Biology subjects

Ma, X.

Publications and source records attributed to Ma, X..

At least 379 records · Page 21Linked to original sources

bioRxiv2019

How do three cytosolic glutamine synthetase isozymes of wheat perform N assimilation and translocation?

To understand how the three cytosolic glutamine synthetase (GS1) isozymes of wheat (Triticum aestivum L., TaGS1) perform nitrogen assimilation and translocation, we studied the kinetic properties of TaGS1 isozymes, the effects of nitrogen on the expression and localization of TaGS1 isozymes with specific antibodies, and the nitrogen metabolism. The results showed TaGS1;1, the dominant TaGS1 isozyme, had a high affinity for substrates, and was widely localized in the mesophyll cells, root pericycle and root tip meristematic zone, suggesting it was the primary isozyme for N assimilation. TaGS1;2, with a high affinity for Glu, was activated by Gln, and was mainly localized in the around vascular tissues, indicating that TaGS1;2 catalyzed Gln synthesis in low Glu concentration, then the Gln returned to activate TaGS1;2, which may lead to the rapid accumulation of Gln around the vascular tissues. TaGS1;3 had low affinity for substrates but the highest Vmax among TaGS1, was mainly localized in the root tip meristematic zone; exogenous NH4+ could promote TaGS1;3 expressing, indicating that TaGS1;3 could rapidly assimilate NH4+ to relieve NH4+ toxicity. In conclusion, TaGS1;1, TaGS1;2 and TaGS1;3 have different role in N assimilation, Gln translocation and relieving ammonium toxicity, respectively, and synergistically perform nitrogen assimilation and translocation.\n\nHighlightThree cytosolic glutamine synthase isozymes of wheat have different role and synergistically perform nitrogen assimilation and translocation.

plant biology↗

bioRxiv2019

The glycine locating at random coil of picornaviruses VP3 enhances viral pathogenicity by targeting p53 to promote apoptosis and autophagy

Picornaviruses, comprising important and widespread pathogens of humans and animals, have evolved to control apoptosis and autophagy for their replication and spread. However, the underlying mechanism of the association between apoptosis/autophage and viral pathogenicity remains unclear. In the present study, VP3 of picornaviruses was demonstrated to induce apoptosis and autophagy. Foot-and-mouth disease virus (FMDV), which served as a research model here, can strongly induce both apoptosis and autophagy in the skin lesions. By directly interacting with p53, FMDV-VP3 facilitates its phosphorylation and translocation, resulting in Bcl-2 family-mediated apoptosis and LC3-dependent autophagy. The single residue Gly129 of FMDV-VP3 plays a crucial role in apoptosis and autophagy induction and the interaction with p53. Consistently, the comparison of rescued FMDV with mutated Gly129 and parental virus showed that the Gly129 is indispensable for viral replication and pathogenicity. More importantly, the Gly129 locates at a bend region of random coil structure, the mutation of Gly to Ala remarkably shrunk the volume of viral cavity. Coincidentally, the Gly is conserved in the similarly location of other picornaviruses, including poliovirus (PV), enterovirus 71 (EV71), coxsackievirus (CV) and seneca valley virus (SVA). This study demonstrates that picornaviruses induce apoptosis and autophagy to facilitate its pathogenicity and the Gly is functional site, providing novel insights into picornavirus biology.

microbiology↗

bioRxiv2019

Genome-wide analysis reveals genetic diversity, linkage disequilibrium, and selection for milk traits in Chinese buffalo breeds

Water buffalo holds the tremendous potential of milk and meat that widespread throughout central and southern China. However, characterization of the population genetics of Chinese buffalo is poorly understood. Using Axiom(R) buffalo genotyping array, we performed the genetic diversity, linkage disequilibrium (LD) pattern and signature of selection in the 176 Chinese buffaloes from thirteen breeds. A total of 35,547 SNPs passed quality control and were used for further analyses. Population genetic analysis revealed a clear separation between the swamp and river types. Ten Chinese indigenous breeds clustered into the swamp group, Murrah and Nili-Ravi breeds were the river group, and the crossbred breed was closer to the river group. Genetic diversity analysis showed that the swamp group had a lower average expected heterozygosities compared to the river group. LD decay distance was much shorter in the swamp group compared with the river group with [Formula] value of approximately 50 Kb. Analysis of runs of homozygosity indicated that extensive remote and recent inbreeding activity was respectively found within swamp and river groups. Moreover, a total of 12 genomic regions under selection were detected between river and swamp groups. Further, 12 QTL regions were found associated with buffalo milk production traits. Some candidate genes within these QTLs were predicted to be involved in the cell structure and function, suggesting that these genes might play vital roles in the buffalo milk performance. Our data contribute to our understanding of the characterization of population genetics in Chinese buffaloes, which in turn may be utilized in buffalo breeding programs.\n\nAuthor SummaryIdentifying the causal genes or markers associated with important economic traits in livestock is critical to increasing the production level on the species. However, current understanding of the genetic basis for milk production traits in buffalo is limited. Here, we confirmed the divergent evolution, distinct population structure, and LD extent among Chinese buffalo breeds. We also identified 12 QTL regions associated with milk production traits in buffaloes using the selective sweeps and haplotype analysis. Further, a total of 7 genes involved in the cell structure and function were predicted within the identified QTLs. These findings suggested that these genes can serve as the candidate genes associated with buffalo milk production, which hold a vital role in the milk trait improvement of dairy buffalo industry.

genetics↗

bioRxiv2019

ORP5 REGULATES TRANSPORT OF LIPIDS AND CALCIUM TO MITOCHONDRIA AT ENDOPLASMIC RETICULUM-MITOCHONDRIA MEMBRANE CONTACT SITES

Mitochondria are dynamic organelles essential for cell survival whose structural and functional integrity rely on selective and regulated transport of lipids from/to the endoplasmic reticulum (ER) and across the mitochondrial intermembrane space. As they are not connected by vesicular transport, the exchange of lipids between ER and mitochondria occurs at sites of close organelle apposition called membrane contact sites. However, the mechanisms and proteins involved in these processes are only beginning to emerge. Here, we show that the main physiological localization of the lipid transfer proteins ORP5 and ORP8 is at mitochondria-associated ER membranes (MAMs) subdomains, physically linked to the MIB/MICOS complexes that bridge the two mitochondrial membranes. We also show that ORP5/8 mediate non-vesicular transport of phosphatidylserine (PS) lipids from the ER to mitochondria by cooperating with the MIB/MICOS complexes. Overall our study reveals a novel physical and functional link between ER-mitochondria contacts involved in lipid transfer and intra-mitochondrial membranes contacts maintained by the MIB/MICOS complexes.

cell biology↗

bioRxiv2019

Assembly properties of FtsZ from cyanobacterium Synechocystis sp. PCC 6803

Tubulin homologue FtsZ is the major cytoskeletal protein in the bacterial cell division machinery. Here, we studied the biochemical and assembly properties of SyFtsZ, FtsZ from cyanobacterium Synechocystis sp. PCC 6803. SyFtsZ had a slow GTPase activity of around 0.4 GTP per FtsZ per minute and assembled into thick, straight protofilament bundles and curved bundles designated toroids. The assembly of SyFtsZ in the presence of GTP occurred in two stages. The first stage was assembled into single straight protofilaments and opened circles; the second stage was association of the protofilaments into straight protofilament bundles and toroids. In addition to these assemblies in GTP, highly curved oligomers and minirings could be observed after GTP hydrolysis or in the presence of GDP. Those three types of protofilaments of SyFtsZ provide support for the hypothesis for a constriction force based on curved protofilaments.

microbiology↗

bioRxiv2019

Tuberculosis treatment outcome: The case of women in Ethiopia and China, Ten-Years Retrospective Cohort study

Every year tuberculosis kills above half million women all over the world. Nonetheless, the difference in the size of deaths among countries was not compared. Hence, this study is aimed to compare the death size of two countries. Socio demographic and clinical data of women treated for all form of tuberculosis in the past ten years 2007-2016 were collected from total of eight hospitals and six treatment centers of Tigray and Zigong respectively. Then, collected data were entered into SPSS version 21 then we estimated the magnitude of TB, level of treatment success and assessed factors associated with the unsuccessful TB outcome. In the past ten years, a total of 5603(41.5%) and 4527 (24.5%) tuberculosis cases were observed in Tigray and Zigong respectively. Of those with treatment outcome record a total of 2602(92%) in Tigray and 3916(96.7%) in Zigong were successfully treated. Total of 170 (6%) cases in Tigray and 36(0.8%) cases in Zigong were dead. In Tigray cases like retreatment (aOR, 0.29; 95% CI: 0.16-0.53) and multi drug resistant (aOR, 0.31; 95% CI: 0.003, 0.27) were less likely to show treatment success. But, HIV co-infected TB cases (aOR, 3.58; 95% CI: 2.47, 5.18) were more likely to show treatment success. In Zigong, women with MDR TB (Adjusted OR, 0.90; 95%CI: 0.24, 0.34) were less likely to show treatment success. On the other hand women in the age category of 15-49 (adjusted OR, 1.55; 95% CI: 1.08, 2.206) showed treatment success. Big number of tuberculosis cases and death were observed in Tigray comparing with Zigong. Hence, a relevant measure should be considered to improve treatment outcome of women in Tigray.

epidemiology↗

bioRxiv2019

Intracellular XBP1-IL-24 axis dismantles cytotoxic unfolded protein response in the liver

Endoplasmic reticulum (ER) stress-associated cell death is prevalent in various liver diseases. However, the determinant mechanism how hepatocytes survive unresolved stress was still unclear. Interleukin-24 (IL-24) was previously found to promote ER stress-mediated cell death, and yet its expression and function in the liver remained elusive. Here we identified an anti-apoptotic role of IL-24, which transiently accumulated within ER-stressed hepatocytes in a X-box binding protein 1 (XBP1)-dependent manner. Disruption of IL-24 increased cell death in the CCL4- or APAP-challenged mouse liver or Tm-treated hepatocytes. In contrast, pharmaceutical blockade of eukaryotic initiation factor 2 (eIF2) or genetical ablation of C/EBP homologous protein (CHOP) restored hepatocyte function in the absence of IL-24. In a clinical setting, patients with acute liver failure manifested a profound decrease of hepatic IL-24 expression, which was associated with disease progression. In conclusion, intrinsic hepatocyte IL-24 maintains ER homeostasis by restricting the eIF2-CHOP pathway-mediated stress signal, which might be exploited as a bio-index for prognosis or therapeutic intervention in patients with liver injury.

cell biology↗

bioRxiv2019

A Compositional Model To Assess Expression Changes From Single-Cell RNA-Seq Data

On the problem of scoring genes for evidence of changes in the distribution of single-cell expression, we introduce an empirical Bayesian mixture approach and evaluate its operating characteristics in a range of numerical experiments. The proposed approach leverages cell-subtype structure revealed in cluster analysis in order to boost gene-level information on expression changes. Cell clustering informs gene-level analysis through a specially-constructed prior distribution over pairs of multinomial probability vectors; this prior meshes with available model-based tools that score patterns of differential expression over multiple subtypes. We derive an explicit formula for the posterior probability that a gene has the same distribution in two cellular conditions, allowing for a gene-specific mixture over subtypes in each condition. Advantage is gained by the compositional structure of the model, in which a host of gene-specific mixture components are allowed, but also in which the mixing proportions are constrained at the whole cell level. This structure leads to a novel form of information sharing through which the cell-clustering results support gene-level scoring of differential distribution. The result, according to our numerical experiments, is improved sensitivity compared to several standard approaches for detecting distributional expression changes.

bioinformatics↗

bioRxiv2019

Transcriptome-wide map of m6A circRNAs identified in hypoxic pulmonary hypertension rat model

Hypoxic pulmonary hypertension (HPH) is a lethal disease. CircRNAs and m6A circRNAs have been reported to be associated with cancer progression, but the expression profiling of m6A circRNAs has not been identified in HPH. This study was to investigate the transcriptome-wide map of m6A circRNAs in HPH. In this study, hypoxia-induced PH rat model was established. Total RNA was extracted and purified from lungs of rats, then circRNAs were detected and annotated by RNA-seq analysis. m6A RNA Immunoprecipitation (MeRIP) was performed following rRNA depletion, and RNA-seq library was constructed. CircRNA-miRNA-mRNA co-expression network was also constructed. In vitro, total m6A was measured. m6A circXpo6 and m6A circTmtc3 were detected in pulmonary artery smooth muscle cells (PASMCs) and pulmonary artery endothelial cells (PAECs) exposed to 21% O2 and 1% O2 for 48 h, respectively. m6A abundance in 166 circRNAs was significantly upregulated and m6A abundance in 191 circRNAs was significantly downregulated in lungs of HPH rats. m6A abundance in circRNAs was significantly reduced in hypoxia in vitro. m6A circRNAs were mainly derived from single exons of protein-coding genes. m6A influenced the circRNA-miRNA-mRNA co-expression network in hypoxia. m6A circXpo6 and m6A circTmtc3 were downregulated in hypoxia. In general, our study firstly identified the transcriptome-wide map of m6A circRNAs in HPH. m6A level in circRNAs was decreased in lungs of HPH rats and in PASMCs and PAECs exposed to hypoxia. Downregulated or upregulated m6A level influenced circRNA-miRNA-mRNA co-expression network in HPH. Moreover, we firstly identified two downregulated m6A circRNAs in HPH: circXpo6 and circTmtc3. We suggested that m6A circRNAs may be used as a potential diagnostic marker or therapy target in the future.\n\nAuthor summaryHPH is a disease with great morbidity and mortality. It is often caused by chronic hypoxic lung diseases, such as chronic obstructive pulmonary disease and interstitial lung diseases. It lacks effective therapy methods so far. CircRNAs are a type of non-coding RNAs and can be used as biomarkers because they are differentially enriched in specific cell types or tissues and not easily degraded. m6A is identified as the most universal modification on non-coding RNAs in eukaryotes. CircRNAs can be modified by m6A. m6A circRNAs in HPH is not well understood yet. Here we identify the transcriptome-wide map of m6A circRNAs in HPH. We elucidate that m6A level in circRNAs is decreased in lungs of HPH rats and in PASMCs and PAECs exposed to hypoxia. We find that downregulated or upregulated m6A level influences circRNA- miRNA-mRNA co-expression network in HPH. Moreover, we are the first to identify two downregulated m6A circRNAs in HPH: circXpo6 and circTmtc3. We suggest that m6A circRNAs may be used as a potential diagnostic marker or therapy target in the future.

genetics↗

bioRxiv2019

CRISPR-Cas9-assisted native end-joining editing offers a simple strategy for efficient genetic engineering in Escherichia coli

Unlike eukaryotes, bacteria are less proficient in homologous recombination (HR) and non-homologous end joining (NHEJ). All existing genomic editing methods for Escherichia coli rely on exogenous HR or NHEJ systems to repair DNA double-strand breaks (DSBs). Although an E. coli native end-joining (ENEJ) system has been reported, its potential in chromosomal engineering has not yet been explored. Here, we present a CRISPR-Cas9-assisted native end-joining editing and show that ENEJ-dependent DNA repair can be used to conduct rapid and efficient knocking-out of E. coli genomic sequence of up to 83 kb. Moreover, the positive rate and editing efficiency is independent of high-efficiency competent cells. The method requires neither exogenous DNA repair systems nor introduced editing template. The Cas9 complex is the only foreign element in this method. This study is the first successful engineering effort to utilize ENEJ mechanism in genomic editing and provides an effective strategy for genetic engineering in bacteria that are inefficient in HR and NHEJ.\n\nSignificanceThe application in prokaryotes is difficult because of the weak homologous recombination and non-homologous end joining systems. E. coli, as the most-used prokaryote in metabolic engineering, has no NHEJ system. All existing genomic editing methods for E. coli rely on exogenous HR or NHEJ systems to repair double-strand breaks introduced by CRISPR/Cas9. In this report, we firstly demonstrate that the weak and previously ignored end-joining mechanism in E. coli can be used for efficient large-scale genetic engineering assisted by CRISPR/Cas9. Our efforts greatly simplify the genomic editing procedure of E. coli and provide an effective strategy for genetic engineering in bacteria that are inefficient in HR and NHEJ.

bioengineering↗

bioRxiv2019

CDC6 regulates both G2/M transition and metaphase-to-anaphase transition during the first meiosis of mouse oocytes

Cell division cycle protein CDC6 is essential for the initiation of DNA replication. CDC6 was recently shown to inhibit the microtubule-organizing activity of the centrosome. Here, we show that CDC6 is localized to the spindle from Pro-MI to MII stages of oocytes, and it plays important roles at two critical steps of oocyte meiotic maturation. CDC6 depletion facilitated the G2/M transition (GV breakdown, GVBD) through regulation of Cdh1 and cyclin B1 expression and CDK1 phosphorylation in a GVBD-inhibiting culture system containing milrinone. Furthermore, GVBD was significantly decreased after knockdown of cyclin B1 in CDC6-depleted oocytes, indicating that the effect of CDC6 loss on GVBD stimulation was mediated, at least in part, by raising cyclin B1. Knockdown of CDC6 also caused abnormal localization of {gamma}-tubulin, resulting in defective spindles, misaligned chromosomes, cyclin B1 accumulation and spindle assembly checkpoint (SAC) activation, leading to significant Pro-MI/MI arrest and PB1 extrusion failure. These phenotypes were also confirmed by time-lapse live cell imaging analysis. The results indicate that CDC6 is indispensable for maintaining G2 arrest of meiosis and functions in G2/M checkpoint regulation in mouse oocytes. Moreover, CDC6 is also a key player regulating meiotic spindle assembly and metaphase-to-anaphase transition in meiotic oocytes.\n\nSummary statementWe show that CDC6 is indispensable for maintaining G2 arrest of mouse oocytes. Moreover, CDC6 is also a key player regulating meiotic spindle assembly and metaphase-to-anaphase transition in meiotic oocytes.

developmental biology↗

bioRxiv2019

Characterization and repurposing of the endogenous Type I-F CRISPR-Cas system of Zymomonas mobilis for genome engineering

Establishment of production platform organisms through prokaryotic engineering represents an efficient means to generate alternatives for yielding renewable biochemicals and biofuels from sustainable resources. Zymomonas mobilis, a natural facultative anaerobic ethanologen, possesses many attractive physiological attributes, making it an important industrial microorganism. To facilitate the broad applications of this strain for biorefinery, an efficient genome engineering toolkit for Z. mobilis was established in this study by repurposing the endogenous Type I-F CRISPR-Cas system upon its functional characterization, and further updated. This toolkit includes a series of genome engineering plasmids, each carrying an artificial self-targeting CRISPR and a donor DNA for the recovery of recombinants. Using the updated toolkit, genome engineering purposes were achieved with efficiencies of up to 100%, including knockout of cas3 gene, replacement of cas3 with the mCherry-encoding rfp gene, nucleotide substitutions in cas3, and deletion of two large genomic fragments up to 10 kb. This study established thus far the most efficient, straightforward and convenient genome engineering toolkit for Z. mobilis, and laid a foundation for further native CRISPRi studies in Z. mobilis, which extended the application scope of CRISPR-based technologies, and could also be applied to other industrial microorganisms with unexploited endogenous CRISPR-Cas systems.

bioengineering↗

bioRxiv2019

RhizoVision Crown: An Integrated Hardware and Software Platform for Root Crown Phenotyping

Root crown phenotyping measures the top portion of crop root systems and can be used for marker-assisted breeding, genetic mapping, and understanding how roots influence soil resource acquisition. Several imaging protocols and image analysis programs exist, but they are not optimized for high-throughput, repeatable, and robust root crown phenotyping. The RhizoVision Crown platform integrates an imaging unit, image capture software, and image analysis software that are optimized for reliable extraction of measurements from large numbers of root crowns. The hardware platform utilizes a back light and a monochrome machine vision camera to capture root crown silhouettes. RhizoVision Imager and RhizoVision Analyzer are free, open-source software that streamline image capture and image analysis with intuitive graphical user interfaces. RhizoVision Analyzer was physically validated using copper wire and features were extensively validated using 10,464 ground-truth simulated images of dicot and monocot root systems. This platform was then used to phenotype soybean and wheat root crowns. A total of 2,799 soybean (Glycine max) root crowns of 187 lines and 1,753 wheat (Triticum aestivum) root crowns of 186 lines were phenotyped. Principal component analysis indicated similar correlations among features in both species. The maximum heritability was 0.74 in soybean and 0.22 in wheat, indicating differences in species and populations need to be considered. The integrated RhizoVision Crown platform facilitates high-throughput phenotyping of crop root crowns, and sets a standard by which open plant phenotyping platforms can be benchmarked.

plant biology↗

bioRxiv2019

Integrative analysis of Hydra head regeneration reveals activation of distal enhancer-like elements

The cnidarian model organism Hydra has long been studied for its remarkable ability to regenerate its head, which is controlled by a head organizer located near the hypostome. Cnidarians and bilaterians diverged about 600 millions years ago but the gene contents of species of both phyla are surprisingly similar despite divergent morphologies and functions. While little is known about the role of cis-regulatory elements in cnidarians, understanding gene regulatory mechanisms in cnidarians can potentially shed light on metazoan evolution. The canonical Wnt pathway plays a central role in head organizer function during regeneration and during bud formation, which is the asexual mode of reproduction in Hydra. However, it is unclear how shared the developmental programs of head organizer genesis are in budding and regeneration. Time-series analysis of gene expression changes during head regeneration and budding revealed a set of 298 differentially expressed genes during the 48-hour head regeneration and 72-hour budding time-courses. In order to understand the regulatory elements controlling hydra head regeneration, we first identified 27,137 open-chromatin elements that are open in one or more sections of organism. We used histone modification ChIP-seq to identify 9998 candidate proximal promoter and 3018 candidate enhancer-like regions respectively. We show that a subset of these regulatory elements is dynamically remodeled during head regeneration and identify a set of transcription factor motifs that are enriched in the enhancer regions activated during head regeneration. Our results show that Hydra displays complex gene regulatory structures of developmentally dynamic enhancers, which suggests that the evolution of complex developmental enhancers predates the split of cnidarians and bilaterians.

genomics↗

bioRxiv2019

China’s Development Assistance for Health on Key Tropical Diseases: A SWOT Analysis

BackgroundWHO focused and gave priority on ten serious tropical diseases, while China has made remarkable achievements on tropical diseases control. In addition, China has a history of more than 60 years in the health assistance, however, its assistance for tropical diseases started late.\n\nMethodsA qualitative questionnaire was distributed to inquiry the opinions of professionals on Chinas health assistance on tropical diseases and published articles were searched to collect those data. SWOT analysis, as a tool of qualitative analysis, was used to classify and evaluate the current strengths, the weakness, the opportunities, and the threats of health assistance on tropical diseases in China.\n\nResultsBased on SWOT analysis, the internal factors and external environments are obtained. The strengths are focused on Chinas achievements on tropical diseases control, surveillance response system of tropical diseases, and human resources of public health; the weakness laid on sustainability of aid projects and funding, applicability of Chinese experience, and lack of composite talents; the opportunities are mainly in the global need of tropical diseases control, Chinas health cooperation in Belt & Road and Africa, and the actively participating of international organizations in health assistance; as well as the threats are reflected in the complex international situation, domestic needs of tropical diseases control, and the significant gaps between China and developed countries.\n\nConclusionThe internal strengths and weaknesses of development assistance for health on tropical diseases are clearly presented in the SWOT framework, as well as the external opportunities and threats and corresponding coping strategies. In the era of global health, China should strengthen and improve the health assistance for tropical diseases.\n\nAuthor summaryTropical diseases are serious infections in tropical and sub-tropical regions, with billions of persons infected and millions of deaths every year, especially in Africa. WHO also called for global efforts to control and eliminate tropical diseases. In the era of global health, development assistance on tropical diseases is important to demonstrate the soft power of national diplomacy, and China has started its health assistance in 1963. In this paper, a qualitative questionnaire and published articles were combined to collect data, and then SWOT analysis was used to analyze the internal factors and external environment, that is the current strengths, the weakness, the opportunities, and the threats of the Chinas Health Assistance on key tropical diseases. Based on those results, we put forward the countermeasures and suggestions for the future cooperation of tropical diseases. At the end of this paper, we call on Chinese professionals should make use of their own advantages and actively improve the global tropical diseases control.

epidemiology↗

bioRxiv2018

Hyocholic acid species and the risk of type 2 diabetes

Hyocholic acid (HCA) and its derivatives are found in only trace amounts in human blood, but constitute approximately 76 % of the bile acid (BA) pool in the pig, a species known for its exceptional resistance to type 2 diabetes mellitus (T2DM). Here we show that HCA species play a crucial role in maintaining glucose homeostasis and preventing T2DM. We found that in two cohort studies (n=1,213), both obesity and diabetes were associated with lower serum concentrations of HCA species. Serum HCA levels in apparently healthy individuals (n=132) were found to be strong predictors for metabolic health 10 years later. Oral administration of HCA increased serum fasting GLP-1, to a greater extent than metformin, in healthy and diabetic mouse models. HCA upregulated GLP-1 secretion in intestinal enteroendocrine cells via simultaneously activating G-protein-coupled BA receptor, TGR5, and inhibiting farnesoid X receptor, a unique mechanism that is not found in other BA species.

systems biology↗

bioRxiv2018

Small RNA bidirectional crosstalk during the interaction between wheat and Zymoseptoria tritici

Cross-kingdom RNAi has been shown to play important roles during plant pathogen interactions. But this cross-kingdom RNAi was still unexplored in the wheat-Zymoseptoria tritici pathosystem. Here we performed a detailed analysis of the sRNA bidirectional crosstalk between wheat and Z. tritici. Using a combination of sRNA-seq and mRNA-seq we were able to identify known and novel sRNAs and study their expression and their action on putative targets in both wheat and Z. tritici. We predicted the target genes of all the sRNAs in either wheat or Z. tritici transcriptome and used degradome analysis to validate the cleavage of these gene transcripts. We could not find any clear evidence of a cross-kingdom RNAi in this pathosystem. We also found that the fungal sRNA enrichment was lower in planta than during in vitro growth, probably due to the lower expression of the only Dicer gene of the fungus during plant infection. However, we found a downregulation of specific wheat sRNAs during the fungal infection, leading to a boost expression of wheat defense related genes, which may be enhancing the plant defense ability against the pathogen. Additionally, the fungal infection also induced sRNAs regulating the expression of specific wheat genes, including auxin related genes, as an immune response. These results confirm the role of sRNAs in the regulation of wheat defenses during Z. tritici infection. Our findings contribute to improve our understanding of the interactions between wheat and Z. tritici.

molecular biology↗

bioRxiv2018

Retinoid X receptor alpha is a spatiotemporally-specific therapeutic target for doxorubicin-induced cardiomyopathy in adult zebrafish

While the genetic suppressor screen is efficient in suggesting therapeutic genes, this strategy has yet to be successful for cardiomyopathies in vertebrates. To develop such a strategy, we recently established a mutagenesis screen platform in zebrafish for systematic discovery of genetic modifiers of doxorubicin-induced cardiomyopathy (DIC). Here, we further revealed both molecular and cellular insights of the first salutary modifier emerged from the screen, i.e. gene-breaking transposon (GBT) 0419 that affects the retinoid X receptor alpha a (rxraa) gene. First, by rescuing the mutation in tissue-specific manner with multiple Cre-loxP systems, we demonstrated that the endothelial, but not myocardial or epicardial, function of rxraa is primary to this cardioprotective effects. Next, we showed that the rxraa-associated salutary effects on DIC were conferred partially by the activation of retinoid acid (RA) signaling. Finally, we identified isotretinoin and bexarotene, 2 US Food and Drug Administration-approved RXRA agonists that are effective in treating adult zebrafish DIC when administered during the early, but not the late, phase of DIC progression. Collectively, we provided the first in vivo genetic evidence in supporting RXRA as the therapeutic target for DIC, and uncovered a previously unrecognized spatiotemporally-restricted mechanism for this gene-based therapeutic strategy. Our study also justified that searching salutary modifiers via zebrafish mutagenesis screen can be effective in discovering new therapeutic targets for cardiomyopathies.

genetics↗