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This study aimed to establish a population pharmacokinetic (PopPK) model using data from 2 clinical trials of zimberelimab, evaluate the pharmacokinetics (PKs) of zimberelimab, explore the feasibility of 360 mg once every 3 weeks (Q3W) and 480 mg once every 4 weeks (Q4W) as alternative dosage regimens, and analyze the exposure‐response relationship of the efficacy and safety of zimberelimab for advanced tumors. The PKs of zimberelimab were described using the 2‐compartment model with time‐dependent nonlinear elimination. The prediction‐corrected visual predictive check was used to evaluate the model's predictive value on blood drug concentrations. In total, 2165 PK observations from 321 participants were included. The PopPK model demonstrated a high level of concordance between the observed data and the predicted values, indicative of a robust fit to the PK data of zimberelimab. The PK variables were similar for the 240 mg once every 2 weeks, 360 mg Q3W, and 480 mg Q4W regimens. No covariates significantly affecting the PK variables in the final model were found. The exposure variables of zimberelimab have no obvious correlations with efficacy and safety, and 360 mg Q3W and 480 mg Q4W are worthy of further study. This study establishes a PopPK model and analyzes the exposure‐response relationship of zimberelimab, which helps to explore the potential for alternative dosing regimens and offers a foundation for optimizing therapeutic strategies for advanced cancer patients through simulation‐based methods.

ABSTRACTPraeruptorin A (PA) is a natural coumarin compound from the roots of Radix Peucedani and is commonly used in the treatment of certain respiratory diseases and hypertension. Although previous studies identified relaxant effects of PA on tracheal and arterial preparations, little is known about its vasodilative effects and underlying mechanisms. Here, an organ bath system and tension recording methods were used to prepare and analyze isolated rat thoracic aorta artery rings. Aorta artery rings were pre-contracted with phenylephrine and then incubated with PA, and the possible mechanism of relaxation was investigated by adding inhibitors of nitric oxide synthase (NG-nitro-L-arginine methyl ester, L-NAME), endothelial nitric oxide synthase (L-NG-nitroarginine, L-NNA), cyclooxygenase (indomethacin), guanylyl cyclase (1 H-[1,2,4]oxadiazolo [4,3-a]quinoxalin-1-one, ODQ), and KCa channels (tetraethylammonium, TEA). Our study showed that PA-induced vasodilation was blocked by L-NAME, L-NNA, and ODQ, while CaCl2-induced vasoconstriction was countered by PA. Thus, PA may exert a vasodilatory effect by influencing the amounts of endothelium-derived relaxing factors through endothelial-dependent NO-cGMP and prostacyclin pathways (such as NO and prostacyclin 2). In the rat thoracic aorta, PA reduces vasoconstriction by inhibiting Ca2+inflow.

We identified a promising compound—4-MU, as a useful tool, to facilitate the drought tolerance of apple dwarfing rootstock by regulating rhizosphere microbial diversity and root architecture.The dwarfing rootstocks-mediated high-density apple orchard is becoming the main practice management. Currently, dwarfing rootstocks are widely used worldwide, but their shallow root system and drought sensitivity necessitate high irrigation requirements. Here, the root transcriptome and metabolome of dwarfing (M9-T337, a drought-sensitive rootstock) and vigorous rootstocks (Malus sieversii, a drought-tolerant species, is commonly used as a rootstock) showed that a coumarin derivative, 4-Methylumbelliferon (4-MU), was found to accumulate significantly in the roots of vigorous rootstock under drought condition. When exogenous 4-MU was applied to the roots of dwarfing rootstock under drought treatment, the plants displayed increased root biomass, higher root-to-shoot ratio, greater photosynthesis, and elevated water use efficiency. In addition, diversity and structure analysis of the rhizosphere soil microbial community demonstrated that 4-MU treatment increased the relative abundance of putatively beneficial bacteria and fungi. Of these, Pseudomonas, Bacillus, Streptomyces, and Chryseolineabacterial strains and Acremonium, Trichoderma, and Phomafungal strains known for root growth, or systemic resistance against drought stress, were significantly accumulated in the roots of dwarfing rootstock after 4-MU treatment under drought stress condition. Taken together, we identified a promising compound—4-MU, as a useful tool, to strengthen the drought tolerance of apple dwarfing rootstock.

Recently, increasing studies have revealed epigenetic variations in crop development and quality formation providing new epigenetic sources for crop improvement. Ongoing advances in epigenomic technologies based on high-throughput sequencing provide new insights into epigenetic variations in important crop traits at a larger scale and higher resolution. The emerging epigenome editing tools enable us to manipulate the epigenetic modifications in specific loci and induce novel phenotypes as human demand increases. This review summarizes current epigenomic technologies corresponding to different epigenetic mechanisms and their applications in uncovering epigenomic variation in crop quality. Finally, we discuss the application of epigenome editing tools in crop improvement to meet food requirements and security by manipulating epigenetic changes in a site-specific manner.

A full-parallax three-dimensional (3D) display using a new directional diffuser is demonstrated. The display could present 3D images with 45 views comprising 9 horizontal views by 5 vertical views. The resolution and size of the 3D images displayed are 226?226 pixels and 300?300 (mm). The new directional diffuser consisting of two perpendicular lenticular sheets can be widely used in the display domain owing to its low cost and simple process.