Biology subjects

Maynard, R.

Publications and source records attributed to Maynard, R..

3 recordsLinked to original sources

bioRxiv2024

Low protein diet protects liver function upon Salmonella infection by metabolic reprogramming of macrophages

Background & AimsWestern diets are the underlying cause of metabolic and liver diseases. Recent trend to limit the consumption of protein-rich animal products has become more prominent. This dietary change entails decreased protein consumption; however, it is still unknown how this affects innate immunity. Here, we studied the influence of a low protein diet (LPD) on the liver response to bacterial infection. MethodsMice were fed a LPD and exposed to Salmonella enterica serotype Typhimurium infection. Mechanistic studies were done in vitro where bone marrow derived macrophages were cultured in a low-aa media to mimic in vivo reduction of protein availability and challenged with bacterial endotoxin. ResultsWe found that a LPD protects from S Typhimurium-induced liver damage. Bulk- and 10xsingle cell-RNA sequencing of liver tissues and isolated immune cells showed reduced activation of myeloid cells in mice fed with LPD after S Typhimurium infection. Mechanistically, we found reduced activation of the mammalian target of rapamycin (mTOR) pathway whilst increased phagocytosis and activation of autophagy in LPD-programmed macrophages. Dietary restoration of leucine reverted the protective effects of a LPD and restored the damaging effects of Salmonella on liver parenchyma in mice. ConclusionsLow protein diet protects the liver form S Typhimurium-induced tissue damage via modulating macrophage autophagy and phagocytosis. Our result support the causal role of dietary components on the fitness of the immune system. SYNOPSISLow protein diet protects the liver from Salmonella-mediated liver injury that associates with reduced mTOR activation and increased autophagy in macrophages. Restoration of the mTOR pathway with aminoacid supplementation reverses the protection of a low protein diet from Salmonella-liver damage.

immunology↗

bioRxiv2022

Limb Specific Failure of Proliferation and Translation in the Mesenchyme Leads to Skeletal Defects in Diamond Blackfan Anemia

AbstractRibosomopathies are a class of disorders caused by defects in the structure or function of the ribosome and characterized by tissue-specific abnormalities. Diamond Blackfan anemia (DBA) arises from different mutations, predominantly in genes encoding ribosomal proteins (RPs). Apart from the anemia, skeletal defects are among the most common anomalies observed in patients with DBA, but they are virtually restricted to radial ray and other upper limb defects. What leads to these site-specific skeletal defects in DBA remains a mystery. Using a novel mouse model for RP haploinsufficiency, we observed specific, differential defects of the limbs. Using complementary in vitro and in vivo approaches, we demonstrate that reduced WNT signaling and subsequent increased {beta}-catenin degradation in concert with increased expression of p53 contribute to mesenchymal lineage failure. We observed differential defects in the proliferation and differentiation of mesenchymal stem cells (MSCs) from the forelimb versus the hind limbs of the RP haploinsufficient mice that persisted after birth and were partially rescued by allelic reduction of Trp53. These defects are associated with a global decrease in protein translation in RP haploinsufficient MSCs, with the effect more pronounced in cells isolated from the forelimbs. Together these results demonstrate translational differences inherent to the MSC, explaining the site-specific skeletal defects observed in DBA.

cell biology↗

bioRxiv2021

Transcriptome-wide Association Study and eQTL colocalization identify potentially causal genes responsible for bone mineral density GWAS associations

Genome-wide association studies (GWASs) for bone mineral density (BMD) have identified over 1,100 associations to date. However, identifying causal genes implicated by such studies has been challenging. Recent advances in the development of transcriptome reference datasets and computational approaches such as transcriptome-wide association studies (TWASs) and expression quantitative trait loci (eQTL) colocalization have proven to be informative in identifying putatively causal genes underlying GWAS associations. Here, we used TWAS/eQTL colocalization in conjunction with transcriptomic data from the Genotype-Tissue Expression (GTEx) project to identify potentially causal genes for the largest BMD GWAS performed to date. Using this approach, we identified 512 genes as significant (Bonferroni <= 0.05) using both TWAS and eQTL colocalization. This set of genes was enriched for regulators of BMD and members of bone relevant biological processes. To investigate the significance of our findings, we selected PPP6R3, the gene with the strongest support from our analysis which was not previously implicated in the regulation of BMD, for further investigation. We observed that Ppp6r3 deletion in mice decreased BMD. In this work, we provide an updated resource of putatively causal BMD genes and demonstrate that PPP6R3 is a putatively causal BMD GWAS gene. These data increase our understanding of the genetics of BMD and provide further evidence for the utility of combined TWAS/colocalization approaches in untangling the genetics of complex traits.

genomics↗