Biology subjects

Liang, Y.

Publications and source records attributed to Liang, Y..

At least 325 records · Page 18Linked to original sources

bioRxiv2020

Small-scale field assessment of efficacy of the autodissemination approach against Aedes sp. in an urban area.

This is the first study to evaluate the efficacy of an autodissemination approach, as suggested by WHO. Therefore, the efficacy of an autodissemination approach in small-scale field trials against wild Aedes sp. population was evaluated in an urbanized setting, Malaysia. Lethal ovitraps enhanced with pyriproxyfen were used to control Aedes sp. populations at treatment sites, with the autodissemination activity was assessed using the WHO larval bioassays. Lethal ovitraps enhanced with pyriproxyfen effectively reduced of Aedes sp. population. All autodissemination stations were shown to be visited by Aedes sp. mosquitoes with 100% complete inhibition against eggs and larvae development. In the larvae bioassay, pupae mortality ranged from 14 to 40%. Statistically, a significant reduction of Aedes sp. population in the treatment sites compared to the untreated areas. The study proved for the autodissemination of pyriproxyfen to breeding habitats by wild Aedes sp. This technique is highly potentially for vector control activities. Future evaluation should focus on large-scale field trials. Author SummarySince 2012, Dataran Automobil, Seksyen 15, Shah Alam, was declared as one of the dengue hotspot areas. Major vector control activities were conducted by government, NGOs, social communities, and local authorities, but the number still rising. We conducted a new invention of autodissemination concepts in this area by an entomological study on mosquito populations reduction and dispersal abilities of the technique. We found that the technique has proven to control mosquito populations, but the other factors such as epidemiology link still unclear and need further clarification. Our finding highlighted the effectiveness of autodissemination strategies that can be considered as one of the alternative tools in vector control programme.

ecology↗

bioRxiv2019

Detection of aberrant splicing events in RNA-seq data with FRASER

Aberrant splicing is a major cause of rare diseases, yet its prediction from genome sequence remains in most cases inconclusive. Recently, RNA sequencing has proven to be an effective complementary avenue to detect aberrant splicing. Here, we developed FRASER, an algorithm to detect aberrant splicing from RNA sequencing data. Unlike existing methods, FRASER captures not only alternative splicing but also intron retention events. This typically doubles the number of detected aberrant events and identified a pathogenic intron retention in MCOLN1. FRASER automatically controls for latent confounders, which are widespread and substantially affect sensitivity. Moreover, FRASER is based on a count distribution and multiple testing correction, reducing the number of calls by two orders of magnitude over commonly applied z score cutoffs, with a minor sensitivity loss. The application to rare disease diagnostics is demonstrated by reprioritizing a pathogenic aberrant exon truncation in TAZ from a published dataset. FRASER is easy to use and freely available.

bioinformatics↗

bioRxiv2019

A screening platform based on epitope editing for drug discovery

The interaction between an antibody and its epitope has been daily utilized in various biological studies; however it has been rarely explored whether small molecules can alter the interaction. We discovered that small molecules could alter/edit surface properties of amyloid beta (A{beta}) epitopes, and consequently inhibit or enhance corresponding antibody recognition. Remarkably, this editing effect could generate functional changes including protein aggregation behaviors, cell cytokine secreting and in vivo microglia activation. According to this discovery, we proposed a screen platform based on epitope editing for drug discovery (SPEED). With a small library of compounds, we validated that SPEED could be used to seek new leads for A{beta} species. We also demonstrated that this platform could potentially be extended to other targets including tau protein and PD-L1 protein. The SPEED is a simple, fast and label-free screening method. We believe that the SPEED strategy could be universally applicable for seeking and validating drug candidates and imaging ligands.

biochemistry↗

bioRxiv2019

PhenomeXcan: Mapping the genome to the phenome through the transcriptome

Large-scale genomic and transcriptomic initiatives offer unprecedented ability to study the biology of complex traits and identify target genes for precision prevention or therapy. Translation to clinical contexts, however, has been slow and challenging due to lack of biological context for identified variant-level associations. Moreover, many translational researchers lack the computational or analytic infrastructures required to fully use these resources. We integrate genome-wide association study (GWAS) summary statistics from multiple publicly available sources and data from Genotype-Tissue Expression (GTEx) v8 using PrediXcan and provide a user-friendly platform for translational researchers based on state-of-the-art algorithms. We develop a novel Bayesian colocalization method, fastENLOC, to prioritize the most likely causal gene-trait associations. Our resource, PhenomeXcan, synthesizes 8.87 million variants from GWAS on 4,091 traits with transcriptome regulation data from 49 tissues in GTEx v8 into an innovative, gene-based resource including 22,255 genes. Across the entire genome/phenome space, we find 65,603 significant associations (Bonferroni-corrected p-value of 5.5 x 10-10), where 19,579 (29.8 percent) were colocalized (locus regional colocalization probability > 0.1). We successfully replicate associations from PheWAS Catalog (AUC=0.61) and OMIM (AUC=0.64). We provide examples of (a) finding novel and underreported genome-to-phenome associations, (b) exploring complex gene-trait clusters within PhenomeXcan, (c) studying phenome-to-phenome relationships between common and rare diseases via further integration of PhenomeXcan with ClinVar, and (d) evaluating potential therapeutic targets. PhenomeXcan (phenomexcan.org) broadens access to complex genomic and transcriptomic data and empowers translational researchers. One-Sentence SummaryPhenomeXcan is a gene-based resource of gene-trait associations with biological context that supports translational research.

genetics↗

bioRxiv2019

Obesity Potentiates TH2 Immunopathology via Dysregulation of PPAR

How obesity affects immune function is not well understood. Clinically, obesity is strongly associated with severe TH2 immunopathology1-3, though the physiological, cellular, and molecular underpinnings of this association remain obscure. Here, we demonstrate that obese mice are susceptible to severe atopic dermatitis (AD), a major manifestation of TH2 immunopathology and disease burden in humans4,5. Mechanistically, we show that dysregulation of the nuclear hormone receptor (NHR) PPAR{gamma} (peroxisome proliferator-activated receptor gamma) in T cells is a causal link between obesity and the increased TH2 immunopathology. We find that PPAR{gamma} oversees a cellular metabolic transcriptional program that restrains nuclear gene expression of the chief TH2 priming and effector cytokine interleukin-4 (IL-4). Accordingly, thiazolidinediones (TZDs), potent PPAR{gamma} agonists, robustly protect obese mice from TH2 immunopathology. Collectively, these findings establish PPAR{gamma} as a molecular link between obesity and TH2 immune homeostasis and identify TZDs as novel therapeutic candidates for TH2 immunopathology. Fundamentally, these findings demonstrate that shifting physiologic metabolic states can shape the tone of adaptive immune responses to modulate differential disease susceptibility.

immunology↗

bioRxiv2019

Computational Assessment of the Regulation-Modulating Potential for Noncoding Variants

Large-scale genome-wide association and expression quantitative trait loci studies have identified multiple noncoding variants associated with genetic diseases via affecting gene expression. However, effectively and efficiently pinpointing causal variants remains a serious challenge. Here, we developed CARMEN, a novel algorithm to identify functional noncoding expression-modulating variants. Multiple evaluations demonstrated CARMENs superior performance over state-of-the-art tools. Its higher sensitivity and low false discovery rate enable CARMEN to identify multiple causal expression-modulating variants that other tools simply missed. Meanwhile, benefitting from extensive annotations generated, CARMEN provides mechanism hints on predicted expression-modulating variants, enabling effectively characterizing functional variants involved in gene expression and disease-related phenotypes. CARMEN scales well with the massive datasets and is available online as a Web server at http://carmen.gao-lab.org.

genomics↗

bioRxiv2019

jYCaMP: An optimized calcium indicator for two-photon imaging at fiber laser wavelengths

State-of-the-art GFP-based calcium indicators do not undergo efficient two-photon excitation at wavelengths above 1000 nm, for which inexpensive and powerful industrial femtosecond lasers are available. Here we report jYCaMP1, a yellow variant of jGCaMP7 that outperforms its parent in mice and flies at excitation wavelengths above 1000 nm and enables improved two-color calcium imaging with RFP-based indicators.

neuroscience↗

bioRxiv2019

Widespread dose-dependent effects of RNA expression and splicing on complex diseases and traits

The resources generated by the GTEx consortium offer unprecedented opportunities to advance our understanding of the biology of human diseases. Here, we present an in-depth examination of the phenotypic consequences of transcriptome regulation and a blueprint for the functional interpretation of genome-wide association study-discovered loci. Across a broad set of complex traits and diseases, we demonstrate widespread dose-dependent effects of RNA expression and splicing. We develop a data-driven framework to benchmark methods that prioritize causal genes and find no single approach outperforms the combination of multiple approaches. Using colocalization and association approaches that take into account the observed allelic heterogeneity of gene expression, we propose potential target genes for 47% (2,519 out of 5,385) of the GWAS loci examined. Our results demonstrate the translational relevance of the GTEx resources and highlight the need to increase their resolution and breadth to further our understanding of the genotype-phenotype link.

genetics↗

bioRxiv2019

The GTEx Consortium atlas of genetic regulatory effects across human tissues

The Genotype-Tissue Expression (GTEx) project was established to characterize genetic effects on the transcriptome across human tissues, and to link these regulatory mechanisms to trait and disease associations. Here, we present analyses of the v8 data, based on 17,382 RNA-sequencing samples from 54 tissues of 948 post-mortem donors. We comprehensively characterize genetic associations for gene expression and splicing in cis and trans, showing that regulatory associations are found for almost all genes, and describe the underlying molecular mechanisms and their contribution to allelic heterogeneity and pleiotropy of complex traits. Leveraging the large diversity of tissues, we provide insights into the tissue-specificity of genetic effects, and show that cell type composition is a key factor in understanding gene regulatory mechanisms in human tissues.

genetics↗

bioRxiv2019

Agrobacterium-mediated transient transformation of sorghum leaves for accelerating functional genomics and genome editing studies.

ObjectivesSorghum is one of the most recalcitrant species for transformation. Considering the time and effort required for stable transformation in sorghum, establishing a transient system to screen the efficiency and full functionality of vector constructs is highly desirable.\n\nResultsHere, we report an Agrobacterium-mediated transient transformation assay with intact sorghum leaves using green fluorescent protein as marker. It also provides a good monocot alternative to tobacco and protoplast assays with a direct, native and more reliable system for testing single guide RNA (sgRNA) expression construct efficiency. Given the simplicity and ease of transformation, high reproducibility, and ability to test large constructs, this method can be widely adopted to speed up functional genomic and genome editing studies.

plant biology↗

bioRxiv2019

A distinct population of L6 neurons in mouse V1 mediate cross-callosal communication

Through the corpus callosum, interhemispheric communication is mediated by callosal projection (CP) neurons. Using retrograde labeling, we identified a population of layer 6 (L6) excitatory neurons as the main conveyer of transcallosal information in the monocular zone of the mouse primary visual cortex (V1). Distinct from L6 corticothalamic (CT) population, V1 L6 CP neurons contribute to an extensive reciprocal network across multiple sensory cortices over two hemispheres. Receiving both local and long-range cortical inputs, they encode orientation, direction, and receptive field information, while are also highly spontaneous active. The spontaneous activity of L6 CP neurons exhibits complex relationships with brain states and stimulus presentation, distinct from the spontaneous activity patterns of the CT population. The anatomical and functional properties of these L6 CP neurons enable them to broadcast visual and nonvisual information across two hemispheres, and thus play a major role in regulating and coordinating brain-wide activity events.

neuroscience↗

bioRxiv2019

Gut Microbiome Biomarkers in Adolescent Obesity：a Regional Study

PurposeThis study aimed to characterize the gut microbiota in obese Shenzhen adolescents, and evaluate the influence of gender on BMI-related differences in the gut microbiome.\n\nMethodsPhysical examinations, blood pressure measurement, serological assay, and body composition evaluation were conducted on two-hundred and five adolescents from Shenzhen. Fecal microbiome composition was profiled via 16S rRNA gene sequencing. A Random Forest (RF) classifier model was built to distinguish the BMI categories based on the gut bacterial composition.\n\nResultsFifty-six taxa consisting mainly of Firmicutes were identified that having significant associations with BMI; two OTUs belonging to Ruminococcaceae and one belonging to Lachnospiraceae had relatively strong positive correlations with body fate rate, waistline, and most of serum biochemical parameters. Based on the 56 BMI-associated OTUs, the RF model showed a robust classification accuracy (AUC 0.96) for predicting the obese phenotype. Gender-specific differences in the gut microbiome composition was obtained, and a lower relative abundance of Odoribacter was particularly found in obese boys. Functional analysis revealed a deficiency in bacterial gene contents related to PPAR signaling pathway in obese subjects for both genders; significantly lower levels of adipocytokine signaling pathway and ethylbenzene degradation were particularly detected in obese girls.\n\nConclusionsThis study revealed unique features of gut microbiome in terms of microbial composition and metabolic functions in obese Shenzhen adolescents. The effect of geographical location, age and gender on the gut microbiome should be carefully considered in case-control studies.

microbiology↗

bioRxiv2019

Dramatically diverse S. pombe wtf meiotic drivers all display high gamete-killing efficiency

Meiotic drivers are selfish genetic loci that force their transmission into more than 50% of the viable gametes made by heterozygotes. Meiotic drivers are known to cause infertility in a diverse range of eukaryotes and are predicted to affect the evolution of genome structure and meiosis. The wtf gene family of Schizosaccharomyces pombe includes both meiotic drivers and drive suppressors and thus offers a tractable model organism to study drive systems. Currently, only a handful of wtf genes have been functionally characterized and those genes only partially reflect the diversity of the wtf gene family. In this work, we functionally test 22 additional wtf genes. We identify eight new drivers that share between 30-90% amino acid identity with previously characterized drivers. Despite the vast divergence between these genes, they generally drive into >85% gametes when heterozygous. We also find three new wtf genes that suppress drive, including two that also act as autonomous drivers. Additionally, we find that wtf genes do not underlie a weak (64%) transmission bias caused by a locus or loci on chromosome 1. Finally, we find that some Wtf proteins have expression or localization patterns that are distinct from the poison and antidote proteins encoded by drivers and suppressors, suggesting some wtf genes may have non-meiotic drive functions. Overall, this work expands our understanding of the wtf gene family and the burden selfish driver genes impose on S. pombe.\n\nArticle SummaryDuring gametogenesis, the two gene copies at a given locus, known as alleles, are each transmitted to 50% of the gametes (e.g. sperm). However, some alleles cheat so that they are found in more than the expected 50% of gametes, often at the expense of fertility. This selfish behavior is known as meiotic drive. Some members of the wtf gene family in the fission yeast, Schizosaccharomyces pombe, kill the gametes (spores) that do not inherit them, resulting in meiotic drive favoring the wtf allele. Other wtf genes act as suppressors of drive. However, the wtf gene family is diverse and only a small subset of the genes has been characterized. Here we analyze the functions of other members of this gene family and found eight new drivers as well as three new suppressors of drive. Surprisingly, we find that drive is relatively insensitive to changes in wtf gene sequence as highly diverged wtf genes execute gamete killing with similar efficiency. Finally, we also find that the expression and localization of some Wtf proteins are distinct from those of known drivers and suppressors, suggesting that these proteins may have non-meiotic drive functions.

genetics↗

bioRxiv2019

Polarized Lung Inflammation and Tie2/Angiopoietin-Mediated Endothelial Dysfunction during Severe Orientia tsutsugamushi Infection

Orientia tsutsugamushi infection can cause acute lung injury and high mortality in humans; however, the underlying mechanisms are unclear. Here, we tested a hypothesis that dysregulated pulmonary inflammation and Tie2-mediated endothelial malfunction contribute to lung damage. Using a murine model of lethal O. tsutsugamushi infection, we demonstrated pathological characteristics of vascular activation and tissue damage: 1) a significant increase of ICAM-1, VEGFR2, and angiopoietin-2 (Ang2) proteins in inflamed tissues and lung-derived endothelial cells (EC), 2) a progressive loss of endothelial quiescent and junction proteins (Ang1, VE-cadherin/CD144, occuludin), and 3) a profound impairment of Tie2 receptor at the transcriptional and functional levels. In vitro infection of primary human EC cultures and serum Ang2 proteins in scrub typhus patients support our animal studies, implying endothelial dysfunction in severe scrub typhus. Flow cytometric analyses of lung-recovered cells further revealed that pulmonary macrophages (M{Phi}) were polarized toward an M1-like phenotype (CD80+CD64+CD11b+Ly6G-) during the onset of disease and prior to host death, which correlated with the significant loss of CD31+CD45- ECs and M2-like (CD206+CD64+CD11b+Ly6G-) cells. In vitro studies indicated extensive bacterial replication in M2-type, but not M1-type, M{Phi}s, implying the protective and pathogenic roles of M1-skewed responses. This is the first detailed investigation of lung cellular immune responses during acute O. tsutsugamushi infection. It uncovers specific biomarkers for vascular dysfunction and M1-skewed inflammatory responses, highlighting future therapeutic research for the control of this neglected tropical disease.\n\nAuthor SummaryScrub typhus is a life-threatening disease, infecting an estimated one million people yearly. Acute lung injury is the most common clinical observation; however, its pathogenic biomarkers and mechanisms of progression remain unknown. Here, we used a lethal infection mouse model that parallels certain aspects of severe scrub typhus, primary human endothelial cell cultures, and patient sera to define pathogenic biomarkers following Orientia tsutsugamushi infections. We found a significant increase in the levels of endothelial activation/stress markers (angiopoietins and ICAM-1) in infected mouse lungs and in patient sera, but a progressive loss of endothelium-specific Tie2 receptor and junction proteins (VE-cadherin), at severe stages of disease. These signs of vasculature disruption positively correlated with the timing and magnitude of recruitment/activation of proinflammatory M{Phi} subsets in infected lungs. Bacterial growth in vitro was favored in M2-like, but not in M1-like, M{Phi}s. This study, for the first time, reveals endothelial malfunction and dysregulated inflammatory responses, suggesting potential therapeutic targets to ameliorate tissue damage and pathogenesis.

microbiology↗

bioRxiv2019

Immune Landscapes Predict Chemotherapy Resistance And Immunotherapy Response In Acute Myeloid Leukemia

This study dissected the complexity of the immune architecture of acute myeloid leukemia (AML) at high resolution and assessed its influence on therapeutic response. Using 387 primary bone marrow samples from three discovery cohorts of children and adults with AML, we defined immune-infiltrated and immune-depleted disease subtypes and unraveled critical differences in immune gene expression across age groups and disease stages. Importantly, interferon (IFN)-{gamma}-related mRNA profiles were predictive for both chemotherapy resistance and response of primary refractory/relapsed AML to flotetuzumab immunotherapy. Our compendium of microenvironmental gene and protein profiles sheds novel insights into the immuno-biology of AML and will inform the delivery of personalized immunotherapies to IFN-{gamma}-dominant AML subtypes.

immunology↗

bioRxiv2019

Shotgun Metagenomics of 361 elderly women reveals gut microbiome change in bone mass loss

Bone mass loss contributes to the risk of bone fracture in the elderly. Many factors including age, obesity, estrogen and diet, are associated with bone mass loss. Mice studies suggest that the intestinal microbiome might influence the bone mass by regulating the immune system, however there has been little evidence from human studies. We have recruited 361 Chinese elderly women to collect data for a metagenomic-wide association study (MWAS) to investigate the influence of the gut microbiome on bone health. Gut microbiome data were produced using BGISEQ500 sequencing, BMD was calculated using Hologic dual energy X-ray machine, BMI (Body Mass Index) and age were also provided. This therefore data allows exploration of gut microbiome diversity and links to bone mass loss, as well as microbial species and modules as markers for bone mineral density. Making these data potentially useful in studying the role the gut microbiota might play in bone mass loss and offering exploration into the bone mass loss process.

microbiology↗

bioRxiv2019

Defining the microenvironment landscape of bladder cancer using highly multiplexed spatial genomic and proteomic analysis

Muscle-invasive bladder cancer (MIBC) is an aggressive disease with limited therapeutic options. PD-1 pathway targeting immunotherapies have been approved to treat advanced bladder cancer, but most patients exhibit primary resistance, suggesting that immune evasion mechanisms exist. The PPAR{gamma} pathway has been identified as a potential therapeutic target in MIBC that is associated with reduced CD8+ T-cell infiltration and increased resistance to immunotherapies. We comprehensively profiled the tumor microenvironment (TME) in formalin-fixed, paraffin-embedded (FFPE) tissues from a cohort of PPAR{gamma}high (n=13) and PPRAR{gamma}low (n=12) MIBC, integrating bulk gene expression, targeted mutation sequencing, immunohistochemistry and multiplex spatial profiling of RNA and protein expression on the GeoMx Digital Spatial Profiling (DSP) platform. Molecular subtyping was consistent between traditional methods and GeoMx profiling, and, in this cohort, we observed little evidence of spatial heterogeneity in tumor subtyping. The previously characterized T-cell exclusion phenotype of PPAR{gamma}high MIBC was recapitulated on the GeoMx platform and was further extended to show that this is a general phenomenon across immune cell types, supporting potential combination of PPAR{gamma} inhibition with ICIs. Furthermore, we found that while immune cells were excluded from PPAR{gamma}high tumors, the stromal compartment from these tumors was not significantly different than those PPAR{gamma}low tumors. By preserving spatial relationships during the GeoMx analysis, we also identify a novel association between lower immune cell expression in the tumors and higher expression of {beta}-catenin in the stroma, and differential expression of other WNT pathway members associated with PPAR{gamma} activity.\n\nOne Sentence SummaryA new method for capturing tumor-immune signaling in FFPE tissues explores how the PPARG signaling axis is associated with immune cell exclusion in bladder cancer.

cancer biology↗

bioRxiv2019

SiaABCD - A threonine phosphorylation pathway that controls biofilm formation in Pseudomonas aeruginosa

The critical role of bacterial biofilms in chronic human infections calls for novel anti-biofilm strategies targeting the regulation of biofilm development. However, the regulation of biofilm development is very complex and can include multiple, highly interconnected signal transduction/response pathways, which are incompletely understood. We demonstrated previously that in the opportunistic, human pathogen P. aeruginosa, the PP2C-like protein phosphatase SiaA and the di-guanylate cyclase SiaD control the formation of macroscopic cellular aggregates, a type of suspended biofilms, in response to surfactant stress. In this study, we demonstrate that the SiaABC proteins represent a signal response pathway that functions through a partner switch mechanism to control biofilm formation. We also demonstrate that SiaABCD functionality is dependent on carbon substrate availability for a variety of substrates, and that upon carbon starvation, SiaB mutants show impaired dispersal, in particular with the primary fermentation product ethanol. This suggests that carbon availability is at least one of the key environmental cues integrated by the SiaABCD system. Further, our biochemical, physiological and crystallographic data reveals that the phosphatase SiaA and its kinase counterpart SiaB balance the phosphorylation status of their target protein SiaC at threonine 68 (T68). Crystallographic analysis of the SiaA-PP2C domain shows that SiaA is present as a dimer. Dynamic modelling of SiaA with SiaC suggested that SiaA interacts strongly with phosphorylated SiaC and dissociates rapidly upon dephosphorylation of SiaC. Further, we show that the known phosphatase inhibitor fumonisin inhibits SiaA mediated phosphatase activity in vitro. In conclusion, the present work improves our understanding of how P. aeuruginosa integrates specific environmental conditions, such as carbon availability and surfactant stress, to regulate cellular aggregation and biofilm formation. With the biochemical and structural characterization of SiaA, initial data on the catalytic inhibition of SiaA, and the interaction between SiaA and SiaC, our study identifies promising targets for the development of biofilm-interference drugs to combat infections of this aggressive opportunistic pathogen. Author SummaryPseudomonas aeruginosa is a Gram-negative bacterium that is feared within clinical environments due to its potential to cause life-threatening acute and chronic infections. One cornerstone of its success is the ability to form and disperse from biofilms, which are self-made, multicellular structures that protect the individual cell from the human immune system and antibiotic treatment. As such, therapies that combine a biofilm-interference strategy and the use of antimicrobial drugs represent one of the promising strategies to tackle infections of this organism. With the current study, we gain a deeper understanding of the SiaABCD mediated biofilm formation in response to clinically relevant environmental conditions. Further, our structural and biochemical characterization of the PP2C-type protein-phosphatase SiaA and the partner switch protein SiaC suggest that both represent promising novel targets for the development of future anti-biofilms drugs based on a signal interference strategy.

microbiology↗