promoting their
permeability on the eye surface. Our results showed that the positively
charged nanomicelles could significantly prolong FK506 retention on
the eye surface and enhance its corneal permeability in ex vivo and
in vivo conditions. FK506 nanomicelles exhibited superior curing effects
against dry eye diseases than the FK506 suspension and a commercial
FK506 formula. It exerted better inhibitory effects on eye surface
inflammation and corneal epithelium apoptosis when examined by a slip
lamp and a transferase-mediated dUTP nick end labeling assay, respectively.
Further assays revealed the higher suppressive effects on the expression
of several inflammation-related factors at an mRNA and protein level.
Hence, our results suggested that these positively charged nanomicelles
might be a good drug delivery system for ocular surface medication.
Salt stress is the main abiotic stress that limits crop yield and agricultural development. Therefore, it is imperative to study the effects of salt stress on plants and the mechanisms through which plants respond to salt stress. In this study, we used transcriptomics and metabolomics to explore the effects of salt stress on Sophora alopecuroides. We found that salt stress incurred significant gene expression and metabolite changes at 0, 4, 24, 48, and 72 h. The integrated transcriptomic and metabolomic analysis revealed that the differentially expressed genes (DEGs) and differential metabolites (DMs) obtained in the phenylpropanoid biosynthesis pathway were significantly correlated under salt stress. Of these, 28 DEGs and seven DMs were involved in lignin synthesis and 23 DEGs and seven DMs were involved in flavonoid synthesis. Under salt stress, the expression of genes and metabolites related to lignin and flavonoid synthesis changed significantly. Lignin and flavonoids may participate in the removal of reactive oxygen species (ROS) in the root tissue of S. alopecuroides and reduced the damage caused under salt stress. Our research provides new ideas and genetic resources to study the mechanism of plant responses to salt stress and further improve the salt tolerance of plants.
A general and efficient Rh(I)-catalyzed decarbonylative direct C2-olefination of indoles with vinyl carboxylic acids has been developed. The reaction exhibits excellent functional group tolerance, regioselectivity and stereoselectivity, giving a broad range of C2-alkenylated indoles in good to excellent yields.
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