Biology subjects

Qiao, Y.

Publications and source records attributed to Qiao, Y..

97 records · Page 6Linked to original sources

bioRxiv2020

Mobile Element Insertions and Associated Structural Variants in Longitudinal Breast Cancer Samples

While mobile elements are largely inactive in healthy somatic tissues, increased activity has been found in cancer tissues, with significant variation among different cancer types. In addition to insertion events, mobile elements have also been found to mediate many structural variation events in the genome. Here, to better understand the timing and impact of mobile element insertions and structural variants involving existing mobile elements in cancer, we examined their activity in longitudinal samples of four metastatic breast cancer patients. With whole-genome sequencing data from multiple timepoints through tumor progression, we used mobile element detection software followed by visual confirmation of the insertions. We identified 11 mobile element insertions or structural variants involving existing elements and found that the majority of these occurred early in tumor progression. Two of the identified insertions were SVA elements, which have rarely been found in previous cancer studies. Most of the variants appear to impact intergenic regions; however, we identified a translocation interrupting MAP2K4 involving Alu elements and a deletion in YTHDF2 involving mobile elements that likely inactivate reported tumor suppressor genes. The high variant allele fraction of the MAP2K4 translocation, the loss of the other copy of MAP2K4, the recurrent loss-of-function mutations found in this gene in other human cancers, and the important function of MAP2K4 indicate that this translocation is potentially a driver mutation. Overall, using a unique longitudinal dataset, we find that most variants are likely passenger mutations in the four patients we examined, but some variants impact tumor progression.

genomics↗

bioRxiv2020

Comparison of High-Throughput Single-Cell RNA Sequencing Data Processing Pipelines

With the development of single-cell RNA sequencing (scRNA-seq) technology, it has become possible to perform large-scale transcript profiling for tens of thousands of cells in a single experiment. Many analysis pipelines have been developed for data generated from different high-throughput scRNA-seq platforms, bringing a new challenge to users to choose a proper workflow that is efficient, robust and reliable for a specific sequencing platform. Moreover, as the amount of public scRNA-seq data has increased rapidly, integrated analysis of scRNA-seq data from different sources has become increasingly popular. How-ever, it remains unclear whether such integrated analysis would be biased if the data were processed by different upstream pipelines. In this study, we encapsulated seven existing high-throughput scRNA-seq data processing pipelines with Nextflow, a general integrative workflow management framework, and evaluated their performances in terms of running time, computational resource consumption, and data processing consistency using nine public datasets generated from five different high-throughput scRNA-seq platforms. Our work provides a useful guideline for the selection of scRNA-seq data processing pipelines based on their performances on different real datasets. In addition, these guidelines can serve as a performance evaluation framework for future developments in high-throughput scRNA-seq data processing.

bioinformatics↗

bioRxiv2019

Computational redesign of PETase for plastic biodegradation by GRAPE strategy

The excessive use of plastics has been accompanied by severe ecologically damaging effects. The recent discovery of a PETase from Ideonella sakaiensis that decomposes poly(ethylene terephthalate) (PET) under mild conditions provides an attractive avenue for the biodegradation of plastics. However, the inherent instability of the enzyme limits its practical utilization. Here, we devised a novel computational strategy (greedy accumulated strategy for protein engineering, GRAPE). A systematic clustering analysis combined with greedy accumulation of beneficial mutations in a computationally derived library enabled the design of a variant, DuraPETase, which exhibits an apparent melting temperature that is drastically elevated by 31 {degrees}C and strikingly enhanced degradation performance toward semicrystalline PET films (23%) at mild temperatures (over two orders of magnitude improvement). The mechanism underlying the robust promotion of enzyme performance has been demonstrated via a crystal structure and molecular dynamics simulations. This work shows the capabilities of computational enzyme design to circumvent antagonistic epistatic effects and provides a valuable tool for further understanding and advancing polyester hydrolysis in the natural environment.

synthetic biology↗

bioRxiv2019

Distinguishing pedigree relationships using multi-way identical by descent sharing and sex-specific genetic maps

The proportion of samples with one or more close relatives in a genetic dataset increases rapidly with sample size, necessitating relatedness modeling and enabling pedigree-based analyses. Despite this, relatives are generally unreported and current inference methods typically detect only the degree of relatedness of sample pairs and not pedigree relationships. We developed CREST, an accurate and fast method that identifies the pedigree relationships of close relatives. CREST utilizes identical by descent (IBD) segments shared between a pair of samples and their mutual relatives, leveraging the fact that sharing rates among these individuals differ across pedigree configurations. Furthermore, CREST exploits the profound differences in sex-specific genetic maps to classify pairs as maternally or paternally related--e.g., paternal half-siblings--using the locations of autosomal IBD segments shared between the pair. In simulated data, CREST correctly classifies 91.5-99.5% of grandparent-grandchild (GP) pairs, 70.5-97.0% of avuncular (AV) pairs, and 79.0-98.0% of half-siblings (HS) pairs compared to PADREs rates of 38.5-76.0% of GP, 60.5-92.0% of AV, 73.0-95.0% of HS pairs. Turning to the real 20,032 sample Generation Scotland (GS) dataset, CREST correctly determines the relationship of 99.0% of GP, 85.7% of AV, and 95.0% of HS pairs that have sufficient mutual relative data, completing this analysis in 10.1 CPU hours including IBD detection. CRESTs maternal and paternal relationship inference is also accurate, as it flagged five pairs as incorrectly labeled in the GS pedigrees-- three of which we confirmed as mistakes, and two with an uncertain relationship--yielding 99.7% of HS and 93.5% of GP pairs correctly classified.

genetics↗

bioRxiv2018

High-definition transcranial direct current stimulation over the dorsal premotor cortex reliably modulates motor network excitability

The effectiveness of transcranial direct current stimulation (tDCS) placed over the motor hotspot (thought to represent the primary motor cortex (M1)) to modulate motor network excitability is highly variable. The premotor cortex--particularly the dorsal premotor cortex (PMd)--may be a promising alternative target to more effectively modulate motor excitability, as it influences motor control across multiple pathways, one independent of M1 and one with direct, modulating connections to M1. This double-blind, placebo-controlled study aimed to differentially excite motor and premotor regions using high-definition tDCS (HD-tDCS) with concurrent functional magnetic resonance imaging (fMRI). HD-tDCS applied over either the motor hotspot or the premotor cortex demonstrated high inter-individual variability in changes on cortical motor excitability. However, HD-tDCS over the premotor cortex led to a higher number of responders and greater changes in local fMRI-based complexity than HD-tDCS over the motor hotspot. Furthermore, an analysis of individual motor hotspot anatomical locations revealed that, in more than half of the participants, the motor hotspot is not located over anatomical M1 boundaries, despite using a canonical definition of the motor hotspot. This heterogeneity in stimulation site may contribute to the variability of tDCS results. Altogether, these findings provide new considerations to enhance tDCS reliability.

neuroscience↗

bioRxiv2018

4-hydroxyphenylpyruvate dioxygenase thermolability is responsible for temperature-dependent melanogenesis in Aeromonas salmonicida subsP salmonicida

Aeromonas salmonicida subsp. salmonicida (A.s.s) is a major pathogen affecting fisheries worldwide. It is a well-known member of the pigmented Aeromonas species, which produces melanin at [≤] 22 {degrees}C. However, melanogenesis decreases as the culture temperature increases and is completely suppressed at 30-35 {degrees}C while bacterial growth is not affected. The mechanism and biological significance of this temperature-dependent melanogenesis are not clear. Heterologous expression of an A.s.s. 4-hydroxyphenylpyruvate dioxygenase (HppD), the most crucial enzyme in the HGA-melanin synthesis pathway, results in thermosensitive pigmentation in Escherichia coli, suggesting that HppD plays a key role in this process. In the current study, we demonstrated that the extreme thermolability of HppD is responsible for the temperature-dependent melanization of A.s.s. Substitutions in three residues, Ser18, Pro103, or Leu119 of HppD from A.s.s increases the thermolability of this enzyme and results in temperature-independent melanogenesis. Moreover, replacing the corresponding residues of HppD from Aeromonas media strain WS, which forms pigment independent of temperature, with those of A.s.s HppD leads to thermosensitive melanogenesis. Structural analysis suggested that mutations at these sites, especially at position P103, can strengthen the secondary structure of HppD and greatly improve its thermal stability. In addition, we found that HppD sequences of all A.s.s isolates are identical and that two of the three residues are completely conserved within A.s.s isolates, which clearly distinguishes these from other Aeromonas strains. We suggest that this property represents an adaptive strategy to the psychrophilic lifestyle of A.s.s.\n\nImportanceAeromonas salmonicida subsp. salmonicida (A.s.s) is the causative agent of furunculosis, a bacterial septicemia of cold water fish of the Salmonidae family. As it has a well-defined host range, A.s.s has become an ideal model to investigate the co-evolution of host and pathogen. For many pathogens, melanin production is associated with virulence. Although other species of Aeromonas can produce melanin, A.s.s is the only member of this genus that has been reported to exhibit temperature-dependent melanization. Here we demonstrate that thermosensitive melanogenesis in A.s.s strains is due to the thermolability of 4-hydroxyphenylpyruvate dioxygenase (HppD). The strictly conserved hppD sequences among A.s.s and the exclusive thermosensitive pigmentation of these strains might provide insight into the role of melanin in the adaptation to a particular host, and offer a novel molecular marker to readily differentiate A.s.s strains from other A. salmonicida subspecies and Aeromonas species.

molecular biology↗

bioRxiv2018

Exosomes exploit the virus entry machinery and pathway to transmit IFN-α-induced antiviral activity.

Interferon- (IFN-) induces the transfer of resistance to hepatitis B virus (HBV) from liver nonparenchymal cells (LNPCs) to hepatocytes via exosomes. However, little is known about the entry machinery and pathway involved in the transmission of IFN--induced antiviral activity. Here, we found that macrophage exosomes depend on T cell immunoglobulin and mucin receptor 1 (TIM-1), a hepatitis A virus (HAV) receptor, to enter hepatocytes for delivering IFN--induced anti-HBV activity. Moreover, two primary endocytic routes for virus infection, clathrin-mediated endocytosis (CME) and macropinocytosis, collaborate to permit exosome entry and anti-HBV activity transfer. Subsequently, lysobisphosphatidic acid (LBPA), an anionic lipid closely related to endosome penetration of virus, facilitates membrane fusion of exosomes in late endosomes/ multivesicular bodies (LEs/MVBs) and the accompanying exosomal cargo uncoating. Together, this study provides comprehensive insights into the transmission route of macrophage exosomes to efficiently deliver IFN--induced anti-HBV activity and highlights the similarities between the entry mechanisms of exosomes and virus.\n\nImportanceOur previous study showed that LNPC-derived exosomes could transmit IFN--induced antiviral activity to HBV replicating hepatocytes, but the concrete transmission mechanisms which include exosome entry and exosomal cargo release remain unclear. In this study, we found that virus entry machinery and pathway were also applied to exosome-mediated cell-to-cell antiviral activity transfer. Macrophage-derived exosomes exploit hepatitis A virus receptor for access to hepatocytes. Later, CME and macropinocytosis are utilized by exosomes which is followed by exosome-endosome fusion for efficient transfer of IFN--induced anti-HBV activity. Dissecting the similarities between exosome and virus entry will be beneficial to designing exosomes as efficient vehicles for antiviral therapy.

microbiology↗