Biology subjects

Zhai, X.

Publications and source records attributed to Zhai, X..

28 records · Page 2Linked to original sources

bioRxiv2021

interpolatedXY: a two-step strategy to normalise DNA methylation microarray data avoiding sex bias

MotivationData normalization is an essential step to reduce technical variation within and between arrays. Due to the different karyotypes and the effects of X chromosome inactivation, females and males exhibit distinct methylation patterns on sex chromosomes, thus it poses a significant challenge to normalise sex chromosome data without introducing bias. Currently, existing methods do not provide unbiased solutions to normalise sex chromosome data, usually, they just process autosomal and sex chromosomes indiscriminately. ResultsHere, we demonstrate that ignoring this sex difference will lead to introducing artificial sex bias, especially for thousands of autosomal CpGs. We present a novel two-step strategy (interpolatedXY) to address this issue, which is applicable to all quantile-based normalisation methods. By this new strategy, the autosomal CpGs are first normalised independently by conventional methods, such as funnorm or dasen; then the corrected methylation values of sex chromosome linked CpGs are estimated as the weighted average of their nearest neighbours on autosomes. The proposed two-step strategy can also be applied to other non-quantile-based normalisation methods, as well as other array-based data types. Moreover, we propose a useful concept: the sex explained fraction of variance, to quantitatively measure the normalisation effect. AvailabilityThe proposed methods are available by calling the function adjustedDasen or adjustedFunnorm in the latest wateRmelon package (https://github.com/schalkwyk/wateRmelon), with methods compatible with all the major workflows, including minfi. Contactxzhai@essex.ac.uk; lschal@essex.ac.uk Supplementary informationSupplementary data are available at...

bioinformatics↗

bioRxiv2021

Large-scale comparative small RNA analyses reveal genomic structural variants in driving expression dynamics and differential selection pressures on distinct small RNA classes during tomato domestication

Tomato has undergone extensive selections during domestication. Recent progress has shown that genomic structural variants (SVs) have contributed to gene expression dynamics during tomato domestication, resulting in changes of important traits. Here, through comprehensive analyses of small RNAs (sRNAs) from nine representative tomato accessions, we demonstrate that SVs substantially contribute to the dynamic expression of the three major classes of plant sRNAs: microRNAs (miRNAs), phased secondary short interfering RNAs (phasiRNAs), and 24-nt heterochromatic siRNAs (hc-siRNAs). Changes in the abundance of phasiRNAs and 24-nt hc-siRNAs likely contribute to the alteration of mRNA gene expression during tomatos recent evolution, particularly for genes associated with biotic and abiotic stress tolerance. We also observe that miRNA expression dynamics are associated with imprecise processing, alternative miRNA-miRNA* selections, and SVs. SVs mainly affect the expression of less-conserved miRNAs that do not have established regulatory functions or low abundant members in highly expressed miRNA families, highlighting different selection pressures on miRNAs compared to phasiRNAs and 24-nt hc-siRNAs. Our findings provide insights into plant sRNA evolution as well as SV-based gene regulation during crop domestication. Furthermore, our dataset provides a rich resource for mining the sRNA regulatory network in tomato.

plant biology↗

bioRxiv2020

DNA methylation-based sex classifier to predict sex and identify sex chromosome aneuploidy

Sex is an important covariate of epigenome-wide association studies due to its strong influence on DNA methylation patterns across numerous genomic positions. Nevertheless, many samples on the Gene Expression Omnibus (GEO) frequently lack a sex annotation or are incorrectly labelled. Considering the influence that sex imposes on DNA methylation patterns, it is necessary to ensure that methods for filtering poor samples and checking of sex assignment are accurate and widely applicable. In this paper, we presented a novel method to predict sex using only DNA methylation density signals, which can be readily applied to almost all DNA methylation datasets of different formats (raw IDATs or text files with only density signals) uploaded to GEO. We identified 4345 significantly (p < 0.01) sex-associated CpG sites present on both 450K and EPIC arrays, and constructed a sex classifier based on the two first components of PCAs from the two sex chromosomes. The proposed method is constructed using whole blood samples and exhibits good performance across a wide range of tissues. We further demonstrated that our method can be used to identify samples with sex chromosome aneuploidy, this function is validated by five Turner syndrome cases and one Klinefelter syndrome case. The proposed method has been integrated into the wateRmelon Bioconductor package.

bioinformatics↗

bioRxiv2020

Enrofloxacin shifts intestinal microbiota and metabolic profiling and hinders recovery from Salmonella enterica subsp. enterica serovar Typhimurium infection in neonatal chickens

Enrofloxacin is an important antibiotic used for prevention and treatment of Salmonella infection in poultry in many countries. However, oral administration of enrofloxacin may lead to the alterations in the microbiota and metabolome in the chicks intestine, thereby reducing colonization resistance to the Salmonella infection. To study the effects of enrofloxacin on chicken cecal Salmonella, we used different concentrations of enrofloxacin to feed 1-day-old chickens, followed by oral challenge with Salmonella enterica subsp. enterica serovar Typhimurium (S. Typhimurium). We then explored the distribution patterns of S. Typhimurium in vivo in intestinal contents using quantitative polymerase chain reaction and microbial 16S amplicon sequencing on days 7, 14, and 21. Metabolome sequencing was used to explore the gut metabolome on day 14. Faecalibacterium and Anaerostipes, which are closely related to the chicken intestinal metabolome, were screened using a multi-omics technique. The abundance of S. Typhimurium was significantly higher in the enrofloxacin-treated group than in the untreated group, and S. Typhimurium persisted longer. Moreover, the cecal colony structures of the three groups exhibited different characteristics, with Lactobacillus reaching its highest abundance on day 21. Notably, S. Typhimurium infection is known to affect the fecal metabolome of chickens differently. Thus, our results suggested that enrofloxacin and Salmonella infections completely altered the intestinal metabolism of chickens. IMPORTANCEIn this study, we examined the effects of S. Typhimurium infection and enrofloxacin treatment on the microbial flora and metabolite synthesis in chicken guts in order to identify target metabolites that may cause S. Typhimurium colonization and severe inflammation and to evaluate the important flora that may be associated with these metabolites. Our findings may facilitate the use of antibiotics to prevent S. Typhimurium infection.

microbiology↗

bioRxiv2020

Comparison of SARS-CoV-2 spike protein binding to human, pet, farm animals, and putative intermediate hosts ACE2 and ACE2 receptors

The emergence of a novel coronavirus, SARS-CoV-2, resulted in a pandemic. Here, we used recently released X-ray structures of human ACE2 bound to the receptor-binding domain (RBD) of the spike protein (S) from SARS-CoV-2 to predict its binding to ACE2 proteins from different animals, including pets, farm animals, and putative intermediate hosts of SARS-CoV-2. Comparing the interaction sites of ACE2 proteins known to serve or not serve as receptor allows to define residues important for binding. From the 20 amino acids in ACE2 that contact S up to seven can be replaced and ACE2 can still function as the SARS-CoV-2 receptor. These variable amino acids are clustered at certain positions, mostly at the periphery of the binding site, while changes of the invariable residues prevent S-binding or infection of the respective animal. Some ACE2 proteins even tolerate the loss or the acquisition of N-glycosylation sites located near the S-interface. Of note, pigs and dogs which are not or not effectively infected, respectively, have only a few changes in the binding site have relatively low levels of ACE2 in the respiratory tract. Comparison of the RBD of S of SARS-CoV-2 with viruses from bat and pangolin revealed that the latter contains only one substitution, whereas the bat virus exhibits five. However, ACE2 of pangolin exhibit seven changes relative to human ACE2, a similar number of substitutions is present in ACE2 of bats, raccoon, and civet suggesting that SARS-CoV-2 may not especially adapted to ACE2 of any of its putative intermediate hosts. These analyses provide new insight into the receptor usage and animal source/origin of SARS-COV-2. IMPORTANCESARS-CoV-2 is threatening people worldwide and there are no drugs or vaccines available to mitigate its spread. The origin of the virus is still unclear and whether pets and livestock can be infected and transmit SARS-CoV-2 are important and unknown scientific questions. Effective binding to the host receptor ACE2 is the first prerequisite for infection of cells and determines the host range. Our analysis provides a framework for the prediction of potential hosts of SARS-CoV-2. We found that ACE2 from species known to support SARS-CoV-2 infection tolerate many amino acid changes indicating that the species barrier might be low. However, the lower expression of ACE2 in the upper respiratory tract of some pets and livestock means more research and monitoring should be done to explore the animal source of infection and the risk of potential cross-species transmission. Finally, the analysis also showed that SARS-CoV-2 may not specifically adapted to any of its putative intermediate hosts.

bioinformatics↗

bioRxiv2020

Distinct midbrain response statistics are associated with sound recognition and discrimination during the construction of natural sound textures

The perception of sound textures, a class of natural sounds defined by statistical sound structure such as fire wind, and rain, has been proposed to arise through the integration of time-averaged summary statistics. Where and how the auditory system might encode these summary statistics to create internal representations of these stationary sounds, however, is unknown. Here, using natural textures and synthetic variants with reduced statistics, we show that summary statistics modulate the correlations between frequency organized neuron ensembles in the awake rabbit inferior colliculus. These neural ensemble correlation statistics capture high-order sound structure and allow for accurate neural decoding in a single trial recognition task with evidence accumulation times approaching 1 s. In contrast, the average activity across the neural ensemble (neural spectrum) provides a fast (tens of ms) and salient signal that contributes primarily to texture discrimination. Intriguingly, perceptual studies in human listeners reveals analogous trends: the sound spectrum is integrated quickly and serves as salient discrimination cue while high-order sound statistics are integrated slowly and contribute substantially more towards recognition. The findings suggest statistical sound cues such as the sound spectrum and correlation structure are represented by distinct response statistics in auditory midbrain ensembles, and that these neural response statistics may have dissociable roles and time scales for the recognition and discrimination of natural sounds. SIGNIFICANCE STATEMENTBeing able to recognize and discriminate natural sounds, such as from a running stream, a crowd clapping, or ruffling leaves is a critical task of the normal functioning auditory system. Humans can easily perform such tasks, yet they can be particularly difficult for the hearing impaired and they challenge our most sophisticated computer algorithms. This difficulty is attributed to the complex physical structure of such natural sounds and the fact they are not unique: they vary randomly in a statistically defined manner from one excerpt to the other. Here we provide the first evidence, to our knowledge, that the central auditory system is able to encode and utilize statistical sound cues for natural sound recognition and discrimination behaviors.

neuroscience↗

bioRxiv2019

Co-translational folding allows misfolding-prone proteins to circumvent deep kinetic traps

Many large proteins suffer from slow or inefficient folding in vitro. Here, we provide evidence that this problem can be alleviated in vivo if proteins start folding co-translationally. Using an all-atom simulation-based algorithm, we compute the folding properties of various large protein domains as a function of nascent chain length, and find that for certain proteins, there exists a narrow window of lengths that confers both thermodynamic stability and fast folding kinetics. Beyond these lengths, folding is drastically slowed by non-native interactions involving C-terminal residues. Thus, co-translational folding is predicted to be beneficial because it allows proteins to take advantage of this optimal window of lengths and thus avoid kinetic traps. Interestingly, many of these proteins sequences contain conserved rare codons that may slow down synthesis at this optimal window, suggesting that synthesis rates may be evolutionarily tuned to optimize folding. Using kinetic modelling, we show that under certain conditions, such a slowdown indeed improves co-translational folding efficiency by giving these nascent chains more time to fold. In contrast, other proteins are predicted not to benefit from co-translational folding due to a lack of significant non-native interactions, and indeed these proteins sequences lack conserved C-terminal rare codons. Together, these results shed light on the factors that promote proper protein folding in the cell, and how biomolecular self-assembly may be optimized evolutionarily.\n\nSignificance StatementMany proteins must adopt a specific structure in order to perform their functions, and failure to do so has been linked to disease. Although small proteins often fold rapidly and spontaneously to their native conformations, larger proteins are less likely to fold correctly due to the myriad incorrect arrangements they can adopt. Here, we show that this problem can be alleviated if proteins start folding while they are being translated, namely, built one amino acid at a time on the ribosome. This process of co-translational folding biases certain proteins away from misfolded states that tend to hinder spontaneous refolding. Signatures of unusually slow translation suggest that some of these proteins have evolved to fold co-translationally.

biophysics↗

bioRxiv2018

A Neural Ensemble Correlation Code for Sound Category Identification

Humans and other animals effortlessly identify sounds and categorize them into behaviorally relevant categories. Yet, the acoustic features and neural transformations that enable the formation of perceptual categories are largely unknown. Here we demonstrate that correlation statistics between frequency-organized cochlear sound channels are reflected in the neural ensemble activity of the auditory midbrain and that such activity, in turn, can contribute to discrimination of perceptual categories. Using multi-channel neural recordings in the auditory midbrain of unanesthetized rabbits, we first demonstrate that neuron ensemble correlations are highly structured in both time and frequency and can be decoded to distinguish sounds. Next, we develop a probabilistic framework for measuring the nonstationary spectro-temporal correlation statistics between frequency organized channels in an auditory model. In a 13-category sound identification task, classification accuracy is consistently high (>80%), improving with sound duration and plateauing at ~ 1-3 seconds, mirroring human performance trends. Nonstationary short-term correlation statistics are more informative about the sound category than the time-average correlation statistics (84% vs. 73% accuracy). When tested independently, the spectral and temporal correlations between the model outputs achieved a similar level of performance and appear to contribute equally. These results outline a plausible neural code in which correlation statistics between neuron ensembles of different frequencies can be read-out to identify and distinguish acoustic categories.

neuroscience↗

bioRxiv2017

A stable beneficial symbiotic relationship between endophytic fungus Schizophyllum commune and host plant Panax ginseng

Endophytes and plants can establish specific long-term symbiosis through the accumulation of secondary metabolites. Interactions between microbial inhabitants represent a novel area of study for natural products research. In this study, a strain of endophyte 3R-2 that can enhance the biomass and contents of ginsenoside Rc, ginsenoside Rg2 and ginsenoside Rg3 of Panax ginseng hairy roots was screened out via HPLC, which was identified as Schizophyllum commune through the morphological and molecular identification. On the base, we found the infection of the endophyte were obviously observed widely in the P. ginseng and the strain formed a stable relationship with P. ginseng hairy roots in parenchyma cells around through tissues embedding slicing, HE ammonium silver staining and immunofluorescence staining. On the other hand, elicitors of fungus 3R-2 can also significantly promote hairy root growth and contents of several ginsenosides, even several times higher than 3R-2 mycelium did. Moreover, S. commune 3R-2 mycelium and its elicitor could enhance the transcriptional activity of key genes during the ginsenosides biosynthetic pathway dramatically. Thus, endophyte S. commune 3R-2 and its elicitor change the chemical substance content by regulating the expression of genes involved in the secondary metabolite biosynthetic pathway.

plant biology↗

bioRxiv2017

Endophyte Chaetomium globosum D38 and its elicitors promote tanshinones accumulation of Salvia miltiorrhiza

Due to the low yield of tanshinones and their analogues in Salvia miltiorrhiza, there are all kinds of stimulation strategies having been applied to improve tanshinones output in plant tissue cultures. Endophytic fungi have formed various different relationships with their host plants withstanding host and environmental factors, including symbiotic, mutualistic, commensalistic, and parasitic. Thus we take the assumption that endophytic fungi may be an emerging microbial tool used to promote secondary metabolism, which will promote the production of active compounds through endophyte-based biology method. Our study therefore aimed to examine the effects of live endophytic fungus Chaetomium globosum D38 and its elicitors on the accumulation of tanshinones in hairy root cultures of Salvia miltiorrhiza. C. globosum D38 mainly colonized in the intercellular gap of xylem parenchyma cells of S. miltiorrhiza hairy root, during long term co-existence without any toxicity against S. miltiorrhiza hairy root. Moreover, both of the live fungus and its mycelia extracts could induce the production of tanshinones, in special dihydrotanshinone I and cryptotanshinone. The effects of mycelia extracts were much stronger than that of the live fungus on tanshinones synthesis, which increased the transcriptional activity of genes with repect to tanshinone biosynthetic pathway obviously. Our results indicated that both of the live C. globosum D38 and its mycelia extracts could be utilized for tanshinones accumulation in S. miltiorrhiza hairy root. Whats more, D38 also could be made into biotic fertilizer applying into S.miltiorrhiza seddlings, which not only promoted host growth but the tanshinones and phenylpropionic acid accumulation. In the soil environment, D38 had formed bitrophic and mutual beneficial relationship with the host and enhanced the primary metabolism on the whole so as to have facilitative effects on phenylpropionic acid accumulation. To sum up, Chaetomium globosum D38 was a highly effective endophytic fungus for S. miltiorrhiza.

developmental biology↗