Biology subjects

Xue, M.

Publications and source records attributed to Xue, M..

42 records · Page 3Linked to original sources

bioRxiv2019

Structure elucidation of colibactin.

Colibactin is a gut microbiome metabolite of unknown structure that has been implicated in colorectal cancer formation. Several studies now suggest that the tumorgenicity of colibactin derives from interstrand cross-linking of host DNA. Here we use a combination of genetics, isotope labeling, tandem MS, and chemical synthesis to deduce the structure of colibactin. Our structural assignment accounts for all known biosynthetic data and suggests roles for the final unaccounted enzymes in the colibactin gene cluster. DNA cross-link degradation products derived from synthetic and natural colibactin were indistinguishable by tandem MS analysis, thereby confirming the structure prediction. This work reveals the structure of colibactin, which has remained incompletely defined for over a decade.

microbiology↗

bioRxiv2018

Transcriptome analysis of fasting caecotrophy on hepatic lipid metabolism in New Zealand rabbits

BackgroundRabbit produce two kinds of feces: hard and soft feces, and they have a preference for consuming the latter. Although this habit of rabbits has been reported for many years, little is known on whether this behavior will impact growth performance and metabolism. The RNA-Seq technology is an effective means of analyzing transcript groups to clarify molecular mechanisms. The aim of the present study was to investigate the effects of fasting caecotrophy on growth performance and lipid metabolism in rabbits.\n\nResultsOur results indicated that, compared with the control group, the final body weight, weight gain, liver weight, specific growth rate and feed conversion ratio were all decreased in the experimental group (P<0.05). Oil red staining of the liver tissue indicated that fasting caecotrophy resulted in decrease of lipid droplet accumulation. RNA sequencing (RNA-seq) analysis revealed a total of 301.2 million raw reads approximately 45.06 Gb of high-quality clean data. The data were mapped to the rabbit genome (http://www.ensembl.org/Oryctolagus_cuniculus). After a five step filtering process, 14964 genes were identified, including 444 differentially expressed genes (P<0.05, foldchange[≥]1). Especially for remarkable changes of genes related to lipid metabolism, RT-PCR further validated the remarkable decrease of these genes in fasting caecotrophy group, including CYP7A1, PPARG, ABCA1, ABCB1, ABCG1, GPAM, SREBP, etc. KEGG annotation of the differentially expressed genes indicated that the main pathways affected were retinol metabolism, pentose and glucuronide interactions, starch and sucrose metabolism, fatty acid degradation, steroid hormone biosynthesis.\n\nConclusionIn conclusion, the present study revealed that banning caecotrophy reduced growth rate and altered lipid metabolism, our results laid instructive basis for rabbit feeding and production. These data also provides a reference for studying the effects of soft feces on other small herbivores.

animal behavior and cognition↗

bioRxiv2018

Model colibactins exhibit human cell genotoxicity in the absence of host bacteria

Colibactins are genotoxic secondary metabolites produced in select Enterobacteriaceae, which induce downstream DNA double-strand breaks (DSBs) in human cell lines and are thought to promote the formation of colorectal tumors. Although key structural and functional features of colibactins have been elucidated, the full molecular mechanisms regulating these phenotypes remain unknown. Here, we demonstrate that free model colibactins induce DSBs in human cell cultures and do not require delivery by host bacteria. Through domain-targeted editing, we demonstrate that a subset of native colibactins generated from observed module skipping in the nonribosomal peptide synthetase-polyketide synthase (NRPS-PKS) biosynthetic assembly line share DNA alkylation phenotypes with the model colibactins in vitro. However, module skipping eliminates the strong DNA interstrand cross-links formed by the wildtype pathway in cell culture. This product diversification during the modular NRPS-PKS biosynthesis produces a family of metabolites with varying observed mechanisms of action - DNA alkylation versus crosslinking - in cell culture. The presence of membranes separating human cells from model colibactins attenuated genotoxicity, suggesting that membrane diffusion limits colibactin activity and could account for the observed bacteria-human cell-to-cell contact phenotype. Additionally, extracellular supplementation of the colibactin resistance protein ClbS was able to intercept colibactins in an E. coli-human cell transient infection model. Our studies demonstrate that free model colibactins recapitulate cellular phenotypes associated with moduleskipped products in the native colibactin pathway and define specific protein domains that are required for efficient DNA interstrand crosslinking in the native pathway.

cancer biology↗

bioRxiv2018

Downregulation of insulin-like growth factor binding protein 5 is involved in intervertebral disc degeneration via the ERK signaling pathway

Introduction Introduction Results Discussion Material and methods Conflict of interest References Intervertebral disc degeneration (IDD) is a disease of discs connecting adjoining vertebrae in which structural damage causes the degeneration of the disc and the surrounding area. This disease represents a common cause of back pain, and its treatment is costly and relatively ineffective (Kepler et al., 2013), with patients who do not achieve improvement with conservative management possibly requiring surgery (Lurie et al., 2014; Postacchini, 1996). It has been reported that the central features of IDD are the reduction in the nucleus pulposus (NP) cell population and the loss of extracellular matrix molecules (ECM), which eventually leads to major changes in the ...

molecular biology↗

bioRxiv2018

Sense-antisense gene overlap causes evolutionary retention of the few introns in Giardia genome and the implications

BackgroundIt is widely accepted that the last eukaryotic common ancestor (LECA) and early eukaryotes were intron-rich and intron loss dominated subsequent evolution, thus the presence of only very few introns in some modern eukaryotes must be the consequence of massive loss. But it is striking that few eukaryotes were found to have completely lost introns. Despite extensive research, the causes of massive intron losses remain elusive, and actually the reverse question - how the few introns are retained under the pressure of loss is equally significant but was rarely studied, except that it was conjectured that the essential functions of some introns prevent their loss. The extremely few (eight) spliceosome-mediated cis-spliced introns in the relatively simple genome of Giardia lamblia provide an excellent opportunity to explore this question.\n\nResultsOur investigation of the intron-containing genes and introns in Giardia found three types of intron distribution patterns: ancient intron in ancient gene, relatively new intron in ancient gene, and relatively new intron in relatively new gene, which can reflect to some extent the dynamic evolution of introns in Giardia. Not finding any special features or functional importance of these introns responsible for the retention, we noticed and experimentally verified that some intron-containing genes form sense-antisense gene pairs with functional genes on their complementary strands, and that the introns just reside in the overlapping regions.\n\nConclusionsIn Giardias evolution, despite constant pressure of intron loss, intron gain can still occur in both ancient and newly-evolved genes, but only a few introns have been retained; the evolutionary retention of introns is most likely not due to the functional constraint of the introns themselves but the causes outside of introns, such as the constraints imposed by other genomic functional elements overlapping with the introns. These findings can not only provide some clues to find new genomic functional elements -- in the areas overlapping with introngs, but suggest that \"functional constraint\" of introns may not be necessarily directly associated with intron loss and gain, or that the real functions or the way of functioning of introns are probably still outside of our current knowledge.

genomics↗

bioRxiv2018

Targeting light-gated chloride channels to neuronal somatodendritic domain reduces their excitatory effect in the axon

Light-gated chloride channels are emerging as promising optogenetic tools for inhibition of neural activity. However, their effects depend on the transmembrane chloride electrochemical gradient and may be complex due to the heterogeneity of this gradient in different developmental stages, neuronal types, and subcellular compartments. Here we characterized a light-gated chloride channel, GtACR2, in mouse cortical neurons. We found that GtACR2 activation inhibited the soma, but unexpectedly depolarized the presynaptic terminals resulting in neurotransmitter release. Other light-gated chloride channels had similar effects. Reducing the chloride concentrations in the axon and presynaptic terminals diminished the GtACR2-induced neurotransmitter release, indicating an excitatory effect of chloride channels in these compartments. A novel hybrid somatodendritic targeting motif reduced the GtACR2-induced neurotransmitter release while enhancing the somatic photocurrents. Our results highlight the necessity of precisely determining the effects of light-gated chloride channels under specific experimental conditions and provide a much-improved light-gated chloride channel for optogenetic inhibition.

neuroscience↗