Notes

Understanding of Liquid Polymorphism from the Complex Phase Behavior of an Straightforward Model.
Cyclin-dependent kinase 6 (CDK6) is an important regulator of the cell cycle. Together with CDK4, it phosphorylates and inactivates retinoblastoma (Rb) protein. In tumour cells, CDK6 is frequently upregulated and CDK4/6 kinase inhibitors like palbociclib possess high activity in breast cancer and other malignancies. Besides its crucial catalytic function, kinase-independent roles of CDK6 have been described. Therefore, targeted degradation of CDK6 may be advantageous over kinase inhibition. Proteolysis targeting chimeras (PROTACs) structurally based on the cereblon (CRBN) ligand thalidomide have recently been described to degrade the targets CDK4/6. However, CRBN-based PROTACs have several limitations including the remaining activity of immunomodulatory drugs (IMiDs) on Ikaros transcription factors as well as CRBN inactivation as a resistance mechanism in cancer. Here, we systematically explored the chemical space of CDK4/6 PROTACs by addressing different E3 ligases and connecting their respective small-molecule binders via various linkers to palbociclib. The spectrum of CDK6-specific PROTACs was extended to von Hippel Lindau (VHL) and cellular inhibitor of apoptosis protein 1 (cIAP1) that are essential for most cancer cells and therefore less likely to be inactivated. Our VHL-based PROTAC series included compounds that were either specific for CDK6 or exhibited dual activity against CDK4 and CDK6. IAP-based PROTACs caused a combined degradation of CDK4/6 and IAPs resulting in synergistic effects on cancer cell growth. Our new degraders showed potent and long-lasting degrading activity in human and mouse cells and inhibited proliferation of several leukemia, myeloma and breast cancer cell lines. In conclusion, we show that VHL- and IAP-based PROTACs are an attractive approach for targeted degradation of CDK4/6 in cancer.Clarifying the endogenous processes that construct gross aerial shapes such as branching architecture in plants is crucial to understanding how branching contributes to plant adaptation to environments. Selleckchem Sitagliptin Architectural analysis is powerful in decomposing the branching process, by comparing observations of plant growth among closely related taxa. The genus Sasa (Gramineae Bambusoideae) contains three major sections Crassinodi, Sasa and Macrochlamys. These sections exhibit characteristic branching architectures and are distributed separately across the Japanese archipelago, in relation to macroclimatic conditions such as snow accumulation. Our study aimed to quantitatively reveal the endogenous processes underlying branching architectures in the three sections of Sasa. Long-term observations were carried out branch architectural development on Hokkaido Island from 1979 to 2012, which corresponded to the flowering interval of the genus. The results revealed that the three characteristic branching systems of the genus arise mainly from four endogenous processes (distribution of lateral buds on a culm, internode length arrangement along a culm, determination of the fate of lateral buds, development of branching with culm fragility due to ageing) and their interactions with environmental conditions, especially snow accumulation. These processes are coordinated with each other over the life span of a single shoot in developing branching architecture.In flowering plants, lateral organs including stamens develop according to the precise regulation of adaxial-abaxial polarity. However, the polarity establishment process is poorly understood in asymmetric stamens. Canna indica (Zingiberales Cannaceae) is a common ornamental plant with an asymmetric stamen comprising a one-theca anther and a petaloid appendage. In this study, we depicted the monosymmetric-to-asymmetric morphogenesis of C. indica stamen, and the morphogenesis of the monosymmetric stamen of a sister species was used as a contrast. We chose a HD-ZIP III gene family member and a YABBY family member as the adaxial and abaxial polarity marker genes, respectively, and tested their expression using mRNA in situ hybridization. The expression patterns of the two genes changed dynamically and asymmetrically during the stamen development process. Compared with their homologues in Arabidopsis thaliana, these two genes exhibited some specific expression patterns. We hypothesize that the distinctive adaxial-abaxial polarity participates in the irregular morphogenesis of C. indica stamen, which mediates the putative stamen-to-petaloid staminode conversion in this species.Wind influences the development, architecture and morphology of plant roots and may modify subsequent interactions between plants and soil (plant-soil feedbacks-PSFs). However, information on wind effects on fine root morphology is scarce and the extent to which wind changes plant-soil interactions remains unclear. Therefore, we investigated the effects of two wind intensity levels by manipulating surrounding vegetation height in a grassland PSF field experiment. We grew four common plant species (two grasses and two non-leguminous forbs) with soil biota either previously conditioned by these or other species and tested the effect of wind on rootshoot ratio, fine root morphological traits as well as the outcome for PSFs. Wind intensity did not affect biomass allocation (i.e. rootshoot ratio) in any species. However, fine-root morphology of all species changed under high wind intensity. High wind intensity increased specific root length and surface area and decreased root tissue density, especially in the two grasses. Similarly, the direction of PSFs changed under high wind intensity in all four species, but differences in biomass production on the different soils between high and low wind intensity were marginal and most pronounced when comparing grasses with forbs. Because soils did not differ in plant-available nor total nutrient content, the results suggest that wind-induced changes in root morphology have the potential to influence plant-soil interactions. Linking wind-induced changes in fine-root morphology to effects on PSF improves our understanding of plant-soil interactions under changing environmental conditions.
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