Biology subjects

Feng, W.

Publications and source records attributed to Feng, W..

106 records · Page 6Linked to original sources

bioRxiv2019

Exponential Growth of Glioblastoma In Vivo Driven by Rapidly Dividing and Outwardly Migrating Cancer Stem Cells

How overall tumor growth emerges from the properties of functionally heterogeneous tumor cell subpopulations is a fundamental question of cancer biology. Here we combined lineage tracing, continuous monitoring of tumor mass, proliferation assays and transcriptomics with mathematical modeling and statistical inference to dissect the growth of glioblastoma in mice. We found that tumors grow exponentially at the rate of symmetric divisions of brain tumor stem cells (BTSCs). Spatial modeling predicts, and data show, that BTSCs accumulate at the tumor rim rather than in the core. The physiological differentiation hierarchy downstream of BTSCs is preserved in mice and humans: transit amplifying progenitors give rise to terminally differentiated cells. Consistent with our quantification of the mechanisms underlying tumor growth, molecular data show elevated expression of cell cycle-and migration-related genes in BTSCs. Our systematic approach reveals fundamental properties of glioblastoma and may be transferable to the study of other animal models of cancer.

cancer biology↗

bioRxiv2019

Computational analysis of transcriptome signature repurposes low dose trifluoperazine for the treatment of fragile X syndrome in mouse model

Fragile X syndrome (FXS), caused by mutations in fragile X mental retardation 1 gene (FMR1), is a prevailing genetic disorder of intellectual disability and autism. Currently, there is no efficacious medication for FXS. Here, we use transcriptome landscape as a holistic molecular phenotype/endpoint to identify potential therapeutic intervention. Through in silico screening with public gene signature database, computational analysis of transcriptome profile in Fmr1 knockout (KO) neurons predicts therapeutic value of an FDA-approved drug trifluoperazine. Through experimental validation, we find that systemic administration of low dose trifluoperazine at 0.05 mg/kg attenuates multiple FXS- and autism-related behavioral symptoms. Moreover, computational analysis of transcriptome alteration caused by trifluoperazine suggests a new mechanism of action against PI3K (Phosphatidylinositol-4,5-bisphosphate 3-kinase) activity. Consistently, trifluoperazine suppresses PI3K activity and its down-stream targets Akt (protein kinase B) and S6K1 (S6 kinase 1) in neurons. Further, trifluoperazine normalizes the aberrantly elevated activity of Akt and S6K1 and enhanced protein synthesis in FXS mouse. In conclusion, our data demonstrate promising value of gene signature-based computation in identification of therapeutic strategy and repurposing drugs for neurological disorders, and suggest trifluoperazine as a potential practical treatment for FXS.

neuroscience↗

bioRxiv2019

Endocytosis of very low-density lipoprotein particles: an unexpected mechanism for lipid acquisition by breast cancer cells

We previously described the expression of CD36 and lipoprotein lipase (LPL) by breast cancer (BC) cells and tissues, and the growth-promoting effect of very low-density lipoprotein (VLDL) supplementation observed in BC cell lines only in the presence of LPL. We now describe the deployment of LPL by BC cells. Our data support a model in which LPL is bound to a heparin-like heparan sulfate proteoglycan motif on the BC cell surface and acts in concert with the VLDL receptor to rapidly internalize intact lipoproteins via receptor-mediated endocytosis. We further observe substantial alterations in gene expression programs related to pathways for lipid acquisition (synthesis vs. uptake) in response to each the availability of exogenous triglyceride in tissue culture media and LPL expression status. Current literature emphasizes de novo fatty acid synthesis as the paramount mechanism for lipid acquisition by cancer cells. Our findings indicate that exogenous lipid uptake can serve as an important method of lipid acquisition for cancer cells, alongside de novo lipogenesis, and that the relative reliance on these two modes of lipid acquisition may vary among different BC cell lines and in response to nutrient availability. This concept has obvious implications for the development of therapies aimed at the lipid dependence of many different cancer types. Moreover, the mechanism that we have elucidated provides a direct connection between dietary fat and tumor biology.

cancer biology↗

bioRxiv2019

Clinically-relevant cell type cross-talk identified from a human lung tumor microenvironment interactome

Tumors comprise a complex microenvironment of interacting malignant and stromal cell types. Much of our understanding of the tumor microenvironment comes from in vitro studies isolating the interactions between malignant cells and a single stromal cell type, often along a single pathway. To develop a deeper understanding of the interactions between cells within human lung tumors we performed RNA-seq profiling of flow-sorted malignant cells, endothelial cells, immune cells, fibroblasts, and bulk cells from freshly resected human primary non-small-cell lung tumors. We mapped the cell-specific differential expression of prognostically-associated secreted factors and cell surface genes, and computationally reconstructed cross-talk between these cell types to generate a novel resource we call the Lung Tumor Microenvironment Interactome (LTMI). Using this resource, we identified and validated a prognostically unfavorable influence of Gremlin-1 production by fibroblasts on proliferation of malignant lung adenocarcinoma cells. We also found a prognostically favorable association between infiltration of mast cells and less aggressive tumor cell behavior. These results illustrate the utility of the LTMI as a resource for generating hypotheses concerning tumor-microenvironment interactions that may have prognostic and therapeutic relevance.\n\nSummaryRNA-seq profiling of sorted populations from primary lung cancer samples identifies prognostically relevant cross-talk between cell types in the tumor microenvironment.

cancer biology↗

bioRxiv2019

A terminal selector prevents a Hox transcriptional switch to safeguard motor neuron identity throughout life

Nervous system function critically relies on continuous expression of neuron type-specific terminal identity features, such as neurotransmitter receptors, ion channels and neuropeptides. How individual neuron types select such features during development and maintain them throughout life is poorly understood. Here, we report an unconventional mechanism that enables cholinergic motor neurons (MNs) in the C. elegans ventral nerve cord to select and maintain their distinct terminal identity features. The conserved terminal selector UNC-3 (Collier/Ebf) UNC-3 is continuously required not only to promote cholinergic MN features, but also to prevent expression of \"unwanted\" terminal identity features normally reserved for other neuron types. Mechanistically, this dual function is achieved by the ability of UNC-3 to prevent a switch in the transcriptional targets of the Hox protein LIN-39 (Scr/Dfd/Hox4-5). The strategy of a terminal selector preventing a Hox transcriptional switch may constitute a general principle for safeguarding neuronal terminal identity features throughout life.

developmental biology↗

bioRxiv2019

Fragile X Mental Retardation Protein regulates R-loop formation and prevents global chromosome fragility

Fragile X syndrome (FXS) is the most prevalent inherited intellectual disability caused by mutations in the Fragile X Mental Retardation 1 (FMR1) gene. The protein product of FMR1, FMRP, is known as a translational repressor whose nuclear function is not understood. Here we report that FMRP is a genome maintenance protein. We show that FX cells exhibit elevated level of chromosome breaks, both spontaneous and replication stress-induced. We demonstrate that FMRP is required for abating R-loop accumulation, thereby preventing chromosome breakage. Through mapping FMRP-bound chromatin loci in normal cells and correlating with FX-specific chromosome breaks, we identified novel FXS-susceptible genes. We show that FX cells have reduced expression of the uridine diphosphoglucuronosyl transferase 1 family enzymes, suggesting defective xenobiotics glucuronidation and consequential neurotoxicity in FXS.

genomics↗

bioRxiv2018

Loud music and the specific sound stress open the blood-brain barrier: new fundamental, biomedical, and social aspects

The blood-brain barrier (BBB) poses a significant challenge for drug brain delivery. The limitation of our knowledge about the nature of BBB explains the slow progress in the therapy of brain diseases and absence of methods for drug brain delivery in the clinical practice.\n\nHere we show that BBB opens for low/high weight molecules and nanocarriers after exposure of loud music/sound of 90 dB and 100 dB (regardless its frequency) as being easily produced by MP3/MP4 players, kitchen appliances, loudspeakers at concerts. The role of sound, sound-induced stress and molecular mechanisms behind is discussed in the framework of BBB opening as an informative platform for a novel fundamental knowledge about the nature of BBB and for the development of a non-invasive brain drug delivery technology.\n\nSocial aspects of music/sound-induced opening of BBB provide completely new information about noise and healthy life conditions that will stimulate new research in this field.

neuroscience↗

bioRxiv2018

Identification of spatially variable genes with graph cuts

Single-cell gene expression data with positional information are critical to dissect mechanisms and architectures of multicellular organisms, but the potential is limited by current data analysis strategies. Here, we present scGCO (single-cell graph cuts optimization), a method based on fast optimization of Markov Random Fields with graph cuts, to identify spatially viable genes. Extensive benchmarking demonstrated that scGCO delivers superior performance with optimal segmentation of spatial patterns, and can process millions of cells in a timely manner owing to its linear scalability.

bioinformatics↗

bioRxiv2018

53BP1 nuclear body-marked replication stress in a human mammary cell model of BRCA2 deficiency

BRCA2 deficiency causes genome instability and breast and ovarian cancer predisposition, but also paradoxically promotes cell lethality. The nature of the acute, detrimental consequences of BRCA2 loss is not fully understood. We recently generated BRCA2 conditional models from a non-transformed human mammary cell line, through allele-specific gene targeting using CRISPR-Cas9, which we now describe. With these models, we discovered that BRCA2 deficiency triggers a DNA under replication-53BP1 nuclear body formation-G1 arrest axis due to homologous recombination defects. In this Extra-view, we extend these findings to show that 53BP1 nuclear bodies are spatially linked with downstream p53 activation. Replication stress that leads to common fragile site expression to induce 53BP1 nuclear body formation is aggravated by the loss of BRCA2. Additionally, replication stress that does not selectively lead to common fragile site expression is also able to induce 53BP1 nuclear body formation in BRCA2-deficient cells, indicating lesions form more globally throughout the genome. Furthermore, compromising replication fork reversal by SMARCAL1 depletion restores replication fork protection but does not diminish the high replication stress in the BRCA2-deficient cells, further emphasizing that fork protection plays a minor role in these cells. These results further elucidate the causes and consequences of replication stresses in the face of BRCA2 inactivation, providing insight into the barriers that need to be overcome for cells to become tumorigenic.

molecular biology↗

bioRxiv2018

TCR-pMHC bond length controls TCR ligand discrimination

T-cell receptors (TCRs) detect specifically and sensitively a small number of agonist peptide-major histocompatibility complexes (pMHCs) from an ocean of structurally similar self-pMHCs to trigger antigen-specific adaptive immune responses1-4. Despite intense efforts, the mechanism underlying TCR ligand discrimination remains a major unanswered question in immunology. Here we show that a TCR discriminates between closely related peptides by forming TCR-pMHC bonds with different lengths, which precisely control the accessibility of CD3{zeta} immunoreceptor tyrosine-based activation motifs (ITAMs) for phosphorylation. Using in situ fluorescence resonance energy transfer (FRET)3,5, we measured the intermolecular length of single TCR-pMHC bonds and the intramolecular distance of individual TCR-CD3{zeta} complexes at the membrane of live primary T cells. We found that an agonist forms a short TCR-pMHC bond to pull the otherwise sequestered CD3{zeta} off the inner leaflet of the plasma membrane, leading to full exposure of its ITAMs for strong phosphorylation. By contrast, a structurally similar weaker peptide forms a longer bond with the TCR, resulting in partial dissociation of CD3{zeta} from the membrane and weak phosphorylation. Furthermore, we found that TCR-pMHC bond length determines 2D TCR binding kinetics and affinity, T-cell calcium signaling and T-cell proliferation, governing the entire process of signal reception, transduction and regulation. Thus, our data reveal the fundamental mechanism by which a TCR deciphers the structural differences between foreign antigens and self-peptides via TCR-pMHC bond length to initiate different TCR signaling for ligand discrimination.

immunology↗

bioRxiv2018

Bclaf1 critically regulates the type I interferon response and is degraded by alphaherpesvirus US3

Type I interferon response plays a prominent role against viral infection, which is frequently disrupted by viruses. Here, we report Bcl-2 associated transcription factor 1 (Bclaf1) is degraded during the alphaherpesvirus Pseudorabies virus (PRV) and Herpes simplex virus type 1 (HSV-1) infections through the viral protein US3. We further reveal that Bclaf1 functions critically in type I interferon signaling. Knockdown or knockout of Bclaf1 in cells significantly impairs interferon- (IFN)-mediated gene transcription and viral inhibition against US3 deficient PRV and HSV-1. Mechanistically, Bclaf1 maintains a mechanism allowing STAT1 and STAT2 to be efficiently phosphorylated in response to IFN, and more importantly, facilitates IFN-stimulated gene factor 3 (ISGF3) binding with IFN-stimulated response elements (ISRE) for efficient gene transcription by directly interacting with ISRE and STAT2. Our studies establish the importance of Bclaf1 in IFN-induced antiviral immunity and in the control of viral infections.

immunology↗

bioRxiv2018

Mining unknown porcine protein isoforms by tissue-based map of proteome enhances the pig genome annotation

A lack of the complete pig proteome has left a gap in our knowledge of the pig genome and has restricted the feasibility of using pigs as a biomedical model. We developed the tissue-based proteome maps using 34 major normal pig tissues. A total of 7,319 unknown protein isoforms were identified and systematically characterized, including 3,703 novel protein isoforms, 669 protein isoforms from 460 genes symbolized beginning with LOC, and 2,947 protein isoforms without clear NCBI annotation in current pig reference genome. These newly identified protein isoforms were functionally annotated through profiling the pig transcriptome with high-throughput RNA sequencing (RNA-seq) of the same pig tissues, further improving the genome annotation of corresponding protein coding genes. Combining the well-annotated genes that having parallel expression pattern and subcellular witness, we predicted the tissue related subcellular components and potential function for these unknown proteins. Finally, we mined 3,656 orthologous genes for 49.95% of unknown protein isoforms across multiple species, referring to 65 KEGG pathways and 25 disease signaling pathways. These findings provided valuable insights and a rich resource for enhancing studies of pig genomics and biology as well as biomedical model application to human medicine.

genomics↗

bioRxiv2018

Gut segments outweigh the diet in shaping the intestinal microbiome composition in grass carp Ctenopharyngodon idellus

ABSTRACTAlthough dynamics of the complex microbial ecosystem populating the gastrointestinal tract of animals has profound and multifaceted impacts on hosts metabolism and health, it remains unclear whether it is the intrinsic or extrinsic factors that play a more dominant role in mediating variations in the composition of intestinal microbiota. To address this, two strikingly different diets were studied: a high-protein, low-fiber formula feed (FF), and low-protein, high-fiber Sudan grass (SG). After a 16-week feeding trial on a herbivorous fish, grass carp, microbial profiles of midgut (M) and hindgut (H) segments of both groups were compared. Bacteroidetes were more abundant in the hindgut (T=-7.246, p<0.001), and Proteobacteria in the midgut (T=4.383, p<0.001). Fusobacteria were more abundant in the FF group (compared to the SG group, T=2.927, p<0.001). Bacterial composition was different (p<0.05) between the midguts of formula feed (M-FF) and Sudan grass (M-SG) groups, but not between the hindguts of two groups (H-FF and H-SG; p=0.269). PerMANOVA and VPA indicated that the gut segment contributed 19.8% (p<0.001) and 28% (p<0.001) of the variation of microbial communities, whereas diet contributed only 8.0% (p<0.001) and 14% (p<0.001), respectively. Overall, results suggest that intestinal compartments are a stronger determinant than diet in shaping the intestinal microbiota. Specifically, whereas diet has a strong impact on the microbiome composition in proximal gut compartments, this impact is much less pronounced distally, which is likely to be a reflection of a limited ability of some microbial taxa to thrive in the anoxic environment in distal segments.\n\nIMPORTANCEThe impact of compositional dynamics of gut microbiota on hosts metabolism and health is so profound that the traditional idea of biological individual is increasingly replaced with \"holobiont\", comprising both the host and its microbiome. Composition of gut microbiota is strongly influenced by extrinsic (such as diet) and intrinsic (such as gut compartment) factors. Despite ample scientific attention both of these factors have received individually, their relative contributions in mediating the dynamics of the microbiome remain unknown. Given the importance of this issue, we set out to disentangle their individual contributions in a herbivorous fish, grass carp. We found that intestinal compartments are a stronger determinant than diet in shaping the intestinal microbiota. Whereas the impact of diet is strongly pronounced in proximal gut compartments, it appears that limited ability of some microbial taxa to thrive in the anoxic environment in distal segments strongly reduces the impact of diet distally.

ecology↗

bioRxiv2018

Next-Generation Sequencing Could be a Promising Diagnostic Approach for Pathogen Detection: Pathogenic Analysis of Pediatric Bacterial Meningitis by Next-Generation Sequencing Technology Directly from Cerebrospinal Fluid Specimens

BackgroundBacterial meningitis remains one of the major challenges in infectious diseases, leading to sequel in many cases. A prompt diagnosis of the causative microorganism is critical to significantly improve outcome of bacterial meningitis. Although various targeted tests for cerebrospinal fluid (CSF) samples are available, it is a big problem for the identification of etiology of bacterial meningitis.\n\nMethodsHere we describe the use of unbiased sequence analyses by next-generation sequencing (NGS) technology for the identification of infectious microorganisms from CSF samples of pediatric bacterial meningitis patients in the Department of Infectious Diseases from Beijing Childrens Hospital.\n\nResultsIn total, we had 99 bacterial meningitis patients in our study, 55 (55.6%) of these were etiologically confirmed by clinical microbiology methods. Combined with NGS, 68 cases (68.7%) were etiologically confirmed. The main pathogens identified in this study were Streptococcus pneumoniae (n=29), group B streptococcus (n=15), Staphylococcus aureus (n=7), Escherichia coli (n=7). In addition, two cases with cytomegalovirus infection and one with Taenia saginata asiatica were confirmed by NGS.\n\nConclusionsNGS could be a promising alternative diagnostic approach for critically ill patients suffering from bacterial meningitis in pediatric population.\n\nSummaryWe conducted the study for the identification of microorganisms by next-generation sequencing directly from CSF samples of pediatric bacterial meningitis patients. And the study showed that NGS could be a promising alternative diagnostic approach for bacterial meningitis in pediatric population.

microbiology↗

bioRxiv2017

A microbially derived tyrosine sulfated peptide mimics a plant peptide hormone

O_LIThe biotrophic pathogen Xanthomonas oryzae pv. oryzae (Xoo) produces a sulfated peptide named RaxX, which shares similarity to peptides in the PSY (plant peptide containing sulfated tyrosine) family. We hypothesize that RaxX functionally mimics the growth stimulating activity of PSY peptides.\nC_LIO_LIRoot length was measured in Arabidopsis and rice treated with synthetic RaxX peptides. We also used comparative genomic analysis and Reactive Oxygen Species (ROS) burst assay to evaluate the activity of RaxX and PSY peptides.\nC_LIO_LIHere we found that a synthetic sulfated RaxX derivative comprising 13 residues (RaxX13-sY), highly conserved between RaxX and PSY, induces root growth in Arabidopsis and rice in a manner similar to that triggered by PSY. We identified residues that are required for activation of immunity mediated by the rice XA21 receptor but that are not essential for root growth induced by PSY. Finally, we showed that a Xanthomonas strain lacking raxX is impaired in virulence.\nC_LIO_LIThese findings suggest that RaxX serves as a molecular mimic of PSY peptides to facilitate Xoo infection and that XA21 has evolved the ability to recognize and respond specifically to the microbial form of the peptide.\nC_LI

plant biology↗

bioRxiv2017

Stability and critical transitions in mutualistic ecological systems

Successful conservation of complex ecosystems, their function and associated services, requires deep understanding of their underlying dynamics and potential instabilities. While the study of ecological dynamics is a mature and diverse field, the lack of a general model that uses basic ecological parameters to predict system-level behaviour has allowed unresolved contradictions to persist. Here, we provide a general model of a mutualistic ecological community and show for the first time how the conditions for instability, the nature of ecological collapse, and potential early-warning signals, can be derived from the basic ecological parameters. We also resolve open questions concerning effects of interaction heterogeneity on both resilience and abundance, and discuss their potential trade-off in real systems. This framework provides a basis for rich investigations of ecological system dynamics, and can be generalised across many ecological contexts.

ecology↗