Biology subjects

Xu, Q.

Publications and source records attributed to Xu, Q..

At least 199 records · Page 11Linked to original sources

bioRxiv2020

Mendelian randomization analysis revealed causal effects from gut microbiota to abdominal obesity

Although recent studies have revealed the association between the gut microbiota and obesity, the causality remains elusive. We performed a Mendelian Randomization (MR) analysis to determine whether there is a causal relationship between gut microbiota and abdominal obesity. We used a two-sample MR approach to assess the causal effect from gut microbiota to obesity based on genome-wide association studies (GWAS) summary statistics. The GWAS summary statistics of gut microbiota obtained from UK-twins cohort (N=1,126) were used as discovery sample exposure, and the GWAS summary statistics from the Genetic Environmental Microbial (GEM) project (N=1,098) were used as replication sample exposure. Trunk fat mass (TFM) summary statistics from the UK Biobank (UKB) cohort (N=330,762) were used as outcome. Bacteria were grouped into taxa features at family level. A total of 16 families were analyzed in the discovery sample. Family Barnesiellaceae was associated with TFM at the nominal significance level (b=-3.81x10-4, P=1.96x10-3). The causal association was successfully replicated in the replication sample (b=-7.34x10-3, P =2.77x10-2). Our findings provided evidence of causal relationship from microbiota to fat development, and may be helpful in selecting potential causal bacteria for manipulating candidate gut microbiota to therapy obesity. IMPORTANCEObesity, as a global public health problem, is one of the most important risk factors contributing to the overall global burden of disease, and is associated with an increased risk of cardiovascular disease, type 2 diabetes, and certain cancers. Recent studies have shown that gut microbiota is closely related to the development of obesity, but the causal relationship is unclear. Therefore, it is necessary to identify the causality between gut microbiota and obesity. The significance of our research is in identifying the causal relationship from specific bacteria to fat development, which will provide the new insights into the microbiota mediated the fat development mechanism.

genomics↗

bioRxiv2020

Reconstruction of Bone Defect Based on the Fusion of Osteoblasts and MSM/HA/PLGA Porous Scaffolds

Reconstruction of bone defect is one of the difficult problems in orthopedic treatment, and bone tissue scaffold implantation is the most promising direction of bone defect reconstruction. In this study, we used the combination of HA (Hydroxyapatite) and PLGA [Poly (lactic-co-glycolic acid)] in the construction of polymer scaffolds, and introduced bioactive MSM (Methyl sulfonyl methane) into polymer scaffolds to prepare porous scaffolds. The osteoblasts, isolated and cultured in vitro, were seeded in the porous scaffolds to construct tissue-engineered scaffolds. Meanwhile, the model of rabbit radius defect was constructed to evaluate the biological aspects of five tissue-engineered scaffolds, which provided experimental basis for the application of the porous scaffolds in bone tissue engineering. The SEM characterization showed the pore size of porous scaffolds was uniform and the porosity was about 90%. The results of contact Angle testing suggested that the hydrophobic porous scaffold surface could effectively promote cell adhesion and cell proliferation, while mechanical property test showed good machinability. The results of drug loading and release efficiency of MSM showed that porous scaffolds could load MSM efficiently and prolong the release time of MSM. In vitro incubation of porous scaffolds and osteoblasts showed that the addition of a small quantity of MSM could promote the infiltration and proliferation of osteoblasts on the porous scaffolds. Similar results were obtained by implanting the tissue-engineered scaffolds, fused with the osteoblasts and MSM/HA/PLGA porous scaffolds, into the rabbit radius defect, which provided experimental basis for the application of the MSM/HA/PLGA porous scaffolds in bone tissue engineering.

bioengineering↗

bioRxiv2020

Senescent stromal cells promote cancer resistance through SIRT1 loss-potentiated overproduction of small extracellular vesicles

Cellular senescence is a potent tumor-suppressive program that prevents neoplastic events. Paradoxically, senescent cells develop an inflammatory secretome, termed the senescence-associated secretory phenotype (SASP) and implicated in age-related pathologies including cancer. Here we report that senescent cells actively synthesize and release small extracellular vesicles (sEVs) with a distinctive size distribution. Mechanistically, SIRT1 loss supports accelerated sEV production despite enhanced proteome-wide ubiquitination, a process correlated with ATP6V1A downregulation and defective lysosomal acidification. Once released, senescent stromal sEVs significantly alter the expression profile of recipient cancer cells and enhance their aggressiveness, specifically drug resistance mediated by expression of ATP binding cassette subfamily B member 4 (ABCB4). Targeting SIRT1 with an agonist SRT2104 prevents development of cancer resistance through restraining sEV production by senescent stromal cells. In clinical oncology, sEVs in peripheral blood of posttreatment cancer patients are readily detectable by routine biotechniques, presenting a novel biomarker to monitor therapeutic efficacy and to predict long term outcome. Together, our study identifies a distinct mechanism supporting pathological activities of senescent cells, and provides a novel avenue to circumvent advanced human malignancies by co-targeting cancer cells and their surrounding microenvironment, which contributes to drug resistance via secretion of sEVs from senescent stromal cells.

cell biology↗

bioRxiv2020

Blunted Diurnal Firing in Lateral Habenula Projections to Dorsal Raphe Nucleus and Delayed Photoentrainment in Stress-Susceptible Mice.

Daily rhythms are disrupted in patients suffering from mood disorders. The lateral habenula (LHb) and dorsal raphe nucleus (DRN) contribute to circadian timekeeping and regulate mood. Thus, pathophysiology in these nuclei may be responsible for aberrations in daily rhythms during mood disorders. Using the chronic social defeat stress (CSDS) paradigm and in-vitro slice electrophysiology we measured the effects of stress on diurnal rhythms in firing of LHb cells projecting to the DRN (cellsLHb[->]DRN) and DRN cells alone. We also performed optogenetic experiments to investigate if increased firing in cellsLHb[->]DRN during exposure to subthreshold social defeat stress (SSDS), induces stress-susceptibility. Last we investigated whether exposure to CSDS affected the ability of mice to phototentrain to a new LD cycle. The cellsLHb[->]DRN and DRN cells alone of stress-susceptible mice express greater blunted diurnal firing compared to stress-naive (control) and stress-resilient mice. Day-time optogenetic activation of cellsLHb[->]DRN during SSDS induces stress-susceptibility which shows the direct correlation between increased activity in this circuit and putative mood disorders. Finally, we found that stress-susceptible mice are slower, while stress-resilient mice are faster, at photoentraining to a new LD cycle. Our findings suggest that CSDS induces blunted daily rhythms in firing in cellsLHb[->]DRN and slow rate of photoentrainment in susceptible-mice. In contrast, resilientmice may undergo homeostatic adaptations that maintain daily rhythms in firing in cellsLHb[->]DRN and also show rapid photoentrainment to a new LD-cycle.

neuroscience↗

bioRxiv2020

Protein domain-based structural interfaces help interpret biologically-relevant interactions in the human interaction network.

A high-quality map of the human protein-protein interaction (PPI) network can help us better understand complex genotype-phenotype relationships. Each edge between two interacting proteins supported through an interface in a three-dimensional (3D) structure of a protein complex adds credibility to the biological relevance of the interaction. Such structure-supported interactions would augment an interaction map primarily built using high-throughput cell-based biophysical methods. Here, we integrate structural information with the human PPI network to build the structure-supported human interactome, a subnetwork of PPI between proteins that contain domains or regions known to form interfaces in the 3D structures of protein complexes. We expand the coverage of our structure-supported human interactome by using Pfam-based domain definitions, whereby we include homologous interactions if a human complex structure is unavailable. The structure-supported interactome predicts one-eighth of the total network PPI to interact through domain-domain interfaces. It identifies with higher resolution the interacting subunits in multi-protein complexes and enables us to characterize functional and disease-relevant neighborhoods in the network map with higher accuracy, allowing for structural insights into disease-associated genes and pathways. We expand the structural coverage beyond domain-domain interfaces by identifying the most common non-enzymatic peptide-binding domains with structural support. Adding these interactions between protein domains on one side and peptide regions on the other approximately doubles the number of structure-supported PPI. The human structure-supported interactome is a resource to prioritize investigations of smaller-scale context-specific experimental PPI neighborhoods of biological or clinical significance. Short abstractA high-quality map of the human protein-protein interaction (PPI) network can help us better understand genotype-phenotype relationships. Each edge between two interacting proteins supported through an interface in a three-dimensional structure of a protein complex adds credibility to the biological relevance of the interaction aiding experimental prioritization. Here, we integrate structural information with the human interactome to build the structure-supported human interactome, a subnetwork of PPI between proteins that contain domains or regions known to form interfaces in the structures of protein complexes. The structure-supported interactome predicts one-eighth of the total PPI to interact through domain-domain interfaces. It identifies with higher resolution the interacting subunits in multi-protein complexes and enables us to structurally characterize functional, disease-relevant network neighborhoods. We also expand the structural coverage by identifying PPI between non-enzymatic peptide-binding domains on one side and peptide regions on the other, thereby doubling the number of structure-supported PPI.

systems biology↗

bioRxiv2020

Role of RgsA in oxidative stress resistance in Pseudomonas aeruginosa

Pseudomonas aeruginosa is an extremely common opportunistic pathogen in clinical practice. Patients with metabolic disorders, hematologic diseases, malignancies, who have undergone surgery or who have received certain treatments are susceptible to this bacterium. In addition, P. aeruginosa is a multidrug-resistant that tends to form biofilms and is refractory to treatment. Small regulatory RNAs are RNA molecules that are 40-500 nucleotides long, possess regulatory function, are ubiquitous in bacteria, and are also known as small RNA (sRNA). sRNAs play important regulatory roles in various vital life processes in diverse bacteria and their quantity and diversity of regulatory functions exceeds that of proteins. In this study, we showed that deletion of the sRNA RgsA decreases the growth rate and ability to resist different concentrations and durations of peroxide in P. aeruginosa. These decreases occur not only in the planktonic state, but also in the biofilm state. Finally, protein mass spectrometry was employed to understand changes in the entire protein spectrum. The results presented herein provide a description of the role of RgsA in the life activities of P. aeruginosa at the molecular, phenotypic, and protein levels.

microbiology↗

bioRxiv2020

Enteric glia as a source of neural progenitors in adult zebrafish

The presence and identity of neural progenitors in the enteric nervous system (ENS) of vertebrates is a matter of intense debate. Here we demonstrate that the non-neuronal ENS cell compartment of teleosts shares molecular and morphological characteristics with mammalian enteric glia but cannot be identified by the expression of canonical glia markers. However, unlike their mammalian counterparts, which are generally quiescent and do not undergo neuronal differentiation during homeostasis, we show that a relatively high proportion of zebrafish enteric glia proliferate under physiological conditions giving rise to progeny that differentiate into enteric neurons. We also provide evidence that, similar to brain neural stem cells, the activation and neuronal differentiation of enteric glia are regulated by Notch signalling. Our experiments reveal remarkable similarities between enteric glia and brain neural stem cells in teleosts and open new possibilities for use of mammalian enteric glia as a potential source of neurons to restore the activity of intestinal neural circuits compromised by injury or disease.

neuroscience↗

bioRxiv2020

RIP1 kinase activity promotes steatohepatitis through mediating cell death and inflammation in macrophages

Hepatocyte cell death and liver inflammation have been well recognized as central characteristics of nonalcoholic steatohepatitis (NASH), however, the underlying molecular basis remains elusive. The kinase receptor-interacting protein 1 (RIP1) is a key regulator of apoptosis, necroptosis and inflammation, we thus hypothesized that the kinase activity of RIP1 may be involved in the pathogenesis of NASH. Wild-type and RIP1 kinase-dead (Rip1K45A/K45A) mice were fed with methionine-and choline-deficient diet (MCD) or high-fat diet (HFD) to establish distinct NASH models. In both models, compared to WT mice, Rip1K45A/K45A mice exhibited significantly less liver injury, less steatosis, decreased inflammation, and less cell death in liver tissue. Moreover, hepatic fibrosis as characterized by Sirius Red staining, expression of -SMA and other fibrosis markers, were significantly alleviated in Rip1K45A/K45A mice than WT controls. Furthermore, using bone marrow transplantation to create chimeric mice, we found that it is the RIP1 kinase in hematopoietic-derived macrophages contributing mostly to the disease progression in NASH. Results from in vitro studies were in agreement with the in vivo data, demonstrating that RIP1 kinase was required for inflammasome activation and cell death induced by saturated fatty acid (palmitic acid) in bone marrow-derived macrophages (BMDMs). At last, we also found that the phosphorylation and expression of RIP1 was obviously increased in patients with NAFLD or NASH, but not in healthy controls. In summary, our results indicate that RIP1 kinase is activated during the pathogenesis of steatohepatitis, and consequently induces inflammation and cell death in macrophages, contributing to the disease progression. Our study suggests that macrophage RIP1 kinase represents a specific and potential target for the treatment of NASH.

immunology↗

bioRxiv2019

The Ocular Glymphatic Clearance System

Despite high metabolic activity, the retina and optic nerve head lack traditional lymphatic drainage. We here identified a novel ocular glymphatic clearance route for fluid and wastes via the proximal optic nerve. Amyloid-{beta} (A{beta}) was cleared from the vitreous via a pathway driven by the ocular-cranial pressure difference. After traversing the lamina barrier, intra-axonal A{beta} was cleared via the perivenous space and subsequently drained to lymphatic vessels. Light-induced pupil constriction enhanced, while atropine or raising intracranial pressure blocked efflux. In two distinct murine models of glaucoma, A{beta} leaked from the eye via defects in the lamina barrier instead of directional axonal efflux. The discovery of a novel pathway for removal of fluid and metabolites from the intraocular space prompts a reevaluation of the core principles governing eye physiology and provides a framework for new therapeutic approaches to treat common eye diseases, including glaucoma. One Sentence SummaryGlymphatic pathway clears ocular amyloid-{beta} via optic nerve and fails in glaucoma.

physiology↗

bioRxiv2019

Role of SHIP2 in cell repulsion regulated by Eph receptor and ephrin signaling

Previous studies have found that activation of EphB2 and ephrinB1 that drives cell segregation leads to phosphorylation of the phosphoinositide phosphatase SHIP2 downstream of forward (EphB2) but not reverse (ephrinB1) signaling. We have analysed whether SHIP2 interacts with EphB2 and contributes to cell responses to EphB2-ephrinB1 signaling. We confirm that EphB2 activation leads to SHIP2 phosphorylation on Y1135 and find that they interact through the SH2 domain of SHIP2. There is thus a distinct mode of interaction from EphA2, which binds SHIP2 via its SAM domain. Knockdown of SHIP2 in EphB2 cells leads to decreased segregation from ephrinB1 cells, and a decrease in the repulsion response of EphB2 cells. SHIP2 knockdown in ephrinB1 cells also decreases their repulsion response, but does not disrupt segregation which is largely driven by forward signaling. These findings show that activation of EphB2 leads to recruitment and phosphorylation of SHIP2, and that SHIP2 contributes to cell repulsion responses that underlie cell segregation.

cell biology↗

bioRxiv2019

Nova proteins direct synaptic integration of somatostatin interneurons through activity-dependent alternative splicing

Somatostatin interneurons are the earliest born population of cortical inhibitory cells. They are crucial to support normal brain development and function; however, the mechanisms underlying their integration into nascent cortical circuitry are not well understood. In this study, we begin by demonstrating that the maturation of somatostatin interneurons is activity dependent. We then investigated the relationship between activity, alternative splicing and synapse formation within this population. Specifically, we discovered that the Nova family of RNA-binding proteins are activity-dependent and are essential for the maturation of somatostatin interneurons, as well as their afferent and efferent connectivity. Within this population, Nova2 preferentially mediates the alternative splicing of genes required for axonal formation and synaptic function independently from its effect on gene expression. Hence, our work demonstrates that the Nova family of proteins through alternative splicing are centrally involved in coupling developmental neuronal activity to cortical circuit formation.

neuroscience↗

bioRxiv2019

Viral manipulation of functionally distinct neurons from mice to humans

Recent success in identifying gene regulatory elements in the context of recombinant adeno-associated virus vectors have enabled cell type-restricted gene expression. However, within the cerebral cortex these tools are presently limited to broad classes of neurons. To overcome this limitation, we developed a strategy that led to the identification of multiple novel enhancers to target functionally distinct neuronal subtypes. By investigating the regulatory landscape of the disease gene Scn1a, we identified enhancers that target the breadth of its expression, including two that are selective for parvalbumin and vasoactive intestinal peptide cortical interneurons. Demonstrating the functional utility of these elements, we found that the PV-specific enhancer allowed for the selective targeting and manipulation of these neurons across species, from mice to humans. Finally, we demonstrate that our selection method is generalizable to other genes and characterize four additional PV-specific enhancers with exquisite specificity for distinct regions of the brain. Altogether, these viral tools can be used for cell-type specific circuit manipulation and hold considerable promise for use in therapeutic interventions.

neuroscience↗

bioRxiv2019

DLO Hi-C Tool for Digestion-Ligation-Only Hi-C Chromosome Conformation Capture Data Analysis

BackgroundIt is becoming increasingly important to understand the mechanism of regulatory elements on target genes in long-range genomic distance. 3C (Chromosome Conformation Capture) and its derived methods are now widely applied to investigate genome organizations and gene regulation. Digestion-Ligation-Only Hi-C (DLO Hi-C) is a new technology with high efficiency and effective cost for whole-genome chromosome conformation capture.\n\nResultsHere, we introduce DLO Hi-C Tool, a flexible and versatile pipeline for processing DLO Hi-C data from raw sequencing reads to normalized contact maps and providing quality controls for different steps. It includes more efficient iterative mapping and linker filtering. We applied DLO Hi-C Tool to different DLO Hi-C datasets, and demonstrated its ability of processing large data in multi-threading.\n\nConclusionsDLO Hi-C Tool is suitable for processing DLO Hi-C and in situ DLO Hi-C datasets. It is convenient and efficient for DLO Hi-C data processing.

bioinformatics↗

bioRxiv2019

Individualized ctDNA Fingerprints to Monitor Treatment Response and Recurrence in Multiple Cancer Types

Circulating tumor DNA (ctDNA) panels hold high promise of accurately predicting the therapeutic response of tumors while being minimally invasive and cost-efficient. However, their use has been limited to a small number of tumor types and patients. Here, we developed individualized ctDNA fingerprints suitable for most patients with multiple cancer types. The panels were designed based on individual whole-exome sequencing data in 521 Chinese patients and targeting high clonal population clusters of somatic mutations. Together, these patients represent 12 types of cancers and seven different treatments. The customized ctDNA panels have a median somatic mutation number of 19, most of which are patient-specific rather than cancer hotspot mutations; 66.8% of the patients were ctDNA-positive. We further evaluated the ctDNA content fraction (CCF) of the mutations, and analyzed the association between the change of ctDNA concentration and therapeutic response. We followed up 106 patients for clinical evaluation, demonstrating a significant correlation of changes in ctDNA with clinical outcomes, with a consistency rate of 93.4%. In particular, the median CCF increased by 204.6% in patients with progressive disease, decreased by 82.5% in patients with remission, and was relatively stable in patients with stable disease. Overall, 85% of the patients with a ctDNA-positive status experienced metastasis or relapse long before imaging detection, except for two patients who developed recurrence and metastasis almost simultaneously. The average lead time between the first ctDNA-positive finding and radiological diagnosis was 76 days in three patients that changed from a ctDNA-negative to -positive status. Our individualized ctDNA analysis can effectively monitor the treatment response, metastasis, and recurrence in multiple cancer types in patients with multiple treatment options, therefore offering great clinical applicability for improving personalized treatment in cancer.\n\nOne Sentence SummaryctDNA fingerprint panels were customized to predict the treatment response for multiple cancer types from individual whole-exome sequencing data.

cancer biology↗

bioRxiv2019

Genetic and molecular mechanism for distinct clinical phenotypes conveyed by allelic truncating mutations implicated in FBN1

The molecular and genetic mechanisms by which different single nucleotide variant (SNV) alleles in specific genes, or at the same genetic locus, bring about distinct disease phenotypes often remain unclear. Allelic truncating mutations of fibrillin-1(FBN1) cause either classical Marfan syndrome (MFS) or a more severe phenotype associated with Marfanoid-progeroid-lipodystrophy syndrome (MPLS). A total of three Marfan syndrome/Marfanoid patients (2 singletons and 1 parent-offspring trio) were recruited. Targeted next-generation sequencing was performed on all the participants. We analyzed the molecular diagnosis, patient clinical features, and the potential molecular mechanism involved in the MPLS subject in our cohort. We investigated a small cohort, consisting of two classical MFS and one MPLS patient from China, whose clinical presentation included scoliosis potentially requiring surgical intervention. We provide evidence that most nonsense and frameshift mutations lead to FBN1 null alleles due to mutant mRNA transcript degradation. In contrast, the more severe disease phenotype, MPLS, is caused by mutant mRNAs that are predicted to escape the nonsense mediated decay (NMD) surveillance pathway, making a mutant protein that exerts a dominant negative interference effect to FBN1 thus generating a gain-of-function (GoF) rather than a loss-of-function (LoF) allele as in MFS. Overall, we provide direct evidence that a dominant negative interaction of FBN1 potentially explains the distinct clinical phenotype in MPLS patients through genetic and functional analysis of the first Chinese patient with MPLS. Moreover, our study expands the mutation spectrum of FBN1 and highlights the potential molecular mechanism for MPLS patients.

genetics↗

bioRxiv2019

Actomyosin regulation by Eph receptor signaling couples boundary cell formation to border sharpness

The segregation of cells with distinct regional identity underlies formation of a sharp border, which in some tissues serves to organise a boundary signaling centre. It is unclear whether or how border sharpness is coordinated with induction of boundary-specific gene expression. We show that forward signaling of EphA4 is required for border sharpening and induction of boundary cells in the zebrafish hindbrain, which we find both require kinase-dependent signaling, with a lesser input of PDZ domain-dependent signaling. We find that boundary-specific gene expression is regulated by myosin II phosphorylation, which increases actomyosin contraction downstream of EphA4 signaling. Myosin phosphorylation leads to nuclear translocation of Taz, which together with Tead1a is required for boundary marker expression. Since actomyosin contraction maintains sharp borders, there is direct coupling of border sharpness to boundary cell induction that ensures correct organisation of signaling centres.

developmental biology↗

bioRxiv2019

Removal of early senescent cells protects retinal ganglion cells loss in experimental ocular hypertension.

Experimental ocular hypertension induces senescence of retinal ganglion cells (RGCs) that mimicks events occurring in human glaucoma. Senescence-related chromatin remodeling leads to profound transcriptional changes including the upregulation of a subset of genes that encode multiple proteins collectively referred to as the senescence-associated secretory phenotype (SASP). Emerging evidence suggests that the presence of these proinflammatory and matrix-degrading molecules has deleterious effects in a variety of tissues. In the current study, we demonstrated in a transgenic mouse model that early removal of senescent cells induced upon elevated intraocular pressure (IOP) protects unaffected RGCs from senescence and apoptosis. Visual evoked potential (VEP) analysis demonstrated that remaining RGCs are functional and that the treatment protected visual functions. Finally, removal of endogenous senescent retinal cells after IOP elevation by a treatment with senolytic drug dasatinib prevented loss of retinal functions and cellular structure. Senolytic drugs may have the potential to mitigate the deleterious impact of elevated IOP on RGC survival in glaucoma and other optic neuropathies.

molecular biology↗

bioRxiv2019

A chromosome-level assembly of the Atlantic herring - detection of a supergene and other signals of selection

The Atlantic herring is a model species for exploring the genetic basis for ecological adaptation, due to its huge population size and extremely low genetic differentiation at selectively neutral loci. However, such studies have so far been hampered because of a highly fragmented genome assembly. Here, we deliver a chromosome-level genome assembly based on a hybrid approach combining a de novo PacBio assembly with Hi-C-supported scaffolding. The assembly comprises 26 autosomes with sizes ranging from 12.4 to 33.1 Mb and a total size, in chromosomes, of 726 Mb. The development of a high-resolution linkage map confirmed the global chromosome organization and the linear order of genomic segments along the chromosomes. A comparison between the herring genome assembly with other high-quality assemblies from bony fishes revealed few interchromosomal but frequent intrachromosomal rearrangements. The improved assembly makes the analysis of previously intractable large-scale structural variation more feasible; allowing, for example, the detection of a 7.8 Mb inversion on chromosome 12 underlying ecological adaptation. This supergene shows strong genetic differentiation between populations from the northern and southern parts of the species distribution. The chromosome-based assembly also markedly improves the interpretation of previously detected signals of selection, allowing us to reveal hundreds of independent loci associated with ecological adaptation in the Atlantic herring.

genomics↗