Biology subjects

Ding, J.

Publications and source records attributed to Ding, J..

At least 127 records · Page 7Linked to original sources

bioRxiv2023

RAMEN identifies effective indicators for severe COVID and Long COVID patients

The COVID-19 pandemic has significantly altered global socioeconomic structures and individual lives. Understanding the disease mechanisms and facilitating diagnosis requires comprehending the complex interplay among clinical factors like demographics, symptoms, comorbidities, treatments, lab results, complications, and other metrics, and their relation to outcomes such as disease severity and long term outcomes (e.g., post-COVID-19 condition/long COVID). Conventional correlational methods struggle with indirect and directional connections among these factors, while standard graphical methods like Bayesian networks are computationally demanding for extensive clinical variables. In response, we introduced RAMEN, a methodology that integrates Genetic Algorithms with random walks for efficient Bayesian network inference, designed to map the intricate relationships among clinical variables. Applying RAMEN to the Biobanque quebecoise de la COVID-19 (BQC19) dataset, we identified critical markers for long COVID and varying disease severity. The Bayesian Network, corroborated by existing literature and supported through multi-omics analyses, highlights significant clinical variables linked to COVID-19 outcomes. RAMENs ability to accurately map these connections contributes substantially to developing early and effective diagnostics for severe COVID-19 and long COVID.

bioinformatics↗

bioRxiv2023

The neural activity of auditory conscious perception

Although recent work has made significant headway in understanding the temporal and spatial dynamics of the neural mechanisms of conscious perception, much of that work has focused on visual paradigms. To determine whether there are shared mechanisms for perceptual consciousness across sensory modalities, here we developed a task to test within the auditory domain. Participants (n=31) completed an auditory perceptual threshold task while undergoing intracranial electroencephalography (icEEG) for intractable epilepsy. Intracranial recordings from over 2,800 grey matter electrodes representing widespread cortical coverage were analyzed for power in the high gamma range (40-115 Hz)--a frequency range that reflects local neural activity. For trials that were perceived, we find activity in early auditory regions which is accompanied by activity in the right caudal middle frontal gyrus, and shortly thereafter by activity in non-auditory thalamus. This is followed by a wave of activity that sweeps through the higher auditory association regions and into parietal and frontal cortices, similar to the wave observed in our visual conscious perception paradigm. However, for not perceived trials, we find that significant activity is restricted to early auditory regions (and areas immediately adjacent to the Sylvian fissure). These findings show that the broad anatomical regions of cortical and subcortical networks involved in auditory perception are similar to the networks observed with vision, suggesting shared general mechanisms for conscious perception.

neuroscience↗

bioRxiv2023

HSV-1 Oncolytic Virus Targeting CEACAM6-Expressing Tumors Using a Bispecific T-Cell Engager

VG21306 is a novel oncolytic virus (OV) that encodes a secretable bispecific T-cell engager targeting Carcinoembryonic antigen cell adhesion molecule 6 (CEACAM6)-expressing tumors. Delivering a T-cell engager locally to a tumor mass will circumvent physical barriers that prevent antibodies from penetrating the tumor, and will mitigate the off-tumor, on-target toxicity risk. Both in vitro and in vivo testing demonstrated the expression of a functional T-cell engager capable of binding both targets. The efficacy of the engager was demonstrated in vitro, where addition of the engager payload to the OV enhanced anti-tumor efficacy against tumor cells overexpressing CEACAM6. Moreover, we have demonstrated the engagers ability to induce bystander killing in cells lacking CEACAM6 expression, as well as engaging exhausted T cells and inducing tumor cell death. The safety of the engager was demonstrated by the lack of binding to normal human tissue or normal tissue adjacent to tumors, as well as the absence of any measurable leakage of the expressed engager into the blood of mice treated by intratumoral OV injection.

cancer biology↗

bioRxiv2022

Functionally dissecting claustrum along anterior-posterior axis in anxiety and higher sensitivity to cocaine

Adolescent cocaine exposure (ACE) induce anxiety and higher sensitivity to drug addiction during adulthood. Here, we show that the claustrum is crucial for control of these two distinct psychiatric disorders in ACE mice. In the process of anxiety test, the CaMKII-positive neurons in median portion of claustrum (MClaustrum) were obviously triggered, and chemogenetic suppressing these neurons efficiently reduced ACE-induced anxiety in adulthood. While, the CaMKII-positive neurons in anterior portion of claustrum (AClaustrum) were obviously activated in response to cocaine-induced conditioned place preference (CPP), and chemogenetic suppressing these neurons efficiently blocked cocaine CPP in ACE mice during adulthood. Our findings dissociating specific sub-portions of claustrum for drug-related anxiety and susceptibility of addiction, extending our understanding to diverse functions of claustrum subregions.

neuroscience↗

bioRxiv2022

Novel mRNA vaccines encoding Monkeypox virus M1R and A35R protect mice from a lethal virus challenge

The outbreak of Monkeypox virus infection urgently need effective vaccines. However, the vaccines so far approved are all based on whole-virus, which raises safety concerns. MRNA vaccines has demonstrated its high efficacy and safety against SARS-Cov-2 infection. Here, we developed three mRNA vaccines encoding Monkeypox proteins M1R and A35R, including A35R-M1R fusions (VGPox1 and VGPox 2) and a combination of encapsulated full-length mRNAs for A35R and M1R (VGPox 3). All three vaccines induced anti-A35R total IgGs as early as day 7 following a single vaccination. However, only VGPox 1 and 2 produced anti-M1R total IgGs at early dates following vaccination while VGPox 3 did not show significant anti-M1R antibody till day 35. Similar results were also found in neutralizing antibodies and T cell immune response. However, all mRNA vaccine groups completely protected mice from a lethal dose virus challenge and effectively cleared virus in lungs. Collectively, our results indicate that the novel mRNA vaccines coding for a fusion protein of A35R and M1R had a better anti-virus immunity than co-expression of the two individual proteins. The mRNA vaccines are highly effective and can be an alternative to the current whole-virus vaccines to defend Monkeypox virus infection.

immunology↗

bioRxiv2022

scCobra: Contrastive cell embedding learning with domain adaptation for single-cell data integration

The rapid development of single-cell technologies has underscored the need for more effective methods in the integration and harmonization of single-cell sequencing data. The prevalent challenge of batch effects, resulting from technical and biological variations across studies, demands accurate and reliable solutions for data integration. Traditional tools often have limitations, both due to reliance on gene expression distribution assumptions and the common issue of over-correction, particularly in methods based on anchor alignments. Here we introduce scCobra, a deep neural network tool designed specifically to address these challenges. By leveraging a deep generative model that combines a contrastive neural network with domain adaptation, scCobra effectively mitigates batch effects and minimizes over-correction without depending on gene expression distribution assumptions. Additionally, scCobra enables online label transfer across datasets with batch effects, facilitating the continuous integration of new data without retraining, and offers features for batch effect simulation and advanced multi-omic batch integration. These capabilities make scCobra a versatile data integration and harmonization tool for achieving accurate and insightful biological interpretations from complex datasets.

bioinformatics↗

bioRxiv2022

Multi-omics of Circular RNAs and Their Responses to Hormones in Moso Bamboo (Phyllostachys edulis)

Circular RNAs are endogenous non-coding RNAs with covalently closed structures, which have important functions in plants. However, their biogenesis, degradation, and function upon treatment with gibberellins (GA) and auxins (NAA) remain unknown. Here, we systematically identified and characterized expression patterns, evolutionary conservation, genomic features, and internal structures of circRNAs using RNase R-treated libraries from moso bamboo (Phyllostachys edulis) seedlings. Moreover, we investigated the biogenesis of circRNAs dependent on both cis- and trans-regulation. We determined details regarding the function of circRNAs, including their roles in regulating microRNA-related genes and modulating the alternative splicing of their linear counterparts. Importantly, we developed a customized degradome sequencing approach to detect microRNA-mediated cleavage of circRNAs. Finally, we present a comprehensive view of the participation of circRNAs in the regulation of hormone metabolism upon treatment of bamboo seedlings with gibberellins (GA) and auxins (NAA). Collectively, our study uncovers important features of circRNAs including overall characteristics, biogenesis, function, and microRNA-mediated degradation of circRNAs in moso bamboo.

plant biology↗

bioRxiv2022

DANCE: A Deep Learning Library and Benchmark for Single-Cell Analysis

In the realm of single-cell analysis, computational approaches have brought an increasing number of fantastic prospects for innovation and invention. Meanwhile, it also presents enormous hurdles to reproducing the results of these models due to their diversity and complexity. In addition, the lack of gold-standard benchmark datasets, metrics, and implementations prevents systematic evaluations and fair comparisons of available methods. Thus, we introduce the DANCE platform, the first standard, generic, and extensible benchmark platform for accessing and evaluating computational methods across the spectrum of benchmark datasets for numerous single-cell analysis tasks. Currently, DANCE supports 3 modules and 8 popular tasks with 32 state-of-art methods on 21 benchmark datasets. People can easily reproduce the results of supported algorithms across major benchmark datasets via minimal efforts (e.g., only one command line). In addition, DANCE provides an ecosystem of deep learning architectures and tools for researchers to develop their own models conveniently. The goal of DANCE is to accelerate the development of deep learning models with complete validation and facilitate the overall advancement of single-cell analysis research. DANCE is an open-source python package that welcomes all kinds of contributions. All resources are integrated and available at https://omicsml.ai/.

bioinformatics↗

bioRxiv2022

Genomic data support Betula halophila and Betula microphylla as one species and reveal unidirectional introgression from Betula pendula to Betula microphylla

Conservation of rare species faces challenges arising from uncertainties in species recognition, interspecific gene flow and global climate change. Betula microphylla and Betula halophila are endangered species in Xinjiang province, Northwest China, where they occur with the abundant Betula pendula. The species status of B. halophila remains dubious. The extent of gene flow between B. microphylla and B. pendula remain unexplored. Here, we first resolve the identity of B. halophila and then assess the extent of gene flow between B. microphylla and B. pendula using restriction-site associated DNA sequencing (RADseq). We sequenced 40 B. pendula individuals, 40 B. microphylla individuals, one B. halophila individual and seven B. tianshanica individuals. Our molecular analyses show that B. halophila and B. microphylla refer to the same species. STRUCTURE analyses show unidirectional genetic admixture from B. pendula to B. microphylla. The ABBA-BABA test indicates that the genetic admixture reflects introgression rather than incomplete lineage sorting. Furthermore, we identified 233 functional genes within the introgressed regions with eight genes related to salt-tolerance, suggesting the possibility of potential adaptive introgression. Our study shows an urgent need to conserve the genetically pure populations of B. microphylla and to shift conservation efforts from B. halophila to B. microphylla. In addition, ex-situ conservation of B. microphylla and conservation strategies to avoid genetic swamping by B. pendula and B. tianshanica should be implemented.

evolutionary biology↗

bioRxiv2022

A nearly 30-years living collection from the Royal Botanic Garden Edinburgh is a new species: a case study of Betula mcallisterii sp. nov. (sect. Acuminatae, Betulaceae) and its little hybridization with Betula luminifera

O_LISpecies description meets challenges arising from various species concepts. Integrating different sources of information and multiple lines of evidence are important for species recognition and discovery. C_LIO_LIHere we use morphology, restriction site-associated DNA sequencing and flow cytometry to study the species status of the unidentified Betula samples collected in this study and to assess the extent of hybridization between the unidentified Betula samples and B. luminifera in natural populations. C_LIO_LIMolecular analyses show the unidentified Betula samples as a distinct lineage and reveal very little genetic admixture between the unidentified samples and B. luminifera. Unexpectedly, the unidentified samples formed a well-supported monophyletic clade with the living collection of B. luminifera 19933472 in the Royal Botanic Garden Edinburgh which was introduced from Southwest China. Flow cytometry shows that the unidentified samples and B. luminifera 19933472 are diploid. C_LIO_LIOur data indicates that B. luminifera 19933472 and the unidentified Betula samples should be recognized as a new species, namely B. mcallisterii. The very little introgression between B. mcallisterii and B. luminifera indicates a strong reproductive barrier. Our research shows the importance of gathering information from wild populations and the value of an integrative approach in species discovery. C_LI Societal Impact StatementA comprehensive survey of plant species from natural populations can aid greatly in taxonomy and species delimitation. Here, we discovered a new birch species from the wild and unexpectedly found that this species has been introduced to the Royal Botanic Garden Edinburgh for nearly 30 years. We found very little introgression between the new species and its closely-related species. Our study highlighted the importance in integrating sources of information from natural populations and botanic gardens for species discovery.

evolutionary biology↗

bioRxiv2022

Electro-acupuncture alleviates ACE-increased anxiety-like behaviors in mice of adulthood by targeting claustrum D1R CaMKII

Adolescent cocaine exposure (ACE) increases risk of developing psychiatric problems such as anxiety, which may drive relapse in later life, however, its underlying molecular mechanism remains poorly understood. Methods: ACE male mice model were established by exposing to cocaine during adolescent period. Elevated plus maze (EPM) were used to assess anxiety-like behaviors in mice. Within claustrum, local injection of SCH-23390, a specific antagonist for dopamine receptor 1 (D1R), or D1R knocking-down virus were used to regulate D1R function or expression on CaMKII-positive neurons (D1RCaMKII) in vivo. Electro-acupuncture (EA) treatment was performed at acupoints of Baihui and Yintang during withdrawal period. Results: We found that ACE mice exhibited anxiety-like behaviors, along with more activated CaMKII-positive neurons and increased D1RCaMKII levels in claustrum during adulthood. Inhibiting D1R function or knocking-down D1RCaMKII levels in claustrum efficiently reduced claustrum activation, and ultimately suppressed anxiety-like behaviors in ACE mice during adulthood. EA treatment alleviated ACE-evoked claustrum activation and anxiety-like behaviors by suppressing claustrum D1RCaMKII. Conclusion: Our findings identified a novel role of claustrum in ACE-induced anxiety-like behaviors, and put new insight into the D1RCaMKII in the claustrum. The claustrum D1RCaMKII might be a promising pharmacological target, such as EA treatment, to treat drugs-induced anxiety-like behaviors. Graphic abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=105 SRC="FIGDIR/small/512685v5_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@1b22744org.highwire.dtl.DTLVardef@12fed83org.highwire.dtl.DTLVardef@1924caforg.highwire.dtl.DTLVardef@1e896ca_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2022

Therapeutic modulation of the blood-brain barrier and ischemic stroke by a bioengineered FZD4-selective WNT surrogate

Derangements of the blood-brain barrier (BBB) or blood-retinal barrier (BRB) occur in disorders ranging from stroke, cancer, diabetic retinopathy, and Alzheimers disease. The Norrin/FZD4/TSPAN12 pathway activates WNT/{beta}-catenin signaling, which is essential for BBB and BRB function. However, systemic pharmacologic FZD4 stimulation is hindered by obligate palmitoylation and insolubility of native WNTs and suboptimal properties of the FZD4-selective ligand Norrin. Here, we developed L6-F4-2, a non-lipidated, FZD4-specific surrogate with significantly improved sub-picomolar affinity versus native Norrin. In Norrin knockout (NdpKO) mice, L6-F4-2 not only potently reversed neonatal retinal angiogenesis deficits, but also restored BRB and BBB function. In adult C57Bl/6J mice, post-stroke systemic delivery of L6-F4-2 strongly reduced BBB permeability, infarction, and edema, while improving neurologic score and capillary pericyte coverage. Our findings reveal systemic efficacy of a bioengineered FZD4-selective WNT surrogate during ischemic BBB dysfunction, with general applicability to adult CNS disorders characterized by an aberrant blood-brain barrier.

physiology↗

bioRxiv2022

Heterologous boost with mRNA vaccines against SARS-CoV-2 Delta/Omicron variants following an inactivated whole-virus vaccine

The coronavirus SARS-CoV-2 has mutated quickly and caused significant global damage. This study characterizes two mRNA vaccines ZSVG-02 (Delta) and ZSVG-02-O (Omicron BA.1), and associating heterologous prime-boost strategy following the prime of a most widely administrated inactivated whole-virus vaccine (BBIBP-CorV). The ZSVG-02-O induces neutralizing antibodies that effectively cross-react with Omicron subvariants following an order of BA.1>BA.2>BA.4/5. In naive animals, ZSVG-02 or ZSVG-02-O induce humoral responses skewed to the vaccines targeting strains, but cellular immune responses cross-react to all variants of concern (VOCs) tested. Following heterologous prime-boost regimes, animals present comparable neutralizing antibody levels and superior protection across all VOCs. Single-boost only generated ancestral and omicron dual-responsive antibodies, probably by "recall" and "reshape" the prime immunity. New Omicron-specific antibody populations, however, appeared only following the second boost with ZSVG-02-O. Overall, our results support a heterologous boost with ZSVG-02-O, providing the best protection against current VOCs in inactivated virus vaccine- primed populations.

molecular biology↗

bioRxiv2022

Genome-wide analysis of Structural Variants in Parkinson's Disease using Short-Read Sequencing data

Parkinsons disease is a complex neurodegenerative disorder, affecting approximately one million individuals in the USA alone. A significant proportion of risk for Parkinsons disease is driven by genetics. Despite this, the majority of the common genetic variation that contributes to disease risk is unknown, in-part because previous genetic studies have focussed solely on the contribution of single nucleotide variants. Structural variants represent a significant source of genetic variation in the human genome. However, because assay of this variability is challenging, structural variants have not been cataloged on a genome-wide scale, and their contribution to the risk of Parkinsons disease remains unknown. In this study, we 1) leveraged the GATK-SV pipeline to detect and genotype structural variants in 7,772 short-read sequencing data and 2) generated a subset of matched whole-genome Oxford Nanopore Technologies long-read sequencing data from the PPMI cohort to allow for comprehensive structural variant confirmation. We detected, genotyped, and tested 3,154 "high-confidence" common structural variant loci, representing over 412 million nucleotides of non-reference genetic variation. Using the long-read sequencing data, we validated three structural variants that may drive the association signals at known Parkinsons disease risk loci, including a 2kb intronic deletion within the gene LRRN4. Further, we confirm that the majority of structural variants in the human genome cannot be detected using short-read sequencing alone, encompassing on average around 4 million nucleotides of inaccessible sequence per genome. Therefore, although these data provide the most comprehensive survey of the contribution of structural variants to the genetic risk of Parkinsons disease to date, this study highlights the need for large-scale long-read datasets to fully elucidate the role of structural variants in Parkinsons disease.

genetics↗

bioRxiv2022

Dissecting the genetic basis of the heterosis of Y900, an elite super-hybrid rice

Y900 is one of the top hybrid rice varieties with a yield exceeding 15 t/hm2. To dissect the mechanism of heterosis, the male parent line R900 and female parent line Y58S were sequenced using long-read and Hi-C technology. High-quality reference genomes of sizes of 396.41 Mb and 398.24 Mb were obtained for R900 and Y58S, respectively. Genome-wide variations between the parents were systematically identified, including 1,367,758 SNPs and 299,149 Indels. No megabase level structural variations exist. >75% of genes exhibited variation between the two parents. Compared with other two-line hybrids sharing the same female parent, the Geng/japonica-type genetic components from different male parents showed an increasing trend from phase 2-4 super-hybrid rice; Transcriptome analysis revealed that additive and dominance effects are the main genetic effects that constitute the heterosis of Y900. Allele-specific expression patterns and expression regulation patterns are quite dynamic in different tissues. For young panicle tissues, cis-regulation is dominant, while trans-regulation is more popular in leaf issues. Overdominance is more likely regulated by the trans-regulation mechanism. The differential gene expression and regulation pattern are closely related to Geng/japonica introgression. Additionally, R900 contained several excellent japonica haplotypes, such as NAL1, OsSPL13, Ghd8, OsBRI1, and DTH2, which make a good complement to Y58S. The fine tune mechanism through dynamic expression or regulation pattern change, especially on some key functional genes, is the base for heterosis.

plant biology↗

bioRxiv2022

Temporal single cell atlas of non-neuronal retinal cells reveals dynamic, coordinated multicellular responses to central nervous system injury

Non-neuronal cells play key roles in the complex cellular interplay that follows central nervous system (CNS) insult. To understand this interplay at a tissue level, we generated a single-cell atlas of immune, glial and retinal pigment epithelial cells from adult mouse retina before and at multiple time points after axonal transection (optic nerve crush; ONC), identifying rare and undescribed subsets, and delineating changes in cell composition, expression programs, and interactions. Computational analysis charted an inflammatory cascade after injury with three phases. The early phase consisted of reactivation of retinal macroglia and microglia, providing chemotactic signals for immune infiltration, concurrent with infiltration of CCR2+ monocytes from the circulation. In the second phase, these differentiated to macrophage subsets resembling resident border-associated macrophages. In parallel, a multicellular interferon program, likely driven by microglia-derived type-I interferon, was synchronously activated across resident glia, expanding beyond rare interferon-responding subsets of glia unexpectedly present in the naive retina. Our findings provide insights regarding post-injury CNS tissue dynamics and a framework to decipher cellular circuitry, spatial relationships and molecular interactions following tissue injury.

immunology↗

bioRxiv2022

Genomic signals of local adaptation and hybridization in Asian white birch

Disentangling the numerous processes that affect patterns of genome-wide diversity in widespread tree species has important implications for taxonomy, conservation, and forestry. Here, we investigate the population genomic structure of Asian white birch (Betula platyphylla) in China and seek to explain it in terms of hybridization, demography and adaptation. We generate whole genome sequence data from 83 individuals across the species range in China. Combining this with an existing dataset for 79 European and Russian white birches, we show a clear distinction between B. pendula and B. platyphylla, which have sometimes been lumped taxonomically. Genomic diversity of B. platyphylla in north-western China and Central Russia is affected greatly by hybridization with B. pendula. Excluding these hybridized populations, B. platyphylla in China has a linear distribution from north-eastern to south-western China, along the edge of the inland mountainous region. Within this distribution, three genetic clusters are found, which we model as long diverged with subsequent episodes of gene flow. Patterns of co-variation between allele frequencies and environmental variables in B. platyphylla suggest the role of natural selection in the distribution of diversity at 7,609 SNPs of which 3,767 were significantly differentiated among the genetic clusters. The putative adaptive SNPs are distributed throughout the genome and span 1,633 genic regions. Of these genic regions, 87 were previously identified as candidates for selective sweeps in Eurasian B. pendula. We use the 7,609 environmentally associated SNPs to estimate the risk of non-adaptedness for each sequenced B. platyphylla individual under a scenario of future climate change, highlighting areas where populations may be under future threat from rising temperatures.

evolutionary biology↗

bioRxiv2022

Multi-task learning for single-cell multi-modality biology

Current biotechnologies can simultaneously measure multi-modality high-dimensional information from the same cell and tissue samples. To analyze the multi-modality data, common tasks such as joint data analysis and cross-modal prediction have been developed. However, current analytical methods are generally designed to process multi-modality data for one specific task without considering the underlying connections between tasks. Here, we present UnitedNet, a multi-task deep neural network that integrates the tasks of joint group identification and cross-modal prediction to analyze multi-modality data. We have found that multi-task learning for joint group identification and cross-modal prediction significantly improves the performance of each task. When applied to various single-cell multi-modality datasets, UnitedNet shows superior performance in each task, achieving better unsupervised and supervised joint group identification and cross-modal prediction performances compared with state-of-the-art methods. Furthermore, by considering the spatial information of cells as one modality, UnitedNet substantially improves the accuracy of tissue region identification and enables spatially resolved cross-modal prediction.

genomics↗