Lanoteplase

Polarized auxin transport regulates fruit shape determination by promoting anisotropic cell growth. Angiosperms produce organs with distinct shape resultant from adaptive evolution. Understanding the cellular basis underlying the development of plant organ has been a central topic in plant biology as it is key to unlock the mechanisms leading to the diversification of plants. Variations in the location of synthesis, polarized auxin transport (PAT) have been proposed to account for the development of diverse organ shapes, but the exact cellular mechanism has yet to be elucidated. The Capsella rubella develops a perfect heart-shaped fruit from an ovate shape gynoecium that is tightly linked to the localized auxin synthesis in the valve tips and provides a unique opportunity to address this question. In this study, we studied auxin movement in the fruits and the cellular effect of N-1-Naphthylphthalamic Acid (NPA) on the fruit shape determination by constructing the pCrPIN3:PIN3:GFP reporter and live-imaging. We found PAT in the valve epidermis is in congruent with fruit shape development and NPA treatment disrupts the heat-shaped fruit development mainly by repressing cell anisotropic growth with minor effect on division. As the Capsella fruit is unusually big in size, we also included a detailed step-by-step protocol on how to conduct live-imaging experiment. We further test the utility of this protocol by conducting a live-imaging analysis of the gynophore in Arachis hypogaea. Collectively, the results of this study elucidated the mechanism on how auxin signal was translated into instructions guiding cell growth during organ shape determination. In addition, the description of the detailed live-imaging protocol will encourage further studies of the cellular mechanisms underlying shape diversification in angiosperms.

Orally bioavailable, synthetic nonpeptide agonists (NPAs) of the glucagon-like peptide-1 receptor (GLP-1R) may offer an effective, scalable pharmacotherapy to address the metabolic disease epidemic. One of the first molecules in the emerging class of GLP-1R NPAs is orforglipron, which is in clinical development for treating type 2 diabetes and obesity. Here, we characterized the pharmacological properties of orforglipron in comparison with peptide-based GLP-1R agonists and other NPAs. Competition binding experiments using either [ 125 I]GLP-1(7-36)NH 2 or [ 3 H]orforglipron indicated that orforglipron is a high-affinity [inhibition constant ( Ki ) = 1 nM], selective ligand of the human GLP-1R. Signal transduction assays showed that orforglipron has low intrinsic efficacy for effector activation and negligible β-arrestin recruitment. To evaluate GLP-1R engagement in vivo, mice expressing the human GLP-1R were administered orforglipron and subjected to a glucose tolerance test. Predicted receptor occupancy was calculated using the receptor Ki value of orforglipron and its unbound concentration in vivo that reduces hyperglycemia. These experiments revealed that low GLP-1R occupancy by orforglipron is sufficient to yield a full biological response. Moreover, in a model where CRISPR-Cas9 gene editing was used to sensitize the rat GLP-1R ( Glp1r S33W ) to GLP-1R NPAs, target engagement by orforglipron in the pancreas and brain was consistent with peptide-based GLP-1R agonists. Diet-induced obesity in Glp1r S33W rats enabled studies showing weight loss in animals orally administered orforglipron versus subcutaneous injection of GLP-1R agonist semaglutide. Furthermore, crossover studies indicated oral orforglipron can sustain efficacy initiated by parenteral semaglutide. The pharmacological properties of orforglipron may inform targeting of other peptide receptors with NPAs.