Biology subjects

Li, Q.

Publications and source records attributed to Li, Q..

At least 505 records · Page 28Linked to original sources

bioRxiv2022

Gene expression signatures underlying inbreeding depression as revealed by whole-transcriptome analysis of selectively bred strains of the Pacific Oyster (Crassostrea gigas)

Exploring molecular mechanisms of inbreeding depression is significant for the conservation and sustainable use of the rare breed with a specific trait of high production value. In this work, we conducted whole-transcriptome analysis of two selectively bred Pacific oyster strains with one inbred strain showing significant growth depression. A total of 7980, 2677, and 28 differentially expressed protein-coding genes (DEGs), lncRNAs (DELs), and miRNAs (DEMs) were identified, respectively. The majority of DEGs and predicted target genes of DELs and DEMs were significantly enriched in biological process including immune response, cell proliferation, and apoptosis pathways. A set of genes with specific expression patterns as revealed by cluster profiling and enrichment analysis were identified, which may underlie inbreeding depression of the inbred strain. Furthermore, a competing endogenous RNA (ceRNA) network was constructed by integrative analysis of DEGs, DELs, and DEMs, supporting that ncRNAs, as regulators of gene expression, could be critical modulators in multiple subsystems involved in inbreeding depression.

genomics↗

bioRxiv2022

Extensive diversity of RNA viruses in ticks revealed by metagenomics in northeastern China

Recently, several emerging tick-borne viruses have been identified to be associated with human diseases in northeastern China. Here, we used metagenomics to investigate the virome diversity in Haemaphysalis japonica, H. conicinna, Dermacentor silvarum, and Ixodes persulcatus ticks in northeastern China. A total of 22 RNA viruses were identified and belonged to more eight viral families, including four each in Nairoviridae and Phenuiviridae, three each in Flaviviridae, Rhabdoviridae, and Solemoviridae, two in Chuviridae, and one each in Partitiviridae, Tombusviridae, and unclassified. Of them, eight viruses were novel species, belonging to Nairoviridae (Jian nairovirus and Yichun nairovirus), Phenuiviridae (Mudanjiang phlebovirus), Rhabdoviridae (Tahe rhabdovirus 1-3), Chuviridae (Yichun mivirus), and Tombusviridae (Yichun tombus-like virus), and five members were established human pathogens, including Alongshan virus, tick-borne encephalitis virus, Songling virus, Beiji nairovirus, and Nuomin virus. I. persulcatus ticks had significant higher viral species than those in H. japonica, H. concinna, and D. silvarum ticks. Significant differences in tick viromes were observed among Daxingan, Xiaoxingan and Changbai mountains. These findings showed an extensive diversity of RNA viruses in ticks in northeastern China, revealed potential public health threats from the emerging tick-borne viruses. Further studies are needed to explain the natural circulation and pathogenicity of these viruses.

microbiology↗

bioRxiv2022

A robust and transformation-free joint model with matching and regularization for metagenomic trajectory and disease onset

BackgroundTo identify operational taxonomy units (OTUs) signaling disease onset in an observational study, a powerful strategy was selecting participants by matched sets and profiling temporal metagenomes, followed by trajectory analysis. Existing trajectory analyses modeled individual OTU or microbial community without adjusting for the within-community correlation and matched-set-specific latent factors. ResultsWe proposed a joint model with matching and regularization (JMR) to detect OTU-specific compositional trajectory predictive of host disease status, using nested random effects and covariate taxa pre-selected by Bray-Curtis distance and elastic net regression. The inherent negative correlation in microbiota composition was adjusted by incorporating the top-correlated taxa as covariate. We designed a simulation pipeline to generate true biomarkers for disease onset and the pseudo biomarkers caused by compositionality or latent noises. We demonstrated that JMR effectively controlled the false discovery and pseudo biomarkers in a simulation study that generated temporal high-dimensional metagenomic counts with random intercept or slope. Application of the competing methods in the simulated data and the TEDDY cohort showed that JMR outperformed the other methods and identified important taxa in infants fecal samples with dynamics preceding host disease status. ConclusionOur method JMR is a robust framework that models taxon-specific compositional trajectory and host disease status in the matched participants, improving the power of detecting disease-predictive microbial features in certain scenarios.

bioinformatics↗

bioRxiv2022

scTour: a deep learning architecture for robust inference and accurate prediction of cellular dynamics

Despite the continued efforts to computationally dissect developmental processes using single-cell genomics, a batch-unaffected tool that is able to both infer and predict the underlying dynamics is lacking. Here, I present scTour, a novel deep learning architecture to perform robust inference and accurate prediction of the cellular dynamics in diverse processes. For inference, scTour can efficiently and simultaneously estimate the developmental pseudotime, intronic read-independent vector field, and transcriptomic latent space under a single, integrated framework. For prediction, scTour can precisely reconstruct the underlying dynamics of unseen cellular states or an independent dataset agnostic to the model. Of note, both the inference and prediction are invariant to batch effects. scTours functionalities are successfully applied to a variety of biological processes from 17 datasets such as cell differentiation, reprogramming and zonation, providing a comprehensive infrastructure to investigate the cellular mechanisms underpinning development in an efficient manner.

bioinformatics↗

bioRxiv2022

WDR47 facilitates cell-specific ciliogenesis by modulating intraflagellar transport

Cilia are conserved organelles found in many cell types in eukaryotes, and their dysfunction causes defects in environmental sensing and signaling transduction; such defects are termed ciliopathies. Distinct cilia have cell-specific morphologies and exert distinct functions. However, the underlying mechanisms of cell-specific ciliogenesis and regulation are unclear. Here we identified a WD40-repeat (WDR) protein, WDR47/NMTN-1, and show that it is specifically required for ciliogenesis of AWB chemosensory neurons in C. elegans. WDR47/NMTN-1 is expressed in the AWB chemosensory neuron pair, and is localized at the basal body (BB) of the AWB cilia. Knockout of wdr47/nmtn-1 causes abnormal AWB neuron cilia morphology, structural integrity, and induces aberrant AWB-mediated aversive behaviors. We further demonstrate that wdr47/nmtn-1 deletion affects movement of intraflagellar transport (IFT) particles and their cargo delivery in AWB neurons. Our results indicate that WDR47/NMTN-1 is essential for AWB neuron ciliary morphology and function, which reveal a novel mechanism for cell-specific ciliogenesis. Since WDR47/NMTN-1 is conserved in mammals, our findings may help understand the process of cell-specific ciliogenesis and provide insights for treating ciliopathies.

developmental biology↗

bioRxiv2022

Cryo-EM Structure of R-loop monoclonal antibody S9.6 in recognizing RNA:DNA hybrids

The three-stranded chromatin structure R-loop is commonly found in the genomes of different species, and functions as the double-edged sword in gene expression and genome stability. The monoclonal antibody S9.6 specifically recognizes RNA:DNA hybrids, and has been widely used as a powerful tool to detect R-loops genome-widely. However, the structure basis and the molecular recognition mechanism of S9.6 to the nucleic acid substrates is still limited. Here, applying cryo-electron microscopy, we have determined a 4.9 [A] structure of S9.6 antigen-binding fragment (Fab) complexed with RNA:DNA hybrids. We found that the native Fab cleaved from S9.6 antibody has much higher affinity to RNA:DNA hybrids than to the double-strand RNAs, and the minimum length of the hybrids should be more than 8 base-pair. The structure of Fab binding to the hybrids suggested one loop of S9.6 heavy chain inserts into the minor groove in the RNA:DNA hybrids, and the other three loops flank to the hybrids. The top of four loop all enrich with aromatic or positive charge residues which are potentially responsible for nucleic acids binding specificity. Our results revealed the recognition mechanism of S9.6 on R-loops, which directs the future engineering of S9.6, and thus could further promote R-loop biology studies.

molecular biology↗

bioRxiv2022

Profiling the diversity of agonist-selective effects on the proximal proteome environment of G protein-coupled receptors

The mu opioid receptor (OR), a prototypic member of the large G protein-coupled receptor (GPCR) family, represents an important target of therapeutic and abused drugs. To date, most of our understanding of OR activity has focused on signal transducers and regulatory molecules including G proteins, GPCR kinases, and beta-arrestins. Yet it is clear that signaling through the OR is coordinated by additional proteins recruited into the proximal interaction network of the activated receptor, which have largely remained invisible given the lack of technologies to interrogate these networks systematically. Here, we implement a quantitative proteomics pipeline leveraging the chemical diversity of OR agonists and APEX-based proximity labeling to investigate the protein networks that underlie OR signaling. We leverage a novel computational framework to extract subcellular location, trafficking, and functional partners of GPCR activity from the proximity labeling datasets. Applying this unbiased, systematic approach to the OR, we demonstrate that opioid agonists exert differences in the OR proximal proteome mediated by endocytosis and subsequent endosomal sorting, exemplified by VPS35 and COMMD3. Moreover, we identify two novel OR network components, EYA4 and KCTD12, that are recruited into the receptor proximal network irrespective of the activating ligand and independent of receptor trafficking but based on receptor-triggered G protein activation. We provide functional evidence that these network components form a previously unrecognized buffering system for G protein activity which broadly modulates cellular GPCR signaling.

systems biology↗

bioRxiv2022

Boosting transformation in wheat by BBM-WUS

Agrobacterium-mediated transformation is a cost-effective and convenient way to introduce foreign genetic elements to plants. However, only limited protocols successfully generates transgenic plants with fielder, a spring wheat variety. Wheat transformation method with higher efficiency and without genotype restriction is heavily demanded. Here, a heat-shock protocol, independent of Japan Tobacco had been established. Transgenic plants can be obtained from immature embryo within only 60 days by this protocol. Morphogenic regulators Baby boom and Wuschel (BBM-WUS) was proved to promote transformation efficiency for five to six times in wheat when co-infiltrated with agrobacterium containing target construct. Notably, half of the transformants are BBM-WUS free and moreover, the BBM-WUS containing plants could be picked by florescent marker that was co-expressed with BBM-WUS. In conclusion, we managed to establish a new wheat transformation protocol with shorter duration than published protocol.

plant biology↗

bioRxiv2022

SRSF10 is essential for progenitor spermatogonia expansion by regulating alternative splicing

Alternative splicing expands the transcriptome and proteome complexity and plays essential roles in tissue development and human diseases. However, how alternative splicing regulates spermatogenesis remains largely unknown. Here, using germ cell-specific knockout mouse model, we demonstrated that the splicing factor Srsf10 is essential for spermatogenesis and male fertility. Depletion of Srsf10 in germ cells had little effect on the formation of SSCs but impeded the expansion of progenitor spermatogonia, leading to the failure of spermatogonia differentiation and meiosis initiation. This was further evidenced by the decreased expression of progenitor cell markers in bulk RNA-seq, and much less progenitor and differentiating spermatogonia in single-cell RNA-seq data. Furthermore, the expression of genes involved in cell cycle was abnormal in all subtypes of spermatogonia identified in single-cell RNA-seq data. Notably, using isolated spermatogonia, we found that Srsf10 depletion disturbed the alternative splicing of hundreds of genes, which were preferentially associated with cell cycle, mitotic cell cycle checkpoint and germ cell development, including Dazl, Kit, Ret, Sycp1, Nasp and Bora. These data suggest that SRSF10 is critical for the expansion of progenitor spermatogonia by regulating alternative splicing, expanding our understanding of the mechanism underlying spermatogenesis.

developmental biology↗

bioRxiv2022

Cholesterol in the cargo membrane reduces kinesin-1 binding to microtubules in the presence of tau

Intracellular cargos are often membrane-bound and transported by microtubule-based motors in the presence of microtubule-associated proteins (MAPs). Whereas increasing evidence reveals how MAPs impact the interactions between motors and microtubules, critical questions remain about the impact of the cargo membrane on transport. Here we combined in vitro optical trapping with theoretical approaches to determine the effect of a lipid cargo membrane on kinesin-based transport in the presence of MAP tau. Attaching kinesins to a fluid lipid membrane decreases the inhibitory effect of tau in comparison to membrane-free cargos. Adding cholesterol, which reduces kinesin diffusion in the cargo membrane, amplifies the inhibitory effect of tau on kinesin in a dosage-dependent manner. Our findings can be understood in a framework in which kinesin diffusion in the cargo membrane counteracts binding-site occlusion by tau. Our study establishes a direct link between the physical properties of cargo membrane and MAP-based regulation of kinesin-1.

biophysics↗

bioRxiv2022

Trophic strategies explain the ocean niches of small eukaryotic phytoplankton

A large fraction of marine primary production is performed by diverse small protists, and many of these phytoplankton are mixotrophs that also consume bacterial prey. However, the mechanisms structuring this diversity and its biogeochemical consequences remain poorly understood. Here we use isolates from seven major taxa to demonstrate tradeoffs between phototrophic and phagotrophic abilities. We then show that trophic strategy along the autotrophy-mixotrophy spectrum correlates strongly with global niche differences, across depths and across gradients of stratification and chlorophyll a. A model of competition shows that community shifts can be explained by greater fitness of faster-grazing mixotrophs when nutrients are scarce and light is plentiful. Our results illustrate how basic physiological constraints and principles of resource competition can organize complexity in the surface ocean ecosystem.

ecology↗

bioRxiv2022

The circ_0002538/miR-138-5p/PLLP axis regulates Schwann cell migration and myelination in diabetic peripheral neuropathy

Diabetic peripheral neuropathy (DPN) is the most common complication of diabetes, but the underlying molecular pathogenesis remains unclear. Accumulating evidence indicates that circular RNAs (circRNAs) play vital roles in DPN, while their expressions and functions in Schwann cell (SC) are rarely reported. Here, we performed protein profiling and circRNA sequencing on the peripheral nerves of patients with or without DPN. A total of 265 differentially expressed proteins were identified in DPN by protein profiling, which mainly enrich in myelination according to Gene Ontology analysis. Further, 15637 circRNAs were identified by circRNA sequencing, of which 11 were verified to be dysregulated. Among them, circ_0002538 was found to be downregulated in DPN and chosen for further investigation. Functional experiments revealed that circ_0002538 overexpression promoted SC migration and relieved demyelination in DPN. Mechanistic studies revealed that circ_0002538 could promote PLLP expression by sponging miR-138-5p, while lack of circ_0002538 led to PLLP deficiency, which further suppressed SC migration and caused demyelination. The present research provided novel insights into the pathogenesis of DPN, in which the circ_0002538/miR-138-5p/PLLP axis was suppressed in SCs and hence caused demyelination. These findings expanded the role of circRNAs in DPN and provided potential therapeutic targets for DPN.

neuroscience↗

bioRxiv2022

Spinning Disk Multifocal Microscopy for Dynamic Arbitrarily Shaped Surface Imaging at Centimetre Scale and Micrometre Resolution

The large-scale fluorescence microscopy has enabled the observation of dynamic physiological activities at the single cellular level across the mouse cortex, such as distributed neuronal population representations. However, video-rate high-resolution microscopy at sophisticated biological surfaces in nature keeps a challenging task for the tradeoff between the speed, resolution, and field of view. Here we propose Spinning Disk Multifocal Microscopy (SDiM) for arbitrarily shaped surfaces, which enables imaging at centimeter field-of-view, micrometer resolution and up to 30 frames per second across the depth range of 450 {micro}m. We apply this technique in various microscopic systems, including customized macroscopic systems and the Real-time Ultra-large-Scale imaging at High resolution macroscopy (RUSH), in both the reflective mode and the fluorescence mode, and in the study of cortex-wide single-neuron imaging and immune cell tracking. SDiM provides an opportunity for studying the cortex-wide multi-scale cellular interactions in biological tissues.

bioengineering↗

bioRxiv2022

Intergenerational transfer and sex differences of DNA methylation patterns in the Pacific oyster (Crassostrea gigas)

Apart from DNA-sequence-based inheritance, inheritance of epigenetic marks such as DNA methylation is controversial across the tree of life. In mammals, post-fertilization and primordial germ cell reprogramming processes erased most parental DNA methylation information. In nonmammalian vertebrates and insects, it has been proposed that DNA methylation is an essential hereditary carrier. However, how and to what extent general DNA methylation reprogramming affects intergenerational inheritance in molluscs remains unclear. Here, we investigated genome-wide DNA methylation in a mollusc model, the Pacific oyster (Crassostrea gigas), to test how epigenetic information transfers from parents to offspring. Analysis of global methylome revealed that the DNA methylation patterns are highly conserved within families. Almost half of the differentially methylated CpG dinucleotides (DMCs) between families in parents could transfer to offspring. These results provided the direct evidence for the hypothesis that the Pacific oyster DNA methylation patterns are inherited in generations. Moreover, distinct DNA methylation differences between male and female somatic tissues in C. gigas are revealed in this study. These sex-differential methylated genes significantly enriched in the regulation of Rho protein signal transduction process, which indicated that DNA methylation might have an essential role in the sexual differentiation of somatic tissues in C. gigas. Author SummaryTransgenerational inheritance of DNA methylation marks varies across the tree of life. In mammals, post-fertilization and primordial germ cell reprogramming processes obstructed the DNA methylation transmission from parents to child, and only some CpG dinucleotides retain gamete-inherited methylation. However, the DNA methylation inheritance seems apparent in nonmammalian vertebrates and insects. As one of the essential mollusc models, the Pacific oyster Crassostrea gigas have received the most substantial epigenetic studies, mainly focusing on the DNA methylation profiles. While a previous study suggested the existence of paternal inheritance of DNA methylation patterns in C. gigas, more data are needed to confirm this hypothesis. In this study, genome-wide DNA methylation analysis was performed to investigate the epigenetic inheritance in C. gigas. Almost half of the DNA methylation differences between families in parents were found to be transferred to children, indicating the absence of global DNA methylation reprogramming in C. gigas. Besides, extensive hypomethylation in C. gigas females compared with males were also unveiled. These hypomethylated genes were significantly enriched in the regulation of Rho protein signal transduction process. For example, guanine nucleotide exchange factors, including KALRN, FGD1, and FGD6, were hypomethylated in C. gigas females, and the corresponding transcriptions were significantly upregulated. Our findings provided insights into the evolution of DNA methylation patterns, transgenerational epigenetic inheritance, and sexual differentiation in molluscs.

evolutionary biology↗

bioRxiv2022

Construction of a High-Density Genetic Map Based on Large-Scale Marker Development in Coix lacryma-jobi L . Using Specifific-Locus Amplifified Fragment Sequencing (SLAF-seq)

Coix lacryma-jobi L. is one of the most important economical and medicine corn. In this study, a high genetic linkage map has been constructed for Coix lacryma-jobi L. from a cross F2 community of "Qianyi NO.2" x "Wenyi NO.2" and their parents through high-throughput sequencing and specfic-locus amplified fragment (SLAF) library construction. After pre-processing, 325.49 Gb of raw data containing 1,628 M reads were obtained. A total of 22,944 high-quality SLAFs were detected, among which 3,952 SLAFs and 3,646 of the polymorphic markers could meet the requirements for construction of a genetic linkage map. The integrated map contains 3,605 high quality SLAFs, which are grouped to 10 genetic linkage groups. The total length of the linkage map is 1,620.39 cM with an average distance of 0.45 cM and 360.5 markers in average of per linkage group. This work will provide an important molecular biology basis for investigating their characteristics, gene cloning, molecular marker-assisted breeding, functional genomics and so on for Jobs tears.

genetics↗

bioRxiv2022

cLD: Rare-variant disequilibrium between genomic regions identifies novel genomic interactions

Linkage disequilibrium (LD) is a fundamental concept in genetics; critical for studying genetic associations and molecular evolution. However, LD measurements are only reliable for common genetic variants, leaving low-frequency variants unanalyzed. In this work, we introduce cumulative LD (cLD), a stable statistic that captures the rare-variant LD between genetic regions, which reflects more biological interactions between variants, in addition to lack of recombination. We derived the theoretical variance of cLD using delta methods to demonstrate its higher stability than LD for rare variants. This property is also verified by bootstrapped simulations using real data. In application, we find cLD reveals an increased genetic association between genes in 3D chromatin interactions, a phenomenon recently reported negatively by calculating standard LD between common variants. Additionally, we show that cLD is higher between gene pairs reported in interaction databases, identifies unreported protein-protein interactions, and reveals interacting genes distinguishing case/control samples in association studies.

bioinformatics↗

bioRxiv2022

RCFGL: Rapid Condition adaptive Fused Graphical Lasso and application to modeling brain region co-expression networks

Inferring gene co-expression networks is a useful process for understanding gene regulation and pathway activity. The networks are usually undirected graphs where genes are represented as nodes and an edge represents a significant co-expression relationship. When gene-expression data from multiple conditions (e.g., treatments, tissues, strains) are available, joint estimation of networks harnessing shared information across them can significantly increase the power of analysis. In addition, examining condition-specific patterns of co-expression can provide insights into the underlying cellular processes activated in a particular condition. Condition adaptive fused graphical lasso (CFGL) is an existing method that incorporates condition specificity in a fused graphical lasso (FGL) model for estimating multiple co-expression networks. However, the current implementation of CFGL is prohibitively slow even for a moderate number of genes and can only be used for a maximum of three conditions. In this paper, we propose a fast alternative of CFGL known as rapid condition adaptive fused graphical lasso (RCFGL). In RCFGL, we incorporate the condition specificity into another popular model for joint network estimation, known as fused multiple graphical lasso (FMGL). We use a more efficient algorithm in the iterative steps compared to CFGL, enabling faster computation and making it easily generalizable for more than three conditions. We also present a novel screening rule to determine if the full network estimation problem can be broken down into estimation of smaller disjoint sub-networks, thereby reducing the complexity further. We demonstrate the computational advantage and superior performance of our method compared to two non-condition adaptive methods, FGL and FMGL, and one condition adaptive method, CFGL in several simulation scenarios. We use RCFGL to jointly estimate the gene co-expression networks of different brain regions (conditions) using a cohort of heterogeneous stock rats. We also provide an accommodating C and Python based package that implements RCFGL. Author summaryInferring gene co-expression networks can be useful for understanding pathway activity and gene regulation. While jointly estimating co-expression networks of multiple conditions, taking into account condition specificity such as information about an edge being present only in a specific condition, substantially increases the power. In this paper, a computationally rapid condition adaptive method for jointly estimating gene co-expression networks of multiple conditions is proposed. The novelty of the method is demonstrated through a broad range of simulation studies and a real data analysis with multiple brain regions from a genetically diverse cohort of rats.

bioinformatics↗

bioRxiv2022

Spatially Resolved and Highly Complexed Protein and RNA in situ Detection by Combining CODEX with RNAscope In Situ Hybridization

Highly multiplexed protein and RNA in situ concurrent detection on a single tissue section is highly desirable for both basic and applied biomedical research. CODEX is a new and powerful platform to visualize up to 60 protein biomarkers in situ and RNAscope in situ hybridization (RNAscope) is a novel RNA detection system with single-copy sensitivity and unprecedent specificity at a single cell level. Nevertheless, to our knowledge, the combination CODEX and RNAscope remained unreported until this study. Here we report a simple and reproducible combination of CODEX and RNAscope (Comb-CODEX-RNAscope). We also determined the cross-reactivities of CODEX anti-human antibodies to rhesus macaques, a widely used animal model of human disease.

pathology↗