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Given the escalating impact of climate change on agriculture and food security, gaining insights into the evolutionary dynamics of climatic adaptation and uncovering climate-adapted variation can empower the breeding of climate-resilient crops to face future climate change. Alfalfa (Medicago sativa subsp. sativa), the queen of forages, shows remarkable adaptability across diverse global environments, making it an excellent model for investigating species responses to climate change. In this study, we performed population genomic analyses using genome resequencing data from 702 accessions of 24 Medicago species to unravel alfalfa's climatic adaptation and genetic susceptibility to future climate change. We found that interspecific genetic exchange has contributed to the gene pool of alfalfa, particularly enriching defense and stress-response genes. Intersubspecific introgression between M. sativa subsp. falcata (subsp. falcata) and alfalfa not only aids alfalfa's climatic adaptation but also introduces genetic burden. A total of 1671 genes were associated with climatic adaptation, and 5.7% of them were introgressions from subsp. falcata. By integrating climate-associated variants and climate data, we identified populations that are vulnerable to future climate change, particularly in higher latitudes of the Northern Hemisphere. These findings serve as a clarion call for targeted conservation initiatives and breeding efforts. We also identified pre-adaptive populations that demonstrate heightened resilience to climate fluctuations, illuminating a pathway for future breeding strategies. Collectively, this study enhances our understanding about the local adaptation mechanisms of alfalfa and facilitates the breeding of climate-resilient alfalfa cultivars, contributing to effective agricultural strategies for facing future climate change. Population genomic analyses are performed in thit study to unravel alfalfa's climatic adaptation and vulnerability to future climate change. It is found that intraspecific gene flow and interspecific introgression have introduced genes that facilitate adaptation to current and future climates. A total of 1671 candidate genes are identified as being associated with climatic adaptation, providing potential targets for the breeding of climate-resilient cultivars to cope with future climate change. [ABSTRACT FROM AUTHOR]

Rice grain oil is a valuable nutrient source. However, the genetic basis of oil biosynthesis in rice grains remains unclear. In this study, we performed a genome-wide association study on oil composition and oil concentration in a diverse panel of 533 cultivated rice accessions. High variation for 11 oil-related traits was observed, and the oil composition of rice grains showed differentiation among the subpopulations. We identified 46 loci that are significantly associated with grain oil concentration or composition, 16 of which were detected in three recombinant inbred line populations. Twenty-six candidate genes encoding enzymes involved in oil metabolism were identified from these 46 loci, four of which (PAL6 , LIN6 , MYR2 , and ARA6) were found to contribute to natural variation in oil composition and to show differentiation among the subpopulations. Interestingly, population genetic analyses revealed that specific haplotypes of PAL6 and LIN6 have been selected in japonica rice. Based on these results, we propose a possible oil biosynthetic pathway in rice grains. Collectively, our results provide new insights into the genetic basis of oil biosynthesis in rice grains and can facilitate marker-based breeding of rice varieties with enhanced oil and grain quality. Grain oil in rice is a valuable nutrient source, but the genetic basis of its biosynthesis is not clear. We identified 99 QTL for 11 oil-related traits, cloned four genes that contribute to the natural variation in oil composition, and proposed a possible oil biosynthetic pathway in rice grains. These findings will facilitate marker- based breeding of rice varieties with enhanced oil and grain quality. [ABSTRACT FROM AUTHOR]

Endothelial cell (EC) damage or dysfunction serves as the initial event in the pathogenesis of various cardiovascular diseases. Progenitor cells have been postulated to be able to differentiate into ECs, facilitate endothelial regeneration, and alleviate vascular pathological remodeling. However, the precise cellular origins and underlying mechanisms remain elusive. Through single-cell RNA sequencing (scRNA-seq), we identified an increasing population of progenitors expressing stem cell antigen 1 (Sca1) during vascular remodeling in mice. Using both mouse femoral artery injury and vein graft models, we determined that Sca1 + cells differentiate into ECs, restored endothelium in arterial and venous remodeling processes. Notably, we have observed that the differentiation of Sca1 + cells into ECs is negatively regulated by the microRNA-145-5p (miR-145-5p)-Erythroblast transformation-specific-related gene (ERG) pathway. Inhibiting miR-145-5p promoted Sca1 + cell differentiation and reduced neointimal formation after vascular injury. Finally, a similar downregulation of miR-145-5p in human arteriovenous fistula was observed comparing to healthy veins., Competing Interests: The authors declared no potential conflicts of interest., (© 2024 The Author(s).)

Organoids are considered a game-changing paradigm of research models for human physiology and disease, which provides unsurpassed opportunities across disciplines in basic medical research, drug development, and personalized medicine. Here, we made a deep investigation for global patents of organoid technologies in the past decade using bibliometric analysis for the first time. We have identified a total of 672 patents related to organoid technology. The number of annual patent applications exhibits an overall upward growth trend over the past decade, especially entering an exponential growth since 2015. Notably, 76.64% of patents are related to the construction of organoid models. Liver, brain, and intestinal models take up the first three places in the physiological models, while tumor models account for 76.30% of the total patents for disease models. Furthermore, drug screening is the most preferred application, revealing the great commercial value of organoid technologies in precision medicine and preclinical drug screening., Competing Interests: The authors declare no conflict of interest., (© 2022 The Author(s).)

MicroRNAs (miRNAs) are emerging as effective therapeutic agents. When testing whether miR-145-5p could alleviate kidney injury, we unexpectedly found that extracellular vesicles loaded with miR-145-5p induced proteinuria and podocyte foot process effacement in normal control mice. To explore the mechanism of miR-145-5p's toxicity to podocytes, we hypothesized that miR-145-5p could enter podocytes and inhibit genes essential for podocytes. We demonstrated that systemically administered miRNA can enter podocytes. Next, we predicted 611 podocyte essential genes based on single-cell RNA sequencing (RNA-seq) and found that 32 of them are predicted to be targeted by miR-145-5p. Functional annotation of the 32 podocyte essential genes revealed small GTPase-mediated signal transduction as the top pathway. We experimentally validated that miR-145-5p targeted Arhgap24 and Srgap1, the essential regulators of the Rho family of small GTPases, increased the activity of Rac1 and Cdc42, and reduced RhoA activity, accompanied by cellular injury, in podocytes. These results explain how miR-145-5p has deleterious effect on podocytes. Most importantly, our study provides a novel approach to investigate how a miRNA affects a given cell type, allowing not only identification of the molecular mechanism underlying an observed side effect of a miRNA drug but also prediction of miRNA drug toxicity on various cell types., Competing Interests: The authors declare no competing interests., (© 2021 The Author(s).)

Nanoparticles (NPs) have been utilized to deliver drugs to the intestinal epithelium in vivo. Moreover, NPs derived from edible plants are less toxic than synthetic NPs. Here, we utilized ginger NP-derived lipid vectors (GDLVs) in a proof-of-concept investigation to test the hypothesis that inhibiting expression of divalent metal-ion transporter 1 (Dmt1) would attenuate iron loading in a mouse model of hereditary hemochromatosis (HH). Initial experiments using duodenal epithelial organ cultures from intestine-specific Dmt1 knockout (KO) (Dmt1 int/int ) mice in the Ussing chamber established that Dmt1 is the only active iron importer during iron-deficiency anemia. Further, when Dmt1 int/int mice were crossed with mice lacking the iron-regulatory hormone, hepcidin (Hepc -/- ), iron loading was abolished. Hence, intestinal Dmt1 is required for the excessive iron absorption that typifies HH. Additional experiments established a protocol to produce GDLVs carrying functional Dmt1 small interfering RNAs (siRNAs) and to target these gene delivery vehicles to the duodenal epithelium in vivo (by incorporating folic acid [FA]). When FA-GDLVs carrying Dmt1 siRNA were administered to weanling Hepc -/- mice for 16 days, intestinal Dmt1 mRNA expression was attenuated and tissue iron accumulation was blunted. Oral delivery of functional siRNAs by FA-GDLVs is a suitable therapeutic approach to mitigate iron loading in murine HH., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)