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Zhang, B.

Publications and source records attributed to Zhang, B..

At least 631 records · Page 35Linked to original sources
bioRxiv2019

Electrospun Ag-doped SnO2 hollow nanofibers with high antibacterial activity

With the continuous improvement in medical science in modern times, the spread of bacterial infection has become a matter of global concern. Therefore, the search for biological medical materials with antibacterial function has become a focus of intense research. In this work, pure SnO2 and Ag-doped SnO2 hollow nanofibers were fabricated by a combination of an electrospinning method and a calcination procedure, and the effects of the doped Ag on antibacterial activity were subsequently investigated. Through the process of high-temperature calcination, a high heating rate would lead to the formation of a hollow tubular structure in SnO2 fibers, and Ag2O would be reduced to Ag0 by a facile process with appropriate thermal treatment. Additionally, the existence of SnO2 as a tetragonal rutile structure was confirmed. On the basis of pure SnO2, doping with silver greatly improved the antibacterial activity of hollow nanofibers. The formation mechanism and the antibacterial mechanism of pure SnO2 and Ag-doped hollow nanofibers are also discussed. This study has broad application prospects for biological medicine.

biochemistry↗
bioRxiv2019

pathwayPCA: an R package for integrative pathway analysis with modern PCA methodology and gene selection

With the advance in high-throughput technology for molecular assays, multi-omics datasets have become increasingly available. However, most currently available pathway analysis software provide little or no functionalities for analyzing multiple types of -omics data simultaneously. In addition, most tools do not provide sample-specific estimates of pathway activities, which are important for precision medicine. To address these challenges, we present pathwayPCA, a unique R package for integrative pathway analysis that utilizes modern statistical methodology including supervised PCA and adaptive elastic-net PCA for principal component analysis. pathwayPCA can analyze continuous, binary, and survival outcomes in studies with multiple covariate and/or interaction effects. We provide three case studies to illustrate pathway analysis with gene selection, integrative analysis of multi-omics datasets to identify driver genes, estimating and visualizing sample-specific pathway activities in ovarian cancer, and identifying sex-specific pathway effects in kidney cancer. pathwayPCA is an open source R package, freely available to the research community. We expect pathwayPCA to be a useful tool for empowering the wide scientific community on the analyses and interpretation of the wealth of multiomics data recently made available by TCGA, CPTAC and other large consortiums.

bioinformatics↗
bioRxiv2019

The gut microbiota regulates mouse biliary regenerative responses

Injury to the biliary epithelium triggers cholangiopathies. However, factors involved in regulating the pathogenesis remains incompletely understood. Here, we report that the gut microbiota is important in regulating hepatobiliary fibroproliferative regenerative process. In helminth Clonorchis sinensis-induced bile duct injury model, wild-type mice showed more extensive peribiliary fibroproliferative responses than non-littermate IL-33-deficient mice. However, these reactions could be attenuated by co-housing of the animals together. In the meantime, the relatively fibroproliferative-resistant IL-33-deficient mice could become fibroproliferative-responsive especially in large intrahepatic bile duct by antibiotics treatment. Furthermore, microbiota-derived metabolite butyrate was able to inhibit biliary organoid expansion in vitro and temper 3,5-diethoxycarbonyl-1,4-dihydrocollidine-induced biliary fibrosis in vivo. Together, our data implies a potential way of management of hepatobiliary diseases by modulating gut microbiota.

microbiology↗
bioRxiv2019

Fenoxaprop-p-ethyl susceptibility and mutation point detection of acetyl-coa carboxylase (ACCase) in different wild oat (Avena fatua L.) populations from China

To explore resistant mechanism of wild oat to fenoxaprop-p-ethyl, the susceptibility of Acetyl-CoA Carboxylase (ACCase) from 24 wild oat populations to fenoxaprop-p-ethyl, the level of gene expression, and mutation site of ACCase were conducted. In vitro ACCase activities were solated and measured by enzyme-linked immunosorbent assay kit (ELISA) assays, the results indicated that the IC50 value of the ACCase of the most unsusceptible to fenoxaprop-p-ethyl in the wild oat population from Yexian2017 (W24) was 7206.557-fold compared to that of the ACCase of most susceptible to fenoxaprop-p-ethyl in the wild oat population from Queshan (W11). The differential expression of genes in wild oat treated by the IC50 fenoxaprop-p-ethyl concentration (6.9 mg/L) for 24 hours using RNA-seq, digital gene expression (DGE) profling was conducted. We found that 8 unigenes annotated as ACCase genes, 0 up-regulaed expression and 3 down-regulated expression were observed. The down-regulaed expressed ACCase was selected for qPCR in the relative susceptible population were significantly more suppressed than the three relative resistant populations. The mutations point of ACCase, Ile-1781-Leu, Trp-1999-Cys, Trp-2027-Cys, Ile-2041-Asn, Asp-2078-Gly, Cys-2088-Arg published were not found in the populations tested by multiple sequence alignment with a model complete ACCase sequence of Alopecurus myosuroides. These findings suggest that ACCase plays a critical role in the development of wild oat resistance to fenoxaprop-p-ethyl.

molecular biology↗
bioRxiv2019

Gut microbiota influence B cell function in a TLR5-dependent manner

Toll-like receptor (TLR) 5-deficient mice display aberrantly low levels of flagellin-specific antibodies (Flic-IgA) secreted into the gut, combined with excess bacterial flagellin in the gut, and together these attributes define microbiome dysbiosis (T5-dysbiosis). How TLR5 signaling deficiency results in T5-dysbiosis is unclear. Here, we address the role of B cells in T-dysbiosis. We observed that B cells do not express TLR5, and that B cell transplantation from TLR5-/- mouse donors into B-cell deficient mice resulted in a slight reduction in Flic-IgA levels compared to B-cells from WT donors. Bone marrow transplants from WT and TLR5-/- donors into recipients of both genotypes confirmed that TLR5 signaling by non-hematopoietic cells is required for T5-dysbiosis. We observed TLR5 deficiency was associated with an expanded population of IgA+ B cells. TLR5-/- mice tended to have higher richness for the IgA gene hypervariable region (CDR3 gene) variants. Transplantation of microbiomes from TLR5-/- and WT microbiomes donors into germfree mice resulted in a higher proportion of IgA-secreting B cells, and higher overall fecal IgA and anti-Flic IgA for TLR5-/- microbiome recipients. This observation indicated that the TLR5-/- mouse microbiome elicits an anti-flagellin antibody response that requires TLR5 signaling. Together these results indicate that TLR5 signaling on epithelial cells influences B cell populations and antibody repertoire.

immunology↗
bioRxiv2019

O-GlcNAc transferase suppresses necroptosis and liver fibrosis

Over a billion people suffer from chronic liver diseases worldwide, which often leads to fibrosis and then cirrhosis. Treatments for fibrosis remain experimental, in part because no unifying mechanism has been identified that initiates liver fibrosis. Here we report that O-linked {beta}-N-acetylglucosamine (O-GlcNAc) modification protects against hepatocyte necroptosis and initiation of liver fibrosis. Decreased O-GlcNAc levels were seen in patients with liver cirrhosis and in mice with ethanol-induced liver injury. Liver-specific O-GlcNAc transferase (OGT) knockout (OGT-LKO) mice exhibited ballooning degeneration and elevated circulating alanine aminotransferase (ALT) levels at an early age and progressed to liver fibrosis and portal inflammation by 10 weeks of age. OGT-deficient hepatocytes underwent excessive necroptosis and exhibited elevated protein expression levels of receptor-interacting protein kinase 3 (RIPK3) and mixed lineage kinase domain-like (MLKL), which are key mediators of necroptosis. Furthermore, glycosylation of RIPK3 by OGT reduced RIPK3 protein stability. Taken together, these findings identify OGT as a key suppressor of hepatocyte necroptosis and OGT-LKO mice may serve as an effective spontaneous genetic model of liver fibrosis.

physiology↗
bioRxiv2019

Low-dose IFN-γ induces tumor cell stemness in tumor microenvironment of non-small cell lung cancer

Interferon-{gamma} (IFN-{gamma}) is conventionally recognized as an inflammatory cytokine that play a central role in antitumor immunity. Clinically, although has been used clinically to treat a variety of malignancies, low-level IFN-{gamma} in the tumor microenvironment (TME) increases the risk of tumor metastasis during immunotherapy. Accumulating evidence has suggested that IFN-{gamma} can induce cancer progression. The mechanisms underlying the controversial role of IFN-{gamma} regulating tumor development remain unclear. Herein, we firstly revealed a dose-dependent effect of IFN-{gamma} in inducing tumor stemness to accelerate cancer progression in patients with a variety of cancer types. Mechanically, low-level IFN-{gamma} endowed cancer stem-like properties via the intercellular adhesion molecule-1 (ICAM1)-PI3K-Akt-Notch1 axis, whereas high-level IFN-{gamma} activated the JAK1-STAT1-caspase pathway to induce apoptosis in non-small cell lung cancer (NSCLC). Inhibition of ICAM1 abrogated the stem-like properties of NSCLC cells induced by the low dose of IFN-{gamma} both in vitro and in vivo. Our study first defines the role of low-level IFN-{gamma} in conferring tumor stemness and clearly elucidate the distinct signaling pathways activated by IFN-{gamma} in a dose-dependent manner, providing new insights into cancer treatment, particularly patients with low-level IFN-{gamma} expression in the TME.

cancer biology↗
bioRxiv2019

Genetic dissection of femoral and tibial microarchitecture

Our understanding of the genetic control of bone has relied almost exclusively on estimates of bone mineral density. In contrast, here we have used high-resolution x-ray tomography (8 m isotropic voxels) to measure femoral and tibial components across a set of ~600 mice belonging to 60 diverse BXD strains of mice. We computed heritabilities of 25 cortical and trabecular compartments. Males and females have well matched trait heritabilities, ranging from 0.25 to 0.75. We mapped 16 QTLs that collectively cover ~8% of all protein-coding genes in mouse. A majority of loci are detected only in females, and there is also a bias in favor of QTLs for cortical traits. To efficiently evaluate candidate genes we developed a method that couples gene ontologies with expression data to compute bone-enrichment scores for almost all protein-coding genes. We carefully collated and aligned murine candidates with recent human BMD genome-wide association results. We highlight a subset of 50 strong candidates that fall into three categories: 1. those linked to bone function that have already been experimentally validated (Adamts4, Ddr2, Darc, Adam12, Fkbp10, E2f6, Adam17, Grem2, Ifi204); 2. candidates with putative bone function but not yet tested (e.g., Greb1, Ifi202b) but several of which have been linked to phenotypes in humans; and 3. candidates that have high bone-enrichment scores but for which there is not yet any specific link to bone biology or skeletal disease, including Ifi202b, Ly9, Ifi205, Mgmt, F2rl1, Iqgap2. Our results highlight contrasting genetic architecture between the sexes and among major bone compartments. The joint use and alignment of murine and human data should greatly facilitate function analysis and preclinical testing.\n\nDisclosureThe authors declare that no competing interests exist.

genetics↗
bioRxiv2019

Meta-analysis of the human brain transcriptome identifies heterogeneity across human AD coexpression modules robust to sample collection and methodological approach

Alzheimers disease (AD) is a complex and heterogenous brain disease that affects multiple inter-related biological processes. This complexity contributes, in part, to existing difficulties in the identification of successful disease-modifying therapeutic strategies. To address this, systems approaches are being used to characterize AD-related disruption in molecular state. To evaluate the consistency across these molecular models, a consensus atlas of the human brain transcriptome was developed through coexpression meta-analysis across the AMP-AD consortium. Consensus analysis was performed across five coexpression methods used to analyze RNA-seq data collected from 2114 samples across 7 brain regions and 3 research studies. From this analysis, five consensus clusters were identified that described the major sources of AD-related alterations in transcriptional state that were consistent across studies, methods, and samples. AD genetic associations, previously studied AD-related biological processes, and AD targets under active investigation were enriched in only three of these five clusters. The remaining two clusters demonstrated strong heterogeneity between males and females in AD-related expression that was consistently observed across studies. AD transcriptional modules identified by systems analysis of individual AMP-AD teams were all represented in one of these five consensus clusters except ROS/MAP-identified Module 109, which was specific for genes that showed the strongest association with changes in AD-related gene expression across consensus clusters. The other two AMP-AD transcriptional analyses reported modules that were enriched in one of the two sex-specific Consensus Clusters. The fifth cluster has not been previously identified and was enriched for genes related to proteostasis. This study provides an atlas to map across biological inquiries of AD with the goal of supporting an expansion in AD target discovery efforts.

systems biology↗
bioRxiv2018

Decreased metabolism and increased tolerability to extreme environment in Staphylococcus warneri with long-term space flight

BackgroundMany studies have shown that space environment can affect bacteria to cause a range of mutations. However, so far, there are less studies on the effects of long-term space flight (>1 month) on bacteria. In this study, a Staphylococcus warneri strain, which was isolated from the Shenzhou-10 spacecraft that had experienced a space flight (15-day), was carried into space again. After 64-day flight, the combined phenotypic, genomic, transcriptomic and proteomic analyses were performed to compare the influence of the two space flights on this bacteria.\n\nResultsCompared with short-term space flight, long-term space flight increased the biofilm formation ability of S. warneri and the cell wall resistance to external environment stress, but reduced the sensitivity to chemical stimulation. Further analysis showed that these changes might be related to the significantly up-regulated gene expression of phosphotransferase system, which regulated glucose metabolism pathway, including glucose, mannose, fructose and cellobiose. The mutation of S. warneri caused by 15-day space flight was limited at phenotype and gene level after ground culture.\n\nConclusionAfter a 79-day space flight, the changes of S. warneri are meaningful. Phosphotransferase system of S. warneri was up-regulated by long-term space stimulation, which resulted in a series of changes in cell wall, biofilm and chemical sensitivity, thus enhancing the resistance and adaptability of bacteria to the external environment.\n\nImportanceTaking S. warneri as an example, we found that the mutation of bacteria in long-term space flight mainly focused on the adaptation and tolerance like environmental adaptation, physical resistance and cell repair to various pressures and these changes should be more obvious or even become stable mutations. But the clinical changes, for example drug resistance and virulence should not be significant because there is no threat of antibiotics.

microbiology↗
bioRxiv2018

Critical Role of Histone Tail Entropy in Nucleosome Unwinding

The nucleosome is the fundamental packaging unit for the genome. It must both remain tightly wound to ensure genome stability while simultaneously being flexible enough to keep the DNA molecule accessible for genome function. The set of physicochemical interactions responsible for the delicate balance between these naturally opposed processes have not been determined due to challenges in resolving partially unwound nucleosome configurations at atomic resolution. Using a near atomistic protein-DNA model and advanced sampling techniques, we calculate the free energy cost of nucleosome DNA unwinding. Our simulations identify a large energetic barrier that decouples the outer and inner DNA unwinding into two separate processes, occurring on different timescales. This dynamical decoupling allows the exposure of outer DNA at a modest cost to ensure accessibility while keeping the inner DNA and the histone core intact to maintain stability. We also reveal that this energetic barrier arises from a delayed loss of contacts between disordered histone tails and the DNA, and is, surprisingly, largely offset by an entropic contribution from these tails. Our study uncovers the balance of energetic and entropic contributions that dictate nucleosome stability, suggesting that tilting this balance may be a previously-unknown mechanism for regulating genome function.

biophysics↗
bioRxiv2018

Cell-to-cell variation in defective virus expression and effects on host responses during influenza virus infection

Virus and host factors contribute to cell-to-cell variation in viral infections and determine the outcome of the overall infection. However, the extent of the variability at the single cell level and how it impacts virus-host interactions at a systems level are not well understood. To characterize the dynamics of viral transcription and host responses, we used single-cell RNA sequencing to quantify at multiple time points the host and viral transcriptomes of human A549 cells and primary bronchial epithelial cells infected with influenza A virus. We observed substantial variability of viral transcription between cells, including the accumulation of defective viral genomes (DVGs) that impact viral replication. We show a correlation between DVGs and viral-induced variation of the host transcriptional program and an association between differential induction of innate immune response genes and attenuated viral transcription in subpopulations of cells. These observations at the single cell level improve our understanding of the complex virus-host interplay during influenza infection.\n\nIMPORTANCEDefective influenza virus particles generated during viral replication carry incomplete viral genomes and can interfere with the replication of competent viruses. These defective genomes are thought to modulate disease severity and pathogenicity of the influenza infection. Different defective viral genomes also introduce another source of variation across a heterogeneous cell population. Evaluating the impact of defective virus genomes on host cell responses cannot be fully resolved at the population level, requiring single cell transcriptional profiling. Here we characterized virus and host transcriptomes in individual influenza-infected cells, including that of defective viruses that arise during influenza A virus infection. We established an association between defective virus transcription and host responses and validated interfering and immunostimulatory functions of identified dominant defective virus genome species in vitro. This study demonstrates the intricate effects of defective viral genomes on host transcriptional responses and highlights the importance of capturing host-virus interactions at the single-cell level.

microbiology↗
bioRxiv2018

Genetic interactions among Ghd7, Ghd7.1, Ghd8 and Hd1 contribute to large variation in heading date in rice

Several major heading date genes are sensitive to photoperiod and jointly regulate heading date in rice. However, it is not clear how these genes coordinate rice heading. In this study, a near-isogenic F2 population with Ghd7, Ghd7.1, Ghd8 and Hd1 segregating in the Zhenshan 97 (ZS97) background was used to evaluate the genetic interactions among these four genes under natural long-day (NLD) and natural short-day (NSD) conditions, and a series of Ghd7.1-segregating populations in different backgrounds were developed to estimate the genetic effects of Ghd7.1 on heading date under both conditions. Tetragenic, trigenic and digenic interactions among these four genes were observed under both conditions. In the functional Hd1 backgrounds, the strongest digenic interaction was Ghd7 by Ghd8 under NLD conditions but was Ghd7 by Ghd7.1 under NSD conditions. Interestingly, Ghd7.1 acted as a flowering suppressor under NLD conditions, while it functioned alternatively as an activator or a suppressor under NSD conditions depending on the status of the other three genes. Based on the performances of 16 homozygous four-gene combinations, a positive correlation between heading date and yield was found under NSD conditions, but changed to a negative correlation when heading date was over 90 days under NLD conditions. These results demonstrate the importance of genetic interactions in the rice flowering regulatory network and will help breeders to select favorable combinations to maximize rice yield potential for different ecological areas.

genetics↗
bioRxiv2018

Multiscale causal network models of Alzheimer’s disease identify VGF as a key regulator of disease

Though discovered over 100 years ago, the molecular foundation of sporadic Alzheimers disease (AD) remains elusive. To elucidate its complex nature, we constructed multiscale causal network models on a large human AD multi-omics dataset, integrating clinical features of AD, DNA variation, and gene and protein expression into probabilistic causal models that enabled detection and prioritization of high-confidence key drivers of AD, including the top predicted key driver VGF. Overexpression of neuropeptide precursor VGF in 5xFAD mice partially rescued beta-amyloid-mediated memory impairment and neuropathology. Molecular validation of network predictions downstream of VGF was achieved, with significant enrichment for homologous genes identified as differentially expressed in 5xFAD brains overexpressing VGF versus controls. Our findings support a causal and/or protective role for VGF in AD pathogenesis and progression.\n\nOne sentence summaryVGF protects against Alzheimers disease

genomics↗
bioRxiv2018

Long Non-Coding RNA LncKdm2b Regulates Cortical Neuronal Differentiation by Cis-Activating Kdm2b

The mechanisms underlying spatial and temporal control of cortical neurogenesis of the brain are largely elusive. Long non-coding RNAs (lncRNAs) have emerged as essential cell fate regulators. Here we found LncKdm2b (also known as Kancr), a lncRNA divergently transcribed from a bidirectional promoter of Kdm2b, is transiently expressed during early differentiation of cortical projection neurons. Interestingly, Kdm2bs transcription is positively regulated in cis by LncKdm2b, which has intrinsic-activating function and facilitates a permissive chromatin environment at the Kdm2bs promoter by associating with hnRNPAB. Lineage tracing experiments and phenotypic analyses indicated LncKdm2b and Kdm2b are crucial in proper differentiation and migration of cortical projection neurons. Moreover, KDM2B exerts its role relying on its leucine-rich repeats (LRR) but independent of its PRC1-related function. These observations unveiled a lncRNA-dependent machinery in regulating cortical neuronal differentiation.

molecular biology↗
bioRxiv2018

Learning mechanism of chromatin domain formation with big data

Chromatin modifications play critical roles in gene regulation and encoding cell phenotypic diversity. The molecular mechanism for their establishment and maintenance is not fully understood due to the complexity of chromatin regulatory pathways. Here we took a data-driven approach and parameterized an information-theoretic model to infer mechanism of chromatin domain formation from genome-wide epigenetic modification profiles. The energy landscape of this model reveals many important chromatin domains that span multiple nucleosomes and exhibit distinct combinatorial patterns of histone modifications, including super (stretch) enhancers, broad H3K4me3 promoter domains, heterochromatin, etc. Transition path analysis further demonstrates that enhancer and promoter domains undergo a sequential maturation process along which the regulatory elements grow from short but stable nucleosome segments to long and potent ones that are modified with many activation marks. On the other hand, the formation of heterochromatin domains is a highly cooperative process, and no intermediate states were found along the transition path. Interaction energies of the information-theoretic model further suggest that heterochromatin domains adopt collapsed, globular three-dimensional conformations that can be stabilized by phase-separated liquid droplets.Our results demonstrate the usefulness of statistical mechanical models and molecular biophysical approaches in interpreting the rich information encoded in epigenomics data.

biophysics↗
bioRxiv2018

Probability cueing of singleton-distractor locations in visual search: priority-map- or dimension-based inhibition?

Observers can learn the likely locations of salient distractors in visual search, reducing their potential to capture attention (Ferrante et al., 2018; Sauter et al., 2018a; Wang & Theeuwes, 2018a). While there is agreement that this involves positional suppression of the likely distractor location(s), it is contentious at which stage of search guidance the suppression operates: the supra-dimensional priority map or feature-contrast signals within the distractor dimension. On the latter account, advocated by Sauter et al., target processing should be unaffected by distractor suppression when the target is defined in a different (non-suppressed) dimension to the target. At odds with this, Wang and Theeuwes found strong suppression not only of the (color) distractor, but also of the (shape) target when it appeared at the likely distractor location. Adopting their paradigm, the present study ruled out that increased cross-trial inhibition of the single frequent (frequently inhibited) as compared to any of the rare (rarely inhibited) distractor locations is responsible for this target-location effect. However, a reduced likelihood of the target appearing at the frequent vs. a rare distractor location contributes to this effect: removing this negative bias abolished the cost to target processing with increasing practice, indicative of a transition from priority-map- to dimension-based - and thus a flexible locus of - distractor suppression.\n\nPublic Significance StatementDistraction by a salient visual stimulus outside the focus of the task at hand occurs frequently. The present study examined whether and how knowledge of the likely location(s) where the distractors occur helps the observer to mitigate distraction. The results confirmed that observers can learn to suppress distracting stimuli at likely locations. Further, they showed that, the suppression may occur at different levels in the hierarchically organized visual system where the priorities of which objects to be attended in the environment are determined.

neuroscience↗