Biology subjects

Hao, L.

Publications and source records attributed to Hao, L..

4 recordsLinked to original sources

bioRxiv2018

Low-dose cadmium potentiates lung inflammatory response to 2009 pandemic H1N1 influenza virus in mice

BACKGROUNDCadmium (Cd) is a toxic, pro-inflammatory metal ubiquitous in the diet that accumulates in body organs due to inefficient elimination. Many individuals exposed to dietary Cd are also infected by seasonal influenza virus. The H1N1 strain causes mild to severe pneumonia which can be fatal.\n\nOBJECTIVESTo determine the influence of low-dose Cd exposure on inflammatory responses to H1N1 influenza A virus.\n\nMETHODSWe exposed mice to low-dose (1 mg CdCl2/l) Cd or vehicle (water) for 16 weeks prior to infection with a sub-lethal dose of H1N1. Lung inflammation was assessed by histopathology and flow cytometry. We used a combination of transcriptomics, metabolomics and bioinformatics to determine the molecular associations of inflammatory cells important in Cd-exacerbated responses.\n\nRESULTSCd-treated mice had increased lung tissue inflammatory cells, including neutrophils, monocytes, T lymphocytes and dendritic cells, following H1N1 infection. Lung genetic responses to infection (increasing TNF-a, interferon and complement, and decreasing myogenesis) were also exacerbated. Global correlations with immune cell counts, leading edge gene transcripts and metabolites revealed that Cd increased correlation of myeloid immune cells with pro-inflammatory genes, particularly interferon-{gamma}, and metabolites in amino acid, nucleobase, glycerophospholipid and vitamin B3 pathways.\n\nDISCUSSIONCd burden in mice increased inflammation in response to sub-lethal H1N1 challenge, which was coordinated by genetic and metabolic responses, and could provide new targets for intervention against lethal inflammatory pathology of clinical H1N1 infection.

pharmacology and toxicology↗

bioRxiv2018

Time-scale separation and stochasticity conspire to impact phenotypic dynamics in the canonical and inverted Bacillus subtilis core genetic regulation circuits.

In this work, we study two seemingly unrelated aspects of core genetic nonlinear dynamical control of the competence phenotype in Bacillus subtilis, a common Gram-positive bacterium living in the soil. We focus on hitherto unchartered aspects of the dynamics by exploring the effect of time scale separation between transcription and translation and, as well, the effect of intrinsic molecular stochasticity. We consider these aspects of regulatory control as two possible evolutionary handles. Hence, using theory and computations, we study how the onset of oscillations breaks the excitability-based competence phenotype in two topologically close evolutionary competing circuits: the canonical \"wild-type\" regulation circuit selected by Evolution and, the indirect-feedback inverted circuit that failed to be selected by Evolution, as was shown elsewhere, due to dynamical reasons.

systems biology↗

bioRxiv2017

GVC: A superfast and universal genomic variant caller

Germline and somatic variant detection from human and cancer whole-genome sequencing data is a challenge task for genome-wide association study and cancer genomics in precision medicine. Many confounding factors contribute the difficulties including complexity of variant, sequencing and alignment error, tumor clonality and sample purity etc. Current genomic variant callers are too time-consuming to meet the requirement of clinical application in precision medicine. We developed superfast and universal Genomic Variant Caller (GVC), which can simultaneously detect various genomic variants including SNV, sINDEL and SV from personal and normal-cancer paired whole-genome/exome sequencing data within fifteen minutes. Whats more, it achieved higher sensitivity and precision than popular variant callers including GATK4, Mutect, NovoBreak in germline and somatic variant detection from NA12878 and ICGC-TCGA Dream Challenge Datasets respectuvely. It is worth mentioning that GVC achieved comparable performance in variant detection from NA12878 sequenced by three different high-throughput sequencing platforms including Illumina HiSeq2000, NovaSeq and BGISEQ-500.

bioinformatics↗

bioRxiv2017

Gαq Mediates Clozapine Effects in Caenorhabditis elegans

Clozapine binds and has significant effects on multiple neurotransmitter receptors, notably including some dopamine receptors. Downstream of these receptors, clozapine affects the balance of Gi- and Gq-dependent second-messenger signaling. We used Caenorhabiditis elegans as a genetic model to study further how clozapine affects both dopamine receptors and downstream Gq mediated signaling. Four of six worm dopamine receptor orthologs, dop-1, dop-2, dop-4, and dop-5 produced resistance to clozapine induced developmental delay when mutated, suggesting that both type I and type II dopamine receptors mediate the behavioral effects of clozapine in C. elegans. Beyond these receptors, reduction of function of one of the G proteins, egl-30 (Gq), produced greatly increased susceptibility to clozapine. Gq has multiple known downstream effects. Among these is the control of acetylcholine release, which is in balance with monoamines in the human brain and is another target of clozapine and other antipsychotic drugs. We tested for downstream effects on acetylcholine at the neuromuscular junction upon clozapine treatment but found no evidence for effects of clozapine. In contrast, modulation of Gq upstream leads to worms that are either more resistant or more susceptible to clozapine, emphasizing the importance of Gq proteins in mediating effects of clozapine. A genetic screen for suppressors of egl-30 recovered eight mutants. By characterizing the behavioral effects of these mutants, we found that clozapine exerts its function on development by affecting Gq signaling through control of the pharyngeal pumping rate. A whole-genome sequencing technique was utilized and identified a list of candidate genes for these suppressor mutations. Further characterization of these mutants promises the discovery of novel components participating in Gq signaling and a better understanding of the mechanisms of action of clozapine.

genetics↗