Biology subjects

Ding, N.

Publications and source records attributed to Ding, N..

At least 37 records · Page 2Linked to original sources

bioRxiv2023

Homocysteine accelerates hepatocyte autophagy by upregulation of TFEB via DNMT3b-mediated DNA hypomethylation

Autophagy plays a critical role in the physiology and pathophysiology of hepatocytes. High levels of homocysteine (Hcy) promote autophagy in hepatocytes, but the underlying mechanism is still unknown. Here, we investigated the relation between Hcy increased autophagy levels and the expression of nuclear transcription factor EB (TFEB). We demonstrate that Hcy increased autophagy levels is mediated by upregulation of TFEB. Silencing TFEB decreases the autophagy-related protein LC3BII/I and increases p62 expression levels in hepatocytes after exposure to Hcy. Moreover, the effect of Hcy on the expression of TFEB is regulated by hypomethylation of TFEB promoter catalyzed by DNA methyltransferase 3b (DNMT3b). In summary, this study shows that Hcy can activate autophagy by inhibiting DNMT3b-mediated DNA methylation and upregulating TFEB expression. These findings provide another new mechanism for Hcy-induced autophagy in hepatocytes.

cell biology↗

bioRxiv2022

Exploring the interaction between immune cells in testicular microenvironment of azoospermia combining RNA-seq and scRNA-seq

Non-obstructive azoospermia is the most serious cause of male infertility. The testis has a special immunological environment, but the relationship between immune cells in the testicular microenvironment is still unclear. Therefore, it is urgent to identify the interaction mechanism and molecular determinants of immune cells in the testicular microenvironment. To further elucidate the etiology of azoospermia and provide a reference for the treatment of azoospermia. The GSE145467 and GSE9210 datasets were analyzed by Limma package, and then the differential genes were analyzed by enrichment analysis and protein-protein interaction analysis. In addition, we combined single-cell analysis(scRNA) to identify immune cell types and verified the expression of Hub genes in these immune cells. Finally, CellChat was used for cell-to-cell communication analysis. We found the distribution of immune cells in the microenvironment of Y chromosome AZF region microdeletions (AZFa_Del), idiopathic NOA (iNOA), and Klinefelter syndrome (KS) was significantly different from that of normal adults, especially monocytes/macrophages. In normal subjects, monocytes/macrophages mainly played the role of the signal source, while in patients with azoospermia, monocytes/macrophages mainly received signals from other immune cells. Monocytes/macrophages in AZFa_Del, iNOA, and KS communicated with other immune cells mainly through MDK-LRP1, PTN-NCL, and MDK-NCL ligand-receptor pairs respectively. Our research provides new ideas for the pathogenesis and treatment of azoospermia. Author SummaryThis article uses the datasets in the public database, including RNA-seq and scRNA-seq. It is a secondary analysis of these databases. Previous studies have found the destruction of Sertoli cells in the testicular microenvironment using scRNA datasets. We have analyzed immune cells in the testicular microenvironment based on previous studies. Found huge changes in macrophages and abnormal macrophages communication through cell communication analysis, The receptor-ligand pairs were screened to provide a basis for the study of macrophages in the testicular microenvironment and the treatment of azoospermia.

cell biology↗

bioRxiv2022

A genome wide association study identifies a new variant associated with word reading fluency in Chinese children

Reading disability exhibited defects in different cognitive domains, including word reading fluency, word reading accuracy, phonological awareness, rapid automatized naming, and morphological awareness. To identify the genetic basis of Chinese reading disability, we conducted a genome wide association study (GWAS) of the cognitive traits related to Chinese reading disability in 2284 unrelated Chinese children. Among the traits analyzed in the present GWAS, we detected one genome wide significant association (p<5x10-8) on reading fluency for one SNP on 4p16.2, within EVC genes (rs6446395, p=7.55x10-10). Rs6446395 also showed significant association with word reading accuracy (p=3.39x10-4), phonological awareness (p=7.12x10-3), and rapid automatized naming (p=4.71x10-3), implying multiple effects of this variant. Gene-based analyses identified a gene to be associated with reading fluency at the genome-wide level. The eQTL data showed that rs6446395 affected EVC expression in the cerebellum. Our study discovered a new candidate susceptibility variant for reading ability and provide new insights into the genetics of development dyslexia in Chinese Children.

genetics↗

bioRxiv2022

Acoustic Correlates of the Syllabic Rhythm of Speech: Modulation Spectrum or Local Features of the Temporal Envelope

The speech envelope is considered as a major acoustic correlate of the syllable rhythm since the peak frequency in the speech modulation spectrum matches the mean syllable rate. Nevertheless, it has not been quantified whether the peak modulation frequency can track the syllable rate of individual utterances and how much variance of the speech envelope can be explained by the syllable rhythm. Here, we address these problems by analyzing large speech corpora (>1000 hours of recording of multiple languages) using advanced sequence-to-sequence modeling. It is found that, only when averaged over minutes of speech recordings, the peak modulation frequency of speech reliably correlates with the syllable rate of a speaker. In contrast, the phase-locking between speech envelope and syllable onsets is robustly observed within a few seconds of recordings. Based on speaker-independent linear and nonlinear models, the timing of syllable onsets explains about 13% and 46% variance of the speech envelope, respectively. These results demonstrate that local temporal features in the speech envelope precisely encodes the syllable onsets but the modulation spectrum is not always dominated by the syllable rhythm.

neuroscience↗

bioRxiv2022

Transcription factor determines the sources of extracellular vesicle DNA

Extracellular vesicle DNAs (evDNAs) possess the important diagnostic value for multiple diseases and play roles for horizontally transferring genetic materials among cells. In this study, we have found that transcription factor FOXM1 can mediate the loading of certain chromatin genes or DNA fragments (named FOXM1-chDNAs) to extracellular vesicles (EVs). FOXM1 interacts with LC3 in nucleus and FOXM1-chDNAs (such as DUX4 gene and Telomere DNA) are specified by FOXM1 and translocated to cytoplasm. These DNAs are released to EVs through the process of an LC3-involved autophagosome-multivesicular body (MVB) transport. The roles of FOXM1 on loading FOXM1-chDNAs to EVs are further confirmed by DNA-FISH experiments, tracing the translocation of selected chromatin loci with the TetO/TetR-GFP method, and PCR analysis of the DNA samples from MVBs and EVs. Furthermore, disrupting the expression of FOXM1 or the process of autophagosome-MVB transport impairs the loading of FOXM1-chDNAs to EVs. This discovery suggests that transcription factor FOXM1 contributes the constitution of evDNAs from nuclear chromatin, providing the first example to explain how chromatin DNA fragments are specified and loaded to EVs. It also provide a foundation to further explore the roles of evDNAs in biological processes such as the horizontal gene transfer.

cell biology↗

bioRxiv2021

The different brain areas occupied for integrating information of hierarchical linguistic units: a study based on EEG and TMS

Human linguistic units are hierarchical, and our brain responds differently when processing linguistic units during sentence comprehension, especially when the modality of the received signal is different (auditory, visual, or audio-visual). However, it is unclear how the brain processes and integrates language information at different linguistic units (words, phrases, and sentences) provided simultaneously in audio and visual modalities. To address the issue, we presented participants with sequences of short Chinese sentences through auditory or visual or combined audio- visual modalities, while electroencephalographic responses were recorded. With a frequency tagging approach, we analyzed the neural representations of basic linguistic units (i.e., characters/monosyllabic words) and higher-level linguistic structures (i.e., phrases and sentences) across the three modalities separately. We found that audio-visual integration occurs at all linguistic units, and the brain areas involved in the integration varied across different linguistic levels. In particular, the integration of sentences activated the local left prefrontal area. Therefore, we used continuous theta-burst stimulation (cTBS) to verify that the left prefrontal cortex plays a vital role in the audio-visual integration of sentence information. Our findings suggest the advantage of bimodal language comprehension at hierarchical stages in language-related information processing and provide evidence for the causal role of the left prefrontal regions in processing information of audio-visual sentences.

neuroscience↗

bioRxiv2021

Genome sequences of the five Sitopsis species of Aegilops and the origin of polyploid wheat B-subgenome

Bread wheat (Triticum aestivum L., BBAADD) is a major staple food crop worldwide. The diploid progenitors of the A- and D-subgenomes have been unequivocally identified, that of B however remains ambiguous and controversial but is suspected to be related to species of Aegilops, section Sitopsis. Here, we report the assembly of chromosome-level genome sequences of all five Sitopsis species, namely Ae. bicornis, Ae. longissima, Ae. searsii, Ae. sharonensis, and Ae. speltoides, as well as partial assembly of Ae. mutica genome for phylogenetic analysis. Our results support that the donor of bread wheat B-subgenome is a distinct, probably extinct, diploid species that diverged from an ancestral progenitor of the B-lineage similar to Ae. mutica and Ae. speltoides. The five Sitopsis species have variable genome sizes (4.11-5.89 Gb) with high proportions of repetitive sequences (85.99-89.81%); nonetheless, they retain high collinearity with other wheat genomes. Differences in genome size are primarily due to independent post-speciation amplification of transposons rather than to inter-specific genetic introgression. We also identified a set of Sitopsis genes pertinent to important agronomic traits that can be harnessed for wheat breeding. These resources provide a new roadmap for evolutionary and genetic studies of the wheat group. SignificanceThe origin of the B-subgenome of hexaploid bread wheat remains unknown. Here we report the assembly of chromosome-level genome sequences of all five Sitopsis species of the genus Aegilops, which are previously considered as possible direct progenitors or contributors to the B-subgenome. Our comparative genomic analyses reveal that the B-subgenome originated from an unknown, most likely extinct species phylogenetically distinct from Ae. speltoides, its extant closest relative. We also provide evidence that Ae. speltoides is neither the direct progenitor of the G-subgenome of tetraploid wheat Triticum timopheevii. The high-quality Sitopsis genomes provide novel avenues to identify new important genes for wheat breeding.

evolutionary biology↗

bioRxiv2020

Precision methylome and in vivo methylation kinetics characterization of Klebsiella pneumoniae

Klebsiella pneumoniae (K. pneumonia) is an important pathogen that can cause severe hospital-/community-acquired infections. To panoramically analyze K. pneumoniaes methylation features, we completed the whole genome sequences of 14 K. pneumoniae strains covering various serotypes, multilocus-sequence typings (MLSTs), clonal groups (CG), viscosity/virulence and drug-resistances, and further characterized their methylomes using PacBio-SMRT and bisulfite technologies. We identified 15 methylation motifs (13 6mA and two 5mC motifs), among which eight were novel ones. Their corresponding MTases were further validated. Additionally, we analyzed the genomic distribution of GATC and CCWGG methylation motifs shared by all strains, and identified differential distributive patterns of some hemi/un-methylated GATC motifs tending to locate in the intergenic regions (IGRs). Specifically, we characterized the in vivo methylation kinetics at single-base resolution on a genome-wide scale by simulating the dynamic processes of replication-mediated passive demethylation and MTase-catalyzed re-methylation. The slower methylation-rates of the GATC motifs in the replication origins (oriC) and IGRs suggest an epigenetic mechanism implicated in the regulation of replication-initiation and transcription. Our findings illustrate the first comprehensive dynamic methylome map of K. pneumonia at single base resolution, and provide an efficient means and important reference for a better understanding of epigenetic regulation in bacteria.

genomics↗

bioRxiv2020

Delta-band Cortical Tracking of Acoustic and Linguistic Features in Natural Spoken Narratives

Speech contains rich acoustic and linguistic information. During speech comprehension, cortical activity tracks the acoustic envelope of speech. Recent studies also observe cortical tracking of higher-level linguistic units, such as words and phrases, using synthesized speech deprived of delta-band acoustic envelope. It remains unclear, however, how cortical activity jointly encodes the acoustic and linguistic information in natural speech. Here, we investigate the neural encoding of words and demonstrate that delta-band cortical activity tracks the rhythm of multi-syllabic words when naturally listening to narratives. Furthermore, by dissociating the word rhythm from acoustic envelope, we find cortical activity primarily tracks the word rhythm during speech comprehension. When listeners attention is diverted, however, neural tracking of words diminishes, and delta-band activity becomes phase locked to the acoustic envelope. These results suggest that large-scale cortical dynamics in the delta band are primarily coupled to the rhythm of linguistic units during natural speech comprehension.

neuroscience↗

bioRxiv2020

Neural harmonics reflect grammaticality

Can neural rhythms reflect purely internal syntactic processes in multi-word constructions? To test this controversial conjecture - relevant to language in particular and cognition more broadly - we recorded electroencephalographic and behavioural data as participants listened to isochronously presented sentences of varying in syntactic complexity. Each trial comprised ten concatenated sentences and was either fully grammatical (regular) or rendered ungrammatical via randomly distributed word order violations. We found that attending the regular repetition of abstract syntactic categories (phrases and sentences) generates neural rhythms whose harmonics are mathematically independent of word rate. This permits to clearly separate endogenous syntactic rhythms from exogenous speech rhythms. We demonstrate that endogenous but not exogenous rhythms predict participants grammaticality judgements, and allow for the neural decoding of regular vs. irregular trials. Neural harmonic series constitute a new form of behaviourally relevant evidence for syntactic competence.

neuroscience↗

bioRxiv2020

Chidamide decreases c-MET mRNA methylation and in turn increases the sensitivity of non-small cell lung cancer to crizotinib

IntroductionCrizotinib is a kinase inhibitor targeting c-MET/ALK/ROS1 used as the first-line chemical for the treatment of non-small cell lung cancer (NSCLC) with ALK mutations. Although c-MET is frequently overexpressed in 35-72% of NSCLC, most NSCLCs are primarily resistant to crizotinib treatment. MethodA set of NSCLC cell lines were used to test the effect of chidamide on the crizotinib sensitivity in vitro and in vivo. Relationships between the synergistic effect of chidamide and c-MET expression and RNA methylation were systemically studied with a battery of molecular biological assays. ResultsWe found for the first time that chidamide could increase the crizotinib sensitivity of a set of ALK mutation-free NSCLC cell lines, especially those with high levels of c-MET expression. Notably, chidamide could not increase the crizotinib sensitivity of NSCLC cells cultured in serum-free medium without hepatocyte growth factor (HGF; a c-MET ligand). In contrast, the addition of HGF into the serum-/HGF-free medium could restore the synergistic effect of chidamide. Moreover, the synergistic effect of chidamide could also be abolished either by treatment with c-MET antibody or siRNA-knockdown of c-MET expression. While cells with low or no c-MET expression were primarily resistant to chidamide-crizotinib cotreatment, enforced c-MET overexpression could increase the sensitivity of these cells to chidamide-crizotinib cotreatment. Furthermore, chidamide could decrease c-MET expression by inhibiting mRNA N6-methyladenosine (m6A) modification through the downregulation of METTL3 and WTAP expression. Chidamide-crizotinib cotreatment significantly suppressed the activity of c-MET downstream molecules. Conclusionchidamide downregulated c-MET expression by decreasing its mRNA m6A methylation, subsequently increasing the crizotinib sensitivity of NSCLC cells in a c-MET-/HGF-dependent manner. GRAPHIC SUMMARY O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=126 SRC="FIGDIR/small/012971v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@5a81d4org.highwire.dtl.DTLVardef@19f1forg.highwire.dtl.DTLVardef@75d74forg.highwire.dtl.DTLVardef@8a9f77_HPS_FORMAT_FIGEXP M_FIG C_FIG

pharmacology and toxicology↗

bioRxiv2020

The lupus autoantigen La is an Xist-binding RNA chaperone involved in Xist folding and cloud formation

Using the programmable RNA-sequence binding domain of the Pumilio protein, we FLAG-tagged Xist (inactivated X chromosome specific transcript) in live cells. Affinity pulldown coupled to mass spectrometry was employed to identify a list of 138 candidate Xist-binding proteins, from which, the lupus autoantigen La (encoding gene Ssb) was validated as a protein functionally critical for X chromosome inactivation (XCI). Extensive XCI defects were detected in Ssb knockdown cells, including chromatin compaction, death of female ES cells during in vitro differentiation and chromosome-wide monoallelic gene expression pattern. Live-cell imaging of Xist RNA reveals the defining XCI defect: Xist cloud formation. La is a ubiquitous and versatile RNA-binding protein with RNA chaperone and RNA helicase activities. Functional dissection of La shows that the RNA chaperone domain and/or the ATP binding motif play critical roles in XCI. In mutant cells, Xist transcripts are unstable and misfolded. These results show that La is critically involved in XCI, possibly as a protein regulating the in-cell structure of Xist.

molecular biology↗

bioRxiv2020

GPU accelerated partial order multiple sequencealignment for long reads self-correction

As third generation sequencing technologies become more reliable and widely used to solve several genome-related problems, self-correction of long reads is becoming the preferred method to reduce the error rate of Pacific Biosciences and Oxford Nanopore long reads, that is now around 10-12%. Several of these self-correction methods rely on some form of Multiple Sequence Alignment (MSA) to obtain a consensus sequence for the original reads. In particular, error-correction tools such as RACON and CONSENT use Partial Order (PO) graph alignment to accomplish this task. PO graph alignment, which is computationally more expensive than optimal global pairwise alignment between two sequences, needs to be performed several times for each read during the error correction process. GPUs have proven very effective in accelerating several compute-intensive tasks in different scientific fields. We harnessed the power of these architectures to accelerate the error correction process of existing self-correction tools, to improve the efficiency of this step of genome analysis. In this paper, we introduce a GPU-accelerated version of the PO alignment presented in the POA v2 software library, implemented on an NVIDIA Tesla V100 GPU. We obtain up to 6.5x speedup compared to 64 CPU threads run on two 2.3 GHz 16-core Intel Xeon Processors E5-2698 v3. In our implementation we focused on the alignment of smaller sequences, as the CONSENT segmentation strategy based on k-mer chaining provides an optimal opportunity to exploit the parallel-processing power of GPUs. To demonstrate this, we have integrated our kernel in the CONSENT software. This accelerated version of CONSENT provides a speedup for the whole error correction step that ranges from 1.95x to 8.5x depending on the input reads.

bioinformatics↗

bioRxiv2020

Fine-tuning biosensor dynamic range based on rational design of cross-ribosome-binding sites in bacteria

Currently, predictive translation tuning of regulatory elements to the desired output of transcription factor based biosensors remains a challenge. The gene expression of a biosensor system must exhibit appropriate translation intensity, which is controlled by the ribosome-binding site (RBS), to achieve fine-tuning of its dynamic range (i.e., fold change in gene expression between the presence and absence of inducer) by adjusting the translation initiation rate of the transcription factor and reporter. However, existing genetically encoded biosensors generally suffer from unpredictable translation tuning of regulatory elements to dynamic range. Here, we elucidated the connections and partial mechanisms between RBS, translation initiation rate, protein folding and dynamic range, and presented a rational design platform that predictably tuned the dynamic range of biosensors based on deep learning of large datasets cross-RBSs (cRBSs). A library containing 24,000 semi-rationally designed cRBSs was constructed using DNA microarray, and was divided into five sub-libraries through fluorescence-activated cell sorting. To explore the relationship between cRBSs and dynamic range, we established a classification model with the cRBSs and average dynamic range of five sub-libraries to accurately predict the dynamic range of biosensors based on convolutional neural network in deep learning. Thus, this work provides a powerful platform to enable predictable translation tuning of RBS to the dynamic range of biosensors.

bioinformatics↗

bioRxiv2019

Genetic and epigenetic mechanisms underpinning the adaptive radiation of Aquilegia species

Elucidating the genetic and epigenetic bases underlying species diversification is crucial to understanding the evolution and persistence of biodiversity. As a well-known horticultural plant grown worldwide, the genus Aquilegia (columbine) is also a model system in adaptive radiation research. In this study, we surveyed the genomes and DNA methylomes of ten representative Aquilegia species from the Asian, European and North American lineages. Our inferences of the phylogenies and population structure revealed clearly high genetic and DNA methylomic divergence across the three lineages. By multi-levelled genome-wide scanning, we identified candidate genes exhibiting lineage-specific genetic or epigenetic variation patterns that are signatures of inter-specific divergence. We demonstrated that these species diversification-associated genetic variations and epigenetic variabilities were partially independent but were both functionally related to various biological processes vital to adaptation, including stress tolerance, cell reproduction and DNA repair. Our study provides an exploratory overview of how the established genetic and epigenetic signatures are associated with the rapid radiation of Aquilegia species.

plant biology↗

bioRxiv2019

ASK1/p38-mediated NLRP3 inflammasome signaling pathway contributed to aberrant retinal angiogenesis in diabetic retinopathy

AbstractsDiabetic retinopathy is the leading cause of blindness in the working-age population in many countries. Despite the available treatments, some patients present late in the course of the disease when treatment is more difficult. Hence, it is crucial that the new targets are found and utilized in clinical therapy of diabetic retinopathy. In this study, we constructed the DR animal model and the high model in HRMEC cell to investigate the relationship between ASK1/p38 and NLRP3 in DR. The results showed that DR could cause the inflammatory response and microvascular proliferation. NLRP3 contributed to DR-mediated inflammatory development and progression, which promoted the inflammatory related cytokine expression. Meanwhile, it could promote the tube formation of retinal microvascular endothelial and angiogenesis. Moreover, further research showed that NLRP3 mediated aberrant retinal angiogenesis in diabetic retinopathy was regulated by ASK1 and p38. It suggested that ASK1/p38 could become a new target in DR treatment.

cell biology↗

bioRxiv2019

Low-frequency Neural Activity Reflects Rule-based Chunking during Speech Listening

Cortical activity tracks the rhythms of phrases and sentences during speech comprehension, which has been taken as strong evidence that the brain groups words into multi-word chunks. It has prominently been argued, in contrast, that the tracking phenomenon could be explained as the neural tracking of word properties. Here we distinguish these two hypotheses based on novel tasks in which we dissociate word properties from the chunk structure of a sequence. Two tasks separately require listeners to group semantically similar or semantically dissimilar words into chunks. We demonstrate that neural activity actively tracks task-related chunks rather than passively reflecting word properties. Furthermore, without an explicit chunk processing task, neural activity barely tracks chunks defined by semantic similarity - but continues to robustly track syntactically well-formed meaningful sentences. These results suggest that cortical activity tracks multi-word chunks constructed by either long-term syntactic rules or temporary task-related rules. The properties of individual words are likely to contribute only in a minor way, contrary to recent claims.

neuroscience↗

bioRxiv2019

Genomic sequencing of the aquatic Fusarium spp. QHM and BWC1 and their potential application in environmental protection

Fusarium species are distributed widely in ecosystems of a wide pH range and play a pivotal role in the aquatic community through the degradation of xenobiotic compounds and secretion of secondary metabolites. The elucidation of their genome would therefore be highly impactful with regard to the control of environmental pollution. Therefore, in this study, two indigenous strains of aquatic Fusarium, QHM and BWC1, were isolated from a coal mine pit and a subterranean river respectively, cultured under acidic conditions, and sequenced. Phylogenetic analysis of these two isolates was conducted based on the sequences of internal transcript (ITS1 and ITS4) and encoding {beta}-microtubulin (TUB2), translation elongation factors (TEFs) and the second large sub-unit of RNA polymerase (RPB2). Fusarium, QHM could potentially represent a new species within the Fusarium fujikuroi species complex. Fusarium BWC1 were found to form a clade with Fusarium subglutinans NRRL 22016, and predicted to be Fusarium subglutinans. Shot-gun sequencing on the Illumina Hiseqx10 Platform was used to elucidate the draft genomes of the two species. Gene annotation and functional analyses revealed that they had bio-degradation pathways for aromatic compounds; further, their main pathogenic mechanism was found to be the efflux pump. To date, the genomes of only a limited number of acidic species from the Fusarium fujikuroi species complex, especially from the aquatic species, have been sequenced. Therefore, the present findings are novel and have important potential for the future in terms of environmental control.\n\nIMPORTANCEFusarium genus has over 300 species and were distributed in a variety of ecosystem. Increasing attention has been drawn to Fusarium due to the importance in aquatic community, pathogenicity and environmental protection. The genomes of the strains in this work isolated in acidic condition, were sequenced. The analysis has indicated that the isolates were able to biodegrade xenobiotics, which makes it potentially function as environmental bio-agent for aromatic pollution control and remediation. Meanwhile, the virulence and pathogenicity were also predicted for reference of infection control. The genome information may lay foundation for the fungal identification, disease prevention resulting from these isolates and other \"-omics\" research. The isolates were phylogenetically classified into Fusarium fujikuroi species complex by means of concatenated gene analysis, serving as new addition to the big complex.

genomics↗