Biology subjects

Qiu, Q.

Publications and source records attributed to Qiu, Q..

41 records · Page 3Linked to original sources

bioRxiv2019

mtor Haploinsufficiency Ameliorates Renal Cyst Formation in Adult Zebrafish tmem67 Mutants

Although zebrafish embryos have been utilized to study ciliogenesis and to model polycystic kidney disease (PKD), adult zebrafish remain unexplored. Here, we report the generation and characterization of a zebrafish mutant of tmem67, a homologue of the mammalian causative gene for Meckel syndrome type 3 (MKS3). Although a small population of homozygous embryos exhibited pronephric cysts, all mutants were able to survive to adulthood and developed progressive mesonephric cysts with full penetrance. The cysts in the adult zebrafish kidneys manifested features of mammalian PKD, including switching of cyst origin from the proximal tubules to the collecting ducts, increased proliferation of cyst-lining epithelial cells, and hyperactive mTOR signaling. Consistent ciliary abnormalities were observed in both the embryonic and adult zebrafish mutants compared with the wild-type fish, including shorter and fewer single cilia in the distal pronephros and all segments of the mesonephros and greater numbers of multiciliated cells (MCCs). Lack of single cilium preceded cystogenesis, suggestive of a primary defect. Expansion of MCCs occurred after pronephric cyst formation and was inversely correlated with the severity of cystogenesis in young adult zebrafish, suggesting an adaptive action. Interestingly, mTOR inhibition ameliorated renal cysts in both the embryonic and adult zebrafish models; however, it only rescued ciliary abnormalities in the adult mutants. In summary, we have established a tmem67 mutant as the first adult zebrafish PKD model, revealed a novel aspect of cilium regulation, and identified sustained mTOR inhibition as a candidate therapeutic strategy for tmem67-based PKD. Significance StatementWhile zebrafish embryos are well recognized for their value in studying ciliogenesis and polycystic kidney disease (PKD), adult zebrafish have not commonly been used. Here, we report the establishment of the first adult zebrafish model for PKD, which exhibits characteristics of mammalian PKD and shows kidney ciliary abnormalities consistent with those observed in an embryonic model. We also provide evidence for mTOR inhibition as a therapeutic strategy for this particular type of cystogenesis. Compared to the embryonic model, the adult fish model exhibits a spectrum of progressive pathogeneses and enables ciliary abnormalities to be discerned as either primary or secondary to cystogenesis. We believe that this novel adult fish model will facilitate mechanistic studies and therapeutic development for PKD.

genetics↗

bioRxiv2019

A Clostridia-rich microbiota contributes to increased excretion of bile acids in diarrhea-predominant irritable bowel syndrome

ObjectiveAn excess of fecal bile acids (BAs) is thought to be one of the mechanisms for diarrhea-predominant irritable bowel syndrome (IBS-D). However, the factors causing excessive BA excretion remains unclear. Given the importance of gut microbiota in BA metabolism, we hypothesized that gut dysbiosis might contribute to excessive BA excretion in IBS-D.\n\nDesignMetabolomic and metagenomic analyses were performed of specimens from 290 IBS-D patients and 89 healthy volunteers. By transplanting human microbiota and manipulating specific microbiome species in mice, the effects of microbiota on host BA metabolism were assessed at metabolic, genetic and protein levels. Effects of individual and mixed BAs on enterohepatic feedback pathways were also tested in vitro and in vivo.\n\nResultsTotal fecal BAs were excessively excreted in 24.5% of IBS-D patients. Their fecal metagenomes showed increased abundances of Clostridia and BA-transforming genes (hdhA and bais). The increases of Clostridia bacteria (e.g. C. scindens) were positively associated with the levels of fecal BAs and serum 7-hydroxy-4-cholesten-3-one (C4), while being negatively correlated with serum fibroblast growth factor 19 (FGF19). Both Clostridia-rich human microbiota and C. scindens enhanced levels of serum C4 and hepatic conjugated BAs in mice recipients and reduced ileal FGF19 expression. Inhibition of Clostridium species by vancomycin yielded opposite findings. Clostridia-derived BAs (e.g. conjugated and free ursodeoxycholic acid) significantly suppressed intestinal FGF19 expression.\n\nConclusionThe Clostridia-rich microbiota contributes to excessive BA excretion in IBS-D patients. This study provided the basis for more precise clinical diagnosis and management for IBS-D.

microbiology↗

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↗

bioRxiv2018

Population based hospitalization burden of laboratory-confirmed hand, foot and mouth disease caused by multiple enterovirus serotypes in southern China

BackgroundHand, foot and mouth disease (HFMD) is spread widely across Asia, and the hospitalization burden is as yet not well understood. Here, we estimated serotype-specific and age-specific hospitalization rates of HFMD in Southern China.\n\nMethodsWe enrolled pediatric patients admitted to 3/3 county-level hospitals and 3/23 township level hospitals in Anhua county, Hunan (CN) with HFMD, and collected samples to identify enterovirus serotypes by RT-PCRs between October 2013 and September 2016. The information of other eligible but un-enrolled patients were retrospectively collected from the same six hospitals. Monthly number of hospitalizations for all causes was collected from each of 23 township level hospitals to extrapolate hospitalizations associated with HFMD among these.\n\nResultsDuring the three years, an estimated 3,236 pediatric patients were hospitalized with lab-confirmed HFMD, and among these only one patient was severe. The mean hospitalization rates were 660 (95% CI: 638-684) per 100,000 person-years for lab-confirmed HFMD, with higher rates among CV-A16 and CV-A6 associated HFMD (213 vs 209 per 100,000 person-years), and lower among EV-A71, CV-A10 and other enteroviruses associated HFMD (134, 39 and 66 per 100,000 person-years, p<0.001). Children aged 12-23 months had the highest hospitalization rates (3,594/100,000 person-years), followed by those aged 24-35 months (1,828/100,000 person-years) and 6-11 months (1,572/100,000 person-years). Compared with other serotypes, CV-A6-associated hospitalizations were evident at younger ages.\n\nConclusionsOur study indicates a substantial hospitalization burden associated with non-severe HFMD in a rural county in southern China. Future mitigation policies should take into account the disease burden identified, and optimize interventions for HFMD.

epidemiology↗

bioRxiv2017

Draft genome of the Reindeer (Rangifer tarandus)

AbstractO_ST_ABSBackgroundC_ST_ABSReindeer (Rangifer tarandus) is the only fully domesticated species in the Cervidae family, and is the only cervid with a circumpolar distribution. Unlike all other cervids, female reindeer regularly grow cranial appendages (antlers, the defining characteristics of cervids), as well as males. Moreover, reindeer milk contains more protein and less lactose than bovids milk. A high quality reference genome of this specie will assist efforts to elucidate these and other important features in the reindeer.\n\nFindingsWe obtained 723.2 Gb (Gigabase) of raw reads by an Illumina Hiseq 4000 platform, and a 2.64 Gb final assembly, representing 95.7% of the estimated genome (2.76 Gb according to k-mer analysis), including 92.6% of expected genes according to BUSCO analysis. The contig N50 and scaffold N50 sizes were 89.7 kilo base (kb) and 0.94 mega base (Mb), respectively. We annotated 21,555 protein-coding genes and 1.07 Gb of repetitive sequences by de novo and homology-based prediction. Homology-based searches detected 159 rRNA, 547 miRNA, 1,339 snRNA and 863 tRNA sequences in the genome of R. tarandus. The divergence time between R. tarandus, and ancestors of Bos taurus and Capra hircus, is estimated to be 29.55 million years ago (Mya).\n\nConclusionsOur results provide the first high-quality reference genome for the reindeer, and a valuable resource for studying evolution, domestication and other unusual characteristics of the reindeer.

genomics↗