Significance: Like other complex disorders, such as diabetes and obesity, osteoporosis is strongly influenced by genetic factors. In this study, we explored the function of the fat mass and obesity-associated gene (FTO), an RNA demethyase that has been strongly linked by genome-wide association studies to obesity and bone density. We show that loss of Fto in mouse osteoblasts leads to age-related bone loss with increased susceptibility of osteoblasts to cell death. RNA profiling of osteoblasts lacking Fto prioritized FTO targets that are members of the DNA repair pathway, which are activated in response to genotoxic stimuli. Our results identify an epigenetic pathway in which FTO normally functions in bone to enhance the stability of mRNA-encoding proteins that protect osteoblasts from genotoxic damage.

Significance: Sensory nerves innervate bone and are required for normal skeletal development, but the molecular mechanisms through which nerves exert these essential functions have remained obscure. Here, we validate a spatial transcriptomics platform, which allowed us to map changes in the molecular landscape across the developing cranium of mice in which sensory nerve innervation is genetically blocked. We show that sensory, nerve-derived signals, including follistatin-like 1, coordinate cranial bone patterning by regulating the proliferation and differentiation of bone precursor cells within the suture mesenchyme.

High-throughput sequencing (HTS) has instigated a paradigm shift in plant pathology, showcasing its transformative role in the management of plant diseases. As a powerful tool, HTS aids in identifying pathogens and enhances disease management strategies by detecting novel and emerging pathogens, tracking disease outbreaks, and contributing to developing disease-resistant cultivars. Despite these benefits, the implementation of HTS faces obstacles due to the complexity of data interpretation and economic factors that affect its widespread adoption. This comprehensive review summarizes the strengths, limitations, and opportunities associated with using HTS in managing plant diseases. The article also delves into the prospects of HTS, incorporating technological advancements, synergy with complementary methodologies, capacity-building initiatives, and the development of best practices and guidelines. By acknowledging and addressing these obstacles while harnessing the full capabilities of HTS, we advocate for a refined approach to managing plant diseases. This approach is critical for ensuring global food security, especially in the context of a growing global population and climate change.

Age-induced osteoporosis is a global problem. Essential amino acids (EAAs) work as an energy source and a molecular pathway modulator in bone, but their functions have not been systematically reviewed in aging bone. This study aimed to discuss the contribution of EAAs on aging bone from in vitro, in vivo, and human investigations. In aged people with osteoporosis, serum EAAs were detected changing up and down, without a well-established conclusion. The supply of EAAs in aged people either rescued or did not affect bone mineral density (BMD) and bone volume. In most signaling studies, EAAs were proven to increase bone mass. Lysine, threonine, methionine, tryptophan, and isoleucine can increase osteoblast proliferation, activation, and differentiation, and decrease osteoclast activity. Oxidized L-tryptophan promotes bone marrow stem cells (BMSCs) differentiating into osteoblasts. However, the oxidation product of tryptophan called kynurenine increases osteoclast activity, and enhances the differentiation of adipocytes from BMSCs. Taken together, in terms of bone minerals and volume, more views consider EAAs to have a positive effect on aging bone, but the function of EAAs in bone metabolism has not been fully demonstrated and more studies are needed in this area in the future.

Dual agonists activating the peroxisome proliferator-activated receptors alpha and gamma (PPARɑ/ɣ) have beneficial effects on glucose and lipid metabolism in patients with type 2 diabetes, but their development was discontinued due to potential adverse effects. Here we report the design and preclinical evaluation of a molecule that covalently links the PPARɑ/ɣ dual-agonist tesaglitazar to a GLP-1 receptor agonist (GLP-1RA) to allow for GLP-1R-dependent cellular delivery of tesaglitazar. GLP-1RA/tesaglitazar does not differ from the pharmacokinetically matched GLP-1RA in GLP-1R signalling, but shows GLP-1R-dependent PPARɣ-retinoic acid receptor heterodimerization and enhanced improvements of body weight, food intake and glucose metabolism relative to the GLP-1RA or tesaglitazar alone in obese male mice. The conjugate fails to affect body weight and glucose metabolism in GLP-1R knockout mice and shows preserved effects in obese mice at subthreshold doses for the GLP-1RA and tesaglitazar. Liquid chromatography–mass spectrometry-based proteomics identified PPAR regulated proteins in the hypothalamus that are acutely upregulated by GLP-1RA/tesaglitazar. Our data show that GLP-1RA/tesaglitazar improves glucose control with superior efficacy to the GLP-1RA or tesaglitazar alone and suggest that this conjugate might hold therapeutic value to acutely treat hyperglycaemia and insulin resistance.