Biology subjects

Qian, F.

Publications and source records attributed to Qian, F..

23 records · Page 2Linked to original sources

bioRxiv2020

Allergen specific Treg upregulated by lung-stage schistosome infection alleviates allergic airway inflammation via inhibiting IgE secretion

Schistosome infection showed protective effects against allergic airway inflammation (AAI). However, controversial findings exist especially regarding the timing of helminth infection and the underlying mechanisms. Moreover, most previous studies focused on understanding the preventive effect of schistosome infection on asthma (infection before allergen sensitization), while its therapeutic effects (infection after allergen sensitization) were rarely investigated. In this study, we investigated the therapeutic effects of schistosome infection on AAI using a mouse model of OVA induced asthma. To explore how the timing of schistosome infection influences its therapeutic effect, the mice were percutaneously infected with cercaria of Schistosoma japonicum at either 1 day before OVA induced asthma attack (infection at lung-stage during AAI) or 14 days before OVA induced asthma attack (infection at post lung-stage during AAI). We found that lung-stage schistosome infection significantly ameliorated OVA-induced AAI, whereas post lung-stage infection showed no therapeutic effect. Mechanistically, the lung-stage schistosome infection significantly upregulated the frequency of Treg, especially OVA specific Treg, in lung tissue, which negatively correlated with the level of OVA specific IgE. Depletion of Treg in vivo counteracted the therapeutic effect. Furthermore, transcriptomic analysis of lung tissue showed that lung-stage schistosome infection during AAI shaped the microenvironment to favor Treg induction. In conclusion, our data showed that lung-stage schistosome infection could relieve OVA induced asthma in a mouse model. The therapeutic effect was mediated by the upregulated OVA specific Treg which suppressed IgE production and Th2 cytokine secretion. Our results may facilitate the discovery of a new therapy for AAI. Author SummaryAsthma is an increasingly common disease especially in industrialized countries, which is still lack of an optimal therapy. The protective effect of schistosome infection against allergic asthma has been shown in previous studies, which represents a promising candidate immune intervention approach. However, controversial findings exist especially regarding the timing of helminth infection and the underlying mechanisms. In this study, we demonstrate that lung-stage schistosome infection could upregulate the frequency of allergen specific Treg, which significantly alleviated OVA induced allergic airway inflammation via inhibiting the production of IgE and Th2 cytokines. Our results proved the therapeutic effect of schistosome infection on allergic asthma. Moreover, we highlighted that lung-stage infection is essential for inducing allergen specific regulatory T cells in lung, which is the key mediator of the observed therapeutic effect. These findings shed new light on exploiting helminths or their derivatives to treat asthma and other allergic diseases.

immunology↗

bioRxiv2019

Kinetic fingerprint of antibody therapies predicts outcomes of Alzheimer clinical trials

The amyloid cascade hypothesis, according to which the self-assembly of amyloid-{beta} peptide (A{beta}) is a causative process in Alzheimers disease, has driven many therapeutic efforts for the past 20 years. Failures of clinical trials investigating A{beta}-targeted therapies have been interpreted as evidence against this hypothesis, irrespective of the characteristics and mechanisms of action of the therapeutic agents, which are highly challenging to assess. We bring together kinetic analysis with quantitative binding measurements to address the mechanisms of action of four clinical stage anti-A{beta} antibodies, aducanumab, gantenerumab, bapineuzumab and solanezumab. We reveal and quantify the striking differences of these antibodies on the aggregation kinetics and on the production of oligomeric aggregates, and link these effects to the affinity and stoichiometry of each antibody for monomeric and fibrillar forms of A{beta}. Our results uncover that, uniquely amongst these four antibodies, aducanumab dramatically reduces the flux of oligomeric forms of A{beta}.

biophysics↗

bioRxiv2019

Trans-epithelial Fluid Pumping Performance of Renal Epithelial Cells and Mechanics of Cystic Expansion

Using a novel microfluidic platform to recapitulate fluid absorption activity of kidney cells, we report that renal epithelial cells can actively generate hydraulic pressure gradients across the epithelium. The fluidic flux declines with increasing hydraulic pressure until a stall pressure, at which the fluidic flux vanishes--in a manner similar to mechanical fluidic pumps. The developed pressure gradient translates to a force of 50-100 nanoNewtons per cell. For normal human kidney cells, the fluidic flux is from apical to basal, and the pressure is higher on the basal side. For human polycystic kidney disease (PKD) cells, the fluidic flux is reversed from basal to apical with a significantly higher stall pressure. Molecular studies and proteomic analysis reveal that renal epithelial cells are highly sensitive to hydraulic pressure gradients, developing different expression profiles and spatial arrangements of ion exchangers and the cytoskeleton in different pressure conditions. These results, together with data from osmotic and pharmacological perturbations of fluidic pumping, implicate mechanical force and hydraulic pressure as important variables during morphological changes in epithelial tubules, and provide further insights into pathophysiological mechanisms underlying the development of high luminal pressure within renal cysts.

biophysics↗

bioRxiv2019

THOC1 deficiency leads to late-onset nonsyndromic hearing loss through p53-mediated hair cell apoptosis

Apoptosis of cochlear hair cells is a key step towards age-related hearing loss. Although numerous genes have been implicated in the genetic causes of late-onset, progressive hearing loss, few show direct links to the proapoptotic process. By genome-wide linkage analysis and whole exome sequencing, we identified a heterozygous p.L183V variant in THOC1 as the probable cause of the late-onset, progressive, non-syndromic hearing loss in a large dominant family. Thoc1, a member of the conserved multisubunit THO/TREX ribonucleoprotein complex, is highly expressed in mouse and zebrafish hair cells. The Thoc1 mutant zebrafish generated by gRNA-Cas9 system lacks the C-startle response, indicative of the hearing dysfunction. Both Thoc1 mutant and knockdown zebrafish have greatly reduced hair cell numbers, while the latter can be rescued by embryonic microinjection of human wild-type THOC1 mRNA but to significantly lesser degree by the p.L183V mutant mRNA. The Thoc1 deficiency resulted in marked apoptosis in zebrafish hair cells. Consistently, transcriptome sequencing of the mutants showed significantly increased gene expression in the p53-associated signaling pathway. Depletion of p53 or applying the p53 inhibitor Pifithrin- significantly rescued the hair cell loss in the Thoc1 knockdown zebrafish. Our results suggested that THOC1 deficiency lead to late-onset, progressive hearing loss through p53-mediated hair cell apoptosis. This is to our knowledge the first human disease associated with THOC1 mutations and may shed light on the molecular mechanism underlying the age-related hearing loss.\n\nSignificance StatementFor the first time, we found that THOC1 deficiency leads to late-onset nonsyndromic hearing loss. Furthermore, we revealed the hypomorphic THOC1 induced p53-mediated hair cell apoptosis. This is to our knowledge the first human disease associated with THOC1 mutations and may shed light on the molecular mechanism underlying the age-related hearing loss.

genetics↗

bioRxiv2017

Insm1a regulates motor neuron development in zebrafish

Insulinoma-associated1a (Insm1a) is a zinc-finger transcription factor playing a series of functions in cell formation and differentiation of vertebrate central and peripheral nervous systems and neuroendocrine system. However, its roles on the development of motor neuron have still remained uncovered. Here, we provided evidences that insmla was a vital regulator of motor neuron development and provide a mechanistic understanding of how it contributes to this process. Firstly, we showed the localization of insmla in spinal cord and primary motor neurons (PMNs) of zebrafish embryos by in situ hybridization and imaging analysis of transgenic reporter line Tg(insmla: mCherry) ntu805. Then we demonstrated that the deficiency of insmla in zebrafish larvae lead to the defects of PMNs development, including the reduction of caudal primary motor neurons (CaP) and middle primary motor neurons (MiP), the excessive branching of motor axons, and the disorganized distance between adjacent CaPs. Additionally, knockout of insm1 impaired motor neuron differentiation in the spinal cord. Locomotion analysis showed that insmla-null zebrafish significantly reduced the swimming activity. Furthermore, we proved that the insmla loss of function significantly decreased the transcripts levels of both olig2 and nkx6.1. Microinjection of olig2 and nkx6.1 mRNA rescued the motor neuron defects in insmla deficient embryos. Taken together, these data indicate that insmla regulates the motor neuron development, at least in part, through modulation of the expressions of olig2 and nkx6.1.

developmental biology↗