Biology subjects

Yan, X.

Publications and source records attributed to Yan, X..

At least 127 records · Page 7Linked to original sources

bioRxiv2024

Non-invasive brain-machine interface control with artificial intelligence copilots

Motor brain-machine interfaces (BMIs) decode neural signals to help people with paralysis move and communicate. Even with important advances in the last two decades, BMIs face key obstacles to clinical viability. Invasive BMIs achieve proficient cursor and robotic arm control but require neurosurgery, posing significant risk to patients. Non-invasive BMIs do not have neurosurgical risk, but achieve lower performance, sometimes being prohibitively frustrating to use and preventing widespread adoption. We take a step toward breaking this performance-risk tradeoff by building performant non-invasive BMIs. The critical limitation that bounds decoder performance in non-invasive BMIs is their poor neural signal-to-noise ratio. To overcome this, we contribute (1) a novel EEG decoding approach and (2) artificial intelligence (AI) copilots that infer task goals and aid action completion. We demonstrate that with this "AI-BMI," in tandem with a new adaptive decoding approach using a convolutional neural network (CNN) and ReFIT-like Kalman filter (KF), healthy users and a paralyzed participant can autonomously and proficiently control computer cursors and robotic arms. Using an AI copilot improves goal acquisition speed by up to 4.3x in the standard center-out 8 cursor control task and enables users to control a robotic arm to perform the sequential pick-and-place task, moving 4 randomly placed blocks to 4 randomly chosen locations. As AI copilots improve, this approach may result in clinically viable non-invasive AI-BMIs.

bioengineering↗

bioRxiv2024

Mosaic integration of spatial multi-omics with SpaMosaic

With the advent of spatial multi-omics, mosaic integration of diverse datasets with partially overlapping modalities enables construction of comprehensive multi-modal spatial atlases from heterogeneous sources. Here, we present SpaMosaic, a tool that employs contrastive learning and graph neural networks to build a modality-agnostic and batch-corrected latent space for spatial domain identification and missing modality imputation. We systematically benchmarked SpaMosaic against existing integration methods using simulated data and experimentally acquired datasets spanning RNA and protein abundance, chromatin accessibility, and histone modifications from brain, embryo, tonsil, and lymph node tissues. SpaMosaic consistently outperformed other methods in identifying coherent spatial domains by reducing noise and mitigating batch effects across diverse technologies and developmental stages. Computationally, SpaMosaic is highly scalable, capable of integrating over 100 sections and processing a single section with more than 800,000 spots. Beyond robust integration, the unified latent space generated by SpaMosaic enables accurate imputation of missing modalities. In a mosaic mouse brain dataset, the imputed histone modifications not only recapitulated expected transcriptome-epigenome correlations but also uncovered more region-specific regulatory links compared to the measured chromatin accessibility data, demonstrating the ability to infer relationships between modalities without co-profiling. In summary, SpaMosaic provides a versatile framework for unifying the rapidly accumulating heterogeneous spatial omics data into comprehensive biological atlases.

bioinformatics↗

bioRxiv2024

A near-complete genome assembly of the bearded dragon Pogona vitticeps provides insights into the origin of Pogona sex chromosomes

BackgroundThe agamid dragon lizard Pogona vitticeps is one of the most popular domesticated reptiles to be kept as pets worldwide. The capacity of breeding in captivity also makes it emerging as a model species for a range of scientific research, especially for the studies of sex chromosome origin and sex determination mechanisms. ResultsBy leveraging the CycloneSEQ and DNBSEQ sequencing technologies, we conducted whole genome and long-range sequencing for a captive-bred ZZ male to construct a chromosome-scale reference genome for P. vitticeps. The new reference genome is [~]1.8 Gb in length, with a contig N50 of 202.5 Mb and all contigs anchored onto 16 chromosomes. Genome annotation assisted by long-read RNA sequencing greatly expanded the P. vitticeps lncRNA catalog. With the chromosome-scale genome, we were able to characterize the whole Z sex chromosome for the first time. We found that over 80% of the Z chromosome remains as pseudo-autosomal region (PAR) where recombination is not suppressed. The sexually differentiated region (SDR) is small and occupied mostly by transposons, yet it aggregates genes involved in male development, such as AMH, AMHR2 and BMPR1A. Finally, by tracking the evolutionary origin and developmental expression of the SDR genes, we proposed a model for the origin of P. vitticeps sex chromosomes which considered the Z-linked AMH as the master sex-determining gene. ConclusionsOur study provides novel insights into the sex chromosome origin and sex determination of this model lizard. The near-complete P. vitticeps reference genome will also benefit future study of amniote evolution and may facilitate genome-assisted breeding.

genomics↗

bioRxiv2024

Reciprocal regulation of m6A modification and miRNA production machineries via phase separation-dependent and -independent mechanisms

Methyltransferase complex (MTC) deposits N6-adenosine (m6A) onto RNA, whereas microprocessor produces miRNA. Whether and how these two distinct complexes cross-regulate each other has been poorly studied. Here we report that the MTC subunit B (MTB) tends to form insoluble condensates with poor activity, with its level monitored by 20S proteasome. Conversely, the microprocessor component SERRATE (SE) forms liquid-like condensates, which in turn promotes solubility and stability of MTB, leading to increased MTC activity. Consistently, the hypomorphic lines expressing SE variants, defective in MTC interaction or liquid-like phase behavior, exhibit reduced m6A level. Reciprocally, MTC can recruit microprocessor to MIRNA loci, prompting co-transcriptional cleavage of primary miRNA (pri-miRNAs) substrates. Additionally, pri-miRNAs carrying m6A modifications at their single-stranded basal regions are enriched by m6A readers, which retain microprocessor in the nucleoplasm for continuing processing. This reveals an unappreciated mechanism of phase separation in RNA modification and processing through MTC and microprocessor coordination.

plant biology↗

bioRxiv2024

MorphLink: Bridging Cell Morphological Behaviors and Molecular Dynamics in Multi-modal Spatial Omics

Multi-modal spatial omics data are invaluable for exploring complex cellular behaviors in diseases from both morphological and molecular perspectives. Current analytical methods primarily focus on clustering and classification, and do not adequately examine the relationship between cell morphology and molecular dynamics. Here, we present MorphLink, a framework designed to systematically identify disease-related morphological-molecular interplays. MorphLink has been evaluated across a wide array of datasets, showcasing its effectiveness in extracting and linking interpretable morphological features with various molecular measurements in multi-modal spatial omics analyses. These linkages provide a transparent depiction of cellular behaviors that drive transcriptomic heterogeneity and immune diversity across different regions within diseased tissues, such as cancer. Additionally, MorphLink is scalable and robust against cross-sample batch effects, making it an efficient method for integrative spatial omics data analysis across samples, cohorts, and modalities, and enhancing the interpretation of results for large-scale studies.

bioinformatics↗

bioRxiv2024

A single-molecule nanopore sequencing platform

Nanopore sequencing, a third-generation sequencing technology, has revolutionized the gene sequencing industry with its advantages of long reads, fast speed, real-time sequencing and analysis, and potential in detecting base modifications. This technology allows researchers to sequence longer DNA fragments in a single read, providing more comprehensive genomic information compared to previous methods. Nanopore sequencing operates on electrical signals generated by a nanopore embedded in a membrane separating two electrolyte-filled chambers. When single-stranded DNA (ssDNA) passes through the nanopore, it creates variations in the current that correspond to different DNA bases. By analyzing these current fluctuations with machine learning algorithms, the DNA sequence can be determined. In this study, we introduced several improvements to nanopore sequencing, including nanopore local chemistry sequencing, novel motor and pore proteins, chip design, and basecalling algorithms. Our new nanopore sequencing platform, CycloneSEQ, demonstrated long-duration sequencing (107 hours) on a single chip with high yield (>50 Gb). In human genomic DNA sequencing, CycloneSEQ was able to produce long reads with N50 33.6 kb and modal identity 97.0%. Preliminary findings on human whole-genome de novo assembly, variant calling, metagenomics sequencing, and single-cell RNA sequencing have further highlighted CycloneSEQs potential across different areas of genomics.

genomics↗

bioRxiv2024

Multipartite complexity of the lichen symbiosis revealed by metagenome and transcriptome analysis of Xanthoria parietina

Lichens are composite symbiotic associations of fungi, algae, and bacteria that result in large, anatomically complex organisms adapted to many of the worlds most challenging environments. How such intricate, self-replicating lichen architectures develop from simple microbial components remains unknown because of their recalcitrance to experimental manipulation. Here we report a metagenomic and metatranscriptomic analysis of the lichen Xanthoria parietina at different developmental stages. We identified 168 genomes of symbionts and lichen-associated microbes within a lichen thallus, including representatives of green algae, three different classes of fungi, and 14 bacterial phyla. By analyzing occurrence of individual species across lichen thalli from diverse environments, we defined both substrate-specific and core microbial components of the lichen. Meta-transcriptomic analysis of the principal fungal symbiont from three different developmental stages of a lichen, compared to axenically grown fungus, revealed differential gene expression profiles indicative of lichen-specific transporter functions, specific cell signalling, transcriptional regulation and secondary metabolic capacity. Putative immunity-related proteins and lichen-specific structurally conserved secreted proteins resembling fungal pathogen effectors were also identified, consistent with a role for immunity modulation in lichen morphogenesis.

bioinformatics↗

bioRxiv2024

The study on the impact of indoleacetic acid on enhancing the ability of the rumen's original microecology to degrade aflatoxin B1.

Aflatoxin B1 (AFB1) poses a serious threat to the health of cattle and is strictly monitored in their diets. Rumen microorganisms in cattle have the ability to degrade AFB1, but this capability is limited. Enhancing the degradation capacity of the original rumen microecology for AFB1 is a novel approach. From a molecular perspective,indoleacetic-3-acid (IAA) promotes the expression of cytochromes, which can improve the degradation of AFB1. Therefore, this study aims to investigate the impact of different concentrations of IAA on the degradation of AFB1 by the rumen microecology. Experiments used rumen fluid from three adult cows as donors, and the cows were all fed the same total mixed ration. Rumen fluid was collected from these three cannulated cows before morning feeding to prepare in vitro fermentation fluid. The experiments used a completely randomized design, with each treatment repeated four times. The results showed that as the fermentation time increased, the content of AFB1 gradually decreased, with a degradation rate of up to 75.73% after 24 h. AFB1 altered the rumen fermentation pattern, with a significant reduction in the content of acetic acid (P<0.05) and a significant decrease in the acetic acid to propionic acid ratio (P<0.05). It also affected the rumen microecology, causing a significant reduction in the abundance of Ruminococcus amylophilus, Prevotella ruminicola, and Fusobacterium succinogenes (P<0.05). In addition, this study found that with the increase in the amount of IAA added, the content of AFB1 in the rumen gradually decreased. IAA enhances the degradation capacity of the original rumen microecology for AFB1, and the addition of IAA alleviates the impact of AFB1 on Ruminococcus amylophilus, Prevotella ruminicola, and Fusobacterium succinogenes in the rumen (P<0.05). Moreover, the addition of IAA can promote the stability of the rumen microecology, with significantly higher acetic acid and acetic acid to propionic acid ratios in the fermentation fluid compared to the non-added group (P<0.05). In summary, the addition of IAA can improve the degradation capacity of the rumen microecology for AFB1, providing a new solution for alleviating the impact of AFB1 on animal health.

microbiology↗

bioRxiv2024

White matter connections of human ventral temporal cortex are organized by cytoarchitecture, eccentricity, and category-selectivity from birth

Category-selective regions in ventral temporal cortex (VTC) have a consistent anatomical organization, which is hypothesized to be scaffolded by white matter connections. However, it is unknown how white matter connections are organized from birth. Here, we scanned newborn to 6-month-old infants and adults to determine the organization of the white matter connections of VTC. We find that white matter connections are organized by cytoarchitecture, eccentricity, and category from birth. Connectivity profiles of functional regions in the same cytoarchitectonic area are similar from birth and develop in parallel, with decreases in endpoint connectivity to lateral occipital, and parietal, and somatosensory cortex, and increases to lateral prefrontal cortex. Additionally, connections between VTC and early visual cortex are organized topographically by eccentricity bands and predict eccentricity biases in VTC. These data show that there are both innate organizing principles of white matter connections of VTC, and the capacity for white matter connections to change over development.

neuroscience↗

bioRxiv2024

Moderate-term dimethyl fumarate treatment reduces pathology of dystrophic skeletal and cardiac muscle in a mouse model

In Duchenne muscular dystrophy (DMD), corticosteroids significantly slow disease progression and have been used as a standard of care tool for more than 30 years. However, corticosteroids also impart side effects severe enough to preclude use in some patients. There remains an unmet need for new therapeutics that target the flow-on pathogenic mechanisms of DMD with a more favourable side-effect profile. We have previously demonstrated that short-term treatment with dual-purpose anti-inflammatory, anti-oxidative dimethyl fumarate (DMF), a drug with indication and established safety data in Multiple Sclerosis, more selectively modulates Duchenne (mdx) immunology than the frequently used corticosteroid, prednisone (PRED). Here, we assess the effect of moderate-term DMF treatment over 5 weeks in the typically mild mdx mouse model that we aggravated using exercise. We show that like PRED, DMF maintains anti-inflammatory action but with additional anti-fibrotic and anti-lipogenic effects on muscle with moderate-term use. This study supports our previous work highlighting DMF as a possible repurposing candidate for DMD, especially for patients who cannot tolerate chronic corticosteroid treatment.

pathology↗

bioRxiv2024

Therapeutic Peptide SS-31 Modulates Membrane Binding and Aggregation of Alpha-Synuclein and Restores Impaired Mitochondrial Function

Membrane binding and aggregation properties of -synuclein are closely associated with Parkinsons disease and a class of related syndromes named as synucleinopathy. This study explored the potential of SS-31 (Elamipretide), a therapeutic tetrapeptide with alternating cationic and aromatic residues and known properties of mitochondrial inner membrane binding and oxidative stress reduction, in modulating -synuclein interaction with the lipid membranes and mitigating impairment of mitochondrial function induced by -synuclein oligomers. It was demonstrated by both fluorescence correlation spectroscopy and fluorescence anisotropy that SS-31 displaces both wild-type and N-terminus acetylated -synuclein from negatively charged small unilamellar vesicles in a dose-dependent manner. Thioflavin-T assay and transmission electron microscopy (TEM) showed that SS-31 inhibits membrane-induced -synuclein aggregation and alters the morphology of -synuclein fibrils. Moreover, Seahorse Mito Stress Test indicated that SS-31 restores impaired mitochondrial function in -synuclein oligomer-treated neuroblastoma cells. Finally, confocal imaging revealed that SS-31 hinders cellular uptake of -synuclein oligomers, possibly by modifying cell membrane electrostatics. These findings underscore the multifaceted protective role of SS-31 against mitochondrial dysfunction caused by -synuclein aggregation. Consequently, SS-31 emerges as a promising therapeutic candidate to attenuate neurodegeneration pertinent to -synuclein misfolding and aggregation. There is a good potential for further refinement of such peptide against many diseases linked to mitochondrial dysfunction and oxidative stress.

biochemistry↗

bioRxiv2024

Cellular and Molecular Changes During Aging in MEC: Unveiling the Role of Bglap3 Neurons in Cognitive Aging

Aging-correlated cognitive declines, including deficiencies in spatial orientation and memory, may reflect dysfunction in the hippocampus and medial entorhinal cortex (MEC). However, aging-related changes in MEC at the cellular and molecular levels remain unclear. In this study, we found fewer grid cells with reduced spatial stability in old mice. We compared gene expression profiles between young and old mice using 10x Genomics Visium technology. Among 1664 differentially expressed genes, we discovered Bglap3, a marker gene for subpopulation in MEC Layer III with decreased cell number with age. Silencing of Bglap3+ neurons in young mice impaired the spatial tuning of neurons in MEC and the spatial learning of a new platform location in water maze. These findings help us to understand the cellular and molecular changes in the MEC in healthy aging animals and the changes of Bglap3+ cells in old mice indicating a possible cause of aging-related MEC deficiency.

neuroscience↗

bioRxiv2024

Individual differences in uncertainty evaluation explain opposing exploratory behaviors in anxiety and apathy

Decision-making in uncertain environments often leads to varied outcomes. Understanding how individuals interpret the causes of unexpected feedback is crucial for adaptive behavior and mental well-being. Uncertainty can be broadly categorized into two components: volatility and stochasticity. Volatility is about how quickly conditions change, impacting results. Stochasticity, on the other hand, refers to outcomes affected by random chance or "luck". Understanding these factors enables individuals to have more effective environmental analysis and strategy implementation (explore or exploit) for future decisions. This study investigates how anxiety and apathy, two prevalent affective states, influence the perceptions of uncertainty and exploratory behavior. Participants (N = 1001) completed a restless three-armed bandit task that was analyzed using latent state models. Anxious individuals perceived uncertainty as more volatile, leading to increased exploration and learning rates, especially after reward omission. Conversely, apathetic individuals viewed uncertainty as more stochastic, resulting in decreased exploration and learning rates. The perceived volatility-to-stochasticity ratio mediated the anxiety-exploration relationship post-adverse outcomes. Dimensionality reduction showed exploration and uncertainty estimation to be distinct but related latent factors shaping a manifold of adaptive behavior that is modulated by anxiety and apathy. These findings reveal distinct computational mechanisms for how anxiety and apathy influence decision-making, providing a framework for understanding cognitive and affective processes in neuropsychiatric disorders.

neuroscience↗

bioRxiv2024

Cyclic di-GMP as an Antitoxin Regulates Bacterial Genome Stability and Antibiotic Persistence in Biofilms

Biofilms are complex bacterial communities characterized by a high persister prevalence, which contributes to chronic and relapsing infections. Historically, persister formation in biofilms has been linked to constraints imposed by their dense structures. However, we observed an elevated persister frequency accompanying the stage of cell adhesion, marking the onset of biofilm development. Subsequent mechanistic studies uncovered a comparable type of toxin-antitoxin (TA) module (TA-like system) triggered by cell adhesion, which is responsible for this elevation. In this module, the toxin HipH acts as a genotoxic deoxyribonuclease, inducing DNA double strand breaks and genome instability. While the second messenger c-di-GMP functions as the antitoxin, exerting control over HipH expression and activity. The dynamic interplay between c-di-GMP and HipH levels emerges as a crucial determinant governing genome stability and persister generation within biofilms. These findings unveil a unique TA system, where small molecules act as the antitoxin, outlining a biofilm-specific molecular mechanism influencing genome stability and antibiotic persistence, with potential implications for treating biofilm infections.

microbiology↗

bioRxiv2024

Identifying Intermolecular Interactions in Single-Molecule Localization Microscopy

Intermolecular interactions underlie all cellular functions, yet visualizing these interactions at the single-molecule level remains challenging. Single-molecule localization microscopy (SMLM) offers a potential solution. Given a nanoscale map of two putative interaction partners, it should be possible to assign molecules either to the class of coupled pairs or to the class of non-coupled bystanders. Here, we developed a probabilistic algorithm that allows accurate determination of both the absolute number and the proportion of molecules that form coupled pairs. The algorithm calculates interaction probabilities for all possible pairs of localized molecules, selects the most likely interaction set, and corrects for any spurious colocalizations. Benchmarking this approach across a set of simulated molecular localization maps with varying densities (up to [~] 50 molecules {micro}m-2) and localization precisions (5 to 50 nm) showed typical errors in the identification of correct pairs of only a few percent. At molecular densities of [~] 5-10 molecules {micro}m-2 and localization precisions of 20-30 nm, which are typical parameters for SMLM imaging, the recall was [~] 90%. The algorithm was effective at differentiating between non-interacting and coupled molecules both in simulations and experiments. Finally, it correctly inferred the number of coupled pairs over time in a simulated reaction-diffusion system, enabling determination of the underlying rate constants. The proposed approach promises to enable direct visualization and quantification of intermolecular interactions using SMLM.

biophysics↗

bioRxiv2024

Identification of Candidate Diagnostic gene CDC25C for Trametinib-induced Cardiotoxicity by Integrating Bioinformatics and Machine Learning

Trametinib is a MEK inhibitor that has been shown to have considerable efficacy in retarding melanoma progression. However, the exact mechanism of cardiotoxicity induced by trametinib remains unclear. Our study was designed to investigate the underlying mechanisms by which trametinib-induced cardiotoxicity (TIC) might exist, offering novel perspectives and guidance for potential prediction, diagnosis, and treatment of TIC. The GSE217421 dataset indicated 574 up-regulated and 705 down-regulated DEGs. According to the KEGG analysis, these genes were implicated in several pathways and functions, including Cell Cycle, Axon Guidance, Cellular Senescence, and Dilated Cardiomyopathy. The GO analysis suggested their association with Mitotic Cell Cycle, Microtubule Cytoskeleton and Adenyl Nucleotide Binding. The hub genes (CDC25C) for TIC were screened through Multiple machine learning algorithms. Next, The expression level of CDC25C was verified using the GSE217423 validation set. Nomogram model based on CDC25C demonstrated excellent diagnostic capability according to three different evaluation measures. To further explore the regulatory mechanism of CDC25C in TIC, we constructed a multi-regulatory network using miRNAs-lncRNAs-TFs-CDC25C and conducted an immunoinfiltration analysis. Our study suggests that CDC25C may be a candidate diagnostic gene and a potential therapeutic target for the early occurrence and development of TIC. This provides new ideas for the prediction, diagnosis and treatment strategies for TIC.

cancer biology↗

bioRxiv2024

Bacterial stress granule protects mRNA through ribonucleases exclusion

Membraneless droplets formed through liquid-liquid phase separation of ribonucleoprotein particles contribute to mRNA storage in eukaryotic cells. How such aggresomes contribute to mRNA dynamics under stress, and their functional role, is less understood in bacteria. Here we used multiple approaches including live-cell imaging, polymer physics modelling and transcriptomics to show that prolonged stress leading to ATP depletion in Escherichia coli results in increased aggresome formation, compaction, and selective mRNA enrichment within these aggresomes. Longer transcripts accumulate more in aggresomes than in the cytosol. Mass spectrometry and mutagenesis studies showed that mRNA ribonucleases are excluded from aggresomes due to electrostatic repulsion arising from their negative surface charges. Experiments with fluorescent reporters and disruption of aggresome formation showed that mRNA storage within aggresomes promoted rapid translation reactivation and associated with reduced lag phases during growth after stress removal. Our findings suggest that mRNA storage within aggresomes confers an advantage for bacterial survival and recovery from stress.

biophysics↗

bioRxiv2024

Bayesian parameter inference for epithelial mechanics

Cell-based mechanical models, such as the Cell Vertex Model (CVM), have proven useful for studying the mechanical control of epithelial tissue dynamics. We recently developed a statistical method called image-based parameter inference for formulating CVM model functions and estimating their parameters from image data of epithelial tissues. In this study, we employed Bayesian statistics to improve the utility and flexibility of image-based parameter inference. Tests on synthetic data confirmed that both our non-hierarchical and hierarchical Bayesian models provide accurate estimates of model parameters. By applying this method to Drosophila wings, we demonstrated that the reliability of parameter estimation is closely linked to the mechanical anisotropies present in the tissue. Moreover, we revealed that the cortical elasticity term is dispensable for explaining force-shape correlations in vivo. We anticipate that the flexibility of the Bayesian statistical framework will facilitate the integration of various types of information, thereby contributing to the quantitative dissection of the mechanical control of tissue dynamics.

biophysics↗