Febrifugine, one of the fifty fundamental herbs of traditional Chinese medicine, has been characterized for its therapeutic activity whilst its molecular target has remained unknown. Febrifugine derivatives have been used to treat malaria, cancer, fibrosis, and inflammatory disease. We recently demonstrated that halofuginone (HF), a widely studied derivative of febrifugine, inhibits the development of Th17-driven autoimmunity in a mouse model of multiple sclerosis by activating the amino acid response pathway (AAR). Here we show that HF binds glutamyl-prolyl-tRNA synthetase (EPRS) inhibiting prolyl-tRNA synthetase activity; this inhibition is reversed by the addition of exogenous proline or EPRS. We further show that inhibition of EPRS underlies the broad bioactivities of this family of natural products. This work both explains the molecular mechanism of a promising family of therapeutics, and highlights the AAR pathway as an important drug target for promoting inflammatory resolution.

EAT and AAI, along eigenvector 1, which explains ~15% of the total variation. AFT Muturu and N'Dama are close to EAT along the eigenvector 1. Most of the AFH cattle cluster together regardless of their breed memberships, leaving only Ankole, Mursi and Sheko outside the main cluster toward the AFT Muturu and N'Dama. The PCA results also show that Muturu and N'Dama, our representative of AFT population, are separated from the other cattle groups (eigenvector 2, ~2.5% of total variation). Sheko positions close to the AFH, as similarly reported in other studies 5,43 . Genetic clustering analysis using ADMIXTURE 44 corroborates the pattern found in PCA (Fig. 2b and Extended Data Fig. 2). Most of AFH show a similar proportion of taurine ancestry, around 25% on average. Only a few AFH breeds have elevated taurine ancestry: Ankole (53.37 ± 1.49%), Sheko (46.28 ± 2.03%) and Mursi (35.90 ± 2.16%). (Fig. 2b).Genetic distance and diversity. Pairwise F st were calculated to estimate the genetic distances between populations (n = 38) (Extended Data Fig. 3). Taurine (EUT, AST and AFT) show F st values of 0.1568 and 0.3287 on average against AFH and AAI, respectively.Across AFH, pairwise F st between breeds is close to zero, regardless of their phenotypic classification as African Zebu, Sanga or Zenga. Muturu and N'Dama show F st value of 0.1769, 0.1847 and 0.3734 against AFH, EAT and AAI, respectively.The genome-wide autosomal SNPs show reduced levels of heterozygosity in the taurine (0.0021 ± 0.0005/bp) compared to all other populations (0.0048 ± 0.0008/bp). Heterozygosity values of AFH are similarly higher across populations (0.0046 ± 0.0003/bp). AAI shows a higher level of heterozygosity compared to AFH (0.0052 ± 0.0014/bp) (Extended Data Fig. 4). The degree of inbreeding measured by runs of homozygosity (ROH) shows that taurine, including Muturu and N'Dama, have a higher level of inbreeding compared to the other and Ethiopia), the University of Khartoum (Sudan), and the National Biotechnology Development Agency (NABDA) (Nigeria). The following institutions and their personnel provided help for the sampling of the African cattle: ILRI Kapiti Ranch, Ministry of Animal Resources, Fisheries and Range (Sudan), Ol Pejeta Conservancy (Kenya), Institute of Biodiversity (Ethiopia), the Directors of Veterinary Services and the cattle keepers from Ethiopia, Kenya, Uganda and Sudan. ILRI livestock genomics program is supported by the

This genome-wide association study (GWAS) was conducted to identify major loci that are significantly associated with carcass weight, and their effects, in order to provide increased understanding of the genetic architecture of carcass weight in Hanwoo. This genome-wide association study identified one major chromosome region ranging from 23 Mb to 25 Mb on chromosome 14 as being associated with carcass weight in Hanwoo. Significant Bonferroni-corrected genome-wide associations (P<1.52×10−6) were detected for 6 Single Nucleotide Polymorphic (SNP) loci for carcass weight on chromosome 14. The most significant SNP was BTB-01280026 (P = 4.02×10−11), located in the 25 Mb region on Bos taurus autosome 14 (BTA14). The other 5 significant SNPs were Hapmap27934-BTC-065223 (P = 4.04×10−11) in 25.2 Mb, BTB-01143580 (P = 6.35×10−11) in 24.3 Mb, Hapmap30932-BTC-011225 (P = 5.92×10−10) in 24.8 Mb, Hapmap27112-BTC-063342 (P = 5.18×10−9) in 25.4 Mb, and Hapmap24414-BTC-073009 (P = 7.38×10−8) in 25.4 Mb, all on BTA 14. One SNP (BTB-01143580; P = 6.35×10−11) lies independently from the other 5 SNPs. The 5 SNPs that lie together showed a large Linkage disequilibrium (LD) block (block size of 553 kb) with LD coefficients ranging from 0.53 to 0.89 within the block. The most significant SNPs accounted for 6.73% to 10.55% of additive genetic variance, which is quite a large proportion of the total additive genetic variance. The most significant SNP (BTB-01280026; P = 4.02×10−11) had 16.96 kg of allele substitution effect, and the second most significant SNP (Hapmap27934-BTC-065223; P = 4.04×10−11) had 18.06 kg of effect on carcass weight, which correspond to 44% and 47%, respectively, of the phenotypic standard deviation for carcass weight in Hanwoo cattle. Our results demonstrated that carcass weight was affected by a major Quantitative Trait Locus (QTL) with a large effect and by many SNPs with small effects that are normally distributed.

The importance of probiotics in swine production is widely acknowledged as crucial. However, gaps still remain in the exact roles played by probiotics in modulation of gut microbiota and immune response. This study determined the roles of probiotic Lactobacillus plantarum strain JDFM LP11in gut microbiota modulation and immune response in weaned piglets. L. plantarum JDFM LP11 increased the population of lactic acid bacteria in feces and enhanced the development of villi in the small intestine. Metagenome analysis showed that microbial diversity and richness (Simpson, Shannon, ACE, Chao1) and the relative abundance of the Firmicutes were higher in weaned piglets fed probiotics. Five bacterial families were different in the relative abundance, especially; Prevotellaceae occupied the largest part of microbial community showed the most difference between two groups. Transcriptome analysis identified 25 differentially expressed genes using RNAsequencing data of the ileum. Further gene ontology and immune DB analysis determined 8 genes associated with innate defense response and cytokine production. BPI, RSAD2, SLPI, LUM, OLFM4, DMBT1 and C6 genes were down-regulated by probiotic supplementation except PLA2G2A. PICRUSt analysis predicting functional profiling of microbial communities indicated branched amino acid biosynthesis and butyrate metabolism promoting gut development and health were increased by probiotics. Altogether, our data suggest that L. plantarum JDFM LP11 increases the diversity and richness in the microbial community, and attenuates the ileal immune gene expression towards gut inflammation, promoting intestinal development in weaned piglets.

Methylsulfonylmethane (MSM) is a naturally occurring sulfur compound with well-known anti-oxidant properties and anti-inflammatory activities. But, its effects on bone are unknown. Growth hormone (GH) is regulator of bone growth and bone metabolism. GH activates several signaling pathways such as the Janus kinase (Jak)/signal transducers and activators of transcription (STAT) pathway, thereby regulating expression of genes including insulin-like growth factor (IGF)-1. GH exerts effects both directly and via IGF-1, which signals by activating the IGF-1 receptor (IGF-1R). In this study, we investigated the effects of MSM on the GH signaling via the Jak/STAT pathway in osteoblasts and the differentiation of primary bone marrow mesenchymal stem cells (MSCs). MSM was not toxic to osteoblastic cells and MSCs. MSM increased the expression of GH-related proteins including IGF-1R, p-IGF-1R, STAT5b, p-STAT5b, and Jak2 in osteoblastic cells and MSCs. MSM increased IGF-1R and GHR mRNA expression in osteoblastic cells. The expression of MSM-induced IGF-1R and GHR was inhibited by AG490, a Jak2 kinase inhibitor. MSM induced binding of STAT5 to the IGF-1R and increased IGF-1 and IGF-1R promoter activities. Analysis of cell extracts by immunoprecipitation and Western blot showed that MSM enhanced GH-induced activation of Jak2/STAT5b. We found that MSM and GH, separately or in combination, activated GH signaling via the Jak2/STAT5b pathway in UMR-106 cells. Using siRNA analysis, we found that STAT5b plays an essential role in GH signaling activation in C3H10T1/2 cells. Osteogenic marker genes (ALP, ON, OCN, BSP, OSX, and Runx2) were activated by MSM, and siRNA-mediated STAT5b knockdown inhibited MSM-induced expression of osteogenic markers. Furthermore, MSM increased ALP activity and the mineralization of MSCs. Taken together, these results indicated that MSM can promote osteogenic differentiation of MSCs through activation of STAT5b.