Background Feed efficiency is a crucial parameter in swine production, given both its economic and environmental impact. The gut microbiota plays an essential role in nutrient digestibility and is, therefore, likely to affect feed efficiency. This study aimed to characterize feed efficiency, fatness traits, and gut microbiome composition in three major breeds of domesticated swine and investigate a possible link between feed efficiency and gut microbiota composition. Results Average daily feed intake (ADFI), average daily gain (ADG), feed conversion ratio (FCR), residual feed intake (RFI), backfat, loin depth, and intramuscular fat of 615 pigs belonging to the Duroc (DR), Landrace (LR), and Large White (LW) breeds were measured. Gut microbiota composition was characterized by 16S rRNA gene sequencing. Orthogonal contrasts between paternal line (DR) and maternal lines (LR+LW) and between the two maternal lines (LR versus LW) were performed. Average daily feed intake and ADG were statistically different with DR having lower ADFI and ADG compared to LR and LW. Landrace and LW had a similar ADG and RFI, with higher ADFI and FCR for LW. Alpha diversity was higher in the fecal microbial communities of LR pigs than in those of DR and LW pigs for all time points considered. Duroc communities had significantly higher proportional representation of the Catenibacterium and Clostridium genera compared to LR and LW, while LR pigs had significantly higher proportions of Bacteroides than LW for all time points considered. Amplicon sequence variants from multiple genera (including Anaerovibrio , Bacteroides , Blautia , Clostridium , Dorea , Eubacterium , Faecalibacterium , Lactobacillus , Oscillibacter , and Ruminococcus ) were found to be significantly associated with feed efficiency, regardless of the time point considered. Conclusions In this study, we characterized differences in the composition of the fecal microbiota of three commercially relevant breeds of swine, both over time and between breeds. Correlations between different microbiome compositions and feed efficiency were established. This suggests that the microbial community may contribute to shaping host productive parameters. Moreover, our study provides important insights into how the intestinal microbial community might influence host energy harvesting capacity. A deeper understanding of this process may allow us to modulate the gut microbiome in order to raise more efficient animals.
Allosteric modulation provides exciting opportunities for drug discovery of enzymes, ion channels, and G protein-coupled receptors. As cation channels gated by extracellular ATP, P2X receptors have attracted wide attention as new drug targets. Although small molecules targeting P2X receptors have entered into clinical trials for rheumatoid arthritis, cough, and pain, negative allosteric modulation of these receptors remains largely unexplored. Here, combining X-ray crystallography, computational modeling, and functional studies of channel mutants, we identified a negative allosteric site on P2X3 receptors, fostered by the left flipper (LF), lower body (LB), and dorsal fin (DF) domains. Using two structurally analogous subtype-specific allosteric inhibitors of P2X3, AF-353 and AF-219, the latter being a drug candidate under phase II clinical trials for refractory chronic cough and idiopathic pulmonary fibrosis, we defined the molecular interactions between the drugs and receptors and the mechanism by which allosteric changes in the LF, DF, and LB domains modulate ATP activation of P2X3. Our detailed characterization of this druggable allosteric site should inspire new strategies to develop P2X3-specific allosteric modulators for clinical use.
The aggregation of TAR DNA-binding protein (TDP-43) has been shown as a hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) since 2006. While evidence has suggested that mutation or truncation in TDP-43 influences its aggregation process, nevertheless, the correlation between the TDP-43 aggregation propensity and its binding substrates has not been fully established in TDP-43 proteinopathy. To address this question, we have established a platform based on the in vitro protein expression system to evaluate the solubility change of TDP-43 in response to factors such as nucleotide binding and temperature. Our results suggest that the solubility of TDP-43 is largely influenced by its cognate single-strand DNA (ssDNA) or RNA (ssRNA) rather than hnRNP, which is known to associate with TDP-43 C-terminus. The direct interaction between the refolded TDP-43, purified from E.coli, and ssDNA were further characterized by Circular Dichroism (CD) as well as turbidity and filter binding assay. In addition, ssDNA or ssRNA failed to prevent the aggregation of the F147L/F149L double mutant or truncated TDP-43 (TDP208–414). Consistently, these two mutants form aggregates, in contrast with the wild-type TDP-43, when expressed in Neuro2a cells. Our results demonstrate an intimate relationship between the solubility of TDP-43 and its DNA or RNA binding affinity, which may shed light on the role of TDP-43 in ALS and FTLD.
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