Biology subjects

Yao, F.

Publications and source records attributed to Yao, F..

22 records · Page 2Linked to original sources

bioRxiv2020

Detection of differential RNA modifications from direct RNA sequencing of human cell lines

Differences in RNA expression can provide insights into the molecular identity of a cell, pathways involved in human diseases, and variation in RNA levels across patients associated with clinical phenotypes. RNA modifications such as m6A have been found to contribute to molecular functions of RNAs. However, quantification of differences in RNA modifications has been challenging. Here we develop a computational method (xPore) to identify differential RNA modifications from direct RNA sequencing data. We evaluate our method on transcriptome-wide m6A profiling data, demonstrating that xPore identifies positions of m6A sites at single base resolution, estimates the fraction of modified RNAs in the cell, and quantifies the differential modification rate across conditions. We apply the method to direct RNA-Sequencing data from 6 cell lines and find that many m6A sites are preserved, while a subset of m6A sites show significant differences in their modification rates across cell types. Together, we show that RNA modifications can be identified from direct RNA-sequencing with high accuracy, enabling the analysis of differential modifications and expression from a single high throughput experiment. AvailabilityxPore is available as open source software (https://github.com/GoekeLab/xpore)

bioinformatics↗

bioRxiv2018

Role of the Fourth Transmembrane Segment in TRAAK Channel Mechanosensitivity

Mechanosensitive ion channels such as Piezo, TRAAK, TRPs and OSCA are important transmembrane proteins that are involved in many physiological processes such as touch, hearing and blood pressure regulation. Unlike ligand-gated channels or voltage-gated ion channels, which have a canonical ligand-binding domain or voltage-sensing domain, the mechanosensitive domain and related gating mechanism remain elusive. TRAAK channels are mechanosensitive channels that convert a physical mechanical force into a flow of potassium ions. The structures of TRAAK channels have been solved, however, the functional roles of the structural domains associated with channel mechanosensitivity remains unclear. Here, we generated a series of chimeric mutations between TRAAK and a non-mechanosensitive silent TWIK-1 K2P channel. We found that the selectivity filter region functions as the major gate of outward rectification and found that lower part of fourth transmembrane domain (M4) is necessary for TRAAK channel mechanosensitivity. We further demonstrated that upper part of M4 can modulate the mechanosensitivity of TRAAK channel. Furthermore, we found that hydrophilic substitutions of W262 and F121 facing each other, and hydrophobic substitutions of Q258 and G124, which are above and below W262 and F121, respectively, greatly increase mechanosensitivity, which suggests that dynamic interactions in the upper part of M4 and PH1 domain are involved in TRAAK channel mechanosensitivity. Interestingly, these gain-of-function mutations are sensitive to cell-poking stimuli, indicating that cell-poking stimuli generate a low membrane mechanical force that opens TRAAK channels. Our results thus showed that fourth transmembrane domain of TRAAK is critical for the gating of TRAAK by mechanical force and suggested that multiple dynamic interactions in the upper part of M4 and PH1 domain are involved in this process.

biophysics↗

bioRxiv2017

Field evidence for manipulation of mosquito host selection by the human malaria parasite, Plasmodium falciparum

Whether the malaria parasite Plasmodium falciparum can manipulate mosquito host choice in ways that enhance parasite transmission toward humans is unknown. We assessed the influence of P. falciparum on the blood-feeding behaviour of three of its major vectors (Anopheles coluzzii, An. gambiae and An. arabiensis) in Burkina Faso. Host preference assays using odour-baited traps revealed no effect of infection on mosquito long-range anthropophily. However, the identification of the blood meal origin of mosquitoes showed that females carrying sporozoites, the mature transmissible stage of the parasite, displayed a 24% increase in anthropophagy compared to both females harbouring oocysts, the parasite immature stage, and uninfected individuals. Using a mathematical model, we further showed that this increased anthropophagy in infectious females resulted in a > 250% increase in parasite transmission potential, everything else being equal. This important epidemiological consequence highlights the importance of vector control tools targeting infectious females.

evolutionary biology↗

bioRxiv2016

Tissue specificity of in vitro drug sensitivity

Research in oncology traditionally focuses on specific tissue type from which the cancer develops. However, advances in high-throughput molecular profiling technologies have enabled the comprehensive characterization of molecular aberrations in multiple cancer types. It was hoped that these large-scale datasets would provide the foundation for a paradigm shift in oncology which would see tumors being classified by their molecular profiles rather than tissue types, but tumors with similar genomic aberrations may respond differently to targeted therapies depending on their tissue of origin. There is therefore a need to reassess the potential association between pharmacological response and tissue of origin for therapeutic drugs, and to test how these associations translate from preclinical to clinical settings.\n\nIn this paper, we investigate the tissue specificity of drug sensitivities in large-scale pharmacological studies and compare these associations to those found in clinical trial descriptions. Our meta-analysis of the four largest in vitro drug screening datasets indicates that tissue of origin is strongly associated with drug response. We identify novel tissue-drug associations, which may present exciting new avenues for drug repurposing. One caveat is that the vast majority of the significant associations found in preclinical settings do not concur with clinical observations. Accordingly, our results call for more testing to find the root cause of the discrepancies between preclinical and clinical observations.

bioinformatics↗