Biology subjects

Xu, D.

Publications and source records attributed to Xu, D..

At least 127 records · Page 7Linked to original sources

bioRxiv2023

pathCLIP: Detection of Genes and Gene Relations from Biological Pathway Figures through Image-Text Contrastive Learning

In biomedical literature, biological pathways are commonly described through a combination of images and text. These pathways contain valuable information, including genes and their relationships, which provide insight into biological mechanisms and precision medicine. Curating pathway information across the literature enables the integration of this information to build a comprehensive knowledge base. While some studies have extracted pathway information from images and text independently, they often overlook the correspondence between the two modalities. In this paper, we present a pathway figure curation system named pathCLIP for identifying genes and gene relations from pathway figures. Our key innovation is the use of an image-text contrastive learning model to learn coordinated embeddings of image snippets and text descriptions of genes and gene relations, thereby improving curation. Our validation results, using pathway figures from PubMed, showed that our multimodal model outperforms models using only a single modality. Additionally, our system effectively curates genes and gene relations from multiple literature sources. A case study on extracting pathway information from non-small cell lung cancer literature further demonstrates the usefulness of our curated pathway information in enhancing related pathways in the KEGG database.

pathology↗

bioRxiv2023

DREDge: robust motion correction for high-density extracellular recordings across species

High-density microelectrode arrays (MEAs) have opened new possibilities for systems neuroscience in human and non-human animals, but brain tissue motion relative to the array poses a challenge for downstream analyses, particularly in human recordings. We introduce DREDge (Decentralized Registration of Electrophysiology Data), a robust algorithm which is well suited for the registration of noisy, nonstationary extracellular electrophysiology recordings. In addition to estimating motion from spikes in the action potential (AP) frequency band, DREDge enables automated tracking of motion at high temporal resolution in the local field potential (LFP) frequency band. In human intraoperative recordings, which often feature fast (period <1s) motion, DREDge correction in the LFP band enabled reliable recovery of evoked potentials, and significantly reduced single-unit spike shape variability and spike sorting error. Applying DREDge to recordings made during deep probe insertions in nonhuman primates demonstrated the possibility of tracking probe motion of centimeters across several brain regions while simultaneously mapping single unit electrophysiological features. DREDge reliably delivered improved motion correction in acute mouse recordings, especially in those made with an recent ultra-high density probe. We also implemented a procedure for applying DREDge to recordings made across tens of days in chronic implantations in mice, reliably yielding stable motion tracking despite changes in neural activity across experimental sessions. Together, these advances enable automated, scalable registration of electrophysiological data across multiple species, probe types, and drift cases, providing a stable foundation for downstream scientific analyses of these rich datasets.

neuroscience↗

bioRxiv2023

Expression of Filaments of the Geobacter Extracellular Cytochrome OmcS in Shewanella oneidensis

The physiological role of Geobacter sulfurreducens extracellular cytochrome filaments is a matter of debate and the development of proposed electronic device applications of cytochrome filaments awaits methods for large-scale cytochrome nanowire production. Functional studies in Geobacter sulfurreducens are stymied by the broad diversity of redox-active proteins on the outer cell surface and the redundancy and plasticity of extracellular electron transport routes. G. sulfurreducens is a poor chassis for producing cytochrome nanowires for electronics because of its slow, anaerobic growth. Here we report that filaments of the G. sulfurreducens cytochrome OmcS can be heterologously expressed in Shewanella oneidensis. Multiple lines of evidence demonstrated that a strain of S. oneidensis, expressing the G. sulfurreducens OmcS gene on a plasmid, localized OmcS on the outer cell surface. Atomic force microscopy revealed filaments with the unique morphology of OmcS filaments emanating from cells. Electron transfer to OmcS appeared to require a functional outer-membrane porin-cytochrome conduit. The results suggest that S. oneidensis, which grows rapidly to high culture densities under aerobic conditions, may be a suitable for development of a chassis for producing cytochrome nanowires for electronics applications and may also be good model microbe for elucidating cytochrome filament function in anaerobic extracellular electron transfer.

synthetic biology↗

bioRxiv2023

Design of universal Ebola virus vaccine candidates via immunofocusing

Ebola virus causes hemorrhagic fever in humans and poses a significant threat to global public health. Although two viral vector vaccines have been approved to prevent Ebola virus disease, they are distributed in the limited ring vaccination setting and only indicated for prevention of infection from orthoebolavirus zairense (EBOV) - one of three orthoebolavirus species that have caused previous outbreaks. Ebola virus glycoprotein GP mediates viral infection and serves as the primary target of neutralizing antibodies. Here we describe a universal Ebola virus vaccine approach using structure-guided design of candidates with hyperglycosylation that aims to direct antibody responses away from variable regions and toward conserved epitopes of GP. We first determined the hyperglycosylation landscape on Ebola virus GP and used that to generate hyperglycosylated GP variants with two to four additional glycosylation sites to mask the highly variable glycan cap region. We then created vaccine candidates by displaying wild-type or hyperglycosylated GP variants on ferritin nanoparticles (Fer). Immunization with these antigens elicited potent neutralizing antisera against EBOV in mice. Importantly, we observed consistent cross-neutralizing activity against Bundibugyo virus and Sudan virus from hyperglycosylated GP-Fer with two or three additional glycans. In comparison, elicitation of cross-neutralizing antisera was rare in mice immunized with wild-type GP-Fer. These results demonstrate a potential strategy to develop universal Ebola virus vaccines that confer cross-protective immunity against existing and emerging filovirus species. SIGNIFICANCE STATEMENTEbola virus outbreaks cause hemorrhagic fever with high mortality rates. Current viral vaccines require cold-chain storage and are distributed in limited ring vaccination settings. They are only indicated for protection against orthoebolavirus zairense (EBOV), one of three human-pathogenic Ebola virus species. Here we harness hyperglycosylation as an immunofocusing approach to design universal Ebola virus vaccine candidates based on Ebola virus glycoprotein (GP) displayed on ferritin nanoparticles (Fer). Compared with wild-type GP-Fer, immunization with hyperglycosylated GP-Fer elicited potently neutralizing antisera against EBOV, and more importantly, consistent cross-neutralizing activity against the other two orthoebolavirus species. Our work shows that immunofocusing antibody responses toward conserved and neutralizing epitopes of GP represents a promising strategy for vaccine design against antigenically diverse Ebola virus species.

immunology↗

bioRxiv2023

Hierarchical replay of multi-regional sequential spiking associated with working memory

How does millisecond-scale neural activity mediate behaviors over seconds? We recorded brain-wide activity in mice performing an olfactory working-memory task to decipher cross-region organization of activity. Spike-correlograms revealed millisecond within- and cross-region spike couplings, more prominent among neurons encoding similar memories. Spike coupling linked neurons into motifs of chains, single loops, and nested loops, especially among hippocampal and prefrontal-cortex neurons. Direction of spike coupling and activity chains was in line with that of memory-associated activity waves. Intriguingly, activity motifs were replayed before and after task performance, and during inter-trial intervals. Motifs were hierarchically organized, with progressively increasing time constants and the number of participating neurons. Thus, hierarchically organized and replayed cross-region spiking motifs are modulated on demand during delay period to mediate perceptual working memory. One Sentence SummaryNested activity motifs of chains, single loops, and nested loops, with progressively increasing time constants and number of participating neurons, are hierarchically organized and replayed to mediate perceptual working-memory maintenance.

neuroscience↗

bioRxiv2023

Geometric constraint of mechanosensing in bone marrow stromal cell cultures prevents stiffness-induced differentiation

Extracellular matrix (ECM) stiffness is fundamental in cell division, movement and differentiation. The stiffness that cells sense is determined not only by the elastic modulus of the ECM material, but also by ECM geometry and cell density. We hypothesised that these factors would influence cell-traction-induced matrix deformations and cellular differentiation in bone marrow stromal cells (BMSCs). To achieve this, we cultivated BMSCs on polyacrylamide hydrogels that varied in elastic modulus and geometry and measured cell spreading, cell-imparted matrix-deformations and differentiation. At low cell density BMSCs spread to a greater extent on stiff compared to soft hydrogels, or on thin compared to thick hydrogels. Cell-imparted matrix deformations were greater on soft compared to stiff hydrogels or thick compared to thin hydrogels. There were no significant differences in osteogenic differentiation relative to hydrogel elastic modulus and thickness. However, increased cell density and/or prolonged culture significantly reduced matrix deformations on soft hydrogels to levels similar to those on stiff substrates. This suggests that at high cell densities cell traction-induced matrix displacements are reduced by both neighbouring cells and the constraint imposed by an underlying stiff support. This may explain observations of the lack of difference in osteogenic differentiation as a function of stiffness.

biophysics↗

bioRxiv2023

Comparative omics reveals unanticipated metabolic rearrangements in a high-oil mutant of plastid acetyl-CoA carboxylase

Heteromeric acetyl-CoA carboxylase (ACCase) catalyzes the ATP-dependent carboxylation of acetyl-CoA to produce malonyl-CoA, the committed step for de novo fatty acid synthesis. In plants, ACCase activity is controlled at multiple levels, including negative regulation by biotin attachment domain-containing (BADC) proteins, of which the badc1/3 double mutant leads to increased seed triacylglycerol accumulation. Unexpectedly, the Arabidopsis badc1/3 mutant also accumulates more protein. The metabolic consequences from both higher oil and protein was investigated in developing badc1/3 seed using global transcriptomics, translatomics, proteomics, and metabolomics. Changes include: reduced plastid pyruvate dehydrogenase; increased acetyl-CoA synthetase; increased storage and lipid-droplet packaging proteins; increased lipases; and increased {beta}-oxidation fatty acid catabolism. We present a model of how Arabidopsis adapted to deregulated ACCase, limiting total oil accumulation, and altering flux through pathways of carbon accumulation that presents possible targets for future bioengineering of valuable seed storage reserves.

plant biology↗

bioRxiv2023

Rule-based modulation of a sensorimotor transformation across cortical areas

Flexible responses to sensory stimuli based on changing rules are critical for adapting to a dynamic environment. However, it remains unclear how the brain encodes rule information and uses this information to guide behavioral responses to sensory stimuli. Here, we made single-unit recordings while head-fixed mice performed a cross-modal sensory selection task in which they switched between two rules in different blocks of trials: licking in response to tactile stimuli applied to a whisker while rejecting visual stimuli, or licking to visual stimuli while rejecting the tactile stimuli. Along a cortical sensorimotor processing stream including the primary (S1) and secondary (S2) somatosensory areas, and the medial (MM) and anterolateral (ALM) motor areas, the single-trial activity of individual neurons distinguished between the two rules both prior to and in response to the tactile stimulus. Variable rule-dependent responses to identical stimuli could in principle occur via appropriate configuration of pre-stimulus preparatory states of a neural population, which would shape the subsequent response. We hypothesized that neural populations in S1, S2, MM and ALM would show preparatory activity states that were set in a rule-dependent manner to cause processing of sensory information according to the current rule. This hypothesis was supported for the motor cortical areas by findings that (1) the current task rule could be decoded from pre-stimulus population activity in ALM and MM; (2) neural subspaces containing the population activity differed between the two rules; and (3) optogenetic disruption of pre-stimulus states within ALM and MM impaired task performance. Our findings indicate that flexible selection of an appropriate action in response to a sensory input can occur via configuration of preparatory states in the motor cortex. HIGHLIGHTSO_LITask rules are reflected in preparatory activity in sensory and motor cortices. C_LIO_LINeural subspaces for processing tactile signals depend on the current task rule. C_LIO_LIMotor cortical activity tracks rule switches and is required for flexible rule-guided behavior. C_LI

neuroscience↗

bioRxiv2023

MarsGT: Multi-omics analysis for rare population inference using single-cell graph transformer

Rare cell populations are key in neoplastic progression and therapeutic response, offering potential intervention targets. However, their computational identification and analysis often lag behind major cell types. To fill this gap, we introduced MarsGT: Multi-omics Analysis for Rare population inference using Single-cell Graph Transformer. It identifies rare cell populations using a probability-based heterogeneous graph transformer on single-cell multi-omics data. MarsGT outperformed existing tools in identifying rare cells across 400 simulated and four real human datasets. In mouse retina data, it revealed unique subpopulations of rare bipolar cells and a Muller glia cell subpopulation. In human lymph node data, MarsGT detected an intermediate B cell population potentially acting as lymphoma precursors. In human melanoma data, it identified a rare MAIT-like population impacted by a high IFN-I response and revealed the mechanism of immunotherapy. Hence, MarsGT offers biological insights and suggests potential strategies for early detection and therapeutic intervention of disease.

bioinformatics↗

bioRxiv2023

S-PLM: Structure-aware Protein Language Model via Contrastive Learning between Sequence and Structure

Proteins play an essential role in various biological and engineering processes. Large protein language models (PLMs) present excellent potential to reshape protein research by accelerating the determination of protein function and the design of proteins with the desired functions. The prediction and design capacity of PLMs relies on the representation gained from the protein sequences. However, the lack of crucial 3D structure information in most PLMs restricts the prediction capacity of PLMs in various applications, especially those heavily dependent on 3D structures. To address this issue, we introduce S-PLM, a 3D structure-aware PLM that utilizes multi-view contrastive learning to align the sequence and 3D structure of a protein in a coordinated latent space. S-PLM applies Swin-Transformer on AlphaFold-predicted protein structures to embed the structural information and fuses it into sequence-based embedding from ESM2. Additionally, we provide a library of lightweight tuning tools to adapt S-PLM for diverse protein property prediction tasks. Our results demonstrate S-PLMs superior performance over sequence-only PLMs on all protein clustering and classification tasks, achieving competitiveness comparable to state-of-the-art methods requiring both sequence and structure inputs. S-PLM and its lightweight tuning tools are available at https://github.com/duolinwang/S-PLM/.

bioinformatics↗

bioRxiv2023

Improved chromosome-level genome assembly for marigold (Tagetes erecta)

Marigold (Tagetes erecta L.) is a popular ornamental plant of the Asteraceae family, and its petals are considered the most abundant source of lutein. A low-continuity chromosome-level genome sequence of marigold was published recently, with poor annotation of the protein-coding genes, which hinders the studies of lutein biosynthesis. Here, we generated a near telomere-to-telomere level genome assembly of marigold based on highly accurate high-fidelity (HiFi) long reads and Hi-C sequencing data. Compared to the previously reported marigold genome, the current assembly had obviously higher contiguity and higher completeness of gene set. The current genome assembly has a 27-fold increase in contig N50 size, a 12.1% increase in chromosome anchoring rate, and a 9.0% increase in BUSCO complete rate for the gene set. Besides, the current assembly has much fewer assembly errors. Based on this high-quality genome assembly, we found that the 170-bp repeats are the most abundant centromeric unit and all centromeric regions are distributed along the whole chromosomes for all 12 centromeres, indicating the existence of the holocentromeres in marigold. In addition, we analyzed the structure and phylogenetic relationship of the four PSY genes, and revealed that these genes have diversified and possibly executed different functions in various tissues. Our near telomere-to-telomere level genome assembly and comprehensive gene annotation will greatly facilitate the breeding of marigold and researches aimed at improving lutein production.

genomics↗

bioRxiv2023

Heparan sulfate promotes TRAIL-induced tumor cell apoptosis

TRAIL (TNF-related apoptosis-inducing ligand) is a potent inducer of tumor cell apoptosis through TRAIL receptors. While it has been previously pursued as a potential anti-tumor therapy, the enthusiasm subsided due to unsuccessful clinical trials and the fact that many tumors are resistant to TRAIL. In this report we identified heparan sulfate (HS) as an important regulator of TRAIL-induced apoptosis. TRAIL binds HS with high affinity (KD = 73 nM) and HS induces TRAIL to form higher-order oligomers. The HS-binding site of TRAIL is located at the N-terminus of soluble TRAIL, which includes three basic residues. Binding to cell surface HS plays an essential role in promoting the apoptotic activity of TRAIL in both breast cancer and myeloma cells, and this promoting effect can be blocked by heparin, which is commonly administered to cancer patients. We also quantified HS content in several lines of myeloma cells and found that the cell line showing the most resistance to TRAIL has the least expression of HS, which suggests that HS expression in tumor cells could play a role in regulating sensitivity towards TRAIL. We also discovered that death receptor 5 (DR5), TRAIL and HS can form a ternary complex and that cell surface HS plays an active role in promoting TRAIL-induced cellular internalization of DR5. Combined, our study suggests that TRAIL-HS interactions could play multiple roles in regulating the apoptotic potency of TRAIL and might be an important point of consideration when designing future TRAIL-based anti-tumor therapy.

cell biology↗

bioRxiv2023

From Asymptomatic to Symptomatic: Multiomics profiling of the temporal response of grapevine viral-mixed infection

Mixed viral infections are common in grapevines. However, our understanding of the factors and signaling pathways that influence the expression of viral symptoms in mixed infections is still incomplete. In a previous study, we revealed that the presence of grapevine leafroll-associated virus species in mixed infections was randomly associated with the devel-opment of virus-like symptoms. To understand what drives the timing of these virus-like symptoms in mixed infections, we used dsRNA and total RNA sequencing and metabolomic analysis to profile the viromes, metabolites, and transcripts of grapevine leaves collected at two different times of the year (summer and autumn). We demonstrated that neither viral titre nor virome composition changes were associated with symptom expression in autumn. The total phenolic content and antioxidant capacity increased in most plants except for those with early onset symptoms. According to the results of differential gene expression analysis, cell wall biosynthesis pathways were significantly downregulated in all grapevine plants infected with grapevine leafroll-associated virus 3, grapevine asteroid mosaic-associated virus, and grape-vine Pinot gris virus. In addition, polyketide pathways were significantly upregulated in all cultivars, while flavonoid precursor (e.g. abscisic acid) production was significantly reduced in plants that expressed strong virus-like symptoms. In the Vidal cultivar, an uncharacterized double-stranded RNA-binding protein (DRB) appears to play a critical role in the plants an-tiviral defences, supporting the recent hypothesis that DRBs make an important contribution to dominant antiviral responses in plants. The seasonality of the expression virus-like symptoms appears to be a consequence of the dynamic interactions between antiviral factors and viral counter-defences that occur at different developmental stages of grapevine.

plant biology↗

bioRxiv2023

A monocarboxylate transporter rescues frontotemporal dementia and Alzheimer's disease models

Brains are highly metabolically active organs, consuming 20% of an organisms energy at resting state. A decline in glucose metabolism is a common feature across a number of neurodegenerative diseases. Another common feature is the progressive accumulation of insoluble protein deposits, its unclear if the two are linked. Glucose metabolism in the brain is highly coupled between neurons and glia, with glucose taken up by glia and metabolised to lactate, which is then shuttled via transporters to neurons, where it is converted back to pyruvate and fed into the TCA cycle for ATP production. Monocarboxylates are also involved in signalling, and play broad ranging roles in brain homeostasis and metabolic reprogramming. However, the role of monocarboxylates in dementia has not been tested. Here, we find that increasing pyruvate import in Drosophila neurons by over-expression of the transporter bumpel, leads to a rescue of lifespan and behavioural phenotypes in fly models of both frontotemporal dementia and Alzheimers disease. The rescue is linked to a clearance of late stage autolysosomes, leading to degradation of toxic peptides associated with disease. We propose upregulation of pyruvate import into neurons as potentially a broad-scope therapeutic approach to increase neuronal autophagy, which could be beneficial for multiple dementias.

neuroscience↗

bioRxiv2023

The Neonatal Gyrencephalic Cortex Maintains Regionally Distinct Streams of Neuroblasts

Neurodevelopmental mechanisms have evolved to support the formation of diverse brain structures, such as in humans, during the perinatal period. Here, we demonstrate that neonatal gyrencephalic brains harbor an expanded subventricular zone, termed the Arc, defined by tiered arrangement of doublecortin (DCX)-expressing neuroblasts and vascular enrichment at the ventricular wall. The Arc is the origin of dorsal and ventral populations of migratory neuroblasts that target multiple regions involved in higher cognitive functions. Arc-derived migratory streams, primarily from the caudal ganglionic eminence, are composed of diverse neuronal subtypes with distinct spatial and migratory-receptor profiles. Our findings indicate the Arc is a structure present in phylogenetically divergent species that supports the expansion of postnatal neuronal migration, contributing to a protracted formation of cortical circuits in gyrencephalic brains. One-Sentence SummaryThe ventricular cytoarchitecture of gyrencephalic brains supports an ongoing supply of migratory neurons to the neonatal cortex.

neuroscience↗

bioRxiv2023

An explainable graph neural framework to identify cancer-associated intratumoral microbial communities

Microbes are extensively present among various cancer tissues and play a vital role in cancer prevention and treatment responses. However, the underlying relationships between intratumoral microbes and tumors are still not well understood. Here, we developed a MIcrobial Cancer-association Analysis using a Heterogeneous graph transformer (MICAH) to identify intratumoral cancer-associated microbial communities. MICAH integrates metabolic and phylogenetic relationships among microbes into a heterogeneous graph representation. It uses a graph attention transformer to holistically capture the relationships between intratumoral microbes and cancer tissues, which improves the explainability of the association between identified microbial communities and cancer. We applied MICAH to intratumoral microbiome data across five cancer types and demonstrated its good generalizability and reproducibility. We believe this graph neural network framework can provide novel insights into cancer pathogenesis associated with the intratumoral microbiome.

bioinformatics↗

bioRxiv2023

An integrated map of genetic variation from 1,062 wheat genomes

The construction of a high-quality wheat genome variation map is important to wheat genetic studies and breeding. In this study, we developed the second-generation whole-genome genetic variation map of wheat (VMap 2.0) by integrating whole-genome sequencing data of 1,062 diverse wheat accessions from 20 species/subspecies. VMap 2.0 contains 195.96 million single nucleotide polymorphisms (SNPs), 2.22 million insertions, and 4.72 million deletions, achieving a high density of variation map in which one variant exists in every 73 base pairs on average. By systematically analyzing the phylogenetic relationships and genetic diversity of tetraploid wheat, hexaploid wheat, and diploid goatgrass (Aegilops tauschii), we found that the genetic diversity of wild emmer wheat was 2.4 times higher than that of common wheat. In contrast, the genetic diversity of diploid goatgrass is 7.8 times higher than the D subgenome of hexaploid wheat. With the high-density genetic variations, VMap 2.0 is anticipated to facilitate high-resolution trait dissection and expedite prediction-based breeding of wheat.

genomics↗

bioRxiv2023

Dimension-agnostic and granularity-based spatially variable gene identification

Identifying spatially variable genes (SVGs) is critical in linking molecular cell functions with tissue phenotypes. Spatially resolved transcriptomics captures cellular-level gene expression with corresponding spatial coordinates in two or three dimensions and can be used to infer SVGs effectively. However, current computational methods may not achieve reliable results and often cannot handle three-dimensional spatial transcriptomic data. Here we introduce BSP (big-small patch), a spatial granularity-guided and non-parametric model to identify SVGs from two or three-dimensional spatial transcriptomics data in a fast and robust manner. This new method has been extensively tested in simulations, demonstrating superior accuracy, robustness, and high efficiency. BSP is further validated by substantiated biological discoveries in cancer, neural science, rheumatoid arthritis, and kidney studies with various types of spatial transcriptomics technologies.

bioinformatics↗