Biology subjects

He, Q.

Publications and source records attributed to He, Q..

149 records · Page 9Linked to original sources

bioRxiv2018

Identification of the interaction of 2-aminosteroids with G-quadruplex in BCR/ABL gene promoter: An emerging potential target for treatment of human chronic myelogenous leukemia

Our preliminary studies have verified that the small molecules aminosteroid could inhibit the mRNA expression of bcr/abl fusion gene in CML (Chronic Myelogenous Leukemia) cells, which may be effective in treating CML and that may have dramatically different mechanism underlying the effects by tyrosine kinase inhibitors (TKI) binding to the BCR/ABL protein. Therefore, the exact mechanism of how the aminosteroid inhibited the CML growth should be clarified and we pay our attention to the promoter domain of BCR/ABL gene to see if any interaction between aminosteroid and the promoter. First, it should be verified if G-quadruplex could be formed in BCR/ABL promoter region. Secondly, it is highly desirable to verify if aminoteroid could be interacted with the G-quadruplex structure. Here, we reported a novel therapeutic strategy based on the targeting of the G-quadruplex which formed in the promoter regions of BCR/ABL gene by aminosteroid compounds KH and BH, verified by using bioinformatics and computer simulation, UV-Vis absorption spectra, circular dichrosism(CD), fluorescence absorption spectra, fluorescence emission lifetime expenditure experiments and polymerase chain stop assays. It showed that G-quadruplex structures can be folded in BCR/ABL promoter regions and aminosteroid inhibits the mRNA expression of BCR/ABL fusion gene by stabilizing the structure of G-quadruplex, and then inhibiting the DNA replication and transcription. This demonstrates the theory that is the so-called \"chemical gene therapy\" by aminosteroid in the interaction with G-quadruplex is an emerging therapeutic protocol in treatment of chronic myeloid leukemia.

cancer biology↗

bioRxiv2018

Baculovirus utilizes cholesterol transporter Niemann-Pick C1 for host cell entry

The dual roles of baculovirus for the control of natural insect populations as an insecticide, and for foreign gene expression and delivery, have called for a comprehensive understanding of the molecular mechanisms governing viral infection. Here, we demonstrate that the Bombyx mori Niemann-Pick C1 (BmNPC1) is essential for baculovirus infection in insect cells. Both pretreatment of Bombyx mori embryonic cells (BmE) with NPC1 antagonists (imipramine or U18666A) and down-regulation of NPC1 expression resulted in a significant reduction in baculovirus BmNPV (Bombyx mori nuclear polyhedrosis virus) infectivity. Furthermore, we show that the major glycoprotein gp64 of BmNPV, responsible for both receptor binding and fusion, is able to interact predominantly with the BmNPC1 C domain, with an enhanced binding capacity at low pH conditions, indicating that NPC1 most likely plays a role during viral fusion in endosomal compartments. Our results, combined with previous studies identifying an essential role of hNPC1 in filovirus infection, suggest that the glycoprotein of several enveloped viruses possess a shared strategy of exploiting host NPC1 proteins during virus intracellular entry events.\n\nIMPORTANCEBmNPV is one of the most important members of the Baculoviridae; many viruses in this family have been frequently employed as viral vectors for foreign gene delivery or expression and as biopesticides, but their host receptors still remain unclear. Here, we describe that the intracellular cholesterol transporter BmNPC1 is indispensable for BmNPV infection in insect cells, and it interacts with the major viral glycoprotein gp64. Our study on the role of BmNPC1 in baculovirus infection has further expanded the list of the enveloped viruses that require host NPC1 proteins for entry, and will ultimately help us to uncover the molecular mechanism of the involvement of NPC1 proteins in the entry process of many enveloped viruses.

microbiology↗

bioRxiv2017

Networks of genetic similarity reveal non-neutral processes shape strain structure in Plasmodium falciparum

Pathogens compete for hosts through patterns of cross-protection conferred by immune responses to antigens. In Plasmodium falciparum malaria, the var multigene family encoding for the major blood-stage antigen PfEMP1 has evolved enormous genetic diversity through ectopic recombination and mutation. With 50-60 var genes per genome, it is unclear whether immune selection can act as a dominant force in structuring var repertoires of local populations. The combinatorial complexity of the var system remains beyond the reach of existing strain theory, and previous evidence for non-random structure cannot demonstrate immune selection without comparison to neutral models. We develop two neutral models that encompass malaria epidemiology but exclude competitive interactions between parasites. These models, combined with networks of genetic similarity, reveal non-neutral strain structure in both simulated systems and an extensively sampled population in Ghana. The unique population structure we identify underlies the large transmission reservoir characteristic of highly endemic regions in Africa.

ecology↗

bioRxiv2017

Rapid adaptation with gene flow via a reservoir of chromosomal inversion variation?

The increased recognition of frequent divergence with gene flow has renewed interest in chromosomal inversions as a source for promoting adaptive divergence. Inversions can suppress recombination between heterokaryotypes so that local adapted inversions will be protected from introgression with the migrants. However, we do not have a clear understanding of the conditions for which adaptive divergence is more or less likely to be promoted by inversions when the availability of inversion variation is considered. Standing genetic variation, as opposed to new mutations, could offer a quick way to respond to sudden environmental changes, making it a likely avenue for rapid adaptation. For a scenario of secondary contact between locally-adapted populations, we might intuit that standing inversion variation would predominate over new inversion mutations in maintaining local divergence. Our results show that this is not always the case. Maladaptive gene flow, as both a demographic parameter and the cause for selection that favors locally-adapted inversions, differentiates the dynamics of standing inversion variation from that of segregating point mutations. Counterintuitively, in general, standing inversion variation will be less important to the adaptation than new inversions under the demographic and genetic conditions that are more conducive to adaptive divergence via inversions.

evolutionary biology↗

bioRxiv2017

A powerful approach to estimating annotation-stratified genetic covariance using GWAS summary statistics

Despite the success of large-scale genome-wide association studies (GWASs) on complex traits, our understanding of their genetic architecture is far from complete. Jointly modeling multiple traits genetic profiles has provided insights into the shared genetic basis of many complex traits. However, large-scale inference sets a high bar for both statistical power and biological interpretability. Here we introduce a principled framework to estimate annotation-stratified genetic covariance between traits using GWAS summary statistics. Through theoretical and numerical analyses we demonstrate that our method provides accurate covariance estimates, thus enabling researchers to dissect both the shared and distinct genetic architecture across traits to better understand their etiologies. Among 50 complex traits with publicly accessible GWAS summary statistics (Ntotal {approx} 4.5 million), we identified more than 170 pairs with statistically significant genetic covariance. In particular, we found strong genetic covariance between late-onset Alzheimers disease (LOAD) and amyotrophic lateral sclerosis (ALS), two major neurodegenerative diseases, in single-nucleotide polymorphisms (SNPs) with high minor allele frequencies and in SNPs located in the predicted functional genome. Joint analysis of LOAD, ALS, and other traits highlights LOADs correlation with cognitive traits and hints at an autoimmune component for ALS.

genetics↗